Composition for the treatment of neuropathic pain

Abstract

A pharmaceutical or nutraceutical composition comprising a therapeutically effective combination of the following active ingredients: Palmitoylethanolamide (PEA) in an amount ranging from 400 mg to 600 mg; Agmatine sulfate in an amount of 500 mg to 600 mg; β -caryophyllene in an amount of 50 mg to 200 mg; and Carnosic acid in an amount of 50 mg to 200 mg and pharmaceutically acceptable excipients qs.

Description

Field of the invention

[0001] The present invention relates to a pharmaceutical composition containing a synergistic combination of N-palmitoylethanolamide (PEA), agmatine sulfate, carnosic acid, and β-caryophyllene, intended for the treatment and relief of neuropathic pain of various etiologies. These include, among others, diabetic peripheral neuropathy (DPN), chemotherapy-induced peripheral neuropathy (CIPN), radiation-induced neuropathy (RIN), uremic or renal neuropathy, fibrotic neuropathy, postherpetic neuralgia, trigeminal neuralgia, sciatica, fibromyalgia, hand-foot syndrome (HFS), and neuropathic pain following postoperative, posttraumatic, or idiopathic nerve injuries. Background of the invention

[0002] Neuropathic pain is a complex, chronic condition caused by damage or dysfunction of the nervous system, primarily injury to neurons. Neurogenic pain, or inflammatory pain, arises from complex interactions within the nerve and surrounding tissue involving nerve fibers, immune cells, mast cells, and microvascular components. This process, known as neurogenic inflammation, contributes to persistent neuropathic pain. It is characterized by symptoms such as burning, tingling, stabbing pain, weakness, numbness, and increased sensitivity to stimuli. Peripheral neuropathy is a neuropathy largely caused by diabetes and chemotherapy. Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. The estimated prevalence ranges from 6% to 51%, depending on factors such as age, disease duration, and glycemic control.Some studies report rates of 42.2% in type 2 diabetes and 29.1% in type 1 diabetes. Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of various chemotherapy drugs such as paclitaxel, oxaliplatin, and vincristine. Symptoms often persist long after chemotherapy has ended. Existing treatments for neuropathic pain, such as anticonvulsants, antidepressants, and opioids, often provide only limited relief and can be associated with significant side effects such as tolerance, dependence, and systemic toxicity.

[0003] Palmitoylethanolamide (PEA) is an endogenous fatty acid amide from the N-acylethanolamine family and the ALIAmide (Autacoid Local Injury Antagonism) class of compounds. It is structurally related to the endocannabinoid family but does not bind directly to the classic cannabinoid receptors CB1 or CB2. Instead, PEA exerts its effects primarily through activation of the peroxisome proliferator-activated receptor alpha (PPAR-α) and indirectly modulates the endocannabinoid system via the so-called "entourage effect" by enhancing anandamide activity (Lambert et al., 2002; LoVerme et al., 2005). In the context of neuropathy, PEA has demonstrated anti-inflammatory, analgesic, and neuroprotective properties. It modulates mast cell degranulation and glial cell activation, which are important factors in the pathogenesis of neuropathic pain (Skaper et al., 2014).Several preclinical and clinical studies have shown that PEA reduces pain perception in conditions such as diabetic neuropathy, sciatic pain, and postherpetic neuralgia by attenuating neuroinflammation and restoring neuroimmune homeostasis (Keppel Hesselink et al., 2013; Paladini et al., 2016). Due to its excellent safety profile, lack of psychoactive effects, and efficacy in the treatment of chronic pain, PEA is being investigated as a promising adjunctive therapy for neuropathic pain syndromes. It is often used in micronized or ultramicronized formulations to improve bioavailability and clinical efficacy (Petrosino & Di Marzo, 2017). In models of oxaliplatin-induced neuropathy, PEA reduced thermal hyperalgesia and mechanical allodynia by attenuating glial activation and preserving mitochondrial integrity (Impellizzeri et al., 2014).

