WO2026018281A1 - A synergistic composition for the treatment of disorders related to central nervous system (cns) excitability. - Google Patents

Abstract

The present invention relates to a synergistic composition for the treatment of disorders related to central nervous system (CNS) excitability. The synergistic composition comprises combination of GABA receptor agonists and synaptic plasticity enhancer or salts thereof along with pharmaceutically acceptable excipients. The GABA receptor agonists are selected from the group consisting of 4-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido]butanoic acid, 4- (Pyridine-3-carbonylamino)butanoic acid and 4-(hexadecanoylamino)butanoic acid or salts thereof. The synaptic plasticity enhancer are selected from magnesium 2- acetamidoethanesulfonate, magnesium bis (2-aminoethane-1-sulfonate), magnesium;(2S,3R)- 2,3,4-trihydroxybutanoate, N-(2-Hydroxyethyl)hexadecanamide, 1-(4-aminobutyl)guanidine and 5'-inosinic acid or salts thereof.

Description

A SYNERGISTIC COMPOSITION FOR THE TREATMENT OF DISORDERS RELATED TO CENTRAL NERVOUS SYSTEM (CNS) EXCITABILITY.

FIELD OF THE INVENTION:

The present invention relates synergistic composition for the treatment of disorders related to central nervous system (CNS) excitability.

Particularly the invention relates to synergistic composition comprising combination of GABA receptor agonists and synaptic plasticity enhancer or salts thereof along with pharmaceutically acceptable excipients.

More particularly, the present composition synergistically treating the disorders related to central nervous system (CNS) excitability; wherein GABA receptor agonists activate one or more GABA receptors in the brain and modulate the transmission of signals within the spinal cord and brain, simultaneously, synaptic plasticity enhancer enhances synaptic plasticity by increasing long-term potentiation (LTP) and promotes synaptic connectivity.

The present synergistic composition is useful in the treatment of disorders related to central nervous system (CNS) excitability, Neurodevel opmental delay such as Epilepsy, Seizures, Alzheimer’s diseases, Parkinson’s diseases, Sluggish Cognitive Tempo, Dyslexia, Cerebral Palsy, Developmental Language disorder, Amyotrophic Lateral Sclerosis (ALS), Social Communication Disorder- Autism Spectrum Disorders (ASD), Inattentive / Attention Deficit Hyperactivity Disorder (ADHD), Tourette syndrome, Preterm Hypoxic- Ischemic Encephalopathy, Neuropathic Pain, Brain Stroke, Retinal Diseases, Tinnitus and like thereof.

BACKGROUND OF THE INVENTION:

Central nervous system (CNS) excitability refers to the ability of neurons in the brain and spinal cord to become activated and generate electrical signals. This concept encompasses the overall responsiveness of the CNS to various stimuli, whether external (like sensory input) or internal (such as neural signals from other parts of the brain). The main two factors which are affecting the central nervous system (CNS) excitability are neurotransmitter levels which comprises balance of neurotransmitters, such as glutamate (which is typically excitatory) and GABA (which is typically inhibitory). CNS excitability is crucial for normal brain function, including sensory perception, motor control, cognition, and emotional regulation. Abnormal CNS excitability can lead to neurological disorders such as epilepsy, chronic pain, and certain psychiatric conditions. Disorders related to CNS excitability generally involve abnormalities in the way neurons generate and transmit electrical signals. These disorders can manifest in various ways, affecting sensory, motor, cognitive, and emotional functions. There are some common disorders associated with CNS excitability such as epilepsy, where epilepsy is characterized by recurrent seizures, which are sudden, unprovoked bursts of electrical activity in the brain. These seizures can vary in intensity and manifestation, depending on the area of the brain affected. Changes in ion channel function, neurotransmitter imbalance (especially involving excessive excitatory neurotransmitters like glutamate). Another common disorder are migraine, neuropathic pain, and bipolar disorder where dysregulation in neurotransmitter systems (especially dopamine and glutamate) and abnormal neuronal connectivity occurs.

The treatment of CNS excitability disorders involves various methodologies aimed at modulating neuronal activity and neurotransmitter levels to restore normal CNS function. A review article provides an in-depth exploration of the different subunits and distribution of GABA receptors in the CNS, which are crucial for understanding how GABAergic modulation can influence CNS excitability. Fritschy, J. M et.al. Journal of Comparative Neurology, 359(1), 154-194.

A wide range of AEDs, such as carbamazepine, valproate, lamotrigine, and levetiracetam, are used to reduce neuronal excitability and prevent seizures in epilepsy. These drugs typically act by modulating ion channels (e.g., sodium and calcium channels) or enhancing inhibitory neurotransmission (e.g., through GABAergic mechanisms).

A review article provides an overview of the neurobiological mechanisms underlying epilepsy and the actions of antiepileptic drugs, which often target CNS excitability. Rogowski, M. A., & Loscher, ffl. (2004). The neurobiology of antiepileptic drugs. Nature Reviews Neuroscience, 5(7), 553-564.

For chronic pain syndromes associated with CNS excitability, medications like opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and certain antidepressants (e.g., tricyclic antidepressants) may be prescribed to alleviate pain and modulate pain signaling pathways.

