US20190008806A1 - Pharmaceutical composition for neuropathic pain - Google Patents
Pharmaceutical composition for neuropathic pain Download PDFInfo
- Publication number
- US20190008806A1 US20190008806A1 US15/923,079 US201815923079A US2019008806A1 US 20190008806 A1 US20190008806 A1 US 20190008806A1 US 201815923079 A US201815923079 A US 201815923079A US 2019008806 A1 US2019008806 A1 US 2019008806A1
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- pharmaceutical composition
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Classifications
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Definitions
- the present invention relates to a pharmaceutical composition/formulation for use in controlling neuropathic pain. More particularly, the invention relates to a composition/formulation comprising a synergistic combination of Palmitoylethanolamide (PEA) and one or more natural ingredients.
- PDA Palmitoylethanolamide
- pharmacological agents are generally employed to treat diverse pathological pain states. Specifically, these pharmacological agents include opiates, nonsteroidal anti-inflammatory drugs, anticonvulsants, antidepressants, ketamine and others (Guindon et al., 2007). However, adverse side effects from these pharmacological agents constrain therapeutic dosing ultimately limiting therapeutic efficacy.
- Neuropathic pain is one such chronic pain, which needs good clinical management.
- Neuropathic pain is defined as a pain that comes from problems with signals from the nerves.
- Neuropathic pain is different from the common type of pain caused by an injury, burn, pressure, etc. Indeed, neuropathic pain results from damage to or dysfunction of the peripheral or central nervous system, rather than stimulation of pain receptors.
- Diagnosis is suggested by out of proportion pain to tissue injury, dysesthesia (e.g., burning, tingling), and signs of nerve injury detected during neurologic examination. While different therapies have been suggested for treating and managing Neuropathic pain, one therapy in particular suggests employing Palmitoylethanolamide (PEA).
- PDA Palmitoylethanolamide
- PEA is an endogenous, fatty acid amide food component first discovered in the late 1950s when it was shown that the anti-allergic and anti-inflammatory activity exerted by egg yolk, peanut oil or soybean lecithin was due to a specific lipid fraction corresponding to PEA (Esposito and Cuzzocrea, 2013). PEA, was used many decades ago in some countries, but due to a lack of insight in its mechanism of action, interest weaned. Since the 1990s, interest surged again due to the discovery of its effects in many different animal paradigms for pain and chronic inflammation (J Pain Res. 2012; 5: 437-442). PEA is synthesized and metabolized by different animal cell types and is also present in herbs or plants. It exerts a multitude of physiological functions related to metabolic and cellular homeostasis. It is a key element in the regulation of pathways linked to the inflammation process particularly in the down-regulation of the mastocytes degranulation process, and processes underlying itching and pain.
- FAAH fatty acid amide hydrolase
- AAH is a membrane-bound serine hydrolase that belongs to the amidase signature family of hydrolases.
- FAAH enzyme breaks down fatty acid amides such as anandamide (N-arachidonoylethanolamide), N-oleoylethanolamide (N-OEA), PEA and oleamide.
- FAAH belongs to a large and diverse class of enzymes referred to as the amidase signature (AS) family.
- FAAH Inhibitors are a class of molecules that inactivate the FAAH Enzymes by preventing the hydrolysis of anandamide, oleoylethanolamide and PEA. It thereby increases endogenous levels.
- Known chemically synthesized FAAH inhibitors are BIA 10-2474, URB524, URB-597, URB694, URB937, etc. These inhibitors are disclosed in the article published by Colombano et al. titled, “O-(Triazolyl) methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors” and in the article published by Otrubova et al. titled, “The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH).”
- U.S. Pat. No. 5,506,224 refers to a method for treating diseases involving mast cell degranulation, as a consequence of a neurogenic and/or immunogenic hyper-stimulation, comprising the administration of an effective amount of a series of compounds included in a general formula, comprising also the PEA.
- EP1082292 discloses a composition comprising anandamide and PEA.
- WO 2001/010434 describes a pharmaceutical composition comprising PEA in micronized form having particle size less than 10 ⁇ m for use in the veterinary field.
