Composition of acylethanolamide from olive oil fatty acids

Abstract

To provide acylethanolamide compositions obtained from olive oil fatty acids, and to provide uses thereof in the treatment of neuroinflammation.SOLUTION: Disclosed are: an acylethanolamide composition containing (wt.%) -Oleoylethanolamide (OEA) (C18:1) 60 to 65%, -Palmitoylethanolamide (PEA) (C16:0) 5 to 20%, -Linoleylethanolamide (LEA) (C18:2) 5 to 20%, - Stearoylethanolamide (SEA) (C18:0) 1 to 2%, - Palmitoylethanolamide (POEA) (C16:1) 0.1 to 0.8%, -Myristoylethanolamide (MEA) (C14:0) 0.02 to 0.15%, -glyceride mixture 4 to 6%, and -glycerol 6 to 8%; additionally, a method for obtaining the same; and also a formulation containing the same.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a composition of acyl ethanolamide obtained from olive oil fatty acids and its use in the treatment of neuroinflammation.

Background Art

[0002] One of the most common pathological conditions associated with mild neuroinflammation in both humans and animals is obesity. Obesity is a chronic pathological condition characterized by excessive and abnormal deposition of fat (World Health Organization, 2017), affecting not only humans but also pets: indeed, so far, it is the most common nutritional disorder seen in dogs, and the incidence in animals under veterinary management varies between 24% and 44%.

[0003] Some experimental evidence indicates that obesity is characterized by a chronic mild inflammatory state caused by the production of different inflammatory mediators. In this pathological condition, it is now established that adipocytes actively participate in the appearance and maintenance of chronic mild inflammation in adipose tissue by releasing chemokines (CCL2, CXCL8), and cytokines (IL-6, IL-8 and TNF-a), together with pro-inflammatory adipokines (leptin, adiponectin and other molecules) released from adipose tissue itself, induce and maintain a persistent neuritis state that tends not to resolve. Such a neuritis state is considered to be the cause of the onset of several chronic and / or degenerative diseases, such as osteoarthritis, rheumatoid arthritis, cardiovascular disease, inflammatory bowel disease, Alzheimer's disease and vascular dementia, in both humans and animals.

[0004] In obesity, the overproduction of adipokines has an adverse effect on multiple functions such as appetite and energy balance, insulin sensitivity / resistance, recruitment of immune cells in adipose tissue, and angiogenesis, and the massive release of cytokines by degranulating adipocytes amplifies the neuroinflammatory process.

[0005] So far, the most effective treatment for weight loss is the relationship between a balanced diet and physical activity. However, while this protocol is useful for weight loss in humans and animals, it cannot "extinguish" the chronic mild inflammation caused primarily by excessive and disordered mast cell degranulation. [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, it is fundamentally important to make available molecules with anti-neuroinflammatory properties that can submodulate the production of pro-neuroinflammatory factors released by activated mast cells.

[0007] Palmitoylethanolamide is a molecule known for its activity in regulating mast cell degranulation, but it has been shown to be virtually ineffective for this type of neuroinflammatory symptom unless administered at fairly high doses. [Means for solving the problem]

[0008] Outline of the invention This invention stems from the remarkable discovery that a composition obtained by direct aminolysis of fatty acids contained in olive oil can determine a distinct synergistic effect of acylethanolamide molecules (particularly OEA and PEA) with respect to the corresponding pure acylamide, in counteracting neuroinflammatory phenomena mediated by mast cell hyperreactivity and thus their increase at the tissue level. Such activity may be particularly relevant to detectable neuroinflammatory phenomena in subject populations suffering from obesity.