[0004] Agmatine sulfate is a biogenic amine formed by the decarboxylation of the amino acid L-arginine by the enzyme arginine decarboxylase. It is considered an endogenous neuromodulator and, due to its structural similarity to other polyamines, is often classified in the polyamine family. Pharmacologically, agmatine acts as a neuroprotective agent, NMDA receptor antagonist, α2-adrenergic receptor agonist, and indirect nitric oxide synthase (NOS) modulator, thereby playing a pleiotropic role in nervous system function and dysfunction (Piletz et al., 2013; Reis & Regunathan, 2000). Agmatine has shown promising therapeutic effects in models of neuropathic pain, primarily through the modulation of multiple pain pathways. It inhibits N-methyl-D-aspartate (NMDA) receptors, which are crucial for central sensitization and the development of chronic pain (Fairbanks et al., 2000).Furthermore, agmatine enhances the analgesic effect by modulating monoaminergic systems and reducing nitric oxide (NO) production, which is elevated in neuroinflammation and neuropathy (Raasch et al., 2001). Preclinical models have shown that agmatine administration attenuates mechanical allodynia and thermal hyperalgesia in chronic constriction injury (CCI) models of peripheral neuropathy. The compound also appears to suppress the release of pro-inflammatory cytokines and restore neurochemical balance, suggesting both symptomatic relief and neuroprotective effects (Zhou et al., 2003; Keynan et al., 2020).Due to its multi-target pharmacological profile, agmatine is being investigated as an adjuvant or stand-alone therapy for neuropathic conditions such as diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), and postherpetic neuralgia, although clinical data in humans are still limited.

[0005] Carnosic acid is a naturally occurring phenolic diterpene and belongs to the broader group of polyphenols. It is found primarily in Rosmarinus officinalis (rosemary) and Salvia officinalis (sage), where it serves as a primary antioxidant component. As a lipophilic antioxidant, carnosic acid can penetrate the blood-brain barrier and thus exert its pharmacological effects in the central nervous system (López-Jiménez et al., 2013). Oxidative stress and neuroinflammation are considered central pathogenic mechanisms in neuropathic diseases. Carnosic acid exerts a potent antioxidant effect by activating the Nrf2 (nuclear factor erythroid 2-related factor 2) signaling pathway, which in turn upregulates phase II detoxifying enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO1), and glutamate-cysteine ​​ligase.This pathway plays a crucial neuroprotective role by attenuating reactive oxygen species (ROS)-mediated neuronal damage, a hallmark of peripheral and central neuropathies (Satoh & Lipton, 2007). Furthermore, carnosic acid exhibits anti-inflammatory properties through the inhibition of NF-κB (nuclear factor kappa-light chain enhancer of activated B cells) signaling, leading to a reduction in the expression of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6. These cytokines are important mediators of neuroinflammation and are heavily involved in the pathophysiology of neuropathic pain (Johnson, 2011). Experimental models have demonstrated the efficacy of carnosic acid in attenuating neuropathic pain behavior.In rodent models of chronic constriction injury (CCI), administration of carnosic acid significantly reduced mechanical allodynia and thermal hyperalgesia, which correlated with reduced markers of oxidative stress and improved mitochondrial function in dorsal root ganglia and spinal cord tissue (Wang et al., 2019). Furthermore, carnosic acid has been shown to suppress apoptosis in neuronal cells by stabilizing mitochondrial membrane potential and reducing cytochrome c release, thereby preventing caspase-mediated cell death (Liu et al., 2018). In summary, carnosic acid is a bioactive diterpene with potent antioxidant, anti-inflammatory, and antiapoptotic properties. These mechanisms collectively contribute to its neuroprotective effects and therapeutic potential in the treatment of neuropathic pain.Its neuroprotective role in CIPN is attributed to the attenuation of oxidative stress, reduction of lipid peroxidation and reduced neuronal apoptosis (Wang et al., 2022).

