DESC:Field of Invention
The invention relates to compositions comprising palmitoylethanolamide, and more particularly to nutraceutical composition comprising palmitoylethanolamide and one or more ingredients in combinations to be used as an adjunct dietary supplement to ongoing pharmaceutical therapies for the 5 treatment of neuropathic pain.
Background
Neuropathic pain is a chronic condition that affects from 7% to 10% of the world population. It is a state characterized by a broad spectrum of symptoms, including paresthesia and dysesthesia manifested as numbness, tingling, and 10 altered touch perception, as well as mechanical or thermal allodynia and hyperalgesia, which are able to negatively affect the quality of life. Current therapies for treatment of Neuropathic pain are mostly Anticonvulsants gabapentin and pregabalin, tricyclic antidepressents and serotonin-noradrenaline reuptake inhibitors are used as first-line treatments. However, the 15 existing pharmacological therapies are not able to fully counteract neuropathic pain and are also associated with multiple side effects.
Beside the existing pharmacological therapies, different approaches for the treatment of neuropathic pain have been proposed, which includes nerve stimulation techniques, acupuncture, surgical nerve decompression, behavioral, 20 cognitive and animal therapies, exercise and dietary or nutraceutical
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supplements. Among the existing therapies in addition to pharmacological therapies, nutraceutical and dietary supplements have become highly relevant due to their synergistic activity with other ongoing pharmacological and non-pharmacological therapies in counteracting neuropathic pain. For example, Omega-3 fatty acids concomitantly administered with paclitaxel showed a 5 protective activity in chemotherapy-induced neuropathic pain (CIPN) patients. Additionally, B vitamins administration in patients with pain syndromes of the lumbar spine treated with diclofenac was found to lead to reduction in pharmacological therapy dosage due to strong pain relief.
Even if the mechanism of action of nutraceutical supplements have not been 10 clearly understood, nutraceutical and dietary supplements have emerged as potential treatments for neuropathic pain or as an adjunct to the pharmacological therapies for neuropathic pain.
Thus there is still need in the art of combination of ingredients that synergistically aids in the treatment of neuropathic pain. The present invention 15 provides a nutraceutical composition as a supplementary or adjunct to pharmacological therapies for neuropathic pain, wherein the composition comprises a synergistic combination of Palmitoylethanolamide, Ubiquinone and one or more additional ingredients selected from Alpha-lipoic acid, Trptophan, Curcumin, Acetyl-l carnatine, N-Acetyl cysteine, Omega-3 fatty acids, vitamin B1, 20 Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, Zinc, Magnesium,
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Boswellia serrata, Hypericum perforatum, Curcumin, Capsicin, Menthol, Bromelain or a combination thereof. Objective An objective of the present invention is to provide a composition for supplementing agents that aids in the recovery from neuropathic pain. 5 An objective of the present invention is to provide a nutraceutical composition as a supplementary or adjunct to pharmacological therapies for neuropathic pain. An objective of the present invention is to provide a nutraceutical composition that supplements agents that helps in recovery from neuropathic pain, wherein the agents are not obtained through normal diet. 10 Summary The present invention relates to a nutraceutical composition comprising nutraceutical ingredient that endogenously aids in the recovery of neuropathic pain, wherein the agents are a synergistic combination of Ubiquinone and Palmitoylethanolamide and one or more additional ingredients selected from 15 Alpha-lipoic acid, Tryptophan, Curcumin, Acetyl-l carnitine, N-Acetyl cysteine, Omega-3 fatty acids, vitamin B1, Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, Zinc, Magnesium, Boswellia serrata, Hypericum perforatum, curcumin, capsicin, Menthol, Bromelain or a combination thereof.
