Lamellar emulsion carrying palmitoylethanolamide

Abstract

The present patent application concerns an emulsion comprising a lipophilic phase comprising; palmitoylethanolamide, an ester solvent selected from: an adipic acid dialkyl and a benzoic acid alkyl, wherein both dialkyl and alkyl are linear and characterized by a number of carbon atoms comprised between 3 and 15, respectively; an aqueous phase comprising: an emulsifying agent comprising hydrogenated lecithin, an alcoholic mixture comprising linear aliphatic alcohols characterized by a number of carbon atoms comprised between 12 and 16, a saturated and linear fatty acid comprising a number of carbon atoms comprised between C12 and C20; water, wherein the emulsion is of lamellar type.

Description

[0001] TITLE: "Lamellar emulsion carrying palnutoylethanolannde'’'’

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The present invention falls within the technical field of solubilisation of active ingredients poorly soluble in water, but also in certain organic solvents, as in the case of palmitoylethanolamide, by means of carrier technologies of the active ingredient.

[0005] STATE OF THE ART

[0006] Palmitoylethanolamide (“PEA”) is an amide of palmitic acid and belongs to the class of ALIAmides (endocannabinoid-like), lipid agonists of nuclear receptors. It is an endogenous molecule, so much so that it is synthesized within the cellular bilayer, and acts locally. Traces of its presence have been found in many human tissues, including the brain.

[0007] PEA is thought to be produced as a pro-homeostatic protective response to cell damage and is usually upregulated in disease states. Its effects comprise anti-inflammatory, analgesic, anticonvulsant, antimicrobial, antipyretic, antiepileptic, immunomodulatory and neuroprotective activities.

[0008] The multifaceted effects of PEA are due to its unique mechanisms of action that affect multiple pathways at different sites, including peroxisome proliferator-activated nuclear receptor alpha (PPAR-a), and other receptors, such as those for cannabinoids. In addition, PEA activates and desensitizes transient potential vanilloid receptor 1 (TRPV1) channels, contributing to a significant desensitizing effect. Thanks to its benefits, over time, many PEA-based products have been developed, both in the pharmaceutical field and in the field of food supplementation.

[0009] Problems of the background art

[0010] PEA has a lipophilic nature, which severely limits its solubility, both in water and in solvents and oily compounds. As a result, it is a poorly bioavailable molecule. Because of these aspects, the development of its applications is complicated.

[0011] To improve bioavailability and functionality, PEA is usually micronized or ultra- micronized. However, ultra / micronization is an expensive process and leads to an increase in the cost of the raw material.

[0012] In addition, traditional emulsions comprising PEA are known in the state of the art, but which are not effective in the complete solubilisation of PEA. This has consequences in terms of cutaneous bioavailability, because poor or no solubilisation of the PEA does not go hand in hand with effective percutaneous delivery of the active ingredient.

[0013] Therefore, the need has been felt to identify a mix of ingredients useful for the constitution of topical emulsions and / or topical compositions that are capable of inducing a more complete solubilisation of the active ingredient with a consequent increase in the bioavailability of the PEA active ingredient.

[0014] SUMMARY OF THE INVENTION

[0015] A first object of the invention is an emulsion comprising a lipophilic phase comprising

[0016] - palmitoylethanolamide,

[0017] - an ester solvent selected from: an adipic acid dialkyl and a benzoic acid alkyl, wherein both dialkyl and alkyl are linear and characterized by a number of carbon atoms comprised between 3 and 15, respectively, an aqueous phase comprising

[0018] - an emulsifying agent comprising hydrogenated lecithin, an alcoholic mixture comprising linear aliphatic alcohols characterized by a number of carbon atoms comprised between 12 and 16, a linear saturated fatty acid comprising a number of carbon atoms comprised between C12 and C20,

[0019] - water, wherein the emulsion is of lamellar type.

[0020] A second object of the invention is the cutaneous topical use of the above emulsion. A third object is a process for preparing the same emulsion, comprising the following steps: a) providing: palmitoylethanolamide, ester solvent, emulsifying agent, water, b) heating the ester solvent to the melting point of palmitoylethanolamide, then adding palmitoylethanolamide, and stirring to homogeneity to obtain the lipophilic / oily phase, c) in parallel, heating water to a temperature comprised between 60 °C and 90 °C, then adding the emulsifying agent and stirring to homogeneity to obtain the hydrophilic phase, d) pouring the lipophilic phase into the hydrophilic phase and simultaneously stirring to obtain the lamellar emulsion.

[0021] Finally, the last object is a composition comprising the above emulsion, suitable excipients and / or diluents, or comprising the above emulsion, suitable excipients and / or diluents, hydrophilic and / or lipophilic active ingredients.

[0022] It should be noted that the composition comprising the emulsion of the invention is suitable for cosmetic use, or is for use as a medicament.

[0023] Advantages of the invention

[0024] The invention allows an effective solubilisation of the PEA thanks to the identification of a mix of components useful for this purpose; consequently, it is possible to convey the PEA, favouring an increase in the bioavailability of the active ingredient and guaranteeing its transcutaneous permeation.

[0025] The Applicant also believes that it is possible to convey the PEA avoiding its crystallization. DESCRIPTION OF THE FIGURES

[0026] Figure F. Optical microscopic image (lOOx, polarized light) of the conventional emulsion “A” referred to in Example 3.

[0027] Figure 2 Optical microscopic image (lOOx, polarized light) of the conventional emulsion “B” referred to in Example 3.

[0028] Figure 3: Optical microscopic image (lOOx, polarized light) of the lamellar emulsion of Example 2.

[0029] Figure 4 Optical microscopic image (lOOx, polarized light) of the lamellar emulsion of Example 1 at halved concentrations.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] In the following, the invention and preferred embodiments thereof are described in more detail.

[0032] Lamellar emulsion carrying PEA

[0033] For brevity, the lamellar emulsion carrying the PEA of the invention is also referred to as an “emulsion” or “lamellar emulsion”.

[0034] Preferably, the emulsion is of the “oil-in-water” (O / W) type.

[0035] As already mentioned, the object of the present invention is an emulsion (or association) comprising a lipophilic phase comprising

[0036] - palmitoylethanolamide,

[0037] - an ester solvent selected from: an adipic acid dialkyl and a benzoic acid alkyl, wherein both the dialkyl and the alkyl are linear and respectively characterized by a number of carbon atoms (“C”) comprised between 3 and 15, a hydrophilic phase comprising

[0038] - an emulsifying agent comprising hydrogenated lecithin, an alcoholic mixture comprising linear aliphatic alcohols characterized by a number of carbon atoms comprised between 12 and 16, a linear saturated fatty acid comprising a number of carbon atoms comprised between C12 and C20,

[0039] - water, wherein the emulsion is of lamellar type.

[0040] The emulsion of the invention is capable of carrying the active palmitoylethanolamide to make the latter more bioavailable, such that it can be more effectively absorbed at the cutaneous topical level. In this sense, the emulsion acts as a vehicle for the PEA.

[0041] By lamellar (or lamellar-type, or liquid crystal) emulsion is meant an emulsion in which the emulsifying agent forms the lamellar structures or lamellae, in which droplets of aqueous phase and lipophilic phase are dispersed. This means that the lamellar emulsion has a biomimetic function that facilitates transcutaneous permeation.

[0042] By classic or traditional emulsion is meant an emulsion not characterized by a lamellar structure.

[0043] Preferably, the weight ratio of the lipophilic phase to the hydrophilic phase (lipophilic phase : hydrophilic phase) is comprised between 1 :2 and 1 :7, preferably comprised between 1 :2 and 1 :6, preferably between 1 :2 and 1 :6, preferably between 1 :3 and 1 :6.

[0044] Lipophilic phase

[0045] By lipophilic or oily phase is meant a phase of the emulsion comprising or consisting of components of a lipophilic nature, i.e. substances that do not dissolve in an aqueous medium, but in a lipophilic one.