US20080319041 discloses methods for the treatment of CNS disease and pathologies by administering Lofexidine enantiomers. Most particularly, it is related to methods of treatment of CNS disease, such as opioid detoxification.

US10870677 relates to C21 -substituted neuroactive steroids designed to act as GABA modulators which are useful as therapeutic agents for treating a CNS-related disorder. This patent also describes that the effect on brain excitability is mediated by GABA, a neurotransmitter. GABA has a profound influence on overall brain excitability because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter.

Disorders related to CNS excitability, such as epilepsy, chronic pain syndromes, migraine, and certain neuropsychiatric conditions, present significant challenges in clinical management due to their diverse etiologies and complex symptom profiles. Current therapies largely focus on modulating neurotransmitter systems or dampening neuronal excitability; however, these strategies often fail to address the underlying synaptic and network-level dysfunctions that drive disease progression. For example, impairment of long-term potentiation (LTP) — a fundamental mechanism of synaptic plasticity — can hinder the formation and refinement of neural circuits critical for higher-order functions such as cognition, speech, motor control, and socialization.

Modulation of inhibitory neurotransmission through GABAergic systems is essential for maintaining the excitatory-inhibitory balance and supporting healthy network plasticity. Traditional GABA receptor agonists act on both subunits of the GABAB receptor, broadly suppressing neuronal activity. While effective in reducing hyperexcitability and providing symptomatic relief, this non-selective activation often suppresses LTP and disrupts synaptic plasticity, leading to adverse effects such as sedation, muscle weakness, dizziness, cognitive impairment, and, with long-term use, tolerance, dependency, and withdrawal.

To overcome these limitations, selective presynaptic partial GABAB agonists (SPPGAs) have emerged as a promising alternative. By preferentially modulating specific subunits at presynaptic terminals, SPPGAs enable precise regulation of neurotransmission, mitigating hyperexcitability while preserving synaptic plasticity. When combined with synaptic plasticity enhancers — agents that promote LTP and strengthen neural connectivity — this approach offers a synergistic therapeutic effect. Plasticity enhancers counteract the suppressive impact of GABAergic modulation on LTP, facilitating the restoration of neural network dynamics essential for cognitive and functional recovery.

The inventors of the present invention have developed a novel composition that integrates a GABA receptor agonist with a synaptic plasticity enhancer to achieve dual benefits: controlled neuronal inhibition and enhanced synaptic plasticity. This unique combination synergistically restores excitatory-inhibitory balance and supports network remodelling, offering a cost-effective, non-toxic, and therapeutically active solution. By addressing both hyperexcitability and synaptic dysfunction, this formulation provides a safer and more effective strategy for treating CNS excitability disorders while minimizing cognitive and systemic side effects. OBJECTIVE OF THE INVENTION:

The primary objective of the invention is to provide a synergistic composition comprising a GABA receptor agonist and a synaptic plasticity enhancer or salts thereof, which effectively modulates central nervous system (CNS) excitability and improves synaptic plasticity.

Another objective of the invention is to develop a bioavailable, non-toxic, and therapeutically active composition that ameliorates disorders associated with CNS excitability or neurodevelopmental delay (NDD) disorders including but not limited to Epilepsy, Seizures, Alzheimer’s diseases, Parkinson’s diseases, Sluggish Cognitive Tempo, Dyslexia, Cerebral Palsy, Developmental Language disorder, Amyotrophic Lateral Sclerosis (ALS), Social Communication Disorder - Autism Spectrum Disorders (ASD), Inattentive / Attention Deficit Hyperactivity Disorder (ADHD), Tourette syndrome, Preterm Hypoxic-Ischemic Encephalopathy, Neuropathic Pain, Brain Stroke, Retinal Diseases, Tinnitus and like thereof.

Further objective of the invention is to provide a composition that exhibits a synergistic effect between GABA receptor activation and enhancement of long-term potentiation (LTP), thereby restoring excitatory-inhibitory balance and supporting cognitive and functional recovery.

Yet another objective of the invention to provide a novel therapeutic approach that minimizes the adverse effects commonly associated with conventional GABA receptor agonists, such as sedation, cognitive impairment, and dependency, by incorporating synaptic plasticity enhancers to preserve network functionality.

SUMMARY OF THE INVENTION:

To meet the above objectives, the inventors of the instant invention carried out thorough experiments to establish significant therapeutic effects of the active ingredients or biomolecules or peptides or amino acids or nutrients present in the composition for improving CNS in a subject in need thereof in safer way.

In an aspect, the present invention relates to synergistic compositions comprising therapeutically active ingredients along with pharmaceutically acceptable carriers for treating disorders related to central nervous system (CNS) excitability.

In yet another aspect, the present invention provides synergistic composition comprising combination of GABA receptor agonists and synaptic plasticity enhancer or salts thereof which synergistically ameliorate the CNS excitability. In yet another aspect, the present invention provides synergistic composition, wherein first therapeutically active ingredient is GABA receptor agonists which is selected from the group consisting of 4-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido]butanoic acid, 4- (Pyridine-3-carbonylamino)butanoic acid and 4-(hexadecanoylamino)butanoic acid or salts thereof and second active ingredient is synaptic plasticity enhancer which is selected from magnesium 2-acetamidoethanesulfonate, magnesium bi s(2-aminoethane-l -sulfonate), magnesium;(2S,3R)-2,3,4-trihydroxybutanoate, N-(2-Hydroxyethyl)hexadecanamide, 1 -(4- aminobutyl)guanidine and 5'-inosinic acid or salts thereof present in specific weight ratio along with pharmaceutically acceptable excipients.

