Propylene Glycol-Free Nanoemulsion

Description

1 / 84 Propylene Glycol-Free Nanoemulsion Description

[001] The present invention relates to a composition for topical use comprising an oil-in-water nanoemulsion and an active ingredient, wherein the composition is essentially propylene glycol-free. The formulation exhibits fewer impurities and byproducts of the active ingredient over time and therefore ensures a higher quality standard and improved shelf life. Background of the invention

[002] Dispersions are colloidal systems, which include micelles, liposomes, virosomes, emulsions and micro-, nanoemulsions, suspensions and polymeric solutions. Emulsions or microemulsions can be oil-in-water, water-in-oil or intermediate-phase dispersions, usually dispersed with surfactants as emulsifiers. Nanoemulsions are a subgroup of emulsions that contain very fine dispersions of oil in water. Nanoemulsions are highly homogeneous, transparent and slightly opalescent dispersions (or emulsions) of oil and water. The dispersed droplets (liquid) or vesicles 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 narrow, monodisperse particle or vesicle size distribution.

[003] Nanoemulsions are thermodynamically more stable than conventional emulsions, making them a favorable vehicle for pharmaceutical compositions that need to maintain stability for extended periods. Nanoemulsions can be in a metastable state, and their structure often depends on the manufacturing process, making them a system Petition 870250088327, dated 09 / 29 / 2025, pages 238 / 333 2 / 84 fragile and complicated to formulate into a pharmaceutical composition with a long shelf life under different storage conditions. If destabilized, they may become heterogeneous, milky, and / or exhibit phase separation. However, they can provide useful applications in skin care, as they may exhibit good textural and sensory properties due to the very fine size of the droplets or globules.

[004] Nanoemulsions are generally manufactured by mechanical fragmentation of an oil phase in an aqueous phase in the presence of a surfactant. The very small size of the oil globules is often achieved by virtue of at least one pass through a high-pressure homogenizer or a sonicator.

[005] Formulations comprising nanoemulsions as vehicles for the delivery of active ingredients generally contain adjuvants, such as organic molecules or solvents, for example, propylene glycol. Propylene glycol is known to have advantageous properties, such as enhanced penetration or preservative effects (Carrer et al., Effect of propylene glycol on the skin penetration of drugs. Arch Dermatol Res 312, 337-352 (2020), https: / / doi.org / 10.1007 / s00403-019-02017-5, McGowan MA et al., Propylene Glycol in Contact Dermatitis: A Systematic Review. Dermatitis, 2018; 29(1):6-12, doi: 10.1097 / DER.0000000000000307). Additionally, it is known to be an excellent solvent for other adjuvants or ingredients and an excellent emulsifier. However, there have been reports of patients with atopic dermatitis experiencing allergic reactions to propylene glycol, which is known to be irritating to the eyes.Furthermore, it is a diol and may suffer undesirable side effects due to its nucleophilic nature. Such reactions are known, for example, with sorbitol or glycerol in the presence of cetirizine, which is well known as an anti-allergic compound. Petition 870250088327, dated 09 / 29 / 2025, pages 239 / 333 3 / 84

[006] Propylene glycol is commonly used as a solvent for hydrophilic compounds. For example, parabens are only slightly soluble in water. In the preparation of an aqueous pharmaceutical formulation or a formulation comprising an aqueous component, parabens must be dissolved in a solvent, such as propylene glycol, suitable for introducing the parabens into the aqueous phase.

[007] 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.

[008] 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 for up to 36 months at refrigerated temperatures (2 to 8 °C), but was susceptible to higher temperatures (standard room temperature and above). Exposure to higher temperatures was tolerated for a few weeks without compromising pharmaceutical quality for human use. Summary of the invention

[009] 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 Petition 870250088327, dated 09 / 29 / 2025, pp. 240 / 333 4 / 84 comprising: (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; and (b) an active agent comprising a carboxylic acid group, or a derivative, or salt of a carboxylic acid group, wherein the formulation comprises less than 1% w / w of propylene glycol or no propylene glycol.

[010] Another aspect of the invention relates to the formulation of the first aspect for use in a method of treating and / or preventing a dermatological disease or condition.

[011] Another aspect of the invention relates to a method for preparing the formulation as described in the present invention, comprising the following steps: (a) mixing at least one lipophilic component, at least one surfactant and at least one alcohol having at least three carbon atoms, and (b) placing the mixture obtained in step (a) in contact with an aqueous component, under conditions that allow the formation of a nanoemulsion, wherein the active agent is added under conditions that allow interactions of the active agent with the surface of the nanovesicles when dissolved in the aqueous phase. Detailed description

[012] 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 for the purpose of describing 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. Petition 870250088327, dated 09 / 29 / 2025, pp. 241 / 333 5 / 84

[013] Preferably, the terms used in the present invention are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, Leuenberger, HGW, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[014] 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.

[015] 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 various examples described and the 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.

[016] Throughout this descriptive report and in the claims that follow, unless the context requires otherwise, the word “include” and variations such as “comprises” or “comprising” should 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 Petition 870250088327, dated 09 / 29 / 2025, pp. 242 / 333 6 / 84 descriptive report and in the attached claims, the singular forms of “a”, “an” and “the” include plural references, unless the wording clearly dictates otherwise.