[0046] Preferably, the lipophilic phase consists of palmitoyl ethanol ami de, an ester solvent selected from: an adipic acid dialkyl and a benzoic acid alkyl, wherein both dialkyl and alkyl are linear and characterized by a number of carbon atoms comprised between 3 to 15, respectively. Preferably, the weight ratio of the palmitoylethanolamide to the ester solvent (palmitoylethanolamide : ester solvent) is comprised between 1:2 and 1 : 15, preferably between 1 :2 and 1 : 10, preferably between 1 :2 and 1 :8, preferably between 1 :2 and 1 :6, preferably between 1 :2.5 and 1 :5, preferably between 1 :3 and 1 :5, preferably between 1 :4 and 1 :5, preferably between 1 :5 and 1 : 10.

[0047] According to another preferred form, the weight ratio between the palmitoylethanolamide and the ester solvent (palmitoylethanolamide : ester solvent) is comprised between 1 :2 and 1 : 15, preferably between 1 :5 and 1 : 15, preferably between 1 :5 and 1 : 10.

[0048] Palmitoylethanolamide

[0049] Palmitoylethanolamide is an active ingredient included in the emulsion of the invention.

[0050] Preferably, the palmitoylethanolamide is in an amount comprised between 0.5% and 8% by weight, preferably between 1% and 7% by weight, preferably between 1% and 6% by weight, preferably between 1% and 5% by weight, preferably between 2% and 5% by weight, preferably between 2% and 4% by weight, preferably equal to 2% or 4% by weight, on the total weight of the emulsion.

[0051] The vehicle of the invention is effective in terms of solubilisation and / or bioavailability of the PEA at the aforesaid relatively high concentrations, as well as preventing crystallization of the same active.

[0052] Preferably, the palmitoylethanolamide used for the purpose of the invention is a crystalline powder, preferably characterized by a purity > 99%.

[0053] Preferably, 50% of the palmitoylethanolamide raw material powder has a particle size comprised between 40 and 60 pm, preferably of 50 pm.

[0054] Ester solvent

[0055] By ester solvent is meant a solvent (or solubilizer). It is an organic chemical substance with an ester structure, wherein, i.e., an organic acid linked to at least one alkyl chain, preferably to at least one linear alkyl chain, can be recognized.

[0056] Preferably the ester solvent is selected from: an adipic acid dialkyl and a benzoic acid alkyl, wherein both dialkyl and alkyl are respectively aliphatic, linear and characterized by a number of carbon atoms comprised between 3 and 15, preferably the number of carbon atoms is comprised between 4 and 15.

[0057] By adipic acid dialkyl is meant that the adipic acid (or hexanedioic acid) is esterified with two linear alkyls (or linear aliphatic alkyl chains) having the same chemical entity.

[0058] Preferably, the adipic acid dialkyl is characterized by a number of carbon atoms comprised between 4 and 6 (C4-C6), preferably between 4 and 5, preferably equal to 4.

[0059] Preferably, the adipic acid dialkyl is adipic acid dibutyl (dibutyl adipate, dibutyl adipate).

[0060] By benzoic acid alkyl is meant that the benzoic acid is esterified with a linear alkyl (or linear aliphatic alkyl chain).

[0061] Preferably, the benzoic acid alkyl is characterized by a number of carbon atoms comprised between 12 and 15.

[0062] Preferably, the benzoic acid alkyl is C 12-15 alkyl benzoate (C 12-15 alkyl benzoate).

[0063] Preferably, the ester solvent is in an amount comprised between 5% and 75% by weight, preferably between 5% and 73% by weight, preferably between 5% and 70% by weight, preferably between 5% and 60% by weight, preferably between 5% and 50% by weight, preferably between 5% and 40% by weight, preferably between 5% and 30% by weight, preferably between 10% and 30% by weight, preferably between 10% and 25% by weight, preferably between 10% and 20% by weight, based on the total weight of the emulsion.

[0064] According to a further preferred form, the ester solvent is in an amount comprised between 5% and 75% by weight, preferably between 10% and 75% by weight, preferably between 20% and 75% by weight, preferably between 25% and 75% by weight, preferably between 30% and 75% by weight, preferably between 40% and 75% by weight, preferably between 50% and 75% by weight, preferably between 60% and 75% by weight, based on the total weight of the emulsion. Preferably, the adipic acid dialkyl, preferably dibutyl adipate, is in an amount comprised between 5% and 75% by weight, preferably between 5% and 73% by weight, preferably between 5% and 70% by weight, preferably between 5% and 60% by weight, preferably between 5% and 50% by weight, preferably between 5% and 40% by weight, preferably between 5% and 30% by weight, preferably between 10% and 30% by weight, preferably between 15% and 25% by weight, preferably between 15% and 20% by weight, preferably equal to 20% by weight, on the total weight of the emulsion.

[0065] According to a further preferred form, the adipic acid dialkyl, preferably dibutyl adipate, is in an amount comprised between 5% and 75% by weight, preferably between 10% and 75% by weight, preferably between 20% and 75% by weight, preferably between 25% and 75% by weight preferably between 30% and 75% by weight, preferably between 40% and 75% by weight, preferably between 50% and 75% by weight, preferably between 60% and 75% by weight, based on the total weight of the emulsion.

[0066] Preferably, the benzoic acid alkyl, preferably C12-15 alkyl benzoate, is in an amount comprised between 5% and 75% by weight, preferably between 5% and 73% by weight, preferably between 5% and 70% by weight, preferably between 5% and 60% by weight, preferably between 5% and 50% by weight, preferably between 5% and 40% by weight, preferably between 5% and 30% by weight, preferably between 5% and 25% by weight, preferably between 5% and 20% by weight, preferably between 5% and 10% by weight, preferably equal to 10% by weight, on the total weight of the emulsion.

[0067] According to a further preferred form, the benzoic acid alkyl, preferably Cl 2- 15 alkyl benzoate, is in an amount comprised between 5% and 75% by weight, preferably between 10% and 75% by weight, preferably between 20% and 75% by weight, preferably between 25% and 75% by weight, preferably between 30% and 75% by weight, preferably between 40% and 75% by weight, preferably between 50% and 75% by weight, preferably between 60% and 75% by weight, based on the total weight of the emulsion. Hydrophilic or aqueous phase

[0068] By aqueous or hydrophilic phase is meant a phase of the emulsion comprising or consisting of components of a hydrophilic nature, i.e. substances that dissolve in an aqueous medium.

[0069] Emulsifying agent

[0070] The emulsifying agent comprises or consists of hydrogenated lecithin, an alcoholic mixture (hereinafter “alcoholic mixture”) comprising linear aliphatic alcohols characterized by a carbon number comprised between 12 and 16 (C12-16), a saturated and linear fatty acid (hereinafter “fatty acid” or “saturated and linear fatty acid”) comprising a carbon number comprised between 12 to 20 (C12- 20), preferably a saturated and linear fatty acid comprising a carbon number comprised between 12 and 18, preferably a saturated and linear fatty acid comprising a carbon number comprised between 12 and 16, preferably a saturated and linear fatty acid comprising a carbon number comprised between 12 to C14.

[0071] By emulsifying agent is meant a substance or a group of more substances with emulsifying capabilities, capable of dispersing the lipophilic phase in the aqueous phase.

[0072] Preferably, the emulsifying agent is in an amount comprised between 2% and 35% by weight, preferably between 2% and 30% by weight, preferably between 2% and 25% by weight, preferably between 2% and 23% by weight, preferably between 2% and 15% by weight, preferably between 2% and 12% by weight, preferably between 2% and 10% by weight, preferably between 3% and 10% by weight, preferably between 4% and 10% by weight, preferably between 5% and 10% by weight, preferably between 5% and 10% by weight, based on the total weight of the emulsion.

[0073] According to an alternative preferred form, the emulsifying agent is in an amount comprised between 2% and 35% by weight, preferably between 5% and 35% by weight, preferably between 10% and 35% by weight, preferably between 15% and 35% by weight, preferably between 20% and 35% by weight, based on the total weight of the emulsion.

[0074] By hydrogenated lecithin is meant a raw material in which lecithin is hydrogenated, in particular lecithin, extracted from soybeans, has been subjected to catalytic hydrogenation.

[0075] Preferably, the hydrogenated lecithin is in an amount comprised between 0.2% and 7% by weight, preferably between 0.2% and 6% by weight, preferably between 0.2% and 5% by weight, preferably between 0.5% and 5% by weight, preferably between 0.5% and 4% by weight, preferably between 1% and 3% by weight, preferably between 1% and 2% by weight, preferably equal to 1% or 2% by weight, on the total weight of the emulsion.

