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WO2025186837A1 - A synergistic bioactive composition for controlling neuromuscular pain and repairing nerve damage - Google Patents

A synergistic bioactive composition for controlling neuromuscular pain and repairing nerve damage

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Publication number
WO2025186837A1
WO2025186837A1 PCT/IN2025/050331 IN2025050331W WO2025186837A1 WO 2025186837 A1 WO2025186837 A1 WO 2025186837A1 IN 2025050331 W IN2025050331 W IN 2025050331W WO 2025186837 A1 WO2025186837 A1 WO 2025186837A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
uridine
palmitoylethanolamide
acetyl
present
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IN2025/050331
Other languages
French (fr)
Other versions
WO2025186837A8 (en
Inventor
Ishan Hareshkumar Patel
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Validus Lifesciences Pvt Ltd
Original Assignee
Validus Lifesciences Pvt Ltd
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Publication of WO2025186837A1 publication Critical patent/WO2025186837A1/en
Publication of WO2025186837A8 publication Critical patent/WO2025186837A8/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine

Definitions

  • This invention relates to a synergistic composition
  • a synergistic composition comprising combination of palmitoylethanolamide, Acetyl carnitine, and uridine, or their pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof for controlling neuromuscular pain and repairing nerve damage.
  • the present invention provides a synergistic composition for the management of nerve health.
  • the invention specifically provides a composition that exhibits a synergistic effect and demonstrates therapeutic effectiveness comparable to standard chemical drug.
  • Neuromuscular pain is a complex, chronic condition characterized by pain originating from nerves and associated muscles. This is different from pain solely affecting muscles or nerves. The abnormality or damage in either system can contribute to the pain through intricate interactions.
  • neuromuscular pain arises from a multimodal pathophysiology, meaning multiple pathways and processes contribute to the pain experience. These can be broadly categorized into:
  • Peripheral Sensitization Damage to nerves leads to increased sensitivity of pain receptors (nociceptors) in nerves and associated muscles. This makes them more responsive to stimuli that wouldn't normally cause pain.
  • Gabapentinoids are often recommended as first-line treatments for the management of neuropathic pain. However, more than half of patients fail to achieve worthwhile pain relief. Dizziness, somnolence, gait disturbances, impaired concentration, confusion, memory loss, altered mood, movement disorders, sleep disorders, speech impairment, vertigo, and other side effects are common with gabapentinoids, often leading to discontinuation of therapy.
  • the use of gabapentinoids has been reported to cause respiratory depression, weight gain, potential for abuse, and withdrawal symptoms.
  • the most conventional pain medications like opioids and some nonsteroidal antiinflammatory drugs (NSAIDs), target specific pain pathways. This "one-size-fits-all" approach fails to address the multiple mechanisms involved in neuromuscular pain, leading to incomplete or ineffective pain relief.
  • NSAIDs nonsteroidal antiinflammatory drugs
  • Some therapies like certain nerve blockers, primarily target pain originating from damaged nerves. While they may provide some relief, they do not address muscle pain, another key component of neuromuscular pain.
  • Alessio Ardizzone et. al. (2021) provides a study on the combined oral administration of ultra-micronized palmitoylethanolamide (um-PEA) and acetyl-1- carnitine (ALC) in a rat model of carrageenan (CAR)-induced paw edema demonstrated superior anti-inflammatory and anti-nociceptive effects compared to the separate and consecutive administration of ALC and um-PEA.
  • This prior-art also fails to provide any information on benefit and effectiveness of above combination with uridine.
  • F. Salaffi et. al. (2023) focuses on fibromyalgia (FM), a condition characterized by persistent pain resistant to standard treatments, the combination of pregabalin (PGB) and duloxetine (DLX) supplemented with palmitoylethanolamide (PEA) and acetyl-L-camitine (ALC) was evaluated over a 24-week period.
  • PEA and ALC are used in combination with standard therapy. Further this reference does not disclose PEA+ALC in combination with uridine. Paul Richard Saunders (2023) also discloses similar study however, they also do not disclose PEA+ALC in combination with uridine.
  • RU2701720 discusses the treatment of chronic pain.
  • the disclosed combination comprises effective amounts of palmitoylethanolamide, along with at least one substance chosen from uridine monophosphate, taurine, and vitamin E, or their pharmaceutically acceptable salts.
  • this patent prior-art does not provide any information on effectiveness of acetyl- L-camitine (ALC) in combination with palmitoylethanolamide (PEA) and uridine.
  • the prior-art fails to provide triple combination of Palmitoyl ethanolamide (PEA), Acetyl carnitine and uridine. Specifically triple combination of Palmitoylethanolamide (PEA), acetyl-L-camitine ( ALC) and uridine for the treatment of neuromuscular pain wherein therapeutic effectiveness is comparable with the standard therapy.
  • PDA Palmitoyl ethanolamide
  • ALC acetyl-L-camitine
  • uridine for the treatment of neuromuscular pain wherein therapeutic effectiveness is comparable with the standard therapy.
  • the principal object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof.
  • Another object of the present invention is to provide a synergistic composition
  • a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective for nerve health.
  • Another object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in the management of neuromuscular pain.
  • Another object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective to control of neuromuscular inflammation.
  • Another object of the present invention is to provide a synergistic composition
  • a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition repairs damaged nerves.
  • Another object of the present invention is to provide a synergistic composition
  • a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition improves nerve functions.
  • One more objective of the present invention is to provide a synergistic composition consisting essentially of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in managing nerve health.
  • One more objective of the present invention is to provide a synergistic composition consisting essentially of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in managing neuromuscular pain.
  • One more objective of the present invention is to provide a synergistic composition consisting essentially of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in facilitating nerve damage repair.
  • composition in the fixed dosage form comprising a dosage range for each component i.e., palmitoylethanolamide, Acetyl carnitine and uridine which provide synergistic therapeutic efficacy.
  • Yet another objective of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof which can be formulated as tablets, capsules, powder, pills, hard capsules filled with liquid or solids, soft capsules, granules, pellets, caplets, mini-tablets, syrup, suspension, sachets, modified-release formulations, gummies or any other suitable dosage forms.
  • This invention provides a synergistic composition comprising a triple combination of palmitoylethanolamide, Acetyl carnitine, and uridine, or their pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof.
  • the present invention provides a synergistic composition for the management of nerve health.
  • the invention specifically provides a composition that exhibits a synergistic effect and demonstrates therapeutic effectiveness comparable to standard chemical drug.
  • Figure-2 Depicts modulatory effects of test substances on hot water tail immersion 55°C latency reaction time
  • Figure-3 Depicts modulatory effects of test substances on Hot plate latency at 50-55°C
  • Figure-4 Depicts modulatory effects of test substances on Randall Selitto test
  • Figure-5 Depicts modulatory effects of test substances on Motor Nerve Conduction Velocity
  • Figure-6 Depicts modulatory effects of test substances on serum PGC-1 Alpha levels
  • Figure-7 Depicts modulatory effects of test substances on serum lactate levels
  • the principal aspect of the present invention is to develop a synergistic bioactive composition aimed at effectively controlling neuromuscular pain and repairing nerve damage.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof.
  • Palmitoylethanolamide is a naturally occurring fatty acid amide with anti- inflammatory, analgesic, and neuroprotective properties. Industrially, it is produced through extraction, chemical synthesis, or enzymatic biocatalysis. According to the present invention, PEA prepared by any of the industrial methods can be used.
  • Acetyl carnitine is a bioactive amino acid derivative known for its neuroprotective, antioxidant, and energy-enhancing properties.
  • ALC is produced through extraction, chemical synthesis, or enzymatic biocatalysis. According to the present invention, ALC prepared by any of the industrial methods can be used.
  • Uridine is a pyrimidine nucleoside essential for RNA synthesis, cognitive function, and mitochondrial health. Industrially, it is produced through extraction, chemical synthesis, or microbial fermentation. According to the present invention, Uridine prepared by any of the industrial methods can be used. According to the present invention, all the active ingredients are commercially available.
