DESC:FIELD OF INVENTION:
The present invention relates to the field of pharmaceutical and nutraceutical compositions. In particular, the present invention relates to a novel therapeutic and synergistic composition comprising Palmitoylethanolamide, Pterostilbene, Quercetin, and Cordycepin for use in the management and treatment of neuropathic pain and neuroinflammation.

BACKGROUND OF THE INVENTION:
Neuropathic pain is a debilitating condition characterized by abnormal sensory processing within the peripheral and central nervous systems, leading to spontaneous pain, allodynia, and hyperalgesia. It affects approximately 7-10% of the global population, presenting a significant clinical challenge due to its complex pathophysiology and resistance to conventional analgesics (Colloca et al., 2017). The mechanisms underlying neuropathic pain involve multiple pathways, including neuroinflammation, oxidative stress, and the maladaptive plasticity of neuronal circuits (Costigan et al., 2009).

Current therapeutic options for neuropathic pain, such as anticonvulsants, antidepressants, and opioids, primarily focus on symptomatic relief without addressing the underlying mechanisms. These treatments are often associated with side effects, limited efficacy, and a risk of dependency (Baron et al., 2010; Finnerup et al., 2015).

Gabrielsson L, Mattsson S, Fowler CJ. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety, and efficacy. Br J Clin Pharmacol. 2016 Dec;82(4):932-942. doi: 10.1111/bcp.13020.

Petrosino S, Di Marzo V. The pharmacology of Palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br J Pharmacol. 2017 Apr;174(11):1349-1365. doi: 10.1111/bph.13580.

McCormack D, McFadden D. Pterostilbene and cancer: current review. J Surg Res. 2013 May;180(1):255-263. doi: 10.1016/j.jss.2012.10.051.
Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008 Apr 7;585(2-3):325-337. doi: 10.1016/j.ejphar.2008.03.008.

Yue K, Ye M, Zhou Z, Sun W, Lin X. The genus Cordyceps: a chemical and pharmacological review. J Pharm Pharmacol. 2013 Dec;65(12):1617-1640. doi: 10.1111/jphp.12091.

Zhou X, Gong Z, Su Y, Lin J, Tang K. Cordycepin: a review of its pharmacological effects and therapeutic prospects. J Pharm Pharmacol. 2016 Mar;68(3):423-430. doi: 10.1111/jphp.12547.

WO2014009936A1 relates to compositions comprising compounds obtained from plant extracts for the treatment of neuropathic pain caused by chemotherapeutic drugs. It discloses that composition for use in the treatment of neuropathic pain, comprises polyphenols between 3 and 20% by weight of said composition of which a') flavonoids, quercetin excluded, account for between 1 and 9% by weight of said composition; a") quercetin accounts for between 0.05 and 0.6% by weight of said composition, b) anthocyanosides account for between 0.1 and 1 % by weight of said composition, wherein the ratio between polyphenols in a) and flavonoids in a') is between 1.5 and 4.5.

US10653737B1 discloses a synergistic nutritional composition(s) for pain management. Particularly, the invention relates to synergistic nutritional composition comprising specific combination of Palmitoylethanolamide (PEA) and standardized red spinach extract enriched with nitrate content, present in the ratio of 1:0.1 to 1:5 along with pharmaceutically acceptable carriers/excipients.

EP3130336 relates to a food and/or nutraceutical composition comprising PEA. In particular, it relates to a food and/or nutraceutical composition comprising PEA in association with at least one component selected from a second active ingredient and an agent that modifies its release in the organism.

IN201721023668 relates to a composition/formulation comprising a synergistic combination of Palmitoylethanolamide (PEA) and one or more natural ingredients that acts as Fatty Acid Amide Hydrolase (FAAH) Inhibitor. The pharmaceutical composition/formulation of this invention comprises a synergistic combination of PEA, Daidzein, Genistein and a pharmaceutically acceptable excipient.

However, there is an unmet clinical need for novel formulations that target the pathological mechanisms of neuropathic pain, providing effective relief while minimizing adverse effects. Further, there is also requirement to provide a highly effective relief for neuropathic pain by PEA and its combination with other active ingredients without any side effects in humans or animals accompanied with good tolerability at an effective dose and good safety profile.

The present invention addresses these needs by providing a composition with a unique combination of bioactive compounds that target neuroinflammation, oxidative stress, and neural regeneration, thus offering comprehensive management of neuropathic pain accompanied by acceptable safety profile and without any adverse effects.

