DESC:FIELD OF THE INVENTION:
The present invention relates to a novel synergistic bioactive composition for treating abnormal electrical brain activity. The present invention relates to a synergistic bioactive composition comprising combination of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - N-methyl-D-aspartate receptor (NMDAR) antagonist complex for treating abnormal electrical brain activity. Particularly, the invention relates to a synergistic bioactive combination of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium along with pharmaceutically acceptable excipients. Further, the present synergistic bioactive composition is useful for treating any subject suffering from seizures or epilepsy or convulsion.

BACKGROUND OF THE INVENTION:
A seizure is a burst of uncontrolled electrical activity between brain cells (also called neurons or nerve cells) that causes temporary abnormalities in muscle tone or movements (stiffness, twitching or limpness), behaviours, sensations, or states of awareness. A seizure can be a single event due to an acute cause, such as medication. When a person has recurring seizures, this is known as epilepsy.

Epilepsy is a disease known worldwide, affecting around 70 million people in the world. Epilepsy is conceptually defined as a disease in which an individual has at least two unprovoked or reflex seizures in a period greater than 24 hours apart, one unprovoked or reflex seizure and a probability of having another seizure similar to the general recurrence risk after two unprovoked seizures (greater than or equal to 60%) over the next ten years or an epilepsy syndrome. Epilepsy is a central nervous system (neurological) disorder in which the brain activity becomes abnormal, causing seizures or periods of unusual behaviour, sensations and sometimes loss of awareness. It is a common condition that affects the brain and causes frequent seizures.

Seizures are bursts of electrical activity in the brain that temporarily affects how it works. They can cause a wide range of symptoms. While epilepsy is one of the most important examples of conditions associated with seizures, many neuropathic and psychotic symptoms and causes of disorders may have seizures or seizures related neuropathic phenomena. Seizures and intractable epilepsy lead to changes in neuronal activity, which can induce abnormal axonal sprouting, expression of immediate early genes alteration of trophic factors, changes in neurotransmission and glial reactivity that lead to synaptic and network remodelling.

Maturation of epileptogenic processes result in the development of “epileptogenic lesions” such that the collection of abnormal discharge neurons or epileptogenic neurons forms a local population, or “epileptogenic area” dispersed throughout the cortical tissue. Epileptogenic regions are biochemical events, which are interconnected such that abnormal burst discharge can proceed continuously region by region. Mood disorders, notably anxiety and depression, are common comorbidities in epilepsy that may be associated with antiepileptic drug (AED) therapy. Overall, adverse effects are a major reason for AED discontinuation. The future of epilepsy treatment awaits a “clean” AED that truly does not cause any adverse effects in most patients. Further, antiepileptic drugs are often insufficient to obtain seizure control and non-pharmacological interventions are often required. Currently available medications simply suppress seizure symptomatically, but do not appear to prevent seizure-induced brain injury or reverse the underlying mechanisms of epileptogenesis. Thus, it is now widely recognized that novel therapies for epilepsy need to be developed that have neuroprotective and antiepileptogenic properties.

Although adverse effects can occur with all AEDs, among them central nervous system (CNS) effects are the most prevalent ones. The failure of an AED regimen may be the result of unacceptable adverse effects (intolerance), inadequate seizure control (inefficacy) or a combination of both. It has been observed that voltage-gated ion channels (VGICs), extensively distributed in the CNS, are responsible for the generation as well as modulation of neuroexcitability and considered as vital players in the pathogenesis of human epilepsy, with regulating the shape and duration of action potentials (APs). Therefore, interpreting the role of epilepsy associated VGICs might not only contribute to clarify the mechanism of epileptogenesis and genetic modifiers but also provide potential targets for the precise treatment of epilepsy [Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability Chapter · January 2019]. Individualized precise treatment using matching VGIC drugs will provide novel research directions and antiepileptic strategies [Zhang, S., Zhu, Y., Cheng, J., & Tao, J. (2019). Ion Channels in Epilepsy].

Sodium (Na) currents are essential for the initiation and propagation of neuronal firing. Alterations of sodium currents can lead to abnormal neuronal activity, which occurs in epilepsy. The transient voltage-gated sodium current mediates the upstroke of the action potential. Sodium valproate is an anticonvulsant (or anti-epileptic) medicine. It prevents epileptic seizures by reducing excessive electrical activity in human brain. There are potential side effects with this medicine that can happen over a long time. Long-term treatment with sodium valproate can cause osteoporosis and osteopenia (increasing your risk of breaking a bone). Sodium valproate can reduce fertility in both men and women. Research has shown that sodium valproate can cause serious problems in a developing baby. Among the babies whose mothers take sodium valproate during pregnancy, up to 1 in 10 children (10%) are at a risk of having a birth defect, and up to 4 in 10 children (up to 40%) have problems with development and learning as they grow. Therefore, it is essential to avoid acid or sodium overload especially for long-term treatment. Further, too much sodium can cause dangerous, even fatal side-effects. When there is too much sodium in the bloodstream, water rushes out of our cells to dilute it, thereby damaging most cells and it is also devastating for the brain cells. As they shrink, they are torn away from their usual locations. Torn blood vessels and fluid build-up in the brain causing seizures and coma. Therefore, there is a need to find out more potent, less toxic compound for the brain.

Magnesium (Mg) is a potential modulator of seizure activity. Magnesium is well known for its diverse actions within the human body. Magnesium plays an essential role in nerve transmission and neuromuscular conduction. It also functions in a protective role against excessive excitation that can lead to neuronal cell death (excitotoxicity) and has been implicated in multiple neurological disorders. Due to these important functions within the nervous system, magnesium is a mineral of intense interest for the potential prevention and treatment of neurological disorders [Nutrients 2018, 10(6), 730].