In yet one more aspect, the invention discloses a synergistic composition is useful in the treatment of disorders related to central nervous system (CNS) excitability, and Neurodevel opmental delay such as Epilepsy, Seizures, Alzheimer’s diseases, Parkinson’s diseases, Sluggish Cognitive Tempo, Dyslexia, Cerebral Palsy, Developmental Language disorder, Amyotrophic Lateral Sclerosis (ALS), Social Communication Disorder- Autism Spectrum Disorders (ASD), Inattentive / Attention Deficit Hyperactivity Disorder (ADHD), Tourette syndrome, Preterm Hypoxic-Ischemic Encephalopathy, Neuropathic Pain, Brain Stroke, Retinal Diseases, Tinnitus and like thereof

Abbreviations

CNS: central nervous system

GABA: gamma-aminobutyric acid

LTP: long-term potentiation

ALS: amyotrophic lateral sclerosis

ASD: autism spectrum disorders

ADHD: attention deficit hyperactivity disorder

AEDs: Anti-epileptic drugs

NSAIDs: nonsteroidal anti-inflammatory drugs

LTD: Long-Term Depression

BDNF: brain-derived neurotrophic factor

BRIEF DESCRIPTION OF FIGURES:

Fig 1 illustrates latency time in seconds for control(Gl), disease (G2) and treatment individual ingredients and combination groups (G3-G14) Fig 2 illustrates Time (in seconds) spent in the preferred and discriminated goal arms for control(Gl), disease(G2) and treatment individual ingredients and combination groups (G3- G14)

Fig 3 illustrates number of squares crossed Ambulation score for control(Gl), disease(G2) and treatment individual ingredients and combination groups (G3-G14)

Fig 4 illustrates frequency of rearing (indicative of exploratory behavior) for control(Gl), disease (G2) and treatment individual ingredients and combination groups (G3-G14)

Fig 5 illustrates number of grooming episodes for control(Gl), disease(G2) and treatment individual ingredients and combination groups (G3-G14)

Fig 6 illustrates BDNF-in Serum (ng/mL) for control(Gl), disease(G2) and treatment individual ingredients and combination groups (G3-G14)

DESCRIPTION OF THE INVENTION:

The invention will now be described 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 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, amino acid salt, sugar-based salt, alkali or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs and the like of the salts.

The term ‘therapeutically active” is an ingredient which is accountable for a therapeutic effect.

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 ‘CNS excitability’ refers to the ability of neurons in the central nervous system (CNS) to respond to stimuli and generate action potentials. It is a measure of how easily neurons can be activated, which is crucial for normal brain function, including processing sensory information, generating motor commands, and supporting cognitive processes such as learning and memory.

In a preferred embodiment, the invention provides novel and synergistic compositions for ameliorating the CNS excitability.

GABA receptor agonists are compounds that bind to and activate GABA receptors in the brain. GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter in the central nervous system. GABA receptor agonists are vital in the pharmacological management of various neurological and psychiatric conditions. Their ability to enhance inhibitory neurotransmission makes them powerful tools in treating disorders characterized by excessive CNS excitability.

Particularly, GABA receptor agonists activate one or more GABA receptors such as GABA A and GABA B. Activation of GABA A receptor opens the channel allowing chloride ions (CP) to flow into the neuron. The influx of Cl" leads to hyperpolarization of the neuron, making it more negative and less likely to fire an action potential. This reduces neuronal excitability and inhibits the transmission of signals, leading to a calming effect.

Similarly, Activation of GABA B receptor led to the opening of potassium (K⁺) channels, causing K⁺ to exit the neuron, or the closing of calcium (Ca²⁺) channels, preventing Ca²⁺ entry. The movement of K⁺ out of the cell also causes hyperpolarization, and the reduced Ca²⁺ entry decreases neurotransmitter release. In another embodiment, the present invention provides a synergistic composition comprising a therapeutically effective amount of GABA receptor agonist or pharmaceutically acceptable salts thereof, wherein GABA receptor agonist is present in a range of 1-1000 mg of the total composition.

In yet another embodiment, the present invention provides a synergistic composition comprising a therapeutically effective amount of GABA receptor agonist or pharmaceutically acceptable salts thereof, wherein GABA receptor agonist is selected from the group consisting of 4-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido] butanoic acid, 4-(Pyridine-3- carbonylamino) butanoic acid and 4-(hexadecanoylamino)butanoic acid.

In preferred embodiment, the invention relates to synergistic composition comprising one or more second therapeutically active ingredients i.e. synaptic plasticity enhancer which is selected from magnesium 2-acetamidoethanesulfonate, magnesium bis(2-aminoethane-l- sulfonate), magnesium (2S,3R)-2,3,4-trihydroxybutanoate, N-(2-Hydroxyethyl) hexadecanamide, l-(4-aminobutyl) guanidine and 5'-inosinic acid or salts thereof.