  • Palmitoylethanolamide includes its pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form.
  • Acetyl carnitine includes its pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form, wherein Acetyl carnitine may be an acetyl-l-camitine, acetyl-d-camitine, or a mixture thereof.
  • Uridine includes its pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form.
  • a synergistic bioactive composition comprises at least three ingredients, wherein the three ingredients are Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof. Additionally, the composition may further comprise vitamins, coenzymes, antioxidants, or a combination thereof. Furthermore, the invention also encompasses a kit comprising the said composition, wherein the composition comprises at least three ingredients Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof. Additionally, each of the three ingredients may be present in a separate composition within the kit.
  • synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof along with pharmaceutically acceptable excipients.
  • One embodiment of the present invention is to provide the optimal combination ratio of Palmitoyl ethanolamide, Acetyl carnitine, Uridine. Additionally, the invention provides the appropriate dosage range for each component to achieve optimal therapeutic efficacy.
  • a synergistic bioactive composition comprising combination of Palmitoylethanolamide, Acetyl carnitine, Uridine, the composition demonstrates therapeutic effectiveness comparable to standard chemical drug.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, wherein palmitoylethanolamide, Acetyl carnitine, and uridine are present in a ratio of 1:0.0125:0.00005 to 1: 160:20, 1:0.0278:0.0002 to 1:30.0000:4.0000, 1:0.0294:0.0002 to 1:27.0000:3.5000, 1:0.0313:0.0002 to 1:25.0000:3.0000, 1:0.0303:0.0002 to 1:23:2.7000, 1:0.0286:0.0002 to 1:33.3333:5.3333, or 1:0.0250:0.0003 to 1:42.6667:4.6667.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, wherein palmitoylethanolamide and uridine are present in a ratio ranging from 1:0.00005 to 1: 20.
  • the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, wherein palmitoylethanolamide and Acetyl carnitine are present in a ratio ranging from 1: 0.0125 to 1: 160.
  • the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, wherein uridine and Acetyl carnitine are present in ratio ranging from 1:0.0500 to 1:40000.
  • the amount of palmitoylethanolamide ranges from 25 mg to 2000 mg, 100 mg to 1800 mg, 150 mg to 1700 mg, 150 mg to 1600 mg, 150 mg to 1500 mg, 250 mg to 1700 mg, 250 mg to 1500 and 300 mg to 1500 mg.
  • the amount of Acetyl carnitine ranges from 25 mg to 4000 mg, 100 mg to 3000 mg, 100 mg to 2500 mg, 100 mg to 2700 mg, 200 mg to 2500 mg, 200 to 2000 mg.
  • the amount of uridine ranges from 0. 1 mg to 500 mg, 5 mg to 400 mg, 10 mg to 300 mg, 15 mg to 200 mg, 20 mg to 150 mg, 25 mg to 100 mg or 25 mg to 50 mg per unit dose.
  • the effective amount of active ingredients is the amount required for the therapeutic effect which can be administered at a time or in divided doses per day.
  • the amount of palmitoylethanolamide is in the range of 0.38 to 98.28 % w/w, 5 to 90 % w/w, 10 to 80 % w/w, 20 to 75 % w/w, 25 to 70 % w/w, 30 to 65 % w/w, or 30 to 70 % w/w of the total composition.
  • the amount of Acetyl carnitine is present in the range of 0.55 to 99.13 % w/w, 5 to 90 % w/w, 5 to 80 % w/w, 10 to 70 % w/w, 20 to 60 % w/w, 25 to 65 % w/w, or 22 to 62 % w/w of the total composition.
  • the amount of uridine is present in the range of 0.0012 to 89.29% w/w, 0.002 to 70% w/w, 0.05 to 60% w/w, 0. 1 to 50% w/w, 0.5 to 40% w/w, 0.5 to 30% w/w, or 0.5 to 25% w/w of the total composition.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used for the management of neuromuscular pain.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used for the management of neuromuscular inflammation.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used for repairing nerve damage.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used for nerve health.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used to improve nerve functions.
  • the present invention provides a synergistic composition consisting essentially of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in managing nerve health.
  • the parameter to measure the therapeutic effectiveness can be Behavioural parameters e.g. cold water tail immersion, hot water tail immersion, hot plate, Randall Selitto; electrophysiology of nerve e.g. Motor nerve conduction velocity and biochemical estimation in serum e.g., Peroxisome Proliferator activated receptor gamma coactivator (PGC)-l Alpha and serum lactic acid level.
  • PPC Peroxisome Proliferator activated receptor gamma coactivator
  • the parameters to evaluate the synergistic therapeutic effectiveness of the present invention can be biochemical estimation in serum e.g. Interleukin-6, and Serum silent information regulator 1" (SIRT1).
  • serum e.g. Interleukin-6, and Serum silent information regulator 1" (SIRT1).
  • the present invention provides a synergistic composition
  • a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition reduces cold allodynia by at least 18 % at 4°C more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
  • the present invention provides a synergistic composition
  • a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition reduces hot allodynia by at least 26% at 55°C more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
  • the present invention provides a synergistic composition
  • a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition enhances hot plate latency at 50-55°C by at least 27% more than the combined individual effects of Palmitoyl ethanolamide, acetyl-l-camitine and Uridine.
  • the present invention provides a synergistic composition
  • a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition reduces mechanical allodynia by at least 42% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
  • the present invention provides a synergistic composition
  • a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition enhances motor nerve conduction velocity by at least 18% more than the combined individual effects of Palmitoyl ethanolamide, acetyl-l-camitine and Uridine.
  • Semm PGC-1 a Mitochondrial degeneration is recognized as a key contributor to peripheral neuropathic pain.
  • Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-la is a crucial regulator of mitochondrial biogenesis, promoting the formation of new mitochondria necessary for neuronal energy production.
  • Lower serum PGC-la levels are associated with the onset and progression of neuropathic pain.
  • increased PGC- la expression supports neuronal protection against inflammation and oxidative stress, thereby aiding in neuropathic pain management.
  • Enhanced PGC-la activity signifies improved therapeutic outcomes.
  • the present invention provides a synergistic composition
  • a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition improves peroxisome proliferator-activated receptorgamma coactivator 1 alpha (PGC-la) by at least 33% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
  • POC-la peroxisome proliferator-activated receptorgamma coactivator 1 alpha
  • Serum lactic acid Eactic acid is traditionally linked to muscle fatigue and exhaustion. Lactic acidosis, characterized by elevated lactic acid levels, impairs muscle contractility, leading to fatigue and reduced physical performance. A reduction in lactic acid levels is indicative of improved muscle endurance and decreased fatigue, thereby contributing to overall pain relief and enhanced physical function.
  • the aforementioned parameters collectively assess the therapeutic efficacy of the composition of the present invention in managing neuropathic pain, improving nerve function, and reducing inflammation.
  • the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein the composition comprises (a) palmitoylethanolamide in an amount ranging from 25 mg to 2000 mg, (b) Acetyl carnitine in an amount ranging from 25 mg to 4000 mg, (c) uridine in an amount ranging from 0.1 mg to 500 mg; wherein palmitoylethanolamide, Acetyl carnitine, and uridine are present in a ratio ranging from 1:0.0125:0.00005 to 1: 160:20; wherein the composition is for oral administration; and wherein oral administration of the composition improves motor nerve conduction velocity by at least 18 % and improves serum peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-la) by at least 33% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
  • PPC-la serum per
  • a pharmaceutical composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof which can be formulated as tablets, capsules, powder, pills, hard capsules fdled with liquid or solids, soft capsules, granules, pellets, caplets, mini-tablets, syrup, suspension, sachets, modified-re lease formulations, gummies or any other suitable dosage forms.
  • oral dosage form is the preferred dosage form.
  • a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, further comprises pharmaceutically acceptable excipients are selected from a bulking agent, disintegrant, binder, solubilizing agent, lubricant, glidant, solvent, or a mixture thereof.
  • the composition of the present invention optionally comprises one or more stabilizers, preservatives, anti-caking agents, surfactants, or a mixture thereof.