OBJECT OF THE INVENTION
To address the foregoing problems, in whole or in part, and/or other problems that may have been observed by persons skilled in the art, the present disclosure provides composition and method as described by way of example as set forth below.

Accordingly, the main object of the present invention is to provide a novel therapeutic composition for use in the management and treatment of neuropathic pain and neuroinflammation.

Another object of the present invention is to provide a composition of N-(2-Hydroxyethyl) hexadecanamide (Palmitoylethanolamide), 4-[(E)-2-(3,5-Dimethoxyphenyl) ethen-1-yl] phenol (Pterostilbene), 3,3',4',5,7-Pentahydroxyflavone (Quercetin), and 3'-Deoxyadenosine (Cordycepin) for use in the management and treatment of neuropathic pain and neuroinflammation.

Yet another object of the present invention is to offer an effective treatment and management strategy for neuropathic pain and neuroinflammation.

SUMMARY OF THE INVENTION
This summary is intended to introduce, in simplified form, a selection of concepts that are further described in the detailed description. This summary is merely presented as a brief overview of the subject matter described and claimed herein and does not aid in determining the scope of the claimed subject matter.

Accordingly, the present invention provides a novel therapeutic composition for management and treatment of neuropathic pain and associated neuroinflammatory conditions.

In another aspect, the present invention provides a composition comprising bioactive compounds that modulate neuroinflammation, reduce oxidative stress, enhance neural regeneration, and alleviate chronic pain.

In yet another aspect, the present invention provides a composition of N-(2-Hydroxyethyl) hexadecanamide (Palmitoylethanolamide), 4-[(E)-2-(3,5-Dimethoxyphenyl) ethen-1-yl] phenol (Pterostilbene), 3,3',4',5,7-Pentahydroxyflavone (Quercetin), and 3'-Deoxyadenosine (Cordycepin) for use in the management and treatment of neuropathic pain and neuroinflammation.

In yet another aspect, the present invention is designed for patients suffering from conditions such as diabetic neuropathy, chemotherapy-induced neuropathy, postherpetic neuralgia, and other peripheral or central neuropathic pain disorders.

In another aspect of the present application, a process for the preparation of a composition/formulation is described.

In another aspect of the present application, N-(2-Hydroxyethyl) hexadecanamide (Palmitoylethanolamide) is present in an amount of 200-800 mg per dosage unit.

In another aspect of the present application, 4-[(E)-2-(3,5-Dimethoxyphenyl) ethen-1-yl] phenol (Pterostilbene) is present in an amount of 5-50 mg per dosage unit.

In another aspect of the present application, wherein 3,3',4',5,7-Pentahydroxyflavone (Quercetin) is present in an amount of 10-100 mg per dosage unit.

In another aspect of the present application, 3'-Deoxyadenosine (Cordycepin) is present in an amount of 5-50 mg per dosage unit.
In another aspect of the present application, the said composition is in the form of tablet, capsule, drop, syrup, suppository oral solution, injectable solution, granules, powder or suspension.

In another aspect of the present application, pharmaceutically acceptable excipient is selected from diluents, disintegrants, binders, lubricants, surfactants, glidants, sweeteners, anti-tacking agents, coloring agents and flavoring agents.

In another aspect of the present application, 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.

In another aspect of the present application, the invention also provides a method of obtaining a synergistic therapeutic composition comprising Palmitoylethanolamide, Pterostilbene, Quercetin and Cordycepin in a pre-determined ratio, with or without additional ingredients. The process comprises blending the active ingredients comprising Palmitoylethanolamide, Pterostilbene, Quercetin and Cordycepin 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.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a novel composition of N-(2-Hydroxyethyl) hexadecanamide (Palmitoylethanolamide), 4-[(E)-2-(3,5-Dimethoxyphenyl) ethen-1-yl] phenol (Pterostilbene), 3,3',4',5,7-Pentahydroxyflavone (Quercetin), and 3'-Deoxyadenosine (Cordycepin) for use in the management and treatment of neuropathic pain and neuroinflammation.
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.

