Formulations for delivering lipophilic active ingredients

Abstract

The present invention relates to a technology platform for delivering lipophilic active ingredients.

Description

[0001] Technical Field of the Invention

[0002] This invention can be applied to the fields of medicine, pharmaceuticals, nutritional medicine, and beauty, and particularly relates to a novel platform for delivering active ingredients.

[0003] Technical status

[0004] PEA (its structure is shown in...) Figure 1 (M) is an amide between palmitic acid and ethanolamine, and PEA is abundant in the central nervous system.

[0005] PEA is significantly produced by glial cells and is an important mediator that functions in both the central and peripheral nervous systems.

[0006] Palmitoylethanolamide (PEA) is produced in the body to combat pain and inflammation. Many animals and plants also produce PEA. The highest levels can be found in soy lecithin, soybeans, egg yolks, and peanuts. This fatty acid can increase endocannabinoids and protect the nervous system throughout the body.

[0007] The benefits of PEA are encouraging for a wide range of difficult-to-treat disorders.

[0008] About 25 years ago, anandamide (AEA), a structural analog of PEA, was discovered to be an endogenous ligand for cannabinoid receptors and a target of Δ9-tetrahydrocannabinol found in cannabis.

[0009] In addition to its well-known anti-inflammatory activity, PEA can also induce analgesia, exert neuroprotective effects, inhibit food intake, reduce intestinal motility and cancer cell proliferation, and protect vascular endothelium in cases of myocardial ischemia.

[0010] Other studies have shown that this endogenous acylethanolamide can inhibit mast cell degranulation and inflammation at the peripheral level, an effect accompanied by changes in macrophage production of nitric oxide and expression of pro-inflammatory proteins such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).

[0011] PEA has been shown to bind to receptors in the cell nucleus (nuclear receptors) and play a variety of biological functions associated with chronic pain and inflammation. Peroxisome proliferator-activated receptor α (PPAR-α) is considered a major target. However, the presence of palmitoylethanolamide and other structure-associated N-acylethanolamines is known to enhance the activity of arachidonic acid ethanolamide through the so-called "entourage effect".

[0012] PEA also attenuated the degree of inflammation in an animal model of peripheral injury (chronic constriction injury), a neuropathic model associated with a severe inflammatory response involving T cells and macrophages. Following nerve injury, PEA reduced edema and macrophage infiltration as assessed by the number of CD86+ cells, which are responsible for producing high levels of nitric oxide, superoxide radicals, and pro-inflammatory cytokines.

[0013] Therefore, the analgesic and neuroprotective properties of PEA are not only related to its anti-inflammatory effects and its ability to prevent macrophage infiltration into nerves. In summary, this evidence suggests that PEA plays a crucial role in maintaining cellular homeostasis during pathological stimuli that induce inflammatory responses and tissue damage.

[0014] Despite their clinical potential, PEA and all endocannabinoids have serious dissolution difficulties.

[0015] PEA is practically insoluble in water, oil, and most common organic solvents. PEA is sparingly soluble in methanol, ethanol, and isopropanol.

[0016] PEA is available on the market in very high doses (600 mg per dose) and in micronized form, and is administered orally as a dietary supplement.

[0017] US Patent Application US2011 / 046225 describes a situation where a mixture of palmitoylethanolamide and stearoylethanolamide used for synergistic treatment may benefit from the endocannabinoid properties of these compounds.

[0018] The publication by Diana Tronino et al. (“Nanoparticles prolong N-palmitoylethanolamide anti-inflammatory and analgesic effects in vivo,” COLLOIDS AND SURFACES B: BIOINTERFACES, VOL. 141, 1 February 2016, pp. 311-317, XP029465877) describes Compritol ATO (triglyceride betaine, HLB2) nanoparticles incorporating palmitoylethanolamide using miglyol (medium-chain triglyceride, MCT) and Lutrol F68 (a high HLB surfactant). This preparation was obtained by thermal homogenization after pre-melting the lipids and dissolving the palmitoylethanolamide in the molten lipids.