[0076] According to a preferred alternative form, the hydrogenated lecithin is in an amount comprised between 0.2% and 7% by weight, preferably between 1% and 7% by weight, preferably between 3% and 7% by weight, on the total weight of the emulsion.

[0077] Preferably, by an alcoholic mixture is meant a mixture comprising linear aliphatic alcohols. Preferably, the alcoholic mixture can be obtained by hydrolysis of the palm oil, then subsequent physical fractionation and reduction to hexadecane- l-ol.

[0078] By linear aliphatic alcohols are meant alcohols characterized by a linear, unbranched structure.

[0079] Preferably, the alcoholic mixture, comprising linear aliphatic alcohols characterized by a number of carbon atoms comprised between 12 and 16, is in an amount comprised between 1% and 23% by weight, preferably between 1% and 20% by weight, preferably between 1% and 15% by weight, preferably between 1% and 10% by weight, preferably between 1% and 8% by weight, preferably between 2% and 8% by weight, preferably between 3% and 6% by weight, preferably equal to 3% or 6% by weight, on the total weight of the emulsion.

[0080] According to an alternative preferred form, the alcoholic mixture, comprising linear aliphatic alcohols characterized by a number of carbon atoms comprised between 12 and 16, is in an amount comprised between 1% and 23% by weight, preferably between 5% and 23% by weight, preferably between 10% and 23% by weight, preferably between 15% and 23% by weight, preferably between 15% and 20% by weight, on the total weight of the emulsion.

[0081] The alcoholic mixture preferably comprises linear aliphatic alcohols which are derived from linear fatty acids which may be saturated or unsaturated, preferably the fatty acids are selected from the group consisting of: myristic acid, palmitic acid.

[0082] Preferably, the saturated and linear fatty acid comprising a number of carbon atoms comprised between 12 and 20, preferably with a number of carbon atoms comprised between 12 and 18, preferably a saturated and linear fatty acid comprising a number of carbon atoms comprised between 12 and 16, preferably a saturated and linear fatty acid comprising a number of carbon atoms comprised between 12 and 14, preferably equal to 14, preferably is palmitic acid.

[0083] Preferably, the linear fatty acid, preferably palmitic acid, is in an amount comprised between 0.2% and 8.5% by weight, preferably between 0.2% and 8% by weight, preferably between 0.2% and 7.5% by weight, preferably between 0.2% and 6% by weight, preferably between 0.2% and 5% by weight, preferably between 0.5% and 5% by weight, preferably between 0.5% and 4% by weight, preferably between 1% and 3% by weight, preferably between 1% and 2% by weight, preferably equal to 1% or 2% by weight, on the total weight of the emulsion.

[0084] Preferably, the linear fatty acid, preferably palmitic acid, is in an amount comprised between 0.2% and 8.5% by weight, preferably between 0.5% and 8.5% by weight, preferably between 1% and 8.5% by weight, preferably between 3% and 8.5% by weight, based on the total weight of the emulsion.

[0085] Water

[0086] Preferably, water is in an amount comprised between 50% and 90% by weight, preferably comprised between 50% and 80% by weight, preferably between 50% and 70% by weight, preferably between 55% and 70% by weight, preferably between 60% and 70% by weight, preferably between 65% and 70% by weight, preferably between 65% and 68% by weight, preferably equal to about 66% by weight, on the total weight of the emulsion. Preferred form of the lamellar emulsion

[0087] According to a preferred form, the lamellar emulsion comprises a lipophilic phase comprising or consisting of

[0088] - palmitoylethanolamide,

[0089] - an ester solvent consisting of adipic acid dialkyl, wherein the dialkyl is a linear alkyl and characterized by a number of carbon atoms (“C”) comprised between 3 and 15, preferably between 4 and 10, preferably between 4 and 6, preferably between 4 and 5, preferably equal to 4, preferably dibutyl adipate; a hydrophilic phase comprising or consisting of

[0090] - an emulsifying agent comprising or consisting of hydrogenated lecithin, an alcoholic mixture comprising linear aliphatic alcohols characterized by a number of carbon atoms comprised between 12 and 16, a saturated and linear fatty acid comprising a number of carbon atoms comprised between 12 to 20, preferably comprised between 12 and 18, preferably between 12 and 16, preferably between 12 and 14, preferably 14, preferably is palmitic acid.

[0091] - water.

[0092] Note that the qualitative-quantitative characteristics of all components included in the emulsion have been described above and apply as such for this preferred form.

[0093] Process for preparing the lamellar emulsion

[0094] The process for preparing the emulsion according to the invention comprises the following steps: a) providing: palmitoylethanolamide, ester solvent, emulsifying agent, water, b) heating the ester solvent to the melting point of palmitoylethanolamide, then adding palmitoylethanolamide, and stirring to homogeneity to obtain the lipophilic / oily phase, c) in parallel, heating water to a temperature comprised between 60 °C and 90 °C, then adding the emulsifying agent and stirring to homogeneity to obtain the hydrophilic phase, d) pouring the lipophilic phase into the aqueous phase and simultaneously stirring to obtain the lamellar emulsion.

[0095] Note that the characteristics of the ingredients palmitoylethanolamide, ester solvent, emulsifying agent, water have been described in the previous sections.

[0096] Step b) of heating the ester solvent to the melting point of the palmitoylethanolamide, then adding the palmitoylethanolamide, and stirring to homogeneity to obtain the lipophilic oily phase.

[0097] Step b) of heating the ester solvent to the melting point of the palmitoylethanolamide, then adding the palmitoylethanolamide, and stirring to homogeneity to obtain the lipophilic / oily phase follows step a) of providing the ingredients.

[0098] Preferably, heating the solvent to the melting point of the palmitoylethanolamide provides for reaching a temperature comprised between 95°C to 105°C, preferably comprised between 98°C to 100°C.

[0099] Note that in this way the palmitoylethanolamide will be dissolved and the oily / lipophilic phase will be clear and homogeneous.

[0100] Step c) of heatins the water to a temperature comprised between 60°C and 90°C, then adding the emulsifying agent and stirring to homogeneity to obtain the hydrophilic phase

[0101] Step c) of heating the water to a temperature comprised between 60°C and 90°C, then adding the emulsifying agent and stirring to homogeneity to obtain the hydrophilic phase, takes place in parallel with step b) of heating the palmitoylethanolamide described above.

[0102] Preferably, the water is heated to a temperature comprised between 60°C and 90°C, preferably between 60°C and 80°C, preferably equal to 70°C. After heating the water, the emulsifying agent is added and left under stirring for a time comprised between 5 and 15 minutes, preferably of 10 minutes, for this component to hydrate.

[0103] Step d) of pouring the lipophilic phase into the aqueous phase and simultaneously stirring to obtain the lamellar emulsion.

[0104] Step d) of pouring the lipophilic phase into the aqueous phase and simultaneously stirring to obtain the lamellar emulsion follows the step c) of heating the water described above.

[0105] Preferably, the lipophilic phase is poured into the aqueous phase slowly under stirring, in particular by gradually increasing the stirring to values comprised between 1,500 and 3,500 rpm, preferably comprised between 2,000 and 3,000 rpm.

[0106] As the lamellar emulsion thus obtained cools, it is possible to observe a change in consistency, which will pass from a rather fluid physical state to a more full-bodied one.

[0107] Lamellar emulsion obtained from the process

[0108] The lamellar emulsion, comprising a lipophilic phase comprising

[0109] - palmitoylethanolamide,

[0110] - an ester solvent selected from: an adipic acid dialkyl and a benzoic acid alkyl, wherein both dialkyl and alkyl are linear and characterized by a number of carbon atoms comprised between 3 and 15, respectively, an aqueous phase comprising

[0111] - an emulsifying agent comprising hydrogenated lecithin, an alcoholic mixture comprising linear aliphatic alcohols characterized by a number of carbon atoms comprised between 12 and 16, a linear saturated fatty acid comprising a number of carbon atoms comprised between C12 and C20, - water, is obtained by a) providing: palmitoylethanolamide, ester solvent, emulsifying agent, water, b) heating the ester solvent to the melting point of palmitoylethanolamide, then adding palmitoylethanolamide, and stirring to homogeneity to obtain the lipophilic / oily phase, c) in parallel, heating water to a temperature comprised between 60°C and 90°C, then adding the emulsifying agent and stirring to homogeneity to obtain the hydrophilic phase, d) pouring the lipophilic phase into the aqueous phase and simultaneously stirring to obtain the lamellar emulsion.