The terms “process(es)” and “method(s)” are considered interchangeable within this disclosure.
For convenience, certain terms used in the specification and examples are collected in this section below:
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
MAPK: Mitogen-Activated Protein Kinase
PI3K/Akt: Phosphoinositide 3-Kinase
COX-2: Cyclooxygenase-2
iNOS: inducible nitric oxide synthase
Nrf2: Nuclear factor erythroid 2-related factor 2
NLRP3: Nucleotide-binding oligomerization domain (NOD) and leucine-rich repeat (LRR) and pyrin domain-containing protein 3

In one specific embodiment, the present invention provides a novel composition of N-(2-Hydroxyethyl) hexadecanamide (Palmitoylethanolamide), 4-[(E)-2-(3,5-Dimethoxyphenyl) ethen-1-yl] phenol (Pterostilbene), 3,3',4',5,7-Pentahydroxyflavone (Quercetin), and 3'-Deoxyadenosine (Cordycepin) for use in the management and treatment of neuropathic pain and neuroinflammation.

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that modulates the immune response and exhibits anti-inflammatory, analgesic, and neuroprotective properties. PEA’s mechanism of action involves inhibition of the NLRP3 inflammasome, reduction of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-a), and activation of PPAR-a receptors, leading to decreased neuroinflammation. PEA has been shown to reduce chronic pain by decreasing mast cell degranulation and stabilizing glial cell activation, making it a potent therapeutic agent for neuropathic pain.

Pterostilbene, a natural dimethylated analog of resveratrol, exhibits superior bioavailability and neuroprotective effects. Pterostilbene’s antioxidant activity involves upregulation of the Nrf2 pathway and downregulation of NF-?B, which helps in mitigating oxidative stress and neuroinflammation. It has been demonstrated to enhance cognitive function, reduce neuroinflammation, and protect neurons from excitotoxicity and apoptotic death.

Quercetin is a naturally occurring polyphenolic flavonoid with strong anti-inflammatory and antioxidant properties. It acts by modulating several signaling pathways, including the NF-?B, MAPK, and PI3K/Akt pathways, which are involved in inflammatory responses. Quercetin decreases the expression of pro-inflammatory mediators such as COX-2 and iNOS, reduces nerve swelling, and promotes recovery of damaged nerves, making it an essential component for neuropathic pain management.

Cordycepin, an adenosine analog extracted from Cordyceps militaris, exerts neuroprotective, anti-inflammatory, and immunomodulatory effects. Cordycepin activates the adenosine A1 receptor, modulates the NF-?B pathway, and reduces the production of pro-inflammatory cytokines, thereby protecting neurons from inflammation-induced apoptosis. Additionally, Cordycepin promotes neurite outgrowth and enhances the survival of neurons under stress conditions, making it beneficial for nerve regeneration and repair.

In one embodiment, the present invention provides a therapeutic composition of Palmitoylethanolamide, Pterostilbene, Quercetin and Cordycepin and one or more excipients.
In another embodiment, the present invention provides a composition wherein the ratio of Palmitoylethanolamide, Pterostilbene, Quercetin and Cordycepin is 60:1:5:1.
In another embodiment, the present invention provides a composition wherein the ratio of Palmitoylethanolamide, Pterostilbene, Quercetin and Cordycepin is 20:1:2:1.
In another embodiment, the present invention provides a composition wherein N-(2-Hydroxyethyl) hexadecanamide (Palmitoylethanolamide) is present in an amount of 200-800mg per dosage unit.

In another embodiment, the present invention provides a composition wherein 4-[(E)-2-(3,5-Dimethoxyphenyl) ethen-1-yl] phenol (Pterostilbene) is present in an amount of 5-50mg per dosage unit.

In another embodiment, the present invention provides a composition wherein 3,3',4',5,7-Pentahydroxyflavone (Quercetin) is present in an amount of 10-100 mg per dosage unit.

In yet another embodiment, the present invention provides a composition wherein 3'-Deoxyadenosine (Cordycepin) is present in an amount of 5-50 mg per dosage unit.

In another embodiment, Palmitoylethanolamide is present in an amount of 600 mg per dosage unit, Pterostilbene is present in an amount of 10 mg per dosage unit, Quercetin is present in an amount of 50 mg per dosage unit and Cordycepin is present in an amount of 10 mg per dosage unit.

In yet another embodiment, the present invention provides a composition wherein the said composition is in the form tablet, capsule, drop, syrup, suppository oral solution, injectable solution, granules, powder or suspension with appropriate excipients, stabilizers, and binders to ensure stability and controlled release of the active ingredients.

In yet another embodiment, the present invention provides a composition wherein excipient 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 pregelatinized 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 capsule shell is made of hydroxypropyl methylcellulose (HPMC), also called vegetative capsule shell, which provides an alternative to animal-based gelatin.