  • the bulking agent is selected from one or more of calcium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, calcium sulfate, magnesium oxide, microcrystalline cellulose, cellulose powder, maltodextrin, lactose anhydrous, lactose monohydrate, sucrose, mannitol, sorbitol, xylitol, starch, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, xanthan gum, or a mixture thereof.
  • the disintegrant is selected from one or more of alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, chitosan, com starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, low-substituted hydroxypropyl cellulose, methylcellulose, povidone, sodium alginate, sodium starch glycolate, cross-linked hydroxypropyl cellulose, or a mixture thereof.
  • the binder is selected from one or more of microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, methylcellulose, pregelatinized starch, starch, povidone, copovidone, carbomer, sodium alginate, acacia, agar, guar gum, maltodextrin, pectin, tragacanth, or a mixture thereof.
  • the solubilizing agent is selected from one or more of poloxamers, sodium lauryl sulfate, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, polyoxyethylene stearates, polyethylene glycol, propylene glycol, glycofurol, glycerin, ethanol, diethylene glycol monoethyl ether, - cyclodextrin, hydroxypropyl- -cyclodextrin, sulfobutyl ether- -cyclodextrin, or a mixture thereof.
  • the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene glycol, colloidal silicon dioxide, or glyceryl behenate, or a mixture thereof.
  • the glidant is selected from one or more of colloidal silicon dioxide, hydrophobic colloidal silica, silicon dioxide, talc, tribasic calcium phosphate, or a mixture thereof.
  • the solvent is selected from one or more of purified water, water for injection, sterile water, ethanol, glycerin, propylene glycol, polyethylene glycol, glycofurol, diethylene glycol monoethyl ether, benzyl alcohol, dimethyl sulfoxide, mediumchain triglycerides, oleic acid, vegetable oils, castor oil, ethyl oleate, triacetin, caprylic/capric triglycerides, or a mixture thereof.
  • the stabilizer is selected from one or more of ascorbic acid, sodium ascorbate, tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, disodium edetate, calcium disodium EDTA, citric acid, tartaric acid, phosphoric acid, sodium citrate, potassium citrate, sodium bicarbonate, monobasic sodium phosphate, dibasic sodium phosphate, acetic acid, sodium acetate, benzyl alcohol, sodium benzoate, potassium sorbate, methylparaben, propylparaben, poloxamers, polysorbates, sorbitan esters, polyethylene glycol, hydroxypropyl methylcellulose, or a mixture thereof.
  • the preservative is selected from one or more of methylparaben, propylparaben, butylparaben, ethylparaben, sodium benzoate, potassium benzoate, benzoic acid, sorbic acid, potassium sorbate, benzyl alcohol, phenethyl alcohol, phenoxyethanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine, chlorhexidine gluconate, thiomersal, dehydroacetic acid, formic acid, or a mixture thereof.
  • the anti-caking agent is selected from one or more of colloidal silicon dioxide, silicon dioxide, hydrophobic colloidal silica, dicalcium phosphate, tricalcium phosphate, sodium calcium aluminum silicate, magnesium phosphate, magnesium stearate, magnesium trisilicate, magnesium carbonate, magnesium oxide, pregelatinized starch, com starch, rice starch, tapioca starch, calcium silicate, calcium carbonate, sodium ferrocyanide, sodium silicoaluminate, kaolin, or a mixture thereof.
  • the surfactant is selected from one or more of polysorbates, sorbitan esters, polyethylene glycol esters, polyoxyethylene stearates, polyoxyethylene castor oil derivatives, poloxamers, sodium lauryl sulfate, sodium dodecyl sulfate, sodium stearate, sodium dioctyl sulfosuccinate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, lecithin, phosphatidylcholine, lauryl betaine, or a mixture thereof.
  • the composition may comprise a bulking agent in an amount ranging from 1% to 98% by w/w, a disintegrant ranging from 0.4% to 15% by w/w, a binder ranging from 0.1%to 12% by w/w, a solubilizing agent ranging from 0.15% to 18% by w/w, a lubricant ranging from 0.5% to 10% by w/w, a glidant ranging from 0.5% to 10% by w/w of the total composition, and a solvent in a quantity sufficient to achieve the desired formulation characteristics.
  • the pharmaceutical composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, can be formulated into any suitable oral dosage form using processes known to a person skilled in the art.
  • Such dosage forms may include, but are not limited to, tablets, capsules, granules, powders, or oral suspensions, which can be prepared by conventional methods such as direct compression, wet granulation, dry granulation, or encapsulation in hard or soft gelatin capsules.
  • Other suitable oral dosage forms can also be developed using standard pharmaceutical techniques known in the art.
  • mice All animals were divided into 10 groups (6 rats per group). Group G1 served as a normal control group whereas in remaining all groups (G2 to GIO) partial sciatic nerve ligation were performed to induce neuromuscular pain as mentioned above.
  • Treatment groups Treatments to be started after induction of neuromuscular pain disorder.
  • ALC Acetyl-L-camitine
  • Behavioural parameters a) Cold water tail immersion (Day 0, Day 28) b) Hot water tail immersion (Day 0, Day 28) c) Hot plate (Day 0, Day 28) d) Randal Selitto (Day 0, Day 28)
  • Electrophysiology of nerve Motor nerve conduction velocity (Day 0, Day 28) 3. Biochemical estimation in serum. a) Peroxisome Proliferator activated receptor gamma coactivator (PGC)-l Alpha (Day 28) b) Serum Lactic acid level (Day 28).
  • PPC Peroxisome Proliferator activated receptor gamma coactivator
  • Cold water (4°C) and Hot water (55 °C) tail immersion Neuropathic pain with cold allodynia and hyperalgesia was assessed by immersing the rat’s tail in water at 4 ⁇ 0.5°C. Hot allodynia and hyperalgesia were evaluated at 55 ⁇ 0.5°C. Cold water tail immersion at 4°C determines cold hyperalgesia and allodynia while hot water tail immersion at 55°C determines hot allodynia and hyperalgesia.
  • the hot plate measures an animal’s conscious removal of a body part from a heat source and its response to acute thermal pain.
  • the hot plate test assesses a more complex behavior that requires neurological processing within the brain, resulting in the lifting and licking of a paw in response to acute heat.
  • the test is performed by placing an animal on a heated surface maintained at 52-55°C. To prevent the animal from moving off the platform, a clear plastic cylinder is placed around it. After a brief period, typically several seconds, the animal will lift and lick a paw as the heat becomes uncomfortable. The animal is then immediately removed from the apparatus.
  • the dependent variable in this test is the time, or latency, to lick the paw, which is manually recorded using a digital stopwatch.
  • the cut-off time for this test is 30 seconds to minimize the risk of the animal sustaining tissue injury from prolonged exposure to the heated surface.
  • a test drug with analgesic properties was result in an increased latency for the animal to respond to placement on the heated surface.
  • the difference in reaction time between the groups was measured.
  • a higher reaction time indicates an increase in pain threshold (pain-bearing capacity) and vice versa.
  • the statistical significance of in vivo data was analyzed by two-way ANOVA followed by Tukey's multiple comparisons test, p-value less than 0.05 is considered as statistically significant difference.
  • Figure-3 demonstrates modulatory effects of test substances on Hot plate latency at 50-55°C
  • the Randall-Selitto (paw pressure) test measures the response threshold to mechanical pressure. Increasing pressure is applied to the paw until withdrawal or vocalization occurs. The nociceptive withdrawal threshold was assessed using the Paw Pressure Analgesia meter (Orchid Scientific). Before testing, each animal was handled for 5 minutes and then immobilized in a soft cotton cloth, with the paw being tested held in one hand. The test applied increasing pressure to the medial portion of the plantar or dorsal surface of the fore and hind paws until a withdrawal response occurred. The application site was marked with ink for consistency across trials. The measured parameter is the threshold (weight in grams) for the appearance of the response. The difference in pressure-bearing capacity (weight in grams) was measured.
  • test drug with analgesic properties will increase the threshold, indicating greater analgesic effects.