[0019] Existing technical document CN 108 451 905B describes a gambogeylic acid nanoemulsion obtained by using two stable surfactants. Invention Overview

[0021] The inventors of this patent application have developed a technology platform for preparing nanoscale formulations of water-insoluble compounds.

[0022] The platform is specifically designed for formulations of active ingredients with very low solubility. Brief description of the attached diagram

[0024] Figure 1 The structural formula of palmitoylethanolamide is shown.

[0025] Figure 2 Scanning electron microscopy images of the original PEA (sx; A = 400X, B = 3,000X) and the formulation according to the invention (dx; C = 8,000X, D = 60,000X) at different magnifications are shown.

[0026] Figure 3 A scanning electron microscope image (28,000× magnification) of the formulation in the absence of squalene is shown.

[0027] Figure 4 An optical microscope image (400× magnification) of the formulation in the absence of surfactant is shown.

[0028] Figure 5 The thermograms of PEA:squalane mixture (A), PEA:squalene mixture (B), and pristine PEA in ethanol obtained by differential scanning calorimetry are shown.

[0029] Figure 6 The inherited graph of PASI (Psoriasis Area Severity Index) is shown, calculated by adding up the scores of erythema, scaling, and thickness in the five treatment groups.

[0030] Figure 7 Psoriatic plaques on the knees are shown before treatment with the formulation of the present invention, 7 days after treatment, and 14 days after treatment.

[0031] Figure 8 The results of treating psoriatic plaques on the feet with the formulation of the present invention before treatment, 7 days after treatment, and 14 days after treatment are shown.

[0032] The subject of this invention

[0033] The first subject of the present invention is represented by a method for preparing a formulation for delivering an active ingredient.

[0034] In a preferred aspect of the invention, the active ingredient is lipophilic.

[0035] The second subject is represented by the formulation obtained according to the method of the present invention.

[0036] The third subject of the present invention is represented by pharmaceutical products, nutritional pharmaceutical products, or cosmetic products comprising the described formulations.

[0037] The fourth subject of this invention is represented by the medical use of the formulations of this invention.

[0038] In a preferred aspect of the invention, a medical use for treating conditions selected from the group consisting of: psoriasis, dermatitis, eczema, acne, folliculitis, and pityriasis alba is described.

[0039] In another aspect of the invention, medical uses for treating conditions selected from the group consisting of: lung infections and inflammation, atherosclerosis, asthma, rheumatoid arthritis, multiple sclerosis, neurodegenerative diseases, Crohn's disease, colitis, and glaucoma are described.

[0040] In another aspect, formulations or articles of the present invention for use in cosmetic and nutritional medicines are described.

[0041] In the fifth aspect of this invention, a method for treating conditions selected from the group consisting of psoriasis, dermatitis, eczema, acne, folliculitis, and pityriasis alba is described. Invention Details

[0043] The first subject of the present invention is represented by a method for preparing a formulation for delivering an active ingredient.

[0044] For the purposes of this patent application, the active ingredient is preferably lipophilic.

[0045] In a particularly preferred embodiment, the active ingredient is palmitoylethanolamide.

[0046] Specifically, the method of the present invention includes the following steps:

[0047] 1) The lipophilic active ingredient is dissolved in a water-miscible solvent in the presence of squalene and a first surfactant;

[0048] 2) Add the resulting solution dropwise into the aqueous phase in the presence of a second surfactant.

[0049] In one particular aspect, the delivered lipophilic active ingredient is a derivative of arachidonic acid or glycolamide.

[0050] For the purposes of this invention, the active ingredient may be one of the endocannabinoids, or it may not be one of the endocannabinoids.

[0051] Such lipophilic active substances can be selected from the group including: oleoylethanolamide (OEA), anandamide (AEA), 2-arachidonoylglycerol (2-AG), stearoylethanolamide (SEA), docosahexaenoylethanolamide (DHEA), linoleoylethanolamide (LEA), and adelmidrol.

[0052] In step 1), the lipophilic active ingredient is preferably palmitoylethanolamide.

[0053] In one aspect of the invention, the solvent used is selected from the group consisting of ethanol, methanol, isopropanol, acetone, and acetonitrile.

