PRESSURIZED NANOEMULSION

Description

1 / 123 PRESSURIZED NANOEMULSION

[001] The present invention relates to the stabilization of an oil-in-water nanoemulsion for pharmaceutical and cosmetic use contained in a pressurized container. The nanovesicles are particularly stable with respect to vesicle size and vesicle size homogeneity after long-term storage at different temperatures. Background of the invention

[002] Liquid nanoemulsions can be stored in pressurized containers with the aid of a propellant. These pressurized nanoemulsions can be released as foam or spray, depending on the shape of the dispenser head.

[003] Foam and spray formulations are easy to distribute evenly over the skin or treatment area and can reach hard-to-reach areas such as wrinkles, skin folds, etc., making them suitable for topical treatment. They are considered a convenient vehicle for topical delivery of active agents.

[004] Foam and spray formulations are generally easier to apply, are less dense, and spread more easily compared to other topical dosage forms. When evaluated, particularly in terms of ointments, or even creams and lotions, foams require negligible mechanical shear force in order to spread the formulation on the skin. This is a major advantage when applying a medication to highly inflamed skin; for example, in cases of sunburn, where rubbing the formulation into the skin to spread it can be painful or cause additional inflammation. Furthermore, even when applied to hirsute areas, such as the scalp, these formulations decompose relatively quickly and Petition 870250089513, dated 10 / 01 / 2025, pages 425 / 568 2 / 123 easily reach the stratum corneum through the hair strands. In this respect, they behave very similarly to lotions and solutions applied to the scalp, resulting, therefore, in improved patient adherence.

[005] Foams are colloidal systems in which gas bubbles are suspended or dispersed in a liquid medium. Liquid foams typically require some type of stabilizing or foaming agent to prevent or retard the coalescence of gas bubbles. Foams are very complex and sensitive systems, especially foams for cosmetic or pharmaceutical use.

[006] There are several types of topical foams, including aqueous foams, such as commonly available shaving foams; hydroalcoholic foams; emulsion-based foams, comprising oil and water components; and oil-based foams, which consist of a high oil content. In skin therapy, oil-containing foams are preferred because oil contributes to skin protection and hydration, which can enhance the therapeutic effect of the formulation. Typically, foams are made using liquefied hydrocarbon gas propellants, such as propane, butane, and isobutane, or hydrofluorocarbon propellants.

[007] Nanoemulsions are homogeneous, transparent, and slightly opalescent dispersions of oil and water. These dispersions are colloidal systems. The particles or vesicles dispersed in such emulsions are composed of a lipid core surrounded by at least one monolayer of surfactant or emulsifier. Nanoemulsions are characterized by an average particle or vesicle size smaller than 200 nm, often smaller than 100 nm, and a predominantly monodisperse particle or vesicle size distribution with a polydispersity index below 0.4.

[008] Although nanoemulsions are generally thermodynamically Petition 870250089513, dated 10 / 01 / 2025, pp. 426 / 568 3 / 123 More stable than conventional emulsions and microemulsions, they are often unstable under stress conditions such as high temperatures or freezing. They may be in a metastable state, and their structure often depends on the manufacturing process, making them a fragile and complicated system to formulate for a pharmaceutical or cosmetic composition that needs to maintain stability for long periods of time. If destabilized, they may become opaque, creamy, or exhibit phase separation. On the other hand, nanoemulsions can provide useful applications in skincare, as they can exhibit good textural and sensory properties due to the fine and homogeneous size of nanovesicles, droplets, or globules, making them a favorable vehicle for pharmaceutical and cosmetic compositions.

[009] In pharmaceutical and cosmetic formulations, nanoemulsions are combined with active agents, such as 5-aminolevulinic acid.

[010] 5-Aminolevulinic acid (also referred to in the present invention as “ALA” or 5-ALA) is a small biogenic amino acid with a molecular weight (as an HCl salt) of 167.59 g / mol and is highly hydrophilic, i.e., readily soluble in water with an octanol-water partition coefficient (logP) of about -3. ALA is used in Photodynamic Therapy (PDT) as a prodrug to stimulate the synthesis of protoporphyrin IX in diseased tissue, which is subsequently illuminated with light of appropriate wavelengths to induce the photodynamic effect.

[011] Known ALA formulations for topical use on the skin are unstable in aqueous solutions (see Reinhold, Future Oncology, 2017) Nov;13(27):2413-2428, doi: 10.2217 / fon-2017-0247). Until now, the nanoemulsion used with ALA contained 10% active ingredient and was formulated as a gel. The previous gel formulation showed stability of up to 36 months in Petition 870250089513, dated 10 / 01 / 2025, pp. 427 / 568 4 / 123 refrigerated temperatures (2 to 8 °C), but was susceptible to higher temperatures (standard room temperature and above). Exposure to higher temperatures was tolerated for only one week without risking loss of pharmaceutical quality for human use.

[012] The prior art does not teach a nanoemulsion composition that is highly stable, even under stress conditions (e.g., elevated temperature or freezing conditions), either alone or combined with active pharmaceutical or cosmetic ingredients. The stability of such nanoemulsion compositions is characterized by a small droplet size (nanovesicle) and a predominantly monodisperse population of nanovesicles. Surprisingly, the inventors found that these two properties are stable for a long period of time and under stress conditions when the nanoemulsion is stored in a pressurized container. The concentration of active agent in cosmetic and pharmaceutical compositions with nanoemulsions is also positively influenced by a pressurized formulation. The same formulations are much less stable, especially under stress conditions, when not stored in a pressurized container.It is also surprising that the stability of the pressurized nanoemulsion is not dependent on the presence and / or concentration of gelling agents, known as emulsion stabilizers.

[013] As described above, nanoemulsions tend to coalesce under certain circumstances, such as exposure to extreme temperatures, leading to larger droplet sizes and impairing nanoemulsion quality.

[014] These aspects make it clear that the design and formulation of a pressurized nanoemulsion composition with high stability with respect to droplet sizes and vesicle size distributions under different storage temperatures compared to a nanoemulsion that Petition 870250089513, dated 10 / 01 / 2025, pages 428 / 568 5 / 123 was not stored in a pressurized container, therefore they could not be considered trivial or simple, but would require considerable inventive activity. Summary of the invention

[015] A first aspect of the invention relates to a formulation comprising: (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; and (b) a propellant, wherein the formulation is comprised in a pressurized container, and wherein the formulation essentially does not comprise any fatty alcohol as a foaming aid.

[016] A second aspect of the invention relates to a method for stabilizing a nanoemulsion, comprising the following steps: (a) providing a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introducing the nanoemulsion into a container; and (c) adding a propellant to the container to pressurize the container.

[017] A third aspect of the invention relates to the use of a nanoemulsion for the preparation of a foam or a spray, comprising the following steps: (a) providing a formulation comprising a nanoemulsion, the nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introducing the formulation comprising the nanoemulsion into a container; (c) adding a propellant to the container to pressurize the container; and (d) releasing a foam or spray from the pressurized container. Petition 870250089513, dated 10 / 01 / 2025, pp. 429 / 568 6 / 123

[018] A fourth aspect of the invention relates to a container or a dispensing product comprising a container, comprising a formulation, wherein said formulation comprises a nanoemulsion comprising (i) at least one aqueous component; (ii) a carrier component comprising (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; and (b) a propellant, wherein the formulation essentially does not comprise any fatty alcohol; and wherein the container further comprises a propellant, wherein the propellant is provided to pressurize the container.

[019] A fifth aspect of the invention relates to a foam obtained from the formulation of the first aspect.

[020] A sixth aspect of the invention relates to a cosmetic use of the formulation of the first aspect or the foam of the fifth aspect.

[021] A seventh aspect of the invention relates to the formulation of the first aspect or to the foam of the fifth aspect for use in medicine. Detailed description

[022] Before the present invention is described in detail below, it should be understood that this invention is not limited to the particular methodology, protocols and reagents described in the present invention, as these may vary. It should also be understood that the terminology used in the present invention is intended to describe particular embodiments and is not intended to limit the scope of the present invention, which will be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as commonly understood by a person skilled in the art.

[023] Preferably, the terms used in the present invention are defined as described in “A multilingual glossary of biotechnological Petition 870250089513, dated 10 / 01 / 2025, pp. 430 / 568 Terms 7 / 123: (IUPAC Recommendations)”, Leuenberger, HGW, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[024] Several documents are cited throughout the text of this descriptive report. Each of the documents cited in the present invention (including all patents, patent applications, scientific publications, manufacturer specifications, instructions, etc.), whether above or below, is incorporated into the present invention by reference in its entirety.

[025] The elements of the present invention will be described below. These elements are listed with specific embodiments; however, it should be understood that they can be combined in any way and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be interpreted as limiting the present invention only to the embodiments explicitly described. This description should be understood to support and encompass embodiments that combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all the elements described in this application should be considered disclosed by the description of the present application, unless the context indicates otherwise.

[026] Throughout this descriptive report and the claims that follow, unless the context requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” will be understood as implying the inclusion of a whole number or step or group of whole numbers or steps, but not the exclusion of any other whole number or step or group of whole numbers or steps. As used in this descriptive report and the appended claims, the singular forms of “a”, “an” and “the” include plural referents, unless the wording clearly dictates otherwise. Petition 870250089513, dated 10 / 01 / 2025, pp. 431 / 568 8 / 123 mode.

[027] Generally, in pharmaceutical technology, topical formulations are chosen to accommodate the physicochemical properties of the API and to enhance or regulate both penetration and stability on the skin / body surface. Typically, APIs with clearly different properties, such as molecular weight or degree of lipophilicity, require markedly different formulations as suitable vehicles.

[028] In preferred embodiments, the formulations of the present invention combine the advantages of foams and nanoemulsions.

[029] The formulations of the invention comprise three phases: (I) an aqueous phase or aqueous component, (II) a lipid phase or carrier component, and (III) a gaseous phase (i.e., a propellant).

[030] The aqueous phase and the lipid phase together form the nanoemulsion. The nanoemulsion is present in liquid form. Thus, the formulations of the invention can also be described as comprising - a liquid element comprising or consisting of a nanoemulsion, and - a gaseous element.

[031] In the context of the present invention, the term “liquid” specifies a low viscosity formulation of one or more fluids in which other components are dissolved or dispersed. Low viscosity in the context of this descriptive report refers to a viscosity of < 8 Pa s (pascalsecond), < 6 Pa s, < 5 Pa s, preferably < 4 Pa ​​s, < 3 Pa s, more preferably < 1.0 Pa s or < 0.5 Pa s.

[032] The person skilled in the art knows appropriate methods for determining viscosity. Preferably, viscosity is determined according to Petition 870250089513, dated 10 / 01 / 2025, pp. 432 / 568 9 / 123 described in the examples section.

[033] The examples of the present invention demonstrate that the stability of a formulation comprising nanovesicles can be improved when stored in a pressurized storage device. In particular, stability is improved when stored under stress conditions, such as storage at elevated temperatures (e.g., 40 °C) or when subjected to a freeze-thaw cycle.

[034] The presence of a gelling agent, such as xanthan gum or poloxamer, can further improve stability, particularly at elevated temperatures (e.g., 40 °C) and / or when subjected to a freeze-thaw cycle. The invention data demonstrate that, surprisingly, nanovesicle size stability is dependent on the interaction between lipid content and gelling agent in formulations stored under pressure. This is not the case for formulations stored in conventional storage devices, such as glass tubes or vials, which do not form a foam. In the formulation of the invention, the addition of poloxamer provides better nanovesicle size stability under stress conditions (e.g., at 40 °C) with high lipid contents (e.g., 20%), while at lower lipid contents (e.g., 10%), the absence of any gelling agent provides better stability under stress conditions (e.g., at 40 °C).The gelling agent poloxamer can have opposing effects on nanovesicle stability, depending on the lipid content of the nanoemulsion. With a high lipid content (such as 20%), poloxamer improves stability, while with a lower lipid content (such as 10%) this effect was not observed. The discovery of this specific interaction is unprecedented in terms of prior knowledge.

[035] The invention data demonstrate that high lipid content (by Petition 870250089513, dated 10 / 01 / 2025, pp. 433 / 568 10 / 123 example, from 15 to 20% w / w relative to nanovesicles) can improve foam strength (characterized by collapse time) of a foam generated from the formulation comprising nanovesicles, as described in the present invention.

[036] In the invention formulation, the presence of xanthan gum provides improved nanovesicle size stability under stress conditions (e.g., 40 °C) in pressurized containers.

[037] Furthermore, the present invention demonstrates that the stability of a formulation comprising nanovesicles can be improved, wherein an active agent is dissolved in the aqueous phase or dissolved in the nanovesicles, when stored in a pressurized device, compared to a conventional storage device, such as a glass vial, stability meaning both or one of the nanovesicle size and / or the chemical stability of the active ingredients. The inventors have found that the stabilizing effect can be observed in nanoemulsions (and foams derived therefrom) therefore active agents with very different properties. Two examples that are useful for understanding the range of properties in terms of molecular weight and hydrophilicity: the hydrophilic compound 5-aminolevulinic acid hydrochloride, with a weight of 131 g / mol, and the lipophilic compound tacrolimus, having a molecular weight of 804 g / mol.These exemplary compounds, without limiting the scope of the invention, encompass hydrophilic and lipophilic compounds with a molecular weight in the range of about 100 g / mol to about 1,000 g / mol.

[038] An exemplary formulation of the invention comprises ALA. A formulation comprising ALA can be prepared with a lipid phase (or carrier component) of, for example, 10%.

[039] Another example of the invention relates to a formulation comprising TC. The release of TC from a formulation and subsequent Petition 870250089513, dated 10 / 01 / 2025, pp. 434 / 568 11 / 123 Skin penetration can be improved by using a nanoemulsion formulation, in particular a nanoemulsion foam, with a lipid phase (or carrier component) of, for example, 20%. Foams can also be beneficial in combination with TC, as they are easier and more pleasant to apply due to their soft texture. This is of added value when treating sensitive or irritated skin, such as in cases of atopic dermatitis or similar conditions. Additionally, nanoemulsion foam formulation in pressurized containers is able to stabilize TC under stress conditions.

[040] Another example of the invention is a nanoemulsion formulation comprising the API betamethasone propionate (BMP), a high-potency topical corticosteroid. BMP can be used to treat inflammatory skin conditions. BMP has a molecular weight of 392.46 g / mol and a logP of 1.14. A BMP nanoemulsion, according to the invention, may comprise 15% carrier component. Thus, it has properties between ALA and TC, further highlighting the versatility of the nanoemulsion formulation of the invention.

[041] A first aspect of the invention relates to a formulation comprising: (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol, and (b) a propellant, wherein the formulation is contained in a pressurized container and Petition 870250089513, dated 10 / 01 / 2025, pages 435 / 568 12 / 123 where the formulation essentially does not comprise any fatty alcohols.

[042] The formulation contained in the pressurized container may also be referred to as the “pressurized formulation” and the nanoemulsion contained in the formulation may be referred to as the “pressurized nanoemulsion”.

[043] In some embodiments, the formulation is a lotion, a spray, a foam, an emulsion, a nanoemulsion, a gel, or a cream. In some embodiments, the formulation comprised in the pressurized container is a lotion, an emulsion, a nanoemulsion, a gel, or a cream. In some embodiments, the formulation comprised in the pressurized container is a lotion. In the context of this descriptive report, a lotion is a low-viscosity topical preparation intended for application to the skin. In preferred embodiments, the formulation is a liquid as specified above. The pressurized formulation may be released from the pressurized container as a spray or foam. In preferred embodiments of any aspect described in the present invention, the formulation comprising the nanoemulsion is a foamable formulation.In the context of this descriptive report, the term "foamable" means that when a formulation is released from the pressurized container by means of a suitable valve, a foam is obtained. A person skilled in the art is familiar with suitable valves for the formation of a foam from a liquid formulation contained in a pressurized container. Relevant information relating to the generation of a foam from a liquid formulation contained in a pressurized container can be found, for example, in "Pharmazeutische Technologie", 9th edition, Rudolf Voigt (Deutscher Apotheker Verlag Stuttgart 2000). Petition 870250089513, dated 10 / 01 / 2025, pp. 436 / 568 13 / 123

[044] In preferred embodiments of the formulations described in the present invention, the aqueous component comprises an aqueous phase or forms an aqueous phase.

[045] In preferred embodiments of the formulations described in the present invention, the carrier component comprises or consists of nanovesicles. In other words, the nanoemulsion comprises nanovesicles. In some embodiments, the nanovesicles comprise at least one lipophilic component, at least one surfactant, and at least one alcohol.

[046] In preferred embodiments, the formulation is provided for topical use.

[047] In pressurized formulations, particularly in foamable formulations, fatty alcohols have been described as acting as foaming aids.

[048] In the context of this descriptive report, the term “foaming aid” relates to compounds capable of increasing the foaming capacity of a formulation and / or stabilizing a foam. In particular, the term “foaming aid” relates to fatty acids and fatty alcohols having at least 6 carbon atoms.

[049] The formulation of the first aspect of the invention essentially does not comprise any fatty alcohol. Preferably, the formulation essentially does not comprise any fatty alcohol and essentially no fatty acid. More preferably, the formulation essentially does not comprise any foaming agent.

[050] In the context of this descriptive report, the expression “essentially none” specifies that the formulation is free of a compound or comprises less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), less than 0.2% (w / w), less than 0.1% (w / w), less than 0.08% (w / w), less than Petition 870250089513, dated 10 / 01 / 2025, pp. 437 / 568 14 / 123 of 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w) or less than 0.01% (w / w) of a compound based on the total weight of the formulation.

[051] Whenever it is specified that the formulation essentially does not comprise any compound X”, it is preferable that the formulation does not comprise any compound X”.

[052] In the context of this descriptive report, the term "fatty alcohol" relates to alcohols having at least 6 carbon atoms, typically 6 to 28 carbon atoms. Fatty alcohols may be saturated or unsaturated and branched or unbranched. Fatty alcohols are typically linear chain primary alcohols. The term "fatty alcohol," as used in the present invention, relates to fatty alcohols in their standalone form and does not include esters comprising fatty alcohols.

[053] In the context of this descriptive report, the term “fatty acids” relates to carboxylic acids with an aliphatic chain of at least 6 carbon atoms, typically 6 to 28 carbon atoms. Fatty acids can be saturated or unsaturated and branched or unbranched. Most naturally occurring fatty acids have an unbranched chain of carbon atoms. The term “fatty acid,” as used in the present invention, relates to fatty acids in their standalone form and does not include esters comprising fatty acids.

[054] The formulation is free of a fatty alcohol (in its standalone form or, in other words, as an isolated molecule) or comprises less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), less than 0.2% (w / w), less than 0.1% (w / w), less than 0.08% (w / w), less than 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w) or less than 0.01% (w / w) of a fatty alcohol (in its standalone form or, in other words, as an isolated molecule) Petition 870250089513, dated 10 / 01 / 2025, pages 438 / 568 15 / 123 autonomous form or, in other words, as an isolated molecule) based on the total weight of the formulation.

[055] In particular, the formulation is free of a fatty acid and a fatty alcohol (in their standalone forms or, in other words, as isolated molecules) or comprises less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), less than 0.2% (w / w), less than 0.1% (w / w), less than 0.08% (w / w), less than 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w) or less than 0.01% (w / w) of a fatty acid and a fatty alcohol (in their standalone forms or, in other words, as isolated molecules) based on the total weight of the formulation.

[056] Preferably, the formulation is free of foaming agent or comprises less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), less than 0.2% (w / w), less than 0.1% (w / w), less than 0.08% (w / w), less than 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w) or less than 0.01% (w / w) of a foaming agent based on the total weight of the formulation.

[057] Surprisingly, the formulation of the present invention comprised in a pressurized container has a high foaming capacity and forms a stable foam (long collapse time) when released from the pressurized container, even in the absence of a fatty alcohol or other foaming aid.

[058] In preferred embodiments, the formulation of the first aspect of the invention does not essentially comprise any emollient selected from a monoester or diester comprising an alcohol and a carboxylic acid.

[059] In the context of this descriptive report, the term “monoester” Petition 870250089513, dated 10 / 01 / 2025, pp. 439 / 568 16 / 123 refers to a molecule containing one and only one ester group, while the term diester refers to a molecule containing two and only two ester groups.

[060] In the context of this descriptive report, the term emollient refers to compounds that have a softening or moisturizing effect when applied to the skin. Emollients are able to coat the skin with a protective film to prevent moisture loss.

[061] Examples of emollients are isostearic acid esters, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, octyl palmitate, cetyl lactate, cetylricinoleate, tocopheryl acetate, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl oleate, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentyl glycol dicaprylate / dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol, Octyl hydroxystearate and sucrose esters of fatty acids. Additional examples are isopropyl myristate and glyceryl monostearate.

[062] In particular, the formulation of the first aspect of the invention essentially comprises no diisopropyl adipate, essentially no isopropyl myristate and essentially no glyceryl monostearate.

[063] Another example of an emollient is petrolatum. In the context of this descriptive report, the term petrolatum relates to a semi-solid mixture of hydrocarbons derived from petroleum distillation. The hydrocarbons that make up petrolatum comprise mainly at least 25 carbon atoms. The CAS number of petrolatum Petition 870250089513, dated 10 / 01 / 2025, pp. 440 / 568 17 / 123 is 8009-03-8. Preferably, the formulation of the first aspect of the invention does not essentially comprise any petrolatum.

[064] In preferred embodiments, the formulation of the first aspect of the invention essentially does not comprise any gelling agent or only small amounts of a gelling agent. If the formulation of the first aspect of the invention comprises a gelling agent, the gelling agent is comprised in an amount that does not affect the formation of a gel. As described above, the formulation of the first aspect of the invention comprises a liquid element (the element comprising the nanoemulsion) and a gaseous element (the propellant). In cases where the formulation comprises a gelling agent, the gelling agent is comprised in a concentration of 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.5% or less, based on the total weight of the formulation.In cases where the formulation includes Poloxamer as a gelling agent, Poloxamer is understood to be present at a concentration of 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.5% or less, based on the total weight of the formulation. In cases where the formulation includes Xanthan Gum as a gelling agent, Xanthan Gum is understood to be present at a concentration of 2% or less, 1% or less, or 0.5% or less, based on the total weight of the formulation.