[0112] Note that the qualitative-quantitative characteristics of all components included in the emulsion have been described above and apply as such for this preferred form.

[0113] Note that the above mentioned procedural steps have been described above and apply as such for this preferred form.

[0114] Topical use of the lamellar emulsion

[0115] Note that the lamellar emulsion described so far can be used, as such, for topical or cutaneous use.

[0116] Preferably, the emulsion of the invention may be employed for topical use without being incorporated into a composition and / or in the absence of suitable excipients and / or diluents.

[0117] Preferably, the emulsion is in a solid or semi-solid form.

[0118] Preferably, the emulsion is in a technological form selected from: cream, ointment, salve, lotion.

[0119] Composition comprising the lamellar emulsion of the invention

[0120] A further object of the present invention is the composition (or formulation) comprising the lamellar emulsion described above, suitable excipients and / or diluents, or comprising the lamellar emulsion described above, suitable excipients and / or diluents, hydrophilic and / or lipophilic active ingredients, wherein the emulsion is in the form of a lamellar emulsion.

[0121] Preferably, the composition is also in the form of an emulsion, preferably in the form of a lamellar emulsion.

[0122] Preferably, the composition is for topical or cutaneous use.

[0123] Preferably, the composition may be applied topically to all body areas.

[0124] Preferably, the composition may be applied to the genitals, preferably to the female genitals, preferably the vulvar area of the female genitals.

[0125] Preferably, the composition is in a solid or semi-solid form.

[0126] Preferably, the composition is in a technological form selected from: cream, ointment, salve, lotion.

[0127] Preferably, suitable excipients and / or diluents that may be included in the composition are selected from the group of functional categories consisting of: viscosifiers, humectants, absorbents, colorants, perfumes, flavourings, antioxidants, preservatives, antimicrobials, emulsifiers, texturizers, chelators, stabilizers, pH or acidity modifiers or adjusters, and combinations of the foregoing.

[0128] Preferably, in addition to the emulsifying agent (alcoholic mixture, saturated and linear fatty acid, hydrogenated lecithin), the composition can contain additive emulsifiers selected from (INCI names): cetearyl alcohol, lecithin, stearic acid.

[0129] Preferably, the additive emulsifiers are in an amount comprised between 0.5% and 5% by weight, preferably between 0.5% and 4.5% by weight, preferably between 1% and 3.5% by weight, based on the total weight of the composition. Preferably, hydrophilic and / or hydrophobic active ingredients are selected from: moisturizing, soothing, emollient, humectant and anti-aging / antioxidant agents, and combinations of the foregoing.

[0130] Preferably, the moisturizing agents are selected from the group consisting of: pentylene glycol, allantoin, and combinations of the foregoing.

[0131] Preferably, the soothing agents are selected from the group consisting of: bisabolol and panthenol, and combinations of the foregoing.

[0132] For the purpose of the invention, preferably oryza sativa starch acts as a texturizer.

[0133] Preferably, the emollient agents are selected from the group consisting of: vitamin E, vitamin F (linoleic acid), and combinations of the foregoing.

[0134] Preferably, the humectants are selected in the group consisting of: alcohols derived from long-chain fatty acids (preferably with a number of carbon atoms between 12 and 18, preferably between 14 and 16), preferably cetearyl alcohol; glycerine; diols, for example 1,2-hexanediol; glycols, for example pentylene glycol; and combinations of the foregoing.

[0135] Preferably, the antioxidants are selected from the group consisting of: ascorbic acid and / or ester derivatives thereof; and combinations of the foregoing.

[0136] Preferably, the hydrophilic and / or hydrophobic active ingredients are selected in the group consisting of: vitamins, peptides, proteins, vegetable oils, vegetable extracts, panthenol, allantoin, hyaluronic acid and / or salts thereof, ascorbic acid and / or ester derivatives thereof, polysaccharides obtained by bacterial fermentation, alcohols derived from long-chain fatty acids (preferably with a number of carbon atoms between 12 and 18, preferably between 14 and 16), glycerin, glycols, diols, amidaceous derivatives, niacinamide, and combinations of the foregoing.

[0137] Preferably, the hydrophilic and / or hydrophobic active ingredients are selected from the group consisting of (INCI nomenclature): tocopheryl acetate, panthenol, cetearyl alcohol, pentylene glycol, palmitamide, oryza sativa starch, 1,2-hexanediol, elaeis guineensis oil, allantoin, tocotrienols, bisabolol, tocopherol, sodium hyaluronate, biosaccharide gum-2, linoleic acid, linolenic acid, Annona Cherimola fruit extract, acetyl hexapeptide-8 (argyrelin), pentapeptide- 18, cyanocobalamin, glycerin, diols, niacinamide, 3-o-ethyl ascorbic acid, Ligustrum lucidum seed extract, and combinations of the foregoing.

[0138] PEA is included as an active in the emulsion of the invention; as such, it is also included in the composition.

[0139] Preferably, the composition contains the hydrophilic and / or hydrophobic active ingredients in an amount comprised between 0.2% and 30% by weight, preferably between 0.2% and 25% by weight, preferably comprised between 0.2% and 20% by weight, preferably between 0.2% and 15% by weight, preferably between 0.5% and 15% by weight, preferably between 1% and 15% by weight, preferably between 1% and 13% by weight, preferably between 1.5% and 12% by weight, based on the total weight of the composition.

[0140] Preferably, the composition comprises the lamellar emulsion in an amount comprised between 10% and 70% by weight, preferably between 15% and 70% by weight, preferably between 15% and 60% by weight, preferably between 15% and 50% by weight, preferably between 15% and 40% by weight, preferably between 15% and 30% by weight, preferably between 15% and 25% by weight, preferably between 20% and 25% by weight. Still preferably, the composition comprises the lamellar emulsion in an amount comprised between 20% and 60% by weight, preferably between 30% and 60% by weight, preferably between 40% and 60% by weight, preferably between 50% and 60% by weight, based on the total weight of the composition.

[0141] Preferably, the composition comprises the ester solvent - as described above - in an amount comprised between 1.5% and 25% by weight, preferably between 2% and 25% by weight, preferably between 2% and 20% by weight, preferably between 3% and 20% by weight, preferably between 3% and 18% by weight, preferably between 4% and 18% by weight, preferably between 10% and 18% by weight, preferably between 15% and 18% by weight, based on the total weight of the composition.

[0142] Preferably, the composition comprises the emulsifying agent - as described above - in an amount comprised between 2% and 10% by weight, preferably between 2% and 7% by weight, preferably between 3% and 6% by weight, based on the total weight of the composition. Preferably, the composition contains the hydrogenated lecithin - as described above - in an amount comprised between 0.05% and 2% by weight, preferably between 0.5% and 2% by weight, preferably between 0.5% and 1.5% by weight, preferably between 0.5% and 1% by weight, preferably between 0.7% and 1% by weight, preferably between 0.9% and 1% by weight, based on the total weight of the composition.

[0143] Preferably, the composition contains the alcoholic mixture - as described above - in an amount comprised between 1% and 5% by weight, preferably between 1% and 4% by weight, preferably between 1.5% and 3.5% by weight, preferably between 2% and 3% by weight, based on the total weight of the composition.

[0144] Preferably, the composition contains the saturated and linear fatty acid - as described above - in an amount comprised between 0.3% and 2.5% by weight, preferably between 0.5% and 2% by weight, preferably between 0.7% and 2% by weight, preferably between 0.7% and 1.5% by weight, preferably between 1% and 1.2% by weight, based on the total weight of the composition.

[0145] 1st embodiment: cosmetic composition comprising the lamellar emulsion of the invention.

[0146] Preferably, the pharmaceutical composition is for cutaneous use.

[0147] Preferably, the composition may be applied topically to the skin of a subject, preferably to any area of the body, for example at the level of the genitals, preferably of the external genitals, still preferably at the level of the vulva.

[0148] Preferably, the composition has a cosmetic use as a moisturizing, emollient, antioxidant, re-epithelializing, elasticizing, plumping, toning and / or hyperpigmentation reducing agent.

