DESC:F O R M 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]

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1. TITLE OF THE INVENTION: METHOD FOR MANUFACTURE OF PALMITOYLETHANOLAMIDE

2. APPLICANT (A) NAME: BIO-GEN EXTRACTS

(B) ADDRESS: BIO-GEN HOUSE, 254/1-9, 3RD
FLOOR, 11TH MAIN ROAD, 3RD PHASE, PEENYA INDUSTRIAL AREA, BANGALORE 560 058, KARNATAKA INDIA

3. NATIONALITY (C) INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

PRIORITY CLAIM
[001] The instant patent application is related to and claims priority from the co-pending India provisional patent application entitled, “METHOD FOR MANUFACTURE OF PALMITOYLETHANOLAMIDE”, Patent Application no.: 202241060443, Filed on: 21 October 2022, which is incorporated in its entirety herewith.
[002] BACKGROUND OF THE DSCLOSED EMBODIMENTS:
[003] Technical field
[004] The disclosed embodiment is in the technical field of a composition and method comprising palmitoylethanolamide (PEA). More particularly, it relates to method for manufacture of palmitoylethanolamide (PEA).
[005] Related art
[006] Palmitoylethanolamide (N-(2-hydroxyethyl) hexadecanamide, PEA)), also known as palmitoylethanolamide or palmidrol, is a naturally occurring C16:0 fatty acid derivative wherein the carboxylate function is amidated by the primary amine of ethanolamine. N-acylethanolamine compounds are known to have anti-inflammatory and anti-nociceptive effects, as described in Lambert et al (Lambert DM, Vandevoorde S, Jonsson KO, and Fowler CJ. Curr Med Chem 2002; 9:663-74); Lambert DM et al (Lambert DM, DiPaolo FG, Sonveaux P Kanyonyo M, Govaerts SJ, Hermans E, Bueb J, Delzenne NM, Tschirhart EJ. Biochim Biophys Acta. 1999, 1410:266-74): Brown AJ (Br J Pharmacol. 2007:152(5):567-75); and US 5,506,224 and US 2005/0054730.
[007] A large number of scientific investigations on the effects of PEA and PEA-related compounds are available and give rise to new therapeutic opportunities. Multiple synthetic procedures of PEA have been reported.
[008] PEA can for example be prepared via the coupling of palmitic acid and ethanolamine in the presence of a coupling reagent. Exemplary coupling routes for synthesis of PEA involve the use of 1-Ethyl-3-(3-dimethylaminopropyl) carbodimide (EDCI) in the presence of 4 dimethylaminopyridine (DMAP) in methylene chloride (WO2015/179190, or 1-Cyano-2-ethoxy-2oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) in the presence of Di-isopropylethylamine (DIPEA) in a mixture of methylene chloride and acetonitrile (Chemistry and physics or lipids 2012, 165, 705).
[009] In addition, further examples involve 2-(1H- Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) in the presence of triethylamine in acetonitrile (Bioorganic and Medicinal Chemistry 2011, 19, 1520), N, N'-carbodimide (CDI) in methylene chloride (Tetrahedron Letters 1980, 21, 841) or N, N'-dicyclohexylcarbodiimide (DCC) in the presence or DMAP in methylene chloride (Chemistry Letters; (1985); p.701).
[010] The synthesis of PEA typically involves aqueous workup and purification using flash chromatography, often in combination with crystallization. Alternatively, PEA can be prepared by reacting palmitic acid with acetic anhydride followed by ethanolamine (J. Am. Chem. Soc., 1952y 74 (13), 3442), or via aminolysis of isopropyl palmitate and ethanolamine in the presence of sodium ethoxide/ethanol (US2016/038443), via aminolysis of ethyl, methyl, or vinyl palmitate or the reaction of palmitoyl chloride and ethanolamine in the presence of a base.
[011] Moreover, synthesis of PEA has been reported using activation of palmitic acid via the formation of an active ester (Archiv der Pharmazie 342 (2009) 34; W02006/109321.
[012] It was shown in various studies that people with pain caused by diverse health conditions such as women with pelvic pain caused by endometriosis, fibromyalgia, Diabetics with pain from carpal tunnel syndrome caused by nerve compression, Cancer pain, and Arthritis pain do not have any specific medication or anti-inflammatory painkiller which could relieve the pain caused.
[013] With chronic pain, the levels of PEA are low as they are constantly having to dampen an overactive immune system. By supplementing this level, the body would be able to dampen the over-excited nerves and thus reduce pain.
[014] However, there is always a challenge to get high purity Palmitoylethanolamide.
[015] Therefore, there is a need to produce Palmitoylethanolamide with high purity in order to combat such pain and inflammation.
[016] SUMMARY OF THE DISCLOSURE:
[017] According to an aspect of the disclosed embodiment relates to a composition and method comprising medicinal chemistry. More particularly, it relates to method for manufacture of palmitoylethanolamide (PEA).
[018] According to an aspect of the disclosed embodiment, a method for producing Palmitoylethanolamide, wherein the method comprising:
(i) combining Palmitic acid and Thionyl chloride in a ratio of 2:1 and reacting for about 3 hours at 80 degrees Celsius;
(ii) removing the unreacted Thionyl chloride using a distillation process to obtain a first mixture;
(iii) adding Tetrahydrofuran, Triethylamine and Ethanolamine to the first mixture and heating for about 3 hours at 80 degrees Celsius;
(iv) removing the Tetrahydrofuran using the distillation process to obtain a second mixture;
(v) adding Diisopropyl ether to the second mixture for crystallization of the second mixture, wherein the crystallization is performed between 0 to 5 degrees Celsius for about 6 to 8 hours;
(vi) centrifuging the crystallized second mixture to obtain a third mixture, wherein the Diisopropyl ether is recovered after centrifugation; and
(vii) drying the third mixture at 60 to 65 degrees Celsius to obtain the Palmitoylethanolamide.
[019] According to one more embodiment, the method includes adding ethyl acetate and caustic soda to the first mixture and heating for about 3 hours at 80 degrees Celsius.
[020] According to another embodiment, isopropyl alcohol is added to the second mixture for crystallization of the second mixture.
[021] According to yet another embodiment, the dried Palmitoylethanolamide is micronized to obtain a particle size between 4 microns to 10 microns.