- WO 2001/024645 discloses a nutritional or therapeutic composition for oral administration, which comprises a naturally occurring precursor that is metabolized to a compound having anandamide activity for use as a medicament, in which such precursor is a long chain polyunsaturated fatty acid (LCPUFA) (e.g. arachidonic acid ARA or docosahexaenoic acid DHA) or a derivative thereof having a given general formula.
- LCPUFA long chain polyunsaturated fatty acid
- the composition also comprises an inhibitor of an anandamide inactivating enzyme (amidase), which is said to include PEA.
- an anandamide inactivating enzyme aminodase
- WO 2002/080860 and WO 2005/046580 refers to a method of reducing food intake or reducing appetite in a mammal, said method comprising orally administering a fatty acid alkanolamide compound, derivative, homolog, or analog.
- PEA is reported to be one of such fatty acid alkanolamide compounds.
- WO 2011/027373 A1 discloses a pharmaceutical composition containing an ultramicronized form of PEA, in which more than 90% by weight of PEA has particle sizes lower than 6 microns (mm).
- NL2011448 discloses a pharmaceutical composition comprising PEA particles and/or pharmaceutically acceptable esters or salts thereof, in which the PEA particles are substantially free of pharmaceutical excipients.
- WO 2013/121449 discloses a use of chemically synthesized FAAH/NAAH inhibitor in association with oxazoline of PEA, for a combined, separate or sequential administration.
- EP2444078 describes the activity of PEA and other Aliamides in the treatment of renal diseases.
- Silymarin is an extract of the plant Silybum marianum , also known as milk thistle, the activity of which in the treatment of liver diseases is known.
- EP2944309 and WO 2016/185468 disclose a pharmaceutical composition comprising a combination of PEA and Opioid use for the treatment of pain.
- WO 2016/063217 discloses a combination of PEA and Spirulina for the treatment of intlammatory states.
- WO 2016/146453 discloses a pharmaceutical composition comprising a combination of PEA and a vitamin B.
- WO 2016/183134 provides compositions comprising PEA, and an anti-inflammatory or anti-pain component.
- WO 2016/193905 discloses a pharmaceutical composition comprising a combination of PEA and lycopene, and/or pharmaceutically acceptable salts and/or derivatives thereof.
- EP3130336 relates to a food and/or nutraceutical composition comprising PEA.
- a food and/or nutraceutical composition comprising PEA in association with at least one component selected from a second active ingredient and an agent that modifies its release in the organism.
- neuropathic pain mainly focus on neuronal system suppressing GABA or other inhibitory receptors.
- Most of the drugs used for neuropathic pain cause drowsiness, dizziness, blurred vision, somnolence, peripheral edema, psychomotor slowing and paresthesia and many more. These side effects decrease the Quality of Life of patient and reduce active working life.
- these drugs require dosage adjustment in different disease conditions such as renal disease or liver disease etc.
- using these drugs for long-term causes de-sensitization of receptors. Therefore, the requirement of increase in the dose of these drugs is required to elicit the desired response and that leads to more number of side effects.
- the current treatment paradigm has some gaps and requires some new arsenal to fight against Neuropathic Pain.
- the present application provides a pharmaceutical composition/formulation comprising a synergistic combination of Palmitoylethanolamide (PEA) and one or more naturally occurring Fatty Acid Amide Hydrolase (FAAH) Inhibitor.
- PDA Palmitoylethanolamide
- FAAH Fatty Acid Amide Hydrolase
- the present invention provides a composition or formulation comprising a synergistic combination of Palmitoylethanolamide and at least two naturally occurring FAAH inhibitors.
- the present invention provides a pharmaceutical composition/formulation comprising a synergistic combination of Palmitoylethanolamide (PEA) and one or more naturally occurring FAAH Inhibitors along with a pharmaceutically acceptable excipient.
- PDA Palmitoylethanolamide
- the pharmaceutical composition/formulation of the present invention additionally comprises vitamins, coenzymes or a combination thereof.
- the natural FAAH Inhibitors in the present invention are selected from Myricetin, Isorhamnetin, Kaempferol, Pristimerin, Biochanin A, Genistein, Daidzein or a combination thereof.
- vitamins are selected from methylcobalamin, cyanocobalamin, benfotiamine or a combination thereof.
- the co-enzymes in the present invention are selected from ubidecarenone, thiamine pyrophosphate, Flavin adenine dinucleotide or a combination thereof.