Magnesium is required by over 300 enzyme systems and is critical for many cellular functions including oxidative phosphorylation, glycolysis, DNA transcription and protein synthesis. Low magnesium concentration in the perfusate is a common method of generating spontaneous epileptiform discharges from the brain. Magnesium is a potential modulator of seizure activity because of its ability to antagonize excitation through the NMDAR. Some studies have shown that people with epilepsy have lower magnesium levels than people without epilepsy [Epilepsy Res. 2012 Jun;100(1-2):152-6]. Magnesium is an endogenous ion and enzymatic co-factor used for the treatment of epileptic seizures resistant to traditional medical therapy. Mg has been used as a prophylaxis and for treatment of seizures associated with eclampsia. Magnesium is a CNS depressant, with numerous functions intracellularly and extracellularly. Oral Mg supplementation may prove to be a worthwhile adjunctive medication in treating drug intractable epilepsy [Can J Neurol Sci. 2012May;39(3):323-7]. Magnesium may modulate seizure activity by antagonizing excitatory calcium influx through the NMDAR.

It is well known that agonists of NMDA or AMPA receptors can elicit seizures in animal or human subjects, while antagonists have been shown to inhibit seizures in animal models, suggesting a potential role for NMDA and AMPA receptor antagonists in anti-seizure drug development. Several such drugs have been evaluated in clinical studies; however, the majority, mainly NMDA-receptor antagonists, failed to demonstrate adequate efficacy and safety for therapeutic use, and only an AMPA-receptor antagonist, Perampanel, has been approved for the treatment of some forms of epilepsy [Biomolecules 2020, 10, 464].

Notably throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting neuronal excitability, AMPA receptor antagonists markedly reduce or abolish epileptiform activity and confer seizure protection in a subject. In view of the physiological constraints associated with NMDA receptor inhibitors or antagonist, its use in the treatment of epilepsy is possibly less effective.

Particularly, the Perampanel, a high-potency, orally active non-competitive AMPA receptor antagonist, supports the concept that AMPARs are critical to epileptic synchronization and the generation and spread of epileptic discharges in human epilepsy. A potential role for combination treatment using Perampanel and dietary decanoic acid to provide enhanced seizure control is disclosed [Epilepsia 59, 11-2018 Pages e172-e178]. Further, EP Patent No. 1764361B1 discloses three anhydrous crystalline forms of Perampanel and a process for preparation thereof. However, Perampanel has found to be less effective in certain types of seizures.

Therefore, the need arises to find out effective bioactive compound that modulate AMPA receptors or inhibit AMPA receptor activity, that have potential to reduce excessive excitatory responses and may be promising future AEDs, with no adverse effects.

In recent days, diet therapy is utilized in some patients with specific forms of epilepsy. Dietary therapies can provide control of seizures in patients with drug refractory epilepsy. There are several types of dietary therapies, all of which are high in fat, restrict carbohydrates to some extent, and are associated with ketosis. The medium-chain triglycerides (MCT) diet can be effective in seizure management and enhanced dietary intake of saturated fatty acid may provide additional therapeutic benefit.

Octanoic acid (OA) and decanoic acid, the major constituents of the medium-chain triglyceride (MCT) emulsion diet, have been detected in appreciable quantities in the peripheral blood of children with intractable seizures treated with the MCT diet. [Archives of Disease in Childhood, 1986, 61, 1173-1177]. Branched derivatives of octanoic acid, a medium chain fat provided in the diet have been suggested as potential new treatments for drug-resistant epilepsy. Octanoic acid is a medium-chained saturated fatty acid found abundantly in the ketogenic dietary supplements containing MCTs along with decanoic acid. The MCT ketogenic diet is commonly consumed for weight loss but has also showcased neuroprotective potential against neurodegenerative disorders. [Scientific Reports (2021) 11:7003].

The MCTs are mixed triglycerides of saturated fatty acids with a chain length of 6 to 12 carbon atoms, mainly C8 (caprylic acid) and C10 (capric acid). MCT oil can be obtained by direct or molecular distillation of virgin coconut oil. The MCT ketogenic diet is widely considered to function by the generation of ketones, in the treatment of a range of disorders including epilepsy, cancer, Alzheimer’s disease, and diabetes. However, the underlying mechanism of the diet is still largely unknown. The role of medium chain fats, provided in the diet, involving direct inhibition of a key neurotransmitter receptor (i.e., the AMPA receptor), and through regulating cellular energy through peroxisome proliferator-activated receptors (PPAR?) activation and mitochondrial biosynthesis have provided alternative therapeutic approach that need to be explored. Understanding the role of AMPA, PPAR and mitochondrial biosynthesis, in relation to MCT ketogenic diet-responsive disorders may provide novel therapeutic targets and facilitate the development of new pharmacological and dietary treatments to achieve long-term remission from epileptic seizures.

Recently, it has been accomplished that decanoic acid has antiseizure effects at clinically relevant concentrations in vitro and in vivo [Neuropharmacology. 2013 Jun; 69:105-14]. Further, in vivo pharmacokinetic data indicates that decanoic acid penetrates the blood-brain barrier. The data suggests that decanoic acid directly contributes to the therapeutic effect of the MCT ketogenic diet (KD). Indeed, decanoic acid is more potent than valproic acid (a branched chain fatty acid isomer of octanoic acid), that is commonly used in the treatment of epilepsy. Further, decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage-and subunit-dependent manner, to exhibit antiseizure effects. This inhibitory effect is likely to be caused by binding to sites on the M3 helix of the AMPA-GluA2 transmembrane domain; independent from the binding site of Perampanel [Brain. 2016 Feb; 139(2): 431–443].

Seizure control by decanoic acid through direct AMPA receptor inhibition in the brain [2016 Feb;139(Pt 2):431-43]. Further it is demonstrated that decanoic acid and octanoic acid are differentially metabolized by neuronal-like cells. Moreover, octanoic acid may be preferentially oxidized thereby sparing decanoic acid from being oxidized. A combination of NMDA and AMPA receptor antagonist retards granule cell dispersion and epileptogenesis in a model of acquired epilepsy [Scientific Reports | 7: 12191 | 2017].

