DESC:Technical Field of the invention:

The present invention relates to synergistic nutritional compositions for treating neurodegenerative diseases. Particularly, the invention provides a synergistic composition of nutrients for improving cognitive function in a subject in need thereof. More particularly, the invention relates to nutritional compositions comprising synergistic combination of magnesium salt of sugar acid, pyrimidine nucleotide and phospholipid along with pharmaceutically acceptable excipients; wherein the magnesium salt of sugar acid is magnesium salt of l- threonic acid (MgT); and pyrimidine nucleotide compound is uridine monophosphate (UMP); and supplementary phospholipid is phosphatidylserine (PS) which are present in specific weight ratio.

Further the instant synergistic nutritional composition is useful for treating neurocognitive disorders and neuropsychiatric disorders such as Alzheimer's disease; early stage adult dementia; early Alzheimer's disease; prodromal Alzheimer's disease; adult ADHD (attention deficit hyperactive disorder); anxiety/sleep depression; schizophrenia, Parkinson’s disease; Alzheimer’s amyotrophic lateral sclerosis (ALS); epilepsy; traumatic brain injury, and dementia.

Background and Prior Art:

CNS disorders are mainly categorized as early-onset neurodevelopmental and late-onset neurodegenerative diseases, based on dysfunction of neuronal activity due to perturbations at the synapse level. They may therefore be collectively regarded as diseases of the synapse or synaptopathies.

The synapse is the basic structural and functional element for neural communication in the brain. Synapses of the central nervous system (CNS) play a key role in neuronal information processing. The presynaptic compartment contains synaptic vesicles (SVs) filled with neurotransmitters. The postsynaptic membrane is covered with neurotransmitter receptors, which detect variations in neurotransmitter concentration. Postsynaptic submembrane cytoplasm is occupied by a complex network of proteins, the postsynaptic density, which modulates the strength of synaptic transmission. The space between both cells is the synaptic cleft.
In particular, the alteration of the structural and functional phenotype of the presynaptic terminal is highly significant evidence for neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) [BMB Reports 2017; 50(5): 237-246].
The loss of cortical and hippocampal synapses is a universal hallmark of Alzheimer's disease, and probably underlies its effects on cognition. Synapses are formed from the interaction of neurites projecting from "presynaptic" neurons with dendritic spines projecting from "postsynaptic" neurons. Both of these structures are vulnerable to the toxic effects of nearby amyloid plaques, and their loss contributes to the decreased number of synapses that characterize the disease. An Alzheimer's diseased brain contains fewer synapses and reduced levels of synaptic proteins and membrane phosphatides.

Synapse loss is associated with sensory, motor, and cognitive impairments in a variety of neurodegenerative conditions, such as major depressive disorder, schizophrenia, Alzheimer’s disease, Huntington disease, and amyotrophic lateral sclerosis (ALS), as well as aging. Loss of excitatory synapses is the strongest indicator of cognitive impairments in Alzheimer’s disease.
Researchers from the University of California observed that progressive loss of synapses is the cause of age-related cognitive decline. The energy demands of a neuron increases as a person ages, but the cells’ ability to generate energy appears to decline.

Normal aging is associated with impairments in cognitive function, including memory. These impairments are linked, not to a loss of neurons in the forebrain, but to specific and relatively indistinct synaptic alterations in the hippocampus and prefrontal cortex. Aging and stress are both known to trigger synapse loss. Aging leads to a decrease in synapse density, which causes cognitive decline. Usually ageing is associated with deterioration in brain function and neurodegeneration. Moreover aged brains are the harbingers of neurodegenerative diseases.

It is reported that synaptic dysfunction precedes neuronal loss in neurodegenerative diseases such as Alzheimer's disease. Proper brain function depends on the fidelity of synaptic transmission. The failure of neuronal synaptic communication is an early indicator of neurodegeneration. Further the accumulation of defective proteins leads to improper synaptic function.

Impaired synaptic plasticity is implicated in the functional decline of the nervous system associated with ageing. Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. In addition to synaptic functional plasticity, synaptic structural plasticity is also found to be directly associated with long-term potentiation (LTP) induction and thus plays very a important role in memory and learning. Alterations in the number and size of synapses, synaptic cleft, the thickness of postsynaptic density, the length of synaptic active zone, and synaptic curvature contribute to changes in synaptic structural plasticity, which is considered to be one physiological base of synaptic functional plasticity.

‘Synaptic plasticity’ describes the effectiveness of communication between two cell synapses. Synapses tend to strengthen and weaken over time in reaction to stimuli. This plastic-like quality allows cell synapses to communicate effectively, which helps maintain cognitive balance. Plastic change often results from the alteration of the number of neurotransmitter receptors located on a synapse. There are several underlying mechanisms that cooperate to achieve synaptic plasticity, including changes in the quantity of neurotransmitters released into a synapse and changes in how effectively cells respond to those neurotransmitters. Synaptic plasticity in both excitatory and inhibitory synapses has been found to be dependent upon postsynaptic calcium release. It is anticipated that loss of spine or synaptic density may be linked to cognitive and memory impairment in AD, although the underlying mechanism(s) remain uncertain.

Neurotrophins (NTs) are expected to play a role in the treatment of AD because neuronal death is prevented by endogenous neurotrophic factors (NFs), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NFs are likely to be useful agents for ameliorating neurodegeneration. Further ‘NTs’ include polyphenols, honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb. and methanol extracts from Zingiber purpureum (BANGLE) and may have potential therapeutic applications in various neurodegenerative disorders [Journal of Pharmacological Sciences 12727 (2015) 155-163].

There are also some natural nootropic supplements available in the market to improve cognitive functions; such products include Mind Lab Pro®, Enhance MHz, Provasil, Optimind etc. Unfortunately, neurotrophins and nootropics do not last very long in the body after administration and show significant side effects. Due to the potent effects on brain chemicals, nootropics tend to be abused and highly addictive. Therefore, there is a substantial need to find alternative nutrient sources having properties for boosting synaptic plasticity or density and thereby improving cognitive function in a subject in need thereof.
Since, synapses are the elemental units of neural communication, synapse loss and reduction of synaptic plasticity should have a major impact on neural signaling, resulting in impaired cognition. Therapeutic strategies that prevent net synapse loss and increase synapse density may have great potential for cognitive impairment.

The inventors of present invention have found that the level of brain magnesium is a critical factor controlling synapse density and plasticity. Elevating neuronal intracellular magnesium can increase functional synapse density and plasticity in cultured hippocampal neurons. Further it is observed that intracellular magnesium in neurons serves as a critical second messenger controlling neuronal energy supply and functional synapse density. In humans, increasing blood magnesium by 300% only changes cerebrospinal fluid (CSF) magnesium by less than 19% [Crit Care Med 33, 661–666, 2005].

Magnesium plays a critical role in a number of brain-related and neurological conditions including depression, anxiety, ADHD, bipolar disorder, schizophrenia, addictions, acute brain injury, seizures, Parkinson’s disease, and Alzheimer’s disease. According to several studies, magnesium deficit may lead to or may be associated with attention deficit hyperactivity disorder (ADHD) in children and symptoms associated therewith [Kozielec et al., Magnes. Res. 10(2), 143-148 (1997) and Mousain-Bosc et al., Magnes. Res. 19(1), 46-52 (2006)].