[065] In preferred embodiments, the formulation of the first aspect of the invention does not essentially comprise any gelling agent.

[066] In the context of this descriptive report, the term “gelling agent” refers to a polymeric agent capable of increasing the viscosity of a formulation. Gelling agents include poloxamer, xanthan gum, bentonite, sodium carboxymethylcellulose, hydroxymethylcellulose, carbomer, hydroxypropylcellulose, gellan gum, guar gum, pectin, oxide of Petition 870250089513, dated 10 / 01 / 2025, pp. 441 / 568 18 / 123 poly(ethylene), polycarbophil, alginate, tragacanth, povidone, and gelatin. Gelling agents have been described to increase the stability of a nanoemulsion formulation.

[067] Surprisingly, the formulation of the present invention contained in a pressurized container is highly stable with respect to nanovesicle size, even in the absence of a gelling agent or in the presence of only low concentrations of a gelling agent.

[068] In some embodiments, the formulation comprises an active agent. The terms “active agent” and “active ingredient” are used interchangeably in the present invention. The active agent may be dissolved in the aqueous phase and capable of interacting with the surface of the nanovesicles, and / or the active agent may be dissolved in the core of the nanovesicles. Surprisingly, the formulation of the present invention comprised in a pressurized container is highly stable with respect to the concentration of the active agent, even in the absence of a gelling agent or in the presence of only low concentrations of a gelling agent.

[069] As used in the present invention, “capable of interacting with the surface of nanovesicles” includes the non-covalent binding of the active agent to the nanovesicles, in particular to the surface of the nanovesicles. For example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 80% or at least 90% of the total amount of active agent interacts with the surface of the nanovesicles, the remainder being dissolved in the aqueous phase.

[070] The small size of the nanovesicles and their high homogeneity give them cosmetically advantageous properties, which distinguish them from conventional emulsions: The nanoemulsions of the present invention are transparent and have a novel texture. Additionally, the nanoemulsion Petition 870250089513, dated 10 / 01 / 2025, pp. 442 / 568 19 / 123 of the present invention can carry active agents more efficiently and thus become increasingly important in the field of medicine and pharmacy.

[071] The formulation of the present invention, supplied in a pressurized container, is surprisingly resistant to aging under stress conditions with respect to API content and nanoemulsion vesicle size, compared to a nanoemulsion that has been stored in a non-pressurized container, for example, in a glass tube or vial. In the formulation of the invention, the active ingredient content is stable for a long period of time. In some embodiments, stability can be further improved if the formulation comprises an adjuvant or gelling agent chosen from polymeric agents, such as xanthan gum or poloxamer, such as Poloxamer 407.

[072] “Aging”, as used in the present invention, refers to the alteration, disintegration and / or degradation of the formulation and / or the active agent, affecting chemical and physical stability during storage, particularly under stress conditions. Such physical or chemical changes due to storage may include, but are not limited to, Ostwald ripening, flocculation or coalescence, which may lead to a change in nanovesicle size or polydispersity index.

[073] “Aging”, as used in the present invention, also refers to the alteration, disintegration and / or degradation of the active agent, affecting chemical and physical stability during storage, particularly under stress conditions. Such physical or chemical changes due to storage may include, but are not limited to, a decrease in the concentration of the active agent or an increase in impurities.

[074] As used in the present invention, “stress conditions” for storage are temperatures that significantly exceed the Petition 870250089513, dated 10 / 01 / 2025, pp. 443 / 568 20 / 123 ambient temperature (e.g., 40 °C) or that are significantly below commonly used storage temperatures (e.g., below 0 °C, such as -15 to -25 °C).

[075] The examples of the present invention demonstrate that the pressurized nanoemulsion of the present invention leads to unexpected stable nanovesicle sizes under different conditions, including stress conditions.

[076] As used in the present invention, a “nanovesicle emulsion” or a “nanoemulsion” is an oil-in-water dispersion (oil-in-water dispersion, oil-in-water emulsion, O / W emulsion). The nanoemulsion may be monophasic, transparent, and slightly opalescent. The nanoemulsions of the present invention may be colloidal systems. The vesicles dispersed in such emulsions may be composed of a lipid core surrounded by at least one surfactant or emulsifier monolayer. The nanoemulsions of the present invention may be characterized by an average vesicle size of less than 500 nm, less than 200 nm, or less than 100 nm. The nanoemulsions of the present invention may have a predominantly monodisperse vesicle size distribution, for example, a vesicle size distribution characterized by a polydispersity index less than or equal to 0.4 or 0.3.

[077] As used in the present invention, “nanovesicle”, “nanovesicle”, “lipid vesicles”, “oil droplets”, “droplets” and “oil globules” are interchangeable and refer to small oil droplets in an oil-in-water emulsion. A medium-sized lipid vesicle (see above, for example, below 500, 200, 100 nm) comprises a monolayer of a surfactant and a lipid core. In the present invention, the nanovesicles may be 500 nm or less in size, or 300 nm or less, Petition 870250089513, dated 10 / 01 / 2025, pp. 444 / 568 21 / 123 or less than or equal to 200 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.

[078] As used in the present invention, the term nanoparticle or nanoparticle is differentiated from nanovesicles and refers to solid particles, which are not described in this invention. The formulation of the present invention may be an essentially nanoparticle-free formulation. Essentially nanoparticle-free means that the formulation comprises less than or equal to 2% by weight, or less than or equal to 1% by weight, or does not comprise nanoparticles. Nanoparticles are primarily inorganic or polymeric solid particles that may have a size below 100 nm, below 200 nm, or below 500 nm. The size may be determined by the methods as described in the present invention. For example, the formulation may be essentially nanoparticle-free with a diameter smaller than 100 nm, as determined by dynamic light scattering.

[079] As used in the present invention, topical use of the formulation of the invention describes application to a specific location on the body, in particular the human body. This includes, but is not limited to, administration of the formulation to body surfaces such as the skin or mucous membranes. Topical use may be epicutaneous, meaning the formulation is administered directly to the skin. Topical use may be pharmaceutical or cosmetic.

[080] As used in the present invention, the stability of a formulation comprising nanovesicles, as described in the present invention, includes, but is not limited to, physical and chemical stability. In particular, in the present invention, a formulation is stable if the integrity of the nanovesicles is considered stable. A measure known to the skilled in the art is... Petition 870250089513, dated 10 / 01 / 2025, pages 445 / 568 22 / 123 The subject for describing the integrity of the nanovesicles is the average size and polydispersity index, as determined, for example, by dynamic light scattering, as described in the present invention. The nanovesicles produced according to the invention may have a size below 200 nm, preferably below 100 nm, more preferably below 50 nm, even more preferably below 30 nm, immediately after fabrication. The Examples of the invention demonstrate that the size of the nanovesicles can increase to more than 1000 nm or 1500 nm in unstabilized comparative formulations when stored under stress conditions. In contrast, the size of nanovesicles remains small in the formulations of the invention contained in a pressurized container.For example, the formulation, as described in the present invention, is stable if the nanovesicles in the formulation of the present invention have a size (or diameter) less than or equal to 500 nm, or less than or equal to 300 nm, or less than or equal to 200 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm when stored, for example, under stress conditions, as described in the present invention.

[081] “Stability” may also refer to the absence of processes described above, such as aging, leading to loss of functionality or pharmaceutical quality. The pharmaceutical composition described in this invention is pharmaceutically functional, provided that the nanovesicle size is less than or equal to 500 nm, or less than or equal to 300 nm or less than or equal to 200 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.

[082] In addition, stability can refer to the stable content of the active pharmaceutical agent or cosmetic agent. During storage, the content of the active pharmaceutical agent or active cosmetic agent is, for example, Petition 870250089513, dated 10 / 01 / 2025, pages 446 / 568 23 / 123 is considered stable if at least 70%, at least 80%, or at least 90% of the active agent content is still present when stored, for example, under stress conditions as described in the present invention.

[083] In the context of this descriptive report, whenever a duration is described as “one month, two months, three months”, etc., this should include modalities in which the duration is “at least one month, at least two months, at least three months”, etc.

[084] In a formulation of the invention comprising ALA, the ALA content may be (i) at least 90% or at least 95% after storage for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months at 40 °C, and / or (ii) at least 95% or at least 97% after storage for 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 or 36 months at 25 °C, and / or (iii) at least 95%, at least 97% or at least 99% after storage for 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 or 36 months at 5 °C.

[085] In a formulation of the invention comprising TC, the TC content may be (i) at least 90% after storage for 1 month at 40 °C, and / or (ii) at least 78% or at least 80% after storage for 1 or 2 months at 40 °C, and / or (iii) at least 71% or at least 75% after storage for 1, 2 or 3 months at 40 °C, and / or (iv) at least 90%, at least 95%, or at least 97% or at least 99% after storage for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months at 25 °C, and / or (v) at least 83% or at least 88% after storage for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months at 25 °C, and / or Petition 870250089513, dated 10 / 01 / 2025, pp. 447 / 568 24 / 123 (vi) at least 90%, at least 95%, at least 97% or at least 99% or 100% after storage for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months at 5 °C.

[086] (vii) at least 90%, at least 95%, or at least 97%, or at least 99% or 100% after storage for 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 or 36 months at 5 °C.

[087] (viii) at least 90%, at least 95%, at least 97% or at least 99% or 100% after storage for 1, 2, 3, 4, 5, 6, 12, 18, 24, 30, 36, 42 or 48 months at 5 °C.

[088] In the present invention, the formulation can be stable for at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months or at least 36 months, for example, at elevated temperature (e.g., 40 °C). In particular, the formulation of the invention can be stable for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 24 months, at least 36 months or at least 48 months at 2 to 25 °C, for example, at 15 to 25 °C or at about 5 °C. In particular, the formulation of the invention can be stable when subjected to 1, 2, 3, 4, 5 or even more freeze-thaw cycles.

[089] The nanovesicles included in the formulation of the present invention have a stable size. The size of the nanovesicles is indicated below by preparation. It is important to note that the size remains within the indicated ranges even after storage under stress conditions, especially storage at high temperatures or freezing and thawing.

[090] The formulation of the present invention is homogeneous (predominantly monodisperse), as characterized by an index of Petition 870250089513, dated 10 / 01 / 2025, pages 448 / 568 25 / 123 Polydispersity less than or equal to 0.4. The formulation of the present invention has a stable polydispersity index. The polydispersity index is less than or equal to 0.4 upon preparation. It is important to note that the polydispersity index is also less than or equal to 0.4, even after storage under stress conditions, in particular storage at elevated temperatures or freezing and thawing. In preferred embodiments of any aspect of the invention, the polydispersity index is less than or equal to 0.3.

[091] The nanovesicles in the formulation of the present invention may have a size less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm, in particular when stored for three, four, five, six, nine, twelve, eighteen or twenty-four months at 40 °C in a pressurized container.

[092] The nanovesicles in the formulation of the present invention may have a size (or diameter) less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 150 nm, particularly when subjected to at least one freeze-thaw cycle, preferably one, two, three, four or five freeze-thaw cycles. In particular, a formulation comprising xanthan, as described in the present invention, may comprise nanovesicles having this size.

[093] At least one freeze-thaw cycle may comprise storage of the formulation independently below 15 °C, preferably at -24 °C, and thawing, for example, at room temperature (e.g., independently selected from 15 to 25 °C). The formulation may be stored for a period allowing for cooling, for example, at least 10 min, at most 30 min, at most Petition 870250089513, dated 10 / 01 / 2025, pp. 449 / 568 26 / 123 h, maximum 2 h, maximum 6 h or maximum 12 h. The formulation can be stored, for example, for a maximum of 1 day, a maximum of 2 days, a maximum of 3 days, a maximum of 4 days, a maximum of 5 days, a maximum of 6 days or even longer.

[094] The nanovesicles in the formulation of the present invention may have a size (or diameter) less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 150 nm, particularly when stored below -15 °C, preferably at -24 °C, in a pressurized container. The formulation may be stored for a period allowing for cooling, for example, at least 10 min, at most 30 min, at most 1 h, at most 2 h, at most 6 h or at most 12 h. The formulation may be stored, for example, for at most 1 day, at most 2 days, at most 3 days, at most 4 days or even longer. In particular, a formulation comprising xanthan, as described in the present invention, may comprise nanovesicles having this size.

[095] The vesicle size or diameter of the nanovesicles, as described in the present invention, can be expressed as the Z-mean (also referred to as “z-mean”). The size distribution of the nanovesicles can be characterized by the polydispersity index. These parameters are well known to those skilled in the art and are widely used in the art to characterize particles or vesicles in emulsions, suspensions and / or polymeric solutions.

[096] In the present invention, the mean z (e.g., in nm) and / or the polydispersity index of nanovesicle formulations can be determined by dynamic light scattering (also referred to as Photon Correlation Spectroscopy (PCS) or Quasi-Elastic Light Scattering (QELS)). Dynamic light scattering is well known in the state of Petition 870250089513, dated 10 / 01 / 2025, pages 450 / 568 27 / 123 technique and well established for determining the size of nano or microparticles or vesicles in emulsions, suspensions and / or polymeric solutions with a laser.

[097] In the formulation, as described in the present invention, the total aqueous component may be present in an amount of 50% to 99% w / w, based on the total weight of the nanoemulsion (a), preferably from 70% to 95% (w / w), and more preferably from 75% to 95% (w / w).

[098] The aqueous component may comprise at least one pH buffering agent. Any suitable buffering agent may be used. Suitable buffering agents are known to those skilled in the art. For example, at least one pH buffering agent may be selected from the group consisting of citrate, phosphate, acetate, and carbonate. [09 9] The pH of the aqueous component may be in the range of 2 to 9. The pH of the aqueous component may also preferably be in the range of 2 to 7 or 2 to 6, such as 2, 3, 4, 5 or 6, more preferably in the range of 3 to 6 or 4 to 6, such as 3, 4, 5 or 6. The pH of the aqueous component may also be in the range of 7 to 9.

[100] In the formulation, as described in the present invention, at least one lipophilic component may be selected from triglycerides and mixtures thereof.

[101] Preferably, at least one lipophilic component is a lipid, a vegetable oil, a synthetic oil and / or an animal oil. Suitable lipids according to the present invention are physiologically acceptable lipids, such as ceramide, mono-, di- and triacylglycerol (triglycerides). In particular, at least one lipophilic component is a triglyceride, in particular a triglyceride comprising a C8-10 fatty acid, or a mixture thereof. More particularly, at least one lipophilic component is Petition 870250089513, dated 10 / 01 / 2025, pp. 451 / 568 28 / 123 a caprylic and / or capric triglyceride and / or a mixture thereof, particularly preferably Miglyol (such as Miglyol 812, available from IOI Oleochemical) or Myritol (such as Myritol 318, available from BASF). Suitable vegetable and animal oils are, for example, sunflower oil, soybean oil, peanut oil, rapeseed oil, fish oil and / or cetacean oil.

[102] In the formulation, as described in the present invention, at least one lipophilic component may be present in an amount from 0.1% to 30% (w / w) based on the total weight of the nanoemulsion (a), preferably from 0.25% to 15% (w / w), preferably from 0.25% to 10% (w / w) and more preferably from 0.5% to 8% (w / w) or 3% to 8% (w / w). It is also preferred that at least one lipophilic component be present in an amount from 10% to 30% (w / w) based on the total weight of the nanoemulsion (a), more preferably 15 to 30% or 20 to 30%.

[103] In the formulation, as described in the present invention, a triglyceride or triglycerides may be present in an amount from 2% to 10% (w / w), based on the total weight of the nanoemulsion (a), preferably from 3% to 8% (w / w).

[104] In the formulation, as described in the present invention, at least one surfactant may be any suitable surfactant known to those skilled in the art.

[105] Surfactants, also referred to as surface-active agents or emulsifiers, are well known in the state of the art and include any agent that binds oil and water in the composition to form an emulsion. They attenuate the surface tension of two liquids and are amphiphilic. In emulsions, they are referred to as emulsifiers and coat the droplets, preventing coalescence. Emulsifiers can be described by the hydrophilic / lipophilic balance (HLB), which expresses their affinity for water or oil. Low Petition 870250089513, dated 10 / 01 / 2025, pages 452 / 568 29 / 123 HLB (e.g., HLB=1) refers to lipophilic emulsifiers and high (e.g., HLB=20) to hydrophilic emulsifiers. In general, lipophilic emulsifiers are used for water-in-oil emulsions and hydrophilic emulsifiers for oil-in-water emulsions. Skilled individuals will identify which emulsifiers or mixtures thereof are suitable for the preferred vehicles and the purpose of the composition. In certain emulsions, combinations of emulsifiers may be advantageous.

[106] A suitable membrane-forming surfactant is a phospholipid, a lysophospholipid, a ceramide and / or a mixture thereof. Preferably, the phospholipid is lecithin or cephalin from soy or chicken eggs. More preferably, at least one surfactant is lecithin, most preferably soy lecithin.

[107] In the formulation, as described in the present invention, the phospholipid, lysophospholipid, ceramide and / or mixture thereof may be present in an amount from 1% to 10% (w / w), based on the total weight of the nanoemulsion (a), preferably from 1.25% to 5% (w / w), and more preferably from 1.5% to 4% (w / w), most preferably from 1.5% to 2% (w / w) based on the total weight of the nanoemulsion (a).

[108] In the formulation, as described in the present invention, the phospholipid, lysophospholipid, ceramide and / or mixture thereof may be present in an amount from 0.1% to 10% (w / w), preferably from 0.15% to 5% (w / w), more preferably from 0.2% to 3% (w / w) or from 0.2% to 4% (w / w), most preferably from 0.2% to 0.4% (w / w) based on the total weight of the formulation.

[109] Preferably, the lecithin has a phosphatidylcholine content of at least 80% by weight, more preferably at least 90% by weight and most preferably at least 94% by weight. The quality of the lecithin, or Petition 870250089513, dated 10 / 01 / 2025, pp. 453 / 568 30 / 123, that is, its phosphatidylcholine content, plays a crucial role in the size of the nanoemulsion vesicles. The higher the phosphatidylcholine content of the lecithin, the smaller the size of the nanoemulsion vesicles.

[110] As O / W emulsion-forming surfactants, anionic, nonionic, cationic and / or amphoteric surfactants are suitable, as are block copolymers. Suitable anionic surfactants are soaps, alkylbenzene sulfonates, alkanes sulfonates, alkyl sulfates and / or alkyl ether sulfates. Suitable cationic surfactants are quaternary ammonium compounds, preferably having one or two hydrophobic groups (e.g., cetyltrimethylammonium bromide and cetyltrimethylammonium chloride) and / or salts of long-chain primary amines. A suitable amphoteric surfactant is N-(acylamidoalkyl)betaine, alkylammonium phosphate compounds, N-alkyl-β-aminopropionate and / or amine-N-oxide. A suitable copolymer building block, for example, is propylene oxide. In the present invention, a nonionic surfactant is particularly preferred as an O / W emulsion-forming surfactant.

[111] In the formulation as described in the present invention, at least one surfactant may be any polyoxyethylene type surfactant. A suitable nonionic surfactant may be selected from the group consisting of fatty alcohol polyglycol ether, alkylphenol polyglycol ether, alkylpolyglucoside, fatty acid glucamide, fatty acid polyglycol ether, ethylene oxide-propylene oxide block polymer, polyglycerol fatty acid ester, fatty acid alkanolamide and sorbitan fatty acid ester (ethoxylated) (sorbitan). A particularly preferred ethoxylated sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate, more preferably Polysorbate 80.

[112] At least one surfactant, such as a type surfactant Petition 870250089513, dated 10 / 01 / 2025, pages 454 / 568 31 / 123 polyoxyethylene, may be present in an amount from 1% to 10% (w / w), based on the total weight of the nanoemulsion (a), preferably from 2% to 10% (w / w), from 2% to 8% (w / w) and more preferably from 3% to 7% (w / w).

[113] The formulation of the invention may comprise at least one hydrophilic surfactant with an HLB of 9 to 17, more preferably 12 to 16, particularly polysorbate 80.

[114] At least one surfactant may be a sugar-based surfactant. Sugar-based surfactants are a group of nonionic surfactants that use hydrophilic sugars to which hydrophobic tails are attached. A common substance in this class is n-dodecyl-D-maltoside, a member of the maltoside surfactants, so named because the sugar unit used is maltose. An example of a pyranoside surfactant is n-octylβ-D-thioglucopyranoside. This class uses pyranose as the sugar unit. Examples of glycoside surfactants are octylglucoside, decylglucoside, and laurylglucoside. An example of a polysugar surfactant is digitonin.

[115] Another very important group of sugar-based surfactants are the Tween surfactants, the most notable being Tween 20 (also referred to in the present invention as Polysorbate 20) and Tween 80 (also referred to in the present invention as Polysorbate 80). These surfactants are based on sorbitan sugar, which is why they are commonly referred to as polysorbate surfactants. Three oligo(ethylene glycol) side groups of varying lengths are attached to the sugar, increasing the hydrophilicity of the main group. This structure forms the core of all Tween surfactants. They branch off at the hydrophobic tail, which is a fatty acid coupled via an ester to four oligo(ethylene glycol) tails. In Tween 20 this fatty acid is lauric acid; in Tween 80 it is oleic acid. Petition 870250089513, dated 10 / 01 / 2025, pages 455 / 568 32 / 123

[116] In some embodiments, at least one surfactant is selected from the group consisting of a phospholipid, in particular phosphatidylcholine, a lysophospholipid, a ceramide and / or a mixture thereof. In some embodiments, at least one surfactant is a polyoxyethylene type surfactant. In some embodiments, at least one surfactant is phosphatidylcholine. In some embodiments, the formulation comprises a phospholipid as a surfactant and a polyoxyethylene type surfactant. In some embodiments, the formulation comprises phosphatidylcholine as a surfactant and a polyoxyethylene type surfactant. In some embodiments, the formulation comprises phosphatidylcholine and polysorbate 80 as surfactants.