Synaptic plasticity enhancers play a crucial role in modulating central nervous system (CNS) excitability. Synaptic plasticity refers to the ability of synapses (the connections between neurons) to strengthen or weaken over time, which is essential for learning, memory, and overall neural network functionality.

Long-Term Potentiation (LTP) is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. Synaptic plasticity enhancers can facilitate LTP, leading to increased synaptic strength and excitability. This process is critical for learning and memory formation. Similarly, Long-Term Depression (LTD) is the opposite of LTP, involving a long-lasting decrease in synaptic strength. While not traditionally thought of as an enhancer, substances that modulate LTD can also impact synaptic plasticity and CNS excitability by providing a balance between strengthening and weakening of synapses.

Synaptic plasticity enhancers also increase the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). These factors support the growth, survival, and differentiation of neurons, promoting synaptic plasticity and, consequently, CNS excitability. Enhancing synaptic plasticity may also have neuroprotective effects, helping to preserve or restore neural function in neurodegenerative diseases or after CNS injuries.

In one embodiment, the present invention provides a synergistic composition comprising a GABA receptor agonist or a pharmaceutically acceptable salt thereof; and a synaptic plasticity enhancer or a pharmaceutically acceptable salt thereof; wherein the GABA receptor agonist and synaptic plasticity enhancer are present in a weight ratio ranging from 1 :0.001 to 1 :2.

In another embodiment, the composition comprises the GABA receptor agonist and synaptic plasticity enhancer in an amount ranging from 0.1% to 98% by weight of the total composition. Preferably, the GABA receptor agonist is present in the range of 10% to 95%, and the synaptic plasticity enhancer is present in the range of 1% to 80% by weight of the total composition, along with pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a synergistic composition comprising a therapeutically effective amount of GABA receptor agonist or pharmaceutically acceptable salts thereof, wherein GABA receptor agonist is present in a range of 1-1000 mg of the total composition.

In another embodiment, the present invention provides a synergistic composition comprising a therapeutically effective amount of synaptic plasticity enhancer or pharmaceutically acceptable salts thereof, wherein synaptic plasticity enhancer is present in a range of 1-1000 mg of the total composition preferably 1-500 mg.

In another embodiment, the present invention provides a synergistic composition for treating neurodevelopment disorders, wherein the composition is in a form selected from the group comprising tablet, capsule, and syrup, and wherein the composition elevates the brain- derived neurotrophic factor (BDNF) levels by 75-95%.

In particular embodiment, the invention provides nutritional composition comprising synergistic exogenous blend of wherein first therapeutically active ingredient is GABA receptor agonists which is selected from the group consisting of 4-[(2R)-2,4-Dihydroxy-3,3- dimethylbutanamido]butanoic acid, 4-(Pyridine-3-carbonylamino)butanoic acid and 4- (hexadecanoylamino) butanoic acid or salts thereof and second active ingredient is synaptic plasticity enhancer which is selected from magnesium 2-acetamidoethanesulfonate, magnesium bis(2-aminoethane-l -sulfonate), magnesium;(2S,3R)-2,3,4-trihydroxybutanoate, N-(2-Hydroxyethyl)hexadecanamide, l-(4-aminobutyl)guanidine and 5'-inosinic acid or salts thereof present in specific weight ratio along with pharmaceutically acceptable excipients.

The present biologically active composition is composed of synergistic combination of GABA receptor agonists which is selected from the group consisting of 4-[(2R)-2,4- Dihydroxy-3,3-dimethylbutanamido]butanoic acid, 4-(Pyridine-3-carbonylamino)butanoic acid and 4-(hexadecanoylamino) butanoic acid or salts thereof and second active ingredient is synaptic plasticity enhancer which is selected from magnesium 2-acetamidoethanesulfonate, magnesium bis(2-aminoethane-l -sulfonate), magnesium;(2S,3R)-2,3,4-trihydroxybutanoate, N-(2-Hydroxyethyl)hexadecanamide, l-(4-aminobutyl)guanidine and 5'-inosinic acid or salts thereof which are present in therapeutically effective amount. The composition significantly ameliorates the CNS excitability.

In another embodiment, the invention provides synergistic combination of GABA receptor agonists which is selected from the group consisting of 4-[(2R)-2,4-Dihydroxy-3,3- dimethylbutanamido] butanoic acid, 4-(Pyridine-3 -carbonylamino) butanoic acid and 4- (hexadecanoylamino) butanoic acid or salts thereof, wherein the salts are selected from but not limiting to Calcium, Sodium, Potassium, Magnesium, Lysine, Arginine and like thereof. These salts are considered acceptable because they are non-toxic, enhance solubility/stability, and are commonly used in the formulations.

Particularly, the present invention provides a composition comprising combination of GABA receptor agonist a compound or combination of compounds capable of activating one or more GABA receptors in the brain, thereby modulating neuronal excitability and inhibiting excessive neurotransmitter release. Simultaneously a second ingredient i.e. synaptic plasticity enhancer, a compound or combination of compounds that enhances synaptic plasticity by promoting long-term potentiation (LTP) and facilitating synaptic connectivity. This synergistically enhances adaptive neuronal responses and improves network function in the CNS.

Further, the composition ameliorates the CNS excitability with enhanced bioavailability, solubility, and therapeutic efficacy.