- the pharmaceutical composition/formulation of the present invention comprises a synergistic combination of PEA, Daidzein, Genistein and a pharmaceutically acceptable excipient.
- a process for the preparation of a composition/formulation comprises (a) weighing and sieving the ingredients through a suitable sieve, (b) mixing the ingredients, (c) preparing a dough by adding a binder solution to the mixed ingredients and sieving to obtain granules, (d) drying the granules till the level of dryness (LOD) is reduced to less than 1.5% w/w to obtain semi dried granules, and (e) sieving the semi dried granules through a suitable sieve to obtain the composition/formulation.
- the process further comprises adding lubricants or glidants to the semi-dried granules and filling the granules in Hydroxypropylmethyl cellulose (HPMC) capsule shells and sealing.
- HPMC Hydroxypropylmethyl cellulose
- the application provides a process for preparing the composition/formulation of the present invention.
- the process comprises sifting previously weighed PEA, Natural FAAH Inhibitor(s), diluent(s), and disintegrating agent(s) separately through a sieve, mixing the contents to obtain a mixture, preparing a binder solution, and optionally adding second natural FAAH Inhibitor(s) in to the binder solution, adding the binder solution to the mixture obtained above and obtaining granules, drying the obtained granules to obtain semi dried granules and sifting the semi dried granules through a sieve, sifting previously weighed Lubricant(s) or glidant(s) separately through a sieve and mixing with the sifted semi dried granules to obtain a blend of the composition/formulation.
- the blend is further filled and sealed with HPMC capsule shells.
- An objective of the present invention is to provide a composition/formulation comprising a synergistic combination of PEA and one or more natural ingredients.
- the present application provides a composition/formulation comprising a synergistic combination of PEA with at least one of a naturally occurring FAAH Inhibitor.
- the composition/formulation of the present invention may optionally comprise vitamins and coenzymes.
- the composition/formulation of the present invention is able to provide a safe composition/formulation of PEA with one or more natural ingredients with enhanced or synergistic effects compared to PEA alone in the treatment of neuropathic pain.
- Another object of the present invention is to provide a composition/formulation comprising a synergistic combination of PEA along with at least one of a naturally occurring FAAH Inhibitor to avoid side effects associated with synthetic FAAH inhibitors.
- Another object of the present invention is to provide a composition/formulation comprising a synergistic combination of PEA along with at least one of a naturally occurring FAAH Inhibitor, and other active ingredients selected from vitamins, coenzymes or a combination thereof.
- composition/formulation comprising PEA in micronized or non-micronized form.
- the composition/formulation includes at least one of a naturally occurring FAAH Inhibitor.
- the composition/formulation optionally includes vitamins or coenzymes.
- the present invention provides a pharmaceutical composition/formulation for treatment of neuropathic pain, wherein said composition/formulation comprises a synergistic combination of PEA with at least one of a naturally occurring FAAH inhibitor and a pharmaceutically acceptable excipient.
- the said composition/formulation optionally comprises vitamins or co-enzymes.
- the ratio of PEA:Natural FAAH Inhibitors is in a range of 99:1 to 50:50. In a more preferred aspect, the ratio of PEA:FAAH Inhibitor is 84:15.
- the pharmaceutical composition/formulation of the present invention comprises PEA in micronized or non-micronized form.
- the amount of PEA in the pharmaceutical composition/formulation of the present invention ranges from 35% by wt. to 80% by wt. of the composition/formulation. In an embodiment the amount of PEA ranges from 45 to 80% by weight. In another embodiment, the amount of PEA ranges from 50 to 80% by weight. In yet another embodiment, the amount of PEA ranges from 60 to 80% by weight. In yet another embodiment, the amount of PEA ranges from 65 to 80% by weight. In yet even another embodiment, the amount of PEA ranges from 70 to 80% by weight. In yet a further embodiment the amount of PEA ranges from 75 to 80% by weight.
- the pharmaceutical composition/formulation of the present invention comprises PEA in micronized or non-micronized form, wherein the amount of PEA in the pharmaceutical composition/formulation ranges from 150 mg to 2400 mg per unit dose.