[117] In the formulation, as described in the present invention, the at least one alcohol comprises no more than 5 carbon atoms and may independently have 3 to 5 or 3 to 4 carbon atoms. Particularly suitable alcohols having 5 carbon atoms are 1-pentanol and / or 4-methyl-2-pentanol. Suitable alcohols having 4 carbon atoms are 1-butyl alcohol, isobutyl alcohol (2-methyl-1-propanol), tert-butyl alcohol (2-methyl-2-propanol) and / or sec-butyl alcohol (2-butanol).

[118] Preferably, the at least one alcohol has 3 to 5 carbon atoms, even more preferably 3 carbon atoms, that is, it is selected from the group consisting of 1-propanol or 2-propanol (isopropyl alcohol) and mixtures thereof. A preferred alcohol is 2-propanol.

[119] In the formulation, as described in the present invention, the alcohol may be present in an amount from 0.1% to 10% w / w based on the total weight of the nanoemulsion (a), preferably from 0.5% to 5% (w / w) and more preferably from 1% to 3% (w / w).

[120] In the formulation, as described in this invention, the alcohol Petition 870250089513, dated 10 / 01 / 2025, pp. 456 / 568 33 / 123 may be a C3 to C5 alcohol present in an amount from 1% to 5% (w / w) based on the total weight of the nanoemulsion (a).

[121] In the formulation as described in the present invention, any suitable propellant may be used. Suitable propellants and mixtures thereof are known to those skilled in the art. Preferably, the propellant is selected from propane, isobutane, n-butane and mixtures thereof. More preferably, the propellant is a mixture of propane and isobutane. In particular, the propellant is provided to pressurize the vessel in which the formulation of the invention is provided.

[122] The formulation, as described in the present invention, may comprise a gelling agent. The inventors have found that a gelling agent in the formulations described in the present invention is not necessary to obtain a stable formulation or to form foams, but may additionally provide resistance to formulation aging. Any suitable gelling agent may be used. Suitable gelling agents and mixtures thereof are known to those skilled in the art. In the formulation, as described in the present invention, the gelling agent may be selected from the group consisting of poloxamer, xanthan gum, bentonite, sodium carboxymethylcellulose, hydroxymethylcellulose, carbomer, hydroxypropylcellulose, gellan gum, guar gum, pectin, poly(ethylene) oxide, polycarbophil, alginate, tragacanth, povidone, gelatin and mixtures thereof.

[123] If the invention formulation includes a gelling agent, it is preferable that the gelling agent be selected from poloxamer, xanthan and / or mixtures thereof.

[124] If the invention formulation comprises a gelling agent, it is particularly preferable that the gelling agent be a poloxamer.

[125] If the invention formulation comprises a gelling agent, it is Petition 870250089513, dated 10 / 01 / 2025, pages 457 / 568 34 / 123 It is particularly preferable that the gelling agent be xanthan gum.

[126] Poloxamers are nonionic triblock copolymers composed of a central hydrophobic polyoxypropylene (poly(propylene oxide)) chain flanked by two hydrophilic polyoxyethylene (poly(ethylene oxide)) chains. Poloxamer 407 and Poloxamer 188 are commercially available. Poloxamer 407 may have an average molecular weight of about 12,600 Daltons. Poloxamer 188 may have an average molecular weight of about 8,400 Daltons. In the formulation as described in the present invention, a preferred poloxamer is Poloxamer 407.

[127] In the formulation, as described in the present invention, the gelling agent may be present in an amount from 0.1% to 10% w / w based on the total weight of the formulation, preferably from 0.25% to 5% (w / w) and more preferably from 0.5% to 4% (w / w).

[128] The nanovesicles in the formulation of the present invention comprising a novel gelling agent may have a size (or diameter) less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 150 nm, when subjected to at least one freeze-thaw cycle, preferably one, two, three, four or five freeze-thaw cycles. A freeze-thaw cycle may be as described in the present invention.

[129] The nanovesicles in the formulation of the present invention, containing at least one gelling agent, may have a size (or diameter) less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 150 nm, when stored at -15 °C to -25 °C, preferably at -24 °C, in a pressurized container, for example, for 4 days. The storage conditions are Petition 870250089513, dated 10 / 01 / 2025, pages 458 / 568 35 / 123 as described in the present invention.

[130] In one embodiment, in the formulation as described in the present invention, at least one lipophilic component is present in an amount from 0.1% to less than 15% (w / w), based on the total weight of the nanoemulsion (a), preferably from 0.1% to less than 10% (w / w), preferably from 0.25% to less than 10% (w / w) and more preferably from 0.5% to 8% (w / w) or 3% to 8% (w / w), and the formulation is essentially free of a gelling agent. In particular, the formulation is free of a gelling agent. In this embodiment, the formulation may be free of a poloxamer, such as Poloxamer 407 and Poloxamer 188. In this embodiment, the formulation may be free of xanthan gum. In this embodiment, the formulation may be free of xanthan gum and a poloxamer, such as Poloxamer 407 and Poloxamer 188. At least one lipophilic component is as described in the present invention.

[131] In another embodiment, in the formulation as described in the present invention, (i) at least one lipophilic component is present in an amount from at least 10% to 30% (w / w) based on the total weight of the nanoemulsion (a), preferably from at least 15% to 30% (w / w) and more preferably from at least 20% to 30% (w / w), and (ii) the formulation comprises a gelling agent, in an amount less than 10% based on the total weight of the formulation, in particular from 0.1% to 10% w / w based on the total weight of the formulation, preferably from 0.25% to 5% (w / w) and more preferably from 0.5% to 4% (w / w). In particular, the gelling agent is a poloxamer, such as Poloxamer 407 and / or Poloxamer 188, as described in this invention.

[132] The at least one lipophilic component is as described in Petition 870250089513, dated 10 / 01 / 2025, pp. 459 / 568 36 / 123 present invention.

[133] The formulation, as described in the present invention, may comprise a preservative. Any suitable preservative may be used. Suitable preservatives are known to those skilled in the art. The preservative may be selected from benzoate, citric acid, EDTA, potassium sorbate, vitamin C and / or derivatives and any mixtures thereof, wherein the preservative is preferably sodium benzoate. Suitable aqueous mixtures of sodium benzoate and potassium sorbate are commercially available, for example, preservative Euxyl™ k 712 (Ashland).

[134] The preservative may be present in the formulation as described in the present invention in an amount from 0.01% to 3% (w / w) based on the total weight of the formulation, preferably from 0.2% to 2% (w / w) or 0.1% to 2% (w / w), and more preferably from 0.2% to 1.5% (w / w).

[135] In particular, the formulation of the present inventions is essentially paraben-free, preferably paraben-free. The class of paraben compounds includes p-hydroxybenzoates and p-hydroxybenzoic acid esters (also known as 4-hydroxybenzoic acid).

[136] Parabens are only slightly soluble in water. In the preparation of an aqueous formulation or a formulation comprising an aqueous component, parabens must be dissolved in a suitable solvent to introduce the parabens into the aqueous phase. A suitable solvent is propylene glycol.

[137] In the context of this descriptive report, the term propylene glycol refers to propane-1,2-diol (also known as 1,2-propanediol, α-propylene glycol, 1,2-dihydroxypropane, methyl ethyl glycol or methylethylene glycol).

[138] In the present invention, this preparation of a solution of a Petition 870250089513, dated 10 / 01 / 2025, pages 460 / 568 37 / 123 paraben in propylene glycol is not required, so the formulation of the present invention can be propylene glycol-free.

[139] The formulation of the present inventions can be essentially propylene glycol-free, preferably propylene glycol-free.

[140] The formulation of the present inventions may be essentially free of propylene glycol and a paraben, preferably free of propylene glycol and a paraben.

[141] In addition to comprising no propylene glycol or only small amounts of propylene glycol, as defined above, it is preferable that the formulation comprise none, essentially none or less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of a non-cyclic polyol having 2 to 3 carbon atoms (i.e. having no more than 3). Preferably, the formulation comprises none, essentially none, or less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% w / w of a non-cyclic polyol having 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, or 2 to 10 carbon atoms (i.e., having no more than 4, 5, 6, 7, 8, 9, or 10 carbon atoms, respectively).More preferably, the formulation comprises none, essentially none, or less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% w / w of a polyol having 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, or 2 to 12 carbon atoms (i.e., with no more than 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, respectively). More preferably, the formulation comprises none, essentially none, or less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% w / w of a non-cyclic polyol having 2 to 15, 2 to 20, 2 to 25, or 2 to 30 carbon atoms (i.e., having no more than 15, 20, 25, or 30 carbon atoms, respectively). Even more preferably, the formulation comprises none, essentially none, or less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, Petition 870250089513, dated 10 / 01 / 2025, pp. 461 / 568 38 / 123 0.4%, 0.3%, 0.2% or 0.1% w / w of a polyol having 2 to 15, 2 to 20, 2 to 25 or 2 to 30 carbon atoms (i.e., with no more than 15, 20, 25 or 30 carbon atoms, respectively). Even more preferably, the formulation comprises none, essentially none or less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of a non-cyclic polyol.

[142] “Non-cyclic polyol” in the context of this descriptive report means that the polyol does not comprise any cyclic hydrocarbon fractions, in particular no cyclic sugar fraction. The non-cyclic polyol may be linear or branched. The non-cyclic polyol may be a diol, a triol, or may comprise more than three OH groups.

[143] In preferred embodiments, the formulation of the invention comprises none, essentially none or less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of a polyol with a molecular weight less than 100 g / mol, less than 200 g / mol, less than 300 g / mol, less than 400 g / mol, less than 500 g / mol, less than 600 g / mol, less than 700 g / mol, less than 800 g / mol, less than 900 g / mol or less than 1000 g / mol.

[144] As used in the present invention, the expressions “essentially free of compound X”, “essentially does not comprise compound X” or “does not essentially comprise any compound X” with respect to a formulation are interchangeable. In particular, unless otherwise defined, these expressions specify that the formulation is free of compound X or comprises less than 0.1% (w / w), less than 0.08% (w / w), less than 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w) or less than 0.01% (w / w) of compound X based on the total weight of the formulation.

[145] As used in the present invention, the expression “the composition comprises less than X% of compound X” shall include embodiments in which the Petition 870250089513, dated 10 / 01 / 2025, pp. 462 / 568 The 39 / 123 composition is essentially free of compound X.

[146] As used in the present invention, “the formulation does not essentially comprise any propylene glycol” or “the formulation does not essentially comprise propylene glycol” means that the formulation is essentially free of propylene glycol. In particular, the pharmaceutical formulation of the invention is free of propylene glycol, that is, the formulation does not comprise propylene glycol.

[147] The formulation of the present invention can be essentially free of propylene glycol.

[148] The formulation of the present invention can be essentially glycerin-free.

[149] The formulation of the present invention can be essentially free of diglycerin.

[150] The formulation of the present invention can be essentially free of polyglycerin.

[151] The formulation of the present invention can be essentially free of diethylene glycol.

[152] The formulation of the present invention can be essentially free of dipropylene glycol.

[153] The formulation of the present invention can be essentially butylene glycol free.

[154] The formulation of the present invention can be essentially free of pentylene glycol.

[155] The formulation of the present invention can be essentially free of hexylene glycol.

[156] The formulation of the present invention can be essentially free of 1,3-propanediol. Petition 870250089513, dated 10 / 01 / 2025, pages 463 / 568 40 / 123

[157] The formulation of the present invention can be essentially free of 1,5-pentanediol.

[158] The formulation of the present invention can be essentially free of octane-1,2-diol.

[159] The formulation of the present invention can be essentially free of polyethylene glycols, particularly having from 2 to 50 ethylene oxide groups.

[160] The formulation of the present invention can be essentially free of monosaccharides and disaccharides, such as sorbitol, mannitol and mixtures thereof.

[161] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of propylene glycol or no propylene glycol. This formulation may be free of a paraben, as described in the present invention.

[162] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of propylene glycol. This formulation may be free of a paraben, as described in the present invention.

[163] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of propylene glycol. This formulation may be free of a paraben, as described in the present invention.

[164] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of propylene glycol. This formulation may be free of a paraben, as described in the present invention.

[165] In preferred embodiments, the formulation of the present invention Petition 870250089513, dated 10 / 01 / 2025, pages 464 / 568 41 / 123 does not contain any propylene glycol.

[166] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of glycerin or no glycerin. This formulation may be free of a paraben, as described in the present invention.

[167] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of glycerin. This formulation may be free of a paraben, as described in the present invention.

[168] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of glycerin. This formulation may be free of a paraben, as described in the present invention.

[169] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of glycerin. This formulation may be free of a paraben, as described in the present invention.

[170] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of diglycerin or no diglycerin. This formulation may be free of a paraben, as described in the present invention.

[171] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of diglycerin. This formulation may be free of a paraben, as described in the present invention.

[172] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of diglycerin. This Petition 870250089513, dated 10 / 01 / 2025, pp. 465 / 568 42 / 123 formulation may be free of a paraben as described in this invention.

[173] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of diglycerin. This formulation may be free of a paraben, as described in the present invention.

[174] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of polyglycerin or no polyglycerin. This formulation may be free of a paraben, as described in the present invention.

[175] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of polyglycerin. This formulation may be free of a paraben, as described in the present invention.

[176] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of polyglycerin. This formulation may be free of a paraben, as described in the present invention.

[177] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of polyglycerin. This formulation may be free of a paraben, as described in the present invention.

[178] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of diethylene glycol or no diethylene glycol. This formulation may be free of a paraben, as described in the present invention.

[179] In particular, the formulation of the present invention may Petition 870250089513, dated 10 / 01 / 2025, pages 466 / 568 43 / 123 comprising less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of diethylene glycol. This formulation may be free of a paraben, as described in the present invention.

[180] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of diethylene glycol. This formulation may be free of a paraben, as described in the present invention.

[181] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of diethylene glycol. This formulation may be free of a paraben, as described in the present invention.

[182] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of dipropylene glycol or no dipropylene glycol. This formulation may be free of a paraben, as described in the present invention.

[183] ​​In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of dipropylene glycol. This formulation may be free of a paraben, as described in the present invention.

[184] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of dipropylene glycol. This formulation may be free of a paraben, as described in the present invention.

[185] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of dipropylene glycol. This formulation may be free of a paraben, as described in the present invention. Petition 870250089513, dated 10 / 01 / 2025, pages 467 / 568 44 / 123

[186] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of butylene glycol or no butylene glycol. This formulation may be free of a paraben, as described in the present invention.

[187] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of butylene glycol. This formulation may be free of a paraben, as described in the present invention.

[188] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of butylene glycol. This formulation may be free of a paraben, as described in the present invention.

[189] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of butylene glycol. This formulation may be free of a paraben, as described in the present invention.

[190] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of pentylene glycol or no pentylene glycol. This formulation may be free of a paraben, as described in the present invention.

[191] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of pentylene glycol. This formulation may be free of a paraben, as described in the present invention.

[192] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of pentylene glycol. This formulation may be free of a paraben, as described herein. Petition 870250089513, dated 10 / 01 / 2025, pages 468 / 568 45 / 123 invention.

[193] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of pentylene glycol. This formulation may be free of a paraben, as described in the present invention.

[194] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of hexylene glycol or no hexylene glycol. This formulation may be free of a paraben, as described in the present invention.

[195] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of hexylene glycol. This formulation may be free of a paraben, as described in the present invention.

[196] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of hexylene glycol. This formulation may be free of a paraben, as described in the present invention.

[197] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of hexylene glycol. This formulation may be free of a paraben, as described in the present invention.

[198] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of 1,3-propanediol or no 1,3-propanediol. This formulation may be free of a paraben, as described in the present invention.

[199] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of 1.3 Petition 870250089513, dated 10 / 01 / 2025, pp. 469 / 568 46 / 123 propanediol. This formulation may be free of a paraben, as described in the present invention.

[200] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of 1,3-propanediol. This formulation may be free of a paraben, as described in the present invention.

[201] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of 1,3-propanediol. This formulation may be free of a paraben, as described in the present invention.

[202] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of 1,5-pentanediol or no 1,5-pentanediol. This formulation may be free of a paraben, as described in the present invention.

[203] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of 1,5-pentanediol. This formulation may be free of a paraben, as described in the present invention.

[204] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of 1,5-pentanediol. This formulation may be free of a paraben, as described in the present invention.

[205] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of 1,5-pentanediol. This formulation may be free of a paraben, as described in the present invention.

[206] The formulation of the present invention may comprise less than Petition 870250089513, dated 10 / 01 / 2025, pp. 470 / 568 47 / 123 or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of octane-1,2-diol or no octane-1,2-diol. This formulation may be free of a paraben, as described in the present invention.

[207] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of octane-1,2-diol. This formulation may be free of a paraben, as described in the present invention.

[208] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of octane-1,2-diol. This formulation may be free of a paraben, as described in the present invention.

[209] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of octane-1,2-diol. This formulation may be free of a paraben, as described in the present invention.

[210] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of polyethylene glycols or no polyethylene glycol, particularly having from 2 to 50 ethylene oxide groups. This formulation may be free of a paraben, as described in the present invention.

[211] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of polyethylene glycols, particularly having from 2 to 50 ethylene oxide groups. This formulation may be free of a paraben, as described in the present invention.

[212] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of polyethylene glycols, Petition 870250089513, dated 10 / 01 / 2025, pp. 471 / 568 48 / 123 particularly having 2 to 50 ethylene oxide groups. This formulation may be free of a paraben, as described in the present invention.

[213] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of polyethylene glycols, particularly having from 2 to 50 ethylene oxide groups. This formulation may be free of a paraben, as described in the present invention.

[214] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of monosaccharides and disaccharides, such as sorbitol, mannitol and mixtures thereof. This formulation may be free of a paraben, as described in the present invention.

[215] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of monosaccharides and disaccharides, such as sorbitol, mannitol and mixtures thereof, or no monosaccharides and disaccharides, such as sorbitol, mannitol and mixtures thereof. This formulation may be free of a paraben, as described in the present invention.

[216] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of monosaccharides and disaccharides, such as sorbitol, mannitol and mixtures thereof. This formulation may be free of a paraben, as described in the present invention.

[217] More particularly, the formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of monosaccharides and disaccharides, such as sorbitol, mannitol and mixtures thereof. This formulation may be free of a paraben, as described in the present invention. Petition 870250089513, dated 10 / 01 / 2025, pages 472 / 568 49 / 123

[218] The formulation of the present invention may be free of, may be essentially free of, or may comprise less than an indicated amount, such as less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2% or less than 0.1% of a polyol, all polyols or any number of polyols selected from the group consisting of glycerin, diglycerin, polyglycerin, diethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,3-propanediol, 1,5-pentanediol, octane-1,2-diol, polyethylene glycols, particularly having from 2 to 50 ethylene oxide groups and sugars such as sorbitol, mannitol and mixtures thereof.The formulation of the present invention may be essentially free of a polyol or any number of polyols selected from the group consisting of glycerin, diglycerin, polyglycerin, diethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,3-propanediol, 1,5-pentanediol, octane-1,2-diol, polyethylene glycols, particularly having from 2 to 50 ethylene oxide groups, and monosaccharides or disaccharides, such as sorbitol, mannitol and mixtures thereof, but may comprise another polyol. The formulation of the present invention may be essentially free of a polyol that is linear or branched. The formulation of the present invention can be essentially free of a polyol having a number of carbon atoms from 2 to 30, more preferably from 2 to 20, even more preferably from 2 to 10 or from 2 to 8, most preferably from 2 to 6 or from 2 to 3.

[219] In particular, the formulation of the present invention may be essentially free of a polyol having a number of carbon atoms from 2 to 8 or from 2 to 6.

[220] The formulation of the present invention may comprise less than or equal to 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of a Petition 870250089513, dated 10 / 01 / 2025, pp. 473 / 568 50 / 123 polyol or no polyol. The polyol may be a polyol as described in the present invention. This formulation may be free of a paraben, as described in the present invention.

[221] The formulation of the present invention may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of a polyol. The polyol may be a polyol as described in the present invention. This formulation may be free of a paraben, as described in the present invention.

[222] The formulation of the present invention may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of a polyol. The polyol may be a polyol as described in the present invention. This formulation may be free of a paraben, as described in the present invention.

[223] The formulation of the present invention may comprise less than or equal to 0.3% or 0.1% w / w of a polyol. The polyol may be a polyol as described in the present invention. This formulation may be free of a paraben, as described in the present invention.

[224] The formulation of the present invention can be essentially free of a polyol.

[225] The formulation of the present inventions may be essentially free of a polyol, as described in the present invention, and of a paraben, preferably free of a polyol and a paraben, as described in the present invention.

[226] The formulation, as described in the present invention, may contain an active agent. The active agent may be present in an amount from 0.0001% to 50% w / w, based on the total weight of the formulation. In particular, the active agent may be present in an amount of 0.001% to 50% w / w, based on the total weight of the formulation, in an amount of 0.01% to 30% w / w, based on the total weight of the formulation, or 0.01% to 10% w / w, based on the total weight. Petition 870250089513, dated 10 / 01 / 2025, pp. 474 / 568 51 / 123 of the formulation.

[227] In formulations where the formulation includes an active agent, the active agent is either Tacrolimus or it is not Tacrolimus.