[0149] By re-epithelializing is meant that the composition promotes the formation of new layers of cells at the cutaneous level.

[0150] By elasticizing is meant that the composition stimulates the production of collagen and elastin, two proteins that support the structure of the skin while keeping it elastic and resistant.

[0151] By plumping is meant that the composition relaxes superficial wrinkles and restores a fuller and fleshy appearance to the skin, reinforcing the structure of the skin. By toning is meant that the composition gives tonicity and firmness to the skin.

[0152] By hyperpigmentation reducing agent is meant that the composition regulates the production of melanin, reduces hyperpigmentation and the formation of dark spots on the cutaneous.

[0153] 2nd embodiment: composition comprising the lamellar emulsion of the invention for use as a medicament

[0154] Preferably, the composition is for use as a medicament.

[0155] More preferably, the composition comprising the emulsion of the invention is for use in the treatment of disorders of the genitals and / or anus, preferably of the external genitals and / or anus, preferably these disorders being characterized by a symptomology selected from the group consisting of dryness, burning, pain, dyspareunia, cutaneous irritation, hypersensitivity to touch, muscular hypertonia, and combinations of the foregoing.

[0156] Still preferably, the composition is for use in the treatment of the symptomatology of disorders of the genitals and / or anus selected from the group consisting of dryness, burning, pain, dyspareunia, cutaneous irritation, hypersensitivity to touch, muscular hypertension, combinations of the foregoing.

[0157] Preferably, the composition is for use in the treatment of disorders at the vulvar and / or vaginal and / or anus level, preferably the disorders being characterized by a symptomology selected from the group consisting of dryness, burning, pain, dyspareunia, cutaneous irritation, vestibular hypersensitivity to touch, levator ani muscle hypertonus, and combinations of the foregoing.

[0158] Preferably, genital (preferably vulvar and / or vaginal) and / or anus disorders occur concomitantly with or are caused by pathological conditions selected from the group consisting of vulvodynia, preferably vestibolodynia; Lichen sclerosus; vaginal dryness; vaginismus; dyspareunia; hemorrhoidal pathology; cutaneous disorders concomitant with the menstrual cycle; cutaneous disorders after surgery; and combinations of the foregoing. Preferably, disorders of the genitals and / or anus, preferably of the external genitals and / or anus, preferably the vulvar and / or vaginal and / or anus disorders, are cutaneous disorders.

[0159] By cutaneous disorders are meant conditions of alteration of the skin that may be dry and / or injured and / or painful and / or hypersensitive and / or hypertonic.

[0160] Preferably, the cutaneous disorders occurring concurrently with the menstrual cycle are selected from the group consisting of: dryness, burning, pain, dyspareunia, cutaneous irritation, vestibular hypersensitivity to touch, levator ani muscle hypertonus, and combinations of the foregoing.

[0161] Preferably, the cutaneous disorders occurring after surgery are selected from the group consisting of: dryness, burning, pain, cutaneous irritation, cutaneous hypersensitivity, muscle hypertonus, and combinations of the foregoing.

[0162] Preferably, the composition is for use as an adjuvant in the treatment of disorders of the genitals and / or anus, preferably of the external genitals and / or anus, preferably vulvar and / or vaginal and / or anus disorders.

[0163] By adjuvant is meant that the composition comprising the emulsion of the invention, in combination with at least one medical therapy known for the aforementioned purposes, completes and / or increases the efficacy of its therapeutic action.

[0164] Disclaimer

[0165] Preferably, the palmitoylethanolamide employed for the purposes of the invention is not in micronized or ultra-micronized form.

[0166] By micronized is meant a particle size < 10 pm, preferably comprised between 2 and 10 pm, preferably comprised between 2 and 8 pm, preferably between 2 and 6 pm.

[0167] By ultramicronized is meant a particle size < 10 pm, preferably comprised between 0.5 and 10 pm, preferably comprised between 0.5 and 0.9 pm, preferably comprised between 0.7 and 0.8 pm, preferably approximately equal to 0.8 ± 2 pm.

[0168] Preferably, the lamellar emulsion is not suitable for use in compositions for oral use, such as supplements. Preferably, the lamellar emulsion does not contain linear aliphatic alcohols characterized by a carbon number > 18, e.g., does not contain behenyl alcohol. The Applicant has noted that, in the presence of these types of alcohols, it is not possible to obtain an effective lamellar emulsion. Preferably, the lamellar emulsion does not contain acetamide MEA.

[0169] EXAMPLES

[0170] Example 1: Lamellar emulsion according to the invention

[0171] Preparation method:

[0172] The melting point of the PEA is between 98 and 100°C. Then, by heating the PEA beyond this temperature it is possible to dissolve it inside the DIBUTYL ADIPATE solvent / solubilizer. Once the melting temperature is reached (>100°C), the mixture will be perfectly clear.

[0173] In the meantime, the water is heated to a temperature of 70°C, and the emulsifying mixture, consisting of HYDROGENATED LECITHIN, C12-16 ALCOHOLS and PALMITIC ACID, is dispersed therein, allowing these components to hydrate for at least 10 minutes, under gentle stirring. Once both mixtures are homogeneous, it is proceeded with pouring the lipophilic phase, composed of DIBUTYL ADIPATE and PEA, very slowly into the water, gradually increasing the stirring level, until it reaches around 2000-3000 rpm.

[0174] We witness the formation of an emulsion, first fluid, then by cooling down, increasingly full-bodied, with a high content of solubilised PEA.

[0175] This preparation can be applied to the skin as such or used to deliver PEA into other topical products at varying concentrations.

[0176] Example 2: Lamellar emulsion according to the invention

[0177] Preparation method: The melting point of the PEA is between 98 and 100°C. Then, by heating the PEA beyond this temperature it is possible to dissolve it inside the solvent / solubilizer C12- 15 ALKYL BENZOATE. Once the melting temperature is reached (>100°C), the mixture will be perfectly clear.

[0178] In the meantime, the water is heated to a temperature of 70°C, and the emulsifying mixture, consisting of HYDROGENATED LECITHIN, C12-16 ALCOHOLS and PALMITIC ACID, is dispersed therein, allowing these components to hydrate for at least 10 minutes, under gentle stirring. Once both mixtures are homogeneous, it is proceeded with pouring the lipophilic phase, composed of C 12-15 ALKYL BENZOATE and PEA, very slowly into the water, gradually increasing the stirring level, until it reaches around 2000-3000 rpm.

[0179] We witness the formation of an emulsion, first fluid, then by cooling down, increasingly full-bodied, with a high content of solubilised PEA.

[0180] This preparation can be applied to the skin as such or used to deliver PEA into other topical products at varying concentrations.

[0181] Example 3: Comparison between the lamellar carrier emulsions according to the invention (Examples 1 and 2) and two traditional emulsions, with a non-lamellar structure.

[0182] Below are the compositions of two traditional comparison emulsions, “A” and “B”.

[0183] The images in Figures 1-4 were obtained by optical microscope at one hundred magnifications, applying a filter for polarized light.

[0184] The comparison between the lamellar emulsion of the invention according to Example 1 (at halved concentrations) or Example 2 above (see respectively Figures 3 and 4) and the traditional / conventional emulsions ^ and B (Figures 1 and 2) is purely visual.

[0185] In Figure 1 for the conventional emulsion A, containing 2% PEA, the crystals of the latter are clearly visible. This means that PEA crystals fail to be effectively solubilizing. The same applies to Figure 2 relating to the conventional emulsion B.

[0186] A reduced presence of crystals is observed in Figure 3, which shows an emulsion with a “lamellar” structure, containing 2% PEA. This means that PEA crystals manage to be solubilizing for the most part.

[0187] In Figure 4, which shows the emulsion with a “lamellar” structure, always at 2% PEA, the presence of crystals cannot be observed, these are completely absent. This means that PEA crystals manage to be completely solubilizing.

[0188] It should be noted that, for the comparison in question, the concentrations of Example 1 were halved to make the solubilisation of the PEA appreciable under the optical microscope, and to standardize the concentration to that of Example 2 and to that of the examples relating to the comparison traditional emulsions A and , in such a way that they were actually comparable. Note that, for Examples 4-6 below, the components of the lamellar emulsion of the invention have been highlighted.