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, polysorbates, polyoxyethylene alkyl ethers, poloxamers, medium-chain triglycerides, polyoxylglycerides, polyoxyethylene castor oil derivates 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.

In another embodiment, the present invention is suitable for managing neuropathic pain by addressing multiple pathological mechanisms. The formulation is designed to reduce neuroinflammation, protect neurons from oxidative stress, and promote the regeneration of damaged neural tissue.

In yet another embodiment, 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. Palmitoylethanolamide, Pterostilbene, Quercetin and Cordycepin accurately and with 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 effect in reducing neuroinflammation, protecting neurons from oxidative stress, and promoting the regeneration of damaged neural tissue.

In another embodiment, the novel therapeutic composition for neuropathic pain as described herein is formulated to provide optimal bioavailability and efficacy. The active ingredients have been selected based on their pharmacokinetic and pharmacodynamic properties to ensure maximum absorption and therapeutic effect.
In yet another embodiment, the present invention provides a composition that is intended for oral administration and offers a non-addictive alternative for long-term neuropathic pain management.
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
Mechanism of Action:
The therapeutic efficacy of the composition is achieved through the synergistic interaction of its components:
? PEA acts as a master regulator of neuroinflammation by inhibiting mast cell degranulation and stabilizing glial cells, thus reducing the inflammatory milieu in the nervous system.
? Pterostilbene offers neuroprotective effects by enhancing the antioxidant defense system through activation of Nrf2 and suppression of oxidative stress pathways.
? Quercetin targets multiple signaling pathways to reduce nerve inflammation, improve blood-brain barrier integrity, and promote the healing of injured nerves.
? Cordycepin enhances the regeneration of neuronal cells and modulates the immune response, facilitating recovery from nerve damage and reducing hypersensitivity associated with neuropathic pain.
Example 1: Compressed tablets were prepared by conventional wet granulation method. Capsules were prepared by filling the physical mixture in appropriate capsule shell.

Table 1:
Ingredient Amount (mg)
Palmitoylethanolamide 600
Pterostilbene 10
Quercetin 50
Cordycepin 10
Microcrystalline Cellulose 5–10
Magnesium Stearate 1–2

Example 2: The ingredients were mixed and compressed into tablets using the conventional wet granulation method. The composition provides a half-strength dose suitable for twice-daily administration.
Table 2:
Ingredient Amount (mg)
Palmitoylethanolamide 300
Pterostilbene 5
Quercetin 25
Cordycepin 5
Microcrystalline Cellulose 10–15
Magnesium Stearate 1–2

Example 3: The ingredients were blended uniformly and filled into HPMC capsules using a semi-automatic capsule filling machine. This formulation is designed for once-daily extended-release delivery.
Table 3:
Ingredient Amount (mg)
Palmitoylethanolamide 800
Pterostilbene 20
Quercetin 75
Cordycepin 20
Microcrystalline Cellulose 10–15
Magnesium Stearate 1–2

Example 4: An oral syrup formulation comprising Palmitoylethanolamide, Pterostilbene, Quercetin and Cordycepin suitable for patients who cannot swallow solid dosage forms or require flexible dosing.
Ingredient (function) Amount per 100 mL
Palmitoylethanolamide 600 mg
Pterostilbene 10 mg
Quercetin 50 mg
Cordycepin 10 mg
Sucrose 60.0 g
Sorbitol 70% solution 10.0 g
Glycerin 5.0 mL
Polyethylene glycol 400 (co-solvent) 5.0 mL
Polysorbate 80 0.20 mL (˜0.2% w/v)
Flavor & color q.s.
Purified water q.s. to 100 mL

Example 4: The formulation of the present invention, when administered to LPS-induced mice, results in a significant reduction in pro-inflammatory cytokines TNF-a, IL-1ß, and IL-6, and downregulates COX-2, iNOS, and NLRP3 expression compared to untreated controls.
TNF-a Levels Across Treatment Groups: In order to assess the anti-inflammatory potential of the composition, TNF-a levels were quantified in LPS-stimulated macrophages and CCI brain homogenates. Treatments were performed with either individual component of the composition and with combined formulation, each administered at a concentration equivalent to 100 µg/mL per test compound. Samples were collected 24 hours post-treatment, and TNF-a was measured using ELISA.
As shown in the TNF-a data table below, the disease model (LPS/CCI) exhibited significantly elevated TNF-a levels compared to normal controls. Individual components i.e. Palmitoylethanolamide, Pterostilbene, Quercetin, and Cordycepin, it can be noted that each reduced TNF-a to a moderate extent. However, the combination demonstrated a marked reduction, bringing TNF-a levels close to baseline. This result highlights the synergistic anti-inflammatory effect of the composition, showing superior efficacy compared to the sum of its parts.
Group TNF-a (pg/mL)
Normal Control 19.8 ± 0.9
LPS / CCI only 56.3 ± 2.1
Palmitoylethanolamide 40.5 ± 1.6
Pterostilbene 37.8 ± 1.5
Quercetin 35.1 ± 1.4
Cordycepin 38.7 ± 1.3
Combination of all four 24.6 ± 1.1