EP3644985A1 discloses decanoic acid for use in treating epilepsy, wherein the decanoic acid is used in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as Perampanel. WO2018/189113A1 discloses a composition comprising a decanoic acid to octanoic acid ratio of 70:30 to 90:10 w/w for use in treating epilepsy or controlling epileptic seizures. Further, it is reported that oral administration of C10 could increase anti-seizure activity in patients with MCT KD [Epileptic Disord 2019; 21 (4): 366-9]. Sodium caprate, a medium chain fatty acid, increases the paracellular permeability through enlarging the tight junctions, thereby expanding paracellular routes for water-soluble, low lipophilic, and poorly absorbable drugs [AAPS PharmSciTech. 2010 Mar; 11(1): 372–382].

However, decanoic acid and its metallic salt such as sodium caprate are having certain physiological limitations. It is observed that decanoic acid or its sodium salts are unsuitable for chronic administration due to its acidic nature, poor palatability, and gastrointestinal side effects. To avoid acid or sodium overload, especially for long-term treatment, there is a need to find out alternative smooth administration approach where decanoic acid and/or octanoic acid can be easily carried out through gastrointestinal (GI) tract.

OBJECTIVE OF THE INVENTION:
The primary objective of the present invention is to provide a synergistic combination of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium present in a specific weight ratio along with pharmaceutically acceptable excipients to treat abnormal electrical brain activity.

Another objective of the present invention is to provide a therapeutic approach, for treating seizure related disorders.

Another objective of the present invention is to provide a non-toxic, safe, bioactive, mineral based composition for treating epileptic seizure.

Further objective of the present invention is to provide potent bioactive composition to regulate electrical brain activity in a subject in need thereof, without any severe side effects.

SUMMARY OF THE INVENTION:
To meet the above objectives, the inventors of the present invention carried out thorough experiments to establish significant effects of the bioactive ingredients or food ingredients or nutrients or exogenous naturally safe agents, minerals, present in the composition that ameliorate abnormally excessive or synchronous neuronal activity in the brain. The present invention relates to a synergistic composition comprising biologically active ingredients along with pharmaceutically acceptable carriers for regulating unusual electrical activity in the brain.

In view of the known prior art, the inventors of the present invention have investigated the effect of mixtures of aliphatic saturated fatty acids like 1-nonanecarboxylic acid and 1-heptanecarboxylic acid and its magnesium salt on AMPA as well as NMDA receptor inhibitions. Although previous studies have suggested that decanoic acid and not octanoic acid was unlikely to have a direct effect on AMPA receptor mediated seizure control. The inventors of the present invention have conducted experiments and found that maximal AMPA receptor inhibition and NMDA inhibition is established when combining 1-nonanecarboxylic acid salt of Mg and 1-heptanecarboxylic acid salt of Mg present in specific weight ratio.

The composition comprising the specific combination of 1-nonanecarboxylic acid salt of Mg and 1-heptanecarboxylic acid salt of Mg upon administration reduces the tendency of brain cells to send excessive and confused electrical signals.

In a particular aspect, the present invention provides a novel synergistic composition comprising exogenous combination of non-competitive AMPA-NMDA receptor antagonists complex present in suitable weight ratio, along with pharmaceutically acceptable excipients.

In another aspect, the present invention provides saturated fatty acid metal salt based synergistic compositions for regulating sudden, uncontrolled electrical disturbance in the brain (epileptic seizures).

In one more aspect, the present invention provides a synergistic combination of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium present in specific weight ratio along with pharmaceutically acceptable excipients.

In the present invention, the AMPA receptor antagonist markedly reduces or abolishes epileptiform by reducing neuronal hyperexcitability and regularizing VGICs. Further, AMPA receptor antagonist increases adenosine triphosphate (ATP) turnover and proton leak in mitochondria, which reduces oxidative stress to protect the brain from seizures and damage. Further the NMDA receptor plays an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Therefore, the inhibition of NMDA receptor reduces glutamate mediated excitotoxicity and potentially treating epilepticus.

In another aspect, the invention provides non-toxic, efficient, and safe, exogenous blend of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium for reducing neuronal hyperexcitation and neuronal loss associated with seizures without severe adverse effects.

In yet another aspect, the invention relates to a synergistic composition comprising a combination of AMPAR and NMDAR antagonists complex which are present in a range of 0.1 to 1000 gm along with pharmaceutically acceptable excipients/carriers.

In yet one more aspect, the invention provides synergistic medicinal composition which is useful for treating seizure disorders such as epilepsy, reflex epilepsy, epileptic seizures, nonepileptic seizures, provoked seizures, idiopathic generalized epilepsy, convulsion, absence seizures, atonic seizures, tonic seizures, clonic seizures, myoclonic seizures, febrile seizure, focal seizures, temporal lobe seizures, occipital lobe seizures, parietal lobe seizures, nocturnal epilepsy.

ABBREVIATIONS:
MCT: Medium-chain triglyceride
NRF2: Nuclear factor erythroid 2-related factor 2
AMPAR: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
NMDAR: N-methyl-D-aspartic acid receptors
GABA: Gamma-aminobutyric acid
PPAR-? / PPARG: Peroxisome proliferator-activated receptor gamma

BRIEF DESCRIPTION OF FIGURES:
Figure 1 illustrates tonic convulsion time (seconds) with respect to test groups.
Figure 2 illustrates stupor phase time (seconds) with respect to test groups.
Figure 3 illustrates clonic convulsion time (seconds) with respect to test groups.

DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended.

However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice. It is further to be understood that all terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting in any manner or scope.

Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain. In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art.

The singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Also, the term “composition” does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.