[0054] In one aspect of the invention, the first surfactant used in step 1) is a surfactant having an HLB < 10.

[0055] In a preferred aspect of the invention, the first surfactant is glyceryl monostearate (GMS) or sorbitan monostearate.

[0056] In one aspect of the invention, the solution of step 1) is obtained by using a concentration of about 0.05% (w / v) to 5% (w / v) of lipophilic active ingredient.

[0057] In one aspect of the invention, the solution in step 1) is obtained by using a squalene concentration of about 0.05% (w / v) to 5% (w / v).

[0058] Regarding step 2), the second surfactant used is a surfactant with HLB ≥ 10.

[0059] For the purposes of this invention, the second surfactant is selected from the group consisting of: triterpenoid saponins or mixtures thereof, polysorbates, poloxamer, gelatin, polyethylene glycol derivatives, and sucrose palmitate.

[0060] In a preferred aspect of the invention, the surfactant is sucrose palmitate.

[0061] In one aspect of the invention, step 2) is carried out under mechanical stirring.

[0062] The solvent in step 2) is preferably water.

[0063] According to a preferred aspect of the invention, the surfactants in step 1) and step 2) are added in a ratio of approximately 1:0.25 to 1:1.75 by weight to obtain a lipophilic active ingredient: the total amount of the surfactants is added (i.e., the weight of the surfactants in step 1) + the weight of the surfactants in step 2).

[0064] Therefore, in a particular aspect of the invention, the surfactant of step 1) and the surfactant of step 2) are added in a total ratio of PEA to total surfactant of about 1:0.25 to 1:1.75 by weight (i.e., the weight of the surfactant of step 1) + the weight of the surfactant of step 2).

[0065] After step 2), allow the mixture to evaporate until the solvent has completely evaporated.

[0066] In one aspect of the invention, evaporation is achieved by magnetic stirring.

[0067] In one aspect of the invention, in step 2), a compound selected from the following is subsequently added:

[0068] -Mannose or its derivatives in monomeric, oligomeric, and polymeric forms; or

[0069] - Fucose or its derivatives in monomeric, oligomeric, and polymeric forms.

[0070] For the purposes of this invention, mannose derivatives include, for example, methyl α-D-mannopyranoside or mannosylated compounds selected from, for example, fatty acids, proteins or N-acetylglucosamine.

[0071] For the purposes of this invention, fucose derivatives include, for example, fucoidylated compounds selected from fatty acids, proteins, or N-acetylglucosamine.

[0072] In a preferred aspect of the invention, fucose is added.

[0073] In one aspect of the invention, mannose or fucose or a derivative thereof are added in a 1:1 molar ratio relative to the hydrophilic surfactant.

[0074] The formulation obtained according to the present invention is of the nanostructure type.

[0075] This means that the method leads to the formation of nanostructured PEA suspensions.

[0076] In particular, the obtained nanostructured PEA suspension has a size of about 200 nm-350 nm, preferably about 280 nm-320 nm, and more preferably about 290 nm-310 nm or about 300 nm, as determined by light scattering.

[0077] As mentioned above, the method described in this patent application can be used to obtain nanostructured formulations for delivering lipophilic active ingredients.

[0078] In one particular aspect, the delivered lipophilic active ingredient is a derivative of arachidonic acid or glycolamide.

[0079] For the purposes of this invention, the active ingredient may be one of the endocannabinoids, or it may not be one of the endocannabinoids.

[0080] The lipophilic active ingredient may be selected from the group including: oleoylethanolamide (OEA), arachidonic acid ethanolamide (AEA), 2-arachidoglycerol (2-AG), stearoylethanolamide (SEA), docosahexaenoic acid ethanolamide (DHEA), linoleoylethanolamide (LEA), and adenomyol.

[0081] The second subject of this invention is a formulation obtained according to the method described above.

[0082] Such formulations are preferably suspensions or dry powders.

[0083] In a preferred aspect, the described formulation comprises about 0.3% (w / v) to 1.5% (w / v) of PEA in nanostructure form.

[0084] A third subject of the present invention is pharmaceutical or cosmetic products comprising the described formulation.