In another embodiment, the invention provides medicinal composition comprising synergistic exogenous blend of wherein first therapeutically active ingredient is GABA receptor agonists which is selected from the group consisting of 4-[(2R)-2,4-Dihydroxy-3,3- dimethylbutanamido]butanoic acid, 4-(Pyridine-3-carbonylamino)butanoic acid and 4- (hexadecanoylamino)butanoic acid or salts thereof and second active ingredient is synaptic plasticity enhancer which is selected from magnesium 2-acetamidoethanesulfonate, magnesium bis(2-aminoethane-l -sulfonate), magnesium;(2S,3R)-2,3,4-trihydroxybutanoate, N-(2-Hydroxyethyl)hexadecanamide, l-(4-aminobutyl)guanidine and 5'-inosinic acid or salts; wherein the individual ingredient is present in the range of 1-3000 mg, preferably in the range of 1-1000 mg of total composition. In another embodiment, the invention relates to synergistic nutritional composition, which is useful for treatment of disorders related to central nervous system (CNS) excitability such as Epilepsy, Seizures, Alzheimer’s diseases, Parkinson’s diseases, Sluggish Cognitive Tempo, Dyslexia, Cerebral Palsy, Developmental Language disorder, Amyotrophic Lateral Sclerosis (ALS), Social Communication Disorder- Autism Spectrum Disorders (ASD), Inattentive / Attention Deficit Hyperactivity Disorder (ADHD), Tourette syndrome, Preterm Hypoxic-Ischemic Encephalopathy, Neuropathic Pain, Brain Stroke, Retinal Diseases, Tinnitus and like thereof

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 CRP level), and/or minimize at least one clinical symptom related to CNS disorder.

The term ‘subject in need thereof pertains to subject preferably mammal, more preferably human suffering or suspected with Neurodevelopmental Delay, Epilepsy, seizures, Alzheimer’s diseases, Parkinson’s diseases, amyotrophic lateral sclerosis (ALS), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), neuropathic pain, brain stroke, retinal diseases, Schizophrenia, depression, tinnitus and other neurodegenerative disorders.

Neurodevelopmental delay refers to a condition in which a child fails to achieve age- appropriate developmental milestones across one or more domains, including motor, cognitive, speech and language, or social-emotional skills. Such delays may arise from genetic factors, prenatal or perinatal complications, infections, metabolic disorders, or environmental influences, and can be either global or specific to a particular domain. The disorder encompasses a spectrum of neurological and neuropsychiatric conditions such as epilepsy, seizures, Alzheimer’s disease, Parkinson’s disease, sluggish cognitive tempo, dyslexia, cerebral palsy, developmental language disorder, amyotrophic lateral sclerosis (ALS), social communication disorders including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), Tourette syndrome, preterm hypoxic-ischemic encephalopathy, neuropathic pain, brain stroke, retinal diseases, tinnitus, and related conditions.

In the context of the present invention, the term “treatment” relates to alleviate, mitigate, prevent, prophylaxis, attenuate, manage, regulate, modulate, control, minimize, lessen, decrease, down regulate, up regulate, moderate, inhibit, restore, suppress, reverse, limit, block, decrease, prevent, stabilize, ameliorate, or cure, heal CNS disorders.

Notably, the present synergistic composition is non-hazardous, non-toxic, and safe for human consumption without any severe adverse effects. The present medicinal composition is also used as preventive therapy/ adjuvant therapy/ add-on therapy/ combination/ adjunctive therapy in a subject in need thereof.

Certain compounds of the present invention exist in unsolvated forms as well as solvated forms, including hydrated forms. Further, some compounds of the present invention exist in multiple crystalline or amorphous forms (“polymorphs”). Compounds of the invention are formulated in geometric or, enantiomeric or stereoisomeric forms.

“In another embodiment, the present invention provides compositions comprising enantiomers of the active compound, wherein the enantiomers are present individually or as a mixture in any proportion. In certain embodiments, the enantiomer is the (R)-enantiomer or the (S)-enantiomer. In some embodiments, the composition comprises the (R) or (S)-enantiomer in an enantiomeric excess of at least 90%, 95%, 98%, or 99%. ”

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 general, the total daily dose (in single or divided doses) ranges from about 1 mg per day to about 5000 mg per day, preferably about 10 mg per day to about 1500 mg per day.

As used herein, the term “pharmaceutically acceptable carriers, diluents, or excipients” refers, without limitation, to any adjuvant, carrier, excipient, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, encapsulating agent, encapsulating polymeric delivery system, or polyethyleneglycol matrix that is suitable for administration to a subject, preferably a human. Excipients may further include, but are not limited to, anti adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, anticaking agents, food additives, waters of hydration, and salts.

In another embodiment, the invention provides a synergistic medicinal composition prepared using methods well known in the pharmaceutical arts, suitable for administration via various routes depending on whether local or systemic treatment is desired and the site of treatment. Preferred routes of administration include, but are not limited to, sublingual, rectal, topical, parenteral, nasal, or oral delivery.