The term “pharmaceutically/nutraceutically acceptable salt” as used herein, represents those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Particularly the term “pharmaceutically-acceptable salts” refers to the relatively non-toxic, inorganic, and organic acid addition salts of compounds, alkali, or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs, and the like of the salts.
All modifications and substitutions that come within the meaning of the description and the range of their legal equivalents are to be embraced within their scope. A description using the transition “comprising” allows the inclusion of other elements to be within the scope of the invention.

The term “non-competitive antagonists” relates to a type of insurmountable antagonist that may act in one of two ways: by binding to an allosteric site of the receptor or by irreversibly binding to the active site of the receptor. Further when antagonists act at an allosteric site, these bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. They do not compete with agonists for binding at the active site. The bound antagonists may prevent conformational changes in the receptor required for receptor activation after the agonist binds.

In a preferred embodiment, the present invention provides a novel, potent synergistic composition for treating seizure disorders, comprising combination of non-competitive AMPAR antagonists present in a suitable weight ratio, along with pharmaceutically acceptable excipients.

The term “AMPA receptor antagonist” refers to the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known AMPAR). It is an ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the CNS. It is a non-NMDA-type receptor. AMPA receptor antagonists are anticonvulsants used in patients with epilepsy in the treatment of partial-onset seizures. They are non-competitive antagonists of AMPA receptors, a type of glutamate receptor that participates in excitatory neurotransmission.

The term ‘Non-competitive antagonist’ relates to ionotropic glutamate receptors, an inhibitor whose blocking action is not reduced progressively as the agonist (glutamate) concentration is increased as occurs for competitive antagonists. Non-competitive antagonists allosterically inhibit the channel by binding to a site other than the ligand binding domain.

In the present invention the long chain carboxylic acid acts as a non-competitive AMPA receptor antagonist present in therapeutically effective amount. In certain embodiment, the present invention provides a synergistic bioactive composition as AMPAR antagonists, wherein they markedly reduce or abolish epileptiform by reducing neuronal hyperexcitability and regularizing VGICs.

In a preferred embodiment, the invention provides a synergistic bioactive composition of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium present in a suitable weight ratio, wherein the 1-nonanecarboxylic acid and 1-heptanecarboxylic acid acts as AMPA antagonist and Magnesium act as NMDA antagonist to provide synergistic effect in balancing the brain's electrical rhythms.

In another embodiment, the invention provides a synergistic bioactive composition for treating seizure disorders, comprising combination of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium present in a suitable weight ratio, along with pharmaceutically acceptable excipients.

In yet another embodiment, the present invention provides a synergistic bioactive composition comprising a therapeutically effective amount of 1-heptanecarboxylic acid salt of magnesium, wherein 1-heptanecarboxylic acid salt of magnesium is present in a range of 0.1-1000 gm of the total composition.

In a preferred embodiment, the present invention provides synergistic bioactive composition comprising combination of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium are present in the weight ratio of 1: 0.008 to 1:1 along with pharmaceutically acceptable excipients.

In one more embodiment, the invention provides synergistic bioactive composition comprising 1-nonanecarboxylic acid salt of magnesium is present in a range of 20% to 90% by weight of the total composition.

In one more embodiment, the invention provides synergistic bioactive composition comprising 1-heptanecarboxylic acid salt of magnesium is present in a range of 3% to 50% by weight of the total composition.

The divalent magnesium ion is linked with two molecules of 1-nonanecarboxylic acid and two molecules 1-heptanecarboxylic acid, hence each single dose of the composition may afford 2-4 folds better effect as compared to medium chain triglyceride ketogenic diet (MCT KD).

Additionally, the inventors have found that the magnesium salt of 1-nonanecarboxylic acid and 1-heptanecarboxylic acid enhances the rate of mitochondrial respiration and ATP turnover, resulting in improvement in the mitochondrial function. The dose to be administered usually ranges from 0.1 gm to 5000 gm, preferably 1 gm to 3000 gm, more preferably 10 gm to 2500 gm per day.

In a further embodiment, the present invention provides synergistic bioactive composition of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium present in a suitable weight ratio additionally in presence of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activators.

In one more embodiment, the invention provides synergistic bioactive composition comprising Nrf2 activators is present in a range of 0.03% to 4% by weight of the total composition.

In another preferred embodiment, the invention provides the synergistic bioactive composition comprising 1-nonanecarboxylic acid salt of magnesium, 1-heptanecarboxylic acid salt of magnesium and Nrf2 activator; wherein 1-nonanecarboxylic acid salt of magnesium, 1-heptanecarboxylic acid salt of magnesium and Nrf2 activator are present in the weight ratio ranges from 1: 0.008: 0.001 to 1: 1: 0.07.

In another embodiment, the invention provides potent synergistic bioactive composition, comprising Nrf2 activator present in the range of 1-100 mg of total composition.

According to the present invention, Nrf2 activators reduce seizure-induced neuronal cell death by regulating Nrf2/ Kelch-like ECH-associated protein 1 (Keap1)/ Antioxidant response element (ARE) antioxidant signalling pathway that protects neurons against oxidative damage and excitotoxic damage. The Nrf2-ARE signalling pathway activation inhibits reactive oxygen species ROS production, mitochondrial depolarization, and cell death in a subject with seizure-like symptoms.

In another embodiment, the Nrf2 activators are selected from, 1-Isothiocyanato-4-(methanesulfinyl)butane and (2S)-3-(2-Sulfanylidene-2,3-dihydro-1H-imidazol-4-yl)-2-(trimethylazaniumyl)propanoate.

In further embodiment, the invention provides a synergistic bioactive composition of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium present in a suitable weight ratio in presence of brain specific magnesium salt. Magnesium deficiency is associated with seizures, as it acts as a natural calcium channel blocker similar to some AEDs.

As used herein, the term “therapeutically effective amount” is intended to mean that, ‘the amount
of active biological compounds or nutrients used in the present invention are significantly more effective for regulating abnormal electrical discharge /signals/impulses of brain cells, when used in combination with suitable weight ratio.