[0085] For the purposes of this invention, the article is prepared for administration via skin, oral, ocular, inhalation, or systemic (intravenous, intramuscular, subcutaneous, or intra-articular) routes.

[0086] For example, the articles of the present invention may be in one of the following forms: cream, gel, spray, emulsion, foam, dry powder or suspension for inhalation, capsule, tablet, granule, suppository, eye drops, aqueous suspension, transdermal patch.

[0087] The fourth subject of this invention is the medical use of the formulations or articles thereof.

[0088] In a preferred aspect of the invention, a medical use for treating conditions selected from the group consisting of: psoriasis, dermatitis, eczema, acne, folliculitis, and pityriasis alba is described.

[0089] According to another aspect of the invention, medical uses for treating conditions selected from the group consisting of: lung infections and inflammation, atherosclerosis, asthma, rheumatoid arthritis, multiple sclerosis, neurodegenerative diseases, Crohn's disease, colitis, and glaucoma are described.

[0090] Specifically, the formulation of the present invention is applied topically twice daily for a period of 14 days.

[0091] According to another subject, the use of the formulations or articles of the present invention according to the foregoing in cosmetic and nutritional medicines is described.

[0092] According to a fifth aspect of the invention, a method for treating conditions selected from the group consisting of psoriasis, dermatitis, eczema, acne, folliculitis, pityriasis alba, lung infections and inflammation, atherosclerosis, asthma, rheumatoid arthritis, multiple sclerosis, neurodegenerative diseases, Crohn's disease, colitis, and glaucoma is described, the method comprising the step of administering the nanostructured formulation, pharmaceutical product, nutritional pharmaceutical product, or cosmetic product of the invention to a patient suffering from such a condition.

[0093] In a preferred embodiment, the application is surface-based.

[0094] In a preferred embodiment, the application is repeated over a 14-day period.

[0095] The application can be performed twice daily.

[0096] When the active ingredient is a compound belonging to the endocannabinoid class and the first and second surfactants are surfactants having a steroidal (cyclopentanoperhydrophenanthrenic) structure, the methods, formulations, articles, medical uses, and treatment methods described above are excluded from the purposes of this patent application.

[0097] The invention will be further described with reference to the following non-limiting embodiments.

[0098] Example 1

[0099] Preparation of formulation

[0100] According to the quantitative proportions of the present invention, palmitoylethanolamide (PEA), squalene, and a first surfactant having an HLB < 10 are dissolved in ethanol. The resulting solution is added dropwise to an aqueous phase with stirring, and a second surfactant having an HLB ≥ 10 and a mannose derivative are added thereto.

[0101] The resulting mixture was placed in a stirring vessel by electromagnetic stirring until the solvent was completely evaporated.

[0102] Example 2

[0103] Solubility determination and dissolution rate

[0104] The solubility of the suspension obtained according to Example 1 was tested and compared with that of the original PEA.

[0105] The solubility of the original PEA and nanostructured PEA of this invention was tested in the following dissolution media:

[0106] - Softened water (demineralized water)

[0107] -Phosphate buffer pH 7.4,

[0108] - Simulated intestinal fluid (pH 6.8), and

[0109] - Simulated lung fluid (pH 7.4)

[0110] To determine any changes in the solubility of the compound.

[0111] After 24 hours, the solubility in different dissolving media was measured at 25°C with magnetic stirring. Specifically, excess raw PEA (17 mg) and 6 mL of Example 1 (corresponding to 17 mg of nanostructured PEA) were added to the different solutions mentioned above to obtain a final volume of 12 mL. After 24 hours, equal portions of the sample were taken, filtered through a 0.2 μm syringe filter, and finally analyzed by HPLC.

[0112] The data is shown in Table I below.

[0113] Table I

[0114] Raw PEA (μg / mL) Example 1 (μg / mL) MilliQ softened water <0.1 16.76±1.33 Phosphate buffer solution, pH 7.4 0.64±0.05 15.51±5.46 The simulated intestinal fluid pH was 6.8. 0.22±0.03 6.22±1.73 The simulated lung fluid pH was 7.4. 0.80±0.12 8.22±0.09

[0115] To evaluate the change in dissolution rate, an experiment was conducted using a 1% aqueous sodium cholate solution.