[0009] Therefore, the present invention is as follows (weight percent): - Oleoylethanolamide (OEA) C18:1 60-65% - Palmitoylethanolamide (PEA) C16:0 5-20% - Linoleyl ethanolamide (LEA) C18:2 5-20% - Stearoylethanolamide (SEA) C18:0 1-2% - Palmitoleoylethanolamide (POEA) C16:1 0.1-0.8% - Myristoylethanolamide (MEA) C14:0 0.02-0.15% - Glyceride mixture 4-6% - Glycerol 6-8% The present invention relates to an acylethanolamide composition, as defined below, which includes the following:

[0010] The present invention further involves the following steps using 2-aminoethanol in the absence of a solvent from olive oil: a) Mix olive oil with 2-aminoethanol; b) Heat the mixture from step a) to a temperature of 120°C to 160°C; c) Separating the acylethanolamide composition obtained in this way in the form of a waxy solid; d) If necessary, the acylethanolamide composition from step c) is adsorbed onto porous amorphous silica to obtain an acylethanolamide composition / porous amorphous silica adsorbed compound; This relates to a direct, catalyst-free aminolysis method, including the method described above.

[0011] Accordingly, the present invention also relates to acylethanolamide compositions defined below, particularly for use in the treatment of mild neuroinflammation in patients suffering from obesity, i.e., for use in the manufacture of agents for treating such diseases.

[0012] These and further objectives are described in the following description, as outlined in the attached claims. The text of the claims should be considered included in the description in order to assess the sufficiency of the description.

[0013] Further features and advantages of the present invention will become apparent from the following description of preferred embodiments given for non-limiting purposes. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1 shows a graph of the increase in foot volume of treated animals versus time measurements after treatment; the values ​​shown in the graph represent the mean ± SEM. One-way ANOVA test: ** p<0.01 vs. CAR, *** p<0.001 vs. CAR; [Figure 2] Figure 2 shows a graph of paw holding time (planter test) in treated animals versus time measurement after treatment; the values ​​shown in the graph represent mean ± SEM. One-way ANOVA test: * p<0.05 vs. CAR, ** p<0.01 vs. CAR, *** p<0.001 vs. CAR. [Figure 3] Figure 3 shows a summary graph of the histological analysis performed using E / E; from left to right, ND = not detected, CAR-vehicle, CAR+PEA 2mg / Kg, CAR+OEA 6mg / Kg, and CAR+acylethanolamide complex / porous amorphous silica; the values ​​shown in the graph represent mean ± SEM. One-way ANOVA test: *** p<0.001 vs. sham (false), ### p<0.001 vs. CAR. [Figure 4] Figure 4 shows a summary graph (displayed as scores) of tissue mast cell analysis; the values ​​shown in the graph represent mean ± SEM. One-way ANOVA test: *** p<0.001 vs. sham, ### p<0.001 vs. CAR. [Modes for carrying out the invention]

[0015] Detailed description of the invention In the first aspect, the present invention relates to the following (weight percent): - Oleoylethanolamide (OEA) C18:1 60-65% - Palmitoylethanolamide (PEA) C16:0 5 - 20% - Linoleoylethanolamide (LEA) C18:2 5 - 20% - Stearoylethanolamide (SEA) C18:0 1 - 2% - Palmitoleoylethanolamide (POEA) C16:1 0.1 - 0.8% - Myristoylethanolamide (MEA) C14:0 0.02 - 0.15% - Mixture of glycerides 4 - 6% - Glycerol 6 - 8% Relates to an acyl ethanolamide composition containing the above.

[0016] The composition of the present invention is characterized by an OEA content of 60% by weight or more, but may have variability in the PEA and LEA contents depending on the origin of the olive oil or the variety of the plant from which it is derived.

[0017] Preferably, in one embodiment, the composition of the present invention is as follows (weight percent):​​​​​​​​​​​​​​​​​​​​​​​​ - Palmitoylethanolamide (PEA) C16:0 7-12% - Linoleyl ethanolamide (LEA) C18:2 8-15% - Stearoylethanolamide (SEA) C18:0 1.2-1.7% - Palmitoleoylethanolamide (POEA) C16:1 0.3-0.5% - Myristoylethanolamide (MEA) C14:0 0.03-0.11% - Glyceride mixture 5-5.5% - Glycerol 7-7.5% Includes.