The present synergistic composition synergistically controls or regulates abnormal electrical signals that interrupts normal electrical brain function. It supports to balance brain's electrical rhythms.

In another embodiment, the present invention provides a synergistic bioactive composition, wherein the composition is useful for treating seizure disorders such as epilepsy, reflex epilepsy, epileptic seizures, nonepileptic seizures, provoked seizures, idiopathic generalized epilepsy, convulsion, absence seizures, atonic seizures, tonic seizures, clonic seizures, myoclonic seizures, febrile seizure, focal seizures, temporal lobe seizures, occipital lobe seizures, parietal lobe seizures, nocturnal epilepsy, fibrotic diseases and insulin regulation.

The term "therapeutically effective amount " denotes an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and/or reduction or restoration or modulation, regulation of at least one indicator/biomarker (e.g., blood or serum C-reactive protein [CRP] level), and/or minimizes at least one clinical symptom related to seizure conditions.

The term ‘subject in need thereof’ pertains to subject preferably mammal, more preferably human suffering or suspected with neurological disorders, particularly with seizures, where the normal electrical pattern is disrupted by sudden and synchronized bursts of electrical energy. Particularly, the subject is human with pre-existing or onset symptoms of seizures or in a subject to prevent occurrence of seizures or subject with AED intolerance or AED medication side effects.

In the context of the present invention, the term “treatment” relates to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, control, minimize, lessen, decrease, down regulate, up regulate, moderate, inhibit, restore, suppress, limit, block, decrease, prevent, inhibit, stabilize, ameliorate, or cure, heal the abnormal neuronal firing and neuronal damage observed in patients with seizures. Notably, the present synergistic composition is non-hazardous, non-toxic, food ingredient and safe for human consumption without any adverse effects, therefore the present composition can also be used under preventive therapy/ adjuvant therapy/ add-on therapy/ combination/ adjunctive therapy in a subject in need thereof.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Further some compounds of the present invention can exist in multiple crystalline or amorphous forms (“polymorphs”). In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the present invention. Compound or a pharmaceutically acceptable salts, hydrates, polymorphs or solvates of a compound intends the inclusive meaning of “or”, in those materials meeting more than one of the stated criteria are included, e.g., a material that is both a salt and a solvate is encompassed. Compounds of the present invention can exist in particular geometric or, enantiomeric or stereoisomeric forms. The present invention contemplates all such compounds, including dextrorotatory and levorotatory-isomers, rectus, and sinister configuration. All such isomers, as well as racemic mixtures thereof, are intended to be included in this invention.

As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is purported to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye/colorant, flavour enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethylene glycol matrix, which is acceptable for use in the subject, preferably humans. Excipients may also include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colours), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration, salts.

In another embodiment of the present invention, the diluents are selected from starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulphate, cellulose acetate, corn starch, pregelatinized starch, dextrin, ß-cyclodextrin, methylated-ß-cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, vehicles like petrolatum, dimethyl sulfoxide and mineral oil or the like.

In some embodiment of the present invention, the diluent in the composition/formulation is present in a range of 0.1% to 30% by weight of the total composition/formulation.

In yet another embodiment of the present invention, the binder is selected from disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose, or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol, or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethyl cellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyl ethyl methyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminium silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, various animal vegetable oils, and white soft paraffin, paraffin, flavorants, colorants and wax.

In a further embodiment of the present invention, the binder in the composition/formulation is present in a range of 0.1 to 30% by weight of the composition/formulation.

In some embodiment, the antioxidant is selected from tocopherol (vitamin E), sesamol, guaiac resin, methionine, beta-carotene, lycopene, lutein, zeaxanthin, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), sodium ascorbate, sodium metabisulfite (SMB), l-carnosine, propyl gallate (PG), tertiary butyl hydroquinone, cysteine (CYS), citric acid, tartaric acid, phosphoric acid and ascorbic acid.

In another embodiment of the present invention, the amount of antioxidant in the composition/formulation is present in the range of 0.01 to 10% by wt. of the composition/ formulation.

In another embodiment of the present invention, the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, potassium, or sodium benzoate or the like.

In another embodiment of the present invention, the lubricant in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total composition/formulation.

In another embodiment of the present invention, the solubilizing agent is selected from polysorbate 80, sodium lauryl sulphate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, starch, stearic acid, sulfobutylether beta cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, alcohol, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like.

In another embodiment of the present invention, the amount of solubilizing agent or surfactant in the composition/formulation ranges from 0.1% to 10% by weight of the composition/formulation.

In a preferred embodiment of the present invention, the solubilizing agent or surfactant is present in a range of 0.1% to 5.0% by weight of the composition/formulation.

In one of the embodiments of the present invention, the glidant is selected from colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or the like.

In another embodiment of the present invention, the glidant in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/formulation.

In some embodiment of the present invention, the stabilizers are selected from the group consisting of alginate, agar, carrageen, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose and likewise.

In some embodiment of the present invention, the stabilizer in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total composition/ formulation.

In some embodiment of the present invention, the plasticizers added to coating of the formulation are selected from the group consisting of propylene glycol, glycerol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, acetylated monoglycerides, castor oil, mineral oil and like thereof.

In some embodiment of the present invention, the plasticizer in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/ formulation.

In some embodiment of the present invention, the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.

In a preferred embodiment of the present invention, the solvent in the composition/formulation is used in a quantity sufficient to make the weight of the composition/formulation 100% by weight.

The additional additives include a polymer, a plasticizer, a sweetener, and a powdered flavor, a preservative, a colorant, a surfactant, and other excipients. The powdered flavor composition includes a flavourant associated with a solid carrier. Coating materials such as synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof are used.

In a preferred embodiment of the present invention, the additives are used in a range of 0.1 to 10% w/w of unit dose.