[0006] β-Caryophyllene (BCP) is a naturally occurring bicyclic sesquiterpene found in the essential oils of numerous edible plants, including black pepper (Piper nigrum), cloves (Syzygium aromaticum), cinnamon (Rosmarinus officinalis), and cannabis (Cannabis sativa). It belongs to the class of phytocannabinoids and acts as a selective agonist of the cannabinoid receptor type 2 (CB2), distinguishing it from psychoactive cannabinoids that act on CB1 receptors (Gertsch et al., 2008). Phytochemically, BCP is classified as a terpenoid, specifically a sesquiterpene, and pharmacologically as a selective CB2 receptor agonist. This receptor subtype is predominantly expressed in peripheral immune cells and the nervous system, particularly in glial cells and dorsal root ganglia, making BCP a non-psychoactive candidate for the treatment of neuroinflammation and pain (Klauke et al., 2014).Neuropathic pain involves both inflammatory and oxidative stress pathways, as well as the sensitization of nociceptive neurons. BCP modulates neuroinflammation through multiple mechanisms. First, through CB2 receptor activation, it attenuates the release of pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6) and suppresses microglial activation in the central nervous system, thereby reducing neuroinflammatory cascades associated with neuropathy (Gertsch et al., 2008; Scandiffio et al., 2020). Second, through antioxidant activity, it enhances endogenous antioxidant defenses by modulating the Nrf2 / ARE signaling pathway, thus reducing oxidative stress-induced neuronal damage, a major factor in the pathogenesis of diabetic and chemotherapy-induced neuropathy (Cho et al., 2014).Third, synergy with other analgesics such as PEA or curcumin offers broader therapeutic coverage for chronic neuropathic diseases (Pecic et al., 2022). Preclinical studies in rodent models have shown significant analgesic effects in chronic constriction injury (CCI), diabetic neuropathy, and chemotherapy-induced peripheral neuropathy (CIPN). These effects are blocked by CB2 antagonists, confirming its receptor-mediated action (Klauke et al., 2014; Romero et al., 2013). β-Caryophyllene is a promising, non-psychoactive cannabinoid with significant potential for the treatment of neuropathic pain. Its selective CB2 agonism, as well as its anti-inflammatory and antioxidant properties, support its utility as a complementary or alternative therapeutic agent in the treatment of neuropathic pain. Summary of the invention

[0007] The present invention relates to a synergistic pharmaceutical composition of palmitoylethanolamide (PEA), agmatine sulfate, carnosic acid, and β-caryophyllene for the treatment or relief of neuropathic pain. Each component of the composition possesses distinct yet complementary pharmacological properties that target the multifactorial pathophysiology of neuropathic pain, including neuroinflammation, oxidative stress, mitochondrial dysfunction, glial cell activation, and maladaptive neuroplasticity. The targeted combination of these four bioactive agents enables a multimodal therapeutic approach by simultaneously targeting multiple, interconnected pathogenic mechanisms underlying neuropathic pain.Their complementary mechanisms of action, which include receptor modulation, anti-inflammatory, antioxidant, and neuroprotective effects, result in a synergistic benefit that exceeds the sum of their individual effects. This combination is intended to enhance therapeutic efficacy, reduce dependence on conventional analgesics (e.g., opioids), and minimize side effects, thus providing a safe and effective treatment alternative for various forms of neuropathic pain.

[0008] The primary objective of the present invention is to provide a safe, effective, and synergistic pharmaceutical composition for the treatment and relief of neuropathic pain of various etiologies, including, but not limited to, diabetic peripheral neuropathy (DPN), chemotherapy-induced peripheral neuropathy (CIPN), radiation-induced neuropathy (RIN), renal or uremic neuropathy, fibrotic neuropathy, postherpetic neuralgia, trigeminal neuralgia, sciatica, fibromyalgia, hand-foot syndrome (HFS), and neuropathic pain following surgical or post-traumatic nerve injury. This composition consists of a rational combination of palmitoylethanolamide (PEA), agmatine sulfate, carnosic acid, and β-caryophyllene—each compound possesses distinct yet complementary pharmacological activities, including anti-inflammatory, antioxidant, neuroprotective, and neuromodulatory effects.The invention aims to address the multifactorial pathophysiology of neuropathic pain by targeting key mechanisms such as neuroinflammation, oxidative stress, glial cell activation, mitochondrial dysfunction, and central sensitization. The synergistic interaction of these active ingredients is intended to enhance overall therapeutic efficacy, reduce dependence on conventional analgesics such as opioids, and minimize side effects. Thus, it offers a comprehensive and safer alternative for the long-term treatment of neuropathic pain in a broad spectrum of underlying diseases.