[022] According to another embodiment, the produced Palmitoylethanolamide comprises 98% to 100% purity.
[023] According to an aspect of the disclosed embodiment, a Palmitoylethanolamide composition, wherein the composition comprising,
(i) 85 to 95% by weight of the Palmitoylethanolamide, and (ii) 5 to 15% by weight of at least one additive,
the additive is selected from Micro Crystalline Cellulose Powder with Vitamin E TPGS, Micro Crystalline Cellulose Powder with Polysorbate 80, Modified Food Starch with Vitamin E TPGS, Modified Food Starch with Polysorbate 80, Gum Arabic with Vitamin E TPGS, Modified Food Starch with Sunflower Lecithin, Gum Arabic with Sunflower Lecithin, Modified Food Starch with Medium Chain Triglycerides, Gum Arabic with the Medium Chain Triglycerides, Modified Food Starch with phosphatidylserine or phosphatidylcholine and Gum Arabic with phosphatidylserine or phosphatidylcholine.
[024] According to one more embodiment, the composition comprising,
(i) 90% by weight of Palmitoylethanolamide, and (ii) 10% by weight of at least one additive,
the additive is selected from Micro Crystalline Cellulose Powder with Vitamin E TPGS, Micro Crystalline Cellulose Powder with Polysorbate 80, Modified Food Starch with Vitamin E TPGS, Modified Food Starch with Polysorbate 80, Gum Arabic with Vitamin E TPGS, Modified Food Starch with Sunflower Lecithin, Gum Arabic with Sunflower Lecithin, Modified Food Starch with Medium Chain Triglycerides, Gum Arabic with the Medium Chain Triglycerides, Modified Food Starch with phosphatidylserine or phosphatidylcholine and Gum Arabic with phosphatidylserine or phosphatidylcholine.
[025] According to yet another embodiment, the Medium Chain Triglycerides are obtained from palm or coconut.
[026] According to another embodiment, the composition is produced as a soft-gel capsule, two-piece hard-shell capsule, tablet, gum, powder mix, stick pack, beverage, pastille, emulsion, functional food, or a tincture.
[027] Several aspects of the disclosed embodiments are described below with reference to examples for illustration. However, one skilled in the relevant art will recognize that the invention can be practiced without one or more of the specific details or with other methods, components, materials and so forth. In other instances, well-known structures, materials, or operations are not shown in detail to avoid obscuring the features of the invention. Furthermore, the features/aspects described can be practiced in various combinations, though only some of the combinations are described herein for conciseness.
[028] BRIEF DESCRIPTION OF THE DRAWINGS:
[029] Example embodiments of the disclosed embodiments will be described with reference to the accompanying drawings briefly described below.
[030] FIG.1 Illustrates a first method of manufacturing Palmitoylethanolamide, according to the aspects of the disclosed embodiment.
[031] FIG.2 Illustrates a second method of manufacturing Palmitoylethanolamide, according to the aspects of the disclosed embodiment.
[032] In the drawings, like reference numbers generally indicate identical, functionally similar, and/or structurally similar elements. The drawing in which an element first appears is indicated by the leftmost digit(s) in the corresponding reference number.
[033] DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS:
[034] It is to be understood that the present disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.
[035] The use of “including”, “comprising” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. The terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. Further, the use of terms “first”, “second”, and “third”, and the like, herein do not denote any order, quantity, or importance, but rather are used to distinguish one element from another.
[036] As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise. By way of example, “a dosage” refers to one or more than one dosage.
[037] The terms “comprising”, “comprises” and “comprised of” as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps.
[038] All documents cited in the present specification are hereby incorporated by reference in their totality. In particular, the teachings of all documents herein specifically referred to are incorporated by reference.
[039] Example embodiments of the disclosed embodiment are described with reference to the accompanying figures.
[040] In the drawings, like reference numbers generally indicate identical, functionally similar, and/or structurally similar elements. The drawing in which an element first appears is indicated by the leftmost digit(s) in the corresponding reference number.
[041] The spray drying process involves the atomization of a solution, slurry, or emulsion containing one or more components of the desired product into droplets by spraying followed by the rapid evaporation of the sprayed droplets into solid powder by hot air at a certain temperature and pressure.
[042] DEFINITIONS:
[043] The term ‘Palmitoylethanolamide (PEA)’ means a chemical made from fat. It is found naturally in foods such as egg yolks and peanuts, and in the human body.
[044] The term ‘Palmitic Acid’ means a saturated long-chain fatty acid with a 16-carbon backbone. Palmitic acid is found naturally in palm oil and palm kernel oil.
[045] The term ‘Distillation’ means the process of separating the components or substances from a liquid mixture by using selective boiling and condensation.
[046] The term ‘Tetrahydrofuran’ means a flammable liquid heterocyclic ether that
[047] is derived from furan and used as a solvent and as an intermediate in organic synthesis.
[048] The term ‘Thionyl chloride’ is an inorganic compound with the chemical formula SOCl2. It is a moderately volatile, colourless liquid with an unpleasant acrid odour.
[049] The term ‘Glial modulators’ a novel pharmacological approach to altering the behavioral effects of abused substances - PMC.
[050] The term ‘Ethyl acetate’ is a widely used solvent, especially for paints, varnishes, lacquers, cleaning mixtures, and perfumes.
[051] The term ‘sodium hydroxide (NaOH), also called caustic soda or lye, a corrosive white crystalline solid that contains the Na+ (sodium) cation and the OH- (hydroxide) anion.
[052] 1. EMBODIMENTS OF THE DISCLOSURE:
[053] The disclosed embodiment relates to a composition and method comprising medicinal chemistry. More particularly, it relates to method for manufacture of palmitoylethanolamide (PEA).
[054] PEA reduces the production of inflammatory compounds. A major effect of PEA is on receptors of cells that control all aspects of cellular function. These receptors are known as PPARs. PEA and other compounds that help activate PPARs reduce pain and also enhance metabolism by burning fat, reduce serum triglycerides, increase serum HDL cholesterol, improve blood sugar control, and promote weight loss.
[055] PEA is a glial cell modulator. Glial cells are central nervous system cells which release many inflammatory substances that act upon neurons, amplifying pain. Over time, it tones down overactive pain receptors into resting states.