  • Statistical significance was analyzed by two-way ANOVA followed by Tukey's multiple comparisons test, p-value less than 0.05 is considered as statistically significant difference.
  • Figure-4 demonstrates modulatory effects of test substances on Randall Selitto test.
  • Motor nerve conduction velocity measures the speed at which an electrical impulse travels along a motor nerve, helping assess nerve function and detect damage.
  • Rats were anesthetized with ketamine (60 mg/kg) and xylazine (10 mg/kg) via i.p. injection.
  • Receiving electrodes were attached 1 cm apart on the dorsal hind paw muscles.
  • the sciatic nerve was stimulated proximally to the sciatic notch with a 5V stimulus using the motor nerve conduction electrode. Recordings from motor fiber stimulation were logged with physiograph software (AD Instruments), and M-wave and H-wave reflexes were documented digitally. M-wave latency, used to calculate MNCV, was measured in seconds.
  • the distance between the recording electrode and stimulation point was manually measured with a tape.
  • a heating pad maintained the rat's body temperature at 37 ⁇ 0.5°C. Slower conduction velocities can indicate peripheral neuropathy or other nerve disorders. An increase in MNCV toward normalization indicates treatment effectiveness.
  • MNCV Motor Nerve Conduction Velocity
  • Serum PGC-la and Serum Lactate were analyzed using ELISA tests. Multimode Reader (Biotek Instruments), Cytation 5 model Serial no. 1909161E was used to measure the PGC- la and lactate using respective ELISA kit leaflet (provided along with kit) under biosafety cabinet.
  • Figure-6 and Figure-7 demonstrate modulatory effects of test substances on serum PGC-1 Alpha levels and modulatory effects of test substances on serum lactate levels respectively.
  • Electrophysiology of nerve Motor nerve conduction velocity Table 5: * - in group GIO compared to the sum of change in individual therapy groups (G4+G5+G6).

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Abstract

This invention relates to a synergistic composition comprising combination of palmitoylethanolamide, Acetyl carnitine, and uridine, or their pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof for controlling neuromuscular pain and repairing nerve damage. The present invention provides a synergistic composition for the management of nerve health. The invention specifically provides a composition that exhibits a synergistic effect and demonstrates therapeutic effectiveness comparable to standard chemical drug.

Description

A SYNERGISTIC BIOACTIVE COMPOSITION FOR CONTROLLING NEUROMUSCULAR PAIN AND REPAIRING NERVE DAMAGE
RELATED APPLICATION:
The present application claims benefit of the Indian Provisional Application No. IN202421016958 filed on, March 8th, 2024 the entire contents of which are hereby incorporated by reference.
FIELD OF THE INVENTION:
This invention relates to a synergistic composition comprising combination of palmitoylethanolamide, Acetyl carnitine, and uridine, or their pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof for controlling neuromuscular pain and repairing nerve damage. The present invention provides a synergistic composition for the management of nerve health. The invention specifically provides a composition that exhibits a synergistic effect and demonstrates therapeutic effectiveness comparable to standard chemical drug.
BACKGROUND OF THE INVENTION:
Neuromuscular pain is a complex, chronic condition characterized by pain originating from nerves and associated muscles. This is different from pain solely affecting muscles or nerves. The abnormality or damage in either system can contribute to the pain through intricate interactions.
Instead of a single mechanism, neuromuscular pain arises from a multimodal pathophysiology, meaning multiple pathways and processes contribute to the pain experience. These can be broadly categorized into:
Peripheral Sensitization: Damage to nerves leads to increased sensitivity of pain receptors (nociceptors) in nerves and associated muscles. This makes them more responsive to stimuli that wouldn't normally cause pain.
Central Sensitization: Overactive nerve signals from the injured regions reach the spinal cord and brain, causing these centers to become hypersensitive and amplify pain signals. This can lead to spontaneous pain even without any triggers. Inflammation: Both nerve and muscle damage can trigger inflammatory processes that release pain-promoting chemicals, further contributing to the discomfort.
Psychological Factors: Chronic pain can significantly impact mental health, leading to anxiety, depression, and increased pain perception.
Understanding the different mechanisms involved in neuromuscular pain is crucial for effective treatment. Conventional therapies often target specific pathways, but their limited scope may not adequately address the complex interplay of factors in this condition. Conventional therapies for neuromuscular pain often fall short due to their limited scope and inability to address the complex, multimodal nature of the condition. Following are some of the limitations:
Selective Mechanism of Action: Gabapentinoids are often recommended as first-line treatments for the management of neuropathic pain. However, more than half of patients fail to achieve worthwhile pain relief. Dizziness, somnolence, gait disturbances, impaired concentration, confusion, memory loss, altered mood, movement disorders, sleep disorders, speech impairment, vertigo, and other side effects are common with gabapentinoids, often leading to discontinuation of therapy. The use of gabapentinoids has been reported to cause respiratory depression, weight gain, potential for abuse, and withdrawal symptoms. Further the most conventional pain medications like opioids and some nonsteroidal antiinflammatory drugs (NSAIDs), target specific pain pathways. This "one-size-fits-all" approach fails to address the multiple mechanisms involved in neuromuscular pain, leading to incomplete or ineffective pain relief.
Risk of Refractoriness: Long-term use of certain medications, like opioids, can lead to refractoriness, where the medication becomes less effective over time. This necessitates increasing the dosage, which can further exacerbate side effects.
Ineffective on Muscle Pain: Some therapies, like certain nerve blockers, primarily target pain originating from damaged nerves. While they may provide some relief, they do not address muscle pain, another key component of neuromuscular pain.
High Doses and Side Effects: Achieving pain relief with conventional medications often requires high doses, which can increase the risk of side effects like drowsiness, addiction, and organ damage. Simone Parisi et. al. (2021) investigates the efficacy of a fixed combination of palmitoylethanolamide and acetyl-L-camitine (PEA+ALC) in treating neuropathies secondary to rheumatic diseases. The research explores the synergistic effect of PEA and ALC, both recognized for their analgesic properties, as a supplementation to standard therapy in patients with peripheral neuropathy. This prior-art fails to provide any information on benefit and effectiveness of above combination with uridine.
Alessio Ardizzone et. al. (2021) provides a study on the combined oral administration of ultra-micronized palmitoylethanolamide (um-PEA) and acetyl-1- carnitine (ALC) in a rat model of carrageenan (CAR)-induced paw edema demonstrated superior anti-inflammatory and anti-nociceptive effects compared to the separate and consecutive administration of ALC and um-PEA. This prior-art also fails to provide any information on benefit and effectiveness of above combination with uridine.
F. Salaffi et. al. (2023) focuses on fibromyalgia (FM), a condition characterized by persistent pain resistant to standard treatments, the combination of pregabalin (PGB) and duloxetine (DLX) supplemented with palmitoylethanolamide (PEA) and acetyl-L-camitine (ALC) was evaluated over a 24-week period. In this reference, PEA and ALC are used in combination with standard therapy. Further this reference does not disclose PEA+ALC in combination with uridine. Paul Richard Saunders (2023) also discloses similar study however, they also do not disclose PEA+ALC in combination with uridine.
RU2701720 discusses the treatment of chronic pain. The disclosed combination comprises effective amounts of palmitoylethanolamide, along with at least one substance chosen from uridine monophosphate, taurine, and vitamin E, or their pharmaceutically acceptable salts. However, this patent prior-art does not provide any information on effectiveness of acetyl- L-camitine (ALC) in combination with palmitoylethanolamide (PEA) and uridine.
Therefore, from the above prior-art it can be said that the prior-art fails to provide triple combination of Palmitoyl ethanolamide (PEA), Acetyl carnitine and uridine. Specifically triple combination of Palmitoylethanolamide (PEA), acetyl-L-camitine ( ALC) and uridine for the treatment of neuromuscular pain wherein therapeutic effectiveness is comparable with the standard therapy.