[0019] For brevity, the composition according to the present invention, which contains the aforementioned components, will also be referred to hereafter as "acylethanolamide," and the term "acylethanolamide" as used for the purposes of the present invention means the following series of components, in which acylethanolamide forms the main part of the composition.

[0020] The composition according to the present invention can be obtained from olive oil by direct, catalyst-free aminolysis in the absence of a solvent, using 2-aminoethanol.

[0021] For more details, the method according to the present invention involves the following steps: a) Mix olive oil with 2-aminoethanol; b) Heat the mixture from step a) to a temperature of 120°C to 160°C; c) Separating the acylethanolamide composition or complex of the present invention in the form of a waxy solid; d) If necessary, obtain an acylethanolamide composition / porous amorphous silica adsorbed compound by adsorbing the acylethanolamide composition or complex from step c) onto porous amorphous silica; Includes.

[0022] The composition of the present invention may vary in terms of PEA and LEA content, in particular, depending on the olive oil used.

[0023] The following are typical average compositions of olive oil from olives grown in European Union countries (Olive Oil A) and olive oil from olives grown in Italy (Olive Oil B).

[0024] Olive oil A - Composition range of major fatty acids in olive oil (EC Regulation 1989 / 03): - Myristic acid (C14:0) <0.1% - Palmitic acid (C16:0) 7.5-20% - Palmitoleic acid (C16:1) 0.3-3.5% - Stearic acid (C18:0) 0.5-5.0% - Oleic acid (C18:1) 55-83% - Linolenic acid (C18:2) 2.5-21% Olive Oil B - Typical composition of major fatty acids in Italian olive oil (average of 1050 samples) (National database of single-varietal extra virgin olive oils in Italy - 2013 DOI:10.5772 / 51772): - Myristic acid (C14:0) <0.1% - Palmitic acid (C16:0) 12% - Palmitoleic acid (C16:1) 1.1% - Stearic acid (C18:0) 2.2% - Oleic acid (C18:1) 73% - Linolenic acid (C18:2) 10.3%

[0025] Step a) is preferably carried out at room temperature. The weight ratio of olive oil to 2-ethanolamine is preferably 100:13 to 100:22, more preferably 100:15 to 100:20, and even more preferably 100:16 to 100:18. Thus, the amount of 2-aminoethanol used is less than the stoichiometric amount necessary to successfully maintain the semisynthetic product, along with the glycerol released in the reaction, which is also part of the monoglyceride useful for improving the bioavailability of the formed acylethanolamide complex.

[0026] Preferably, step a) is carried out in an inert gas atmosphere, for example, under nitrogen.

[0027] Step b) is preferably carried out at a temperature of 130°C to 150°C, more preferably at 135°C to 145°C, for a period of 2 hours or more, more preferably 3 hours or more but less than 5 hours.

[0028] Step c) is preferably carried out by slowly cooling to room temperature.

[0029] Step d) is preferably carried out by melting the acylethanolamide complex from step c) at a temperature of 70°C to 90°C, and then adding porous amorphous silica. The weight ratio of the acylethanolamide complex to porous amorphous silica is preferably 0.9:1 to 1.1:1, and more preferably about 1:1.

[0030] As better illustrated by the following biological experiments and associated graphs, the acylethanolamide compositions according to the present invention demonstrate significant synergistic effects in animal models and tissue evaluations of neuroinflammation compared to the administration of the individual compounds PEA and OEA (which form the main components of the composition) at the same doses. While such synergistic effects may be related to the single-component combination of PEA and OEA, they may also be related to the presence of other acylethanolamides in the same composition, and to non-insignificant amounts of fatty acid monoglycerides that improve the bioavailability of the composition.