In yet another embodiment, the present invention provides the bioactive composition/formulation comprising a combination of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - N-methyl-D-aspartate receptor (NMDAR) antagonists complex along with pharmaceutical excipients, wherein the pharmaceutical excipients are selected from a diluent, a binder, a lubricant, a glidant, an additive, a surfactant, a stabilizer or mixtures thereof.

In a preferred embodiment, the present invention provides the composition/formulation wherein the pharmaceutically acceptable excipients are selected from a group consisting of the diluent is present in a range of 0.1 to 30%; the binder is present in a range of 0.1 to 30%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 10%; the antioxidant is present in a range of
0.01 to 10%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.

In further embodiment, compositions containing compounds of the present invention, can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof.

In further embodiment, compositions containing compounds of the present invention, can be in the form of solid, liquid, semi-solid, spray-dried, emulsion, premix powder, granules and gel.

The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.

In another embodiment, the invention relates to a synergistic composition, which can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. The preferable route of administration includes but not limited to sublingual, rectal, topical, parenteral, nasal, or oral.

In some embodiment, the present synergistic medicinal composition can be administered to the subject in need thereof, in the form which is suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, liquid, solution, suspension, rapidly dissolving film, powder, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including transmucosal and transdermal use, such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, parch or plaster; for nasal use, such as a snuff nasal spray or nasal drops; for vaginal or rectal use, such as a suppository; for administration by inhalation, such as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, such as a tablet, capsule, film, spray. Further, the composition can be formulated for parenteral use including intravenous, subcutaneous, intramuscular, intravascular, infusion, intraperitoneal, intracerebral, intracerebroventricular, or intradermal.

Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules (e.g., soft-gel capsules), sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a liquid, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, syrup; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredients can also be presented in the form of a bolus, electuary or paste, bar, energy bars (candy bars), powder, or granule sachet.

Further the present composition can be formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, minitablets, chewable formulations, orodispersible films, or orodispersible tablets. It can also be prepared in the form of snack, chocolate bars or other confectionery food products. The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.

In certain embodiments, the present invention provides the oral composition wherein the effective unit dose for an oral administration is formulated in solid form which is present in a range of 1 to 3000 gm, preferably 10 to 1000 gm.

In yet another embodiment, it is further recommended that children, patients over 65 years old, initially receive low doses and that the dosage be titrated based on individual physiological responses and/or pharmacokinetics. It can be necessary to use dosages outside these ranges in some cases, as will be apparent to those in the art. Further, it is noted that the clinician or treating physician knows how and when to interrupt, adjust, or terminate therapy in conjunction with an individual patient's response.

The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention, and does not pose a limitation on the scope of the invention unless otherwise claimed.

Various other examples of compositions and modifications or adaptations thereof can be devised by a person skilled in the art after reading the foregoing preferred embodiments without departing from the spirit and scope of the invention. All such further examples, modifications and adaptations are included within the scope of the invention.

It will be appreciated by those versed in the art that the present invention makes available novel and useful compositions, which have effects in several administration forms. Also, it will be understood by those with knowledge in the dietary supplement and nutraceutical art, that many embodiments of this invention may be made without departing from the spirit and scope of the invention, and the invention is not to be construed as limited, as it embraces all equivalents therein.

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway.

The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims and examples, and all changes or alterations which come within the ambit of equivalency are intended to be encompassed therein.

Examples:
Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention.

Example 1: Various compositions/formulations.
i. Composition 1: Premix Powder/Granules
Ingredient Per 100 gm
1-nonanecarboxylic acid salt of magnesium 40 gm
1-heptanecarboxylic acid salt of magnesium 4 gm
Protein 16 gm
Carbohydrate 19.5 gm
Vitamins 0.5 gm
Minerals 20 gm

ii. Composition 2: Premix Powder/Granules
Ingredient Per 100 gm
1-nonanecarboxylic acid salt of magnesium 25 gm
1-heptanecarboxylic acid salt of magnesium 25 gm
Protein 12 gm
Carbohydrate 17.5 gm
Vitamins 0.5 gm
Minerals 20 gm

iii. Composition 3: Premix Powder/Granules
Ingredient Per 100 gm
1-nonanecarboxylic acid salt of magnesium 40 gm
1-heptanecarboxylic acid salt of magnesium 4 gm
1-Isothiocyanato-4-(methanesulfinyl)butane 0.035 gm
Protein 16 gm
Carbohydrate 19.5 gm
Vitamins 0.465 gm
Minerals 20 gm

iv. Composition 4: Premix Powder/Granules
Ingredient Per 100 gm
1-nonanecarboxylic acid salt of magnesium 25 gm
1-heptanecarboxylic acid salt of magnesium 25 gm
1-Isothiocyanato-4-(methanesulfinyl)butane 0.035 gm
Protein 12 gm
Carbohydrate 17.5 gm
Vitamins 0.465 gm
Minerals 20 gm

v. Composition 5: Premix Powder/Granules
Ingredient Per 30 gm
1-nonanecarboxylic acid salt of magnesium 12 gm
1-heptanecarboxylic acid salt of magnesium 1 gm
Protein 7 gm
Carbohydrate 5 gm
Vitamins 0.4 gm
Minerals 3 gm
Trace elements 1.6 gm

vi. Composition 6: Premix Powder/Granules
Ingredient Per 30 gm
1-nonanecarboxylic acid salt of magnesium 13 gm
1-heptanecarboxylic acid salt of magnesium 3 gm
Protein 6 gm
Carbohydrate 3 gm
Vitamins 0.5 gm
Minerals 3 gm
Trace elements 1.5 gm

vii. Composition 7: Premix Powder/Granules
Ingredient Per 30 gm
1-nonanecarboxylic acid salt of magnesium 12 gm
1-heptanecarboxylic acid salt of magnesium 1 gm
1-Isothiocyanato-4-(methanesulfinyl)butane 0.035 gm
Protein 7 gm
Carbohydrate 5 gm
Vitamins 0.5 gm
Minerals 3 gm
Trace elements 1.465 gm