Accordingly, it can be said that conventional chemical drugs, though effective in managing conditions such as pain, neuromuscular pain, neuromuscular inflammation, and nerve- related disorders, often come with significant drawbacks, particularly when used for longterm treatment. Prolonged use of conventional drugs is associated with adverse effects such as gastrointestinal issues, liver and kidney toxicity, dependency, and tolerance development, leading to reduced efficacy over time. Additionally, many chemical -based treatments only provide symptomatic relief rather than addressing the underlying cause of the condition. Given these limitations, there is a growing need for alternative solutions that offer comparable therapeutic benefits without these side effects. Nutraceutical compositions, derived from natural bioactive ingredients, present a promising alternative by providing sustained relief, promoting nerve health, and reducing inflammation while ensuring better safety and tolerability for long-term use. The present invention fulfills this need by offering a synergistic combination of natural ingredients that effectively manage these conditions without the risks associated with prolonged chemical drug use.
OBJECT OF THE INVENTION:
The principal object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof.
Another object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective for nerve health.
Another object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in the management of neuromuscular pain. Another object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective to control of neuromuscular inflammation.
Another object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition repairs damaged nerves.
Another object of the present invention is to provide a synergistic composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition improves nerve functions.
One more objective of the present invention is to provide a synergistic composition consisting essentially of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in managing nerve health.
One more objective of the present invention is to provide a synergistic composition consisting essentially of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in managing neuromuscular pain.
One more objective of the present invention is to provide a synergistic composition consisting essentially of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in facilitating nerve damage repair.
Another objective of the present invention is to provide composition in the fixed dosage form comprising a dosage range for each component i.e., palmitoylethanolamide, Acetyl carnitine and uridine which provide synergistic therapeutic efficacy.
Yet another objective of the present invention is to provide a pharmaceutical composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof which can be formulated as tablets, capsules, powder, pills, hard capsules filled with liquid or solids, soft capsules, granules, pellets, caplets, mini-tablets, syrup, suspension, sachets, modified-release formulations, gummies or any other suitable dosage forms.
SUMMARY OF THE INVENTION:
This invention provides a synergistic composition comprising a triple combination of palmitoylethanolamide, Acetyl carnitine, and uridine, or their pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof. The present invention provides a synergistic composition for the management of nerve health. The invention specifically provides a composition that exhibits a synergistic effect and demonstrates therapeutic effectiveness comparable to standard chemical drug.
BRIEF DESCRIPTION OF DRAWINGS:
In order that disclosure may be readily understood and put into practical effect, reference will now be made to exemplary embodiments as illustrated with reference to the accompanying figures. The figure with a detailed description below, are incorporated in and form part of the specification, and serve to further illustrate the embodiments and explain various principles and advantages, in accordance with the present invention:
The tests were conducted on various groups, following is the details of the same: Gl- Normal control group, G2- Disease control group, G3- Standard group (Pregabalin), G4 - Palmitoylethanolamide, G5- Acetyl -L- Carnitine, G6- Uridine monophosphate, G7- Palmitoylethanolamide + Acetyl -L- Carnitine, G8- Acetyl -L- Carnitine + Uridine monophosphate, G9- Palmitoylethanolamide + Uridine monophosphate, G10- Palmitoylethanolamide + Acetyl -L- Carnitine + Uridine monophosphate (Triple combination group as per present invention) Figure- 1: Depicts modulatory effects of test substances on cold water tail immersion 4°C latency reaction time
Figure-2: Depicts modulatory effects of test substances on hot water tail immersion 55°C latency reaction time
Figure-3: Depicts modulatory effects of test substances on Hot plate latency at 50-55°C Figure-4: Depicts modulatory effects of test substances on Randall Selitto test
Figure-5: Depicts modulatory effects of test substances on Motor Nerve Conduction Velocity
Figure-6: Depicts modulatory effects of test substances on serum PGC-1 Alpha levels Figure-7: Depicts modulatory effects of test substances on serum lactate levels
DETAILED DESCRIPTION OF THE INVENTION:
The following detailed description of the present subject matter the various embodiments. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized and changes may be made without departing from the scope of the present subject matter.
References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.
The principal aspect of the present invention is to develop a synergistic bioactive composition aimed at effectively controlling neuromuscular pain and repairing nerve damage.
The present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof.
Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide with anti- inflammatory, analgesic, and neuroprotective properties. Industrially, it is produced through extraction, chemical synthesis, or enzymatic biocatalysis. According to the present invention, PEA prepared by any of the industrial methods can be used.
Acetyl carnitine, particularly Acetyl -L-Carnitine (ALC), is a bioactive amino acid derivative known for its neuroprotective, antioxidant, and energy-enhancing properties. Industrially, ALC is produced through extraction, chemical synthesis, or enzymatic biocatalysis. According to the present invention, ALC prepared by any of the industrial methods can be used.
Uridine is a pyrimidine nucleoside essential for RNA synthesis, cognitive function, and mitochondrial health. Industrially, it is produced through extraction, chemical synthesis, or microbial fermentation. According to the present invention, Uridine prepared by any of the industrial methods can be used. According to the present invention, all the active ingredients are commercially available.
According to the present invention, Palmitoylethanolamide includes its pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form. Acetyl carnitine includes its pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form, wherein Acetyl carnitine may be an acetyl-l-camitine, acetyl-d-camitine, or a mixture thereof. Uridine includes its pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form.
According to the present invention, a synergistic bioactive composition comprises at least three ingredients, wherein the three ingredients are Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof. Additionally, the composition may further comprise vitamins, coenzymes, antioxidants, or a combination thereof. furthermore, the invention also encompasses a kit comprising the said composition, wherein the composition comprises at least three ingredients Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof. Additionally, each of the three ingredients may be present in a separate composition within the kit.
In one embodiment of the present invention provides synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof along with pharmaceutically acceptable excipients.
One embodiment of the present invention is to provide the optimal combination ratio of Palmitoyl ethanolamide, Acetyl carnitine, Uridine. Additionally, the invention provides the appropriate dosage range for each component to achieve optimal therapeutic efficacy.
According to present invention, a synergistic bioactive composition comprising combination of Palmitoylethanolamide, Acetyl carnitine, Uridine, the composition demonstrates therapeutic effectiveness comparable to standard chemical drug.
In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, wherein palmitoylethanolamide, Acetyl carnitine, and uridine are present in a ratio of 1:0.0125:0.00005 to 1: 160:20, 1:0.0278:0.0002 to 1:30.0000:4.0000, 1:0.0294:0.0002 to 1:27.0000:3.5000, 1:0.0313:0.0002 to 1:25.0000:3.0000, 1:0.0303:0.0002 to 1:23:2.7000, 1:0.0286:0.0002 to 1:33.3333:5.3333, or 1:0.0250:0.0003 to 1:42.6667:4.6667.
In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, wherein palmitoylethanolamide and uridine are present in a ratio ranging from 1:0.00005 to 1: 20.
In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, wherein palmitoylethanolamide and Acetyl carnitine are present in a ratio ranging from 1: 0.0125 to 1: 160. In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, wherein uridine and Acetyl carnitine are present in ratio ranging from 1:0.0500 to 1:40000.
According to the present invention, the amount of palmitoylethanolamide ranges from 25 mg to 2000 mg, 100 mg to 1800 mg, 150 mg to 1700 mg, 150 mg to 1600 mg, 150 mg to 1500 mg, 250 mg to 1700 mg, 250 mg to 1500 and 300 mg to 1500 mg. According to the present invention the amount of Acetyl carnitine ranges from 25 mg to 4000 mg, 100 mg to 3000 mg, 100 mg to 2500 mg, 100 mg to 2700 mg, 200 mg to 2500 mg, 200 to 2000 mg. Further, according to the present invention the amount of uridine ranges from 0. 1 mg to 500 mg, 5 mg to 400 mg, 10 mg to 300 mg, 15 mg to 200 mg, 20 mg to 150 mg, 25 mg to 100 mg or 25 mg to 50 mg per unit dose.
According to the present invention, the effective amount of active ingredients is the amount required for the therapeutic effect which can be administered at a time or in divided doses per day.