[017] Formulating a topical pharmaceutical gel composition is a highly complex process that needs to take into account different aspects, such as pH, solubility, polymorphism, applicability, and overall stability of the pharmaceutical composition. Additionally, it is necessary to consider the benefits and limitations of the active pharmaceutical ingredient (API), excipients, the interaction of all components, and the manufacturing process. In oil-in-water nanoemulsion formulations, there are two different phases that may need to be stabilized and patient-compatible: one is the hydrophobic carrier component, which is usually the carrier and needs to stabilize and release the API, and the other is the aqueous component. All these aspects lead to complex formulations with a large number of ingredients.However, the more ingredients a composition has, the more problems / pitfalls can arise during formulation, such as undesirable side effects / interactions of ingredients or higher impurity profiles. Additionally, patients may experience allergic reactions or skin irritations to various components after application to the skin. Therefore, a pharmaceutical composition should only contain the necessary ingredients and omit as many adjuvants and / or excipients as possible. A very popular class of excipients in cosmetics, pharmaceuticals, or food products are polyols, particularly propylene glycol. It can be used as a solvent, humectant, preservative, or emulsion stabilizer. A particularly attractive property in topical pharmaceuticals is its ability to enhance the penetration of active ingredients.

[018] The state of the art does not teach that a pharmaceutical composition Petition 870250088327, dated 09 / 29 / 2025, pages 243 / 333 7 / 84 comprising a nanoemulsion composition containing an active agent comprising a carboxylic acid group or a derivative, or pharmaceutically acceptable salt of a carboxylic acid group, whether propylene glycol-free.

[019] In the context of this specification, 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).

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

[021] These aspects make it clear that the design and formulation of a composition with high penetration and improved impurity profile are highly desirable.

[022] The examples of the present invention demonstrate that the omission of propylene glycol in a pharmaceutical formulation comprising an active agent, in particular a hydrophilic active agent and / or an active agent comprising a carboxylic acid group or a pharmaceutically acceptable derivative or salt of a carboxylic acid, shows a better impurity profile without restricting the penetration properties of the topical pharmaceutical composition compared with a pharmaceutical formulation comprising propylene glycol. Surprisingly, the penetration of the vehicles is improved by the omission of propylene glycol, which is a finding not obvious to a person skilled in the art.

[023] The terms active agent and active ingredient are used interchangeably in the present invention. As used in the present invention, active agent includes an active pharmaceutical ingredient (also referred to in the present invention). Petition 870250088327, dated 09 / 29 / 2025, pp. 244 / 333 8 / 84 The present invention comprises an “active pharmaceutical agent” or “active pharmaceutical ingredient,” (“API”) and an active cosmetic agent (also referred to in the present invention as an “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. The active agent may be present as a pharmaceutically acceptable salt. The active agent may be present as a cosmetically acceptable salt.

[024] In the following specification, unless specifically mentioned otherwise, the term “active agent comprising a carboxylic acid group” also refers to active agents comprising a derivative of a carboxylic acid group, or a salt of a carboxylic acid group.

[025] Preferably, the active agent comprising a carboxylic acid group is a hydrophilic active agent. It is preferred that the hydrophilic active agent has a logP value equal to or less than 1, less than 0.5, less than 0.4, less than 0.3, less than 0.2, less than 0.1 or a negative lg P value, where P is the octanol-water partition coefficient.

[026] In the context of this specification, the term “derivative of a carboxylic acid group” refers to a carboxylic acid group that has formed a chemical compound by reacting with another chemical moiety, in particular a carboxylic acid group that has formed an ester by reacting with a hydroxyl group.

[027] Without wanting to get bogged down in theory, active agents comprising a carboxylic acid group can undergo nucleophilic reactions to form Petition 870250088327, dated 09 / 29 / 2025, pages 245 / 333 9 / 84 unwanted products, such as esters, with propylene glycol. In cases where the active agent comprises a carboxylic acid derivative in the form of an ester, the active agent may still undergo nucleophilic reactions to form unwanted products, such as esters, with propylene glycol, for example, by transesterification. Omitting propylene glycol may therefore lead to fewer unwanted side products.

[028] In addition to the extinction of the expected esters formed by 5-ALA and propylene glycol, the examples show that in a 5-ALA gel formulation of the invention, being propylene glycol-free, a previously detected impurity with m / z of 246 was surprisingly and significantly reduced. This reduction represents a significant improvement over prior art formulations: Firstly, this impurity represents the greatest likelihood of “out-of-specification” results during stability tests. Secondly, the amount of this impurity increases at higher temperatures and after longer storage. The reduction of this impurity, as observed in the formulation of the invention, by being propylene glycol-free, improves stability under stress conditions and allows for longer storage. Additionally, unknown impurities can be harmful to patients, as it is impossible to predict their metabolism and long-term influence on the human body.

[029] Furthermore, the in vitro functional tests described in the Examples revealed that the omission of propylene glycol does not in any way impair the drug release and skin penetration qualities of the formulation at any rate. Improved ALA penetration results were achieved with the formulation of the invention without propylene glycol compared to the comparative formulation with propylene glycol. The formulation without propylene glycol exhibits non-inferior penetration properties compared to the formulation Petition 870250088327, dated 09 / 29 / 2025, pp. 246 / 333 10 / 84 containing propylene glycol. This discovery is surprising, as propylene glycol is a well-known and highly effective penetration enhancer used in topical pharmaceutical formulations.

[030] In an in vitro release assay, the formulation of the invention, being free of propylene glycol, released more 5-ALA than the comparative formulation comprising propylene glycol. This finding is surprising, as it is expected that the addition of polyols, in particular glycerol or propylene glycol, which do not evaporate during application, would improve adhesion and thus drug release.

[031] The formulations of the invention comprise two phases: (I) an aqueous phase or aqueous component, (II) a lipid carrier phase.