viii. Composition 8: Solution/Emulsion
Ingredient Per 100 ml
1-nonanecarboxylic acid salt of magnesium 10 gm
1-heptanecarboxylic acid salt of magnesium 1 gm
Protein 4 gm
Carbohydrate 4.875 gm
Vitamins 0.125 gm
Minerals 5 gm

ix. Composition 9: Solution /Emulsion
Ingredient Per 100 ml
1-nonanecarboxylic acid salt of magnesium 6.25 gm
1-heptanecarboxylic acid salt of magnesium 6.25 gm
Protein 3 gm
Carbohydrate 4.375 gm
Vitamins 0.125 gm
Minerals 5 gm

x. Composition 10: Solution/ Emulsion
Ingredient Per 100 ml
1-nonanecarboxylic acid salt of magnesium 10 gm
1-heptanecarboxylic acid salt of magnesium 1 gm
1-Isothiocyanato-4-(methanesulfinyl)butane 0.00875 gm
Protein 4 gm
Carbohydrate 4.875 gm
Vitamins 0.11625 gm
Minerals 5 gm

xi. Composition 11: Solution/Emulsion
Ingredient Per 100 ml
1-nonanecarboxylic acid salt of magnesium 6.25 gm
1-heptanecarboxylic acid salt of magnesium 6.25 gm
1-Isothiocyanato-4-(methanesulfinyl)butane 0.00875 gm
Protein 3 gm
Carbohydrate 4.375 gm
Vitamins 0.11625 gm
Minerals 5 gm

xii. Composition 12: Tablet /Capsule
Ingredient mg per unit dose
1-nonanecarboxylic acid salt of magnesium 500 mg
1-heptanecarboxylic acid salt of magnesium 500 mg
Magnesium Stearate 0.1-5
Ascorbic acid 0.1-5
Microcrystalline Cellulose 0.1-10
Colloidal Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Polyvinylpyrrolidone 0.1-5
Talc 0.1-5
Tween 80 0.1-5
Sucrose 0.1-2
Sorbitol 0.1-1
Alcohol QS
Water QS
Average weight 1055-1100 mg

xiii. Composition 13: Tablet / Capsule
Ingredient mg per unit dose
1-nonanecarboxylic acid salt of magnesium 1000 mg
1-heptanecarboxylic acid salt of magnesium 100 mg
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Mineral Oil 0.1-2
Sodium benzoate 0.1-1
Ascorbic Acid 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-5
Mannitol 0.1-1
Water QS
Average weight 1155-1200 mg

xiv. Composition 14: Tablet / Capsule
Ingredient mg per unit dose
1-nonanecarboxylic acid salt of magnesium 500 mg
1-heptanecarboxylic acid salt of magnesium 500 mg
1-Isothiocyanato-4-(methanesulfinyl)butane 35 mg
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Mineral Oil 0.1-2
Sodium benzoate 0.1-1
Ascorbic Acid 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-5
Mannitol 0.1-1
Water QS
Average weight 1055-1100 mg

xv. Composition 15: Tablet / Capsule
Ingredient mg per unit dose
1-nonanecarboxylic acid salt of magnesium 1000 mg
1-heptanecarboxylic acid salt of magnesium 100 mg
1-Isothiocyanato-4-(methanesulfinyl)butane 35 mg
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Mineral Oil 0.1-2
Sodium benzoate 0.1-1
Ascorbic Acid 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-5
Mannitol 0.1-1
Water QS
Average weight 1155-1200 mg

xvi. Composition 16: Tablet / Capsule
Ingredient mg per unit dose
1-nonanecarboxylic acid salt of magnesium 700 mg
1-heptanecarboxylic acid salt of magnesium 300 mg
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Mineral Oil 0.1-2
Sodium benzoate 0.1-1
Ascorbic Acid 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-5
Mannitol 0.1-1
Water QS
Average weight 1055-1100 mg

Example 2: Animal Study
The purpose of this study is to evaluate the effect of Anti-convulsant activity of the test compound in Wistar Rats.
Test System and Animal Husbandry
Species: Rats
Strain: Wistar
Sex: Male
No. of animals: 48 Animals (n=8 per group)
Body weight: 200- 220gm
CPCSEA Registration Number-1803/PO/RcBi/S/2015/CPCSEA

Animal House conditions
Lighting: 12 / 12-hour light-dark cycle
Temperature: 22 ± 3 °C
Relative Humidity: 30 to 70%
Animals had continuous access to fresh, potable, uncontaminated drinking water.

Feed: Normal chow diet [PURINA 5L79 from PMI Nutritional, USA]

Acclimatization
All rats were allowed to the experimental room conditions for at least five days prior to the commencement of dosing, during the acclimatization period animals were observed for any clinical signs prior to commencement of treatment, a detailed physical health examination was performed for all animals by the veterinarian and the animals with any evidence of ill health or poor physical condition were not chosen for the study.
Individual body weights will be recorded at receipt, on the day of randomization, on the first day of treatment before dosing and weekly once thereafter throughout the treatment period. Terminal (fasting) body weights will be taken on the day of scheduled necropsy. The body weight changes for all the animals will be calculated and reported along with the body weight data.

Induction of PTZ (Pentylene-tetrazole)
The systemic administration of PTZ is one of the most commonly employed methods for anti convulsant screening. The preference has given for this model due to its ease of performance, reliability, ease of expressing results and the shorter time period to produce convulsions.
The PTZ was injected 60mg/kg body weight intraperitonally 1 h after the test item administration.
The main mechanism involved in PTZ seems to related to the inhibition of the inhibitory functions of the GABA neurotransmitter. PTZ has affinity towards the chloride ionophore of the post synaptic GABA receptor complex and to antagonize GABA nergic function.