[228] Tacrolimus (also referred to in the present invention as TC) is a macrolide lactone molecule cultivated from the soil bacterium Streptomyces tsukubaensis. In pharmaceutical medicine, it is described as a calcineurin inhibitor with immunosuppressive capacity. It is applied topically to treat immune-mediated skin conditions such as atopic dermatitis or psoriasis. TC is a molecule with a molecular weight of 804.03 g / mol and highly lipophilic properties (logP > 3), i.e., six orders of magnitude more lipophilic than ALA. Due to its highly lipophilic nature, TC has been formulated in mixtures of mineral oil, paraffin, propylene carbonate, white petrolatum, and white wax. Previously, TC was found to be weakly stable in aqueous formulations (approximately 90 days at room temperature).

[229] Liquid TC formulations in predominantly water-based systems (such as nanoemulsions) have not been commercialized as finished pharmaceutical products by pharmaceutical companies to date, likely hampered by the challenges of solubilizing and stabilizing it in such formulations. With the pharmaceutical use of a topical TC formulation, there are two additional challenges. The first being its high lipophilicity, which can hinder its release from a fat-based formulation into the skin. The other being its poor distribution capacity in the aqueous compartments of the skin (such as living cells).

[230] In preferred embodiments, the active agent is not Tacrolimus. In embodiments where the active agent is not Tacrolimus, the active agent is another active agent, such as, for example, 5-aminolevulinic acid. Petition 870250089513, dated 10 / 01 / 2025, pages 475 / 568 52 / 123

[231] In some embodiments, the active agent is not a highly lipophilic macrolide lactone.

[232] In some embodiments, the active agent is a highly lipophilic macrolide lactone.

[233] In some embodiments, the active agent is not a macrolide lactone having a logP value of 3.0 or higher, where P is the octanol-water partition coefficient.

[234] In some embodiments, the active agent is a macrolide lactone having a logP value of 3.0 or higher, where P is the octanol-water partition coefficient.

[235] In some embodiments, the active agent is not Tacrolimus, Pimecrolimus, Everolimus or Sirolimus, but a derivative, a precursor, a metabolite, a hydrate and / or a pharmaceutically acceptable salt thereof.

[236] In some embodiments, the active agent is Tacrolimus, Pimecrolimus, Everolimus or Sirolimus, a derivative, a precursor, a metabolite, hydrate and / or a pharmaceutically acceptable salt thereof. In some embodiments, the active agent is Tacrolimus, a derivative, a precursor, a metabolite, hydrate and / or a pharmaceutically acceptable salt thereof.

[237] In preferred embodiments, the active agent is a biogenic substance. In the context of this descriptive report, the term “biogenic substance” is a substance that is produced or can be produced by a living organism. For example, 5-aminolevulinic acid is a biogenic substance that is produced by living organisms, including plants, algae, bacteria, fungi, and animals. 5-aminolevulinic acid can also be produced in vitro by chemical synthesis. Because it can be produced by a living organism, 5-aminolevulinic acid is a biogenic substance in the context of this descriptive report, regardless of whether it was produced by Petition 870250089513, dated 10 / 01 / 2025, pp. 476 / 568 53 / 123 chemical synthesis or by a living organism.

[238] As used in the present invention, “active agent” includes an active pharmaceutical agent (also referred to in the present invention as “active pharmaceutical agent” or “active pharmaceutical ingredient”, “API”) and an active cosmetic agent (also referred to in the present invention as “active cosmetic agent”). As used in the present invention, an active pharmaceutical agent is defined as the chemical, biological, mineral or any other entity or component responsible for the therapeutic effects (pharmacological, physiological, physical, etc.) in a product. As used in the present invention, an active cosmetic agent is defined as the chemical, biological, mineral or any other entity or component responsible for the cosmetic effects of a product. The active agent may be a plant extract.

[239] The formulations of the invention provide a very efficient delivery system for a wide variety of active agents. The active agent can be any agent suitable for a pharmaceutical or cosmetic use, as described in the present invention. Examples of active agents that may be useful include, but are not limited to, an anti-infective, an antibiotic, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an immunosuppressant, an immunomodulator, an immunoregulatory agent, a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, a derivative of vitamin C, vitamin D, a derivative of vitamin D, vitamin E, a derivative of vitamin E, vitamin F, a derivative of vitamin F, vitamin K, a vitamin K derivative, a wound-healing agent, a disinfectant, an anesthetic, an anti-allergic agent, an alpha-hydroxy acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a Petition 870250089513, dated 10 / 01 / 2025, pp. 477 / 568 54 / 123 peptide, a neuropeptide, an allergen, an immunogenic substance, a hapten, an oxidizing agent, an antioxidant, a dicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaric acid, a retinoid, an antiproliferative agent, an anticancer agent, a photodynamic therapy agent, an anti-wrinkle agent, a free radical scavenger, a chemical sunscreen, a metal oxide (e.g., titanium dioxide, zinc oxide, zirconium oxide, iron oxide), silicon dioxide, an anti-wrinkle agent, a skin-lightening agent, a skin-protecting agent, a masking agent, an anti-wart agent, and a fat-reducing agent.

[240] The active agent can be a hydrophilic agent, such as 5-aminolevulinic acid, which can be dissolved in the aqueous phase (or aqueous component) and is able to interact with the surface of the nanovesicles. The active agent can also be a hydrophobic agent, such as diclofenac or tacrolimus, which can be dissolved in the lipid phase (or carrier component) and thus be incorporated into the lipid core of the nanovesicles.

[241] Another aspect of the present invention relates to the formulation of the first aspect as described in the present invention, which is a pharmaceutical formulation.

[242] In the formulation, as described in the present invention, in particular in the pharmaceutical formulation, the active agent may be a small organic molecule, for example, with a molecular weight from 50 to 2500 g / mol, preferably from 100 to 1000 g / mol, more preferably from 115 to 950 g / mol, and even more preferably from 130 to 900 g / mol.

[243] The active agent may be present in the form of pharmaceutically and / or cosmetically acceptable salts, such as hydrochloride, phosphates, acetates, sodium and sulfates. The active agent may be present in the form Petition 870250089513, dated 10 / 01 / 2025, pages 478 / 568 55 / 123 of pharmaceutically and / or cosmetically acceptable derivatives or analogues, such as esters, ethers, (methyl-)thioesters, (methyl-)thioethers, methoxy-substituted benzyl ethers, silyl ethers, sulfonates, sulfenates, sulfinates, (cyclic) carbonates, carbamates, cyclic acetals or ketals, (chiral) ketones, hydrazones, enamines and enols. Such derivatives or protecting groups are well known to a person skilled in the art and are not limited to the groups mentioned.

[244] In particular, the formulation of the present invention may comprise or consist of: (a) a nanoemulsion comprising (i) an aqueous component, present in an amount of 60 to 96% w / w, preferably 70 to 95% w / w, based on the total weight of the nanoemulsion (a).

[245] (ii) nanovesicles, comprising (1) 1 to 5% of at least one phospholipid, based on the total weight of the nanoemulsion (a); (2) 2 to 10% of at least one polyoxyethylene type surfactant, based on the total weight of the nanoemulsion (a); (3) 1 to 5% of C3 to C5 alcohol, based on the total weight of the nanoemulsion (a); and (4) 2 to 10% triglycerides, based on the total weight of the nanoemulsion (a); (b) 0.0001 to 50%, preferably 0.001 to 30% of a pharmaceutically active organic molecule with a molecular weight from 100 to 1000 g / mol, preferably from 115 to 950 g / mol and more preferably from 130 to 900 g / mol; (c) optionally 0.5 to 4% of at least one gelling agent, based on the total weight of the formulation; Petition 870250089513, dated 10 / 01 / 2025, pp. 479 / 568 56 / 123 (d) optionally 0.1 to 2% of at least one preservative, based on the total weight of the formulation; and (e) a propellant.

[246] In cases where the active agent is Tacrolimus and / or a pharmaceutically acceptable analogue or derivative thereof, Tacrolimus may be present in an amount from 0.001-5% w / w, based on the total weight of the formulation. In particular, tacrolimus may be present in an amount from 0.01-3% w / w, based on the total weight of the formulation, or 0.05-1% w / w, based on the total weight of the formulation or 0.01-1%, based on the total weight of the formulation.

[247] In cases where the active agent is Tacrolimus, the formulation of the present invention may comprise or consist of: (a) a nanoemulsion comprising (i) an aqueous component, present in an amount of 70 to 95% w / w, based on the total weight of the nanoemulsion (a).

[248] nanovesicles, comprising (1) 1 to 5% of at least one phospholipid, based on the total weight of the nanoemulsion (a); (2) 2 to 10% of at least one polyoxyethylene type surfactant, based on the total weight of the nanoemulsion (a); (3) 1 to 5% C3 to C5 alcohol, based on the total weight of the nanoemulsion (a); and (4) 2 to 10% triglycerides, based on the total weight of the nanoemulsion (a); (b) 0.01 to 1% tacrolimus, based on the total weight of the formulation; (c) optionally 0.5 to 4% of at least one gelling agent, based on the total weight of the formulation; Petition 870250089513, dated 10 / 01 / 2025, pp. 480 / 568 57 / 123 (d) optionally 0.1 to 2% of at least one preservative, based on the total weight of the formulation; and (e) a propellant.

[249] The formulation comprising a pharmaceutically acceptable macrolide lactone, preferably a calcineurin inhibitor, such as tacrolimus and / or a pharmaceutically acceptable analogue or derivative thereof, may contain the aqueous component, at least one phospholipid, at least one polyoxyethylene type surfactant, C3 to C5 alcohol, triglycerides, gelling agent, at least one preservative and propellant selected independently in accordance with the disclosure described in the present invention.

[250] The active agent may be a photosensitizer or a metabolic photosensitizer precursor, such as 5-aminolevulinic acid (also referred to in the present invention as ALA or 5-ALA), a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof. A preferred salt of 5-aminolevulinic acid is 5-aminolevulinic acid hydrochloride.

[251] 5-aminolevulinic acid has the following chemical structure: H2N Molecular Weight: 131.13 g / mol

[252] 5-Aminolevulinic acid and / or a pharmaceutically acceptable salt thereof may be present in an amount from 0.1-30% w / w, based on the total weight of the formulation. In particular, 5-Aminolevulinic acid and / or a pharmaceutically acceptable salt, ester or other derivative Petition 870250089513, dated 10 / 01 / 2025, pp. 481 / 568 58 / 123 pharmaceutically relevant, such as methyl- or hexyl-aminolevulinic acid thereof, may be present in an amount of 1 to 20% w / w, based on the total weight of the formulation, or 1 to 10% w / w, based on the total weight of the formulation.

[253] The active agent may be a non-steroidal anti-inflammatory drug (NSAID), such as Diclofenac, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof.

[254] Diclofenac has the following chemical structure: Molecular Weight: 296.15

[255] Diclofenac and / or a pharmaceutically acceptable salt thereof may be present in an amount from 0.01 to 30% w / w, based on the total weight of the formulation. In particular, diclofenac and / or a pharmaceutically acceptable salt, ester or other pharmaceutically relevant derivative may be present in an amount from 0.1 to 20% w / w, based on the total weight of the formulation, or 0.1 to 10% w / w, based on the total weight of the formulation.

[256] Another aspect of the present invention relates to the formulation of the first aspect as described in the present invention, which is a cosmetic formulation.

[257] In the cosmetic formulation of the present invention, the active agent is a cosmetic active agent. In particular, the cosmetic active agent is selected from plant extracts, natural or synthetic moisturizers, natural or synthetic cleansing agents, natural or synthetic protective agents, natural or synthetic detergents, natural or synthetic antioxidants, natural or synthetic skin conditioning agents and natural or synthetic vitamins. Petition 870250089513, dated 10 / 01 / 2025, pages 482 / 568 59 / 123

[258] Suitable plant extracts include, but are not limited to, extracts obtained from Mahonia root, Matricaria chamomilla, Camellia sinensis, Salvia officinalis (common sage), Achillea millefolium, Hamamelis virginiana, yeast, Glycyrrhiza glabra (licorice), shea (e.g., shea butter), vegetable oils containing squalane, avocado, and Acmella oleracea (main compound: spilanthol), and mixtures thereof. An extract of Salvia officinalis or Mahonia is preferred. Furthermore, the plant extracts disclosed in Faccio, 2020, iScience (https: / / doi.org / 10.1016 / Jjsci.2020.101358), the disclosure of which is incorporated herein by reference, are suitable cosmetic ingredients in the formulation of the present invention.

[259] Suitable cosmetic active agents also include, but are not limited to, berberine (an alkaloid from Mahonia aquifolium, which can also be found in other plants) and α-(-)-bisabolol (a monocyclic sesquiterpene alcohol, which can be found in German chamomile).

[260] The cosmetic formulation of the present invention can be used to moisturize the skin, cleanse the skin, protect from the sun (UV rays) or other external influences, help maintain the skin barrier function, beautify the skin, reduce signs of skin aging and as supportive care for stressed or diseased skin.

[261] In particular, the formulation of the first aspect of the present invention may comprise or consist of: (a) a nanoemulsion comprising (i) an aqueous component, present in an amount of 70% to 95% w / w, based on the total weight of the nanoemulsion (a); (ii) nanovesicles, comprising (1) 1 to 5% of at least one phospholipid, based on the total weight of the nanoemulsion (a); Petition 870250089513, dated 10 / 01 / 2025, pp. 483 / 568 60 / 123 (2) 2 to 10% of at least one polyoxyethylene type surfactant, based on the total weight of the nanoemulsion (a); (3) 1 to 5% C3 to C5 alcohol, based on the total weight of the nanoemulsion (a); and (4) 2 to 10% triglycerides, based on the total weight of the nanoemulsion (a); (b) 1 to 20% of a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid hydrochloride, based on the total weight of the formulation; (c) optionally 0.5 to 4% of at least one gelling agent, based on the total weight of the formulation; (d) optionally 0.1 to 2% of at least one preservative, based on the total weight of the formulation; and (e) a propellant.

[262] The formulation comprising 5-aminolevulinic acid and / or a pharmaceutically acceptable salt thereof, the aqueous component, may contain at least one phospholipid, at least one polyoxyethylene type surfactant, C3 to C5 alcohol, triglycerides, gelling agent, at least one preservative and propellant selected independently in accordance with the disclosure described in the present invention.

[263] The present invention also relates to a nanovesicle comprising (i) 16 to 19% w / w soy lecithin, (ii) 32 to 36% w / w Polysorbate 80, (iii) 32 to 36% w / w caprylic / capric triglycerides and (iv) 12 to 16% w / w isopropyl alcohol.

[264] A preferred nanovesicle of the invention comprises Petition 870250089513, dated 10 / 01 / 2025, pp. 484 / 568 61 / 123 (i) 17% w / w soy lecithin (ii) 34% w / w Polysorbate 80 (iii) 35% w / w caprylic / capric triglycerides (iv) 14% w / w isopropyl alcohol.

[265] The present invention also relates to a nanoemulsion comprising (a) 1.6 to 3.6% w / w soy lecithin (b) 3.3 to 6.9% w / w Polysorbate 80 (c) 3.3 to 7.0% w / w caprylic / capric triglycerides (d) 1.3 to 2.9% w / w isopropyl alcohol (e) aqueous phosphate buffer, for example 5 to 20 mM aqueous phosphate buffer, pH 2 to 8, preferably pH 2 to 7, more preferably pH 3 to 6, up to 100%.

[266] A preferred nanoemulsion of the present invention comprises: (a) 1.7% w / w soy lecithin (b) 3.4% w / w Polysorbate 80 (c) 3.5% w / w caprylic / capric triglycerides (d) 1.4% w / w isopropyl alcohol (e) 10 mM aqueous phosphate buffer, pH 6, ad 100%.

[267] This formulation is referred to as “BF200” in the present invention. The BF200 nanoemulsion can be obtained by contacting a mixture of ingredients (a)-(d) in a total amount of 10% w / w 90% w / w of an aqueous phosphate buffer at 10 mM, pH 6, under conditions that allow the formation of a nanoemulsion, thus forming the nanoemulsion. An exemplary method for manufacturing the BF200 formulation is described in Example 1.

[268] Another preferred nanoemulsion of the present invention comprises: Petition 870250089513, dated 10 / 01 / 2025, pages 485 / 568 62 / 123 (a) 2 to 3% w / w soy lecithin (b) 4.5 to 5.5% w / w Polysorbate 80 (c) 4.5 to 5.5% w / w caprylic / capric triglycerides (d) 2 to 3% w / w isopropyl alcohol (e) 10 mM aqueous phosphate buffer, pH 6, ad 100%.

[269] This formulation is designated BF215 in the present invention. The BF215 nanoemulsion can be obtained by contacting a mixture of ingredients (a)-(d) in a total amount of 15% w / w 85% w / w of an aqueous phosphate buffer at 10 mM, pH 6, under conditions that allow the formation of a nanoemulsion, thus forming the nanoemulsion. An exemplary method for manufacturing the BF215 formulation is described in Example 1.

[270] Yet another preferred nanoemulsion of the present invention comprises: (a) 3 to 4% w / w soy lecithin (b) 6 to 7% w / w Polysorbate 80 (c) 6 to 8% w / w caprylic / capric triglycerides (d) 2 to 4% w / w isopropyl alcohol (e) 10 mM aqueous phosphate buffer, pH 6, ad 100%.

[271] This formulation is designated BF220 in the present invention. The BF220 nanoemulsion can be obtained by contacting a mixture of ingredients (a)-(d) in a total amount of 20% w / w 80% w / w of an aqueous phosphate buffer at 10 mM, pH 6, under conditions that allow the formation of a nanoemulsion, thus forming the nanoemulsion. An exemplary method for manufacturing the BF220 formulation is described in Example 1.

[272] A preferred formulation of the present invention comprises: (1) 17.5% BF200 nanoemulsion, as described in the present invention, Petition 870250089513, dated 10 / 01 / 2025, pages 486 / 568 63 / 123 (2) 0 to 4% w / w Poloxamer 407 (3) 0.1 to 0.3% w / w sodium benzoate (4) 3% w / w 5-ALA hydrochloride (5) water, ad 100% This formulation can have a pH of 2.5 to 3.5.

[273] Another preferred formulation of the present invention comprises: (1) 17.5% BF200 nanoemulsion, as described in this invention, (2) 0 to 4% w / w Poloxamer 407 (3) 0.1 to 0.3% w / w sodium benzoate (4) 3% w / w 5-ALA hydrochloride (5) water, up to 100%.

[274] This formulation can have a pH of 2.5 to 3.5.

[275] Another preferred formulation of the present invention comprises: (1) 35% BF200 nanoemulsion, as described in this invention, (2) 2 to 4% w / w Poloxamer 407 (3) 0.1 to 0.3% w / w sodium benzoate (4) 3% w / w 5-ALA hydrochloride (5) water, up to 100%.

[276] This formulation can have a pH of 2.5 to 3.5.

[277] Another preferred formulation of the present invention comprises: (1) 18 to 20% BF220 nanoemulsion, as described in this invention, (2) 0 to 4% w / w Poloxamer 407 (3) 0.1 to 0.3% w / w sodium benzoate (4) 0.1 to 1% w / w citric acid (5) 0 to 1% w / w EDTA Petition 870250089513, dated 10 / 01 / 2025, pp. 487 / 568 64 / 123 (6) 0 to 1% w / w of α-tocopheryl acetate (7) 0.03, 0.06 or 0.1% w / w of tacrolimus (8) water, ad 100% This formulation can have a pH of 3.0 to 4.0.

[278] Another preferred formulation of the present invention comprises: (1) 18 to 20% BF200 nanoemulsion, as described in this invention, (2) 0 to 4% w / w Poloxamer 407 (3) 0 to 1% xanthan gum (4) 4 to 6% w / w pentylene glycol (5) 0 to 2% w / w aqueous mixture of water, sodium benzoate and sodium sorbate (e.g., Euxyl 712 K) (6) 0 to 1% w / w α-tocopheryl acetate (7) 0 to 1% w / w perfume (8) 0 to 1% w / w D-panthenol (9) 10% propellant (mixture of isobutane, n-butane and propane) (10) 1 to 3% w / w Mahonia extract (11) Water, ad 100%.

[279] This formulation can have a pH of 5.0 to 6.5.

[280] The formulations of the first aspect of the invention comprise the preferred formulations described above and additionally a propellant and are contained in a pressurized container. The formulations of the first aspect of the invention do not essentially comprise any fatty alcohol.

[281] All terms defined with respect to the first aspect of the invention have the same meaning when used with respect to other aspects of the invention, when applicable and unless specifically defined. Petition 870250089513, dated 10 / 01 / 2025, pp. 488 / 568 65 / 123 otherwise. Additionally, all embodiments specified for the first aspect of the invention are also provided for in the other aspects of the invention, where applicable.

[282] Another aspect of the present invention is a formulation, said formulation comprising (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol, (iii) optionally an active agent (1) dissolved in the aqueous phase and capable of interacting with the surface of the nanovesicles, and / or (2) dissolved in the lipid core of the nanovesicles, (b) optionally a gelling agent, wherein the formulation is provided in a container further comprising a propellant, wherein the propellant is provided to pressurize the container. The nanoemulsion (a) is a nanoemulsion as described in the present invention. In contrast to the formulation of the first aspect, in this formulation, the propellant is not defined as an integral component of the formulation. Instead, the formulation is defined as such and the propellant is provided to pressurize the container in which the formulation is comprised.In preferred embodiments, the formulation of this aspect essentially does not comprise any fatty alcohol, preferably essentially no foaming agent. In preferred embodiments, the formulation of this aspect essentially does not comprise any alcohol. Petition 870250089513, dated 10 / 01 / 2025, pages 489 / 568 66 / 123 greasy, preferably essentially no foaming agent. The optional gelling agent (b) is a gelling agent as described in the present invention. The propellant provided for pressurizing the container is a propellant as described in the present invention.

[283] The container may be a container, as described in the present invention, in particular a dispenser, such as a foam dispenser or a spray dispenser, preferably a foam dispenser, as described in the present invention.

[284] The formulation provided in a container can be used in medicine. Medical use can be any medical use as described in the present invention, in particular the treatment and / or prevention of a dermatological disease or condition in an individual, as described in the present invention.