[0009] The composition can be formulated in a wide range of dosage forms for oral administration, such as tablets, caplets, hard or soft gelatin capsules (including delayed, extended, or sustained-release, as well as gastro-resistant versions), sublingual granules, chewable tablets, lozenges, effervescent tablets, rapidly dissolving films, elixirs, syrups, solutions, and gels. Furthermore, it can be prepared as aqueous or oily solutions, suspensions, emulsions, spheres, nanoparticles, microparticles, encapsulated matrices, coated granules, particles, agglomerates, spansules, or as a dry powder for reconstitution with a suitable liquid medium prior to administration. Alternatively, the composition can also be formulated for parenteral administration via intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intravascular, or infusion systems.The flexibility in formulation and route of administration enables optimized bioavailability, improved treatment outcomes, and improved patient adherence, making the invention suitable for a wide range of clinical applications in the treatment of neuropathic pain.

[0010] To further clarify the advantages and features of the present disclosure, the invention will be explained in more detail with reference to specific embodiments illustrated in the accompanying drawings. These drawings illustrate only typical embodiments of the invention and are therefore not to be considered as limiting its scope. The invention will be described and explained in more detail with reference to the accompanying drawings. SHORT DESCRIPTION OF THE FIGURE

[0011] These and other features, aspects, and advantages of the present disclosure will become better understood when the following detailed description is read with reference to the accompanying drawings, in which like characters represent like parts throughout. Fig. 1 shows a table illustrating various embodiments of the composition according to an embodiment of the present disclosure.

[0012] Those skilled in the art will also appreciate that the elements in the drawings are shown for convenience and are not necessarily to scale. For example, the flowcharts illustrate the method by key steps to enhance understanding of aspects of the present disclosure. Furthermore, with respect to device construction, one or more components of the device may be represented in the drawings by conventional symbols. The drawing may show only the specific details relevant to understanding embodiments of the present disclosure in order not to clutter the drawing with details that would be readily apparent to those skilled in the art from the present description. Detailed description of the invention

[0013] To facilitate understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the drawings and a clear description will be given. However, the scope of the invention is not limited thereby. Changes and further modifications to the illustrated system, as well as further applications of the principles of the invention, are possible, as would normally occur to one skilled in the art to which the invention pertains.

[0014] It will be understood by those skilled in the art that the foregoing general description and the following detailed description are exemplary and explanatory of the invention and are not intended to be limiting thereof.

[0015] References in this specification to "one aspect," "another aspect," or similar language mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Therefore, the language "in one embodiment," "in another embodiment," and similar language throughout this specification may or may not refer to the same embodiment.

[0016] The terms "comprises," "comprising," or other variations thereof are intended to cover non-exclusive inclusion, such that a process or method comprising a list of steps may include not only those steps, but also additional steps not expressly listed or inherent in that process or method. Likewise, the statement "comprises" for one or more devices, subsystems, elements, structures, or components does not exclude, without further limitation, the existence of other devices, subsystems, elements, structures, components, or additional devices, subsystems, elements, structures, or components.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. The systems, methods, and examples provided herein are for illustrative purposes only and should not be considered limiting.

[0018] Embodiments of the present disclosure will be described in detail below with reference to the accompanying drawings.

