DESC:FIELD OF INVENTION:
The present invention relates to the field of nutraceuticals and pharmaceuticals. In particular, the present invention relates to a neuroprotective and cognitive enhancing composition comprising Fisetin, Inosine Monophosphate (IMP), L-Carnosine.

BACKGROUND OF THE INVENTION:
Cognitive decline, often associated with aging, stress, and neurological disorders, poses significant challenges to individual quality of life. Conventional pharmacological treatments for cognitive decline and neurodegenerative diseases primarily manage symptoms rather than addressing underlying causes or providing comprehensive neuroprotection. Nutraceuticals with neuroprotective properties present a promising approach for supporting brain health through safe, natural compounds.

Nutraceuticals present in a healthy diet provide energy and nutrient supplements to body, which are required for maintaining optimal health. Nutraceuticals are food supplements that are helpful in treating and preventing diseases. Nutraceuticals may also be fortified food products that are used to provide medical benefits. Nutraceutical foods are specially designed and formulated for nutrition and dietary management of diseases.

Maher P, 2015, Frontiers in Bioscience (Scholar Edition), 01 Jun 2015, 7(1):58-82 teaches that Fisetin has direct antioxidant activity. It can also increase the intracellular levels of glutathione, the major intracellular antioxidant. Fisetin can also activate key neurotrophic factor signaling pathways. In addition, it has anti-inflammatory activity and inhibits the activity of lipoxygenases, thereby reducing the production of pro-inflammatory eicosanoids and their by-products. This wide range of actions suggests that fisetin has the ability to reduce the impact of age-related neurological diseases on brain function.

Jin-Qiong Zhan et. al.; J Neurochem, 2021 Jul;158(2):413-428, doi: 10.1111/jnc.15370. Epub 2021 May 12, teaches that Flavonoid fisetin reverses impaired hippocampal synaptic plasticity and cognitive function by regulating the function of AMPARs in a male rat model of schizophrenia.

Marianna Lovászi et. al., FASEB J. 2021 Nov; 35(11): e21935. demonstrates that IMP suppresses TNF-a production in endotoxemia, which likely occurs through its degradation to inosine. Since inosine was previously proposed as a new modality for the treatment of inflammatory diseases (44), IMP may be similarly useful.

Alan R. Hipkiss et. al. Advances in Food and Nutrition Research Volume 57, 2009, Pages 87-154, discusses carnosine and its possible roles in nutrition and health. Evidence for carnosine's possible protective action against secondary diabetic complications, neurodegeneration, cancer, and other age-related pathologies is briefly discussed.

The present invention addresses a multi-faceted approach to brain health by providing a novel combination of Fisetin, Inosine Monophosphate (IMP), and L-carnosine. Each of these components has demonstrated potential in enhancing cognitive function and protecting neural tissue.

OBJECT OF THE INVENTION
Accordingly, the main object of the present invention is to provide a composition for neuroprotective and cognitive enhancement.

Another object of the present invention is to provide a composition of Fisetin, Inosine Monophosphate (IMP), L-Carnosine for prevention and treatment of neurodegenerative disorders and cognitive disorders.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a composition comprising Fisetin, Inosine Monophosphate (IMP) and L-Carnosine.

The composition of the present disclosure exerts synergistic effects, enhancing cognitive functions such as memory and focus, while providing comprehensive neuroprotection.

The disclosure further comprises suitable excipients to form a stable oral dosage form, such as, but not limiting to, tablets or capsules.

The composition shows antioxidant properties by reducing oxidative stress, anti-inflammatory effects, neuroprotection and cognitive enhancement, metabolism enhancement, neurotransmitter modulation, etc.

The composition comprises Fisetin, Inosine Monophosphate (IMP) and L-Carnosine in a pre-determined ratio.

The invention also comprises a method of obtaining a neuroprotective composition comprising Fisetin, Inosine Monophosphate (IMP) and L-Carnosine in a pre-determined ratio, with or without additional ingredients. The process comprises blending the active ingredients comprising Fisetin, Inosine Monophosphate (IMP) and L-Carnosine with pharmaceutically acceptable excipients, such as binders, fillers, and disintegrants, to create a homogeneous mixture. The blend is then compressed into tablets or filled into capsules using standard pharmaceutical techniques.

The composition of the present disclosure maintains overall brain health, particularly in aging populations and is administered orally according to individual’s need and medical advice..