[056] 2. DESCRIPTION – PALMITOYLETHANOLAMIDE:
[057] PEA was identified in the 1950s as being an active anti-inflammatory agent in chicken egg yolk. In mammals, PEA is produced on demand from the lipid bilayer and is ubiquitous, with tissue concentrations in the mid to high pmol/g range being found in rodents. Preclinical and clinical studies suggest PEA may potentially be useful in a wide range of therapeutic areas, including eczema, pain and neurodegeneration and at the same time to be essentially devoid of unwanted effects in humans.
[058] Mechanism of action of Palmitoylethanolamide:
[059] PEA has been shown to exert its anti-hyperalgesic effects by down-modulating several inflammatory mediators such as inflammatory cytokines, neutrophil infiltration, pro-inflammatory enzymes such as cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS), pro inflammatory kinases such as mitogen-activated protein kinase (MAPK), neurotrophic factors such as nerve growth factor (NGF) and mast cell degranulation via the ‘Autocoid Local Injury Antagonism’ (ALIA) mechanism, inhibiting the release of histamine, PGD2 and TNF-a. Studies using animal models of chronic inflammation and chronic or neuropathic pain suggest that PEA can reduce the recruitment and activation of mast cells, the production of pro-inflammatory mediators, and endoneural edema, thus reducing both pain and inflammation while preserving peripheral nerve morphology. This is supported by evidence indicating a crucial role of the endocannabinoids in controlling neuronal excitability at the level of the spinal cord in a clinically relevant rat model of OA. PEA also affects endocannabinoid (eCB) signaling through peroxisome proliferator-activated receptor alpha (PPAR-a) activation. It does so by inducing the expression of anti-inflammatory proteins such as I?Ba, which inhibits NF-?b translocation. This in turn suppresses the expression of pro-inflammatory proteins, such as TNF-a, which reduces the recruitment of immune cells. PEA is known to indirectly activate the cannabinoid receptor type 1 (CB1), cannabinoid receptor type 2 (CB2), transient receptor potential cation channel subfamily V member 1/vanilloid receptor 1 (TrpV1) and peroxisome proliferator activated receptor gamma (PPAR-?). It does so by preventing the FAAH mediated degradation of homologous cannabinoid, N-arachidonoylethanolamine/anandamide (AEA) that activates these receptors. CB1 and CB2 are two G-protein-coupled receptors (GPCRs) that have analgesic properties when activated. CB1 receptors are often expressed in the presynaptic terminals of the brain where they inhibit neurotransmitter release, in the peripheral nervous system and in the adipose tissue, skeletal muscle, bone, skin, heart, liver, reproductive organs and gastrointestinal system. Effects on chronic and neuropathic pain symptoms have been confirmed in numerous clinical conditions.
[060] Clinical efficacy: The use of Palmitoylethanolamide in the clinical practice has shown to improve clinical symptoms, including pain and functionality, manifesting in many diseases of inflammatory, traumatic and neurodegenerative type and affecting both Central and Peripheral Nervous Systems. Knee osteoarthritis (KOA) affects nearly 30% of adults aged 60 years or older and causes significant pain and disability.
[061] Neurophysiological testing (quantitative sensory testing (QST)) demonstrates that KOA pain has both peripheral and central mechanisms, which vary by individual.
[062] Adults with central KOA pain tend to be resistant to traditional pain treatment and have substantial pain even after knee replacement surgery.
[063] There is a growing body of evidence to support the scientific premise that endocannabinoids and related molecules, in particular PEA, can improve KOA pain through anti-inflammatory and analgesic pathways.
[064] PEA has little or no known side effects and is safe for human consumption.
[065] PEA reportedly inhibits the release of pro-inflammatory mediators from activated mast cells and reduces the recruitment and activation of mast cells at sites of nerve injury, events associated with anti-allodynic and anti-hyperalgesic effects in a model of neuropathic pain. Moreover, after peripheral nerve injury as well as following spinal neuroinflammation or spinal cord injury, PEA treatment inhibited microglia activation and the recruitment of mast cells into spinal cord. PEA
[066] PHARMACOLOGY:
[067] PHARMACODYNAMICS: Palmitoylethanolamide is an endogenous n-acylethanolamine, chemically similar to the endocannabinoid anandamide with a biological activity spectrum largely common. The main difference between these two molecules concerns the inability of Palmitoylethanolamide to interact with the CB1 receptor, responsible for the psychotropic effects of endocannabinoid, thus its intake is not associated to these central effects. Palmitoylethanolamide has anti-inflammatory effects, concerning the peripheral inflammatory processes and the central neuroinflammation, and analgesic effects, which are evident both in acute and chronic neuropathic pain conditions, and highlighted by several clinical trials in vitro and in vivo and by an increasing number of clinical trials.
[068] PHARMACOKINETICS:
[069] The Palmitoylethanolamide time profile in human plasma, following oral administration of a single dose ranging from 300 and 1200mg, shows a dose-dependent increase of Palmitoylethanolamide concentration. The peak plasma level of Palmitoylethanolamide is observed 1 hour after the intake; then plasma level decreases returning to basal value within 6 hours. After 1 hour, Palmitoylethanolamide plasma levels become about the double of basal ones after the intake of a 300mg tablet, while increase seven times after the intake of 1200mg. Trials studies have shown that after oral administration, Palmitoylethanolamide spreads equally over all the tissues; a small percentage of the molecule passes across the hemato·encephalic barrier, reaching the brain tissues. The pharmacokinetics of PEA have been well characterized in the rat. Tissue uptake of 14 labelled PEA administered intraperitoneally was demonstrated to be greatest in the adrenal glands, followed by the diaphragm, spleen, kidneys, testis, lung, liver, heart, brain, plasma, and erythrocytes. Uptake of orally administered 3H-labelled PEA, however, was found to be highest in the hypothalamus, followed by the pituitary and adrenal glands. Peak plasma concentration (20-fold increase from baseline) was found to occur 15 minutes after oral administration.43 However, in humans, oral administration of PEA (in micronized and ultra-micronized forms) has been demonstrated to result in a two-fold increase in plasma PEA levels at two hours. Thus, orally administered PEA accumulates in plasma and is able to penetrate target organs including the blood-brain barrier.