According to the present invention, the amount of palmitoylethanolamide is in the range of 0.38 to 98.28 % w/w, 5 to 90 % w/w, 10 to 80 % w/w, 20 to 75 % w/w, 25 to 70 % w/w, 30 to 65 % w/w, or 30 to 70 % w/w of the total composition. According to the present invention the amount of Acetyl carnitine is present in the range of 0.55 to 99.13 % w/w, 5 to 90 % w/w, 5 to 80 % w/w, 10 to 70 % w/w, 20 to 60 % w/w, 25 to 65 % w/w, or 22 to 62 % w/w of the total composition. Further, according to the present invention the amount of uridine is present in the range of 0.0012 to 89.29% w/w, 0.002 to 70% w/w, 0.05 to 60% w/w, 0. 1 to 50% w/w, 0.5 to 40% w/w, 0.5 to 30% w/w, or 0.5 to 25% w/w of the total composition.
In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used for the management of neuromuscular pain.
In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used for the management of neuromuscular inflammation.
In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used for repairing nerve damage.
In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used for nerve health.
In one of the embodiment, the present invention provides a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is used to improve nerve functions.
In one of the embodiment, the present invention provides a synergistic composition consisting essentially of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, wherein the composition is effective in managing nerve health.
A preclinical study was conducted to evaluate the synergistic therapeutic effectiveness of the present invention using multiple parameters. The parameter to measure the therapeutic effectiveness can be Behavioural parameters e.g. cold water tail immersion, hot water tail immersion, hot plate, Randall Selitto; electrophysiology of nerve e.g. Motor nerve conduction velocity and biochemical estimation in serum e.g., Peroxisome Proliferator activated receptor gamma coactivator (PGC)-l Alpha and serum lactic acid level.
The parameters to evaluate the synergistic therapeutic effectiveness of the present invention can be biochemical estimation in serum e.g. Interleukin-6, and Serum silent information regulator 1" (SIRT1).
In one of the embodiment, the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition reduces cold allodynia by at least 18 % at 4°C more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
In one of the embodiment, the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition reduces hot allodynia by at least 26% at 55°C more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
In one of the embodiment, the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition enhances hot plate latency at 50-55°C by at least 27% more than the combined individual effects of Palmitoyl ethanolamide, acetyl-l-camitine and Uridine.
In one of the embodiment, the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition reduces mechanical allodynia by at least 42% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
In one of the embodiment, the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition enhances motor nerve conduction velocity by at least 18% more than the combined individual effects of Palmitoyl ethanolamide, acetyl-l-camitine and Uridine.
Semm PGC-1 a: Mitochondrial degeneration is recognized as a key contributor to peripheral neuropathic pain. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-la is a crucial regulator of mitochondrial biogenesis, promoting the formation of new mitochondria necessary for neuronal energy production. Lower serum PGC-la levels are associated with the onset and progression of neuropathic pain. Conversely, increased PGC- la expression supports neuronal protection against inflammation and oxidative stress, thereby aiding in neuropathic pain management. Enhanced PGC-la activity signifies improved therapeutic outcomes.
In one of the embodiment, the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition improves peroxisome proliferator-activated receptorgamma coactivator 1 alpha (PGC-la) by at least 33% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
Serum lactic acid: Eactic acid is traditionally linked to muscle fatigue and exhaustion. Lactic acidosis, characterized by elevated lactic acid levels, impairs muscle contractility, leading to fatigue and reduced physical performance. A reduction in lactic acid levels is indicative of improved muscle endurance and decreased fatigue, thereby contributing to overall pain relief and enhanced physical function.
In one of the embodiment, the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein oral administration of the composition reduces serum lactic acid by at least 17% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
The aforementioned parameters collectively assess the therapeutic efficacy of the composition of the present invention in managing neuropathic pain, improving nerve function, and reducing inflammation.
In one of the embodiment, the present invention provides a synergistic composition comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, wherein the composition comprises (a) palmitoylethanolamide in an amount ranging from 25 mg to 2000 mg, (b) Acetyl carnitine in an amount ranging from 25 mg to 4000 mg, (c) uridine in an amount ranging from 0.1 mg to 500 mg; wherein palmitoylethanolamide, Acetyl carnitine, and uridine are present in a ratio ranging from 1:0.0125:0.00005 to 1: 160:20; wherein the composition is for oral administration; and wherein oral administration of the composition improves motor nerve conduction velocity by at least 18 % and improves serum peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-la) by at least 33% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine.
In another embodiment of the present invention is to provide a pharmaceutical composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof which can be formulated as tablets, capsules, powder, pills, hard capsules fdled with liquid or solids, soft capsules, granules, pellets, caplets, mini-tablets, syrup, suspension, sachets, modified-re lease formulations, gummies or any other suitable dosage forms. According to present invention, oral dosage form is the preferred dosage form.
According to present invention, a synergistic bioactive composition comprising Palmitoylethanolamide, Acetyl carnitine, Uridine, further comprises pharmaceutically acceptable excipients are selected from a bulking agent, disintegrant, binder, solubilizing agent, lubricant, glidant, solvent, or a mixture thereof. Further, the composition of the present invention optionally comprises one or more stabilizers, preservatives, anti-caking agents, surfactants, or a mixture thereof.
According to present invention the bulking agent is selected from one or more of calcium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, calcium sulfate, magnesium oxide, microcrystalline cellulose, cellulose powder, maltodextrin, lactose anhydrous, lactose monohydrate, sucrose, mannitol, sorbitol, xylitol, starch, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, xanthan gum, or a mixture thereof.
According to present invention the disintegrant is selected from one or more of alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, chitosan, com starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, low-substituted hydroxypropyl cellulose, methylcellulose, povidone, sodium alginate, sodium starch glycolate, cross-linked hydroxypropyl cellulose, or a mixture thereof.
According to present invention the binder is selected from one or more of microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, methylcellulose, pregelatinized starch, starch, povidone, copovidone, carbomer, sodium alginate, acacia, agar, guar gum, maltodextrin, pectin, tragacanth, or a mixture thereof.
According to present invention the solubilizing agent is selected from one or more of poloxamers, sodium lauryl sulfate, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, polyoxyethylene stearates, polyethylene glycol, propylene glycol, glycofurol, glycerin, ethanol, diethylene glycol monoethyl ether, - cyclodextrin, hydroxypropyl- -cyclodextrin, sulfobutyl ether- -cyclodextrin, or a mixture thereof.
According to present invention the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene glycol, colloidal silicon dioxide, or glyceryl behenate, or a mixture thereof.
According to present invention the glidant is selected from one or more of colloidal silicon dioxide, hydrophobic colloidal silica, silicon dioxide, talc, tribasic calcium phosphate, or a mixture thereof.
According to present invention the solvent is selected from one or more of purified water, water for injection, sterile water, ethanol, glycerin, propylene glycol, polyethylene glycol, glycofurol, diethylene glycol monoethyl ether, benzyl alcohol, dimethyl sulfoxide, mediumchain triglycerides, oleic acid, vegetable oils, castor oil, ethyl oleate, triacetin, caprylic/capric triglycerides, or a mixture thereof. According to present invention the stabilizer is selected from one or more of ascorbic acid, sodium ascorbate, tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, disodium edetate, calcium disodium EDTA, citric acid, tartaric acid, phosphoric acid, sodium citrate, potassium citrate, sodium bicarbonate, monobasic sodium phosphate, dibasic sodium phosphate, acetic acid, sodium acetate, benzyl alcohol, sodium benzoate, potassium sorbate, methylparaben, propylparaben, poloxamers, polysorbates, sorbitan esters, polyethylene glycol, hydroxypropyl methylcellulose, or a mixture thereof.
According to present invention the preservative is selected from one or more of methylparaben, propylparaben, butylparaben, ethylparaben, sodium benzoate, potassium benzoate, benzoic acid, sorbic acid, potassium sorbate, benzyl alcohol, phenethyl alcohol, phenoxyethanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine, chlorhexidine gluconate, thiomersal, dehydroacetic acid, formic acid, or a mixture thereof.