[032] 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) an active agent comprising a carboxylic acid group, or a derivative, or salt of a carboxylic acid group, wherein the formulation comprises less than 1% w / w of propylene glycol or no propylene glycol.

[033] In preferred embodiments, the formulation is a pharmaceutical formulation.

[034] In some forms, the formulation is a lotion, a spray, a Petition 870250088327, dated 09 / 29 / 2025, pp. 247 / 333 11 / 84 foam, an emulsion, a nanoemulsion, a gel or a cream. In some embodiments, the formulation is a lotion. In the context of this specification, a lotion is a low-viscosity topical preparation intended for application to the skin. A lotion has a lower viscosity than a cream or a gel due to its higher water content. In some embodiments, the lotion has a viscosity of < 8 Pa s (pascal-second), < 6 Pa s, < 5 Pa s, < 4 Pa ​​s, < 3 Pa s, < 1.0 Pa s or < 0.5 Pa s.

[035] A person skilled in the art knows appropriate methods for determining viscosity. Preferably, viscosity is determined as described in the examples section.

[036] In preferred forms, the formulation is for topical use.

[037] In preferred embodiments of the formulations described in the present invention, the aqueous component comprises an aqueous phase or forms an aqueous phase. Preferably, the active agent is dissolved in the aqueous phase.

[038] In preferred embodiments of the formulations described in the present invention, the carrier component comprises or consists of nanovesicles. Preferably, the active agent is capable of interacting with the surface of the nanovesicles.

[039] The active agent may be present as a salt. Examples where the active agent is present as a salt are, for example, 5-aminolevulinic acid HCl and 5-aminolevulinic acid phosphate.

[040] In even more preferred embodiments of the formulations described in the present invention, the active agent is dissolved in the aqueous phase and is able to interact with the surface of the nanovesicles. The active agent preferably comprises a carboxylic acid group, a derivative of a carboxylic acid group, or a pharmaceutically acceptable salt of a carboxylic acid group. Petition 870250088327, dated 09 / 29 / 2025, pp. 248 / 333 12 / 84 carboxylic.

[041] Examples in which the active agent comprises a derivative of a carboxylic acid group are, for example, 5-aminolevulinic acid esters, such as methyl δ-aminolevulinate (MAL) and hexyl δ-aminolevulinate (HAL).

[042] Examples in which the active agent comprises a pharmaceutically acceptable salt of a derivative of a carboxylic acid group are, for example, methyl δ-aminolevulinate hydrochloride, hexyl δ-aminolevulinate hydrochloride.

[043] In all embodiments described in the present invention, the salt of a carboxylic acid group is preferably a pharmaceutically acceptable salt of a carboxylic acid group. As used in the present invention, “capable of interacting with the surface of the 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.

[044] In the context of this descriptive report, the expression “the formulation comprises less than or equal to 0.9% w / w of propylene glycol” is intended to include embodiments in which the formulation essentially does not comprise any propylene glycol.

[045] In preferred embodiments, the formulation essentially does not comprise any propylene glycol.

[046] 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 Petition 870250088327, dated 09 / 29 / 2025, pp. 249 / 333 13 / 84 in relation to a formulation are interchangeable. In particular, 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.

[047] As used in the present invention, the expression “the composition comprises less than X% of compound X” shall include embodiments in which the composition is free of compound X.

[048] The formulation may comprise less than or equal to 0.99%, 0.95%, 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.

[049] In particular, the formulation may comprise less than or equal to 0.7%, 0.5%, 0.3% or 0.1% w / w of propylene glycol.

[050] More specifically, the formulation may comprise less than or equal to 0.5%, 0.3% or 0.1% w / w of propylene glycol.

[051] More specifically, the formulation may comprise less than or equal to 0.3% or 0.1% w / w of propylene glycol.

[052] In preferred embodiments, the formulation does not contain propylene glycol.

[053] In addition to not comprising propylene glycol or containing only small amounts of propylene glycol, as defined above, it is preferable that the formulation does not contain, essentially does not contain, less than 1%, or less than or equal to 0.99%, 0.95%, 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., with no more than 3). Preferably, the formulation comprises none, essentially none, less than 1%, or less or Petition 870250088327, dated 09 / 29 / 2025, pages 250 / 333 14 / 84 equals 0.99%, 0.95%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of a noncyclic 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, less than 1%, or less than or equal to 0.99%, 0.95%, 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., having no more than 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, respectively).More preferably, the formulation comprises none, essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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 from 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, less than 1%, or less than or equal to 0.99%, 0.95%, 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 from 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 does not comprise, essentially, not less than 1%, or less than or equal to 0.99%, 0.95%, 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.

[054] “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 fractions. 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.

[055] In preferred embodiments, the formulation of the invention Petition 870250088327, dated 09 / 29 / 2025, pp. 251 / 333 15 / 84 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 a molecular weight of 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.

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

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

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

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

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

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

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

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

[064] The formulation of the present invention can be essentially free of 1,3-propanediol.

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

[066] The formulation of the present invention can be essentially free of octane-1,2-diol. Petition 870250088327, dated 09 / 29 / 2025, pages 252 / 333 16 / 84

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

[068] The formulation of the present invention can be essentially sorbitol-free.

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

[070] 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 paraben-free, as described in the present invention.

[071] 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 paraben-free, as described in the present invention.

[072] 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 paraben-free, as described in the present invention.

[073] 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 paraben-free, as described in the present invention.

[074] 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 paraben-free, as described in the present invention. Petition 870250088327, dated 09 / 29 / 2025, pages 253 / 333 17 / 84

[075] 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 paraben-free, as described in the present invention.