[070] INDICATIONS:
[071] Palmitoylethanolamide acts in the body promoting the control of the physiologic tissue reactivity, also in presence of a high oxidative stress. Thus, it is intended to be used under medical supervision in the dietary regimen of those subjects affected by disorders sustained by tissue mast cell hyper-reactivity. In these subjects, it appears useful as a physiological intervention to counteract the endogenous production deficit of Palmitoylethanolamide, when recurrent inflammatory conditions compromise their endogenous biosynthetic rate.
[072] The clinical indications of PEA are:
[073] Neuropathic and inflammatory pain.
[074] Neurodegenerative conditions.
[075] Ischaemic stroke and brain injury.
[076] Topical use for dermatitis.
[077] Use for allergies (preventing mast cell de-granulation).
[078] 3. COMPOSITION OF THE DISCLOSED EMBODIMENT:
[079] According to the embodiment, invention comprises a water dispersible or water-soluble version of PEA with certain additives and excipients, which can be used independently or in combination.
[080] In one embodiment composition comprises:
[081] A. PEA - 85% to 95%, and
[082] B. Combinations of the following that make up the remaining 5%-15%:
a. Micro Crystalline Cellulose Powder with Vitamin E TPGS combined 5% to 15%
b. Micro Crystalline Cellulose Powder with Polysorbate 80 combined 5% to 15%
c. Modified Food Starch with Vitamin E TPGS combined 5% to 15%
d. Modified Food Starch with Polysorbate 80 combined 5% to 15%
e. Gum Arabic with Vitamin E TPGS combined 5% to 15%
f. Modified Food Starch with Sunflower Lecithin combined 5% to 15%
g. Gum Arabic with Sunflower Lecithin combined 5% to 15%
h. Modified Food Starch with Medium Chain Triglycerides from palm or coconut combined 5% to 15%
i. Gum Arabic with Medium Chain Triglycerides combined 5% to 15%
j. Modified Food Starch with phosphatidylserine or phosphatidylcholine combined 5% to 15%
k. Gum Arabic with phosphatidylserine or phosphatidylcholine combined 5% to 15%
[083] 4. METHOD OF PREPARATION OF PALMITOYLETHANOLAMIDE:
[084] EXAMPLE EMBODIMENT METHOD 1:
[085] Method of preparation: The steps involve in the manufacturing method of PEA -
[086] Initiating a 3-hour reaction at 80 degrees Celsius (104) between 100 kg of Palmitic acid and 53 kg of Thionyl chloride (102). Employing distillation to remove any unreacted Thionyl chloride (106). Adding 700 L of Tetrahydrofuran to the distillate, along with 39.4 kgs of Triethylamine and 25 kgs of Ethanolamine (108), and maintaining this mixture for 2 hours. Conducting a second distillation to remove Tetrahydrofuran (110), followed by introducing 800 L of Diisopropyl ether (120) and initiating a crystallization process lasting 6-8 hours (112). Subsequent to the crystallization process, subjecting the obtained product to centrifugation to recover Diisopropyl ether (114). Allowing the recovered Diisopropyl ether to dry at temperatures ranging from 60 to 65 degrees Celsius (116). Carrying out milling (118) to obtain the product Palmitoylethanolamide (120) (FIG.1).
[087] EXAMPLE EMBODIMENT METHOD 2:
[088] Method of preparation: The steps involve in the manufacturing method of Palimtoylethanolaminde. In this second method, Tetrahydrofuran & triethylamine are replaced with ethyl acetate + caustic soda and Di-isopropyl ether is replaced with isopropyl alcohol in centrifuge.
[089] Taking Palmitic Acid and Thionyl Chloride (202) Reducing the temperature at 800 C for 3 hours (204). Distilling for removing unreacted Thionyl Chloride (206). Adding Ethanolamine and Dimethyl Formamide (208). Forming Reageant A Methylene dichloride (210). Stiring Acetyl Chloride at 10- 150 C (212). Distillation/ Recovering MDC (214). Maintaining for Ethyl Acetate adding with 20%Caustic Soda for 2 hours (216). Distilling/ removing Ethyl Acetate (218). Crystalizing Isopropyl Alcohol (220) Centrifuging/ Recovering Isopropyl Alcohol (222). Drying (224) Micronisating (226) Palmitoylethanolaminde (228) (FIG.2).
[090] EXAMPLE EMBODIMENT 3:
[091] CLINICAL STUDY PROTOCOL:
[092] STUDY TITLE: A multi-center, double-blind, randomized, three-arm, interventional, parallel, placebo-controlled study to evaluate the efficacy, safety and tolerability of Palmitoylethanolamide in subjects with symptoms of knee osteoarthritis.
[093] PRIMARY OBJECTIVE: To assess the efficacy of Palmitoylethanolamide in subjects with symptoms of knee osteoarthritis
[094] SECONDARY OBJECTIVE: To assess safety and tolerability of Palmitoylethanolamide in subjects with symptoms of knee osteoarthritis.
[095] STUDY DESIGN: This is a randomized, double-blind, and three-arm, parallel, placebo-controlled multi-centre study to evaluate the efficacy and safety of Palmitoylethanolamide in subjects with symptoms of knee osteoarthritis. Enrollment will include approximately 40 knee osteoarthritis subjects in each arm meeting inclusion criteria and none of the exclusion criteria. The trial is composed of a Screening Period of 7 days, a Treatment Period of 12 weeks, and a Safety Follow-up Period of 2 weeks. After completing the 12-week Treatment Period, subjects will enter into safety follow up period.
[096] STUDY POPULATION: The study will be conducted at approximately 2-3 sites in INDIA. Sites will be selected based on previous study experience in KOA and accessibility to study required populations. It is expected that each research centre will be able to identify sufficient subjects that meet all the inclusion and none of the exclusion criteria.
[097] The study population will consist of male and female subjects (35-65 years) with KOA.
[098] INCLUSION CRITERIA:
[099] In order to be eligible to participate in this study, a subject must meet all of the following criteria: 1. Males and females between 35 to 65 years of age (including both). 2. Subjects having pain associated to mild to moderate Knee Osteoarthritis in one or both Knees. 3. A pain intensity score of = 4 as evaluated by the NRS (Numerical Rating Scale). 4. Ability to communicate effectively. 5. Voluntary participation. 6. Self-reported average knee pain over the past month at least 4 out of 10 on a 0-10 NRS (Numerical Rating Scale). 7. No anticipated surgical procedures. 8. Assessed as otherwise healthy (except for Knee Osteoarthritis), based on a pre-study examination including medical history, physical examination, and clinical laboratory investigations. The examination will be performed by a physician. 9. Willingness and ability to give written informed consent and willingness and ability to comply with the study requirements.