The combination of Fisetin, IMP, and L-Carnosine shows synergistic effect and provides comprehensive neuroprotection through multiple pathways, providing a broader range of benefits compared to single-ingredient supplements.

The composition comprises naturally occurring compounds, thereby minimizing the risk of side effects and providing a safer alternative to synthetic drugs. The composition shows enhanced bioavailability, ensuring optimal therapeutic effects.

The composition is intended for daily oral administration in the form of tablets or capsules, offering a safe and natural approach to maintaining and improving brain health.

The foregoing has broadly outlined the features and technical advantages of the present disclosure in order that the detailed description of the disclosure that follows may be better understood. It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other assemblies for carrying out the same purposes of the present disclosure.

The terms “comprise”, “comprising”, or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a setup, device or method that comprises a list of components or steps does not include only those components or steps but may include other components or steps not expressly listed or inherent to such method. In other words, one or more elements proceeded by “comprises… a” does not, without more constraints, preclude the existence of other elements or additional elements in the composition or method.
Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The singular ‘a’, ‘an’, ‘the’ include plural referents unless context clearly indicates otherwise. Similarly, the word ‘or’ is intended to include ‘and’ unless the context clearly indicates otherwise. The examples given are non-limiting in nature and will be further described in the complete specification.

BRIEF DISCRIPTION OF DRAWINGS:
Fig. 1 depicts neuroprotective efficacy results in mice.

DETAILED DESCRIPTION OF THE INVENTION WITH NON-LIMITING EMBODIMENTS AND EXAMPLES

Accordingly, the present invention provides a novel composition for neuroprotection and neurorestoration comprising 3,3',4',7-Tetrahydroxyflavone (Fisetin), Inosine 5'-monophosphate (IMP), ß-Alanyl-L-histidine (L-Carnosine) and pharmaceutically acceptable excipients.

The present disclosure can be understood more readily by reference to the following description, taken in conjunction with the accompanying Figures and Examples, all of which form a part of this disclosure.

At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of the invention covered in the present disclosure. However, such a particular form is only an exemplary embodiment, and without intending to imply any limitation on the scope of the invention. Accordingly, the description is to be understood as an exemplary embodiment and teaching of invention and not intended to be taken restrictively.

Before the present disclosure or methods of the present disclosure are described in greater detail, it is to be understood that the specific products, methods, processes, conditions or parameters, are not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the methods. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the methods. Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. For example, "about" can mean within one or more standard deviations, or within ± 30%, 25%, 20%, 15%, 10% or 5% of the stated value.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

It is appreciated that certain features of the methods, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the methods, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace operable processes and/or composites/scaffolds.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

As used herein, the term "comprises", "comprising", or “comprising of” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. The term "comprises", "comprising", or “comprising of” when placed before the recitation of steps in a process or method means that the process or method encompasses one or more steps that are additional to those expressly recited, and that the additional one or more steps may be performed before, between, and/or after the recited steps.

Reference throughout this specification to “certain embodiments”, “further embodiments”, “specific embodiments”, “further specific embodiment”, “one embodiment”, “a non-limiting embodiment”, “an exemplary embodiment”, “some instances”, or “further instances”, means that a particular feature, structure or characteristic described in connection with the embodiment may be included in at least one embodiment of the present disclosure.

As used herein, the terms ‘include’, ‘have’, ‘comprise’, ‘contain’ etc. or any form of said terms such as ‘having’, ‘including’, ‘containing’, ‘comprising’ or ‘comprises’ are inclusive and will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.

As used herein, the term “invention”, “present invention”, “disclosure” or “present disclosure” as used herein is a non-limiting term and is not intended to refer to any single embodiment of the particular invention but encompasses all possible embodiments as described in the specification.