[076] 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 formulation may be paraben-free, as described in the present invention.

[077] 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 paraben-free, as described in the present invention.

[078] 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 paraben-free, as described in the present invention.

[079] 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 paraben-free, as described in the present invention.

[080] 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 paraben-free, as described in the present invention.

[081] 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 paraben-free, as described in the present invention. Petition 870250088327, dated 09 / 29 / 2025, pages 254 / 333 18 / 84

[082] 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 paraben-free, as described in the present invention.

[083] 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 diethylene glycol. This formulation may be paraben-free, as described in the present invention.

[084] 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 paraben-free, as described in the present invention.

[085] 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 paraben-free, as described in the present invention.

[086] 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 paraben-free, as described in the present invention.

[087] 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 paraben-free, as described in the present invention.

[088] 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 paraben-free, as described herein. Petition 870250088327, dated 09 / 29 / 2025, pages 255 / 333 19 / 84 invention.

[089] 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 paraben-free, as described in the present invention.

[090] 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 paraben-free, as described in the present invention.

[091] 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 paraben-free, as described in the present invention.

[092] 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 paraben-free, as described in the present invention.

[093] 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 paraben-free, as described in the present invention.

[094] 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 paraben-free, as described in the present invention.

[095] 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. Petition 870250088327, dated 09 / 29 / 2025, pp. 256 / 333 20 / 84 This formulation can be paraben-free, as described in the present invention.

[096] 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 paraben-free, as described in the present invention.

[097] 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 paraben-free, as described in the present invention.

[098] 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 paraben-free, as described in the present invention.

[099] 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 paraben-free, as described in the present invention.

[100] 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 paraben-free, as described in the present invention.

[101] 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 paraben-free, as described in the present invention.

[102] The formulation of the present invention may comprise less or Petition 870250088327, dated 09 / 29 / 2025, pages 257 / 333 21 / 84 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 paraben-free, as described in the present invention.

[103] 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 1,3propanediol. This formulation may be paraben-free, as described in the present invention.

[104] 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 paraben-free, as described in the present invention.

[105] 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 paraben-free, as described in the present invention.

[106] 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 paraben-free, as described in the present invention.

[107] 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 paraben-free, as described in this invention.

[108] 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 paraben-free, as described in this invention. Petition 870250088327, dated 09 / 29 / 2025, pp. 258 / 333 22 / 84

[109] 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 paraben-free, as described in this invention.

[110] 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 octane-1,2-diol or no octane-1,2-diol. This formulation may be paraben-free, as described in the present invention.

[111] 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 paraben-free, as described in the present invention.

[112] 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 paraben-free, as described in the present invention.

[113] 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 paraben-free, as described in the present invention.

[114] 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, particularly having from 2 to 50 ethylene oxide groups or no polyethylene glycol. This formulation may be paraben-free, as described in the present invention.

[115] 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 Petition 870250088327, dated 09 / 29 / 2025, pp. 259 / 333 23 / 84 polyethylene glycols, particularly having from 2 to 50 ethylene oxide groups. This formulation may be paraben-free, as described in the present invention.

[116] 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, particularly having from 2 to 50 ethylene oxide groups. This formulation may be paraben-free, as described in the present invention.

[117] 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 paraben-free, as described in the present invention.

[118] 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 sorbitol or no sorbitol. This formulation may be free of parabens, as described in the present invention.

[119] In particular, the formulation of the present invention may comprise less than or equal to 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of sorbitol or no sorbitol. This formulation may be paraben-free, as described in the present invention.

[120] More particularly, the formulation of the present invention may comprise less than or equal to 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of sorbitol or no sorbitol. This formulation may be paraben-free, as described in the present invention.

[121] More particularly, the formulation of the present invention may comprise less than or equal to 0.3%, 0.2% or 0.1% w / w of sorbitol or none. Petition 870250088327, dated 09 / 29 / 2025, pp. 260 / 333 24 / 84 sorbitol. This formulation may be paraben-free, as described in the present invention.

[122] 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, or no sugar, such as sorbitol, mannitol and mixtures thereof. This formulation may be paraben-free, as described in the present invention.

[123] 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. This formulation may be paraben-free, as described in the present invention.

[124] 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 paraben-free, as described in the present invention.

[125] 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 paraben-free, as described in the present invention.

[126] The formulation of the present invention may be free of, may be essentially free of, or may comprise less than an amount indicated, such as less than 1%, less than 0.99%, less than 0.95%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, Petition 870250088327, dated 09 / 29 / 2025, pp. 261 / 333 25 / 84 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 monosaccharides or disaccharides, 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 linear or branched, but not cyclic, polyol. 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.

[127] The formulation may comprise less than or equal to 0.99%, 0.95%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1% w / w of a polyol or no polyol. The polyol may be a polyol as described in the present invention.

[128] The formulation 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.

[129] The formulation may comprise less than or equal to 0.5%, 0.3% or Petition 870250088327, dated 09 / 29 / 2025, pp. 262 / 333 26 / 84 0.1% w / w of a polyol. The polyol may be a polyol as described in the present invention.

[130] The formulation 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.

[131] The formulation may not include polyol.

[132] The small size of the nanovesicles and their high homogeneity give them advantageous properties that distinguish them from conventional emulsions: The nanoemulsions and formulations comprising nanoemulsions of the present invention are transparent. Additionally, the nanoemulsion and formulations comprising nanoemulsions of the present invention can transport active agents more efficiently and thus become increasingly important in the field of medicine and pharmacy.