[0100] EXCLUSION CRITERIA:
[0101] A potential subject who meets any of the following criteria will be excluded from participation in this study:
[0102] 1. Known history of hypersensitivity to PEA or herbal extracts or dietary supplements. 2. Having a pain intensity score 35kg/m23. Subjects diagnosed to have arthritis other than Knee osteoarthritis.4. BMI >35kg/m25. Knee injury in the past 06 months. 6. Knee surgery in the past 12 months or total knee replacement. 7. Enrolled in other knee osteoarthritis rehabilitation programs or clinical trials.8. Any condition likely to interfere with normal gastro-intestinal absorption of PEA. 9. History or presence of diseases attributable to psychiatric disorders and subjects undergoing, or scheduled to undergo, physiotherapy, radiotherapy, or chemotherapeutic treatment. 10. Presence of systemic diseases like hyper-cholesterolemia, renal disorder, liver disorder, and other debilitating diseases. 11. Oral or intra-articular glucocorticoid use in the prior 3 months; intra-articular hyaluronate use in the prior 6 months. 12. Allergy to oat, coconut, citrus, olive, or sunflower oils, or maltodextrin.13. On-going treatment with herbals drugs. 14. History of having received any investigational drug or participated in any other clinical trial which ended in the preceding three months or currently ongoing.15. Females who are pregnant, lactating or nursing. 16. Females who intend to become pregnant during the study. 17. Have a family history (more than one first degree relative) of multiple thrombotic events (more than one per person) or a personal history of any venous or arteria thrombotic event including deep vein thrombosis, stroke, myocardial infarction, pulmonary embolus, and peripheral arterial thromboembolic events or abnormal ECG which may impact the subject’s safety as per Investigator’s opinion.
[0103] 18. Positive hepatitis panel (including hepatitis B surface antigen [HBsAg], and / or antihepatitis B core antibodies, and / or hepatitis C virus antibody [anti-HCV]), and / or a positive Human immunodeficiency virus (HIV) antibody screen, based on the current medical data of the subject. 19. History of active or latent tuberculosis. 20. Abnormal hepatic function [alanine aminotransferase (ALT)/aspartate aminotransferase (AST) or bilirubin > 2 x upper limit of normal] at the time of the Screening Visit. 21. Abnormal renal function [Blood Urea Nitrogen (BUN) or creatinine >1.25 x upper limit of normal] at the time of the Screening Visit. 22. Clinically significant out-of-range values on hematology panel, at the discretion of the investigator. 23. Any other relevant abnormalities in the routine laboratory tests 24. Any condition that in the opinion of the investigator does not justify the subject’s inclusion for the study. 25. History of substance abuse or alcohol abuse. 26. History of blood donation within 3 months before screening.
[0104] RANDOMIZATION:
[0105] Subject randomization will take place before the start of administration of the IMP. Subjects will be randomized in a 1:1:1 ratio to the three treatment arms and stratified by site. Randomization of the subjects will be performed by GK analytics, Hyderabad, India. The randomization number will be recorded on the CRF. Once the numbers have been assigned, they cannot be reassigned. Subjects in this trial will be randomized in a 1:1:1 ratio to receive one of three dose groups. Palmitoylethanolamide Capsules 300 mg (150mg x 2) from day 1 to end of the treatment. Palmitoylethanolamide Capsules 600 mg (300mg x 2) from day 1 to end of the treatment. Placebo from day 1 to end of the treatment.
[0106] INVESTIGATIONAL PRODUCTS DETAILS:
[0107] Treatment Arm (A):
[0108] Name of IP: Palmitoylethanolamide Capsules 150 mg (150 mg x 2 Capsules).
[0109] Dose Strength: (150 mg x 2 Capsules = 300 mg per day).
[0110] Supplied by: Science and technology
[0111] Treatment Arm (B):
[0112] Name of IP: Palmitoylethanolamide Capsules 300 mg (300 mg x 2 Capsules).
[0113] Dose Strength: (300 mg x 2 Capsules = 600 mg per day)
[0114] Supplied by: Science and technology
[0115] Treatment Arm (C): Placebo.
[0116] ADMINISTRATION OF INVESTIGATIONAL PRODUCTS:
[0117] Subjects will receive the treatment products or placebo as per the randomization schedule. The investigational products will be administered as per the below procedure:
[0118] 120 subjects will be randomly assigned one of the three treatment arms (A, B or C) as per the randomization schedule.
[0119] Each subject will self-administer the investigational products as per PI discretion and details will be recorded by the subjects in the subject diary.
[0120] The subject diary and remaining IP’s will be checked at the time of next visit.
[0121] Subject diary and remaining IP’s will be collected from the subject at last visit at week 12.
[0122] STUDY PROCEDURES:
[0123] The Schedule of Assessments (Appendix 3) included in the protocol summarizes the timing of the efficacy and safety measurements.
[0124] The day of the first dose administered to a subject is considered Day 1 for that individual subject. Other study days are calculated with Day 1 as the reference point. Screening will be performed within 07 days prior to the baseline visit and those subjects that are still eligible after the screening visit will be randomized to one of the three treatment groups.
[0125] Treatment will be given from Day 1 to Day 84 (week 12). The subject will be followed up for 14 Weeks (i.e., end of safety follow-up). In the event of early termination, subjects are asked to return for the Week 12 assessments if possible. Otherwise, the subjects are assessed as per Week 12 assessment schedule on the Day of termination.
[0126] PHYSICAL EXAMINATION:
[0127] A full physical examination should include: General appearance, Skin, Head and Neck, Eyes Ears-Nose, Throat, Lymph Nodes palpation, Cardiovascular, Lungs & Chest, Abdomen, Musculoskeletal, and Neurological Function. All other body systems should be assessed at the Investigator’s discretion. A full physical examination will be done at Screening, Baseline and End of treatment and End of study. For remaining visits, it will be up to the judgement of the Investigator if a full or abbreviated exam is completed.