[0019] The present invention relates to a pharmaceutical or nutraceutical composition comprising a therapeutically effective combination of the following active ingredients: palmitoylethanolamide (PEA) in an amount of 400 mg to 600 mg; agmatine sulfate in an amount of 500 mg to 600 mg; β-caryophyllene in an amount of 50 mg to 200 mg; and carnosic acid in an amount of 50 mg to 200 mg; as well as pharmaceutically acceptable excipients qs.

[0020] In one embodiment, the active ingredients are present in a fixed ratio of 8:10:1:1 to 12:12:4:4 (PEA: agmatine sulfate: β-caryophyllene: carnosic acid) to achieve synergistic antioxidant and anti-inflammatory effects.

[0021] In one embodiment, the β-caryophyllene is derived from natural or synthetic sources, optionally including, but not limited to, cloves, copaiba oil, or hemp.

[0022] In one embodiment, the carnosic acid is obtained from Rosmarinus officinalis (rosemary) or another suitable botanical or synthetic source.

[0023] In one embodiment, the active ingredients are derived from natural, semi-synthetic or synthetic sources and are formulated with pharmaceutically acceptable excipients.

[0024] In one embodiment, the combination exhibits synergistic therapeutic effects by enhancing antioxidant and anti-inflammatory responses, with the increased content of β-caryophyllene and carnosic acid improving efficacy without proportionally increasing the risk of side effects.

[0025] In one embodiment, the fixed ratios of the active ingredients support personalized or condition-specific titration, maintain bioavailability balance, and ensure therapeutic consistency.

[0026] In one embodiment, the active compounds may exist in any stereochemical form, including but not limited to optical isomers (D / L or R / S), racemic mixtures, diastereomers, or enantiomerically enriched forms, and include salts, hydrates, solvates, polymorphs, co-crystals, nanoformulations, micronized, or ultramicronized forms thereof.

[0027] In one embodiment, the formulation comprises the following exemplary embodiments, wherein the amounts of PEA, agmatine sulfate, β-caryophyllene, and carnosic acid follow fixed ratios selected from the group consisting of: 8:10:1:1, 10:10:1:1, 12:10:1:1, 12:12:1:1, 8:10:2:1, 10:10:2:1, 12:10:2:1, 12:12:2:1, 8:10:2:2, 10:10:2:2, 12:10:2:2, 12:12:2:2, 8:10:3:2, 10:10:3:2, 12:10:3:2, 12:12:3:2, 8:10:3:3, 10:10:3:3, 12:10:3:3, 12:12:3:3, 8:10:4:3, 10:10:4:3, 12:10:4:3, 12:12:4:3, 8:10:4:4, 10:10:4:4, 12:10:4:4 and 12:12:4:4.

[0028] In one embodiment, the composition is not limited to fixed ratios, allowing modifications depending on the disease state or to optimize bioavailability.

[0029] The present invention also provides a dosage formulation suitable for children comprising combinations of the following active ingredients in lower concentration: palmitoylethanolamide (PEA) at 200-300 mg, agmatine sulfate at 250-300 mg, β-caryophyllene at 25-100 mg and carnosic acid at 25-100 mg.

[0030] In one embodiment, the formulation is not limited to fixed ratios, allowing flexibility for dose adjustments depending on disease severity, patient-specific needs, or optimization of bioavailability.

[0031] The present invention relates to a pharmaceutical or nutraceutical composition for the treatment or relief of neuropathic pain, comprising a therapeutically effective combination of palmitoylethanolamide (PEA), agmatine sulfate, carnosic acid and β-caryophyllene, formulated in a pharmaceutically acceptable dosage form.

[0032] According to various embodiments of the present invention, additional ingredients of natural or synthetic origin that enhance therapeutic efficacy, improve the pharmacokinetic or pharmacodynamic profile, increase bioavailability, or exhibit synergistic effects when administered together with the solid composition of PEA, agmatine sulfate, β-caryophyllene, and carnosic acid fall within the scope of the present invention. These additional components may include, among others, absorption enhancers, enzyme inhibitors, antioxidants, or other bioactive compounds that contribute to or enhance the overall therapeutic outcome.