[133] “Aging, as used in the present invention, refers to the alteration, disintegration and / or degradation of the formulation, affecting chemical and physical stability during storage, particularly under stressful conditions. Such physical or chemical changes due to storage may include, but are not limited to, Ostwald ripening, flocculation, coalescence and / or breakage, which may lead to a change in vesicle size or polydispersity index. The term aging, as used in the present invention, may include the formation of impurities after storage, for example, for 6 months at 25 °C or 40 °C. Typical impurities in formulations comprising 5-aminolevulinic acid as the active agent are 2-hydroxypropyl-aminolevulinate and an impurity characterized by m / z = 246.

[134] The inventors found that the formulations of the present invention are surprisingly stable and resistant to aging. Petition 870250088327, dated 09 / 29 / 2025, pages 263 / 333 27 / 84 In particular, the formulations of the present invention comprise fewer impurities than prior art formulations, even after storage, for example, for 6 months at 25 °C or 40 °C.

[135] As used in the present invention, “stressful conditions” for storage are temperatures that significantly exceed ambient temperature (e.g., 40 °C).

[136] 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 / or slightly opalescent. The nanoemulsions of the present invention may be colloidal systems, which include dispersed nanovesicles comprising a lipid core surrounded by at least one surfactant or emulsifier monolayer. The nanoemulsions and formulations comprising the nanoemulsions of the present invention are characterized by an average particle or nanovesicle size of less than 500 nm, less than 200 nm or less than 100 nm. The nanoemulsions and formulations comprising the nanoemulsions of the present invention have a narrow (homogeneous) nanovesicle size distribution, for example, a nanovesicle size distribution characterized by a polydispersity index less than or equal to 0.4.

[137] 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. Medium-sized lipid vesicle (see above, for example, below 500, 200, 100 nm) that is compiled from a monolayer of a surfactant and a lipid core. In the present invention, nanovesicles may have a size less than or equal to 500 nm, or less than or Petition 870250088327, dated 09 / 29 / 2025, pp. 264 / 333 28 / 84 equals 300 nm, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.

[138] As used in the present invention, the term nanoparticle or nanovesicle 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 of, or does not comprise nanoparticles. Nanoparticles are primarily inorganic solid lipids 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 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.

[139] 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 that the formulation is administered directly to the skin. In particular, topical use is a pharmaceutical use.

[140] 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 870250088327, dated 09 / 29 / 2025, pages 265 / 333 29 / 84 The subject for describing the integrity of the nanovesicles is size, as for example determined by dynamic light scattering, as described in the present invention. The nanovesicles produced according to the invention may have a size below 100 nm, preferably below 50 nm, more preferably in the range of 20 to 30 nm, immediately after fabrication. 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, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.

[141] Stability may also refer to the absence of processes described above as aging, leading to loss of functionality or pharmaceutical quality. The composition described in this invention is functional or pharmaceutically functional, provided that the vesicle size is 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.

[142] Furthermore, stability may refer to the stable content of the hydrophilic active compound, in particular 5-ALA. During storage, the 5-ALA content is, for example, 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 stressful conditions, as described in the present invention.

[143] In one formulation of the invention, the 5-ALA content may be (i) at least 95% after storage for 3 months at 40 °C, and / or (ii) at least 95% or at least 97% after storage for 3, 6, 9 or 12 months at 25 °C, and / or (iii) at least 95%, at least 97% or at least 99% after Petition 870250088327, dated 09 / 29 / 2025, pp. 266 / 333 30 / 84 storage for 12, 18, 24 or 36 months at 5 °C.

[144] As used in the present invention, stability of compositions also refers to a low impurity content or a small amount of impurities. For example, the formulation of the invention is stable if it contains an entity with m / z = 246 in an amount less than or equal to 1.5%, 1.0% or 0.75% when stored for 6 months at 40 °C, or in an amount less than or equal to 0.5%, 0.4%, 0.3% or 0.2% when stored for 6 months at 25 °C.

[145] In the present invention, the formulation can be stable for at least one month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, for example, at room temperature (e.g., 15 to 25 °C). In particular, the formulation of the invention can be stable for at least one month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 24 months or at least 36 months, at 2 to 8 °C or at about 5 °C.

[146] The formulation of the present invention may have a nanovesicle size 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 150 nm, when stored for one month at 40 °C.

[147] The formulation of the present invention may have a nanovesicle size 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, when stored for six months at 25 °C.

[148] The size or diameter of the nanovesicles, as described in the present invention, can be expressed as the Z-mean (also called z-mean). The size distribution of the nanovesicles can be characterized Petition 870250088327, dated 09 / 29 / 2025, pp. 267 / 333 31 / 84 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.

[149] In the present invention, the size of nanovesicles (e.g., average z in nm) and / or the heterogeneity of nanovesicle formulations (characterized by the polydispersity index) can be determined by dynamic light scattering (also known as Photon Correlation Spectroscopy (PCS) or Quasi-Elastic Light Scattering (QELS)). Dynamic light scattering is well known in the state of the art and well established for determining the size of nano or microparticles or vesicles in polymer emulsions, suspensions and / or solutions with a laser.

[150] 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), or 80% to 95%.

[151] As used in the present invention, “weight for weight,” “weight / weight,” or “w / w” means the weight concentration or mass concentration of a component in a formulation described in the present invention. The weight or mass of a component is expressed as a percentage of a reference formulation. For example, the weight or mass of a component may be expressed as a percentage of the total weight or mass of the formulation of the invention, or as a percentage of the total weight or mass of the nanoemulsion (a).