[0116] The dissolution rate of PEA was evaluated over time, starting with 0.3 mg of raw PEA or a suspension of nanostructured PEA obtained according to Example 1 in 10 mL of 1% w / v sodium cholate solution (final total concentration of 30 μg / mL).

[0117] Dissolution data are shown in Table II.

[0118] Table II

[0119] PEA (μg / mL) Example 1 (μg / mL) 30min 3.31±2.30 25.5±1.43 1 hour 4.56±1.02 25.03±2.36 2 hours 6.15±1.22 25.23±2.66 4 hours 8.61±0.68 25.37±2.70 6 hours 9.31±0.71 25.83±0.18

[0120] HPLC method

[0121] The concentration of PEA in the solution to be analyzed (Example 2) was determined by HPLC-UV / Vis analysis.

[0122] The system used consisted of two PU-2080Plus pumps, an HG-980-30 solvent mixing module, a Degasys DG-1210 degassing module (Uniflows Co., Ltd., Tokyo, Japan), and a UV-VIS UV-2075Plus detector. Data were recorded and processed using the Hercule Lite chromatographic interface and Borwin software (Jasco Corporation, Tokyo, Japan). Chromatographic analysis was performed on a Purospher Rp-18e column (125 mm × 4.0 mm; 5.0 μm) equipped with a Purospher C18 pre-column (4.0 mm × 4.0 mm; 5.0 μm) (Merck Darmstadt, Germany) (both are thermally stable at 30 °C). Chromatographic data were recorded at 210 nm. The mobile phase used consisted of an 18:82 (v / v) H₂O:acetonitrile mixture, eluted isocratically at a flow rate of 1 mL / min. Under the analytical conditions listed above, the retention time of PEA was found to be 4.6 min.

[0123] The products obtained according to Example 1, but excluding mannose derivatives, exhibited similar solubility and dissolution rate.

[0124] Example 3

[0125] Particle size and morphological characterization

[0126] The size of the nanoparticles was evaluated by light scattering analysis of the PEA suspension obtained according to Example 1.

[0127] The results are shown in Table III below.

[0128] Table III

[0129] Original PEA PEA Example 1 Dimensions (nm±SD) Macroscopic and microscopic flakes 261.6nm±68.11nm

[0130] Morphologically, both forms were analyzed using scanning electron microscopy (SEM). Figure 2 As can be seen from the images, the original form of PEA appears as irregular macroscopic aggregates (tens of micrometers), while the nanostructured PEA according to the present invention appears as comprising distinctive nanometer formations.

[0131] The product obtained according to Example 1, excluding mannose derivatives, has been characterized, and the results are similar to those of Example 3.

[0132] Example 4

[0133] Comparative determination

[0134] A similar formulation was prepared following the method of Example 1, but with certain components omitted one by one:

[0135] 1) Squalene is not present.

[0136] 2) Replace squalene with squalane.

[0137] 3) The surfactants in steps 1 and 2 are not present.

[0138] 1) Tests conducted showed that in the absence of squalene, the formulation was unstable and showed no visible macroscopic aggregates; however, SEM analysis (see [link to SEM analysis]) revealed that the product was unstable and showed no visible macroscopic aggregates. Figure 3 Microscopic aggregates were observed instead of clearly defined nanostructures. The dissolution rate of PEA in a 1% sodium cholate solution of this formulation was found to be 15.52 μg / m³ after 30 min (see Table 1).

[0139] 2) The use of hydrogenated forms of squalene and squalane did not allow for the same acquisition of nanostructured PEA, assuming a selective affinity between PEA and squalene. This was confirmed by DSC analysis of a mixture of PEA + squalane and PEA + squalene prepared in an alcohol solution according to Example 1. Figure 5 In the first case, there are three polymorphic forms of PEA, and the same applies to the original PEA. In the second case, there is a single form of stabilization, namely metastable polymorph II.