- the pharmaceutical composition/formulation of the present invention comprises at least one natural FAAH Inhibitor selected from Myricetin, Isorhamnetin, Kaempferol, Pristimerin, Biochanin A, Genistein, Daidzein.
- the amount of natural FAAH Inhibitor in the pharmaceutical composition/formulation of the present invention ranges from 0.5% by wt. to 40% by wt. of the composition/formulation. In an embodiment, the amount of natural FAAH Inhibitor ranges from about 1 to 40% by weight. In an embodiment, the amount of natural FAAH Inhibitor ranges from about 10 to 40% by weight. In an embodiment, the amount of natural FAAH Inhibitor ranges from about 20 to 40% by weight. In a further embodiment, the amount of natural FAAH Inhibitor ranges from about 30 to 40% by weight.
- the pharmaceutical composition/formulation of the invention comprises at least one natural FAAH Inhibitors selected from Myricetin, Isorhamnetin, Kaempferol, Pristimerin, Biochanin A, Genistein, Daidzein, wherein the amount of natural FAAH Inhibitor in the pharmaceutical composition/formulation ranges from 2 mg to 2722 mg per unit dose.
- the pharmaceutical composition/formulation of the invention optionally comprises vitamins, co-enzymes or a combination thereof.
- the vitamins are selected from methylcobalamin, cyanocobalamin, benfotiamine or a combination thereof.
- the amount of vitamins in the pharmaceutical composition/formulation of the present invention ranges from 0.01% by wt. to 30% by wt. of the composition/formulation.
- the amount of vitamins in the pharmaceutical composition/formulation of the present invention ranges from 0.1 mg to 200 mg per unit dose.
- the co-enzymes are selected from ubidecarenone, thiamine pyrophosphate, flavin adenine dinucleotide or a combination thereof.
- the amount of co-enzymes in the pharmaceutical composition/formulation of the present invention ranges from 10% by wt. to 40% by wt. of the composition/formulation.
- the amount of co-enzymes in the pharmaceutical composition/formulation of the present invention ranges from 50 mg to 200 mg per unit dose.
- composition/formulation of the present invention can be formulated as tablets, capsules, granules, powder, sachets, suspension, solution, modified release formulations, topical formulations, etc.
- the formulations of the present invention comprise suitable excipients such as diluents, disintegrants, binders, solubilizing agent, lubricants, glidants, solvents etc.
- the diluents are selected from microcrystalline cellulose, lactose (anhydrous/monohydrate/spray dried), starch, cellulose powder, silicified microcrystalline, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/dibasic dehydrate/tribasic), calcium silicate, calcium sulfate, cellulose acetate, compressible sugar, confectioner's sugar, corn starch, pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium-chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol
- the disintegrating agent is selected from croscarmellose sodium, crospovidone, carboxymethyl cellulose (sodium/calcium), sodium starch glycolate, alginic acid, calcium alginate, cellulose powdered, chitosan, colloidal silicon dioxide, corn starch, docusate sodium, glycine, guar gum, hydroxypropyl cellulose low-substituted, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, povidone, sodium alginate, pregelatinized starch or the like.
- the amount of disintegrating agent in the pharmaceutical composition/formulation of the present invention ranges from 0.5% by wt. to 10% by wt. of the composition/formulation.
- the binder is selected from hypromellose, starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylrnmethyl cellulose, hydroxypropyl cellulose, inulin, lactose, liquid glucose, low-substituted Hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium al
- the solubilizing agent is selected from polysorbate 80, sodium lauryl sulfate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol,
- the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type 1, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, potassium benzoate or the like.
- the amount of Lubricant in the pharmaceutical composition/formulation of the present invention ranges from 1% by wt. to 10% by wt. of the composition/formulation.
- the glidant is selected from Colloidal silicon dioxide, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, silicon dioxide or the like.
- the amount of Glidant in the pharmaceutical composition/formulation of the present invention ranges from 1% by wt. to 10% by wt. of the composition/formulation.
- the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, almond oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dibutyl phthalate, diethyl phthalate, dimethyl ether, albumin, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, ethyl acetate, ethyl lactate, ethyl oleate, glycerin, glycofurol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium-chain triglycerides, methyl lactate, mineral oil, monoethanolamine, octyldodecanol, olive oil, peanut oil, polyethylene glycol, polyoxyl 35 castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, tri
- the pharmaceutical composition/formulation is formulated for oral administration.