ABBREVIATIONS:

Fisetin: 3,3',4',7-Tetrahydroxyflavone
IMP: Inosine 5'-monophosphate
L-Carnosine: ß-Alanyl-L-histidine
TBI: traumatic brain injury
SCI: spinal cord injury
CNS: Central nervous system
SCIM: Spinal Cord Independence Measure
mRS: modified Rankin Scale
HPMC: hydroxypropyl methylcellulose
HO-1: Heme oxygenase-1
NQO1: NAD(P)H quinone oxidoreductase 1
SOD1: Superoxide dismutase 1
BDNF: Brain-Derived Neurotrophic Factor
NGF: Nerve Growth Factor
NF-?B: Nuclear Factor kappa-light-chain-enhancer of activated B cells
TNF-a: Tumor Necrosis Factor-alpha
IL-1ß: Interleukin-1 beta
IL-6: Interleukin-6
PI3K/Akt: phosphoinositide 3-kinase/protein kinase B
ERK1/2: extracellular signal-regulated kinase 1 and 2
Caspase-3: cysteine-aspartic acid protease 3
Bcl-2: B-cell lymphoma/leukemia 2
PGC-1a: Peroxisome proliferator-activated receptor gamma coactivator 1 alpha
GABA: gamma-aminobutyric acid
GAP-43: growth associated protein 43

It is to be noted that the terms “neuroprotective” and “neurorestorative” as used herein can be used interchangeably.

In one specific embodiment, the present invention provides a neuroprotective and neurorestorative composition comprising 3,3',4',7-Tetrahydroxyflavone (Fisetin), Inosine 5'-monophosphate (Inosine Monophosphate), ß-Alanyl-L-histidine (L-Carnosine)

Fisetin Inosine 5'-monophosphate

L-Carnosine

Fisetin: (3,3',4',7-Tetrahydroxyflavone) :
Fisetin is a neuroactive flavonol that exerts pleiotropic effects across neuronal signaling, inflammatory regulation, redox homeostasis, and mitochondrial stability. It activates the Nrf2-ARE pathway, enhancing transcription of endogenous antioxidant genes such as HO-1, NQO1, and SOD1, thereby increasing the intracellular defense against reactive oxygen species. It upregulates BDNF and NGF, promoting neurotrophic support essential for synaptogenesis and dendritic branching. Fisetin also inhibits NF-?B nuclear translocation, thereby downregulating pro-inflammatory cytokines (TNF-a, IL-1ß, IL-6) and preventing microglial overactivation.
Through PI3K/Akt and ERK1/2 activation, Fisetin suppresses apoptotic cascades by inhibiting caspase-3 and upregulating Bcl-2 family proteins. It preserves mitochondrial membrane potential and limits cytochrome-c release, thus preventing mitochondrial-dependent neuronal apoptosis.

Inosine Monophosphate (IMP):

Inosine 5'-monophosphate: IMP, a purine nucleotide precursor, enhances neuronal structural recovery via multiple converging mechanisms. It facilitates axonal regeneration by increasing expression of GAP-43 (a membrane-associated growth cone protein) and neurofilament heavy chains (NF-H), both critical for axonal elongation and stabilization. IMP is metabolized into inosine, which acts on adenosine A2A and A3 receptors, promoting neuroplasticity and modulating excitatory neurotransmission.
Inosine boosts PGC-1a transcription and stimulates mitochondrial biogenesis, aiding in ATP recovery in metabolically compromised neurons. By elevating extracellular adenosine, it enhances GABAergic (neurons that release or utilize GABA) inhibition and suppresses post-injury glutamate excitotoxicity. It also promotes dendritic arbor complexity and corticospinal tract reorganization, crucial for functional restoration after CNS injury.

L-Carnosine (ß-Alanyl-L-histidine):
L-Carnosine is a naturally occurring dipeptide with pronounced antioxidant, anti-glycation, and pH-buffering properties. It directly neutralizes hydroxyl radicals, peroxynitrite, and singlet oxygen, protecting cellular lipids, proteins, and nucleic acids from oxidative degradation. Carnosine inhibits formation of advanced glycation end-products (AGEs) by scavenging reactive carbonyl species, and chelates divalent metal ions (Cu²+, Zn²+), mitigating metal-induced oxidative cascades that contribute to neurodegeneration. Its proton-accepting imidazole ring allows it to buffer intracellular pH during ischemia-induced lactic acidosis, maintaining neuronal viability. Carnosine also supports mitochondrial integrity by preventing permeability transition pore (mPTP) opening and reducing mitochondrial calcium overload, which is central to preventing neuronal apoptosis. It regulates proteostasis by preventing misfolded protein aggregation and supports clearance mechanisms such as proteasomal degradation and autophagy, especially relevant in post-ischemic and post-traumatic neurodegeneration

In one embodiment, the present invention provides a neuroprotective composition Inosine 5'-Monophosphate, fisetin, L carnosine and one or more excipients.