[0031] Accordingly, the present invention further relates to an acylethanolamide composition itself or an acylethanolamide composition / porous amorphous silica adsorbent compound for use in the treatment of mild neuroinflammation, preferably in a population of patients suffering from obesity.

[0032] Chemical Examples (Semi-Synthetic) Production of acylethanolamide compositions (acylethanolamide complexes) Place 295.0 g of olive oil from olive trees grown in European Union countries into a glass flask equipped with stirring and reflux refrigerant. Nitrogen saturation is activated to remove oxygen during semisynthesis. Add 55.0 g of 2-aminoethanol while stirring at room temperature, then slowly raise the temperature to 140°C in an oil bath (over approximately 1 hour); The amount of 2-aminoethanol used, along with the glycerol released in the reaction, is less than the stoichiometric amount necessary to successfully maintain the semisynthetic product, as it is also part of the monoglyceride that is useful in improving the bioavailability of the formed acylethanolamide complex. Heating is maintained under a constant flow of nitrogen for 4 hours. The semisynthetic mixture is then cooled slowly (reaching room temperature in about 1 hour); a yellowish solid with waxy viscosity is obtained. The composition of the obtained solid (average of 5 semisyntheses) is shown in Table 1 below: Table 1 - Weight composition of acylethanolamide complex [Table 1]

[0033] The acylethanolamide complex thus obtained can be directly used to prepare a liquid form for oral use through a suitable emulsification process; or, it can be used for lipid adsorption onto silica, as shown below.

[0034] Lipid adsorption of acylethanolamide complex onto silica 100 g of the semi-synthesized acylethanolamide complex is melted in a nitrogen stream at 80°C. After melting, 100 g of porous amorphous silica (Syloid XDP-Grace) is slowly added while stirring. After vigorous stirring for a long time, the resulting mass is slowly cooled to room temperature. A homogeneous, fluid powder is obtained, which can be easily used to prepare oral solid dosage forms.

[0035] Biological examples The study involved free-feeding male Sprague-Dolly rats (200–235 g; Harlan, Nossan, Italy) housed in cages with controlled sleep / wake cycles. Prior to the start of the experiment, the animals underwent a one-week acclimatization period, adhering to the principles of laboratory animal care approved by the Italian Ministry of Health, respecting the guidelines of the European Economic Community, and considering all experimental procedures and protocols.

[0036] A single injection of 100 μl of saline containing 1% carrageenan (CAR) was administered to one of the two hind legs of the animals. Paw edema was measured using a plethysmometer (Ugo Basile, Comerio, Varese, Italy) at one-hour intervals for 6 hours before and after CAR injection (Salvemini D et al. Nitric oxide: A key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br. J. Pharmacol. 1996;118:829-838). Hyperalgesia response to heat was assessed using the planter test with a 20-second cutoff latency to avoid tissue damage. Before applying the heat stimulus, the rats were housed individually in plexiglass compartments to allow them to acclimate. The suspension latency period of the injected paw was determined by an electronic circuit, and the results were expressed in seconds.

[0037] Edema was expressed as the increased foot volume (mL) after CAR injection compared to the pre-injection value for all animals.

[0038] The animals were randomly divided into five groups, each consisting of 10 animals: Group 1: A rat (sham) that was not injected with CAR into its hind leg and was orally administered saline solution; Group 2: Rats were given a single CAR injection in the hind leg, and 30 minutes prior to the CAR injection, they were orally administered 2% carboxymethylcellulose (CMC), the vehicle used to suspend the molecule to be tested (CAR + vehicle); Group 3: Rats that received a single CAR injection in their hind legs, and were orally administered natural PEA (2 mg / kg) suspended in 2% CMC 30 minutes prior to the CAR injection (CAR + PEA 2 mg / kg); Group 4: Rats that received a single CAR injection in their hind legs, and were orally administered OEA (6 mg / kg) suspended in 2% CMC 30 minutes prior to the CAR injection (CAR + OEA 6 mg / kg); Group 5: Rats received a single CAR injection in the hind leg, and 30 minutes prior to the CAR injection, were orally administered 20 mg / kg of an acylethanolamide composition / porous amorphous silica adsorbent suspended in 2% CMC (CAR + acylethanolamide complex / porous amorphous silica 20 mg / kg, corresponding to the 10 mg / kg acylethanolamide complex).