[0033] Active ingredients and their synergistic effect: 1. Palmitoylethanolamide (PEA): An endogenous fatty acid amide with anti-inflammatory, analgesic, and neuroprotective properties. It modulates mast cell degranulation and glial cell activation, the main causes of neuropathic pain. PEA acts primarily through PPAR-α activation and indirectly modulates the endocannabinoid system via the "entourage effect." 2. Agmatine sulfate: A biogenic amine that acts as a neuroprotective agent, NMDA receptor antagonist, α2-adrenergic receptor agonist, and indirect nitric oxide synthase (NOS) modulator. It inhibits NMDA receptors, which are critical for central sensitization and chronic pain, and enhances analgesic effects by modulating monoaminergic systems and reducing nitric oxide production. 3. Carnosic acid: A naturally occurring phenolic diterpene with potent antioxidant and anti-inflammatory properties. It activates the Nrf2 signaling pathway, upregulates detoxifying enzymes, and mitigates reactive oxygen species (ROS)-mediated neuronal damage. It also inhibits NF-κB signaling, thus reducing the production of pro-inflammatory cytokines. 4. β-Caryophyllene (BCP): A bicyclic sesquiterpene that acts as a selective agonist of the cannabinoid receptor type 2 (CB2). By activating the CB2 receptor, it attenuates the release of pro-inflammatory cytokines and suppresses microglial activation. It also exhibits antioxidant activity by modulating the Nrf2 / ARE signaling pathway.

[0034] The synergistic combination of these four active ingredients enables a multimodal therapeutic approach that simultaneously targets multiple interconnected pathogenic mechanisms underlying neuropathic pain, including neuroinflammation, oxidative stress, mitochondrial dysfunction, glial cell activation, and maladaptive neuroplasticity. This results in improved therapeutic efficacy and reduced side effects compared to individual components. Dosage ranges and ratios:

[0035] The composition contains the active ingredients in the following areas: • Palmitoylethanolamide (PEA): 400 to 600 mg • Agmatine sulfate: 500 to 600 mg • β -Caryophyllene: 50 to 200 mg • Carnosic acid: 50 to 200 mg • Pharmaceutically acceptable excipients qs.

[0036] The active ingredients are present in a fixed ratio of 8:10:1:1 to 12:12:4:4 (PEA: agmatine sulfate: BCP: carnosic acid) to achieve synergistic antioxidant and anti-inflammatory effects.

[0037] Fig. 1 shows a table illustrating various embodiments of the composition according to an embodiment of the present disclosure. Example formulations (amounts in mg):

[0038] in Fig. 1 illustrate various embodiments of the composition and show the specified ratios of PEA: agmatine sulfate: β-caryophyllene: carnosic acid. These examples are not exhaustive, but serve to illustrate the range and ratios of the active ingredients. Pediatric formulations:

[0039] The invention also provides dosage formulations suitable for children comprising lower strength combinations of the active ingredients: • Palmitoylethanolamide (PEA): 200-300 mg • Agmatine sulfate: 250-300 mg • β -Caryophyllene: 25-100 mg • Carnosic acid: 25-100 mg

[0040] These pediatric formulations are not limited to fixed ratios and allow flexible dose adjustment depending on the severity of the disease, patient-specific needs, or optimization of bioavailability. Sources and forms of active ingredients:

[0041] The active ingredients can come from natural, semi-synthetic or synthetic sources. • β-Caryophyllene can be obtained from natural or synthetic sources, optionally including but not limited to clove, copaiba oil or hemp. • Carnosic acid can be obtained from Rosmarinus officinalis (rosemary) or any other suitable botanical or synthetic source.