[0128] VITAL SIGNS:
[0129] Vital signs will be measured in supine posture after 5 minutes of rest and will include blood pressure (BP), heart rate, respiratory rate, and temperature. The method of temperature assessment must remain consistent for each individual subject throughout the study. Subject blood pressure and heart rate will be measured using an automatic device (whenever possible) after the subject has rested (supine) comfortably for 5 min. Vital signs will be measured at the time points specified in the schedule of assessments.
[0130] QUALITY OF LIFE (PROMIS-29) MEASUREMENT:
[0131] PROMIS Pain Interference (PROMIS-PI) scale measures the extent to which pain hinders an individual's engagement with physical, mental, cognitive, emotional, recreational, and social activities. PROMIS-PI also includes items related to enjoyment in life and sleep.
[0132] NUMERICAL RATING SCALE (NRS):
[0133] The Numeric Rating Scale (NRS) is the simplest and most commonly used numeric scale in which the individual rates the pain from 0 (no pain) to 10 (worst pain).
[0134] WOMAC SCALE: Index (WOMAC) is widely used in the evaluation of Knee Osteoarthritis.Subjects will be given an explanation on use of different scales at screening.
[0135] VISIT-1 (SCREENING VISIT) (DAY 0- WITHIN 07 DAYS PRIOR TO BASELINE VISIT):
[0136] Obtaining written informed consent for the study.
[0137] Measurement of Demographics.
[0138] Complete clinical examination including past history (Medical, family, surgical and Drug history) and vitals measurement.
[0139] History of KOA diagnosis.
[0140] Recording of 12-lead ECG.
[0141] Recording of chest X-Ray (within 30 days prior to enrollment).
[0142] Clinical laboratory investigations.
[0143] Numerical Rating Scale (NRS) experience of pain (subject).
[0144] Measurement of WOMAC scale.
[0145] Evaluation of inclusion and exclusion criteria.
[0146] Table 1: The following Clinical laboratory tests will be performed during screening:
Clinical Laboratory Tests
Hematology RBC count, Platelet count, Hemoglobin, WBC count, Differential count, Peripheral smear, Blood grouping & Rh typing.
Biochemistry Random blood glucose, serum sodium, potassium, chloride.
Hepatic profile – AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin, indirect bilirubin, total protein and albumin.
Renal profile – Serum creatinine, serum urea and serum uric acid.
Urine analysis Complete Urine Examination, which include physical, bio-chemical and microscopic examination.
Serology HIV 1 & 2, HBs (Ag), HCV and VDRL

Clinical Laboratory Tests
Additional tests Serum pregnancy test for female subjects.
[0147] Visit-2: (Baseline Visit/Randomization visit) (Day 1):
[0148] Review of laboratory investigations.
[0149] Full Physical examination.
[0150] Vital signs measurement in supine posture after 5 minutes of rest (blood pressure, heart rate, respiration rate and body temperature.
[0151] Recording of concomitant medication if any.
[0152] Measurement of WOMAC scale.
[0153] Quality of life (PROMIS-29) questionnaire.
[0154] Numerical rating scale (NRS) experience of pain (subject) assessment will be recorded and documented.
[0155] Urine pregnancy test (as applicable).
[0156] Hs-CRP test.
[0157] Any other clinical laboratory investigations if required.
[0158] Reassess the eligibility for enrollment.
[0159] Randomization.
[0160] Issue of subject diary.
[0161] Instructions for self-administration of the IP’s.
[0162] Dispensing of Ips. • Recording of Adverse Events (AE)/ Serious Adverse Events (SAE), if any.
[0163] Visit-3 Follow up visit (Day 28: week 4):
[0164] Full/abbreviated Physical examination.
[0165] Vital signs measurement in supine posture for after 5 minutes of rest (blood pressure, heart rate, respiration rate and body temperature).
[0166] Recording of Adverse Events (AE)/ Serious Adverse Events (SAE), if any.
[0167] Recording of concomitant medication if any.
[0168] Measurement of WOMAC scale.
[0169] Quality of life (PROMIS-29) questionnaire
[0170] Numerical rating scale (NRS) experience of pain (subject) assessment will be recorded and documented.
[0171] Urine pregnancy test (as applicable).
[0172] Clinical laboratory investigations if required.
[0173] Review of subject diary.
[0174] Dispensing of IPs, accountability and compliance check.
[0175] Visit-4 Follow up visit (Day 56: week 8):
[0176] Full/abbreviated Physical examination.
[0177] Vital signs measurement in supine posture for after 5 minutes of rest (blood pressure, heart rate, respiration rate and body temperature).
[0178] Recording of Adverse Events (AE)/ Serious Adverse Events (SAE), if any.
[0179] Recording of concomitant medication if any.
[0180] Measurement of WOMAC scale.
[0181] Quality of life (PROMIS-29) questionnaire.
[0182] Numerical rating scale (NRS) experience of pain (subject) assessment will be recorded and documented.
[0183] Urine pregnancy test (as applicable).
[0184] Clinical laboratory investigations if required.
[0185] Review of subject diary.
[0186] Dispensing of IPs, accountability and compliance check.
[0187] Visit 5- End of treatment and end point assessment (Day 84: week 12):
[0188] Full Physical examination.
[0189] Vital signs measurement in supine posture for after 5 minutes of rest (blood pressure, heart rate, respiration rate and body temperature).
[0190] Recording of Adverse Events (AE)/ Serious Adverse Events (SAE), if any.
[0191] Recording of concomitant medication if any.
[0192] Measurement of WOMAC scale.
[0193] Quality of life (PROMIS-29) questionnaire.
[0194] Numerical rating scale (NRS) experience of pain (subject) assessment will be recorded and documented.
[0195] Hs-CRP test.
[0196] Clinical laboratory investigations.
[0197] ECG will be performed.
[0198] Review and retrieval of subject dairy.
[0199] IP’s accountability and compliance check.
[0200] Visit 6- Telephonic follow up for Safety/End of visit (Day 98: week 14):
[0201] Enquire about concomitant medications, if any.
[0202] Enquire and recording of Adverse Events (AE)/ Serious Adverse Events (SAE), if any. Note: Subjects can visit the hospital within ± 03 days for each visit post the baseline visit.
[0203] EFFICACY VARIABLES AND ANALYSIS:
[0204] Primary Efficacy variables
[0205] Reduction in WOMAC total score from baseline to end of the study duration (12 weeks).