In another embodiment the ratio between Inosine 5'-Monophosphate and fisetin is 10:1 to 2:1 and that between fisetin and L-Carnosine is 5:1 to 1:1.

In another embodiment the ratio between Inosine 5'-Monophosphate, fisetin, L-Carnosine is 5:2:1.

In one embodiment, the composition of the present invention is in the form of tablet, capsule, granules or suspension.

In another embodiment fisetin is present in an amount of 80-100mg per dosage unit, inosine monophosphate is present in an amount of 300-1000mg per dosage unit and L-carnosine is present in an amount of 30-100mg per dosage unit.

In another embodiment fisetin is present in an amount of 100mg per dosage unit, inosine monophosphate is present in an amount of 500mg per dosage unit and L-carnosine is present in an amount of 50mg per dosage unit.

The excipient as used in the present invention is selected from diluents, disintegrants, binders, lubricants, surfactants, glidants, sweeteners, anti-tacking agents, coloring agents and flavoring agents.

The disintegrants may be selected from crospovidone, starch, starch derivatives such as pregelatinised starch and sodium starch glycollate, microcrystalline cellulose, carboxymethylcellulose sodium (CMC-Na, croscarmellose sodium) or calcium (CMC-Ca), cross-linked CMC-Na, polacrilin potassium, low substituted hydroxypropyl cellulose and/or mixtures thereof and can be present in an amount of 1 to 50 weight%. preferably 2 to 45 weight% based on the weight composition.

The binders may be selected from polyvinylpyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethyl cellulose, hydroxypropy1 cellulose, hydroxypropy1 methylcellulose, corn starch, maize starch, pregelatinised starch, polymethacry1ate, or mixtures thereof. The binder can be present in a range of 0.5 to 25 weight%, preferably 1 to 20 weight% on the weight of the composition.

The lubricants may be selected from stearic acid, magnesium stearate, magnesium palmitate, magnesium oleate, magnesium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, glyceryl behanate, macrogols and/or mixtures thereof and can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of the composition. Preferably, the pharmaceutical composition comprises a lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate.

The surfactants may be selected from anionic surfactants such as sodium lauryl sulfate and docusate sodium, cationic surfactants such as cetrimide, ampholytic surfactants such as N-dodecyl-N,N-dimethylbetaine, non-ionic surfactants such as sorbitan fatty acid esters (e.g. Spans®), polysorbates (e.g. polyoxyethylene alkyl ethers, poloxamers, medium-chain triglycerides, polyoxylglycerides, polyoxyethylene castor oil derivates (e. g. Cremophor®) and/or mixtures thereof & can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of the composition.

The glidants may be selected from colloidal silicon dioxide, talc, stearic acid, palmitic acid, polyethylene glycol, carnauba wax and/ or mixtures thereof and can be present in a range of 0.1 to 10 weight%, preferably 0.5 to 5 weight% based on the weight of the composition.

The sweetener can be selected from acesulfame K, sucralose, alitame, aspartame, saccharin sodium, dipotassium glycyrrhizinate, thaumatin and the like.

The coloring agents may be selected from natural pigments and inorganic materials.

The flavoring agents may be selected from natural or synthetic materials, such as orange, spearmint, strawberry and cream flavour and the like.

The composition of the present invention is suitable for the prevention or treatment of neurogenerative disorders and cognitive disorders selected from Alzheimer’s disease, Parkinson’s disease, dementia or mild cognitive impairment.

The tablet/ capsule of the present invention can be prepared by conventional methods known in the art. A compressed tablet for example is prepared by blending the actives, i.e fisetin, IMP and L-carnosine accurately and one or more excipients; Granulating using a binder solution; Drying the granulated blend; Compressing the dried granulated blend into tablets or encapsulating into hard capsules.

In another embodiment, the formulation is designed for oral administration and provides synergistic neuroprotective and neurorestorative effects in post-stroke, traumatic brain injury and spinal cord injury patients.

In yet another embodiment, the formulation is a neurotherapeutic engineered to address the multifactorial pathology underlying central nervous system injury. By modulating neurotrophic signaling, synaptic regeneration, oxidative stress response, and glial reactivity, it promotes structural and functional neural recovery in conditions such as ischemic stroke, traumatic brain injury (TBI), and spinal cord injury (SCI).