In certain embodiments, the synergistic medicinal composition may be administered in a form suitable for oral use, including but not limited to tablets, capsules (delayed-release, extended-release, sustained-release, or enteric-coated), hard gelatin capsules, soft gelatin capsules in oily vehicles, vegetarian capsules, cellulose-based capsules, granulates for sublingual use, effervescent or carbon tablets, aqueous or oily solutions, suspensions, emulsions, encapsulated matrices, coatings, beadlets, nanoparticles, caplets, granules, micronized, ultramicronized, particulates, agglomerates, spansules, chewable tablets, lozenges, troches, rapidly dissolving films, elixirs, gels, and reconstituted dry powders for use with a liquid medium or syrup. For topical applications, the composition may be formulated as creams, ointments, gels, aqueous or oil solutions or suspensions, salves, patches, or plasters; for nasal use, as snuff, nasal sprays, or drops; for rectal or vaginal use, as suppositories; for inhalation, as finely divided powders or liquid aerosols; and for sublingual or buccal use, as tablets, capsules, films, or sprays. Additionally, the composition may be formulated for parenteral use, including intravenous, subcutaneous, intramuscular, intravascular, infusion, intraperitoneal, intracerebral, intracerebroventricular, or intradermal administration.

Formulations suitable for oral administration may be presented as discrete units such as capsules (e.g., soft-gel or hard-gel capsules), cachets, or tablets, each containing a predetermined quantity of active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. The active ingredients may also be provided in the form of boluses, electuaries, pastes, nutritional bars, energy bars, powders, or granule sachets.

Further, the present composition may be formulated as age-appropriate pediatric oral dosage forms such as syrups, minitablets, chewable formulations, orodispersible films, or orodispersible tablets. The formulation may also include food-based vehicles such as snacks, chocolate bars, or other confectionery products.

The synergistic composition of the present invention is characterized as stable, non- hazardous, non-toxic, and safe for human consumption without adverse side effects. Accordingly, it may be utilized in preventive therapy, adjuvant therapy, add-on therapy, or combination therapy in subjects in need thereof. In one embodiment, the synergistic composition is non-toxic, cost-effective, nutritionally enriched with biomolecules, and offers protection against disorders associated with neurotransmission without adverse effects.

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 1 to 30%; the binder present is present in a range of 0.1 to 25%; 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 5.0%; %; the antioxidant is present in a range of 0.1 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.

In some optional embodiment of the present invention, the buffering or alkalizing agent in the composition/formulation is present in a range of 1% to 25% by weight of the total composition/ formulation

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

In a further embodiment, the antioxidant is present in an amount ranging from about 0.1% to about 10% by weight of the total composition, preferably from about 0.1% to about 5.0% by weight of the total composition.

In some embodiments, the diluent is selected from the group consisting of 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 dihydrate, or tribasic), calcium silicate, calcium sulphate, cellulose acetate, corn starch, pregelatinized starch, dextrin, P-cyclodextrin, methylated-P-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, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, and the like. In a further embodiment, the diluent is present in an amount ranging from about 1% to about 30% by weight of the total composition or formulation.

In some embodiments, the binder is selected from the group consisting of disaccharides such as sucrose and lactose; polysaccharides and their derivatives including starches, cellulose, and modified celluloses such as microcrystalline cellulose and cellulose ethers including hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol, or mannitol; proteins such as gelatin; synthetic polymers including polyvinylpyrrolidone (PVP), polyethylene glycol (PEG); starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, co-povidone, pregelatinized starch, dextrates, dextrin, dextrose, ethyl cellulose, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, inulin, methyl cellulose, hypromellose, maltodextrin, pectin, poloxamer, polydextrose, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, and paraffins such as white soft paraffin and the like.

In a further embodiment, the binder is present in an amount ranging from about 0.1% to about 40% by weight of the total composition, preferably from about 0.1% to about 25% by weight.

In some embodiments, the lubricant is selected from the group consisting of 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, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, and potassium or sodium salts of fatty acids, or the like.

In some embodiments, the stabilizer is selected from the group consisting of alginate, agar, carrageenan, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose, and the like.

In a further embodiment, the stabilizer is present in an amount ranging from about 0.1% to about 8% by weight of the total composition, preferably from about 0.1% to about 5% by weight.

In a further embodiment, the lubricant is present in an amount ranging from about 0.1% to about 10% by weight of the total composition.

In some embodiments, the glidant is selected from the group consisting of colloidal silicon dioxide, fumed silica, hydrophobic colloidal silica, magnesium stearate, magnesium oxide, magnesium silicate, magnesium trisilicate, zinc stearate, talc, starch, calcium phosphate tribasic, and powdered cellulose, or the like.

In a further embodiment, the glidant is present in an amount ranging from about 0.1% to about 5% by weight of the total composition.

In some embodiments, the plasticizer is 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 the like.

In a further embodiment, the plasticizer is present in an amount ranging from about 0.1% to about 5% by weight of the total composition.

In some embodiments, the surfactant or solubilizing agent is selected from the group consisting of polysorbate 80, sodium lauryl sulphate, anionic and nonionic emulsifying waxes, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sorbitan esters, triethyl citrate, polyethylene glycol succinate, lecithin, cyclodextrins, sulfobutylether- beta-cyclodextrin, docusate sodium, and the like.

In a further embodiment, the surfactant is present in an amount ranging from about 0.1% to about 10% by weight of the total composition, preferably from about 0.1% to about 5% by weight.