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Detailed Description In an embodiment the present invention provides a nutraceutical composition that supplements ingredients that aids in the recovery of neuropathic pain, wherein the ingredients are selected from agents are a synergistic combination of Palmitoylethanolamide and Ubiquinone and one or more additional 5 ingredients selected from Alpha-lipoic acid, Tryptophan, Curcumin, Acetyl-l carnitine, N-Acetyl cysteine, Omega-3 fatty acids, vitamin B1, Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, Zinc, Magnesium, Boswellia serrata, Hypericum perforatum, Curcumin, Capsicin, Menthol, Bromelain or a combination thereof. 10 Ubiquinone is an endogenously synthesized compound that acts as an electron carrier in the mitochondrial respiratory chain. In addition to its unique role in mitochondria, it also functions as a potent antioxidant, scavenging free radicals and inhibiting lipid peroxidation. Ubiquinone aids in reduction of neuropathic pain by lowering the oxidative stress. Ubiquinone is an endogenous synthesized 15 lipid and a vitamin-like substance present in almost all living cells, primarily in the mitochondria. It is also capable of regenerating and recycling other antioxidants like the vitamin E and ascorbate. A few studies have disclosed the potential use of Ubiquinone with existing pharmacological therapies for treatment of neuropathic pain. Amini et al., in 20 their study on 112 patients with Peripheral Diabetic neuropathy found that
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patients who receive ubiquinone in addition to pregabalin reported greater relief then patient who received only ubiquinone. [Amini P. et al., European Journal of Clinical Pharmacology. 2022 Dec; 78(12)]. Khuankaew et al., in their study compared the effect of ubiquinone when given as an add-on therapy to carbamazepine in patients suffering from Trigeminal neuralgia. They found that 5 increased oxidative stress could be involved in the pathogenesis of Trigeminal neuralgia and Ubiquinone supplements can reduce oxidative stress. The study concluded that ubiquinone can be effective in pain reduction in Trigemnial neuralgia patient being treated with carbamazepine. [Chutikorn Khuankaew et al, (2018), Free Radical Research, 52:4, 415-425, DOI: 10 10.1080/10715762.2018.1438608]. Sawaddiruk P. et al., also reported that the use of ubiquinone further provides benefit in relieving pain sensation in pregabalin-treated fibromyalgia patients by reducing brain activity and mitochondrial dysfunction [Passakorn Sawaddiruk et al. (2019), Free Radical Research, 53:8, 901-909, DOI: 10.1080/10715762.2019.1645955]. 15 Palmitoylethanolamide (PEA) is an endocannabinoid-like bioactive lipid mediator, belonging to the N-acyl-ethanolamine (NAE) fatty acid amide like family. PEA is produced on demand in response to cellular injury and is usually up-regulated in disease states. A number of PEA containing products are already present in market as nutraceutical, food supplements or foods for medical 20 purposes in multiple countries. PEA has multi-faceted effects due to its unique mechanism of action that affects multiple pathways at different sites. The
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multifaceted effects generate therapeutic benefits in multiple disorders, including neuropathic pain, allergic reaction, influenza, common cold, chronic pain, joint pain, psychopathologies. A large proportion of existing research into PEA is devoted to its analgesic properties. The use of PEA has been found to be progressively effective in 5 reducing chronic neuropathic pain with the report concluding that it has potential as a therapeutic strategy to manage chronic neuropathic pain. Pickering et al., RCT study on 70 participants receiving 600mg of PEA, reported that PEA formulation reduced diabetic peripheral neuropathic pain and inflammation along with improving mood and sleep. [Pickering E.,(2022) Dec; 10 30(6):2063-2077 (doi: 10.1007/s10787-022-01033-8)]. Steels E. et al., studied the effect of PEA in symptoms of knee osteroarthritis in 111 participants. They authors concluded that the study demonstrated that PEA attenuates pain and reduces other associated symptoms of knee osteorathiritis [Steels E., (2019) Inflammopharmacology; 27(3):475-485. doi: 10.1007/s10787-15 019-00582-9]. The effect of PEA in micronized forms has also been studied in patients suffering from Diabetic neuropathy. A study conducted in 30 diabetic patients reported that PEA is a promising and well-tolerated new treatment for symptomatology experienced by diabetic patients suffering from peripheral neuropathy[Schifilliti C., Pain Res Treat. 2014;2014:849623. doi: 20 10.1155/2014/849623]. PEA has also been studied in reducing swelling and pain
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after the surgical extraction of impacted lower third molars. Bacci et al. reported that when PEA 300mg twice a day for 15 days was provided as an adjunct to NSAID, it was able to improve the post-operative pain after lower third molar extraction. PEA has also been studied on treating pain associated with Fibromyalgia syndrome (FM). The therapeutic efficacy of duloxetine(DLX) + 5 pregabalin(PGB) in patients suffering from FM and the possible added benefit of PEA was studied in 80 patients. The study confirmed that efficacy of DLX and pregabalin and demonstrated the added benefit and safety of PEA in the treatment of pain in patients affected with FM. The mechanism of action of PEA is multifaceted, it acts directly on PPAR-á and 10 GPR55 receptors and indirectly on CB1, CB2 and TRPV1 receptors. It has also been extensively reported the PEA suppress inflammation by inhibiting MC activation, down-regulates iNOS and inhibits microglia and astrocyte activation. In chronic inflammatory states this allows PEA to preserve peripheral nerve morphology and reduce endoneurial edema. 15 It has also been reported that endogenous PEA is generally insufficient to counter chronic allostatic load as seen in chronic inflammatory disorders, making exogenous administration a viable therapeutic strategy to top-up endogenous levels and restores bodily homeostasis. [Skaper SD. et al., (2014), Immunology. Mar;141(3):314-27. doi: 10.1111/imm.12170] [Skaper SD, et al (2012) Philos 20