[152] 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. Petition 870250088327, dated 09 / 29 / 2025, pp. 268 / 333 32 / 84 For example, at least one pH buffering agent can be selected from the group consisting of citrate, phosphate, acetate, and carbonate.

[153] 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 6, such as 2, 3, 4, 5 or 6, more preferably in the range of 4 to 6, such as 4, 5 or 6, or 2 to 4, such as 2, 3 or 4.

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

[155] Preferably, the at least one lipophilic component is a lipid, a synthetic oil, a vegetable 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, the at least one lipophilic component is a triglyceride, preferably a triglyceride comprising a C8-10 fatty acid, or a mixture thereof. More particularly, the at least one lipophilic component is a caprylic and / or capric triglyceride and / or a mixture thereof, particularly preferably Miglyol (such as Miglyol 812, available, for example, from IOI Oleochemical) or Myritol (such as Myritol 318, available, for example, from BASF). Suitable vegetable and animal oils include, for example, sunflower oil, soybean oil, peanut oil, rapeseed oil, fish oil, and / or cetacean oil.

[156] In the formulation as described in the present invention, at least one lipophilic component may be present in an amount of 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). Also Petition 870250088327, dated 09 / 29 / 2025, pp. 269 / 333 33 / 84 it is preferable 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 10 to 20%.

[157] 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).

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

[159] Surfactants, also called 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 decrease the surface tension of two liquids and are amphiphilic. In emulsions, they are called 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 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. Persons skilled in the art will identify which emulsifiers or mixtures thereof are suitable for the preferred vehicles and the intended purpose of the composition. In certain emulsions, combinations of emulsifiers can be advantageous.

[160] 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 eggs. Petition 870250088327, dated 09 / 29 / 2025, pp. 270 / 333 34 / 84 chicken. More preferably, at least one surfactant is lecithin, most preferably soy lecithin.

[161] In the formulation as described in the present invention, the phospholipid, in particular phosphatidylcholine, lysophospholipid, ceramide and / or a mixture thereof may be present in an amount of 0.1% to 10% (w / w), based on the total weight of the nanoemulsion(a), preferably from 0.15% to 5% (w / w), more preferably from 1% to 5% and even more preferably from 0.2% to 3% (w / w).

[162] 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, i.e. 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.

[163] 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, N-alkyl-e-aminopropionate, alkylammonium phosphate compounds 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. Petition 870250088327, dated 09 / 29 / 2025, pp. 271 / 333 35 / 84

[164] In the formulation 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.

[165] At least one surfactant, such as a polyoxyethylene type surfactant, may be present in an amount of 0.1% to 10% (w / w), based on the total weight of the nanoemulsion (a), more preferably from 2% to 10% (w / w), even more preferably from 0.2% to 5% (w / w) and most preferably from 1% to 5% (w / w) or 0.5% to 5% (w / w).

[166] 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 to form a nanoemulsion.

[167] 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-octyl-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. Petition 870250088327, dated 09 / 29 / 2025, pp. 272 / 333 36 / 84

[168] 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 called 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.

[169] 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.

[170] In preferred embodiments, at least one alcohol comprises at least three carbon atoms.

[171] In the formulation as described in the present invention, the at least one alcohol preferably has, independently, 3 to 5 (i.e., not more than 5) or 3 or 4 (i.e., not more than 4) carbon atoms. The Petition 870250088327, dated 09 / 29 / 2025, pages 273 / 333 37 / 84 minus one alcohol must be at least one monohydric alcohol. 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). The alcohol is not propylene glycol.

[172] Preferably, at least one alcohol has 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.

[173] In the formulation as described in the present invention, the alcohol may be present in an amount of 0.1% to 10% w / w based on the total weight of the nanoemulsion (a), preferably from 1% to 5% (w / w) or 0.5% to 5% (w / w), and more preferably from 1% to 2% (w / w).

[174] The formulation as described in the present invention may comprise a gelling agent. 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.

[175] It is preferable that the gelling agent be selected from poloxamer, xanthan gum and / or mixtures thereof.

[176] It is also preferable that the gelling agent be xanthan gum.

[177] It is also preferable that the gelling agent be a poloxamer. Petition 870250088327, dated 09 / 29 / 2025, pp. 274 / 333 38 / 84

[178] 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 described in the present invention, a preferred poloxamer is Poloxamer 407.

[179] In the formulation as described in the present invention, the gelling agent may be present in an amount of 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) or 1% to 4% (w / w).

[180] 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).

[181] 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 0.1-2% (w / w), and more preferably from 0.2% to 1.5% (w / w).

[182] In particular, the formulation of the present invention is essentially paraben-free, preferably paraben-free. The class of paraben compounds includes p-hydroxybenzoates and PHB esters (p-hydroxybenzoates). Petition 870250088327, dated 09 / 29 / 2025, pp. 275 / 333 39 / 84 hydroxybenzoic acid, also known as 4-hydroxybenzoic acid).

[183] ​​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 may be a polyol, in particular propylene glycol (1,2-propanediol). In the present invention, this preparation of a solution of a paraben in propylene glycol is not necessary, so the formulation of the present invention may be free of a polyol and / or a mixture of two or more polyols, such as propylene glycol.

[184] The formulation of the present invention may be essentially free of a polyol and / or a mixture of two or more polyols and a paraben, preferably free of propylene glycol and a paraben.

[185] The formulation of the present invention may be a gel formulation. As used in the present invention, a “gel” is a biphasic elastic colloidal material, consisting of a dispersed liquid embedded in the solid phase, frequently consisting of a gelling agent. Suitable gelling agents, such as xanthan gum, are described in the present invention.