[0039] It should be noted that the weights of PEA and OEA in the tested acylethanolamide complex were approximately 6 mg and 2 mg per 10 mg of the acylethanolamide complex, respectively, and therefore the same dosages used for the individual compounds.

[0040] The animals were euthanized 6 hours after CAR injection. Foot tissue was collected, immediately fixed in 10% formaldehyde in saline for 24 hours at room temperature, and histologically stained with hematoxylin / eosin (E / E). Section morphology was observed using an Axiovision Zeiss microscope (Milan, Italy), and several tissue injury severity scores were assigned: 0 = no inflammation; 1 = mild inflammation; 2 = mild / moderate inflammation; 3 = moderate inflammation; 4 = moderate / severe inflammation; 5 = severe inflammation.

[0041] To assess the presence of mast cells, tissue sections were stained with toluidine blue.

[0042] result 1. A lipid-adsorbing acylethanolamide complex at 20 mg / kg on porous amorphous silica reduces edema in the feet of animals injected with CAR. Injection of CAR into the hind legs of experimental animals induces a significant time-dependent increase in the volume of the animals' hind legs (Figure 1). Edema caused by CAR is significantly reduced only by treatment with acylethanolamide complex / porous amorphous silica 20 mg / kg (white column on the right), as early as 1 hour after CAR injection and in subsequent time measurements analyzed up to the end of the experimental period (6 hours). No significant reduction in edema was observed in the untreated group or in the groups of rats treated with PEA 2 mg / kg alone or OEA 6 mg / kg alone.

[0043] 2. Lipid-adsorbing acylethanolamide complex at 20 mg / kg on porous amorphous silica significantly reduces thermal hyperalgesia. Intraplantar CAR injection induces time-dependent thermal hyperalgesia that persists until the end of the experiment (6 hours). Only oral administration of acylethanolamide complex / porous amorphous silica 20 mg / kg (white column on the right) significantly counteracts the onset of CAR-induced thermal hyperalgesia, already 1 hour after injection and in all time measurements for the vehicle-treated group (Figure 2). No analgesic effect was observed in the groups of animals treated with PEA 2 mg / kg and OEA 6 mg / kg alone.

[0044] 3. A lipid-adsorbing acylethanolamide complex at 20 mg / kg on porous amorphous silica can protect and significantly reduce tissue damage in the feet of CAR-injected animals. To histologically evaluate the anti-neuroinflammatory effect of the acylethanolamide complex / porous amorphous silica, foot tissue from each experimental group was stained with E / E stain. The results are summarized as scores in Figure 3. As expected, no tissue damage was observed in the sham rats. In contrast, injection of CAR into the animal feet caused a clear increase in tissue damage compared to the healthy animal group. Treatment with acylethanolamide complex / porous amorphous silica 20 mg / kg (white column on the right) significantly reduced tissue destruction, but single molecules of PEA 2 mg / kg alone and OEA 6 mg / kg alone could not protect foot tissue from the neuroinflammatory effects of CAR.

[0045] 4. A lipid-adsorbing acylethanolamide complex at 20 mg / kg on porous amorphous silica can significantly reduce the number of mast cells in animal foot tissue. Staining with toluidine blue highlights the presence of mast cells in foot tissue 6 hours after edema induction. Specifically, rats injected with CAR and treated with vehicle, PEA 2 mg / kg only, and OEA 6 mg / kg only show a significant increase in the number of mast cells compared to the sham group. In contrast, mast cell infiltration is significantly reduced only by treatment with acylethanolamide complex / porous amorphous silica 20 mg / kg. The graph in Figure 4 summarizes the data obtained with toluidine blue staining (in the form of scores).