- the solid pharmaceutical compositions for example, can be in the form of tablets, capsules, pills, hard capsules filled with liquids or solids, soft capsules, sachets, powders, granules, suspensions, solutions or modified release formulations.
- Developing pharmaceutical compositions or formulations wherein one or more ingredients are obtained from natural sources poses challenges for the formulator. Such challenges include providing a suitable size dosage form containing the effective amount of the active ingredients. Challenges also include providing stable formulations while retaining desirable pharmacokinetic properties. As currently understood, synthetic FAAH Inhibitors are not approved for therapeutic use in any country by any drug regulatory authority. The present invention provides stable and therapeutically effective compositions and formulations comprising PEA and one or more natural ingredients.
- compositions/formulations of the present invention are described below:
- Example 18 Stability and Dissolution Study of Formulation of Example 1
- Example 20 Stability and Dissolution Study of Formulation of Example 8
- Rat Rat norvegicus
- Standard certified rat pellet feed Manufactured by Keval Sales Corporation, Vadodara
- drinking water treated by reverse osmosis were provided ad libitum to all animals.
- Group 1 served as the normal control
- Group 2 served as the disease control
- Group 3 served as component (A, B and C)
- Group 6 served as formulation of test drug
- Group 9 served as the Reference standard group.
- Table 1 represents various treatments to respective groups. No. of S. No. Group Animals Test Drug 1 G1 6 Normal Control 2 G2 6 Disease Control 3 G3 6 PEA (60 mg/kg, P.O.) 4 G4 6 DAIDZEIN (10 mg/kg, P.O.) 5 G5 6 GENISTEIN (0.8 mg/kg, P.O.) 6 G6 6 PEA (60 mg/kg, P.O.) + DAIDZEIN (10 mg/kg, P.O.) (Example 1) 7 G7 6 PEA (60 mg/kg, P.O.) + GENISTEIN (0.8 mg/kg, P.O.) (Example 7) 8 G8 6 PEA (60 mg/kg, P.O.) + DAIDZEIN (10 mg/kg, P.O.) + GENISTEIN (0.8 mg/kg, P.O.) (Example 8) 9 G9 6 Pregabalin (20 mg/kg, P.O.)
- Group-1 received vehicle (0.25% w/v Sodium CMC) orally (p.o.) for three consecutive days (Day 1, 2 & 3).
- Group-2 to Group-8 received test drugs, while Group 9 received Pregabalin orally (p.o.) on Day-1, Day-2 and Day-3. All treatment groups (Group 2 to 9) were administered with oxaliplatin (12 mg/kg, i.p.) on Day-3 prior to 2 hrs of test drug administration. After 24 hrs of oxaliplatin administration, treated groups as well as the normal control group were assessed using the Cold hyperalgesia method.
- Tail-immersion test water was maintained at low (0 to 4° C.) temperature.
- the tail of the rat was immersed in cold water and the duration (time in seconds) of tail immersion was recorded, until the tail was withdrawn from water.
- the cut-off time of 20 seconds was used.
- the decrease in tail contact time with cold water was indicative pain whereas prolonged contact time was noted as anti-allodynic effect.
- Oxaliplatin (12 mg/kg) was administered via intraperitoneal injection in rats. After intraperitoneal injection of Oxaliplatin, there was a significant reduction in tail withdrawal latency in the disease control group. In all treatment groups, either alone or in combination, tail withdrawal latency periods were significantly increased compared to the disease control group. This indicates that treatments were effective against peripheral neuralgia induced by oxaliplatin injection. The effect of treatment groups 6-8 was comparable with that of the standard drug pregabalin as shown in Table 2-3.