Despite the physiological role of magnesium in human health, people may not consume enough of the mineral in their diets. There are various dietary magnesium salts like Mg-oxide, Mg- hydroxide and Mg- carbonate, M-sulphate reported in the art. However poor solubility in water restricts their applications as effective medicines for improving cognitive function.

The veteran scientists have found that magnesium salt, particularly L-Threonic acid Magnesium salt, enhances absorption, bioavailability and palatability of Mg. Magnesium L-threonate (MgT) formulation differs from other magnesium supplements because it crosses the blood brain barrier. Further, this salt can effectively enhance CSF magnesium concentration and increase synapse density in brain regions critical for executive function and memory, such as the prefrontal cortex and hippocampus. Furthermore MgT treatment increases the number of N-methyl-D-aspartate receptors (NMDARs), resulting in an enhancement of synaptic plasticity in aging with memory improvement [J Alzheimer’s Dis. 2016; 49(4): 971–990].

It has been reported that deceased humans who had been afflicted with AD had significantly lower levels of magnesium in regions of their brains vis-à-vis deceased humans of the same age who had not been afflicted with AD [Andrasi et al., Magnesium Res. 13(3), 189-196 (2000)].

Xu ZP et al. has reported that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3ß in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy [PLoS One. 2014 Sep 30;9(9)].

CN106083567B provides an industrial preparation method of magnesium L-threonate from vitamin C and magnesium peroxide.
Further it is reported that magnesium plays a major role in the regulation of synaptic plasticity. Magnesium appears to increase the signal to noise ratio (S/N) of synaptic transmission and thereby enhancing synaptic plasticity [Slutsky et al., Neuron, 44, 835-849 (2004)].

US8178132B2 describes a food composition comprising a food carrier and magnesium threonate which is useful for maintaining, enhancing, and/or improving health, nutrition, and/or another condition of a subject, and/or cognitive, learning, and/or memory function.

In a preliminary study, it was found that dietary supplement brands of magnesium L-threonate like (Magtein or Clarimem) are useful for improving memory and/or magnesium deficiency in people with mild to moderate dementia and a magnesium deficiency. Overall, however, there is very limited evidence that taking magnesium improves memory or learning, or prevents Alzheimer's disease, in humans.
WO 2014/109863 Al discloses a method of promoting neurological health in a pediatric subject by providing a nutritional composition comprising a carbohydrate source, a protein source, a fat source, and magnesium threonate.
US20170258828A1 discloses use of magnesium threonate to modify presynaptic terminal density.
WO2019/209943A1 provides a dosage form comprising magnesium threonate having enhanced efficacy. Also provided is a pharmacokinetic profile of magnesium threonate having enhanced efficacy. The dosage forms and pharmacokinetic profile of magnesium threonate are used to treat a variety of diseases, disorders, syndromes and/or conditions.

Jun Wang in Pain Physician 2013; 16:E563-E575 discloses oral application of MgT to prevent and restore the short-term memory deficits in an animal model of chronic neuropathic pain by reversing the dysfunction of the NMDAR, and normalization of TNF-a expression.

In the current scenario, more work or research is needed to explore use of non-toxic minerals or salts like magnesium L-threonate as cognitive enhancer.

The role of MgT for improving synaptic plasticity is reported in many literatures; however, the current inventors observed that mere use of MgT in monotherapy does not afford significant effect on synaptogenesis or restoration of neuron loss for efficient transmission of excitatory and inhibitory neurotransmitters.
A combination therapy or treatment that increases the formation of neurites and dendritic spines might reverse the synapse loss, thereby increasing the number of synapses and slowing the decline in cognition.

Uridine is a neuroactive molecule, which is involved in the regulation of certain neural functions apart from its role in pyrimidine metabolism. Uridine improves memory function and influences neuronal plasticity via its actions on membrane formation. Further uridine, as a dietary component, is not toxic and has access to the brain from the plasma through transporters; it is an appealing lead molecule for the development of drugs with central site of action.
US8518882B2 is directed to methods for ameliorating hippocampal dysfunction and improving or inhibiting decline in intelligence or cognitive or hippocampal-dependent memory of a subject and of increasing synthesis and release of neurotransmitters, neurite outgrowth, and levels of neurofilament proteins in the brain and CNS of a subject, comprising administering to the subject a uridine, an acyl derivative thereof, a uridine phosphate, uracil, or a salt thereof.

Further US4960759A discloses use of uridine for the protection of the cholecystokinin level in the brain tissue.

Likewise WO2013049686A1 relates to uridine diphosphate (UDP) derivatives, compositions in treating neuronal disorders, including neurodegenerative disorders (e.g., Alzheimer's disease) and traumatic CNS injury, as well as pain.

Further it is reported that oral administration of uridine and DHA combination enhances the synapse formation [J Nutr Health Aging. 2009 Mar;13(3):189-97].
Further it is reported that UMP-fortified mixture, like SOUVENAID® which includes omega-3 fatty acids, choline, uridine monophosphate and a mixture of antioxidants and B vitamins supports memory improvement in aging adults.

In view of above prior arts, it is concluded that for better cognitive function there is need of combined effect which imparts synergy to the composition with significant results.
Accordingly the present inventors have performed rigorous experiments and developed nutritional compositions which give synergistic effects for treating cognitive disorders by ameliorating synaptic function.

Object of the invention:
The primary object of the invention is to provide synergistic nutritional compositions for treating neurodegenerative diseases.

Another object of the invention is to provide synergistic composition of nutrients for improving cognitive function in a subject.

Further object of the invention is to provide a synergistic combination of therapeutically active cognitive enhancers for improving synaptic health.

A preferred object of the invention is to provide a synergistic combination of therapeutically active magnesium salt and pyrimidine nucleotide and phospholipid as bioenhnacer.

Another object of the invention is to provide a nutritional composition with synergistic effects for treating cognitive dysfunction by enhancing synaptic plasticity and concomitantly improving synaptic membrane and enhancing neurotransmission.

Yet another object of the invention is to provide a synergistic remedy for treating neurocognitive disorders through site specific action with no side effects.

Summary of the invention:
To meet the above objects, the inventors of the instant invention carried out thorough experiments to establish therapeutic effects of the active ingredients or minerals or nutrients or lipids or sugar acids or nucleotides present in the composition that improve cognitive function in a subject in need thereof in a safe way.

In an aspect, the invention relates to synergistic nutraceutical compositions comprising therapeutically active nutrients along with pharmaceutically acceptable carriers for treating cognitive impairment or cognitive decline.

In another aspect, the invention relates to a synergistic, nutritional composition comprising a combination of magnesium salt and pyrimidine nucleotide and phospholipid along with pharmaceutically acceptable excipients; wherein the magnesium salt is magnesium L- threonate (MgT); pyrimidine nucleotide is uridine monophosphate (UMP); and phospholipid is phosphatidylserine (PS).

In a preferred aspect, the invention relates to a nutritional composition composed of synergistic combination of magnesium L- threonate (MgT), uridine monophosphate (UMP) and phosphatidylserine (PS) in therapeutically effective amounts.