According to present invention the anti-caking agent is selected from one or more of colloidal silicon dioxide, silicon dioxide, hydrophobic colloidal silica, dicalcium phosphate, tricalcium phosphate, sodium calcium aluminum silicate, magnesium phosphate, magnesium stearate, magnesium trisilicate, magnesium carbonate, magnesium oxide, pregelatinized starch, com starch, rice starch, tapioca starch, calcium silicate, calcium carbonate, sodium ferrocyanide, sodium silicoaluminate, kaolin, or a mixture thereof.
According to present invention the surfactant is selected from one or more of polysorbates, sorbitan esters, polyethylene glycol esters, polyoxyethylene stearates, polyoxyethylene castor oil derivatives, poloxamers, sodium lauryl sulfate, sodium dodecyl sulfate, sodium stearate, sodium dioctyl sulfosuccinate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, lecithin, phosphatidylcholine, lauryl betaine, or a mixture thereof.
According to the present invention, the composition may comprise a bulking agent in an amount ranging from 1% to 98% by w/w, a disintegrant ranging from 0.4% to 15% by w/w, a binder ranging from 0.1%to 12% by w/w, a solubilizing agent ranging from 0.15% to 18% by w/w, a lubricant ranging from 0.5% to 10% by w/w, a glidant ranging from 0.5% to 10% by w/w of the total composition, and a solvent in a quantity sufficient to achieve the desired formulation characteristics.
According to the present invention, the pharmaceutical composition comprising a combination of Palmitoylethanolamide, Acetyl carnitine, and Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof, can be formulated into any suitable oral dosage form using processes known to a person skilled in the art. Such dosage forms may include, but are not limited to, tablets, capsules, granules, powders, or oral suspensions, which can be prepared by conventional methods such as direct compression, wet granulation, dry granulation, or encapsulation in hard or soft gelatin capsules. Other suitable oral dosage forms can also be developed using standard pharmaceutical techniques known in the art.
EXAMPLES:
The present invention has been described by way of example only, and it is to be recognized that modifications thereto filling within the scope and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this invention.
EXAMPLE-1: COMPOSITION:
Following is the general composition formula as per the present invention:
EXAMPLE-2: COMPOSITION:
Following is general composition formula as per the present invention:
EXAMPLE-3-7: COMPOSITION:
EXAMPLE-8: ANIMAL STUDY:
Objective of the animal study: To evaluate the synergistic effect of Palmitoylethanolamide, Acetyl-L-Camitine and uridine in neuromuscular pain in rats.
Materials and Methods: 60 female Wistar rats, aged 9-10 weeks and weighing 190-240 gm were included in the study at the start of the experiment. Neuromuscular pain induction: This study was designed to evaluate the synergistic effect of Palmitoylethanolamide + Acetyl -L-Camitine + Uridine in partial sciatic nerve ligation induced neuromuscular pain in rats.
Animals were anesthetized by ketamine 40 mg/kg b.wt. and xylazine 10 mg/kg b.wt., place the animal in aseptic conditions, the right sciatic nerve was exposed at high-thigh level. Animals underwent the sciatic nerve partial injury. Under a magnification of 25X, the dorsum of the nerve was carefully freed from surrounding connective tissues at a site near the trochanter just distal to the point at which the posterior biceps semitendinosus (‘PBST’) nerve branches off the common sciatic nerve. Using honed (no. 5) jewellers’ forceps the nerve was fixed in its place by pinching the epineurium on its dorsal aspect, taking care not to press the nerve against underlying structures. An 8-0 silicon treated silk suture was inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle, and tightly ligated so that the dorsal 1/3- 1/2 of the nerve thickness was trapped in the ligature. The wound was then closed. In all rats the left leg and sciatic nerve were untouched.
Animal grouping: All animals were divided into 10 groups (6 rats per group). Group G1 served as a normal control group whereas in remaining all groups (G2 to GIO) partial sciatic nerve ligation were performed to induce neuromuscular pain as mentioned above.
Experimental design of the study was as follows:
Treatment groups: Treatments to be started after induction of neuromuscular pain disorder.
BID: Twice a day.
PEA: Palmitoylethanolamide
ALC: Acetyl-L-camitine
UM: Uridine monophosphate
Evaluation parameters:
1. Behavioural parameters: a) Cold water tail immersion (Day 0, Day 28) b) Hot water tail immersion (Day 0, Day 28) c) Hot plate (Day 0, Day 28) d) Randal Selitto (Day 0, Day 28)
2. Electrophysiology of nerve: Motor nerve conduction velocity (Day 0, Day 28) 3. Biochemical estimation in serum. a) Peroxisome Proliferator activated receptor gamma coactivator (PGC)-l Alpha (Day 28) b) Serum Lactic acid level (Day 28).
Test procedure:
Cold water (4°C) and Hot water (55 °C) tail immersion: Neuropathic pain with cold allodynia and hyperalgesia was assessed by immersing the rat’s tail in water at 4 ± 0.5°C. Hot allodynia and hyperalgesia were evaluated at 55 ± 0.5°C. Cold water tail immersion at 4°C determines cold hyperalgesia and allodynia while hot water tail immersion at 55°C determines hot allodynia and hyperalgesia.
Animals were placed in cylindrical holders with their tails hanging freely and allowed to acclimatize for 30 minutes. The lower 5 cm of the tail was marked and immersed in water at 4°C, and 55°C. Tail-flick latency was measured three times, and the average was reported. The tail was dried after each measurement, with a 30-second cutoff time for immersion. A higher tail-flick latency indicates an increased pain threshold and therefore better therapeutic effect. Statistical significance was determined using two-way ANOVA followed by Tukey's test, p-value less than 0.05 is considered as statistically significant difference. Figure- 1 and Figure-2 demonstrates modulatory effects of test substances on cold water tail immersion 4°C latency reaction time and modulatory effects of test substances on hot water tail immersion 55°C latency reaction time respectively.
Hot plate latency (50-55°C):
The hot plate measures an animal’s conscious removal of a body part from a heat source and its response to acute thermal pain. The hot plate test assesses a more complex behavior that requires neurological processing within the brain, resulting in the lifting and licking of a paw in response to acute heat. The test is performed by placing an animal on a heated surface maintained at 52-55°C. To prevent the animal from moving off the platform, a clear plastic cylinder is placed around it. After a brief period, typically several seconds, the animal will lift and lick a paw as the heat becomes uncomfortable. The animal is then immediately removed from the apparatus. The dependent variable in this test is the time, or latency, to lick the paw, which is manually recorded using a digital stopwatch. The cut-off time for this test is 30 seconds to minimize the risk of the animal sustaining tissue injury from prolonged exposure to the heated surface. A test drug with analgesic properties was result in an increased latency for the animal to respond to placement on the heated surface. The difference in reaction time between the groups was measured. A higher reaction time indicates an increase in pain threshold (pain-bearing capacity) and vice versa. The statistical significance of in vivo data was analyzed by two-way ANOVA followed by Tukey's multiple comparisons test, p-value less than 0.05 is considered as statistically significant difference. Figure-3 demonstrates modulatory effects of test substances on Hot plate latency at 50-55°C
Randall-Selitto test (Mechanical hyperalgesia):
The Randall-Selitto (paw pressure) test measures the response threshold to mechanical pressure. Increasing pressure is applied to the paw until withdrawal or vocalization occurs. The nociceptive withdrawal threshold was assessed using the Paw Pressure Analgesia meter (Orchid Scientific). Before testing, each animal was handled for 5 minutes and then immobilized in a soft cotton cloth, with the paw being tested held in one hand. The test applied increasing pressure to the medial portion of the plantar or dorsal surface of the fore and hind paws until a withdrawal response occurred. The application site was marked with ink for consistency across trials. The measured parameter is the threshold (weight in grams) for the appearance of the response. The difference in pressure-bearing capacity (weight in grams) was measured. A test drug with analgesic properties will increase the threshold, indicating greater analgesic effects. Statistical significance was analyzed by two-way ANOVA followed by Tukey's multiple comparisons test, p-value less than 0.05 is considered as statistically significant difference. Figure-4 demonstrates modulatory effects of test substances on Randall Selitto test.