It is noted that in the present invention molecularly targeted strategy is designed to address the multifactorial nature of neural injury through complementary mechanisms. The composition is intended for use in subacute and chronic stages of neurorehabilitation, where regeneration and functional recovery are the primary goals.

Even though we have explained the invention of the present disclosure using specific examples, this explanation is not meant to limit how you understand it. People who are skilled in this field may think of various changes and different versions of the invention after reading this description. We expect that such changes can be made without straying from the main idea or purpose of the invention as defined in the claims.

The present disclosure is further described with reference to the following examples, which are only illustrative in nature and should not be construed to limit the scope of the present disclosure in any manner.

Examples

Example 1: Compressed tablets were prepared by conventional wet granulation method. Capsules were prepared by filling the physical mixture in appropriate capsule shell.

Example 1 (a)
Table 1:
Ingredient Amount (mg)
Insosine monophosphate 500
Fisetin 100
L-carnosine 50
Microcrystalline cellulose 5-10
Magenesium stearate 1-2
Mannitol 5-10

Example 1 (b)
Table 2:
Ingredient Amount (mg)
Insosine monophosphate 400
Fisetin 80
L-carnosine 40
Microcrystalline cellulose 5-10
Magenesium stearate 1-2
Mannitol 5-10

Example 1 (c)
Table 3:
Ingredient Amount (mg)
Insosine monophosphate 1000
Fisetin 200
L-carnosine 80
Microcrystalline cellulose 5-10
Polysorbate 80 2-10
Magenesium stearate 1-2
Mannitol 5-10

Example 2

The composition of the present invention was evaluated for its neuroprotective activity on mice. Mice (male. 8 weeks old) were adaptively reared for 7 days and they were raised in a cycle environment with a temperature of 22-25°C and adequate humidity and light for 12h each day and night. The mice were divided in three groups of 7 mice each. The first group which was not given any treatment, the second group was given only Fisetin, only IMP, only Carnosine, combination of two Fisetin-IMP, IMP- Carnosine and Fisetin-Carnosine and the third group was given the Fis-IMP-Car of the present invention. The neuroprotective efficacy was measured as reduction in oxidative stress and axon growth. The results are tabulated as below in table 4 and figure 1:

Table 4:
Group Axon Growth (mm) ROS Levels
Vehicle 0.5 ± 0.1 1.0
Fisetin only 1.2 ± 0.2 0.7
IMP only 1.5 ± 0.3 0.8
L-Carnosine only 1.0 ± 0.1 0.6
Fisetin + IMP 2.5 ± 0.3 0.5
Fisetin + L-Carnosine 2.3 ± 0.2 0.4
IMP + L-Carnosine 2.4 ± 0.3 0.5
Fisetin + IMP + L-Carnosine 3.7 ± 0.4 0.3

,CLAIMS:We claim

1. A neuroprotective and neurorestorative composition for reducing oxidative stress, neuroinflammation, and promotes structural and functional neural recovery said composition comprising Inosine 5'-Monophosphate, fisetin, L-Carnosine and one or more excipients.

2. The composition as claimed in claim 1 wherein the ratio between Inosine 5'-Monophosphate and fisetin is 10:1 to 2:1

3. The composition as claimed in claim 1 wherein the ratio between fisetin and L-Carnosine is 5:1 to 1:1.

4. The composition as claimed in claim 1 wherein the ratio between Inosine 5'-Monophosphate, fisetin, L-Carnosine is 5:2:1.

5. The composition as claimed in claim 1, wherein fisetin is present in an amount of 100mg per dosage unit.

6. The composition as claimed in claim 1, wherein the inosine monophosphate is present in an amount of 500mg per dosage unit.

7. The composition as claimed in claim 1, wherein L-carnosine is present in an amount of 50mg per dosage unit.

8. The composition as claimed in claim 1, wherein the said composition is in the form of tablet, capsule, granules or suspension.

9. The composition as claimed in claim 1, wherein excipient is selected from diluents, disintegrants, binders, lubricants, surfactants, glidants, sweeteners, anti-tacking agents, coloring agents and flavoring agents.

10. The composition as claimed in claim 1, wherein the composition is suitable for the prevention or treatment of neurogenerative disorders and cognitive disorders selected from Alzheimer’s disease, Parkinson’s disease, dementia or mild cognitive impairment.