[0189] The compositions of Examples 4-6 are in the form of lamellar emulsions and are obtained by methods known to the person skilled in the art.

[0190] Specifically, the preparation method is preferably as follows:

[0191] The melting point of the PEA is between 98 and 100°C. Then, by heating the PEA beyond this temperature it is possible to dissolve it inside the solvent / solubilizer C12- 15 ALKYL BENZOATE. Once the melting temperature is reached (>100°C), the mixture will be perfectly clear.

[0192] In the meantime, the water is heated to a temperature of 70°C, and the emulsifying mixture, consisting of HYDROGENATED LECITHIN, C12-16 ALCOHOLS and PALMITIC ACID, is dispersed therein, allowing these components to hydrate for at least 10 minutes, under gentle stirring.

[0193] Once both mixtures are homogeneous, it is proceeded with pouring the lipophilic phase, composed of C 12-15 ALKYL BENZOATE and PEA, very slowly into the water, gradually increasing the stirring level, until it reaches around 2000-3000 rpm.

[0194] All the other lipophilic components previously dispersed between them are added (Cl 5- 19 ALKANE, CETEARYL ALCOHOL, TOCOPHERYL ACETATE, BISABOLOL, etc.) and immediately afterwards also POLYACRYLATE CROSSPOLYMER-6, always under stirring 2000-3000 rpm.

[0195] At this point the cooling step begins.

[0196] One at a time, below 30 °C, all thermolabile actives, as well as the preservatives and ORYZA SATIVA STARCH are added.

[0197] Example 4: Composition comprising the lamellar emulsion for use in treating vaginal dryness, counteracting reduced lubrication; as an adjuvant for the therapy of Lichen Sclerosus; in the case of atrophied tissues; or for cosmetic use as an elasticizing, toning agent.

[0198] Example 5: Composition comprising the lamellar emulsion of the invention for use in the treatment of vulvodynia.

[0199] Example 6: Composition comprising the lamellar emulsion of the invention for cosmetic use as an elasticizing, toning, moisturizing, hyperpigmentation reducing, antioxidant agent. Example 7: Evaluation of efficacy and safety of the topical preparation of palmitoylethanolamide for the treatment of vestibolodynia (vestibular vulvodynia) referred to in Example 5 - double-blind randomized controlled trial.

[0200] Vulvodynia is a very common form of chronic genital pain in women, so much so that prevalence studies estimate a range between 10% and 28% in women of reproductive age.

[0201] Localized provoked vulvodynia at the vestibule, known as vestibolodynia (VBD), is the most common manifestation of the disease (about 80%). Women with VBD often describe vulvar pain as burning, irritation, and dyspareunia (difficult or painful sexual intercourse). Most patients with VBD described the pain as “hot”, “burning” or “stinging” and that the vestibular area is sensitive to touch (for example during sexual intercourse or the use of tampons) and that the pain increases with rubbing.

[0202] The pattern of VBD responses is suggestive of sensory abnormalities in the form of evoked pain (e.g., hyperalgesia or allodynia), suggesting a sensitization, manifestation underlying the neuropathic pain. This is consistent with biopsy studies that have demonstrated increased innervation of the vulvar vestibule and an increase in subepithelial heparinase and cytokine activity that have been linked to neuroinflammatory processes; patients with VBD also experience alterations in body sensitivity, suggesting that sensory dysregulation may be involved in the expression of this pain condition. In addition, the discomfort inherent in VBD is always associated with hyperactivity of the pelvic floor muscles. This prolonged pattern may result in decreased tissue perfusion, dysfunctional muscle hyperactivity, and the development of myofascial trigger points, resulting in localized or radiated pain and / or intense tenderness. Neuropathic pain and hypertonicity can be considered a multifactorial and complex consequence of maladaptive neuronal plasticity. Probably VBD is not a single disease, but rather several diseases, the common endpoint of which is vestibular hypersensitivity and hypertonic dysfunction of the pelvic floor. VBD represents a sum and overlap of various triggers (infections, hormonal disorders, allergies, genetic aspects, psychological vulnerability and others) with varying weight and predominance from patient to patient. There is no standard treatment for the disease and few are randomized.

[0203] Controlled studies have been performed and the recommendations are in favour of a multidimensional treatment.

[0204] OBJECTIVE OF THE STUDY

[0205] The research hypothesis of the present study is to prospectively document the efficacy and safety of a topical preparation of palmitoylethanolamide (PEA), which is the composition of Example 5, in patients with VBD. In recent years, the scientific literature has expressed positive opinions on PEA.

[0206] While mast cells and glial cells are recognized to play a central role in chronic inflammatory disorders, PEA is able to block the persistent activation of these cells, thus playing an important role in the resolution of pain and neuroinflammation in several models of chronic and neurodegenerative diseases. The premise is that topical PEA may contribute to a downregulation of hyperactivated mast cells, responsible for the proliferation and irradiation of vestibular pain fibres found in VBD.

[0207] DESCRIPTION OF THE RESEARCH DESIGN

[0208] Overall study plan

[0209] This is a randomized, double-blind, controlled study.

[0210] Duration of the study

[0211] Each eligible subject will participate in the study for about 2 months.

[0212] This researcher-initiated research study is expected to be completed approximately 6 months after initial approval by the Institutional Ethics Committee.

[0213] Approval by the Institutional Ethics Committee (IEB)

[0214] Prior to conducting any study-related procedure, principal investigators will obtain the written approval of the respective IEB for the informed consent form, protocol, recruitment material, and any written information provided to subjects regarding the procedure. SUBJECT SELECTION AND WITHDRAWAL

[0215] The study population will comprise women affected by VBD.

[0216] Subjects inclusion criteria

[0217] For a Subject to be eligible to participate in the study, all of the following criteria must be met.

[0218] - Women aged at least 18 years and before menopause (no menstruation for 12 months).

[0219] - Experience moderate to severe pain (minimum 5 / 10 on a numerical rating scale in at least 90% of attempted sexual intercourse).

[0220] - Limited pain at the vestibule during vaginal intercourses and during activities that put pressure on the vestibule (insertion of tampons, tight jeans or trousers, cycling, horseback riding).

[0221] - Presence of VBD for at least 6 months and diagnosed according to the standardized gynaecological examination protocol by one of the collaborating gynaecologists.

[0222] - the Subject is willing to attempt sexual activity between visits.

[0223] - Read and sign informed consent.

[0224] Subject exclusion criteria

[0225] Subjects who meet any of the following criteria are excluded:

[0226] - Vulvo-vaginal infections active at the time of gynaecological examination.

[0227] - Genital haemorrhage of unknown origin.

[0228] - Patients included in several interventional clinical studies at the same time.

[0229] - She is not willing to give informed consent to the study.

[0230] - Women who have used topical medications in the last 30 days.

[0231] - Women with concomitant vulvar dermatosis or other vulvar disorders.

[0232] Subject withdrawal criteria

[0233] The principal investigator may discontinue a subject's participation in the study at any time if they believe it is in the subject's interest to do so. Such a decision may be determined by adverse events, new diseases, clinically important changes in vital signs, physical examinations or laboratory tests. Subjects who do not comply with study procedures and visits may be withdrawn by the principal researcher. Subjects may withdraw from the study at any time and for any reason. A subject's decision to withdraw will not cause them to lose any benefit to which they are entitled. The subject who withdraws prematurely from the study will return to the clinic as soon as possible to undergo the assessments of the final visit.

[0234] If a subject withdraws prematurely or is withdrawn from study participation, the reason for withdrawal must be recorded in the Case Report Form (CRF).

[0235] • Adverse event: the Subject experiences an intolerable event, which may or could not be correlated to the study drug.

[0236] • Withdrawal of consent: The Subject withdraws from participation in the study for personal reasons (exclude adverse experiences before indicating this category).

[0237] • Concomitant drug violation: the Subject initiates, discontinues, or modifies the dosing regimen of a concomitant drug in violation of protocol which, in the opinion of the principal investigator, may adversely affect the safety assessment.

[0238] • Lost-to-Follow-up: the Subject does not return for evaluation and is no longer contacted by subject after three documented attempts by phone or email and one last attempt by certified mail.