[0042] The active compounds may exist in any stereochemical form, including but not limited to optical isomers (D / L or R / S), racemic mixtures, diastereomers, or enantiomerically enriched forms, and include salts, hydrates, solvates, polymorphs, co-crystals, nanoformulations, micronized, or ultramicronized forms thereof. Pharmaceutically acceptable excipients and dosage forms:

[0043] The composition is formulated with pharmaceutically acceptable excipients. The composition can be formulated in a wide range of dosage forms for oral administration, such as tablets, caplets, hard or soft gelatin capsules (including delayed-release, extended-release, or sustained-release, as well as gastro-resistant versions), sublingual granules, chewable tablets, lozenges, effervescent tablets, rapidly dissolving films, elixirs, syrups, solutions, and gels. In addition, it can be manufactured as an aqueous or oily solution, suspension, emulsion, spheres, nanoparticles, microparticles, encapsulated matrices, coated granules, particles, agglomerates, spansules, or as a dry powder for reconstitution with a suitable liquid medium prior to administration.In an alternative embodiment, the composition may also be formulated for parenteral administration via routes such as intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intravascular or infusion-based systems.

[0044] The drawings and the foregoing description illustrate examples of embodiments. Those skilled in the art will recognize that one or more of the described elements may well be combined to form a single functional element. Alternatively, certain elements may be separated into multiple functional elements. Elements of one embodiment may be added to another embodiment. For example, the order of the processes described herein may be changed and is not limited to the manner described herein. Furthermore, the actions of a flowchart need not be performed in the order shown; nor do all actions need to be performed. Also, actions that are not dependent on other actions may be performed in parallel with the other actions. The scope of the embodiments is in no way limited by these specific examples.Numerous variations, whether explicitly stated in the specification or not, such as differences in structure, dimensions, and use of materials, are possible. The scope of the embodiments is at least as broad as indicated in the following claims.

[0045] Advantages, further benefits, and solutions to problems have been described above with reference to specific embodiments. However, the advantages, advantages, solutions to problems, and any components that may result in or enhance an advantage, advantage, or solution are not to be construed as critical, required, or essential features or components of any or all of the claims.

Claims

[1] A pharmaceutical or nutraceutical composition comprising a therapeutically effective combination of the following active ingredients: Palmitoylethanolamide (PEA) in an amount ranging from 400 mg to 600 mg; Agmatine sulfate in an amount of 500 mg to 600 mg; β -caryophyllene in an amount of 50 mg to 200 mg; and Carnosic acid in an amount of 50 mg to 200 mg and pharmaceutically acceptable excipients qs. [2] Composition according to claim 1, wherein the active ingredients are present in a fixed ratio of 8:10:1:1 to 12:12:4:4 (PEA: agmatine sulfate: β-caryophyllene: carnosic acid). [3] A composition according to claim 1, wherein the β-caryophyllene is obtained from natural or synthetic sources, optionally including cloves, copaiba oil or hemp. [4] A composition according to claim 1, wherein the carnosic acid is obtained from Rosmarinus officinalis (rosemary) or a botanical or synthetic source. [5] Composition according to claim 1, wherein the active ingredients are derived from natural, semi-synthetic or synthetic sources and are formulated with pharmaceutically acceptable excipients. [6] Composition according to claim 1, wherein the active ingredients are present in any stereochemical form, including optical isomers (D / L or R / S), racemic mixtures, diastereomers or enantiomerically enriched forms, and comprises salts, hydrates, solvates, polymorphs, cocrystals, nanoformulations, micronized or ultramicronized forms thereof. [7] The composition of claim 1, wherein the formulation comprises the following exemplary embodiments, wherein the amounts of PEA, agmatine sulfate, β-caryophyllene and carnosic acid follow fixed ratios selected from the group consisting of: 8:10:1:1, 10:10:1:1, 12:10:1:1, 12:12:1:1, 8:10:2:1, 10:10:2:1, 12:10:2:1, 12:12:2:1, 8:10:2:2, 10:10:2:2, 12:10:2:2, 12:12:2:2, 8:10:3:2, 10:10:3:2, 12:10:3:2, 12:12:3:2, 8:10:3:3, 10:10:3:3, 12:10:3:3, 12:12:3:3, 8:10:4:3, 10:10:4:3, 12:10:4:3, 12:12:4:3, 8:10:4:4, 10:10:4:4, 12:10:4:4 and 12:12:4:4.