[0206] The study hypothesis for the primary objective is if Treatment A and B is superior in pain intensity reduction as measured with WOMAC scale from baseline to week 12, relative to Treatment C.
[0207] The WOMAC consists of three subdomains; pain (6 questions), stiffness (2 questions) and function (12 questions) (Bellamy et al. 1988).
[0208] WOMAC total score reductions, and reductions in 3 subdomain scores will be analyzed using Mixed Models for Repeated Measures (MMRM) model, including treatment, visit, treatment-by visit interaction with fixed effects, baseline outcome variable as covariate. The Kenward-Roger approximation will be used to estimate denominator degrees of freedom for the MMRM models. Appropriate covariance structure will be used to model the within-subject errors.
[0209] The 2-sided 95% CI of the least-squares (LS) means for individual treatment groups, treatment LS mean differences will be estimated along with p-values for two sets of treatment comparisons (Treatment A vs Treatment C) and (Treatment B vs Treatment C). This primary analysis will be performed on ITT population. Same analysis will be performed on PP population as sensitivity analysis.
[0210] To check the effect of missing data at week 12, ANCOVA analysis will be performed for WOMAC scores at week 12 considering LOCF imputation.
[0211] Requirement of additional multiple imputation approaches to handle missing data will be determined, and implemented through describing in SAP, later after study started.
[0212] Appropriate figure output will be produced with mean and SD reductions in WOMAC scores over visits (Baseline, visit 4, visit 8, visit 12) for each of three treatments.
[0213] Secondary Efficacy Variables.
[0214] Change in inflammatory biomarkers (hs-CRP) from baseline to end of the treatment i.e., 12 weeks.
[0215] Difference in the knee pain intensity
[0216] Improvement in Quality-of-Life (PROMIS-29) measured from baseline to week 4, week 8 and week 12.
[0217] Reduction of WOMAC total score from baseline to week 4 and week 8 as measured with WOMAC scale.
[0218] Change in the usage of rescue medication in the study subjects from week 1 to week 12.
[0219] All secondary efficacy variables data are continuous and similar to primary outcome data, similar primary model analysis will be performed for these secondary efficacy variables.
[0220] All the efficacy variable data including changes from baseline will be summarized using descriptive statistics as well. ITT and PP population will be used for all the secondary efficacy data analysis.
[0221] SAFETY DATA ANALYSIS:
[0222] All the safety data Incidence of adverse events (AEs) and Serious Adverse Events (SAEs), vital signs and laboratory results collected from baseline to Week 12, will be summarized by treatment group descriptive statistics over visits and number of percentages for the events as appropriate.
[0223] ANALYSIS POPULATIONS:
[0224] Below analysis population are defined for the purpose of analysis:
[0225] Safety Population: All subjects who receives at least one dose of the study medication are considered as safety population.
[0226] Intent to Treat (ITT) population: All subjects who receive at least one treatment product or placebo and had at least one post baseline efficacy assessment.
[0227] The Per Protocol (PP) population: It is defined as a subset of the ITT population excluding major protocol violators. The following is a list of some of the conditions which, if met, would likely exclude the patient from the PP population.
[0228] Violation of inclusion or exclusion criteria
[0229] Breaking the blind
[0230] Withdrawal from the study before week 12
[0231] Any other relevant violations observed during the conduct of the trial.
[0232] Blinded Review Report of Deviations Leading to Exclusion from the Per-Protocol Analysis’ document.
[0233] Subjects will be analyzed based on the treatment received. Analyses on the PP population will be seen as sensitivity analyses. The primary and secondary efficacy endpoints will be analyzed for the PP population.
[0234] The list of protocol deviations leading to exclusion from the PP population will be finalized before database lock. During the blinded data review before database lock the PP population will be defined by determining subjects not eligible for the PP population and the reason they cannot be included.
[0235] Analysis of safety data will be based on the safety population (SAF). The primary analysis population for efficacy will be the Intent-to-Treat (ITT) population. Analysis of primary efficacy endpoint and key secondary endpoints will also be performed on the Per-Protocol (PP) population to confirm the findings from the ITT population.
[0236] SAMPLE SIZE JUSTIFICATION
[0237] Sample size was calculated on the primary outcome variable, the WOMAC total score. Based on a power of 80%, a sample size of 35 participants in each of the three arms will be required, with 120 participants recruited to account for potential withdrawals.
[0238] 6. USES, APPLICATIONS AND BENEFITS OF THE INVENTION
[0239] Palmitoylethanolamide (PEA) is a chemical made from fat.
[0240] It is found naturally in foods such as egg yolks and peanuts, and in the human body.
[0241] Palmitoylethanolamide (PEA) is a lipid mediator used in the clinic for its neuroprotective, anti-neuroinflammatory and analgesic properties.
[0242] It is a naturally occurring anti-allergic and anti-inflammatory compound.
[0243] Due to its analgesic and neuroprotective properties, it can provide age-related solutions for pain relief.
[0244] Additionally, due to its analgesic and neuroprotective properties, it can help with muscle health and exercise recovery.
[0245] BEST MODE TO PRACTICE
[0246] The invention can be reconstituted into finished products for use as a dietary supplement.
[0247] In additional embodiments, the dietary supplement is a softgel capsule, two-piece hard-shell capsule, tablet, gummy, powder mix, stick pack, beverage, pastille, emulsion, functional food, tincture or any combination thereof.
[0248] Merely for illustration, only representative number/type of graph, chart, block, and sub-block diagrams were shown. Many environments often contain many more block and sub-block diagrams or systems and sub-systems, both in number and type, depending on the purpose for which the environment is designed.
[0249] While specific embodiments of the invention have been shown and described in detail to illustrate the inventive principles, it will be understood that the invention may be embodied otherwise without departing from such principles.
[0250] Reference throughout this specification to “one embodiment”, “an embodiment”, or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment”, “in an embodiment” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.
[0251] It should be understood that the figures and/or screen shots illustrated in the attachments highlighting the functionality and advantages of the present invention are presented for example purposes only. The present invention is sufficiently flexible and configurable, such that it may be utilized in ways other than that shown in the accompanying figures.