Further, the invention provides compositions for improving cognitive function with improved bioavailability and efficacy.

In a particular aspect, the present invention provides a synergistic composition for improving cognitive function which comprises a specific combination of magnesium L- threonate and uridine monophosphate; wherein the magnesium L- threonate increases neurotransmitter signaling between neurons by promoting neural plasticity and synaptic density; while uridine monophosphate enhances receptor (neurogenesis) and synapse (synaptogenesis) densities simultaneously or subsequently. Additionally the bioenhancer i.e. phosphatidylserine (PS) is added to ameliorate release of neurotransmitters into the synaptic cleft.

Further, in the present invention one active moiety of the composition significantly promotes optimal cognitive function by increasing brain’s magnesium levels or concentration; while the other moiety, simultaneously promotes synaptogenesis by increasing membrane phosphatides, synaptic proteins and hippocampal dendritic spine densities.

In yet another aspect, the invention relates to synergistic nutritional compositions comprising combination of Magnesium L- threonate present in the range of 10-3500 mg, wherein elemental Mg2+ is present in the range of 1-250 mg and uridine monophosphate is present in the range of 1-500 mg along with pharmaceutically acceptable excipients / carriers. Further phosphatidylserine is present in the range of 10 to 500 mg of total composition.

In yet one more aspect, the invention discloses synergistic nutritional compositions useful for treating or controlling cognitive disorders such as magnesium deficiency, mild cognitive impairment, Alzheimer's disease, Huntington's disease, autism, schizophrenia, cognitive decline, depression, dementia, attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis (ALS), Parkinson's disease, migraine, anxiety, mood disorder, epilepsy and traumatic brain injury.

Abbreviations:

MgT: Magnesium L- threonate
UMP: Uridine Monophosphate
PS: Phosphatidylserin
CDP-choline: Cytidine 5'-diphosphocholine, or citicoline
NMDARs: N-Methyl-D-Aspartate receptors
CMC: Carboxy Methyl Cellulose Sodium

Brief description of Drawings:

Fig 1 illustrates the number of arm entries in each groups [G1-Vehicle control, G2-Positive control, G3- Standard- Piracetam, G4-Test Sample-1 (MgT+ Scopolamine), G5- Test Sample-2, (UMP+ Scopolamine), G6- Test Sample-3, (PS +Scopolamine), G7- Test Sample-4, (MgT+UMP+ Scopolamine), G8-Test Sample-5, (MgT+ PS +Scopolamine), G9-Test Sample-6, (MgT+UMP+PS)];

Fig 2 illustrates the percentage alterations in each groups [G1-Vehicle control, G2-Positive control, G3- Standard- Piracetam, G4-Test Sample-1 (MgT+ Scopolamine), G5- Test Sample-2, (UMP+ Scopolamine), G6- Test Sample-3, (PS +Scopolamine), G7- Test Sample-4, (MgT+UMP+ Scopolamine), G8-Test Sample-5, (MgT+ PS +Scopolamine), G9-Test Sample-6, (MgT+UMP+PS)].

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 can be illustrated for best mode of the invention.

The term “pharmaceutically/ nutraceutically acceptable salt,” as use 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.
In a preferred embodiment, the invention provides synergistic nutritional compositions comprising specific combination of a ‘magnesium salt’ and a ‘pyrimidine nucleotide’, wherein the ‘magnesium salt’ is magnesium salt of L-threonic acid or magnesium l-threonate (MgT) and the ‘pyrimidine nucleotide’ is uridine monophosphate (UMP); in presence of a phospholipid, wherein the phospholipid is phosphatidylserine (PS) along with pharmaceutically acceptable carriers.

In another embodiment, the invention provides a synergistic nutritional composition for improving cognitive functions including learning, memory, perception, and problem solving capacity. The term cognitive dysfunction can be used interchangeably with cognitive impairment, cognitive imbalance, cognitive decline, cognitive deficit, cognitive problems, cognitive instability, cognitive disorders, cognitive issues, neurocognitive disorder, synaptic loss.
More particularly, the instant bioactive composition is composed of a synergistic combination of magnesium L- threonate and uridine monophosphate along with phosphatidylserine which are present in therapeutically effective amounts. The composition exhibits significant cognitive effect with enhanced bioavailability and efficacy.

The improvement in cognitive function is accompanied by synergistic effects of nutrients; wherein magnesium l-threonate increases neurotransmitter signaling between neurons by promoting neural plasticity and synaptic density; while uridine monophosphate enhances receptor (neurogenesis), and synapse (synaptogenesis) densities by increasing the level of citicoline. Additionally bioenhancer i.e. phosphatidylserine (PS) is added to enhance the release of neurotransmitters into the synaptic cleft.

In another embodiment, the invention provides the nutritional combination, wherein the synergistic effect for improving cognitive function is achieved by concomitant synaptic functioning of cognitive enhancers, wherein one enhancer is Magnesium L- threonate.

According to the invention, magnesium threonate is a salt of magnesium and L-threonate with neuroprotective and cognitive enhancing effects. Magnesium L-threonate or Magnesium L- threonate significantly improves memory and learning ability.
‘Magnesium threonate’ also referred to as magnesium L-threonate/ L-Threonic acid Magnesium salt (L-TAMS) is chemically known as magnesium (2R, 3S)-2,3,4-trihydroxybutanoate and is represented by the Formula (I) below. It has chemical formula C8H14MgO10.

Magnesium L-threonate
(I)
Magnesium L-threonate is the latest magnesium chelate. It was developed by a team of neuroscientists at Massachusetts Institute of Technology and Tsinghua University in Beijing who bound magnesium to L-threonate, a vitamin C metabolite. L-Threonate is a deriviative of L-ascorbic acid 2-phosphate (which in itself is a derivative of Ascorbic Acid, otherwise known as Vitamin C). Ascorbic acid is a type of aldonic sugar acid, in which the aldehyde group (-CHO) located at the initial end of an aldose is oxidized. It is prominent that therapeutically active mineral chelations of L-threonate significantly enhance bioavailability of magnesium in the synaptic region.
Particularly, the term "elemental magnesium" used in connection with a magnesium- counter ion compound described herein, may refer to a total amount of magnesium that is present as free ion and magnesium that is bound with one or more counter ions particularly sugar acid.
The term ‘threonate’ describes an ester derivative of threonic acid or threonate, or a lactonized threonic acid. Generally, threonate as used in the present invention refers to L-threonate. L-threonic acid is the L-enantiomer of threonic acid which is a sugar acid or a sugar acid derivative. L-threonic acid is considered to be soluble in water and acidic. L-threonic acid can be found naturally in foods such as capers, muscadine grapes, black huckleberries and pecan nuts.

In another embodiment, the invention provides a synergistic nutritional composition of cognitive enhancing nutrients, wherein one of the active cognitive enhancer is Magnesium L- threonate. It improves cognitive function in a subject suffering from neurocognitive disorders such as Alzheimer's disease, dementia by promoting neural plasticity and synaptic density.
Neural plasticity also refers to brain plasticity or synaptic plasticity. Plasticity is the brain’s ability to change and grow, and is fundamental for memory and learning to take place.