[0140] 3) Tests conducted showed that the formulation was unstable in the absence of the first and second surfactants. Macroscopic aggregates of PEA without nanostructures were indicated by optical microscopy (see [reference needed]). Figure 4 It is visible in both the naked eye and the naked eye.

[0141] Example 5

[0142] Treatment of animal models of psoriasis

[0143] A psoriasis mouse model (8-week-old female C57bl / 6) was used for preliminary studies to compare the activity of nanostructured PEA with that of raw PEA and commercially available corticosteroids. Nanostructured PEA and raw PEA were added, respectively, to an oil-in-water emulsion cream primarily composed of almond oil, a plant emulsifier, and caprylic / capric triglycerides. Psoriasis was induced by imiquimod, a compound widely used in preclinical drug development due to its ease of use, convenience, and ability to produce a skin phenotype similar to acute psoriasis, including erythema, scaling, and epidermal thickening. Specifically, treatment began 2 days after imiquimod administration. Different creams were applied to the backs of the animals daily for 8 days. Animals were divided into 5 groups: (1) mediator cream, (2) mediator cream + raw PEA 0.4%, (3) mediator cream + nanostructured PEA 0.4%, (4) mediator cream + nanostructured PEA 0.8%, and (5) betamethasone dipropionate cream (a commercial corticosteroid product).

[0144] Throughout the study period (10 days), mice were monitored daily for various indicators such as stress, weight loss, loss of appetite, and decreased activity. No changes in these indicators were observed except in group (5), where the initial signs of distress appeared in the last two days of treatment, likely due to initial toxicity of the corticosteroids. Erythema, desquamation, and lesion thickness were evaluated daily as indicative parameters of psoriasis.

[0145] For all these parameters, group 4 of the treated animals (nanostructured PEA 0.8%) was the only group with values ​​similar to the positive control group (commercial corticosteroids). Finally, the PASI index was calculated ( Figure 6 PASI is the Psoriasis Area and Severity Index, used in the clinical evaluation of psoriasis to monitor the severity of psoriasis-like lesions. The index is calculated by averaging all values ​​of plaque parameters (erythema, scaling, and thickness) measured during treatment using electronic calipers. The animal group receiving the highest dose of nanostructured PEA (Group 4) responded very similarly to the animal group receiving corticosteroids (Group 5), but showed no signs of adverse side effects.

[0146] Example 6

[0147] Treatment of psoriatic plaques

[0148] The nanostructured PEA suspension obtained according to Example 1 was used to prepare a 0.2% surface nanostructured PEA cream.

[0149] The cream was applied to the skin of approximately 15 volunteers with mild psoriasis twice daily for 15 days.

[0150] Significant improvement in psoriatic plaques was observed only after 1 to 2 weeks, such as Figure 7 The image shows the effect after application to the knee, and Figure 8 Images showing the effect after application to the feet are provided, as confirmed by the volunteers.

[0151] From the foregoing description, many advantages of the present invention will be apparent to those skilled in the art.

[0152] In particular, from a technical point of view, the formulations of the present invention are advantageously soluble in water and phosphate buffer at physiological pH, as well as in intestinal and lung matrix.

[0153] In addition to the above, the described method also allows for the preparation of other and different active ingredients with lipophilic properties that would otherwise be unapplicable, in addition to having known limitations and drawbacks.

[0154] The resulting formulation is nanostructured and not an emulsion; in fact, its composition and preparation method differ from those of emulsions because they involve the use of water-miscible solvents.

[0155] Furthermore, it is surprising that the use of squalene cannot be replaced by other molecules, despite their great similarity.

Claims

1. A method for preparing a nanostructured suspension of palmitoylethanolamide (PEA), comprising the following steps: 1) Dissolve PEA in a water-miscible solvent in the presence of squalene and a first surfactant having HLB < 10; 2) The solution thus obtained is added dropwise to the aqueous phase in the presence of a second surfactant having an HLB ≥ 10, wherein the first surfactant and the second surfactant are not surfactants having a steroidal structure. The suspension contains nanoparticles made of PEA.