[285] Another aspect of the present invention is a formulation, said formulation comprising (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol, (iii) optionally an active agent (1) dissolved in the aqueous phase and capable of interacting with the surface of the nanovesicles, and / or (2) dissolved in the lipid core of the nanovesicles, (b) optionally a gelling agent, wherein the formulation is prepared as a pressurized formulation, in Petition 870250089513, dated 10 / 01 / 2025, pages 490 / 568 67 / 123 that a propellant is provided to pressurize the formulation. The nanoemulsion (a) is a nanoemulsion as described in the present invention. In contrast to the formulation of the first aspect, in this formulation, the propellant is not defined as an integral component of the formulation. Instead, the formulation is defined as such and the propellant is provided to pressurize the formulation, thus providing a pressurized formulation. In preferred embodiments, the formulation of this aspect essentially comprises no fatty alcohol, preferably essentially no foaming aid. The optional gelling agent (b) is a gelling agent as described in the present invention. The propellant provided to pressurize the container is a propellant as described in the present invention.

[286] The pressurized formulation can be used in medicine. Medical use can be any medical use as described in the present invention, in particular the treatment and / or prevention of a dermatological disease or condition in an individual, as described in the present invention.

[287] Another aspect of the present invention relates to a formulation that is defined as the formulation of the first aspect of the invention, but may comprise a fatty alcohol or other foaming agent.

[288] A second aspect of the invention relates to a method for stabilizing a nanoemulsion, comprising the following steps: (a) providing a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introducing the nanoemulsion into a container; and (c) adding a propellant to the container to pressurize the container.

[289] This aspect is based on the surprising discovery that the stability of a nanoemulsion can be significantly increased. Petition 870250089513, dated 10 / 01 / 2025, pp. 491 / 568 68 / 123 when the nanoemulsion is stored together with a propellant in a pressurized container, compared to storage in another receptacle, such as a glass bottle. The overall increase in stability does not depend on the presence of a gelling agent. The increase in stability is particularly noticeable under stress conditions, such as storage at elevated temperatures.

[290] A person skilled in the art is aware of suitable methods for filling a container of the nanoemulsion or of the formulation comprising the nanoemulsion and the propellant to obtain a pressurized container comprising the nanoemulsion or the formulation comprising the nanoemulsion and the propellant. In preferred embodiments, the propellant is added to the container comprising the nanoemulsion or to the formulation comprising the nanoemulsion by means of a valve.

[291] The method also provides stabilization of a nanoemulsion formulation, that is, a formulation comprising a nanoemulsion and additionally an active agent and / or an additional aqueous component, such as water, a buffer or a gelling agent. Thus, in some embodiments, the method of the second aspect is a method for stabilizing a formulation comprising a nanoemulsion. In embodiments where the nanoemulsion formulation comprises an active agent, the active agent is also stabilized, that is, the concentration of the active agent remains stable, even under stress conditions.

[292] In this second aspect, the nanoemulsion is a nanoemulsion as defined in relation to the first aspect. In this second aspect, the formulation comprising the nanoemulsion corresponds to the formulation as defined in relation to the first aspect, with the difference that the formulation does not comprise a propellant (the propellant is supplied in the step Petition 870250089513, dated 10 / 01 / 2025, pages 492 / 568 69 / 123 (c)) and that the formulation comprising the nanoemulsion may comprise a fatty alcohol or other foaming aid. In preferred embodiments, the formulation comprising the nanoemulsion essentially does not comprise any fatty alcohol, preferably essentially no foaming aid. In preferred embodiments, the formulation comprising the nanoemulsion essentially does not comprise any gelling agent.

[293] In preferred embodiments, the nanovesicles comprised in the nanoemulsion have a stable size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, nine months, twelve months, eighteen months, twenty-four months, thirty-six months or at least one month, at least two months, at least three months, at least six months, at least nine months, at least twelve months, at least eighteen months or at least twenty-four months at 4 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in the pressurized container. Preferably, the size is determined by dynamic light scattering.

[294] In preferred embodiments, the nanoemulsion is characterized by a stable polydispersity index less than or equal to 0.4 and / or 0.3, when stored for one month, two months, three months, six months, nine months, twelve months, eighteen months, twenty-four months, thirty-six months or at least one month, at least two months, at least three months, at least six months, at least nine months, at least twelve months, at least eighteen months or at least twenty-four months at 4 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in the pressurized container. Preferably, the polydispersity index is determined by dynamic light scattering.

[295] A third aspect of the invention relates to the use of a nanoemulsion for the preparation of a foam, comprising the following Petition 870250089513, dated 10 / 01 / 2025, pp. 493 / 568 70 / 123 steps: (a) provide a formulation comprising a nanoemulsion, the nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introduce the formulation comprising the nanoemulsion into a container; (c) add a propellant to the container to pressurize the container; and (d) release a foam from the pressurized container. The foam comprises the nanoemulsion.

[296] This third aspect is based on the surprising discovery that a stable foam can be prepared from a formulation comprising a nanoemulsion that is contained in a pressurized container, even in the absence of a fatty alcohol or other foaming aid.

[297] The foam is characterized by high stability and a long collapse time. For example, the collapse time is at least 8 minutes, at least 9 minutes or at least 10 minutes at temperatures below 40 °C, for example, at 25 °C or 36 °C.

[298] In addition to this, this third aspect is based on the surprising discovery that the stability of a nanoemulsion can be significantly increased when the nanoemulsion is stored together with a propellant in a pressurized container, compared to storage in another receptacle, such as a glass bottle, even in the absence of a fatty alcohol or other foaming adjuvant.

[299] In embodiments where the nanoemulsion formulation comprises an active agent, the active agent is also stabilized, that is, the concentration of the active agent remains stable, even under stress conditions.

[300] In this third aspect, the nanoemulsion is a nanoemulsion Petition 870250089513, dated 10 / 01 / 2025, pages 494 / 568 71 / 123 as defined in relation to the first aspect. In this third aspect, the formulation comprising the nanoemulsion corresponds to the formulation as defined in relation to the first aspect, with the difference that the formulation does not comprise a propellant (the propellant is provided in step (c)) and that the formulation comprising the nanoemulsion may comprise a fatty alcohol or other foaming aid. In preferred embodiments, the formulation comprising the nanoemulsion essentially does not comprise any fatty alcohol, preferably essentially no foaming aid. In preferred embodiments, the formulation comprising the nanoemulsion essentially does not comprise any gelling agent.

[301] Yet another aspect of the present invention is a method for preparing the formulation of the first aspect of the present invention, comprising the following steps: (a) mix at least one lipophilic component, at least one surfactant and at least one alcohol, (b) bring the mixture obtained in step (a) into contact with an aqueous component, under conditions that allow the formation of a nanoemulsion, (c) introduce the formulation obtained in steps (c) into the container, and (d) add a propellant to the container to pressurize the container.

[302] The method may include a step of adding an active agent.

[303] In step (b), the conditions that allow the formation of the nanoemulsion may include mixing both phases at an appropriate temperature and stirring so as to form nanovesicles. A person skilled in the art knows the appropriate temperature and stirring conditions. A vesicle size less than or equal to 500 nm or less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm, can be obtained. In Petition 870250089513, dated 10 / 01 / 2025, pp. 495 / 568 72 / 123 In particular, the preparation of the nanoemulsion of the present invention according to step (b) can be prepared without the use of high-energy methods, which are well known in the state of the art. The high-energy method includes high-pressure homogenization, microfluidization, and ultrasonication (Prev Nutr Food Sci. September 2019; 24(3): 225-234).

[304] In some embodiments, the container is composed of a dispenser, such as a foam dispenser or a spray dispenser, preferably a foam dispenser. In other words, the container may be part of a dispenser.

[305] The dispenser may be any suitable dispenser. Examples of a foam dispenser and a spray dispenser are shown in Fig. 1. Suitable dispensers are known to those skilled in the art. The container may be any suitable container capable of being pressurized. Suitable containers are known to those skilled in the art.

[306] The active agent can be added in step (a), or it can be added to the aqueous component before contacting the mixture obtained in step (a) with an aqueous component in step (b), or it can be added to the nanoemulsion obtained in step (b).

[307] The conditions that allow interactions of the active agent with the surface of the nanovesicles when dissolved in the aqueous phase and / or dissolution of the active agent in the lipid core of the nanovesicles may depend on the hydrophilicity or lipophilicity of the active agent.

[308] A hydrophilic compound, such as an amino acid, preferably a photosensitizer or a metabolic precursor, such as ALA, and / or a pharmaceutically acceptable salt thereof (such as ALA hydrochloride) or acceptable derivative (such as Methyl-ALA), may be added to the aqueous component before bringing the mixture obtained in step (a) into contact. Petition 870250089513, dated 10 / 01 / 2025, pages 496 / 568 73 / 123 with an aqueous component in step (b), so that the active agent is dissolved in the aqueous phase and able to interact with the nanovesicles (in particular with the nanovesicle surface) in step (b).

[309] A hydrophilic compound, such as an amino acid, preferably a photosensitizer or a metabolic precursor, such as ALA, and / or a pharmaceutically acceptable salt thereof (such as ALA hydrochloride) or acceptable derivative (such as Methyl-ALA), may also be added to the nanoemulsion obtained in step (b), so that the active agent is dissolved in the aqueous phase and able to interact with the nanovesicles (in particular with the nanovesicle surface).

[310] A lipophilic compound, such as a pharmaceutically acceptable macrolide lactone, preferably a calcineurin inhibitor, such as tacrolimus, or / and a pharmaceutically acceptable derivative, may be added in step (a), so that the active agent is dissolved in the lipid core of the nanovesicles.

[311] The method for preparing the formulation of the present invention may further comprise: (i) add a gelling agent and / or (ii) add a preservative.

[312] A fourth aspect of the invention relates to a container or a dispensing product comprising a container, comprising a formulation, wherein said formulation comprises a nanoemulsion comprising (i) at least one aqueous component; (ii) a carrier component comprising (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; and (b) a propellant, wherein the formulation essentially does not comprise any emollient, essentially any fatty alcohol, preferably essentially Petition 870250089513, dated 10 / 01 / 2025, pages 497 / 568 74 / 123 no foaming agent and / or essentially no gelling agent; and wherein the container further comprises a propellant, wherein the propellant is provided to pressurize the container.

[313] In preferred embodiments, the dispensing product is a foam dispenser or a spray dispenser, preferably a foam dispenser. The dispensing product comprises a container containing the formulation and a pressurized propellant, and a foam generating device mounted on the container. Said foam generating device may comprise a valve for releasing and dispensing the formulation and a push button for actuating the valve. By actuating the push button, the formulation can be released and can form a foam. Examples of dispensers are shown in Fig. 1. Suitable dispensers are known to those skilled in the art.

[314] A fifth aspect of the invention relates to a foam obtained from the formulation of the first aspect.

[315] The foam comprises the formulation as described in the present invention. The foam is formed by releasing the formulation from a suitable pressurized device, for example, from the foam dispensing product as described in the present invention.

[316] Surprisingly, the inventors discovered that the nanoemulsion foam, obtained from the formulation of the invention, has a collapse time of at least 10 minutes at room temperature, without any foaming agents, after the formulation contained in a pressurized container has been subjected to stress conditions, such as freeze-thaw cycles or storage at elevated temperatures (40 °C). As used in the present invention, the collapse time is the time for the foam to collapse to half its initial foam volume. Petition 870250089513, dated 10 / 01 / 2025, pages 498 / 568 75 / 123 by release. The nanoemulsion foam described in the present invention does not require any foaming agent to form a stable foam by release, but breaks down under shear force. Furthermore, it has been found that with a higher lipophilic content (e.g., 20% lipid content), the foam described in the present invention has a collapse time of at least 8 min at 36 °C (skin temperature). It is preferable that the formulation of the invention has a collapse time of at least 8 minutes or at least 10 minutes at room temperature, for example 20 to 25 °C.

[317] A sixth aspect of the invention relates to a cosmetic use of the formulation of the first aspect or the foam of the fifth aspect.

[318] In this respect, the formulation comprises a cosmetic agent, as described in this invention. A seventh aspect of the invention relates to the formulation of the first aspect or to the foam of the fifth aspect for use in medicine.

[319] In preferred embodiments, the formulation or foam is provided for use in a method of treating and / or preventing a dermatological disease or condition in an individual.

[320] Treatment and / or prevention of dermatological disease or condition may include: (a) administering topically to the individual a pharmaceutically effective amount of the formulation comprising a pharmaceutically acceptable macrolide lactone, preferably a calcineurin inhibitor such as tacrolimus, a derivative, precursor, analogue and / or metabolite thereof, as described in the present invention, to a diseased or affected area and an area around the diseased or affected area of ​​skin, wherein the formulation forms a foam, and (b) optionally incubating the pharmaceutical formulation on the skin of Petition 870250089513, dated 10 / 01 / 2025, pages 499 / 568 76 / 123 individual with or without occlusion of the skin area to which the formulation was administered, occlusion preferably performed using polyethylene or low-density polyurethane film, to enhance penetration into deep tissue layers.

[321] The treatment and / or prevention of dermatological disease or condition may also include: (a) administering topically to the individual a pharmaceutically effective amount of the formulation comprising a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof, as described in the present invention, to a diseased or affected area and, optionally, an area around the diseased or affected area of ​​skin, wherein the formulation forms a foam, and (b) optionally incubating the pharmaceutical formulation on the individual's skin with or without occlusion of the skin area to which the formulation was administered, the occlusion preferably performed using low-density polyethylene or polyurethane film, to enhance penetration into deep tissue layers.

[322] The treatment and / or prevention of dermatological disease or condition may also include: (a) to administer topically to the individual a pharmaceutically effective amount of the formulation comprising a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof, as described in the present invention, to a diseased or affected area and, optionally, an area around the diseased or affected area of ​​skin, wherein the formulation forms a foam, and Petition 870250089513, dated 10 / 01 / 2025, pages 500 / 568 77 / 123 (b) optionally incubate the pharmaceutical formulation on the individual's skin with or without occlusion of the skin area to which the formulation was administered, occlusion preferably performed using low-density polyethylene or polyurethane film, to enhance penetration into deep tissue layers, and (c) irradiate the skin area to which the formulation was administered with light.

[323] The light spectrum used for irradiation in step (c) may be compatible with the absorption spectrum of a fluorescent porphyrin. For example, the light spectrum may be compatible with the absorption peaks of protoporphyrin IX. In particular, the light used for irradiation in step (c) may comprise any visible wavelength in the range of 380 nm to 780 nm, preferably with equal irradiance throughout the range or irradiance peak(s) around 410 and / or 505 and / or 542 and / or 575 and / or 635 nm. The wavelength spectrum may be essentially free of radiation with wavelengths less than 380 nm and / or greater than 780 nm. In particular, the light used for irradiation in step (c) may comprise any visible wavelength in the range of 380 to 440 nm and / or 580 to 650 nm. The light used for irradiation in step (c) may additionally be capable of inducing red fluorescence of accumulated porphyrins.

[324] The light used in step (c) may be red light, blue light, green light and / or violet light, preferably red light and / or violet light, more preferably wherein (a) red light results in a radiant exposure of 10 to 75 J / cm2, preferably 25 to 45 J / cm2; and / or violet light results in a radiant exposure of 1 to 30 J / cm2, preferably 5 to 15 J / cm2.

[325] Irradiation in step (c) can be carried out with artificial light, sunlight and / or daylight or with an artificial light source that emits light with a wavelength spectrum and, preferably, also irradiance Petition 870250089513, dated 10 / 01 / 2025, pp. 501 / 568 78 / 123 similar or identical to sunlight. Light with a wavelength spectrum and, preferably, irradiance similar or identical to sunlight may have a wavelength spectrum from 100 nm to 1000 nm, a wavelength spectrum from 380 nm to 780 nm, preferably with equal irradiance throughout the range or irradiance peak(s) around 410 and / or 505 and / or 635 nm, or a wavelength spectrum from 570 nm to 650 nm or 570 nm to 630 nm, and / or a wavelength spectrum from 380 nm to 440 nm. Artificial light may be provided by an LED. A suitable device providing artificial light is described, for example, in U.S. Patent No. 11235169 B1 and U.S. Patent No. 11219781 B2, the disclosure of which is incorporated into the present invention by reference.

[326] The area around the diseased or affected area of ​​skin may include an unaffected surrounding area, to ensure that the diseased or affected area is adequately treated in the peripheral diseased or affected areas. For example, the area around the diseased or affected area of ​​skin may include an area at least about 5 mm wide.

[327] The dermatological disease or condition to be treated with the pharmaceutical formulation, as described in this invention, may include, but is not limited to, diseases or conditions of the skin, skin appendages or mucous membranes.

[328] The dermatological disease or condition to be treated with the pharmaceutical formulation, as described in the present invention, may be selected from the group consisting of inflammatory, neoplastic, proliferative, infectious and / or autoimmune diseases or conditions, and / or the cutaneous manifestation thereof, and / or diseases associated with single lesions or fields of lesions, neoplastic, proliferative and / or inflammatory changes.

[329] The inflammatory dermatological disease or condition to be treated with Petition 870250089513, dated 10 / 01 / 2025, pages 502 / 568 79 / 123 The pharmaceutical formulation, as described in the present invention, may be selected from the group consisting of dermatitis, contact dermatitis, acne, atopic dermatitis, eczema, pustular dermatitis, seborrheic dermatitis, perioral dermatitis, chronic wound, urticaria, skin ulcer, rosacea, rash, drug eruptions, toxic epidermal necrolysis; erythema multiforme, erythema nodosum, granuloma annulare and other cutaneous manifestations of inflammation.

[330] The neoplastic and / or proliferative dermatological disease or condition to be treated with the pharmaceutical formulation, as described in the present invention, may be selected from the group consisting of basal cell carcinoma, preferably superficial basal cell carcinoma or nodular basal cell carcinoma; squamous cell carcinoma, preferably Bowen's disease or invasive squamous cell carcinoma; vulvar intraepithelial neoplasia (VIN); cutaneous T-cell lymphoma; Merkel cell carcinoma; hemangioma; a nodular or subcutaneous cancerous disease; field cancerization; non-melanoma skin cancer in organ transplant recipients; and prevention of non-melanoma skin cancer in organ transplant recipients.

[331] The infectious dermatological disease or condition to be treated with the pharmaceutical formulation, as described in the present invention, may be selected from the group consisting of bacterial infections, viral infections, fungal infections, parasitic infections and combinations thereof.

[332] The autoimmune dermatological disease or condition, or the cutaneous manifestation of the autoimmune condition to be treated with the pharmaceutical formulation, as described in the present invention, may be selected from the group consisting of psoriasis, pemphigus, systemic lupus erythematosus, lichen planus, morphea, scleroderma, epidermolysis bullosa, dermatomyositis, syndrome of Petition 870250089513, dated 10 / 01 / 2025, pages 503 / 568 80 / 123 graft versus host.

[333] The dermatological disease or condition to be treated with the pharmaceutical formulation, as described in the present invention, may be selected from the group consisting of sweating disorders, pigmentation disorders including hypopigmentation, such as vitiligo, albinism and post-inflammatory hypopigmentation and hyperpigmentation, such as melasma, reactions to sunlight, such as sunburn, skin aging, photosensitivity, disorders of hair follicles and sebaceous glands, such as hypertrichosis, alopecia, male pattern baldness.

[334] The formulation, as described in the present invention, in particular a pharmaceutical composition comprising a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof, as described in the present invention, can be used in a photodynamic diagnostic method of a neoplastic and / or proliferative dermatological disease or condition, such as benign or malignant neoplasia or precursors thereof; an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation, such as acne.

[335] The formulation, as described in the present invention, in particular a pharmaceutical composition comprising (a) a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof, or (b) a pharmaceutically acceptable macrolide lactone, preferably a calcineurin inhibitor, such as tacrolimus, a derivative, precursor and / or metabolite thereof, Petition 870250089513, dated 10 / 01 / 2025, pages 504 / 568 81 / 123 can be used in the treatment of a disease or condition, as described in the present invention, for example, neoplastic and / or proliferative dermatological diseases or conditions, such as benign or malignant skin neoplasms or precursors thereof, inflammatory dermatological diseases or conditions, such as atopic dermatitis, eczema, psoriasis, rosacea or chronic wounds, and conditions associated with bacterial proliferation, such as acne.

[336] Yet another aspect of the present invention is the use of the formulation of the present invention, as described in the present invention, for the manufacture of a medicament for the treatment and / or prevention of a dermatological disease or condition in an individual. In particular, the dermatological disease is a dermatological disease or condition, as described in the present invention.

[337] Yet another aspect of the present invention is a method of treating and / or preventing a dermatological disease or condition in an individual, said method comprising administering to the individual a pharmaceutically effective amount of the formulation as described in the present invention. In particular, the dermatological disease is a dermatological disease or condition as described in this invention.

[338] Yet another aspect of the present invention is a photodynamic diagnostic method for a neoplastic and / or proliferative dermatological disease or condition, such as benign or malignant neoplasia or precursors thereof; an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation, such as acne.

[339] Drugs containing ALA (and derivatives) stimulate the synthesis of fluorescent porphyrins that accumulate preferentially in cells / tissues with increased metabolic activity. This can be exploited in the method of Petition 870250089513, dated 10 / 01 / 2025, pages 505 / 568 82 / 123 Photodynamic diagnosis, which can be applied to neoplastic skin diseases, such as benign or malignant neoplasms or their precursors, inflammatory conditions, or conditions associated with bacterial proliferation, such as acne. For photodynamic diagnosis, a formulation containing ALA (or derivative) is applied to the area of ​​skin to be diagnosed and incubated for an appropriate time. Subsequently, blue spectrum light is applied to induce red fluorescence of accumulated porphyrins. The fluorescence can be detected by visual inspection or appropriate technical devices for qualitative or quantitative evaluation.