In a further embodiment, the invention provides a synergistic composition comprising magnesium l-threonate, wherein the magnesium l-threonate easily crosses the blood-brain barrier and once it reaches the brain, magnesium increases NMDA receptor signaling, BDNF expression and synaptic plasticity in the pre-frontal cortex, thereby improving cognitive function.
Brain-derived neurotrophic factor (BDNF) is a protein that stimulates the formation of new brain cells. The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel protein found in nerve cells. N-Methyl-D-Aspartate receptors (NMDARs) are the major subtype of glutamate receptors that participate in rapid excitatory synaptic transmission.

Magnesium potentiates activation of NMDA receptors and blocks calcium channels, decreasing neuronal hyperexcitation and excititoxicity.
When magnesium reaches the brain, it interacts with the NMDA receptors, which play a key role in the formation of memories. The NMDA receptor contains a specialized site within the receptor to which magnesium can bind. When magnesium binds to this site, it blocks the receptor, which prevents the receptor from activating. This protects the brain from the negative effects of over-activation of the NMDA receptor. It increases the amount of NMDA receptors in the brain, whilst blocking background activation. This means that when the NMDA receptors get activated during memory formation, there is much stronger NMDA receptor response, leading to deeper and faster encoding of memories.

In another embodiment, the invention provides a synergistic composition comprising Magnesium L- threonate as cognitive enhancer wherein magnesium induces increase in synaptophysin and synaptobrevin (Syn- / SNB1-(+)) puncta that subsequently enhance synaptic transmission. Synaptophysin and synaptobrevin are two proteins that are critical to the neuron’s ability to store and transport neurotransmitters for release into the synaptic cleft. Increasing the levels of these proteins in neurons positively affect neurotransmitter signaling between neurons.

In yet another embodiment, the present invention provides a synergistic nutritional composition comprising a therapeutically effective amount of Magnesium L- threonate along with pharmaceutically acceptable salts thereof, wherein Magnesium L- threonate is present in the range of 10-3500 mg and elemental Mg2+ is present in the range of 1-250 mg of total composition.

In one additional embodiment, the present invention provides a synergistic nutritional composition comprising magnesium L-threonate containing 6 to 8 % w/w of elemental magnesium. More particularly 300 mg to 800 mg unit dose of magnesium salt of L-threonic acid contains 20 mg to 60 mg of elemental magnesium.

In another embodiment, the present invention provides a synergistic nutritional composition comprising L-threonate salt of Mg wherein L-threonic acid acts as a counter ion to enhance the bioavailability of Mg and thus improves the synapse density in the brain.

In another embodiment, the invention provides a nutritional combination wherein the synergistic effect for improving cognitive function is achieved by concomitant synaptic functioning of cognitive enhancers, wherein the other enhancer is uridine 5’ monophosphate (UMP).

Circulating uridine is carried across cellular membranes in all tissues, including the brain, which can maintain a concentration gradient between brain and blood. On entering brain cells, uridine is phosphorylated uridine monophosphate, and subsequently retained.

In an additional embodiment, the uridine compound is used as pharmaceutically acceptable phosphate salts such as monophosphate, diphosphate or triphosphate.
In a preferred embodiment, uridine is in the form of UMP i.e. uridine monophosphate and gives significant synergistic effect in cognitive health when administered with Magnesium L- threonate.

In another embodiment, the invention discloses a nutritional composition comprising uridine monophosphate, wherein uridine monophosphate enhances receptor (neurogenesis) and synapse (synaptogenesis) densities by increasing the level of citicoline.

Memory is largely dependent on neuroplasticity which is associated with the ability to learn and form memories. This process of turning experiences into memories relies on the growth of new neurons (neurogenesis), new synapses (synaptogenesis), dendrite formation and network reorganization.
Uridine monophosphate (UMP) is a nucleotide with chemical formula C9H13N2O9P. It is also known as 5'-uridylic acid (conjugate base uridylate), Uridylic acid; Uridine 5'-monophosphate; 5'-Uridylic acid; Uridine 5'-phosphate; Uridine phosphate; 5'-UMP; Uridine 5'-phosphoric acid. Uridine 5'-monophosphate is a pyrimidine ribonucleoside 5'-monophosphate having uracil as the nucleobase. Uridine monophosphate is represented by Formula (II) provided below:

Uridine monophosphate
(II)
Uridine is a major building block for the synthesis of neurons and synapses. It enhances the growth of neurites, which are projections from neurons that facilitate connections with other neurons. The decreased number of cortical synapses leads to cognitive memory impairment. Uridine treatment promotes synaptogenesis. The formation of a new synapse (for example, by hippocampal neurons that use glutamate as their neurotransmitter) can be initiated by the coming together of a presynaptic terminal and a dendritic spine. Thus the availability of dendritic spines is an important factor controlling the rate of synaptogenesis.

New neurons (neurogenesis) are encased in a phospholipid layer made up partly of phosphatidylcholine (PC). PC is made from CDP-Choline which is produced with the help of uridine. Supplementing with uridine gives the brain the ability to create more phospholipids by providing an abundance of CDP-Choline, which yields in new and stronger neurons.
Uridine is a precursor to the formation of CDP-Choline which is a precursor to the formation of phosphatidylcholine (PC). PC separates into choline and sphingomyelin in brain. Choline is then available to form essential neurotransmitter acetylcholine (ACh). An optimal ACh level is crucial for cognitive performance. Thus, the instant composition maintains optimal acetylcholine level.

In a further embodiment, the invention provides a synergistic composition of uridine to improve cognitive function by increasing receptor (neurogenesis) and synapse (synaptogenesis) densities through increase in acetylcholine level that improves cellular phospholipid membrane health and consequently boosts learning and memory ability.

In another embodiment, the synergistic nutritional composition comprises therapeutically effective amount of uridine monophosphate along with pharmaceutically acceptable salts thereof, wherein uridine monophosphate is present in the range of 1-500 mg,
In a preferred embodiment, the uridine monophosphate is present in the range of 1-250 mg of the total composition.

In another embodiment, the invention provides a synergistic composition comprising an additional bioenhancer, wherein the additional bioenhancer is phosphatidylserine (PS). Phosphatidylserine increases brain cell fluidity and permeability, enabling cells to stay adaptable and effectively respond to stressors. This neuroplasticity helps neurons form connections needed for memory formation.
Phosphatidylserine having chemical Formula C13H24NO10P is also known as 1,2-Distearoyl phosphatidyl serine; 1,2-Distearoyl-sn-3-glycerophosphoserine; 1,2-Distearoyl-sn-glycero-3-phosphatidylserine. Phosphatidylserine is represented by Formula (III) provided below:

Phosphatidylserine
(III)

Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is an essential phospholipid type nutrient for healthy, optimally-functioning brain cells. Phosphatidylserine (PS) is an amino acid derivative compound that is fat-soluble and found in high amounts in the brain, where it contributes to cognitive functioning. Phosphatidylserine (PS) supplementation in older individuals improves memory and cognitive capacity.