[0239] • Other: Any reason that does not fall into the 4 categories above: the reason will also be recorded on the CRF.

[0240] RESULTS

[0241] The primary efficacy outcome comprises the changes in symptoms and signs as assessed by:

[0242] - Visual scale from 0 to 10 points (VAS) related to burning / vulvar pain and dyspareunia.

[0243] - Vestibular cotton swab test (small applicator with slightly rolled cotton tip on the surfaces of the vestibule (mean of values at hours 1, 3, 5, 6, 7, 9 and 11 asking the subject to report the intensity of pain on a discrete visual analogue scale from 1 (no pain) to 10 (worst possible pain).

[0244] -Clinical evaluation of hypertonic levator ani complex by an expert examiner using an empirical score:

[0245] - Grade 0 = no hypertonicity

[0246] - Grade 1 = mild hypertonicity

[0247] - Grade 2 = moderate hypertonicity

[0248] - Grade 3 = severe hypertonicity

[0249] Secondary objectives include evaluation of the Current Perception Threshold (CPT) test, a technique that quantifies the sensitivity of the vestibular nerve fibres.

[0250] CPT values will be measured using the Neurometer CPT / C electrodiagnostic Neurostimulator (Neurotron, Inc., Baltimore, MD), which emits alternating sinusoidal waveform constant current stimuli at frequencies of 2000 Hz (specific for large, myelinated Ab fibres), 250 Hz (specific for Ad fibres), and 5 Hz (specific for C fibres), at intensity levels from 0.001 to 9.99 mA. CPT values of the vulvar vestibule (1=0.01 mA) will be determined using a G-rode vaginal / rectal electrode (Neurotron, Inc., Baltimore, MD).

[0251] Clinical procedures

[0252] The clinical procedures of the study are described in the following sections.

[0253] Informed consent

[0254] Each potential study Subject must provide written informed consent and authorize the release of protected health information before performing any study procedures.

[0255] Study Day 0 - Screened subjects and visit 1

[0256] Enrolled candidates will be screened within 15 days prior to enrolment. Prior to initiation of any testing procedures, subjects will be fully informed of the study plan, procedures, and risks associated with participation in the study. Each potential Subject shall read and indicate their understanding by signing and dating the ICF (Informed Consent Form) prior to initiation of any screening procedures. Screening procedures will consist of the following:

[0257] - The physical examination and medical history will be collected

[0258] - Symptoms evaluation: Visual scale (VAS) from 0 to 10 points related to dyspareunia and vulvo-vaginal pain / burning

[0259] - Vulvoscopy with evaluation of the vestibular cotton swab test

[0260] - Clinical evaluation of hypertonic levator ani complex

[0261] - Evaluation of CPT values will be measured with the neurometer CPT / C electrodiagnostic Neurostimulator (Neurotron, Inc., Baltimore, MD).

[0262] Subjects who meet the inclusion and exclusion criteria will be enrolled and receive a dispensing system containing topical PEA (cream from Example 5). One or more staff members who do not work directly with the subject will be responsible for assignment to active treatment or placebo based on random assignment. Patients will be instructed to apply the compound to the vulvar vestibule (approximately one unit of fingertip) once per day for 60 days, before bedtime.

[0263] Study day 60 3 days

[0264] Patients who have completed treatment will receive:

[0265] - Symptoms evaluation: Visual scale (VAS) from 0 to 10 points related to dyspareunia and vulvo-vaginal pain / burning.

[0266] - Vulvoscopy with evaluation of the vestibular cotton swab test - Clinical evaluation of the hypertonus of the levator ani complex.

[0267] - Evaluation of CPT values will be measured with the neurometer CPT / C electrodiagnostic Neurostimulator (Neurotron, Inc., Baltimore, MD).

[0268] - evaluation of side effects.

[0269] Statistical methods

[0270] Determination of sample size

[0271] We used the program http: / / statulator.com which calculated the sample size for pairwise differences. With a power of 80% and a significance level of 5%, to detect an average of the differences of the VAS scale of 1.5 (20%) between the pairs, assuming that the standard deviation of the differences is 2, we will have to enrol 40 participants, 20 for each group.

[0272] Example 8: Evaluation of the efficacy of a proactive maintenance therapy alternative to topical corticosteroid for Lichen sclerosus vulvare - randomized trial.

[0273] Lichen sclerosus (LS) is a chronic inflammatory disease that predominantly affects the cutaneous and mucous membranes of the ano-genital region. Among the multiple etiopathogenic factors, immunological alterations and chronic inflammatory mechanisms appear to play a significant role.

[0274] Currently, a 3-month topical application of potent or ultra-potent corticosteroids forms the mainstay of medical treatment of vulvar LS (VLS).

[0275] The chronic and relapsing nature of VLS is a major problem, with relapses common upon cessation of treatment. Once VLS has stabilized with corticosteroid therapy, long-term management has traditionally relied on the reactive application of topical corticosteroids as needed. However, there is no established consensus on maintenance treatment strategies for long-term disease control or for prolonging the relapse-free interval after effective corticosteroid therapy.

[0276] An alternative to this reactive strategy can be a proactive approach. This involves an intensive topical corticosteroid therapy until resolution of active signs and symptoms, followed by intermittent, low-dose, long-term application of the same drug to previously affected areas, in order to prevent disease exacerbation and maintain clinical remission.

[0277] However, the long-term use of very potent steroids (such as clobetasol propionate) can have the negative effect of secondary cutaneous atrophy, which can make it difficult to differentiate sites of atrophy from the primary signs of progressive VLS.

[0278] To date, no comparative clinical studies have prospectively evaluated the efficacy and safety of alternative proactive treatment regimens for the long-term management of VLS. Furthermore, patient adherence to and acceptance of topical therapies remain poorly characterized.

[0279] Palmitoylethanolamide (PEA) is an endogenous fatty acid amide recognized for its anti-inflammatory and analgesic properties. Bisabolol, a key component of chamomile essential oil, is known for its anti-inflammatory, corticosteroid, anti-irritant and soothing effects, which make it a promising ingredient in dermatological treatments. The composition of Example 4 in cream form is a novel formulation combining palmitoylethanolamide and bisabolol.

[0280] This randomized, parallel-group, open-label comparative study aims to investigate the efficacy of several long-term therapeutic strategies in the management of VLS after a 12-week treatment regimen with a topical corticosteroid. The primary objective of this study is to determine whether daily application of the cream of Example 4 is effective and safe in preventing exacerbation of VLS, as compared to daily application of a neutral emollient.

[0281] Patients and methods

[0282] Study design and objectives

[0283] This study is conducted at the gynaecology and Obstetrics Unit of the IRCCS Policlinico San Martino in Genoa. Approximately 100 patients with VLS will be subjected to eligibility screening.

[0284] The treatment protocol comprises two distinct phases: an open-label 12-week Active Treatment Phase (AP) followed by a 40-week Maintenance Phase (MP). This last phase will be a randomized, parallel-group, open-label comparative study.

[0285] The study aims to (i) compare the efficacy of the daily administered cream of Example 4 to the daily application of a neutral emollient; (ii) evaluate patients' adherence to prolonged topical therapies and preferences between daily emollients and twice weekly corticosteroid regimens; and (iii) evaluate the prognostic significance of demographic and clinical characteristics as potential risk factors for recurrence of VLS.

[0286] Study patients

[0287] Eligible women with a clinical and, when available, histological diagnosis of VLS will be enrolled.

[0288] Exclusion criteria instead include: systemic treatment with steroids, retinoids, hormone replacement therapies, or oestrogen-progestin drugs within 4 weeks prior to enrolment; use of topical therapies (e.g., corticosteroids, tacrolimus, pimecrolimus, hormone therapy) on the affected area during 4 weeks prior to enrolment; hypersensitivity to any component of study drug; active vulvar infectious diseases, dermatoses, or carcinoma; pregnancy or lactation.

[0289] Study and evaluation procedures

[0290] After completion of the screening process, the enrolled patients will be subjected to a subjective evaluation of two symptoms - burning and dyspareunia (if applicable) - via interview, using a visual analogue scale (VAS).

[0291] A score of 10 will indicate the maximum intensity of the symptoms, while a score of 0 will indicate the absence of symptoms. A global subjective score will be calculated by summing the scores of all symptom parameters (maximum score = 30).