[340] The photodynamic diagnostic method may include: (i) administering the formulation comprising a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof, as described in the present invention, to the area of ​​skin to be diagnosed, under conditions that permit the synthesis of fluorescent porphyrins in the cells and / or tissues, and (ii) irradiating the area of ​​skin to which the formulation was administered, under conditions that induce fluorescence of the accumulated porphyrins, wherein the increase in porphyrin fluorescence indicates increased metabolic activity, being indicative of a neoplastic and / or proliferative dermatological disease or condition, an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation.

[341] In step (i), a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof may be incubated on the skin for an appropriate duration. Petition 870250089513, dated 10 / 01 / 2025, pp. 506 / 568 83 / 123

[342] In step (ii), the skin can be irradiated with light capable of inducing red fluorescence of accumulated porphyrins. Suitable irradiation conditions are described in the present invention.

[343] The diagnosis of neoplastic and / or proliferative dermatological disease or condition can be performed by detecting increased fluorescence (e.g., in comparison with healthy tissue and / or skin, for example, adjacent to the suspected area). Fluorescence detection can be performed by visual inspection or appropriate technical devices for qualitative or quantitative assessment.

[344] Diagnosis according to the method described in the present invention can be performed for tumor border demarcation to assist in surgery, to evaluate treatment efficacy and / or the evaluation of light-induced photobleaching for light dosimetry in photodynamic therapy.

[345] Yet another aspect of the present invention is a method of cosmetic treatment and / or prevention of a dermatological condition in an individual, said method comprising administering to the individual an effective amount of the formulation as described in the present invention. In particular, cosmetic treatment and / or prevention may include moisturizing the skin, cleansing the skin, protecting the skin from the sun (UV rays) or other external influences, helping to maintain the skin barrier function, beautifying the skin, reducing signs of skin aging, and as supportive care for stressed or diseased skin.

[346] The invention also belongs to the following embodiments: 1. A formulation comprising: (a) a nanoemulsion comprising: (i) at least one aqueous component; Petition 870250089513, dated 10 / 01 / 2025, pages 507 / 568 84 / 123 (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; and (b) a propellant, wherein the formulation is comprised in a pressurized container and wherein the formulation does not essentially comprise any fatty alcohol.

[347] 2. The formulation of embodiment 1, in which the formulation essentially does not comprise any fatty acid.

[348] 3. The formulation of embodiment 1 or 2, preferably 2, in which the formulation essentially does not comprise any gelling agent.

[349] 4. A formulation of any of the embodiments 1 to 3, preferably 3, wherein the formulation essentially does not comprise any emollient selected from a monoester or diester comprising an alcohol and a fatty acid.

[350] 5. The formulation of either embodiment 1 or 2, preferably 2, wherein the formulation comprises a gelling agent, wherein the gelling agent is present in an amount of 0.1% to 10% (w / w) based on the total weight of the formulation.

[351] 6. The formulation of embodiment 5, in which the gelling agent is a poloxamer, wherein the poloxamer is present in an amount of 0.5% to 4% (w / w) based on the total weight of the formulation.

[352] 7. The formulation of embodiment 6, in which at least one lipophilic component is present in an amount of 10% to 30% (w / w), preferably 15% to 30% (w / w) and more preferably 20% to 30% (w / w) based on the total weight of the nanoemulsion (a). Petition 870250089513, dated 10 / 01 / 2025, pp. 508 / 568 85 / 123

[353] 8. The formulation of any of the embodiments 1 to 7, in which the nanoemulsion a. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months or thirty-six months, at 2 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in the pressurized container; and / or b. is characterized by a polydispersity index less than or equal to 0.4, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months or thirty-six months, at 2 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in a pressurized container; and / or c. comprises nanovesicles with a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months or thirty-six months, at 2 to 25 °C, at 10 to 25 °C, at 15 to 25 °C, at 2 to 8 °C, at 5 °C or at 25 °C in the pressurized container; and / or d. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when subjected to 1, 2, 3, 4, 5 or more freeze-thaw cycles; and / or (e.) is characterized by a polydispersity index less than or equal to 0.4 when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, or thirty-six months at 2 to 25 °C, 10 to 25 °C, 15 to 25 °C, 2 to 8 °C, 5 °C, or 25 °C in a pressurized container; and / or f. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored by a Petition 870250089513, dated 10 / 01 / 2025, pp. 509 / 568 86 / 123 month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, thirty-six months or forty-eight months at 2 to 8 °C or at 5 °C in the pressurized container; and / or g. is characterized by a polydispersity index less than or equal to 0.4, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, thirty-six months or forty-eight months at 2 to 8 °C or at 5 °C in the pressurized container and / or h. is characterized by a polydispersity index less than or equal to 0.4 when subjected to 1, 2, 3, 4, 5 or more freeze-thaw cycles.

[354] 9. The formulation of any of the modalities 1 to 8, comprising an active agent.

[355] 10. The formulation of embodiment 9, in which the active agent is 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof.

[356] 11. The formulation of any of the modalities 1 to 10, in which - at least one lipophilic component is selected from triglycerides and mixtures thereof; - at least one surfactant is selected from the group consisting of a phospholipid, a lysophospholipid, a ceramide and / or a mixture thereof, and / or at least one surfactant is a polyoxyethylene type surfactant; - at least one alcohol has 3 to 5 carbon atoms; and / or The propellant is propane, isobutane, or n-butane, or a mixture thereof.

[357] 12. The formulation of any of the embodiments 1 to 11, comprising a total aqueous component in an amount from Petition 870250089513, dated 10 / 01 / 2025, pages 510 / 568 87 / 123 50% to 99% (p / p).

[358] 13. The formulation of embodiment 5, in which the gelling agent is selected from the group consisting of poloxamer, xanthan gum, bentonite, sodium carboxymethylcellulose, hydroxymethylcellulose, carbomer, hydroxypropylcellulose, gellan gum, guar gum, pectin, poly(ethylene) oxide, polycarbophil, alginate, tragacanth, povidone, gelatin and mixtures thereof.

[359] 14. Method for stabilizing a nanoemulsion, comprising the following steps: (a) provide a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introduce the nanoemulsion into a container; and (c) add a propellant to the container to pressurize the container and / or the nanoemulsion in the container.

[360] 15. The method of modality 14, in which the nanoemulsion a. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months or thirty-six months, at 2 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in the pressurized container; and / or b. is characterized by a polydispersity index less than or equal to 0.4, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months or thirty-six months, at 2 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in the container Petition 870250089513, dated 10 / 01 / 2025, pp. 511 / 568 88 / 123 pressurized; and / or c. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, twelve months, 18 months, 24 months or 36 months at 2 to 25 °C, at 10 to 25 °C, at 15 to 25 °C, at 2 to 8 °C, at 5 °C or at 25 °C in the pressurized container; and / or d. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when subjected to 1, 2, 3, 4, 5 or more freeze-thaw cycles; and / or (e.) is characterized by a polydispersity index less than or equal to 0.4 when stored for one month, two months, three months, six months, twelve months, 18 months, 24 months, or 36 months at 2 to 25 °C, 10 to 25 °C, 15 to 25 °C, 2 to 8 °C, 5 °C, or 25 °C in a pressurized container; and / or f. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, thirty-six months or forty-eight months, at 2 to 8 °C or at 5 °C in the pressurized container; and / or g. is characterized by a polydispersity index less than or equal to 0.4, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, thirty-six months or forty-eight months, at 2 to 8 °C or at 5 °C in the pressurized container and / or h. is characterized by a polydispersity index less than or equal to 0.4 when subjected to 1, 2, 3, 4, 5 or more freeze-thaw cycles.

[361] 16. Use of a nanoemulsion for the preparation of a foam or a spray, comprising the following steps: Petition 870250089513, dated 10 / 01 / 2025, pp. 512 / 568 89 / 123 (a) provide a formulation comprising a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introducing the formulation comprising a nanoemulsion into a container; and (c) adding a propellant to the container to pressurize the container; and (d) releasing a foam or spray from the pressurized container.

[362] 17. A container or a foam dispensing or spray dispensing product comprising a container, comprising the formulation of any of the embodiments 1 to 13.

[363] 18. A foam obtained from the formulation of any of the embodiments 1 to 13.

[364] 19. Cosmetic use of the formulation of any of the modalities 1 to 13.

[365] 20. A method of treating a dermatological disease or condition, comprising administering an effective amount of the formulation of modality 9 to an individual who needs it.

[366] The invention also belongs to the following items: 1. A formulation comprising: (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, Petition 870250089513, dated 10 / 01 / 2025, pages 513 / 568 90 / 123 (2) at least one surfactant and (3) at least one alcohol; and (b) a propellant, wherein the formulation is comprised in a pressurized container and wherein the formulation essentially comprises no fatty alcohol, preferably essentially no fatty alcohol and no fatty acid.

[367] 2. The formulation of item 1, in which the formulation does not essentially comprise any foaming agent.

[368] 3. The formulation of any of the preceding items, wherein the formulation does not essentially comprise any emollient.

[369] 4. Formulation items wherein the formulation does not essentially comprise any emollient selected from a monoester or diester of an alcohol and a fatty acid.

[370] 5. The formulation of any of the preceding items, wherein the formulation does not essentially comprise any gelling agent.

[371] 6. The formulation of any of the preceding items, wherein the nanoemulsion comprises nanovesicles comprising the carrier component.

[372] 7. The formulation of item 6, wherein the nanovesicles have a stable size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm when stored for one, two, three, six, nine, twelve, eighteen, twenty-four or at least thirty-six months at 40 °C in a pressurized container.

[373] 8. The formulation of any of the above items, in which the total aqueous component is present in an amount of 50% to 99% w / w, Petition 870250089513, dated 10 / 01 / 2025, pp. 514 / 568 91 / 123 preferably 70% to 95% (w / w) and more preferably 75% to 95% (w / w), based on the total weight of the nanoemulsion (a).

[374] 9. The formulation of any of the above items, wherein the aqueous component comprises at least one pH buffering agent, preferably wherein the at least one pH buffering agent is selected from the group consisting of citrate, phosphate, acetate and carbonate.

[375] 10. The formulation of any of the above items, in which at least one lipophilic component is selected from triglycerides and mixtures thereof, preferably in which at least one lipophilic component is a caprylic and / or capric triglyceride or a mixture thereof.

[376] 11. The formulation of any of the preceding items, in which at least one lipophilic component is present in an amount from 0.1% to 30% (w / w), preferably from 0.25% to 15% (w / w), preferably from 0.25% to 10% (w / w) and more preferably from 0.5% to 8% (w / w) or 3% to 8% (w / w), based on the total weight of the nanoemulsion (a).

[377] 12. The formulation of any of the preceding items, in which at least one surfactant is selected from the group consisting of a phospholipid, a lysophospholipid, a ceramide and / or a mixture thereof, and / or at least one surfactant is a polyoxyethylene type surfactant.

[378] 13. The formulation of any of the above items, in which at least one surfactant is lecithin, preferably soy lecithin, preferably in which the lecithin has a phosphatidylcholine content of at least 80% by weight.

[379] 14. The formulation of item 12, in which phospholipid, lysophospholipid, ceramide and / or a mixture thereof are present in a Petition 870250089513, dated 10 / 01 / 2025, pp. 515 / 568 92 / 123 quantity from 1% to 10% (w / w), preferably from 1.25% to 5% (w / w) and more preferably from 1.5% to 4% (w / w), most preferably from 1.5% to 2% (w / w) based on the total weight of the nanoemulsion (a), or from 0.1% to 10% (w / w), preferably from 0.15% to 5% (w / w), more preferably from 0.2% to 3% (w / w) or from 0.2% to 4% (w / w), most preferably from 0.2% to 0.4% (w / w) based on the total weight of the formulation.

[380] 15. The formulation of item 12, in which the polyoxyethylene type surfactant is Polysorbate 80.

[381] 16. The formulation of either item 12 or 15, in which the polyoxyethylene type surfactant is present in an amount from 1% to 10% (w / w), more preferably from 2% to 8% (w / w) and most preferably from 3% to 7% (w / w), based on the total weight of the nanoemulsion (a).

[382] 17. The formulation of any of the above items, in which at least one alcohol is selected from the group consisting of 1-propanol or 2-propanol and mixtures thereof.

[383] 18. The formulation of any of the preceding items, in which alcohol is present in an amount from 0.1% to 10% w / w, preferably from 0.5% to 5% (w / w) and more preferably from 1% to 3% (w / w), based on the total weight of the nanoemulsion (a).

[384] 19. The formulation of any of the preceding items, wherein the propellant is propane, isobutane or n-butane or a mixture thereof, preferably the propellant is a mixture of propane and isobutane.

[385] 20. The formulation of any of items 1 to 4 or 6 to 19, comprising a gelling agent.

[386] 21. The formulation of item 20, in which the gelling agent is Petition 870250089513, dated 10 / 01 / 2025, pp. 516 / 568 93 / 123 selected from the group consisting of poloxamer, xanthan gum, bentonite, sodium carboxymethylcellulose, hydroxymethylcellulose, carbomer, hydroxypropylcellulose, gellan gum, guar gum, pectin, poly(ethylene) oxide, polycarbophil, alginate, tragacanth, povidone, gelatin and mixtures thereof.

[387] 22. The formulation of item 20 or 21, in which the gelling agent is selected from poloxamer, xanthan and / or mixtures thereof.

[388] 23. The formulation of any of items 20 to 22, in which the gelling agent is present in an amount from 0.1% to 10% w / w, preferably from 0.25% to 5% (w / w) and more preferably from 0.5% to 4% (w / w), based on the total weight of the formulation.

[389] 24. The formulation of any of items 20 to 23, wherein the nanoemulsion comprises nanovesicles comprising the carrier component, and wherein the nanovesicles have a stable size less than or equal to 300 nm, preferably in the range of 5 nm to 200 nm, when stored at -15 °C to -25 °C, preferably at -24 °C, for 4 days in a pressurized container, wherein the size is determined by dynamic light scattering.

[390] 25. The formulation of any of the above items, comprising a preservative, preferably wherein the preservative is selected from benzoate, citric acid, EDTA, potassium sorbate, wherein the preservative is preferably sodium benzoate.

[391] 26. The formulation of item 23 or 24, in which the preservative is present in an amount from 0.01% to 3% w / w, preferably from 0.2% to 2% (w / w) or 0.1% to 2% (w / w), and more preferably from 0.2% to 1.5% (w / w), based on the total weight of the formulation.

[392] 27. The wording of any of the above items, which is essentially paraben-free. Petition 870250089513, dated 10 / 01 / 2025, pp. 517 / 568 94 / 123

[393] 28. The formulation of any of the preceding items, characterized by a polydispersity index less than or equal to one of the following values ​​0.4 or 0.3, wherein the polydispersity index is determined by dynamic light scattering.

[394] 29. The formulation of any of the above items, in which the active agent is present in an amount from 0.001% to 50% w / w, based on the total weight of the formulation.

[395] 30. The formulation, according to any of items 1 to 29, which is a pharmaceutical formulation comprising an active agent.

[396] 31. The formulation of item 30, in which the active agent is a small organic molecule and has a molecular weight from 100 to 1000 g / mol, preferably from 115 to 950 g / mol and more preferably from 130 to 900 g / mol.

[397] 32. The formulation of item 30 or 31, in which the active agent is not a pharmaceutically acceptable macrolide lactone.

[398] 33. The formulation of item 32, in which the active agent is not tacrolimus.

[399] 34. The formulation of item 30 or 31, in which the active agent is a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof.

[400] 35. The formulation of item 34, comprising (a) a nanoemulsion comprising (i) an aqueous component, present in an amount of 70% to 95% w / w, based on the total weight of the nanoemulsion (a); (ii) nanovesicles, comprising (1) 1 to 5% of at least one phospholipid, based on weight Petition 870250089513, dated 10 / 01 / 2025, pp. 518 / 568 95 / 123 total of the nanoemulsion (a); (2) 3 to 7% of at least one polyoxyethylene type surfactant, based on the total weight of the nanoemulsion (a); (3) 1 to 3% C3 to C5 alcohol, based on the total weight of the nanoemulsion (a); and (4) 3 to 8% triglycerides, based on the total weight of the nanoemulsion (a); (b) 1 to 20% of a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid hydrochloride, based on the total weight of the formulation; (c) optionally 0.5 to 4% of at least one gelling agent, based on the total weight of the formulation; (d) optionally 0.1 to 2% of at least one preservative, based on the total weight of the formulation; and (e) a propellant.

[401] 36. The formulation of any of items 1 to 35, for use in medicine.

[402] 37. The formulation of any of items 32 to 35, for use in a method of treatment and / or prevention of a dermatological disease or condition in an individual.

[403] 38. The formulation for use of item 37, in which the treatment and / or prevention of the dermatological disease or condition comprises: (a) administer topically to the individual a pharmaceutically effective amount of the formulation of any of items 32 to 35, to a diseased or affected area and to the area around the diseased or affected area of ​​skin, where the formulation forms a foam, and (b) optionally incubate the pharmaceutical formulation on the skin of Petition 870250089513, dated 10 / 01 / 2025, pp. 519 / 568 96 / 123 individual with or without occlusion of the skin area to which the formulation was administered, occlusion preferably performed using polyethylene or low-density polyurethane film, to enhance penetration into deep tissue layers.

[404] 39. The formulation of either item 34 or 35, for use in a method of treating and / or preventing a dermatological disease or condition in an individual, wherein the treatment and / or prevention of the dermatological disease or condition comprises: (a) administer topically to the individual a pharmaceutically effective amount of the formulation of either item 33 or 34, to a diseased or affected area and, optionally, to an area around the diseased or affected area of ​​skin, wherein the formulation forms a foam, and (b) optionally incubate the pharmaceutical formulation on the individual's skin with or without occlusion of the skin area to which the formulation was administered, occlusion preferably performed using low-density polyethylene or polyurethane film, to enhance penetration into deep-layer tissue, and (c) irradiate the skin area to which the formulation was administered with light.

[405] 40. The formulation for use of either of items 38 or 39, wherein the area around the diseased or affected area of ​​skin includes an area of ​​at least about 5 mm in width.

[406] 41. The formulation for use of any of items 37 to 40, wherein the dermatological disease or condition includes diseases or conditions of the skin, skin appendages or mucous membranes.

[407] 42. The formulation for use of any of items 37 to 41, wherein the dermatological disease or condition is selected from the group consisting of inflammatory, neoplastic, proliferative diseases or conditions, Petition 870250089513, dated 10 / 01 / 2025, pp. 520 / 568 97 / 123 infectious and / or autoimmune diseases, and / or their cutaneous manifestation, and / or diseases associated with single lesions or fields of lesions, neoplastic, proliferative and / or inflammatory changes.

[408] 43. The formulation for use of item 42, in which the inflammatory dermatological disease or condition is selected from the group consisting of dermatitis, contact dermatitis, acne, atopic dermatitis, eczema, pustular dermatitis, seborrheic dermatitis, perioral dermatitis, chronic wound, urticaria, skin ulcer, rosacea, rash, drug eruptions, toxic epidermal necrolysis; erythema multiforme, erythema nodosum, granuloma annulare and other cutaneous manifestations of inflammation.

[409] 44. The formulation for use of item 42, in which the neoplastic and / or proliferative dermatological disease or condition is selected from the group consisting of basal cell carcinoma, preferably superficial basal cell carcinoma or nodular basal cell carcinoma; squamous cell carcinoma, preferably Bowen's disease or invasive squamous cell carcinoma; vulvar intraepithelial neoplasia (VIN); cutaneous T-cell lymphoma; Merkel cell carcinoma; hemangioma; a nodular or subcutaneous cancerous disease; field cancerization; non-melanoma skin cancer in organ transplant recipients; and prevention of non-melanoma skin cancer in organ transplant recipients.

[410] 45. The formulation for use of item 42, in which the infectious dermatological disease or condition is selected from the group consisting of bacterial infections, viral infections, fungal infections, parasitic infections and combinations thereof.

[411] 46. The formulation for use of item 42, in which the autoimmune dermatological disease or condition, or the cutaneous manifestation of the autoimmune condition, is selected from the group consisting of psoriasis, pemphigus, lupus Petition 870250089513, dated 10 / 01 / 2025, pages 521 / 568 98 / 123 systemic erythematosus, lichen planus, morphea, scleroderma, epidermolysis bullosa, dermatomyositis, graft-versus-host syndrome.

[412] 47. The formulation for use of any of items 37 to 46, wherein the dermatological disease or condition is selected from the group consisting of sweating disorders, pigmentation disorders, including hypopigmentation, such as vitiligo, albinism and post-inflammatory hypopigmentation and hyperpigmentation, such as melasma, reactions to sunlight, such as sunburn, skin aging, photosensitivity, disorders of hair follicles and sebaceous glands, such as hypertrichosis, alopecia, male pattern baldness.

[413] 48. The formulation of either item 34 or 35, for use in a photodynamic diagnostic method of a neoplastic and / or proliferative dermatological disease or condition, such as benign or malignant neoplasm or precursors thereof; an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation, such as acne.

[414] 49. The formulation, according to any of items 1 to 29, that is a cosmetic formulation.

[415] 50. The formulation of item 49, in which the active agent is a cosmetic active agent selected from plant extracts, natural or synthetic moisturizers, natural or synthetic cleansing agents, natural or synthetic protective agents, natural or synthetic detergents, natural or synthetic antioxidants, natural or synthetic skin conditioning agents and natural or synthetic vitamins.

[416] 51. Use of the formulation in item 49 or 50 to moisturize the skin, cleanse the skin, protect from the sun (UV rays) or other external influences, help maintain the skin's barrier function, beautify the skin, reduce signs of Petition 870250089513, dated 10 / 01 / 2025, pages 522 / 568 99 / 123 skin aging or as supportive care for stressed or diseased skin.