2. The method according to claim 1, wherein the water-miscible solvent is selected from the group consisting of ethanol, methanol, isopropanol, acetone and acetonitrile.

3. The method according to claim 1 or 2, wherein in step 1), the surfactant is glyceryl monostearate or sorbitan monostearate.

4. The method according to any one of claims 1-2, wherein in step 2), the second surfactant is selected from the group consisting of: triterpenoid saponins or mixtures thereof, polysorbates, poloxamer, gelatin, polyethylene glycol derivatives, and sucrose palmitate.

5. The method according to claim 3, wherein in step 2), the second surfactant is selected from the group consisting of: triterpenoid saponins or mixtures thereof, polysorbates, poloxamer, gelatin, polyethylene glycol derivatives, and sucrose palmitate.

6. The method according to any one of claims 1-2 and 5, wherein the surfactant in step 1) and the surfactant in step 2) are added in total to obtain a PEA:total surfactant ratio of 1:0.25 to 1:1.75 by weight.

7. The method of claim 3, wherein the surfactant of step 1) and the surfactant of step 2) are added in a total amount to obtain a PEA:total surfactant ratio of 1:0.25 to 1:1.75 by weight.

8. The method of claim 4, wherein the surfactant of step 1) and the surfactant of step 2) are added in a total amount to obtain a PEA:total surfactant ratio of 1:0.25 to 1:1.75 by weight.

9. The method according to any one of claims 1-2, 5 and 7-8, wherein in step 2), a compound selected from the group consisting of fucose or mannose or derivatives thereof in monomeric, oligomeric or polymeric form, or methyl α-D-mannopyranoside, or a fucoidylated compound or mannose selected from the group consisting of fatty acids, proteins or N-acetylglucosamine.

10. The method of claim 3, wherein in step 2), a compound selected from the group consisting of fucose or mannose or derivatives thereof in monomeric, oligomeric or polymeric form, or methyl α-D-mannopyranoside, or a fucoidylated compound or mannose selected from the group consisting of fatty acids, proteins or N-acetylglucosamine.

11. The method according to claim 4, wherein in step 2), a compound selected from the group consisting of fucose or mannose or derivatives thereof in monomeric, oligomeric or polymeric form, or methyl α-D-mannopyranoside, or a fucoidylated compound or mannose selected from the group consisting of fatty acids, proteins or N-acetylglucosamine.

12. The method of claim 6, wherein in step 2), a compound selected from the group consisting of fucose or mannose or derivatives thereof in monomeric, oligomeric or polymeric form, or methyl α-D-mannopyranoside, or a fucoidylated compound or mannose selected from the group consisting of fatty acids, proteins or N-acetylglucosamine.

13. A nanostructured suspension of palmitoylethanolamide (PEA), the nanostructured suspension comprising nanoparticles made of PEA, the nanostructured suspension being obtained by the method according to any one of claims 1-12.

14. The nanostructured suspension according to claim 13, wherein the suspension comprises nanoparticles characterized by a diameter of 250 nm to 350 nm.

15. The nanostructured suspension of claim 14, wherein the suspension comprises nanoparticles characterized by a diameter of 280 nm to 320 nm.

16. A pharmaceutical product, nutritional product, or cosmetic product comprising a nanostructured suspension according to any one of claims 13-15.

17. The pharmaceutical, nutritional, or cosmetic product comprising the nanostructured suspension according to claim 16, formulated as: cream, gel, spray, emulsion, foam, dry powder or suspension for inhalation, capsule, tablet, granule, suppository, eye drops, or transdermal patch.

18. The pharmaceutical product, nutritional product, or cosmetic product comprising the nanostructure suspension according to claim 16, is formulated as an aqueous suspension.

19. Use of the nanostructured suspension according to any one of claims 13-15 or the pharmaceutical article as defined in any one of claims 16-18 in the preparation of a medicament for treating a condition selected from the group consisting of: psoriasis, dermatitis, eczema, acne, folliculitis, pityriasis alba, lung infections and inflammation, atherosclerosis, asthma, rheumatoid arthritis, multiple sclerosis, neurodegenerative diseases, Crohn's disease, colitis, and glaucoma.

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