In a further embodiment, the invention provides a synergistic combination for improvement of cognitive function, wherein phosphatidylserine (PS) facilitates release of neurotransmitters. It further helps to enhance the bioavailability of the instant active ingredients.
PS is integral to cleaning up of damaged neurons and maintaining an optimized brain. Further PS boosts mental energy by easing the flow of glucose and oxygen needed to power brain cells. Notably, phosphatidylserine is an integral part of the flow of crucial neurotransmitters like serotonin, dopamine, acetylcholine (ACh) and phospholipids containing choline (which is a precursor to acetylcholine), thus improving cognition, memory and mood.

In another embodiment, the invention provides a synergistic combination of cognitive enhancers, wherein the bioenhancer phospholipid phosphatidylserine acts as a neuroprotective agent enhancing both cholinergic function and neuroplasticity, thereby affording significant combined effect for improving cognitive decline and dementia in elderly population.

Notably, dietary phosphatidylserine is efficiently and rapidly absorbed in the intestine, taken up into the blood, and readily crosses the blood-brain barrier to reach the nerve cells in the brain. The interaction of Mg with phosphatidylserine improves cognitive activity, cognitive aging, and retention of cognitive functioning ability.
In another embodiment, the effective amount of phosphatidylserine ameliorates the absorption of Mg ion in the brain to enhance the synaptic density.

In another embodiment, the invention provides synergistic nutritional composition comprises therapeutically effective amount of phosphatidylserine (PS) along with pharmaceutically acceptable salts thereof, wherein phosphatidylserine is present in the range of 1-1000 mg.
In a preferred embodiment, phosphatidylserine is present in the range of 1-500 mg of the total composition.

In another preferred embodiment, the invention provides nutritional composition, wherein the cognitive function in a subject in need thereof is improved with synergy and efficacy.

Moreover, Magnesium L- threonate enhances synaptic density; while uridine monophosphate concomitantly induces synapse formation and the additional bioenhancer i.e. phosphatidylserine (PS) facilitate release of neurotransmitters into the synaptic cleft.
Therefore, the improved neurotransmitter coordination between presynaptic and postsynaptic membrane leads to long-term positive effects on synaptic function and cognitive ability in a subject in need thereof.
In one preferred embodiment, the invention provides synergistic, nutritional compositions comprising Magnesium L- threonate containing 6-8 % w/w of elemental Mg in the range of 100- 1000 mg, uridine monophosphate salt in the range of 1-10 mg and phosphatidylserine (PS) in the range of 1-500 mg per unit dose along with pharmaceutically acceptable carriers.
In a preferred embodiment, the Magnesium salt of L- threonic acid is in a crystalline form.

In another preferred embodiment, the invention provides synergistic nutritional compositions for treating neurocognitive disorders comprising an exogenous blend of crystalline form of a magnesium salt of L-threonic acid; a uridine monophosphate and salts thereof; phosphatidylserine and salts thereof; wherein the crystalline form of magnesium salt of l-threonic acid, the uridine monophosphate and the phosphatidylserine are present in a weight ratio of 1:0.001: 0.001 to 1:0.01: 0.1 along with pharmaceutically acceptable excipients.

In yet another preferred embodiment, the invention provides synergistic nutritional compositions for improving memory, learning ability and cognition comprising synergistic exogenous blend of crystalline form of Magnesium L- threonic acid, uridine monophosphate and phosphatidylserine, present in the weight ratio of 1:0.05: 0.05 to 1:0.2: 2 along with pharmaceutically acceptable excipients.
In further embodiment, the invention provides synergistic nutritional compositions comprising crystalline form of Magnesium salt of L- threonic acid containing 6.0% to 8.0 % w/w of elemental Mg, which is present in the range of 70.0% to 98.8% by weight of the total composition.
In a preferred embodiment, uridine monophosphate is in the form of a disodium salt hydrate, in a crystalline form.
In another embodiment, the invention provides synergistic nutritional compositions comprising crystalline form of uridine monophosphate disodium salt hydrate present in the range of 0.3% to 1.0% by weight of the total composition.
In a preferred embodiment, phosphatidylserine is in the form of a sodium salt.
In another embodiment, the invention provides synergistic nutritional compositions comprising phosphatidylserine or its sodium salt present in the range of 0.3 % to 10.0% by weight of the total composition.
In another preferred embodiment, the invention provides synergistic nutritional compositions for treating neurocognitive disorders comprising an exogenous blend of a crystalline form of magnesium salt of L-threonic acid and phosphatidylserine or its salt in the weight ratio of 1:0.001 to 1:1 along with pharmaceutically acceptable excipients.
In another embodiment, the invention provides synergistic nutritional compositions comprising an exogenous blend of crystalline form of Magnesium salt of L- threonic acid and phosphatidylserine or its sodium salt wherein the crystalline form of magnesium salt of L-threonic acid containing 6.0% to 8.0 % w/w of elemental magnesium is present in the range of 50.0% to 98.8% by weight of the total composition.
In another embodiment, the invention provides synergistic nutritional compositions comprising exogenous blend of crystalline form of Magnesium salt of L- threonic acid and phosphatidylserine or its sodium salt, wherein phosphatidylserine is present in the range of 0.3 % to 50.0% by weight of the total composition.
In another embodiment, the invention provides synergistic nutritional composition for treating neurocognitive disorders. The composition is useful for restoration of synaptic health in subject suffering from cognitive dysfunction such as Alzheimer’s disease and dementia. The neurocognitive disorders are selected from Alzheimer's disease, mild cognitive impairment (MCI), Parkinson's disease, dementia, Huntington's disease, autism, schizophrenia, cognitive decline, depression, sleep disorder, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, headache, stroke, neuropathy, epilepsy, cerebral palsy, chronic pain, involuntary muscular contractions and convulsive twitches, spasm, wrinkling, dystonia and tremor, anxiety and depression associated with sustained neural activity in prefrontal cortex (PFC) and amygdala and insomnia.

In another embodiment, the instant synergistic combination is useful for treating Alzheimer's disease; prodromal Alzheimer's disease; Adult (ADHD); anxiety/sleep depression; schizophrenia, Parkinson’s disease; Alzheimer’s Amyotrophic Lateral Sclerosis (ALS); epilepsy, traumatic brain injury, and dementia.

As used herein, the term “therapeutically effective amount” is an amount of the compound of the present invention that is effective for controlling cognitive dysfunction or impairment through synergistic effect. Generally, the term "effective amount" in reference to an active agent may refer to the amount of the active agent sufficient to elicit a particular biological condition, effect, and/or response such as maintaining and/or improving of a subject's performance of a task involving or associated with cognitive function, slowing a rate of decline in cognitive function. An effective amount of an active agent may be administered in a single dose or in multiple doses.
Compounds of the present invention can exist in particular geometric isomeric or enatiomeric, enantiomeric excess or diastereomeric, diastereomeric excess or stereoisomeric forms. The invention contemplates all such compounds, including dextrorotatory and levorotatory (DL) isomers, rectus and sinister (RS) configuration, cis and trans configurations, optically active isomers (DL). 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 intended to mean, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in the subject, preferably humans. Excipients may also include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), 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.

In the context of the present invention, the terms “treatment” and the like refer to alleviate, slow the progression, prophylaxis, attenuation, or cure the pre-existing or occurrence of cognitive decline or impairment. The instant composition is used for treating cognitive decline in the subject in need thereof, means either the administration of the remedy to prevent occurrence or pre-existing cause of cognitive decline or impairment or dysfunction or cognitive deficit.