Effect on IL-1ß and NF-?B Expression: To assess the efficacy of present composition in neuropathic pain, inflammatory mediators IL-1ß (pg/mL) and NF-?B activation (AU) were quantified in the chronic constriction injury (CCI) rat brain homogenates. Treatments were administered at 100 µg/mL equivalent concentrations and tissue was collected at 24 hours post-treatment.
The LPS/CCI group displayed a marked increase in IL-1ß (~55 pg/mL) and NF-?B activity, compared to normal control animals (~23 pg/mL). Treatment with individual components (Palmitoylethanolamide, Pterostilbene, Quercetin, or Cordycepin) reduced IL-1ß to a moderate extent (~34–40 pg/mL) and partially suppressed NF-?B activity. In contrast, the Palneuro combined formulation significantly reduced IL-1ß (~26 pg/mL) and restored NF-?B activity near baseline levels, indicating robust suppression of neuroinflammatory signaling. The results are shown in the table below:
Treatment Group IL-1ß (pg/mL) NF-?B
Normal Control 23 ± 2 1.0 ± 0.1
LPS/CCI Only 55 ± 3 3.8 ± 0.2
Palmitoylethanolamide 39 ± 2 2.5 ± 0.2
Pterostilbene 37 ± 2 2.3 ± 0.2
Quercetin 34 ± 2 2.1 ± 0.1
Cordycepin 38 ± 2 2.4 ± 0.2
Composition 26 ± 2 1.2 ± 0.1

Effect of composition on COX-2, iNOS, Nrf2, and NLRP3 expression: In the LPS/CCI model, expression of inflammatory mediators was markedly altered compared to normal controls. COX-2 and iNOS were significantly upregulated (3.2 ± 0.2 and 2.8 ± 0.2, respectively), while the antioxidant regulator Nrf2 was suppressed (0.6 ± 0.05) and the inflammasome marker NLRP3 was elevated (2.9 ± 0.2). Treatment with the Palneuro formulation restored these dysregulated biomarkers, as evidenced by reduced COX-2 (1.4 ± 0.1) and iNOS (1.3 ± 0.1) expression, suppression of NLRP3 (1.2 ± 0.1), and a marked upregulation of Nrf2 (1.7 ± 0.1). These results demonstrate the dual anti-inflammatory and antioxidant actions of Palneuro, highlighting its potential in the management of neuroinflammatory and neuropathic conditions.
Group COX-2 iNOS Nrf2 NLRP3
Normal Control 1.0 ± 0.1 1.0 ± 0.1 1.0 ± 0.1 1.0 ± 0.1
LPS/CCI Only 3.2 ± 0.2 2.8 ± 0.2 0.6 ± 0.05 2.9 ± 0.2
Composition Treated 1.4 ± 0.1 1.3 ± 0.1 1.7 ± 0.1 1.2 ± 0.1

Effect on Gamma-Aminobutyric Acid (GABA) Levels: Gamma-Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. In neuropathic pain, there often a breakdown of inhibitory signaling, including a reduction in GABAergic transmission, which leads to neuronal hyperexcitability and increased pain perception. The following data shows the effect of Present composition and its individual components on GABA levels in a rat model of Chronic Constriction Injury (CCI).
In the CCI group, GABA levels were markedly reduced (55 ± 4 ng/mg protein) compared to the normal control (100 ± 5 ng/mg protein), confirming loss of inhibitory neurotransmission under neuroinflammatory stress. Treatment with individual components such as Palmitoylethanolamide, Pterostilbene, Quercetin, and Cordycepin produced moderate improvements (ranging from 68 ± 4 to 72 ± 5 ng/mg protein). In contrast, the formulation significantly restored GABA content (95 ± 6 ng/mg protein), approaching near-normal levels. These results demonstrate the synergistic potential of Palneuro in maintaining excitatory-inhibitory balance by preserving GABAergic neurotransmission in neuropathic conditions.
Model: CCI-induced neuroinflammation (rat brain homogenates)
Assay: HPLC quantification of GABA
Unit: ng/mg protein
Timepoint: 24 hours post-treatment
Group GABA Levels (ng/mg protein)
Normal Control 100 ± 5
CCI Only 55 ± 4
Palmitoylethanolamide 70 ± 5
Pterostilbene 68 ± 4
Quercetin 72 ± 5
Cordycepin 69 ± 4
Composition 95 ± 6