[186] The formulation of the present invention may be supplied in a container or dispenser. Suitable dispensers and containers are known to those skilled in the art. For example, the dispenser may be a compression tube comprising the formulation as described in the present invention. The compression tube may contain the gel formulation as described in the present invention. The dispenser may also be a metered dose dispenser or a foam dispenser or a spray dispenser.

[187] The container or dispenser may comprise a propellant, in Petition 870250088327, dated 09 / 29 / 2025, pp. 276 / 333 40 / 84 that the propellant is supplied to pressurize the container or dispenser. 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.

[188] The formulation of the present invention can be prepared as a foamable formulation.

[189] The formulation of the present invention can be prepared as a pressurized formulation, wherein a propellant is provided to pressurize the formulation. Any propellant as described in the present invention can be used.

[190] The formulation of the present invention can be prepared as a pressurized and foamable formulation, wherein a propellant is provided to pressurize the formulation. Any propellant as described in the present invention can be used.

[191] The formulation of the invention may be provided in a foam dispenser, as described in the present invention. The foam dispenser comprises a container, wherein said container comprises the formulation as described in the present invention, and a propellant. The propellant is provided to pressurize the foam dispenser. Any suitable propellant may be used, as described in the present invention. A foam generating device is mounted in the container. In particular, the formulation is prepared as a foamable formulation.

[192] The invention also provides a foam, comprising the formulation of the present invention, as described in the present invention.

[193] In preferred embodiments, the active agent in the formulation of the invention comprises at least one carboxylic acid group, capable of undergoing Petition 870250088327, dated 09 / 29 / 2025, pages 277 / 333 41 / 84 esterification reactions. Preferably, the active agent is a small molecule containing a carboxylic acid group, having a molecular weight of 50 to 1000 g / mol, more preferably a molecular weight of 50 to 900 g / mol, and most preferably from 100 to 850 g / mol.

[194] The active agent may be present in an amount from 0.001% to 50% w / w, based on the total weight of the formulation. In particular, the active agent may be present in an amount from 0.01% to 30% w / w, based on the total weight of the formulation, or 0.1% to 25% w / w, 0.5% to 25% w / w, 1% to 25% w / w, or 5% to 25% w / w, based on the total weight of the formulation.

[195] In particular, the active agent in the formulation of the invention is a hydrophilic compound possessing a carboxylic acid group. The active agent may be a photosensitizer or a metabolic precursor thereof, most preferably 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. Another preferred salt of 5-aminolevulinic acid is 5-aminolevulinic acid phosphate.

[196] 5-Aminolevulinic acid has the following chemical structure: the H2N THE Molecular Weight: 131.13 g / mol

[197] 5-aminolevulinic acid is a hydrophilic agent that can interact with the surface of nanovesicles when dissolved in the aqueous phase.

[198] 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof may be present in a Petition 870250088327, dated 09 / 29 / 2025, pp. 278 / 333 42 / 84 quantity from 0.001% to 50% w / w, based on the total weight of the formulation. In particular, 5-aminolevulinic acid, a pharmaceutically acceptable salt, a derivative, precursor and / or metabolite thereof may be present in an amount from 0.01% to 30% w / w, based on the total weight of the formulation, or 0.1% to 25% w / w, 0.5% to 25% w / w, 1% to 25% w / w, or 5% to 25% w / w, based on the total weight of the formulation.

[199] 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 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); (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) 0.1 to 20% of an active agent, preferably an active agent comprising a carboxylic acid group, based on the total weight of the formulation; and (c) 0.1 to 2% of at least one preservative, based on the total weight of the formulation; wherein the formulation essentially does not comprise any propylene glycol, and wherein the formulation preferably has a pH of 2 to 4. Petition 870250088327, dated 09 / 29 / 2025, pp. 279 / 333 43 / 84 Preferably, the formulation may comprise two surfactants, most preferably soy lecithin and Polysorbate 80.

[200] In this formulation, at least one phospholipid, at least one polyoxyethylene type surfactant, C3a C5 alcohol, triglycerides and at least one preservative can be selected independently according to the disclosure described in the present invention.

[201] In particular, the formulation of the present invention may comprise, consist essentially of, or consist of: (a) a nanovesicle emulsion 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); (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) 0.1 to 20% of an active agent, preferably a hydrophilic active agent, preferably a photosensitizer or a metabolic precursor thereof, most preferably 5-aminolevulinic acid hydrochloride, based on the total weight of the formulation; (c) 0.1 to 2% of at least one preservative, based on the total weight of the formulation; and wherein the formulation essentially does not comprise propylene glycol, and Petition 870250088327, dated 09 / 29 / 2025, pages 280 / 333 44 / 84 where the formulation preferably has a pH of 2 to 4.

[202] Preferably, the formulation may comprise two surfactants, most preferably soy lecithin and Polysorbate 80.

[203] In this formulation, at least one phospholipid, at least one polyoxyethylene type surfactant, the C3 to C5 alcohol, the triglycerides and at least one preservative can be selected independently according to the disclosure described in the present invention.

[204] The present invention also relates to a nanovesicle comprising, consisting essentially of or 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.

[205] A preferred nanovesicle of the invention essentially comprises or consists of (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.

[206] The present invention also relates to a nanoemulsion comprising, consisting essentially of or 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 520 mM aqueous phosphate buffer, pH 2-8, preferably pH 2-7, more preferably pH 3-6, up to Petition 870250088327, dated 09 / 29 / 2025, pp. 281 / 333 45 / 84 100%.