[0046] This data confirms the effectiveness of acylethanolamide complexes in a population of patients suffering from obesity, a disease characterized by increased mast cell degranulation.

[0047] Furthermore, the present invention further relates to a formulation comprising the composition of the present invention (acylethanolamide complex) or an acylethanolamide composition / porous amorphous silica adsorbent compound, wherein the formulation is in dosage form for oral, oral, parenteral, rectal, or transdermal administration.

[0048] In particular, the acylethanolamide composition itself is preferably in the form of an emulsion in liquid dosage form; in contrast, the acylethanolamide composition / porous amorphous silica adsorbent compound may be formulated preferably in solid dosage form.

[0049] For oral administration, pharmaceutical compositions can be found in the form of tablets or hard or soft capsules prepared by conventional methods with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or methylcellulose hydroxypropyl); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or inhibitors (e.g., sodium lauryl sulfate). Tablets can be coated by methods well known in the art. Liquid formulations for oral administration may be, for example, in the form of solutions, syrups, or suspensions, or they may be lyophilized products that are reconstituted with water or other suitable vehicle before use. Such liquid formulations can be prepared by conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible oils); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl- or propyl-p-hydroxybenzoic acid or sorbic acid). The formulations may also conveniently contain flavorings, dyes, and sweeteners.

[0050] Oral formulations can be appropriately formulated to allow for controlled release of the active ingredient.

[0051] For oral administration, the composition may be in the form of conventionally formulated tablets or pills adapted for absorption at the level of the buccal mucosa. A typical oral formulation is a tablet for sublingual administration.

[0052] The acylethanolamide complex of the present invention can be formulated for parenteral administration by injection. The injectable formulation can be presented, for example, in a vial as a single dose with added preservatives. The composition can be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain formulation agents such as suspensions, stabilizers, and / or dispersants. Alternatively, the active ingredient can be found in the form of a powder that is reconstituted with a suitable vehicle, for example, sterile water, before use.

[0053] According to the present invention, the acylethanolamide complex can also be formulated into rectal compositions such as suppositories or retaining enemas, which contain, for example, common suppository base components such as cocoa butter or other glycerides.

[0054] In addition to the compositions described above, acylethanolamide complexes can also be formulated as depot formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous, transdermal, or intramuscular) or intramuscular injection. For example, they can be formulated using a suitable polymer or hydrophobic material (e.g., in the form of an emulsion in a suitable oil) or an ion exchange resin, or as a minimally soluble derivative.

[0055] According to the present invention, the recommended dose of acylethanolamide complex for administration to a human (weighing approximately 70 kg) is 1 mg to 2 g or 10 mg to 700 mg of the active ingredient per unit dose. The dose unit can be administered, for example, 1 to 4 times a day. The dose varies depending on the route of administration. It should be considered that the dosage may need to be continuously adjusted depending on the patient's age and weight, and the severity of the clinical condition being treated. The exact dosage and route of administration are ultimately left to the discretion of the attending physician or veterinarian.

[0056] The present invention further relates to food compositions, nutritional supplements, specialty medical foods (FSMPs), and cosmetic compositions (for example, in the form of creams) comprising the acylethanolamide complex of the present invention.

[0057] "Foods for Special Medical Use" refers to products authorized in accordance with European Commission Directive 1999 / 21 / EC or later. Such terminology means products "intended to meet the specific nutritional needs of persons suffering from a particular disease, disorder or condition" in order to treat or assist in the treatment of a particular medical condition, and therefore, these FSMP products are incorporated into medicines.

[0058] The formulations according to the present invention can be prepared according to conventional methods, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., NY, USA, 17th edition, 1985.