Motor nerve conduction velocity:
Motor nerve conduction velocity (MNCV) measures the speed at which an electrical impulse travels along a motor nerve, helping assess nerve function and detect damage. Rats were anesthetized with ketamine (60 mg/kg) and xylazine (10 mg/kg) via i.p. injection. Receiving electrodes were attached 1 cm apart on the dorsal hind paw muscles. The sciatic nerve was stimulated proximally to the sciatic notch with a 5V stimulus using the motor nerve conduction electrode. Recordings from motor fiber stimulation were logged with physiograph software (AD Instruments), and M-wave and H-wave reflexes were documented digitally. M-wave latency, used to calculate MNCV, was measured in seconds. The distance between the recording electrode and stimulation point was manually measured with a tape. A heating pad maintained the rat's body temperature at 37 ± 0.5°C. Slower conduction velocities can indicate peripheral neuropathy or other nerve disorders. An increase in MNCV toward normalization indicates treatment effectiveness.
Motor Nerve Conduction Velocity (MNCV) = Distance between the nerve stimulation points in meter (m) Latency in seconds(s)
The statistical significance of in vivo data was analyzed by two-way ANOVA followed by Tukey's multiple comparisons test, p-value less than 0.05 is considered as statistically significant difference. Figure-5 demonstrates modulatory effects of test substances on Motor Nerve Conduction Velocity.
Process for Serum Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-la, and Serum Lactate:
Serum PGC-la and Serum Lactate were analyzed using ELISA tests. Multimode Reader (Biotek Instruments), Cytation 5 model Serial no. 1909161E was used to measure the PGC- la and lactate using respective ELISA kit leaflet (provided along with kit) under biosafety cabinet. Figure-6 and Figure-7 demonstrate modulatory effects of test substances on serum PGC-1 Alpha levels and modulatory effects of test substances on serum lactate levels respectively.
Animal study results:
1. Behavioural parameters:
Table 1:
Cold water tail immersion test (4°C) - Cold thermal allodynia and hyperalgesia
* - in group GIO compared to the sum of change in individual therapy groups (G4+G5+G6).
Table 2:
* - in group GIO compared to the sum of change in individual therapy groups (G4±G5±G6).
Table 3:
* - in group GIO compared to the sum of change in individual therapy groups (G4±G5±G6).
Table 4:
* - in group GIO compared to the sum of change in individual therapy groups (G4+G5+G6).
2. Electrophysiology of nerve: Motor nerve conduction velocity Table 5: * - in group GIO compared to the sum of change in individual therapy groups (G4+G5+G6).
3. Biochemical estimation in serum. Table 6:
* - in group GIO compared to the sum of change in individual therapy groups (G4+G5+G6).
Table 7:
* - in group GIO compared to the sum of change in individual therapy groups (G4±G5±G6).
The study results, as presented in the tables above, confirm that the triple combination of the present invention leads to a significant improvement in efficacy. The experiments were conducted on animals under various conditions, both before and after disease induction. The recorded observations demonstrate the animals' responses to the induced disease and their reaction to the composition. The data clearly establishes that the present composition, comprising Palmitoylethanolamide, Acetyl carnitine, and Uridine, exhibits a synergistic effect in addressing conditions such as pain, neuromuscular pain, neuromuscular inflammation, nerve damage, nerve health, nerve function, and related conditions.

Claims

WE CLAIM:
1. A synergistic bioactive composition comprising: a) Palmitoylethanolamide, b) Acetyl carnitine, c) Uridine, or pharmaceutically acceptable salts, derivatives, isomers, or deacetylated form thereof.
2. The synergistic bioactive composition as claimed in claim 1, wherein the Acetyl carnitine is acetyl-l-camitine.
3. The synergistic bioactive composition as claimed in claim 1, wherein palmitoylethanolamide, Acetyl carnitine, and uridine are present in a ratio of 1:0.0125:0.00005 to 1: 160:20.
4. The synergistic bioactive composition as claimed in claim 1, wherein the composition is formulated as tablets, capsules, powder, pills, hard capsules fdled with liquid or solids, soft capsules, granules, pellets, caplets, mini-tablets, syrup, suspension, sachets, modified-release formulations, gummies or any other suitable oral dosage forms.
5. The synergistic bioactive composition as claimed in claim 1, wherein; a) Palmitoylethanolamide or its pharmaceutically acceptable salts or derivative is present in the range of 0.38 to 98.28 % w/w of the total composition. b) Acetyl carnitine or its pharmaceutically acceptable salts or derivative is present in the range of 0.55 to 99. 13 % w/w of the total composition. c) Uridine or its pharmaceutically acceptable salts or derivative is present in the range of 0.0012 to 89.29 % w/w of the total composition.
6. The synergistic bioactive composition as claimed in claim 1, wherein a) Palmitoylethanolamide is present in an amount ranging from 25 mg to 2000 mg. b) Acetyl carnitine is present in an amount ranging from 25 mg to 4000 mg. c) Uridine is present in an amount ranging from 0. 1 mg to 500 mg.
7. The synergistic bioactive composition as claimed in claim 1, further comprises pharmaceutically acceptable excipients are selected from a bulking agent, disintegrant, binder, solubilizing agent, lubricant, glidant, solvent, or a mixture thereof.
8. The synergistic bioactive composition as claimed in claim 1, wherein; a) oral administration of the composition enhances motor nerve conduction velocity by at least 18% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine; or b) oral administration of the composition reduces serum lactic acid by at least 17% more than the combined individual effects of Palmitoylethanolamide, acetyl-l- camitine and Uridine; or c) oral administration of the composition improves peroxisome proliferator- activated receptor-gamma coactivator 1 alpha (PGC-la) by at least 33% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine; or d) oral administration of the composition reduces cold allodynia by at least 18 % at 4°C more than the combined individual effects of Palmitoylethanolamide, acetyl- l-camitine and Uridine; or e) oral administration of the composition reduces hot allodynia by at least 26 % at 55 °C more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine; or f) oral administration of the composition reduces mechanical allodynia by at least 42% more than the combined individual effects of Palmitoylethanolamide, acetyl-l-camitine and Uridine. g) oral administration of the composition enhances hot plate latency by at least 27% more than the combined individual effects of Palmitoylethanolamide, acetyl-l- camitine and Uridine.
9. The synergistic bioactive composition as claimed in claim 1, wherein the composition is used for the treatment or management of a condition selected from pain, neuromuscular pain, neuromuscular inflammation, nerve damage, nerve health, or nerve function.
10. The synergistic bioactive composition as claimed in claim 1, wherein the composition comprises: a) palmitoylethanolamide in an amount ranging from 25 mg to 2000 mg, b) Acetyl carnitine in an amount ranging from 25 mg to 4000 mg, c) uridine in an amount ranging from 0.1 mg to 500 mg; wherein palmitoylethanolamide, Acetyl carnitine, and uridine are present in a ratio ranging from 1:0.0125:0.00005 to 1: 160:20; wherein the composition is for oral administration; and wherein oral administration of the composition improves motor nerve conduction velocity by at least 18 % and improves serum peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-la) by at least 33% more than the combined individual effects of Palmitoylethanolamide, acetyl -1 -carnitine and
Uridine.
PCT/IN2025/050331 2024-03-08 2025-03-07 A synergistic bioactive composition for controlling neuromuscular pain and repairing nerve damage Pending WO2025186837A1 (en)

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Citations (3)

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RU2701720C1 (en) * 2018-04-12 2019-10-01 Общество С Ограниченной Ответственностью "Валента - Интеллект" Combinations of palmitoylethanolamide for treating chronic pain
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2701720C1 (en) * 2018-04-12 2019-10-01 Общество С Ограниченной Ответственностью "Валента - Интеллект" Combinations of palmitoylethanolamide for treating chronic pain
IN201921010547A (en) * 2019-03-19 2021-02-05
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