The ‘subject in need thereof’ pertains to a subject preferably mammal, more preferably a human with pre-existing symptoms of neurocognitive disorders or in a subject to whom the composition is administered to prevent occurrence of cognitive dysfunction.

The therapeutically effective amount of such actives will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

Thus, a "therapeutically effective" amount is an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides some alleviation, mitigation, and/or reduction or restoration of at least one indicator/biomarker (e.g., blood or serum CRP level), and/or decrease in at least one clinical symptom of a neurocognitive disorders (e.g., Alzheimer's disease).

In another embodiment, the invention relates to a synergistic composition prepared in a manner well known in the pharmaceutical art, and 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 is not limited to topical, parenteral, or oral.
Therapeutic (prescription) supplements are generally administered by the oral or parenteral routes for the treatment of indications including cognitive dysfunction. The therapeutic administration of compositions of the present invention may be in conjunction with other therapies.
In one embodiment, the instant synergistic nutritional composition is administered to a subject in a form 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, granulate for sublingual use, effervescent tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, or syrup.
In another embodiment, the composition is formulated for parenteral use including intravenous, subcutaneous, intramuscular, and intravascular or infusion routes of administration.

In another embodiment, the oral administration of effective dose of the present synergistic nutritional composition comprising exogenous blend of Magnesium L- threonate and uridine monophosphate and phosphatidylserine in specific weight ratio not only significantly improves synaptic density but also improves cognitive function.
In some embodiment, the pharmaceutically acceptable carriers, diluents or excipients are selected from the group consisting of adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, such as liposomes and cyclodextrins, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in the subject, preferably humans. Excipients may also include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, additives, or waters of hydration.

In some embodiment of the invention, the diluents are selected from starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, and 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 sulfate, cellulose acetate, corn starch, pregelatinized starch, dextrin, ß-cyclodextrin, dextrates, dextrose, erythritol, ethylcellulose, 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 invention, the amount of diluent in the composition/formulation is present in the range of 1 % to 30% by weight of the total composition/formulation.

In some embodiment of the 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, ethylcellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose hydroxyl ethylmethyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminum 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, colourants and wax.
In some embodiment of the invention, the amount of binder in the composition/formulation is present in the range of 0.1 to 40% by weight of the composition/formulation.

In a further embodiment of the 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 sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, potassium, or sodium benzoate or the like.

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

In another embodiment of the invention, the solubilizing agent is selected from polysorbate 80, sodium lauryl sulfate, 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 an embodiment of the invention, the amount of solubilizing agent or surfactant in the composition/formulation is present in the range of 0.1% to 10% by weight of the composition/formulation. In a preferred embodiment of the invention, the amount of solubilizing agent or surfactant is present in the range of 0.1% to 5.0% by weight of the composition/formulation.

In some embodiment of the 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 some embodiment of the invention, the amount of glidant is present in the range of 0.1% to 5.0% by weight of the total composition/ formulation.
In some embodiment of the inventions, 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 invention, the amount of stabilizers in the composition/formulation ranges from 0.1% to 10.0% by weight of the total composition/ formulation.

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

The additional additives include polymer, a plasticizer, a sweetener, and a powdered flavor, preservative, colorant, 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. The additives are used in the range of 1 to 30 % w/w of unit dose.

In another embodiment, the present invention provides synergistic nutritional composition comprising an exogenous blend of Magnesium L- threonate and uridine monophosphate and phosphatidylserine along with pharmaceutical excipients, wherein the pharmaceutically acceptable excipients are selected from a diluent, a binder, a surfactant, a lubricant, a glidant, an additive, a stabilizer or mixtures thereof.
In a preferred embodiment, the diluent is present in the range of 1 to 30%; the binder is present in the range of 0.1 to 30%; the lubricant is present in the range of 0.1 to 5.0 %; the glidant is present in the range of 0.1 to 5.0%; the additive is present in the range of 1 to 20%; the surfactant is present in the range of 0.1 to 5.0%; the stabilizer is present in the range of 0.1 to 10.0% by weight of total composition.

In another embodiment, the invention provides synergistic nutritional composition comprising exogenous blend of Magnesium L- threonate and phosphatidylserine along with pharmaceutical excipients, wherein pharmaceutical excipients are selected from a diluent, a binder, a surfactant, a lubricant, a glidant, an additive, a stabilizer or mixtures thereof.
In a preferred embodiment, the diluent is present in the range of 1 to 20%; the binder present is in the range of 0.1 to 20%; the lubricant is present in the range of 0.1 to 3.0 %; the glidant present is in the range of 0.1 to 3.0%; the additive is present in the range of 1 to 10%; the surfactant is present in the range of 0.1 to 3.0%; the stabilizer is present in the range of 0.1 to 10.0% by weight of total composition.

Surprisingly, the instant synergistic nutritional composition of the present invention is non-hazardous, non-toxic and safe for human consumption without any severe side effects and is also used under preventive therapy in healthy subjects.

In a preferred embodiment, the present medicinal composition/formulation is formulated for oral administration. Specifically, the solid medicinal compositions are in the form of tablets, capsules, pills, hard capsules filled with liquids or solids, soft capsules, sachets, powders, granules, suspensions, solutions or modified release formulations.
In one embodiment, formulations of the present invention suitable for oral administration is presented as discrete units such as capsules (e.g., soft-gel capsules, hard-gel capsule), cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; 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. In another embodiment, the present composition is formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, minitablets, chewable formulations, orodispersible films orodispersible tablets.

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.
In a preferred embodiment, the total daily dose ranges from about 100 mg per day to about 1500 mg per day.

In some embodiment, the total daily dose is administered orally in the range of about 5 mg to about 2000 mg per day.
In a preferred embodiment, the total daily dose ranges from about 10 mg to about 1000 mg per day.
It is further recommended that children, patients over 60 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.
While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been put forth for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention.
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.
This invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential characteristics thereof. 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:
Example-1
i. Composition 1: Synergistic blend
Ingredients w/w%
Magnesium L threonate (MgT) 95±4%
Uridine monophosphate (UMP) disodium salt hydrate 0.5±0.4%
Phosphatidylserine (PS) 0.5±0.4%

ii. Composition 2: Synergistic blend
Ingredients w/w%
Magnesium L threonate (MgT) 95±4%
Uridine monophosphate (UMP) disodium salt hydrate 0.5±0.4%
Phosphatidylserine (PS) 5.0± 3.0%

iii. Composition 3: Synergistic blend
Ingredients w/w%
Magnesium L threonate (MgT) 6-8% elemental Mg
Uridine monophosphate (UMP) disodium salt hydrate 0.5±0.4%
Phosphatidylserine (PS) 0.5±0.4%

iv. Composition 4: Synergistic blend
Ingredients w/w%
Magnesium L threonate (MgT)
6-8% elemental Mg 60±10%
Phosphatidylserine (PS) 40±10%

v. Composition 5: Tablet / Capsule
Ingredients w/w% unit dose
Magnesium L threonate (MgT)
containing 6-8% elemental Mg 70.0-98.0%
Uridine monophosphate (UMP) disodium salt hydrate 0.5-0.8%
Phosphatidylserine (PS) 0.5- 8%
Excipients 1-25%
Average Weight (%) 100%
Average weight in mg 350-450 mg