In some embodiment of the present invention, the buffering agent or alkalizing agent is selected from acetate, phosphate, citrate, and glutamate wherein the citrate salt is selected from sodium citrate, potassium citrate, monosodium citrate, citric acid anhydrous.

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.

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 general, the total daily dose (in single or divided doses) ranges from about 1 mg per day to about 2500 mg per day, preferably about 10 mg per day to about 1500 mg per day. In certain embodiments, the present invention provides the synergistic bioactive composition wherein the effective unit dose for an oral administration is formulated in solid form which is present in a range of 5 to 1500 mg, preferably 10 to 1000 mg.

Other excipients, such as antioxidants, lubricants, solubilizing agents, glidants, stabilizers, plasticizers, solvents, and additional additives, may also be incorporated in appropriate quantities, as described in detail in the foregoing specification.

Preferred embodiments of the invention encompass oral dosage forms wherein excipients are incorporated within specified ranges to optimize stability, bioavailability, and patient compliance. The total daily dose may range from about 1 mg to about 2500 mg, preferably from about 1 mg to about 1000 mg, with adjustments made based on age, weight, and physiological response of the patient.

It will be appreciated by those skilled in the art that the present invention provides novel, stable, and effective nutraceutical compositions and nutraceuticals acceptable salts thereof, offering neuroprotective benefits across multiple administration forms. The invention is to be construed as illustrative and not limiting, encompassing all equivalents, modifications, and adaptations falling within the scope of the appended claims Examples:

Example 1: Various compositions/formulations. i. Composition 1: Tablet / Capsule ii. Composition 2: Syrup iii. Composition 3: Tablet / Capsule iv. Composition 4: Tablet / Capsule v. Composition 5: Tablet / Capsule vi. Composition 6: Tablet / Capsule vii. Composition 7: Tablet / Capsule viii. Composition 8: Tablet / Capsule ix. Composition 9: Tablet / Capsule x. Composition 10: Tablet / Capsule

Example -2 Animal Study:

Evaluation of Test Substances on Scopolamine-Induced Behavioral and biochemical changes in Swiss Albino Mice Using T-Maze and Open Field Tests followed by BDNF level. The study was approved by the Institutional Animal Ethics Committee (IAEC) and conducted in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) for the care and use of laboratory animals.

Test System Details

Parameter Details

Species: Mouse

Strain: Swiss Albino

Sex: Male/Female

Age: 8-10 weeks

Body Weight: 25-30 g

Source: In-house bred

Number of Animals: 84 (14 groups x 6 animals per group)

Housing and Husbandry

Caging: 3 animals per autoclaved polypropylene cage with paddy husk bedding.

Lighting: 12 h light / 12 h dark cycle

Temperature: 22 ± 3°C

Humidity: 30-70% RH

Feed: Standard rodent chow (Purina Lab Diet 5L79 Rat and Mouse 18%)

Water: Filtered, autoclaved water provided ad libitum

Table-1 Experimental Design

The vehicle used for the study was a 0.5% Carboxy Methyl Cellulose (CMC -Na) solution. All treatments were administered via oral gavage for 14 consecutive days. Scopolamine was administered as an intraperitoneal injection at a dose of 1 mg/kg, 30 minutes after the oral dosing.

Animals were acclimatized to the animal house conditions for a period of five days prior to the initiation of experimental procedures. From Day 1 to Day 14, animals received daily treatments with either the vehicle, or test compounds as per their assigned groups. On Day 14, behavioral assessments were conducted, starting with the T-Maze test followed by the Open Field test.

Behavioral Tests

T-Maze Test

The T-Maze test was performed to evaluate spatial learning and memory in mice. The apparatus consisted of a T-shaped maze with one start arm and two goal arms. Animals underwent habituation by freely exploring the maze for 10 minutes per day over two consecutive days. On the test day, each animal was placed in the start arm, and the following parameters were recorded:

• Latency time (in seconds) to enter the correct goal arm.

• Time (in seconds) spent in the preferred and discriminated goal arms.

To reinforce learning, a reward such as sweetened milk was placed in the correct goal arm. Between trials, the maze was cleaned with 70% ethanol to eliminate olfactory cues

7.2 Open Field Test

The Open Field test was conducted to assess locomotor activity, exploratory behaviour, and anxiety-like behaviour in mice. The apparatus comprised a square arena measuring 50 x 50 cm with walls 40 cm in height; the floor was virtually divided into squares. The central zone and peripheral zone were defined for analysis.

Each mouse was gently placed in the center of the arena and observed for a duration of five minutes. Behavioral parameters were recorded either manually or using a video tracking system. The following parameters were analyzed:

• Number of squares crossed (to assess locomotor activity).

• Frequency of rearing (indicative of exploratory behavior). • Number of grooming episodes.

The arena was cleaned with 70% ethanol between animals to minimize olfactory bias

8. Biochemical Correlates

Following the completion of behavioral testing, animals were sacrificed for the collection of brain tissue to perform biochemical assays. Brain-derived neurotrophic factor (BDNF) levels were measured to correlate behavioral outcomes with neurochemical changes.