[0059] Next, the present invention will be further explained through the following formulation examples. [Examples]

[0060] Examples of formulations Example 1: Oral liquid suspension Per 100ml: Acylethanolamide (complex) composition 12.0 g Corn dextrin 30 g Microcrystalline cellulose 1.35 g Carboxymethylcellulose 0.65 g Polysorbate 80 0.10 g Benzoic acid 0.08 g Potassium sorbate 0.10 g Citric acid 0.05 g Water 67.7 g

[0061] Example 2: Tablets Per tablet: Acylethanolamide (complex) composition / porous amorphous silica 600mg Microcrystalline cellulose 250 mg Cross-linked carboxymethylcellulose sodium 80mg Hydroxypropylcellulose 20mg Polysorbate 80 5mg Magnesium stearate 6mg Silicon dioxide 10mg

[0062] Example 3: Veterinary Tablets Per tablet: Acylethanolamide (complex) composition / porous amorphous silica 600mg Flavor enhancer F20729 85mg Microcrystalline cellulose 140 mg Cross-linked carboxymethylcellulose sodium 54 mg Glyceryl dibehenate 90mg Hydroxypropylcellulose 20mg Polysorbate 80 5mg Magnesium stearate 6mg

[0063] Example 4: Hard gelatin capsules Vegetable gelatin capsules (acid resistant) per capsule: Acylethanolamide (complex) composition / porous amorphous silica 360mg Glyceryl dibehenate 40mg

[0064] Example 5: Effervescent Tablets Per tablet: Acylethanolamide (complex) composition / porous amorphous silica 400mg Potassium bicarbonate 343mg Potassium carbonate 108mg Anhydrous citric acid 384mg Fructose 130mg Polysorbate 80 15mg Lemon flavoring 10mg

[0065] Example 6: High-grade soluble (Oro-soluble) granules 1g of granules: Acylethanolamide (complex) composition 600 mg Fructose 230mg Sorbitol 90mg Anhydrous citric acid 20mg Sucrose palmitate 18mg Polysorbate 80 5mg Polyvinylpyrrolidone 30 15mg Cross-linked carboxymethylcellulose sodium 12 mg Flavoring agent 10mg

Claims

1. Below (by weight percentage): - Oleoylethanolamide (OEA) C18:1 60-65% - Palmitoylethanolamide (PEA) C16:0 5-20% - Linoleyl ethanolamide (LEA) C18:2 5-20% - Stearoylethanolamide (SEA) C18:0 1-2% - Palmitoleoylethanolamide (POEA) C16:1 0.1-0.8% - Myristoylethanolamide (MEA) C14:0 0.02-0.15% - Glyceride mixture 4-6% - Glycerol 6-8% An acylethanolamide composition containing the following:

2. Below (by weight percentage): - Oleoylethanolamide (OEA) C18:1 61-63% - Palmitoylethanolamide (PEA) C16:0 17-19% - Linoleyl ethanolamide (LEA) C18:2 5-5.7% - Stearoylethanolamide (SEA) C18:0 1.2-1.7% - Palmitoleoylethanolamide (POEA) C16:1 0.3-0.5% - Myristoylethanolamide (MEA) C14:0 0.03-0.11% - Glyceride mixture 5-5.5% - Glycerol 7-7.5% The acylethanolamide composition according to claim 1, comprising:

3. Below (by weight percentage): - Oleoylethanolamide (OEA) C18:1 61-63% - Palmitoylethanolamide (PEA) C16:0 7-12% - Linoleyl ethanolamide (LEA) C18:2 8-15% - Stearoylethanolamide (SEA) C18:0 1.2-1.7% - Palmitoleoylethanolamide (POEA) C16:1 0.3-0.5% - Myristoylethanolamide (MEA) C14:0 0.03-0.11% - Glyceride mixture 5-5.5% - Glycerol 7-7.5% The acylethanolamide composition according to claim 1, comprising:

4. A method for direct, catalyst-free aminolysis from olive oil in the absence of a solvent, using 2-aminoethanol, The following steps: a) Mix olive oil with 2-aminoethanol; b) Heat the mixture from step a) to a temperature of 120°C to 160°C; c) Separating the acylethanolamide composition of the present invention in the form of a waxy solid; d) If necessary, the acylethanolamide composition from step c) is adsorbed onto porous amorphous silica to obtain an acylethanolamide composition / porous amorphous silica adsorbed compound; Methods that include...