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Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3312-25. doi: 10.1098/rstb.2011.0391] Thus in an embodiment the present invention provides a nutraceutical composition for supplementation of endogenous bioactive lipids and antioxidants for the reduction of neuropathic pain. In an embodiment the 5 endogenous bioactive lipid is PEA and antioxidant is Ubiquinone. In an embodiment the present invention provides a nutraceutical composition comprising PEA and Ubiquinone as an adjunct to pharmacological therapies for neuropathic pain, wherein the composition further comprises additional one or more ingredients which synergistically contributes to the efficacy of the 10 composition, wherein the additional ingredients are selected from antioxidants, agents that aids in the regeneration of nerves, amino acids, fatty acids, Trace elements, vitamins, plant extracts, phytochemicals or a combination thereof. In a preferable embodiment the present invention relates to a nutraceutical composition comprising ubiquinone in combination with palmitoylethanolamide 15 and one or more ingredient selected from Alpha-lipoic acid, Tryptophan, Curcumin, Acetyl-l carnitine, N-Acetyl cysteine, Omega-3 fatty acids, vitamin B1, Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, Zinc, Magnesium, Boswellia serrata, Hypericum perforatum, Curcumin, Capsicin, Menthol, Bromelain or a combination thereof. 20
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The role of vitamin B complex has already been reported. Neurotropic B vitamins thiamine (B1), pyridoxine (B6), and cobalamin (B12) maintains the neuronal viability by protecting nerves against damaging environment influences, by acting as site directed antioxidants, by balancing nerve metabolism, by maintaining myelin sheaths, by facilitating the usage of carbohydrates for energy 5 production, by promoting nerve cell survival and remyelination. Thus Vitamin B aids in the regeneration by supporting development of new cell structures. [Baltrusch S. The Role of Neurotropic B Vitamins in Nerve Regeneration. Biomed Res Int. 2021 Jul 13;2021:9968228. doi: 10.1155/2021/9968228]
In a preferred embodiment the present invention relates to a nutraceutical 10 composition for the supplementation of ingredient that aids in the recovery of neuropathic pain and wherein the composition is provided as an adjunct to the ongoing pharmacological therapies, and wherein the composition comprises of Ubiquinone, palmitoylethanolamide, and Alpha lipoic acid.
Alpha lipoic acid is a natural compound that acts as a co-enzyme in the Kerbs 15 cycle and as a cofactor for mitochondrial enzymes. The oxidized and reduced forms of ALA are known to function as potent antioxidants. Mulitple clinical studies have reported the advantageous effect of ALA on models of disease marked by an increase in oxidative stress such as neurodegenerative disease, diabetes and its complications. Ziegler et al., in their study conducted on 328 20 patients with symptomatic neuropathy reported that intravenous treatment of
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ALA (600mg/day) over 3 weeks was safe and effective in reducing symptoms of diabetic peripheral neuropathy[Ziegler D, et al., Diabetes. 1997 Sep;46 Suppl 2:S62-6. doi: 10.2337/diab.46.2.s62]. In the ISLAND study conducted by Sola et al., reported that administration of ALA 300mg/d with irbestan 150mg/d to patients with metabolic syndromes improved endothelial function and reduces 5 proinflammatory markets, factors that are implicated in pathogenesis of atherosclerosis.
In a preferred embodiment the present invention also relates to a nutraceutical composition comprising Ubiquinone, Palmitoylethanolamide and one or more ingredients selected from Alpha-lipoic acid, Vitamin B1, Vitamin B6, Vitamin B9 10 and Vitamin B12 or a combination thereof. In a most preferred embodiment the present invention relates to a pharmaceutical composition comprising Palmitoylethamolamide, Ubiquinone, Alpha-lipoic acid, Vitamin B1, Vitamin B6, Vitamin B9 and Vitamin B1.
In an another embodiment Palmitoylethamolamide (PEA) is present in an 15 amount ranging from 400 to 1000 mg. In an another embodiment Ubiquinone is present in an amount ranging from 100 to 500 mg. In one embodiment Alpha-lipoic acid (ALA) is present in an amount ranging from 50 to 500 mg. 20
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In an another embodiment vitamin B1 is present in an amount ranging from 0.5 to 5 mg. In an another embodiment vitamin B6 is present in an amount ranging from 0.5 to 5 mg. In an another embodiment vitamin B12 is present in an amount ranging from 0.5 5 to 5 mg. In an another embodiment vitamin B3 is present in an amount ranging from 5 to 20 mg.
In another embodiment the present invention provides a nutraceutical composition to be used as an adjunct dietary supplement to ongoing 10 pharmaceutical therapies for the treatment of neuropathic pain, wherein the composition comprises of Palmitoylethamolamide, Ubiquinone, Alpha-lipoic acid, Vitamin B1, Vitamin B6, Vitamin B9 and Vitamin B1.