vi. Composition 6: Tablet / Capsule
Ingredients w/w% unit dose
Magnesium L threonate (MgT) containing 6-8% elemental Mg 80.0-98.0%
Uridine monophosphate (UMP) disodium salt hydrate 0.5 -0.8%
Phosphatidylserine (PS) 0.5-8%
Excipients 1-20%
Average Weight (%) 100%
Average weight in mg 675-750mg

vii. Composition 7: Tablet / Capsule
Ingredients w/w% unit dose
Magnesium L threonate (MgT)
containing 6-8% elemental Mg 70±5 %
Uridine monophosphate (UMP) disodium salt hydrate 0.5±0.2 %
Phosphatidylserine (PS) 0.5±0.2%
Diluents 1-10%
Binders 0.5-5%
Glidants 0.5-5%
Lubricants 0.5-5%
Stabilizers 0.1-10%
Additives 1-10%
Solvents QS

viii. Composition 8: Tablet / Capsule
Ingredients w/w% unit dose
Magnesium L threonate (MgT)
containing 6-8% elemental Mg 80±5 %
Uridine monophosphate (UMP) disodium salt hydrate 0.5±0.2 %
Phosphatidylserine (PS) 5.0±2.0%
Diluents 1-10%
Binders 0.5-5%
Glidants 0.5-5%
Lubricants 0.5-5%
Stabilizers 0.1-10%
Additives 1-10%
Solvents QS

ix. Composition 9: Tablet / Capsule
Ingredients mg per unit dose
Magnesium L threonate (MgT)
Containing 6-8% elemental Mg 665
Uridine monophosphate (UMP) disodium salt hydrate 5
Phosphatidylserine (PS) 5
Microcrystalline Cellulose 1-10
Silicon dioxide 1-5
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 1-5
PVP K-30 1-5
Talc 1-5
Tween 80 1-10
Mannitol 1-10
IPA QS
Water QS
Average weight 680-750 mg

x. Composition 10: Tablet / Capsule
Ingredients mg per unit dose
Magnesium L threonate (MgT)
Containing 6-8% elemental Mg 665
Uridine monophosphate (UMP) disodium salt hydrate 5
Phosphatidylserine (PS) 50
Acacia 1-10
Silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 1-5
PVP K-30 1-5
Talc 1-5
Tween 80 1-10
Mannitol 1-10
Propylene glycol 1-5
IPA QS
Water QS
Average weight 730-800 mg

xi. Composition 11: Tablet / Capsule
Ingredients mg per unit dose
Magnesium L threonate (MgT)
Containing 6-8% elemental Mg 335
Uridine monophosphate (UMP) disodium salt hydrate 2.5
Phosphatidylserine (PS) 10
Acacia 1-10
Silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 1-5
PVP K-30 1-5
Talc 1-5
Tween 80 1-10
Mannitol 1-10
Propylene glycol 1-5
IPA QS
Water QS
Average weight 350-450 mg

xii. Composition 12: Tablet / Capsule
Ingredients mg per unit dose
Magnesium L threonate (MgT)
Containing 6-8% elemental Mg 335
Phosphatidylserine (PS) 300
Acacia 1-5
Silicon dioxide 1-5
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 1-5
PVP K-30 1-5
Talc 1-5
Tween 80 1-10
Mannitol 1-10
Propylene glycol 1-5
IPA QS
Water QS
Average weight 650-750 mg

xiii. Composition 13: Tablet / Capsule
Ingredients mg per unit dose
Magnesium L threonate (MgT)
Containing 6-8% elemental Mg 665
Phosphatidylserine (PS) 100
Silicon dioxide 1-10
Microcrystalline Cellulose 1-10
Magnesium Stearate 1-5
PVP K-30 1-5
Talc 1-5
Tween 80 1-10
Mannitol 1-10
Propylene glycol 1-5
IPA QS
Water QS
Average weight 770-800 mg

Example 2: Animal Study
To assess the improvement in learning and memory of the test substances in experimental mice model using Y-Maze apparatus.
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 lab diet 5L79 Rat and Mouse 18%) (PMI Nutrition International)

Test System Details:
• Animals: Mice
• Strain: Swiss Albino
• Sex: Male
• Body weight: 20 – 25 gms
• Groups: 09 [06 animals each]
• Source: In house breed
CPCSEA Registration Number-1803/PO/RcBi/S/2015/CPCSEA

Group, Designation and Dose Levels
Swiss albino mice of either sex weighing around 20 -25 g were used in the study.

Table 1: Animal grouping and treatment details
Groups Group Description Treatment Description No. of animals
G1 Negative Control 0.5 % (Saline) 6
G2 Positive Control –Scopolamine Hydro bromide (0.5mg/kg;I.P) 6
G3 Standard (Piracetam) +Scopolamine 200mg/kg-STD +0.5mg/kg/I.P 6
G4 MgT+ Scopolamine 410mg/kg+0.5mg/kg/I.P 6
G5 UMP + Scopolamine 0.610mg/kg+0.5mg/kg/I.P 6
G6 PS+ Scopolamine 61.65 mg/kg +0.5mg/kg/I.P 6
G7 (MgT+ UMP) +Scopolamine [410mg/kg+0.610mg/kg] +0.5mg/kg/I.P 6
G8 (MgT+ PS) +Scopolamine [410mg/kg+61.65 mg/kg] +0.5mg/kg/I.P 6
G9 (MgT+UMP+ PS) +Scopolamine [410mg/kg +0.610mg/kg+61.65 mg/kg] +0.5mg/kg/I.P 6

Experimental Procedure:
2.1 Assessment of Learning and Memory using Y Maze apparatus
It is well known that spontaneous alternation is a measure of spatial working memory. The Y-maze can be used as a measure of short term memory, general locomotor activity and stereotypic behaviour. Therefore, spontaneous alternation was assessed using a Y- maze composed of three equally spaced arms (120°, 41cm long and 15cm high).
The test samples (G4-G9) were administered to adult Swiss albino Wistar mice and the acquisition, retention and retrieval of spatial recognition memory was determined, by using Y-maze. Piracetam was used as the standard drug while Scopolamine Hydrobromide as the amnestic agent. The calculated dose of the test samples, exhibited significantly promising nootropic potential.

2.2 Method:

Training for animals:

Before administration of the test substances in all the group of animals, on the first day all the mice were familiarized with the Y-Maze for a period of 10 minutes and from the 2nd to the 5th day the mice received training on two trails per day.
Procedure:
Swiss albino mice of either sex weighing around 20 -25 g were used in this study.
Group I - Negative Control- Vehicle only
Group II - Positive Control - Scopolamine Hydrobromide (0.5mg/kg; I.P)
Group III - Piracetam (200mg/kg b.wt-STD) +Scopolamine (0.5mg/kg/I.P)
Group IV - Test Sample-1: MgT with calculated dose- + Scopolamine (0.5mg/kg/I.P)
Group V - Test Sample-2: UMP with calculated dose- + Scopolamine (0.5mg/kg/I.P)
Group VI - Test Sample-3: PS with calculated dose- + Scopolamine (0.5mg/kg/I.P)
Group VII - Test Sample-4: MgT+UMP with calculated dose- + Scopolamine (0.5mg/kg/I.P)
Group VIII - Test Sample-5: MgT+PS with calculated dose- + Scopolamine (0.5mg/kg/I.P)
Group IX - Test Sample-6: MgT+UMP+PS with calculated dose- + Scopolamine (0.5mg/kg/I.P)

After the training period, the treatment was intiated (as per the groups mentioned) for animals from day 1 and continued to day 8. On day 8 after 30 minutes of amnestic agent induction, trails were taken on Y-maze and retention was observed on 8th and 9th day.