Group, Designation and Dose Levels

Phosphate-buffered saline [PBS] was used as a vehicle for test formulation.
Table 1: Animal grouping and treatment details
Groups Group Description Dose Level [Human] No. of animals
Group 1 Normal control - 6
Group 2 Diseased Control - 6
Group 3 Test I
[1-nonanecarboxylic acid salt of magnesium] 12 gm 6
Group 4 Test II
[1-heptanecarboxylic acid salt of magnesium] 1 gm 6
Group 5 Test III
[Sulforaphane] 0.035 gm 6
Group 6 Combination 1 [Test I+ Test II]
12 gm + 1 gm
6
Group 7 Combination 2 [Test I+ Test II] 6 gm + 6 gm
6
Group 8 Combination 3 [Test I+ Test II+ Test III] 12 gm + 1 gm + 0.035 gm
6

Experimental Procedure:
All animals will be acclimatized for five days and the seizures were induced by administering PTZ 60 mg/kg body 1 hr after test item administration. Normal control group was injected with phosphate buffer solution.
As Group 1 (Vehicle control), Group 2 will be served as diseased control, Group-3, Group 4, Group 5, Group 6, Group 7 & Group 8 will be served as test substance. The dose was administered for short term (single day administration) or long term (14 or 21 days) after acclimatization.

The time was recorded for convulsion phase clonic, tonic and stupor after test administration.
All values were expressed as MEAN± SD. The significant difference between the treatment and control group was estimated using oneway ANOVA with Dennett’s test. All results of the statistical analysis were summarized in separate tables.

Results:
Table 2: Overall effects of treatment determined by one-way ANOVA
Grp. No. Treatment Group Tonic Convulsions
(Seconds) Straub Tail Clonic Convulsions
(Seconds) Stupor
(Seconds) Recovery
G1 Normal control 12.03 Present 6.91 120.98 Recovery
G2 Diseased Control 24.12 Present 13.01 141.37 Death
G3 Test I
[1-nonanecarboxylic acid salt of magnesium] 17.89 Absent 9.82 125.16 Recovery
G4 Test II
[1-heptanecarboxylic acid salt of magnesium] 20.17 Absent 11.60 132.03 Recovery
G5 Test III
[Sulforaphane] 22.76 Absent 12.04 135.25 Recovery
G6 Combination 1 [Test I+ Test II]
6.07 Absent 3.20 48.16 Recovery
G7 Combination 2 [Test I+ Test II] 8.53 Absent 4.52 61.75 Recovery
G8 Combination 3 [Test I+ Test II+ Test III] 5.56 Absent 2.45 45.67 Recovery

Conclusion:
It was clearly indicated that treatment with test substances (G3-G8) are able to lower the convulsion phases time. The reduction of tonic- clonic convulsion time observed in combination of G6, G7 & G8 is more significant than individual components G3, G4 and G5. Thus, it is concluded that systemic administration of present composition produces synergistic anticonvulsant effects in seizure experimental models. ,CLAIMS:1. A synergistic bioactive composition for treating seizure disorders, comprising combination of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - N-methyl-D-aspartate receptor (NMDAR) antagonist complex along with pharmaceutically acceptable excipients.

2. The composition as claimed in claim 1, wherein said combination is 1-nonanecarboxylic acid and 1-heptanecarboxylic acid salt of magnesium.

3. The composition as claimed in claim 1, wherein the combination of 1-nonanecarboxylic acid salt of magnesium and 1-heptanecarboxylic acid salt of magnesium present in a specific weight ratio of 1: 0.008 to 1:1 along with pharmaceutically acceptable excipients.

4. The composition as claimed in claim 1, wherein the 1-nonanecarboxylic acid salt of magnesium is present in a range of 20% to 90% by weight of the total composition.

5. The composition as claimed in claim 1, wherein the 1-heptanecarboxylic acid salt of magnesium is present in a range of 3% to 50% by weight of the total composition.

6. The composition as claimed in claim 1, further comprises nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activator wherein Nrf2 activators are selected from 1-Isothiocyanato-4-(methanesulfinyl)butane and (2S)-3-(2-Sulfanylidene-2,3-dihydro-1H-imidazol-4-yl)-2-(trimethylazaniumyl)propanoate.

7. The composition as claimed in claim 1, wherein the Nrf-2 activator is present in a range of 0.03% to 4% by weight of the total composition.

8. The composition as claimed in claim 1 and 6, wherein 1-nonanecarboxylic acid salt of magnesium, 1-heptanecarboxylic acid salt of magnesium and Nrf2 activator are present in the weight ratio ranges from 1: 0.008: 0.001 to 1: 1: 0.07 along with pharmaceutically acceptable excipients.

9. The composition as claimed in claim 1 or 6, wherein the pharmaceutically acceptable excipient is selected from a group comprising of diluent, binder, surfactant, lubricant, glidant, additive, stabilizer, antioxidant, plasticizer, solvent or any combination thereof.

10. The composition as claimed in claim 9, wherein the diluent is present in a range of 0.1 to 30%; the binder is present in a range of 0.1 to 30%; the surfactant is present in a range of 0.1 to 5.0%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10%; the stabilizer is present in a range of 0.1 to 10%; the antioxidant is present in a range of 0.01 to 10%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.

11. The composition as claimed in any of claims 1-10, wherein the administration of effective dose is useful for treating seizure disorders such as epilepsy, reflex epilepsy, epileptic seizures, nonepileptic seizures, provoked seizures, idiopathic generalized epilepsy, convulsion, absence seizures, atonic seizures, tonic seizures, clonic seizures, myoclonic seizures, febrile seizure, focal seizures, temporal lobe seizures, occipital lobe seizures, parietal lobe seizures, nocturnal epilepsy.

12. The composition as claimed in claim 9, wherein the composition is in the form of solid, liquid, semi-solid, spray-dried, emulsion, premix powder, granules and gel.