Example 5: Enhanced Bioavailability of Pterostilbene in Composition
One of the potential advantages of the present composition is the enhanced bioavailability of its components. Quercetin is known to have poor water solubility and low bioavailability, but within the composition it inhibits metabolic enzymes that degrade other compounds, thereby extending their systemic residence time. The following data shows this effect on Pterostilbene.
Treatment Group AUC (µg·h/mL) T½ (h)
PTE Monotherapy 15.6 ± 1.3 2.5 ± 0.3
Combined (composition) 28.9 ± 2.1* 4.1 ± 0.4*

AUC: Area Under the Curve (a measure of total drug exposure)
T½: Half-life (the time it takes for the drug concentration to be reduced by half)
*p < 0.05 compared to the PTE Monotherapy group.
The data suggests that when Pterostilbene is administered as part of the composition, its bioavailability is significantly enhanced.
Area Under the Curve (AUC), which reflects the overall drug exposure, is almost double in the composition group compared to the Pterostilbene monotherapy group.
Additionally, the half-life (T½) of Pterostilbene is extended, indicating that it remains in the body for a longer period. This enhanced bioavailability is likely due to the presence of three other components in the formulation, such as Quercetin, which may inhibit the enzymes responsible for Pterostilbene metabolism. This synergistic effect could allow for a lower effective dose and improve the therapeutic efficacy of the composition.
Potential Advantages of this Composition
Multi-Target Efficacy: It addresses the multifaceted nature of neuropathic pain, moving beyond single-target drugs that often have limited success.
Disease Modification: Instead of just masking pain, this composition aims to resolve the underlying pathology (inflammation, oxidative stress) which could lead to more sustained relief and potential nerve recovery.
Enhanced Bioavailability: In some cases, compounds like Quercetin can inhibit enzymes in the gut and liver (like CYP450 enzymes) that metabolize other drugs. This could potentially increase the bioavailability and residence time of Pterostilbene or other components.
It will be appreciated by those skilled in the art that the embodiments of the present invention described herein are merely illustrative and not restrictive in nature. Various modifications, substitutions, or equivalents may be employed without departing from the scope and spirit of the invention. The examples and methods provided are intended to demonstrate the novelty and efficacy of the formulation, and should not be construed as limiting.
,CLAIMS:We claim

1. A novel therapeutic composition for the management and treatment of neuropathic pain, comprising N-(2-Hydroxyethyl) hexadecanamide (Palmitoylethanolamide), 4-[(E)-2-(3,5-Dimethoxyphenyl) ethen-1-yl] phenol (Pterostilbene), 3,3',4',5,7-Pentahydroxyflavone (Quercetin) and 3'-Deoxyadenosine (Cordycepin) along with one or more pharmaceutically acceptable excipients.

2. The composition as claimed in claim 1, wherein the ratio of Palmitoylethanolamide, Pterostilbene, Quercetin and Cordycepin is 60:1:5:1.

3. The composition as claimed in claim 1, wherein N-(2-Hydroxyethyl) hexadecanamide (Palmitoylethanolamide) is present in an amount of 600mg per dosage unit.

4. The composition as claimed in claim 1, wherein 4-[(E)-2-(3,5-Dimethoxyphenyl) ethen-1-yl] phenol (Pterostilbene) is present in an amount of 10mg per dosage unit.

5. The composition as claimed in claim 1, wherein 3,3',4',5,7-Pentahydroxyflavone (Quercetin) is present in an amount of 50 mg per dosage unit.

6. The composition as claimed in claim 1, wherein 3'-Deoxyadenosine (Cordycepin) is present in an amount of 10 mg per dosage unit.

7. The composition as claimed in claim 1, wherein the said composition is in the form of tablet, capsule, drop, syrup, suppository, oral solution, injectable solution, granules, powder or suspension.

8. 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.