The data were expressed as mean ± standard deviation (SD). Statistical analysis was performed using one-way analysis of variance (ANOVA), followed by Dunnett’ s post hoc test for multiple comparisons. A p-value of less than 0.05 was considered statistically significant. Result :

T-Maze test

Table 2: (Latency time (sec) arm)

Table 3: T-Maze test (Time spent in the preferred and discriminated (sec) arm) Open Filed Test

Table -4: Ambulation score [number of squares crossed]

Table 5: Rearing Responses [the number of times the animal raised both forefeet off the floor and extended its body]

Table 6: Grooming [the number of grooming bouts exhibited by the mice]

Table 7: BDNF-in Serum (ng/mL)

Discussion

The present study demonstrated the efficacy of a novel synergistic composition combining GABA receptor agonists and synaptic plasticity enhancers for managing central nervous system (CNS) excitability disorders. While GABAergic agents effectively attenuated hyperexcitability by activating inhibitory pathways, their conventional use often impaired long-term potentiation (LTP) and synaptic plasticity, leading to cognitive and functional deficits. The composition described herein overcame these limitations by integrating GABA receptor agonists with synaptic plasticity enhancers, which promoted neurotrophic factor expression, restored LTP, and supported neural network remodeling.

In vivo studies in scopolamine-induced cognitive impairment models in Swiss albino mice demonstrated significant behavioral improvements with the synergistic composition. In the T-maze test, latency times were markedly reduced to 8.15 s and 13.36 s at low (1 :0.001) and high (1 :2) dose ratios, respectively, versus 25.33 s in the disease control, indicating enhanced learning and memory. Time spent in the preferred arm increased to 135.01s, compared to 50.33 s in controls, reflecting improved spatial memory.

In the open field test, treated groups showed higher ambulation (114 to 130 squares vs. 55), increased rearing (13.2 to 23.3 vs. 4.3), and reduced grooming episodes (2.5 to 1.3 vs. 7.8), suggesting anxiolytic effects. BDNF levels were elevated by 75-95% over disease controls, supporting enhanced neuroplasticity. These results confirmed the synergistic composition effectively mitigated hyperexcitability and promoted synaptic recovery.

Overall, the dual mechanism — targeting both inhibitory neurotransmission and synaptic reinforcement — produced a synergistic therapeutic effect that surpassed the efficacy of individual components. This integrated approach addressed the complex pathophysiology of CNS excitability disorders and offered advantages over conventional monotherapies.

Claims

We claim:

1. A synergistic pharmaceutical composition for the treatment of neurodevelopmental disorders, the composition comprising: an exogenous combination of (i) a GABA receptor agonist or a pharmaceutically acceptable salt thereof, and

(ii) one or more synaptic plasticity enhancers or pharmaceutically acceptable salts thereof; and one or more pharmaceutically acceptable excipients.

2. The composition as claimed in claim 1, wherein the GABA receptor agonist is selected from the group consisting of 4-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido] butanoic acid, 4- (Pyridine-3 -carbonylamino) butanoic acid, and 4-(hexadecanoylamino)butanoic acid, or pharmaceutically acceptable salts thereof.

3. The composition as claimed in claim 1, wherein the synaptic plasticity enhancer is selected from the group consisting of magnesium 2-acetamidoethanesulfonate, magnesium bis(2- aminoethane-1 -sulfonate), magnesium (2S,3R)-2,3,4-trihydroxybutanoate, N-(2-

Hydroxyethyl)hexadecanamide, l-(4-aminobutyl)guanidine, and 5'-inosinic acid, or salts thereof.

4. The composition as claimed in claim 1, wherein the exogenous blend of the GABA receptor agonist and the synaptic plasticity enhancer is present in a weight ratio of 1 :0.001 to 1 :2.

5. The composition as claimed in claim 1, wherein the GABA receptor agonist is present in a range of 10% to 95% by weight of the total composition.

6. The composition as claimed in claim 1, wherein the synaptic plasticity enhancer is present in a range of 1% to 80% by weight of the total composition.

7. The composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from a group consisting of: a diluent present in a range of 1% to 30%, a binder present in a range of 0.1% to 25%, a lubricant present in a range of 0.1% to 10%, a glidant present in a range of 0.1% to 5%, a surfactant present in a range of 0.1% to 5%, a stabilizer present in a range of 0.1% to 5%, an antioxidant present in a range of 0.1% to 5%, and a plasticizer present in a range of 0.1% to 5%, by weight of the total composition.

8. The composition as claimed in claim 1, wherein the composition is useful for treating neurocognitive disorders selected from the group consisting of Epilepsy, Seizures, Alzheimer’s diseases, Parkinson’s diseases, Sluggish Cognitive Tempo, Dyslexia, Cerebral Palsy, Developmental Language disorder, Amyotrophic Lateral Sclerosis (ALS), Social Communication Disorder - Autism Spectrum Disorders (ASD), Inattentive / Attention Deficit Hyperactivity Disorder (ADHD), Tourette syndrome, Preterm Hypoxic-Ischemic Encephalopathy, Neuropathic Pain, Brain Stroke, Retinal Diseases, Tinnitus and like thereof.

9. The composition as claimed in claim 1, wherein the composition is in a form selected from the group comprising tablet, capsule, and syrup, and wherein the composition elevates the brain-derived neurotrophic factor (BDNF) levels by 75-95%.

10. The composition as claimed in claim 1, wherein effective unit dose for an oral administration of the composition is formulated in a range of 10 to 1000 mg.