[417] 52. A method for preparing the formulation of any of items 1 to 50, comprising the following steps: (a) mix at least one lipophilic component, at least one surfactant and at least one alcohol having at least three carbon atoms, (b) bring the mixture obtained in step (a) into contact with an aqueous component, under conditions that allow the formation of a nanoemulsion, (c) introduce the formulation obtained in steps (c) into a dispenser or container, and (d) add a propellant to the dispenser or container to pressurize the dispenser or container.

[418] 53. The method in item 52, additionally comprising (i) adding an active agent; (ii) add a gelling agent and / or (iii) add a preservative.

[419] 54. A container comprising a formulation, wherein said formulation comprises a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; wherein the formulation essentially does not comprise any emollient; and wherein the container additionally comprises a propellant, wherein the propellant is provided to pressurize the container. Petition 870250089513, dated 10 / 01 / 2025, pages 523 / 568 100 / 123

[420] 55. A dispensing product comprising a container, comprising a formulation, wherein said formulation comprises a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; wherein the formulation essentially does not comprise any foaming agent; and wherein the container further comprises a propellant, wherein the propellant is provided for pressurizing the container.

[421] 56. The container of item 54 or the dispensing product of item 55, wherein the formulation and propellant are independently as defined in any of items 1 to 50.

[422] 57. A formulation, said formulation comprising (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol having at least three carbon atoms, (iii) optionally an active agent (b) optionally a gelling agent, wherein the formulation is provided in a container further comprising a propellant, wherein the propellant is provided for Petition 870250089513, dated 10 / 01 / 2025, pp. 524 / 568 101 / 123 Pressurize the container.

[423] 58. A formulation, said formulation comprising (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol having at least three carbon atoms, (iii) optionally an active agent (b) optionally a gelling agent, wherein the formulation is prepared as a pressurized formulation, wherein a propellant is provided to pressurize the formulation.

[424] 59. The formulation of item 57 or 58, in which the constituents of the formulation, in particular the nanoemulsion, the gelling agent and the propellant, are independently as defined in any of items 1 to 50.

[425] 60. The formulation of any of items 57 to 59, for use in medicine.

[426] 61. The formulation of any of items 57 to 59, for use in a method of treatment and / or prevention of a dermatological disease or condition in an individual.

[427] 62. A foam, obtained from or comprising the formulation of any of items 1 to 50 or 57 to 61.

[428] 63. Cosmetic use of the formulation, in accordance with any of items 1 to 29, 57, 58 and 59.

[429] 64. Use of the formulation, in accordance with any of items 1 to 48, 57, 58 and 59, for the manufacture of a medicine for the treatment and / or Petition 870250089513, dated 10 / 01 / 2025, pages 525 / 568 102 / 123 prevention of a dermatological disease or condition in an individual.

[430] 65. Method of treatment and / or prevention of a dermatological disease or condition in an individual, said method comprising administering to the individual a pharmaceutically effective amount of the formulation of any of items 1 to 48, 57, 58 and 59.

[431] 66. Photodynamic diagnostic method for a neoplastic and / or proliferative dermatological disease or condition, such as benign or malignant neoplasm or precursors thereof; an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation, such as acne, comprising (i) administering the formulation, in accordance with item 34 or 35, to the area of ​​skin to be diagnosed, under conditions that allow the synthesis of fluorescent porphyrins in the cells and / or tissues, and (ii) irradiating the area of ​​skin to which the formulation was administered, under conditions that induce fluorescence of the accumulated porphyrins, wherein the increase in porphyrin fluorescence indicates increased metabolic activity, being indicative of a neoplastic and / or proliferative dermatological disease or condition, an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation.

[432] 67. A cosmetic treatment and / or prevention method for a dermatological condition in an individual, said method comprising administering to the individual an effective amount of the formulation of any of items 1 to 29 and 49 to 51 and 57 to 59.

[433] 68. A method for stabilizing a nanoemulsion, comprising the following steps (a) providing a nanoemulsion comprising: Petition 870250089513, dated 10 / 01 / 2025, pp. 526 / 568 103 / 123 (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introduce the nanoemulsion into a container; and (c) add a propellant to the container to pressurize the container.

[434] 69. The method of item 68, in which - the nanoemulsion comprises nanovesicles comprising the carrier component, wherein the nanovesicles have a stable size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months or at least one month, at least two months, three months, six months, nine months, twelve months, eighteen months, twenty-four months or at least thirty-six months, at 4 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in the pressurized container; and / or - The nanoemulsion is characterized by a stable polydispersity index of less than or equal to 0.4 and / or 0.3 when stored for one month, two months, three months, six months, nine months, twelve months, eighteen months, twenty-four months, or at least thirty-six months, or at least one month, at least two months, at least three months, at least six months, at least nine months, at least twelve months, at least eighteen months, or at least twenty-four months at 4 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C, or at 40 °C in a pressurized container.

[435] 70. The method of item 68 or 69, wherein the method is for stabilizing a formulation comprising a nanoemulsion.

[436] 71. The method of item 70, in which the formulation, nanoemulsion and Petition 870250089513, dated 10 / 01 / 2025, pp. 527 / 568 104 / 123 propellant are independently as defined in any of items 1 to 50.

[437] 72. Use of a nanoemulsion for the preparation of a foam or a spray, comprising the following steps: (a) provide a formulation comprising a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introducing the formulation comprising a nanoemulsion into a container; and (c) adding a propellant to the container to pressurize the container; and (d) releasing a foam or spray from the pressurized container.

[438] 73. The use of item 72, wherein the formulation comprising the nanoemulsion, the nanoemulsion and the propellant are independently as defined in any of items 1 to 50.

[439] 74. The formulation of item 30 or 31, wherein the active agent is a pharmaceutically acceptable macrolide lactone, preferably a calcineurin inhibitor, most preferably tacrolimus, a pharmaceutically acceptable derivative, precursor, analogue and / or metabolite thereof.

[440] The present invention is further illustrated by the following Figures and Examples. Figure captions

[441] Figure 1: Exemplary pressurized dispensers (or containers) with spray head (middle) or foam dispensing valve (left) Petition 870250089513, dated 10 / 01 / 2025, pages 528 / 568 105 / 123 used in the Examples of the invention for storing the exemplary formulations. Glass bottle used in the Examples of the invention for storing the exemplary non-pressurized comparative formulations (right).

[442] Figure 2: Comparison of nanoemulsion formulations with different lipophilic contents and without gelling agent: vesicle size over time at different temperatures.

[443] Figure 3: Comparison of nanoemulsion formulations with different pH values ​​and without gelling agent: vesicle size over time at different temperatures.

[444] Figure 4: Comparison of nanoemulsion formulations with different lipophilic contents and with XT=1%: vesicle size over time at different temperatures.

[445] Figure 5: Comparison of nanoemulsion formulations with different lipophilic contents and with XT=0.5%: vesicle size over time at different temperatures.

[446] Figure 6: Comparison of nanoemulsion formulations with different lipophilic contents and with PX=2%: vesicle size over time at different temperatures.

[447] Figure 7: Comparison of nanoemulsion formulations with different lipophilic contents and with PX=1%: vesicle size over time at different temperatures.

[448] Figure 8: Comparison of nanoemulsion formulations with different lipophilic contents and with xanthan gum as freeze protection (freezing for 4 days, once). From left to right: BF200 XT=0.5% / 1.0% glass, BF200 XT=0.5% / 1.0% foam, BF215 XT=0.5% / 1.0% glass, BF215 XT=0.5% / 1.0% foam, BF220 XT=0.5% / 1.0% glass, Petition 870250089513, dated 10 / 01 / 2025, pages 529 / 568 106 / 123 BF220 XT=0.5% / 1.0% foam.

[449] Figure 9: Comparison of nanoemulsion formulations with different lipophilic contents and with xanthan gum as freeze protection (5 freeze-thaw cycles). From left to right: BF200 XT=1% glass, BF200 XT=1% foam, BF215 XT=1% glass, BF215 XT=1% foam, BF220 XT=1% glass, BF220 XT=1% foam.

[450] Figure 10: Comparison of TC content over time in BF220 with PX=4% as gelling agent at 5 °C.

[451] Figure 11: Comparison of ALA content over time in BF200 with PX=2% as gelling agent at 5 °C and 25 °C.

[452] Figure 12: Analysis of foam collapse times at room temperature and 36 °C of nanoemulsions BF200 and BF220, as described in Table 2.

[453] Some data shown in the figures result from grouped experiments. Examples

[454] In the Examples, vesicle size and API content, describing the stability of nanoemulsion formulations, are determined depending on lipophilic content, pH and gelling agents under various conditions (0 °C, 25 °C, 40 °C, freeze-thaw cycles). Example 1: Preparation of BF200, BF215 and BF220 Nanoemulsions and Nanoemulsion Formulations Table 1: Lipophilic content of the nanoemulsions used in the Examples BF200 10% lipophilic content BF215 15% lipophilic content BF220 20% lipophilic content

[455] The qualitative and quantitative compositions of nanoemulsions BF200, BF215 and BF220 are given in Table 2. Petition 870250089513, dated 10 / 01 / 2025, pp. 530 / 568 107 / 123 Table 2: Composition of nanoemulsions BF200, BF215 and BF220 Ingredient Content (% w / w) BF200 Content (% w / w) BF215 Content (% w / w) BF220 Function Quality 1 Soy lecithin 1.7 2.0 to 3.0 3.0 to 4.0 surfactant >90% phosphatidylcholine, for pharmaceutical use, USP 2 Polysorbate 80 (polyoxyethylene sorbitol monooleate) 3.4 4.5 to 5.5 6.0 to 7.0 surfactant Ph. Eur. 3 Caprylic / capric triglycerides 3.5 4.5 to 5.5 6.0 to 8.0 lipid core Ph. Eur. 4 Isopropyl alcohol 1.4 2.0 to 3.0 2.0 to 4.0 solvent Ph. Eur. Content (% w / w) ingredients 1 to 4 10.0 15.0 20.0 Phosphate buffer at 10 mM, pH 6 ad 100.00 ad 100.00 ad 100.00 solvent Water for injection: Ph. Eur.; Disodium phosphate and sodium hydrogen phosphate: Ph. Eur.

[456] The formulations are free of a gelling agent, such as Poloxamer 407.

[457] The manufacturing process of nanoemulsions in a typical batch size consists of the following steps 1 to 4: Step 1: Preparation of a 10 mM phosphate buffer (aqueous component)

[458] 10 mM phosphate buffer (1000 g), pH 6, was optionally prepared and sterilized by filtration through a sterile filter. Step 2: Preparation of a carrier containing the lipophilic component, surfactants, and alcohol. Table 3: Carrier component Ingredient Weight (g) Soy lecithin 17 Polysorbate 80 (polyoxyethylene monooleate 34 Petition 870250089513, dated 10 / 01 / 2025, pages 531 / 568 108 / 123 Ingredient Weight (g) sorbitol) Caprylic / capric triglycerides 35 Isopropyl alcohol 14

[459] Soy lecithin (17 g) was weighed into a suitable receptacle, isopropyl alcohol (14 g) was added, and the receptacle was covered to prevent alcohol evaporation. The soy lecithin was dissolved under continuous stirring with a suitable stirrer at room temperature. Caprylic / capric triglycerides (35 g) and Polysorbate 80 (34 g) were weighed and added to the soy lecithin solution. The mixture was stirred with a suitable stirrer at room temperature until a clear, homogeneous solution was obtained. This solution is the carrier phase to be included in the nanoemulsion containing all the emulsifiers and lipid components of nanoemulsion BF200. According to this procedure, BF215 and BF220 were prepared by adjusting the amount of the components (see Table 2). Step 3: Manufacturing the nanoemulsion by mixing the aqueous component from Step 1 and the carrier from Step 2 to a lipid content of 10% (BF200).

[460] Fabrication of an emulsion by mixing 900 g of phosphate buffer (from Step 1) and 100 g of carrier (from Step 2). First, the aqueous component comprising the phosphate buffer was heated to approximately 45 °C to 60 °C in a suitable receptacle. Then, the carrier (concentrate) from Step 2 was heated to approximately 45 °C to 60 °C. Subsequently, the carrier was poured into the phosphate buffer under continuous stirring with a propeller mixer, resulting in the formation of a stable trombe (or nozzle) having the maximum possible diameter, without causing foaming or splashing. The resulting nanoemulsion was stirred for about 15 min. Finally, the nanoemulsion was cooled to room temperature.

[461] In the BF215 nanoemulsion, 850 g of phosphate buffer (from Step 1) and 150 Petition 870250089513, dated 10 / 01 / 2025, pages 532 / 568 109 / 123 g of carrier were mixed. In the BF220 nanoemulsion, 800 g of phosphate buffer (from Step 1) and 200 g of carrier were mixed.

[462] In the following examples, the terms “BF200 nanoemulsion”, “BF215 nanoemulsion” and “BF220 nanoemulsion” are used to describe nanoemulsions prepared according to steps 1 to 3.

[463] Nanoemulsions BF200, BF215 and BF220 were used in Examples A and G. Step 4: Preparation of the final nanoemulsion formulation and primary packaging.

[464] The nanoemulsion was optionally sterilized by filtration through a sterile filter and placed in 100 ml sterile glass bottles under laminar flow cover.

[465] Depending on the purpose of the nanoemulsion, adjuvants and / or excipients and / or active ingredients may be added (at the appropriate step according to the description) and / or the nanoemulsion may be diluted in order to obtain a suitable “nanoemulsion formulation”, for example by adding water, a suitable buffer or an additional aqueous gel base with poloxamer 407 or xanthan gum.

[466] In the following examples, the terms “BF200 nanoemulsion formulation”, “BF215 nanoemulsion formulation” and “BF220 nanoemulsion formulation” are used to describe nanoemulsion formulations prepared according to steps 1 to 4.

[467] The abbreviations “BF200”, “BF215” and “BF220” are used for both nanoemulsions (stock) and nanoemulsion formulations.

[468] Nanoemulsions or nanoemulsion formulations were placed in a conventional glass vial (“BF200 glass vial”, “BF215 glass vial” and “BF220 glass vial”) or in a foam dispenser, Petition 870250089513, dated 10 / 01 / 2025, pages 533 / 568 110 / 123 pressurized with a mixture of propane, isobutane and n-butane (pressurized BF200, pressurized BF215 and pressurized BF220). Typical examples of dispensers (pressurized containers) and a glass bottle are shown in Figure 1. Example 2: Preparation of BF200, BF215 and BF220 Nanoemulsions at pH 3 or 5

[469] Nanoemulsions BF200, BF215 and BF220 are produced according to Example 1, Steps 1 to 3, except that in Step 3 (manufacturing the nanoemulsion by mixing the aqueous component of Step 1 and the carrier of Step 2), a phosphate buffer with an appropriate pH is used. Acids other than phosphoric acid and its salts may be used for pH adjustment. If necessary, the pH may be further adjusted by adding suitable acids, salts or buffers.

[470] Nanoemulsions BF200, BF215 and BF220 were placed in a conventional glass bottle (“BF200 pH=3 in glass”, BF200 pH=5 in glass”, BF215 pH=3 in glass”, BF220 pH=3 in glass”) or in a foam dispenser (“BF200 pH=3 in foam”, BF200 pH=5 in foam”, BF215 pH=3 in foam”, BF220 pH=3 in foam”), as described in Example 1.

[471] The nanoemulsions described in this example were used in Example B. Example 3: Preparation of BF200, BF215 and BF220 nanoemulsion formulations containing 0.5 or 1% w / w xanthan gum.

[472] The BF200, BF215 and BF220 nanoemulsion formulations are produced according to Example 1 by adding the appropriate amount of an aqueous gel base with xanthan gum in step 4.

[473] The formulations were placed in a conventional glass vial (BF200 XT=0.5% in glass”, BF215 XT=0.5% in glass”, BF220 Petition 870250089513, dated 10 / 01 / 2025, pages 534 / 568 111 / 123 XT=0.5% in glass”) or in a foam dispenser (“BF200 XT=0.5% in foam”, “BF215 XT=0.5% in foam” and “BF220 XT=0.5% in foam”), as described in Example 1.

[474] The formulations were placed in a conventional glass bottle (“BF200 XT=1.0% in glass”, “BF215 XT=1.0% in glass”, “BF220 XT=1.0% in glass”) or in a foam dispenser (“BF200 XT=1.0% in foam”, “BF215 XT=1.0% in foam” and “BF220 XT=1.0% in foam”), as described in Example 1.

[475] The nanoemulsion formulations described in this example were used in Examples C, D, G and H. Example 4: Preparation of BF200, BF215 and BF220 nanoemulsion formulations containing 1 or 2% w / w of Poloxamer 407 (PX)

[476] Nanoemulsion formulations are produced according to Example 1 by adding the appropriate amount of an aqueous gel base with poloxamer 407 in step 4.

[477] The formulations were placed in a conventional glass bottle (“BF200 PX=2.0% % in glass”, “BF215 PX=2.0% % in glass”, “BF220 PX=2.0% % in glass”) or in a foam dispenser (“BF200 PX=2.0% % in foam”, “BF215 PX=2.0% % in foam” and “BF220 PX=2.0% % in foam”), as described in Example 1.

[478] Nanoemulsion formulations BF200 PX=2.0% glass, BF215 PX=2.0% glass, BF220 PX=2.0% glass, BF200 PX=2.0% foam, BF215 PX=2.0% foam and BF220 PX=2.0% foam, as described in the present invention, were used in Example E.

[479] The formulations were placed in a conventional glass bottle (“BF200 PX=1.0% % in glass”, “BF215 PX=1.0% % in glass”, “BF220 PX=1.0% % in glass”) or in a foam dispenser (“BF200 Petition 870250089513, dated 10 / 01 / 2025, pages 535 / 568 112 / 123 PX=1.0% % in foam”, “BF215 PX=1.0% % in foam” and “BF220 PX=1.0% % in foam”), as described in Example 1.

[480] Nanoemulsion formulations BF200 PX=1.0% glass, BF215 PX=1.0% glass, BF220 PX=1.0% glass, BF200 PX=1.0% foam, BF215 PX=1.0% foam and BF220 PX=1.0% foam, as described in the present invention, were used in Example F. Example 5: Preparation of the BF200 nanoemulsion formulation containing 3% 5-aminolevulinic acid and 2% Poloxamer 407

[481] The formulations were prepared according to Example 1 with the addition of the appropriate amount of an aqueous gel base with poloxamer 407 in step 4. 5-ALA was added in the amount of 3%.

[482] The nanoemulsion formulations described in this example were used in Example I. Example 6: Preparation of the BF220 nanoemulsion formulation containing 0.1% tacrolimus (TC) and 4% poloxamer 407

[483] The formulations were prepared according to Example 1 with the addition of the appropriate amount of an aqueous gel base with poloxamer 407 in step 4. TC was added in the amount of 0.1%.

[484] The nanoemulsion formulations described in this example were used in Example J. Example 7: Determination of vesicle size and polydispersity index by dynamic light scattering

[485] The size, expressed as average z-size (e.g., in nm), and the polydispersity index of nanoemulsion formulations were determined by dynamic light scattering (sometimes referred to as Photon Correlation Spectroscopy (PCS) or Quasi-Elastic Light Scattering (QELS)). The technique is well known in the state of the art and well Petition 870250089513, dated 10 / 01 / 2025, pages 536 / 568 113 / 123 established to determine the size of nano or microparticles or vesicles in emulsions, suspensions or polymeric solutions using a laser. For foam samples, the analysis was performed following foam collapse. Measurements were performed with a Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, United Kingdom). The measurement was performed according to the manufacturer's instructions.

[486] The Zetasizer Nano ZS is instrumented with a 633 nm green laser and optics with a 173° scattering detection angle for size measurement. The device can be operated under vacuum for measurements, but in these cases, vacuum was not applied to the samples for size and homogeneity measurements. Example 8: Determination of viscosity

[487] Viscosity was measured by rotation (measurement geometry: cone / plate) with a constant shear rate of 90.0 s-1 at 20 °C. Example A Comparison of nanoemulsions with different lipophilic contents and without gelling agent: vesicle size over time at different temperatures and polydispersity index over time.

[488] Nanoemulsions BF200, BF215, and BF220 were prepared as described in Example 1. The nanoemulsions were stored for 36 months at 25 °C or 12 months at 40 °C. The size of the nanovesicles was determined at 0 (initial point) and at various time points during the storage period by dynamic light scattering, as described in Example 7. The results are shown in Figure 2 and Table 4. Table 4: Polydispersity index of BF200, BF215 and BF220 nanoemulsions stored at 40 °C Petition 870250089513, dated 10 / 01 / 2025, pages 537 / 568 114 / 123 Storage time and container closure system BF200 BF215 BF220 Month 0 0.07 0.15 0.17 1 month pressurized 0.19 0.14 0.11 1 month in glass bottle 0.22 0.25 0.15 3 months pressurized 0.06 0.06 0.02 3 months in glass bottle Phase separation 6 months pressurized 0.06 0.07 0.04 6 months in glass bottle Phase separation 9 months pressurized 0.20 0.06 0.02 9 months in glass bottle Phase separation 12 months pressurized 0.16 0.05 0.02 12 months in glass bottle Phase separation

[489] · When the nanoemulsion (without gelling agents) is stored in a pressurized can, the vesicle size is extremely stable under ambient conditions (25 °C) and under stress conditions (40 °C), compared to conventional storage in a glass vial, which degrades much earlier under phase separation.

[490] · Conclusion: The pressurized can is extremely advantageous for storage under ambient and stress conditions. Example B Comparison of nanoemulsions with different pH values ​​and without gelling agent: vesicle size over time at different temperatures.