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CA (1) | CA2999030C (es) |
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EA (1) | EA035667B1 (es) |
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Cited By (4)
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WO2023133555A3 (en) * | 2022-01-10 | 2023-09-21 | Zilker Sciences Llc | Palmitoylethanolamide treatment for covid-19-related inflammation |
WO2024055006A3 (en) * | 2022-09-09 | 2024-04-18 | The Regents Of The University Of California | Compositions for preventing transition from acute to chronic pain |
US11998525B2 (en) | 2021-05-04 | 2024-06-04 | Janssen Pharmaceuticals, Inc. | Compositions and methods for the treatment of depression |
US11998524B2 (en) | 2022-03-07 | 2024-06-04 | Janssen Pharmaceuticals, Inc. | Forms of aticaprant |
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EP4331577A1 (en) * | 2022-08-30 | 2024-03-06 | Unifarco S.p.A. | A nutraceutic tablet comprising palmitoylethanolamide |
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MX2007010076A (es) * | 2005-02-17 | 2007-10-16 | Astellas Pharma Inc | Derivado de heterociclico-1-carboxilato que contiene nitrogeno no aromatico de piridilo. |
ITPD20050224A1 (it) * | 2005-07-19 | 2007-01-20 | Actimex Srl | Composizioni contenenti micronutrienti aventi in particolare attivita' antiossidante e loro impiego |
WO2008030752A2 (en) * | 2006-09-07 | 2008-03-13 | N.V. Organon | Methods for determining effective doses of fatty acid amide hydrolase inhibitors in vivo |
EP2300438A4 (en) * | 2008-06-11 | 2012-06-27 | Merck Sharp & Dohme | IMIDAZOLE DERIVATIVES AS FAAH INHIBITORS |
CA2735037C (en) * | 2008-09-04 | 2016-07-12 | Cargill Incorporated | Tabletting of erythritol |
JP5746178B2 (ja) * | 2009-09-07 | 2015-07-08 | エピテック・グループ・エス.アール.エル. | 超微粉化パルミトイル−エタノールアミドを含む組成物 |
US9512091B2 (en) * | 2012-02-17 | 2016-12-06 | Epitech Group S.R.L. | Compositions and methods for the modulation of specific amidases for N-acylethanolamines for use in the therapy of inflammatory diseases |
NL2014464B1 (en) * | 2015-03-16 | 2017-01-13 | Vanderbilt Science Holding Ltd | Composition for use in the treatment of neuropathic pain. |
WO2016183134A1 (en) * | 2015-05-12 | 2016-11-17 | Cutting Edge Medical Solutions, Llc | Palmitoylethanolamide compositions |
ITUB20153066A1 (it) * | 2015-08-11 | 2017-02-11 | Graal S R L | Composizione alimentare e/o nutraceutica contenente pea |
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Cited By (4)
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US11998525B2 (en) | 2021-05-04 | 2024-06-04 | Janssen Pharmaceuticals, Inc. | Compositions and methods for the treatment of depression |
WO2023133555A3 (en) * | 2022-01-10 | 2023-09-21 | Zilker Sciences Llc | Palmitoylethanolamide treatment for covid-19-related inflammation |
US11998524B2 (en) | 2022-03-07 | 2024-06-04 | Janssen Pharmaceuticals, Inc. | Forms of aticaprant |
WO2024055006A3 (en) * | 2022-09-09 | 2024-04-18 | The Regents Of The University Of California | Compositions for preventing transition from acute to chronic pain |
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PH12018000077A1 (en) | 2019-01-21 |
LT3424499T (lt) | 2020-03-25 |
CA2999030A1 (en) | 2019-01-05 |
MY172113A (en) | 2019-11-14 |
PL3424499T3 (pl) | 2020-06-29 |
EA201891337A2 (ru) | 2019-01-31 |
ME03680B (me) | 2020-10-20 |
UA122080C2 (uk) | 2020-09-10 |
EP3424499B1 (en) | 2019-12-25 |
BR102018013710A2 (pt) | 2019-01-22 |
SI3424499T1 (sl) | 2020-06-30 |
CA2999030C (en) | 2019-10-29 |
RS60127B1 (sr) | 2020-05-29 |
EA201891337A3 (ru) | 2019-05-31 |
HRP20200328T1 (hr) | 2020-07-24 |
ES2776879T3 (es) | 2020-08-03 |
EA035667B1 (ru) | 2020-07-23 |
PT3424499T (pt) | 2020-03-31 |
DK3424499T3 (da) | 2020-03-23 |
PH12018000077B1 (en) | 2019-01-21 |
SG10201802129QA (en) | 2019-02-27 |
CY1122829T1 (el) | 2021-05-05 |
EP3424499A1 (en) | 2019-01-09 |
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