2.3 Observation/parameters for evaluation:
The study observations wereto investigate the cognitive effects on memory deficit mice i.e. to find the memory enhancement of the sample compound in mice. Observation includes the tendency to reach the less frequently visit arm and the alteration in arm visits.
2.4 Results:
Y maze model used in the present study proved to be a sensitive measure of spatial recognition memory. The effect on alteration behavior was studied on two parameters, % alteration (Table 2 ) and No. of arm entries (Table 1).

Table 2: No. of arm entries in each groups
Sr No. Groups Treatment Dose Arm entries 8th day Arm entries 9th day
1. Normal control vehicle -- 28±0.6 24.2±0.7
2. Positive control scopalamine 0.4mg/kg 37.5±0.4 31±1.0
3. Standard piracetam + scopalamine 40mg + 0.5mg 19.7±0.4 16.3±0.5
4. Test -1 MgT + scopolamine 410mg + 0.5mg 24.5±0.6 21.8±0.7
5. Test -2 UMP+ scopolamine 0.61mg + 0.5mg 28.5±0.5 25.4±0.5
6. Test -3 PS+ scopolamine 61.65+0.5mg 26.3±0.5 23±0.5
7. Test -4 (MgT+UMP) + scopolamine 411mg + 0.5mg 23.5±0.6 22.1±0.5
8. Test -5 (MgT+PS) + scopolamine 472mg + 0.5mg 20.5±0.6 17.2±0.5
9. Test -6 (MgT+UMP+PS) + scopolamine 473mg + 0.5mg 17.5±0.5 14.2±0.5

Effect on % alteration:
Group 3 achieved a higher alteration than the vehicle group (Group 1; normal control).
The alteration showcased by Groups 1, 3-9 is indicative of the natural tendency of mice to exhibit an alteration of around 50-70% in an 8 min session, however the alteration achieved on the second trial (Day 9) was higher elaborating higher % alteration (ability to alternate) on account of acquisition of memory.
Group 2 exhibited a low spontaneous alteration (a characteristic feature of amnestic agents), elaborating the amnestic effects of scopolamine.
However in Group 3; there was a significant increase in % alteration thus supporting their memory enhancing effects to reverse the effects of scopolamine.
The greatest alteration was achieved by the standard Piracetam; in presence of amnesia (Group 3) followed by the dose of test samples in presence of amnesia (Group 4-9). It succeeded in close ranging the alteration response of the standard Piracetam.
Assuming generalization, % alteration on Day 09 was found to be greater than that observed on Day 08.
Table 3: (Percentage alterations in each group)
Sr. no. Groups Treatment Dose % Alteration day-8 % Alteration day-9
1. Normal control vehicle -- 50 % 53.7 %
2. Positive control scopalamine 0.4mg/kg 40 % 44.5 %
3. Standard piracetam + scopalamine 40mg + 0.5mg 60.9 % 67.5 %
4. Test -1 MgT + scopolamine 410mg + 0.5mg 58.2 % 64.5%
5. Test -2 UMP+ scopolamine 0.61mg + 0.5mg 54.5% 60.3%
6. Test -3 PS+ scopolamine 61.65+0.5mg 55.8% 62.3%
7. Test -4 (MgT+UMP) + scopolamine 411mg + 0.5mg 58.9% 65.8%
8. Test -5 (MgT+PS) + scopolamine 472mg + 0.5mg 59.5 % 66.5 %
9. Test -6 (MgT+UMP+PS) + scopolamine 473mg + 0.5mg 62.5% 70.3%

2.5 Discussion and conclusion
The given test sample (G9) afforded significant memory enhancing effects with the test dose evoking pronounced alteration of behavior and better learning assessments.
The instant composition provides better cognitive function as compared to control and nearly similar results when compared with standard.
,CLAIMS:1. A synergistic nutritional composition(s) for treating neurocognitive disorders comprising an exogenous blend of crystalline form of a magnesium salt of L-threonic acid; a uridine monophosphate and salts thereof; and a phosphatidylserine and salts thereof, wherein the crystalline form of the magnesium salt of L-threonic acid, the uridine monophosphate and the phosphatidylserine are present in a weight ratio of 1:0.001: 0.001 to 1:0.01: 0.1 along with pharmaceutically acceptable excipients.

2. The synergistic nutritional composition as claimed in claim 1, wherein the crystalline form the magnesium salt of L-threonic acid contains 6.0% to 8.0 % w/w of elemental magnesium and is present in a range of 70.0% to 98.8% by weight of the total composition.

3. The synergistic nutritional composition as claimed in claim 1, wherein the salt of the uridine monophosphate is a crystalline form of uridine monophosphate disodium salt hydrate, present in a range of 0.3% to 1.0% by weight of the total composition.

4. The synergistic nutritional composition as claimed in claim 1, wherein the salt of the phosphatidylserine is a sodium salt, present in a range of 0.3 % to 10.0% by weight of the total composition.
5. The synergistic nutritional composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are a diluent present in a range of 1 to 30%; a binder present in a range of 0.1 to 20%; a lubricant present in a range of 0.1 to 5.0 %; a glidant present in a range of 0.1 to 5.0%; an additive present in a range of 1 to 10%; a surfactant is present in a range of 0.1 to 5.0%; and a stabilizer present in a range of 0.1 to 10.0%, by weight of the total composition.

6. A method for enhancing memory and learning ability, comprising orally administrating the composition as claimed in claim 1.

7. A synergistic nutritional composition for treating neurocognitive disorders comprising an exogenous blend of a crystalline form of a magnesium salt of L-threonic acid and a phosphatidylserine or its salt in a weight ratio of 1:0.001 to 1:1 along with pharmaceutically acceptable excipients.

8. The synergistic nutritional composition as claimed in claim 7, wherein the wherein the crystalline form of the magnesium salt of L-threonic acid contains 6.0% to 8.0 % w/w of elemental magnesium and is present in a range of 50.0% to 98.8% by weight of the total composition.

9. The synergistic nutritional composition as claimed in claim 7, wherein the pharmaceutically acceptable excipients are a diluent present in a range of 1 to 20%; a binder present in a range of 0.1 to 10%; a lubricant present in a range of 0.1 to 3.0 %; a glidant present in a range of 0.1 to 3.0%; an additive present in a range of 1 to 5%; a surfactant is present in a range of 0.1 to 5.0%, and a stabilizer present in a range of 0.1 to 5.0%, by weight of the total composition.

10. The synergistic nutritional composition as claimed in claim 1 and 7, wherein an effective unit dose for oral administration is in a range of 100 to 1000 mg.