5. The method according to claim 4, wherein in step a), the weight ratio of olive oil to 2-ethanolamine is 100:13 to 100:22, or 100:15 to 100:20, or 100:16 to 100:

18.

6. The method according to claim 4, wherein step b) is carried out at a temperature of 130°C to 150°C, or 135°C to 145°C, for a period of 2 hours or more, or 3 hours or more but less than 5 hours.

7. The method according to claim 4, wherein step d) is carried out by melting the acylethanolamide composition of step c) at a temperature of 70°C to 90°C, and then adding porous amorphous silica, wherein the weight ratio of the acylethanolamide composition to porous amorphous silica is 0.9:1 to 1.1:1, or about 1:

1.

8. Acylethanolamide composition / porous amorphous silica adsorbent compound, wherein the acylethanolamide composition is the composition described in claim 1, 2, or 3.

9. A human or veterinary pharmaceutical formulation comprising the acylethanolamide composition according to claim 1, 2, or 3, wherein the formulation is in a dosage form for oral, oral, parenteral, rectal, or transdermal administration.

10. A human or veterinary pharmaceutical formulation comprising the acylethanolamide composition / porous amorphous silica adsorbent compound described in claim 8, wherein the formulation is in a dosage form for oral, oral, parenteral, rectal, or transdermal administration.

11. The pharmaceutical formulation according to claim 9, wherein the acylethanolamide composition is included in a liquid dosage form.

12. The pharmaceutical formulation according to claim 10, wherein the acylethanolamide composition is included in a liquid dosage form.

13. The pharmaceutical formulation according to claim 9, comprising an acylethanolamide composition / porous amorphous silica adsorbent compound in a solid dosage form.

14. The pharmaceutical formulation according to claim 10, comprising an acylethanolamide composition / porous amorphous silica adsorbent compound in a solid dosage form.

15. A food preparation, nutritional supplement, or specialty medical food (FSMP) comprising the acylethanolamide composition according to claim 1, 2, or 3.

16. A food preparation, nutritional supplement, or specialty medical food (FSMP) comprising the acylethanolamide composition / porous amorphous silica adsorbent compound described in claim 8.

17. An acylethanolamide composition according to claim 1, 2, or 3 for use in the treatment of mild neuroinflammation.

18. The acylethanolamide composition / porous amorphous silica adsorbent compound according to claim 8, for use in the treatment of mild neuroinflammation.

19. The acylethanolamide composition according to claim 1, 2, or 3 for use in the treatment of mild neuroinflammation in a population of patients suffering from obesity.

20. The acylethanolamide composition / porous amorphous silica adsorbent compound according to claim 8, for use in the treatment of mild neuroinflammation in a population of patients suffering from obesity.

21. The formulation according to claim 9 for use in the treatment of mild neuroinflammation in a population of patients suffering from obesity.

22. The formulation according to claim 10 for use in the treatment of mild neuroinflammation in a population of patients suffering from obesity.

23. The formulation according to claim 11 for use in the treatment of mild neuroinflammation in a population of patients suffering from obesity.

24. The formulation according to claim 12 for use in the treatment of mild neuroinflammation in a population of patients suffering from obesity.

25. The formulation according to claim 13 for use in the treatment of mild neuroinflammation in a population of patients suffering from obesity.

26. The formulation according to claim 14 for use in the treatment of mild neuroinflammation in a population of patients suffering from obesity.

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