[0252] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
[000] REFERENCES
1. British Journal of clinical Pharmacology: Review of Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy: Author: Linda Gabrielsson, Sofia Mattsson and Christopher J. Fowler: Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy (nih.gov)
2. Monograph of Palmitoylethanolamide (PEA) supports cellular Homeostasis: https://aor.ca/wp-content/uploads/AOR-Marketing-PRO-PEA-Monograph.pdf
3. Summary of Product Characteristics of Normast®: Clinical Study Protocol of Palmitoylethanolamide Protocol/Study No.: AR022-23 Version No & Date.: 01 & 30 May 2023 CONFIDENTIAL Page 39 of 39 https://averin-pharmaceuticals.gr/wpcontent/uploads/2017/08/IMG_20170831_0015.pdf
4. Palmitoylethanolamide (Normast®) in chronic neuropathic pain due to compressiontype lumbosciatic pain: a multicenter clinical study: Author: GUIDA G, DE MARTINO M, DE FABIANI A, CANTIERI L, ALEXANDRE A, VASSALLO GM, ROGAI M, LANAIA F, PETROSINO S: https://medes.com/publication/57184
5. Journal Article: Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different Etiopathogenesis: https://pubmed.ncbi.nlm.nih.gov/22845893/
6. A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain, Published Article 04 September 2022, Pickering, E., Steels, E.L., Steadman, K.J. et al. A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain. Inflammopharmacol 30, 2063–2077 (2022): https://link.springer.com/article/10.1007/s10787-022-01033-8
7. Clinical trials.gov; Mechanisms of Palmitoylethanolamide (PEA) to Alter Pain Sensitivity in Knee Osteoarthritis; Sponsor: University of Maryland, Baltimore: https://clinicaltrials.gov/ct2/show/NCT05406726
8. Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L. A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology. 2019 Jun;27(3):475-485. doi: 10.1007/s10787-019-00582-
9. Epub 2019 Mar 29. PMID: 30927159: https://pubmed.ncbi.nlm.nih.gov/30927159/ 9. Western ontario and mcmaster osteoarthritis index (WOMAC); available in:
10. https://www.yrmc.org/docs/default-source/medservices/womac-osteoarthritisindex.pdf?sfvrsn=0
11. https://clinicaltrials.gov/ct2/show/NCT05406726
12. Petrosino S, Schiano Moriello A. Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review. Int J Mol Sci. 2020 Dec 15;21(24):9526. doi: 10.3390/ijms21249526. PMID: 33333772; PMCID: PMC7765232.
13. https://aci.health.nsw.gov.au/__data/assets/pdf_file/0006/632859/Patient-ReportedOutcome-Measures-Information-System-PROMIS-29-Profile.pdf

,CLAIMS:I / WE claim:
1. A method for producing Palmitoylethanolamide, wherein the method comprising:
i. combining Palmitic acid and Thionyl chloride in a ratio of 2:1 and reacting for about 3 hours at 80 degrees Celsius;
ii. removing the unreacted Thionyl chloride using a distillation process to obtain a first mixture;
iii. adding Tetrahydrofuran, Triethylamine and Ethanolamine to the first mixture and heating for about 3 hours at 80 degrees Celsius;
iv. removing the Tetrahydrofuran using the distillation process to obtain a second mixture;
v. adding Diisopropyl ether to the second mixture for crystallization of the second mixture, wherein the crystallization is performed between 0 to 5 degrees Celsius for about 6 to 8 hours;
vi. centrifuging the crystallized second mixture to obtain a third mixture, wherein the Diisopropyl ether is recovered after centrifugation; and
vii. drying the third mixture at 60 to 65 degrees Celsius to obtain the Palmitoylethanolamide.
2. The method as claimed in claim 1, wherein the method includes adding ethyl acetate and caustic soda to the first mixture and heating for about 3 hours at 80 degrees Celsius.
3. The method as claimed in claim 1, wherein isopropyl alcohol is added to the second mixture for crystallization of the second mixture.
4. The method as claimed in claim 1, wherein the dried Palmitoylethanolamide is micronized to obtain a particle size between 4 microns to 10 microns.
5. The method as claimed in claim 1, wherein the produced Palmitoylethanolamide comprises 98% to 100% purity.
6. A Palmitoylethanolamide composition, wherein the composition comprising,
(i) 85 to 95% by weight of the Palmitoylethanolamide, and (ii) 5 to 15% by weight of at least one additive,
wherein the additive is selected from Micro Crystalline Cellulose Powder with Vitamin E TPGS, Micro Crystalline Cellulose Powder with Polysorbate 80, Modified Food Starch with Vitamin E TPGS, Modified Food Starch with Polysorbate 80, Gum Arabic with Vitamin E TPGS, Modified Food Starch with Sunflower Lecithin, Gum Arabic with Sunflower Lecithin, Modified Food Starch with Medium Chain Triglycerides, Gum Arabic with the Medium Chain Triglycerides, Modified Food Starch with phosphatidylserine or phosphatidylcholine and Gum Arabic with phosphatidylserine or phosphatidylcholine.
7. The composition as claimed in claim 6, wherein the composition comprising,
(i) 90% by weight of Palmitoylethanolamide, and (ii) 10% by weight of at least one additive,
wherein the additive is selected from Micro Crystalline Cellulose Powder with Vitamin E TPGS, Micro Crystalline Cellulose Powder with Polysorbate 80, Modified Food Starch with Vitamin E TPGS, Modified Food Starch with Polysorbate 80, Gum Arabic with Vitamin E TPGS, Modified Food Starch with Sunflower Lecithin, Gum Arabic with Sunflower Lecithin, Modified Food Starch with Medium Chain Triglycerides, Gum Arabic with the Medium Chain Triglycerides, Modified Food Starch with phosphatidylserine or phosphatidylcholine and Gum Arabic with phosphatidylserine or phosphatidylcholine.
8. The composition as claimed in claim 6, wherein the Medium Chain Triglycerides are obtained from palm or coconut.
9. The composition as claimed in claim 6, wherein the composition is produced as a soft-gel capsule, two-piece hard-shell capsule, tablet, gum, powder mix, stick pack, beverage, pastille, emulsion, functional food, or a tincture.

Dated this 14th day of October, 2023
Signature.......................................................
(LIPIKA SAHOO)
Registration Number: IN/PA-2467
Agent for Applicant
This document is signed with the digital signature of Patent Agent for the Applicant
LIPIKA SAHOO (IN/PA-2467)