In a preferred embodiment the present invention relates to a nutraceutical composition for the supplementation of ingredient that aids in the recovery of 15 neuropathic pain and wherein the composition is provided as an adjunct to the ongoing pharmacological therapies, and wherein the composition comprises of Ubiquinone, Palmitoylethanolamide, and further comprises Vitamin B1, Vitamin B6, Vitamin B9 and Vitamin B12. In an embodiment the nutraceutical composition of present invention comprises: 20
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i. Palmitoylethamolamide (PEA) is present in an amount ranging from 400 to 1000 mg and; ii. Ubiquinone is present in an amount ranging from 100 to 500 mg. iii. Alpha-lipoic acid (ALA) is present in an amount ranging from 50 to 500 mg. 5 iv. vitamin B1 is present in an amount ranging from 0.5 to 5 mg. v. vitamin B6 is present in an amount ranging from 0.5 to 5 mg. vi. vitamin B12 is present in an amount ranging from 0.5 to 5 mg. vii. vitamin B3 is present in an amount ranging from 5 to 20 mg. in an another embodiment the present invention provides oral nutraceutical 10 composition comprises: i. about 600 mg PEA and; ii. about 300 mg Ubiquinone and; iii. about 200 mg ALA iv. about 1.4 mg Vitamin B1 and; 15 v. about 1.9 mg Vitamin B6 and; vi. about 2.2 mg Vitamin B12 and;
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vii. about 11 mg vitamin B3 In another embodiment the nutraceutical composition of the present invention further comprises pharmaceutically acceptable excipients, wherein the excipients are diluents, disintegrants, binders, binder solutions, solvents, polymers, lubricants, anti-adherent agents, surfactants, solubilisers, 5 preservative, coating agents, flavors, coloring agents and the likes thereof. In another embodiment the nutraceutical composition of the present invention is in the form of tablets, capsules, minitablets, pellets, granules, solution, suspension, syrup, powder and the likes thereof. In another embodiment the nutraceutical composition of the present invention 10 may optionally comprise Tryptophan, Curcumin, Acetyl-l carnatine, N-Acetyl cysteine, Omega-3 fatty acids, Vitamin C, Vitamin D, Zinc, Magnesium, Boswellia serrata, Hypericum perforatum, Curcumin, Capsicin, Menthol, Bromelain or a combination thereof.
In an embodiment the present invention also provides a process of preparation 15 of the nutraceutical composition.
Examples- The following examples and descriptions further clarify embodiments within the scope of the present invention. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention ,CLAIMS:We claim:
1. A nutraceutical composition comprising synergistic combination of Ubiquinone and Palmitoylethanolamide and one or more additional ingredients selected from Alpha-lipoic acid, Tryptophan, Curcumin, Acetyl-l carnitine, N-Acetyl cysteine, Omega-3 fatty acids, vitamin B1, Vitamin B6, Vitamin B9, Vitamin B12, Vitamin C, Vitamin D, Zinc, Magnesium, Boswellia serrata, Hypericum perforatum, curcumin, capsicin, Menthol, Bromelain or a combination thereof.
2. A nutraceutical composition as claimed in claim 1 comprises synergistic combination of Palmitoylethamolamide, Ubiquinone, Alpha-lipoic acid, Vitamin B1, Vitamin B6, Vitamin B9 and Vitamin B1.
3. A nutraceutical composition as claimed in claim 1 comprises:
i. Palmitoylethamolamide (PEA) is present in an amount ranging from 400 to 1000 mg and;
ii. Ubiquinone is present in an amount ranging from 100 to 500 mg.
iii. Alpha-lipoic acid (ALA) is present in an amount ranging from 50 to 500 mg.
iv. vitamin B1 is present in an amount ranging from 0.5 to 5 mg
v. vitamin B6 is present in an amount ranging from 0.5 to 5 mg
vi. vitamin B12 is present in an amount ranging from 0.5 to 5 mg
vii. vitamin B3 is present in an amount ranging from 5 to 20 mg
4. An oral nutraceutical composition as claimed in claim 3 comprises:
i. about 600 mg PEA and;
ii. about 300 mg Ubiquinone and;
iii. about 200 mg ALA and;
iv. about 1.4 mg Vitamin B1 and;
v. about 1.4 mg Vitamin B1 and;
vi. about 2.2 mg Vitamin B12 and;
vii. about 11 mg vitamin B3
5. An oral nutraceutical composition as claimed in claim 4 is in the form of tablets, capsules, minitablets, pellets, granules, solution, suspension, syrup, powder.
6. An oral nutraceutical composition as claimed in claim 1-5 further comprises pharmaceutically acceptable excipients, wherein the excipients are diluents, disintegrants, binders, binder solutions, solvents, polymers, lubricants, anti-adherent agents, surfactants, solubilisers, preservative, coating agents, flavors, coloring agents and the likes thereof.