[491] Nanoemulsions BF200 pH=3 in glass, BF200 pH=5 in glass, BF200 pH=3 in foam and BF200 pH=5 in foam, BF215 pH=3 in glass, BF220 pH=3 in glass, BF215 pH=3 in foam and BF220 pH=3 in foam were prepared as described in Example 2. The nanoemulsions were stored for 36 months at 25 °C or for up to 36 months at 40 °C. The size of the nanovesicles was determined at 0 (initial point) and at various time points during the storage period by dynamic light scattering, as described in Example 7. The results are shown in Figure 3 and Petition 870250089513, dated 10 / 01 / 2025, pages 538 / 568 115 / 123 in Table 5. Table 5: Gallbladder size after 12 months of storage at 40 °C without any stabilizing agent. Formulation Vesicle size of samples stored in glass vial Vesicle size of samples stored under pressure 10% lipophilic content (BF200), pH=3 Phase separation 143.4 nm 10% lipophilic content (BF200), pH=5 Phase separation 70.78 nm 15% lipophilic content (BF215), pH=3 Phase separation 142.85 nm 20% lipophilic content (BF220), pH=3 Phase separation 186.35 nm

[492] · In a glass vial, the combination of acidic pH and high temperatures (e.g., 40 °C) impairs vesicle size stability in the nanoemulsion (phase separation) over storage for 12 months.

[493] • At 40 °C, in the pressurized can as a storage unit, the vesicle size remained below 190 nm over 12 months.

[494] · At 40 °C, a formulation with a pH of five and stored in the pressurized can, the vesicle size remained below 133 nm over 36 months.

[495] • In a glass vial, the combination of acidic pH and ambient temperatures (e.g., 25 °C) impairs vesicle size stability in the nanoemulsion (phase separation) over storage for 18 months.

[496] • At 25 °C, in the pressurized can as a storage unit, the vesicle size remained below 116 nm over 36 months.

[497] · Conclusion: The pressurized can is extremely advantageous for storing nanoemulsions at pH 3 or pH 5 at ambient and elevated temperatures (e.g., 25 °C and 40 °C). Example C Comparison of nanoemulsion formulations with different contents Petition 870250089513, dated 10 / 01 / 2025, pages 539 / 568 116 / 123 lipophilic and with Xanthan Gum (XT)=1%: vesicle size over time at different temperatures

[498] Nanoemulsion formulations BF200 XT=1.0% in glass, BF215 XT=1.0% in glass, BF220 XT=1.0% in glass, BF200 XT=1.0% in foam, BF215 XT=1.0% in foam, and BF220 XT=1.0% in foam were prepared as described in Example 3. The nanoemulsion formulations were stored for 36 months at 25 °C or 12 months at 40 °C. The size of the nanovesicles was determined at 0 (initial point) and at various time points during the storage period by dynamic light scattering, as described in Example 7. The results are shown in Figure 4.

[499] · In a glass vial, high temperatures (e.g., 40 °C) impair vesicle size stability in the nanoemulsion (phase separation) over storage for 12 months.

[500] • At 40 °C, in the pressurized can as a storage unit, the vesicle size remained below 315 nm over 12 months.

[501] · In a glass vial, ambient temperatures (e.g., °C) impair vesicle size stability in the nanoemulsion (phase separation) over storage for 18 months.

[502] • At 25 °C, in the pressurized can as a storage unit, the vesicle size remained below 107 nm over 36 months.

[503] · Conclusion: The pressurized can is extremely advantageous for storing nanoemulsion formulations containing xanthan gum as a gelling agent at ambient (25 °C) and elevated temperatures (e.g., 40 °C). XT=1% has a stabilizing effect under standard conditions (glass bottle) and lower temperatures (5 °C), especially for nanoemulsion formulations with high lipophilic content (BF215, BF220). Example D Petition 870250089513, dated 10 / 01 / 2025, pages 540 / 568 117 / 123 Comparison of nanoemulsion formulations with different lipophilic contents and XT=0.5%: vesicle size over time at different temperatures.

[504] Nanoemulsion formulations BF200 XT=0.5% in glass, BF215 XT=0.5% in glass, BF220 XT=0.5% in glass, BF200 XT=0.5% in foam, BF215 XT=0.5% in foam, and BF220 XT=0.5% in foam were prepared as described in Example 3. The nanoemulsion formulations were stored for 36 months at 25 °C or 12 months at 40 °C. The size of the nanovesicles was determined at 0 (initial point) and at various time points during the storage period by dynamic light scattering, as described in Example 7. The results are shown in Figure 5.

[505] · In a glass vial, high temperatures (e.g., 40 °C) impair vesicle size stability in the nanoemulsion (phase separation) over storage for 12 months.

[506] • At 40 °C, in the pressurized can as a storage unit, the vesicle size remained below 250 nm over 12 months.

[507] · In a glass vial, ambient temperatures (e.g., °C) impair vesicle size stability in the nanoemulsion (phase separation) over storage for 18 months.

[508] • At 25 °C, in the pressurized can as a storage unit, the vesicle size remained below 115 nm over 36 months.

[509] · Conclusion: The pressurized can is extremely advantageous for storing nanoemulsion formulations containing xanthan gum as a gelling agent at ambient (25 °C) and elevated temperatures (e.g., 40 °C). Example E Comparison of nanoemulsion formulations with different contents Petition 870250089513, dated 10 / 01 / 2025, pages 541 / 568 118 / 123 lipophilic and with Poloxamer 407 (PX) = 2%: vesicle size over time at different temperatures

[510] Nanoemulsion formulations BF200 PX=2.0% in glass, BF215 PX=2.0% in glass, BF220 PX=2.0% in glass, BF200 PX=2.0% in foam, BF215 PX=2.0% in foam, and BF220 PX=2.0% in foam were prepared as described in Example 4. The nanoemulsion formulations were stored for 36 months at 25 °C or 12 months at 40 °C. The size of the nanovesicles was determined at 0 (initial point) and at various time points during the storage period by dynamic light scattering, as described in Example 7. The results are shown in Figure 6.

[511] · Under all conditions, the vesicle size after 12 months of storage was below 160 nm (40 °C) or 110 nm (25 °C), indicating a stabilizing effect of 2% Poloxamer 407 in a pressurized can as in a conventional storage unit (glass vial).

[512] · Conclusion: Poloxamer 407 stabilizes the nanoemulsion over 36 months of storage at 25 °C in a pressurized can and a glass vial. Poloxamer 407 stabilizes the nanoemulsion over 18 months of storage at 40 °C in a pressurized can and a glass vial. Example F Comparison of nanoemulsion formulations with different lipophilic contents and with Poloxamer 407 (PX) = 1%: vesicle size over time at different temperatures.

[513] Nanoemulsion formulations BF200 PX=1.0% in glass, BF215 PX=1.0% in glass, BF220 PX=1.0% in glass, BF200 PX=1.0% in foam, BF215 PX=1.0% in foam, and BF220 PX=1.0% in foam were prepared as described in Example 4. The nanoemulsion formulations were stored for 36 months at 25 °C or 12 months at 40 °C. The size of the nanovesicles was Petition 870250089513, dated 10 / 01 / 2025, pages 542 / 568 119 / 123 determined at 0 (initial point) and at various time points during the dynamic light scattering storage period, as described in Example 7. The results are shown in Figure 7.

[514] · When stored at 40 °C for 12 months, the vesicle size increases to 234-541 nm with high lipid content (BF215, BF220) in glass vials. In samples stored in pressurized cans, the vesicle size remained below 160 nm.

[515] · After 36 months, vesicle size remained at or below 121 nm (25 °C). With high lipid content (BF220) in a glass vial it increased to 144 nm.

[516] · Conclusion: PX=1% has a stabilizing effect at room temperature (25 °C), this effect is reinforced by the pressurized container closure system. A pressurized container closure system improves stability at 40 °C. Example G Comparison of nanoemulsion formulations with different lipophilic contents and with xanthan gum as freeze protection.

[517] The nanoemulsion formulations BF200 XT=0% in glass (=BF200 in glass), BF215 XT=0% in glass (=BF215 in glass), BF220 XT=0% in glass (=BF220 in glass), BF200 XT=0% in foam (=BF200 in foam), BF215 XT=0% in foam (=BF215 in foam) and BF220 XT=0% in foam (=BF220 in foam) were prepared as described in Example 1.

[518] The nanoemulsion formulations BF200 XT=0.5% in glass, BF215 XT=0.5% in glass, BF220 XT=0.5% in glass, BF200 XT=0.5% in foam, BF215 XT=0.5% in foam and BF220 XT=0.5% in foam were prepared as described in Example 3.

[519] Nanoemulsion formulations BF200 XT=1.0% in glass, BF215 Petition 870250089513, dated 10 / 01 / 2025, pages 543 / 568 120 / 123 XT=1.0% in glass, BF220 XT=1.0% in glass, BF200 XT=1.0% in foam, BF215 XT=1.0% in foam, and BF220 XT=1.0% in foam were prepared as described in Example 3.

[520] The formulations were stored for 4 days at -24 °C and subsequently thawed (one freeze-thaw cycle). Vesicle size was determined as described in Example 7. The results are described in Figure 8 and Table 6. Table 6: Vesicle size after a freeze-thaw cycle with pH = 3. Formulation Vesicle size of samples stored in glass vial Vesicle size of samples stored under pressure 10% lipophilic content (BF200) c (xanthan gum) = 0.5%* 465.8 nm 138.1 nm 10% lipophilic content (BF200) c (xanthan gum) = 1.0% 258.0 nm 79.0 nm 15% lipophilic content (BF215) c (xanthan gum) = 0.5% 379.3 nm 157.5 nm 15% lipophilic content (BF215) c (xanthan gum) = 1.0% 362.0 nm 97.0 nm 20% lipophilic content (BF220) c (xanthan gum) = 0.5% 353.6 nm 186.5 nm 20% of lipophilic content (BF220) c (xanthan gum) = 1.0% 407.0 nm 177.0 nm

[521] * c (xanthan gum): xanthan gum content, % w / w.

[522] Nanoemulsion formulations containing xanthan gum are better protected under freezing conditions when stored in pressurized cans (compared to conventional storage units, i.e., glass bottles) • In the absence of xanthan (XT=0%), this is not the case.

[523] · Conclusion: Protection against freezing, for example by xanthan gum, can ensure adequate protection against freezing in pressurized cans. The combination of xanthan gum and a pressurized can is Petition 870250089513, dated 10 / 01 / 2025, pages 544 / 568 121 / 123 superior to any "non-pressurized" conditions, such as storage in a conventional glass bottle. Example H Comparison of nanoemulsion formulations with different lipophilic contents and with xanthan gum as freeze protection.

[524] The nanoemulsion formulations BF200 XT=1.0% in glass, BF215 XT=1.0% in glass, BF220 XT=1.0% in glass, BF200 XT=1.0% in foam, BF215 XT=1.0% in foam and BF220 XT=1.0% in foam will be prepared as described in Example 3.

[525] Other nanoemulsions were not prepared based on the results of example G.

[526] The formulations undergo 5 freeze-thaw cycles. In one cycle, the nanoemulsion will be frozen at -24 °C and then thawed at room temperature. After final thawing, the vesicle size will be determined post-thaw, as described in Example 7. The results are described in Figure 9 and Table 7. Table 7: Vesicle size after five freeze-thaw cycles with pH=3. Formulation Vesicle size of samples stored in glass vial Vesicle size of samples stored under pressure 10% lipophilic content (BF200) c (xanthan gum) = 1.0% 420.5 nm 150.0 nm 15% lipophilic content (BF215) c (xanthan gum) = 1.0% 388.6 nm 119.1 nm 20% lipophilic content (BF220) c (xanthan gum) = 1.0% 388.1 nm 94.0 nm

[527] Under all conditions tested, improved stability was found after 5 freeze-thaw cycles in a nanovesicle formulation stored in a pressurized container, wherein the formulations comprised a gelling agent as a protector against Petition 870250089513, dated 10 / 01 / 2025, pages 545 / 568 122 / 123 freezing, for example, xanthan gum. The combination of xanthan gum and a pressurized container is considered superior to any "non-pressurized" conditions, such as storage in a conventional glass jar. Example I Comparison of 5-aminolevulinic acid (ALA, 5-ALA) content over time in BF200 with PX=2% as a gelling agent at different temperatures.

[528] Nanoemulsion formulations BF200 PX=2% in glass and BF200 PX=2% in foam were prepared as described in Example 5. The nanoemulsion formulations were stored at 25 °C and 2 to 8 °C. The ALA content was determined at 0 (baseline) and at various time points during the 36-month storage period. The results are shown in Figure 11.

[529] Conclusion: under all conditions: pressurized cans preserve API (5-ALA) content better than conventional storage units (e.g., glass jars). After 36 months of storage at 2 to 25 °C, the ALA content was at least 90%. Example J Comparison of tacrolimus (TC) content over time in BF220 with PX=4% as a gelling agent at different temperatures.

[530] Nanoemulsion formulations BF220 TC=0.1% in glass and BF220 TC=0.1% in foam were prepared as described in Example 6. The nanoemulsion formulations were stored at 2 to 8 °C and 25 °C. The TC content was determined at 0 (baseline) and at various time points over a storage period of up to 48 months. The results are shown in Figure 10.

[531] Conclusion: At 2 to 8 °C and 25 °C: pressurized cans preserve the contents Petition 870250089513, dated 10 / 01 / 2025, pages 546 / 568 123 / 123 API (TC) better than conventional storage units (e.g., glass bottles). The formulation stored in a pressurized container proved stable for at least 48 months of storage at 2 to 8 °C (5 °C) and 6 months at 25 °C. After 48 months of storage at 2 to 8 °C or 6 months at 25 °C, the TC content was at least 95%. Petition 870250089513, dated 10 / 01 / 2025, pages 547 / 568

Claims

1 / 8 CLAIMS 1. Formulation, characterized in that it comprises: (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; and (b) a propellant, wherein the formulation is comprised in a pressurized container and wherein the formulation essentially does not comprise any fatty alcohol.

2. Formulation according to claim 1, characterized in that it essentially does not comprise any emollient selected from a monoester or diester comprising an alcohol and a fatty acid.

3. Formulation according to claim 1 or 2, characterized in that it essentially does not comprise any gelling agent.

4. Formulation, according to any one of claims 1 to 3, characterized in that at least one lipophilic component is selected from triglycerides and mixtures thereof, preferably wherein the at least one lipophilic component is a caprylic and / or capric triglyceride or a mixture thereof.

5. Formulation, according to any one of claims 1 to 4, characterized in that at least one surfactant is selected from the group consisting of a phospholipid, a lysophospholipid, a ceramide and / or a mixture thereof, and / or at least one surfactant is a polyoxyethylene type surfactant. Petition 870250089513, dated 10 / 01 / 2025, pp. 548 / 568 2 / 8 6. Formulation, according to any one of claims 1 to 5, characterized in that at least one alcohol has 3 to 5 carbon atoms, more preferably the at least one alcohol is selected from the group consisting of 1-propanol and 2-propanol and mixtures thereof.

7. Formulation according to any one of claims 1 to 6, characterized in that the propellant is propane, isobutane or n-butane or a mixture thereof.

8. Formulation, according to any one of claims 1 to 7, characterized in that it comprises a total aqueous component in an amount from 50% to 99% (w / w), preferably from 70% to 95% (w / w), more preferably from 75% to 95% (w / w), even more preferably from 80% to 90% (w / w).

9. Formulation, according to any one of claims 1 to 8, characterized in that it comprises (a) at least one lipophilic component in an amount from 0.1% to 30% (w / w), preferably from 0.25% to 15% (w / w), preferably from 0.25% to 10% (w / w) and more preferably from 0.5% to 8% (w / w) or 3% to 8% (w / w); and / or (b) at least one alcohol in an amount from 0.1% to 10% (w / w), preferably from 0.5% to 5% (w / w) and more preferably from 1% to 3% (w / w), based on the total weight of the nanoemulsion (a).

10. Formulation, according to any one of claims 1, 2 or 4 to 9, characterized in that it comprises a gelling agent, preferably wherein the gelling agent is selected from the group consisting of poloxamer, xanthan gum, bentonite, sodium carboxymethylcellulose, hydroxymethylcellulose, carbomer, hydroxypropylcellulose, gellan gum, gum Petition 870250089513, dated 01 / 10 / 2025, page. 549 / 568 3 / 8 guar, pectin, poly(ethylene) oxide, polycarbophil, alginate, tragacanth, povidone, gelatin and mixtures thereof, more preferably wherein the gelling agent is selected from poloxamer, xanthan and mixtures thereof, in particular wherein the gelling agent is present in an amount from 0.1% to 10% (w / w), preferably from 0.25% to 5% (w / w) and more preferably from 0.5% to 4% (w / w), based on the total weight of the formulation.

11. Formulation according to claim 10, characterized in that - at least one lipophilic component is present in an amount of 10% to 30% (w / w), preferably 15% to 30% (w / w) and more preferably 20% to 30% (w / w), based on the total weight of the nanoemulsion (a), and - the gelling agent, preferably a poloxamer, is present in an amount of 0.1% to 10% (w / w), preferably 0.25% to 5% (w / w), more preferably 0.5% to 4% (w / w), based on the total weight of the formulation.

12. Formulation, according to any one of claims 1 to 11, characterized in that the nanoemulsion a. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months or twelve months at 2 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in a pressurized container; and / or b. has a polydispersity index less than or equal to 0.4, when stored for one month, two months, three months, six months or twelve months, at 2 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in a pressurized container; and / or c. includes nanovesicles having a size less than or equal to 500. Petition 870250089513, dated 10 / 01 / 2025, page 1.550 / 568 4 / 8 nm, preferably in the 5 nm to 200 nm range, when stored for one month, two months, three months, six months, twelve months, eighteen months or twenty-four months at 2 to 25 °C, at 10 to 25 °C, at 15 to 25 °C, at 2 to 8 °C, at 5 °C or at 25 °C in the pressurized container; and / or d. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the 5 nm to 200 nm range, when subjected to 1, 2, 3, 4, 5 or more freeze-thaw cycles; and / or e. It is characterized by a polydispersity index of less than or equal to 0.4 when stored for one month, two months, three months, six months, twelve months, eighteen months, or twenty-four months at 2 to 25 °C, 10 to 25 °C, 15 to 25 °C, 2 to 8 °C, 5 °C, or 25 °C in a pressurized container; and / or f.comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months or thirty-six months at 2 to 8 °C or at 5 °C in a pressurized container; and / or g. has a polydispersity index less than or equal to 0.4, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months or thirty-six months, at 2 to 8 °C or at 5 °C in a pressurized container; and / or h. has a polydispersity index less than or equal to 0.4, when subjected to 1, 2, 3, 4, 5 or more freeze-thaw cycles.

13. Formulation, according to any one of claims 1 to 12, characterized in that it comprises an active agent, preferably a biogenic substance, more preferably - 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof, - or diclofenac, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof.

14. Formulation, according to any one of claims 1 to 13, characterized in that it comprises 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof.

15. Method for stabilizing a nanoemulsion, characterized in that it comprises the following steps: (a) providing a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introducing the nanoemulsion into a container; and (c) adding a propellant to the container to pressurize the container and / or the nanoemulsion in the container.

16. Method according to claim 15, characterized in that the nanoemulsion is a nanoemulsion formulation comprising an active agent.

17. Method according to claim 16, characterized in that the nanoemulsion a. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months or twelve months at 2 to 40 °C, at 10 to 40 °C, at 20 to 40 °C, at 30 to 40 °C or at 40 °C in the pressurized container; and / or Petition 870250089513, dated 10 / 01 / 2025, pp. 552 / 568 6 / 8 b. It is characterized by a polydispersity index of less than or equal to 0.4 when stored for one month, two months, three months, six months, or twelve months at 2 to 40 °C, 10 to 40 °C, 20 to 40 °C, 30 to 40 °C, or 40 °C in a pressurized container; and / or c.comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, twelve months, 18 months or 24 months at 2 to 25 °C, at 10 to 25 °C, at 15 to 25 °C, at 2 to 8 °C, at 5 °C or at 25 °C in a pressurized container; and / or d. comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when subjected to 1, 2, 3, 4, 5 or more freeze-thaw cycles; and / or e. It is characterized by a polydispersity index of less than or equal to 0.4 when stored for one month, two months, three months, six months, twelve months, 18 months, or 24 months at 2 to 25 °C, 10 to 25 °C, 15 to 25 °C, 2 to 8 °C, 5 °C, or 25 °C in a pressurized container; and / or f.comprises nanovesicles having a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months or thirty-six months at 2 to 8 °C or at 5 °C in a pressurized container; and / or g. has a polydispersity index less than or equal to 0.4, when stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months or thirty-six months, at 2 to 8 °C or at 5 °C in a pressurized container; and / or h. has a polydispersity index less than or equal to 0.4, when subjected to 1, 2, 3, 4, 5 or more freeze cycles. Petition 870250089513, dated 01 / 10 / 2025, page. 553 / 568 7 / 8 defrosting.

18. Use of a nanoemulsion for the preparation of a foam or a spray, characterized in that it comprises the following steps: (a) providing a formulation comprising a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; (b) introducing the formulation comprising a nanoemulsion into a container; and (c) adding a propellant to the container to pressurize the container; and (d) releasing a foam or a spray from the pressurized container.

19. Use according to claim 18, characterized in that the formulation comprises an active agent.

20. Foam dispensing container or product or spray dispenser, characterized in that it comprises a container comprising a formulation, wherein said formulation comprises a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; wherein the formulation does not essentially comprise any fatty alcohol; and Petition 870250089513, dated 10 / 01 / 2025, pp. 554 / 568 8 / 8 wherein the container further comprises a propellant, wherein the propellant is provided to pressurize the container.

21. Foam dispensing container or spray dispenser, according to claim 20, characterized in that the formulation comprises an active agent.

22. Foam or spray, characterized in that it is obtained from the formulation defined in any one of claims 1 to 14.

23. Cosmetic use, characterized in that it is of the formulation, defined in any one of claims 1 to 14, or of the foam or spray, defined in claim 22.

24. Formulation according to claim 13 or 14, or foam or spray according to claim 22, characterized in that it is for use in medicine, preferably for use in a method of treatment and / or prevention of a dermatological disease or condition. Petition 870250089513, dated 10 / 01 / 2025, pp. 555 / 568

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