[0292] Four objective parameters will be evaluated to assess the clinical characteristics and severity of VLS at baseline: (i) leukoderma (pallor), (ii) sclerosis / discharge, (iii) hyperkeratosis, and (iv) purpuric lesions and excoriations.

[0293] Objective evaluations will be conducted by the investigators using a four-point scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe.

[0294] Among these parameters, only signs potentially reversible to therapy (leukoderma, hyperkeratosis, and purpuric lesions / excoriations) will be objectively monitored to evaluate VLS response to active and maintenance therapies at each follow-up visit. An overall target score (OS) will be calculated by summing each clinical parameter (maximum score = 12).

[0295] All enrolled subjects will participate in a 12-week open-label AP, during which patients will apply a 0.1% mometasone furoate topical ointment once daily to the affected vulvar surfaces. At the end of 12 weeks, patients who achieve a score of 3 for each evaluable subjective symptom and an overall OS of 4 will be considered as “treatment responsive” and will qualify for MP. Subjects who do not demonstrate improvement at the end of 12 weeks of PA will be withdrawn from the study and receive further treatment with topical corticosteroids.

[0296] The MP will be a randomized, three-arm, parallel-group, open-label, comparative study phase. Patients entering this second 40-week phase will be randomized, according to a simple computer-generated randomization scheme, to daily apply the topical cream of Example 4 or a neutral topical emollient. Baseline balance of demographic and clinical characteristics between treatment groups will be evaluated using one-way analysis of variance (ANOVA).

[0297] Objective and subjective evaluations will be conducted by two investigators, blinded with respect to treatment assignment, at baseline, and at each subsequent 12-week follow-up visit. Patients who experience exacerbations of VLS at any time during MP will be re-evaluated at our facility.

[0298] During MP, relapse will be defined as a score > 5 for at least one evaluable subjective symptom and / or a score = 3 for any of the four reversible signs. Any worsening of the sclerosis / scar will also be a relapse. Patients who relapse will discontinue the maintenance protocol and begin a new treatment cycle with daily topical corticosteroids.

[0299] The primary efficacy endpoint will be the relapse rate at the 40-week MP, while the secondary efficacy endpoint will be the mean time to relapse, defined as the duration in weeks from entry into the MP to relapse into the VLS. These results will be compared between the three maintenance treatment groups and adverse events will be recorded, along with any causal relationship to the medications used.

[0300] Patient adherence to treatment regimens, particularly the comparison between daily and biweekly topical therapy, and patient satisfaction will be evaluated at the final visit (at the end of the 40-week MP or at relapse).

[0301] Given the absence of a gold standard to measure adherence and satisfaction with topical therapies, these parameters will be evaluated through structured interviews. Adherence will be evaluated according to the frequency of the skipped treatments, using a scale from 1 to 4: 1 = never, 2 = sometimes (once or twice a week), 3 = often (three to four times a week) and 4 = always / almost always (five or more times a week). Patients will be classified as “adherent” if they have never skipped treatments (score = 1) or sometimes (score = 2); those who have skipped treatments most frequently will be considered “non-adherent”.

[0302] To assess patient satisfaction with topical treatment regimens, patients will categorize their treatment protocol as either (i) convenient or (ii) uncomfortable. In addition, several demographic and clinical characteristics of the enrolled subjects will be statistically analysed to identify factors potentially predisposing to relapse of VLS, including age at onset and diagnosis of VLS, duration of disease prior to enrolment in the study, delay between onset and diagnosis, and severity of signs and symptoms at the beginning of PA and at the end of PA, coinciding with the beginning of MP.

[0303] Statistical analysis

[0304] The efficacy analysis will be based on the intent-to-treat (ITT) population, defined as all randomized subjects enrolled in the MP. The percentage of patients experiencing a protocol-defined relapse will be compared across maintenance treatment groups using a chi-square test (%2). The mean time to relapse will be compared between the three maintenance treatment groups using a t-test. The demographic and clinical characteristics will be compared between relapsed and non-relapsed patients using the t-test. The normality of the distributions will be evaluated with the Kolmogorov- Smirnov test and the homogeneity of the variances with the Levene test and the Brown- Forsythe test. Comparison of patient adherence between relapsed and non-relapsed patients and between maintenance treatment groups will be conducted using Fisher's Exact Test. Satisfaction for maintenance regimens will also be analysed with Fisher's Exact Test. For confirmation, primary analyses will be performed on the per-protocol (PP) population, comprising all enrolled and randomized patients, excluding those considered as non-evaluable due to significant deviations from the protocol. In case of patient dropping out during MP, a worst-case scenario analysis will be performed, treating all drop-outs as relapses. Statistical significance will be defined as P < 0.05.

Claims

CLAIMS1. An emulsion comprising a lipophilic phase comprising- palmitoylethanolamide,- an ester solvent selected from: an adipic acid dialkyl and a benzoic acid alkyl, wherein both dialkyl and alkyl are linear and characterized by a number of carbon atoms comprised between 3 and 15, respectively, an aqueous phase comprising- an emulsifying agent comprising hydrogenated lecithin, an alcoholic mixture comprising linear aliphatic alcohols characterized by a number of carbon atoms between 12 and 16, a linear, saturated fatty acid comprising a number of carbon atoms comprised between C12 and C20,- water, wherein the emulsion is of lamellar type.

2. The emulsion according to claim 1, wherein the weight ratio of palmitoylethanolamide to ester solvent is comprised between 1 :2 and 1 : 15.

3. The emulsion according to claim 1 or 2, wherein the weight ratio of the lipophilic phase to the hydrophilic phase is comprised between 1 :2 and 1 :7.

4. The emulsion according to any one of claims from 1 to 3, wherein the adipic acid dialkyl is characterized by a number of carbon atoms comprised between 4 and 6.

5. The emulsion according to any one of claims from 1 to 4, wherein the benzoic acid alkyl is characterized by a number of carbon atoms comprised between 12 and 15.

6. The emulsion according to any one of claims from 1 to 5, wherein the palmitoylethanolamide is not micronized or ultramicronized.

7. The emulsion according to any one of claims from 1 to 6, wherein the linear, saturated fatty acid comprising a number of carbon atoms comprised between C12 and C20 is palmitic acid.

8. A cutaneous topical use of the emulsion according to any one of claims from 1 to 7.

9. A process for preparing the emulsion according to any one of claims from 1 to 7, comprising the following steps: a) providing: palmitoylethanolamide, ester solvent, emulsifying agent, water, b) heating the ester solvent to the melting point of palmitoylethanolamide, then adding palmitoylethanolamide, and stirring to homogeneity to obtain the lipophilic phase, c) in parallel, heating water to a temperature comprised between 60°C and 90°C, then adding the emulsifying agent, and stirring to homogeneity to obtain the aqueous phase, d) pouring the lipophilic phase into the aqueous phase and simultaneously stirring to obtain the lamellar emulsion.

10. Composition comprising the emulsion according to any one of claims from 1 to 7, suitable excipients and / or diluents, or comprising the emulsion according to any one of claims from 1 to 7, suitable excipients and / or diluents, hydrophilic and / or lipophilic active ingredients, wherein the emulsion according to any one of claims from 1 to 7 is in the form of a lamellar emulsion.

11. Cosmetic use of the composition according to claim 10, preferably as a moisturiser, emollient, antioxidant, re-epithelializing, elasticizing, plumping, toning and / or skin hyperpigmentation reducing agent.

12. Composition comprising the emulsion according to claim 10, for use as a medicament.

13. Composition for use comprising the emulsion according to claim 12, for use in the treatment of disorders of the genitals and / or the anus, preferably of the external genitals and / or the anus, preferably the disorders being characterised by a symptomatology selected in the group consisting of: dryness, burning, pain, dyspareunia, skin irritation, hypersensitivity to touch, muscle hypertonus, and combinations of the preceding.

14. Composition for use comprising the emulsion according to claim 13, wherein the disorders of the genitals and / or the anus occur concomitantly with or are caused by pathological conditions selected in the group consisting of: vulvodynia; Lichen sclerosus; vaginal dryness; vaginismus; dyspareunia; haemorrhoidal pathology; skin disorders in conjunction with the menstrual cycle; skin disorders post-surgery; and combinations of the preceding.

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