[207] A preferred nanoemulsion of the present invention comprises, consists essentially of, or consists of: (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%.

[208] This formulation is designated 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.

[209] Another preferred nanoemulsion of the present invention comprises, consists essentially of, or consists of: (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 or less, ad 100%.

[210] This formulation is referred to as “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. Petition 870250088327, dated 09 / 29 / 2025, pages 282 / 333 46 / 84

[211] Yet another preferred nanoemulsion of the present invention comprises, consists essentially of, or consists of: (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%.

[212] This formulation is referred to as “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.

[213] A preferred formulation of the present invention being essentially propylene glycol-free comprises, consists essentially of, or consists of: (1) 17.5% w / w of BF200 nanoemulsions, as described in the present invention, (2) 2.9% w / w xanthan gum, (3) 0.24% w / w sodium benzoate, (4) 10% w / w 5-ALA hydrochloride and (5) water, up to 100% This formulation can have a pH of 2 to 3. The preparation of this formulation is described in Example 3.

[214] An exemplary comparative formulation, not covered by the claims, may comprise, consist essentially of, or consist of: (1) 17.5% w / w of BF200 nanoemulsions, as described in this Petition 870250088327, dated 09 / 29 / 2025, pp. 283 / 333 47 / 84 invention (2) 2.9% w / w xanthan gum, (3) 1% w / w propylene glycol, (4) 0.24% w / w sodium benzoate, (5) 10% w / w 5-ALA hydrochloride and (6) water, ad 100% This formulation can have a pH of 2 to 3. The preparation of this formulation is described in Example 2.

[215] All definitions and embodiments described for the first aspect are also provided for all other aspects described in the present invention, where applicable.

[216] Yet another aspect of the present invention relates to the formulations, as described in the present invention, for use in medicine.

[217] Yet another aspect of the present invention relates to the formulations as described in the present invention, for use in a method of treating and / or preventing a dermatological disease or condition in an individual.

[218] The treatment and / or prevention of dermatological disease or condition may also include: (a) 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, to an area around the diseased or affected area of ​​the skin, and (b) optionally incubate the pharmaceutical formulation on the skin of Petition 870250088327, dated 09 / 29 / 2025, pp. 284 / 333 48 / 84 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 the deep tissue layer.

[219] 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, to an area around the diseased or affected area of ​​skin, 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 the deep tissue layer, and (c) irradiating the skin area to which the formulation was administered with light.

[220] The light spectrum used for irradiation in step (c) may correspond to the absorption spectrum of a fluorescent porphyrin. For example, the light spectrum may correspond to 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 peak irradiance(s) around 410 nm and / or 505 nm and / or 542 nm and / or 575 nm and / or 635 nm. The wavelength spectrum may be essentially free of Petition 870250088327, dated 09 / 29 / 2025, pp. 285 / 333 49 / 84 radiation with wavelengths shorter than 380 nm and / or longer 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.

[221] 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 10-75 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.

[222] Irradiation in step (c) may be carried out with sunlight and / or daylight or with an artificial light source emitting light with a wavelength spectrum and, preferably, irradiance 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 peak irradiance(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 that provides 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.

[223] The area around the diseased or affected area of ​​skin may include a surrounding unaffected area, to ensure that the diseased or affected area is adequately treated in the peripheral diseased or affected areas. For example, Petition 870250088327, dated 09 / 29 / 2025, pp. 286 / 333 50 / 84 The area around the diseased or affected area of ​​skin may include an area at least about 5 mm wide.

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

[225] The dermatological disease or condition to be treated with the 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.

[226] The inflammatory dermatological disease or condition to be treated with the 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.

[227] The neoplastic and / or proliferative dermatological disease or condition to be treated with the 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; cancer Petition 870250088327, dated 09 / 29 / 2025, pages 287 / 333 51 / 84 of non-melanoma skin cancer in organ transplant recipients; and prevention of non-melanoma skin cancer in organ transplant recipients.

[228] The infectious dermatological disease or condition to be treated with the 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.

[229] The autoimmune dermatological disease or condition, or the cutaneous manifestation of the autoimmune condition to be treated with the 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, graft-versus-host syndrome.

[230] The dermatological disease or condition to be treated with the formulation 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.

[231] The pharmaceutical product 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 neoplasia Petition 870250088327, dated 09 / 29 / 2025, pages 288 / 333 52 / 84 benign or malignant or precursors thereof; an inflammatory dermatological disease or condition; and / or a condition associated with bacterial overgrowth, such as acne.

[232] The formulation, as described in the present invention, 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.

[233] Yet another aspect of the present invention is a method for preparing the formulation as described in the present invention, comprising the following steps: (a) mixing at least one lipophilic component, at least one surfactant and at least one alcohol having at least three carbon atoms, and (b) bringing the mixture obtained in step (a) into contact with an aqueous component, under conditions that allow the formation of a nanoemulsion, wherein the active agent is added under conditions that allow interactions of the active agent with the surface of the nanovesicles when dissolved in the aqueous phase.

[234] In step (b), the conditions that allow the formation of the nanoemulsion may include mixing both phases at an appropriate temperature and agitation so as to form nanovesicles. A person skilled in the art knows the appropriate temperature and agitation conditions. A vesicle size less than or equal to 500 nm or less than or equal to 300 nm may be obtained, preferably in the range of 5 nm to 200 nm, more preferably in the range Petition 870250088327, dated 09 / 29 / 2025, pp. 289 / 333 53 / 84 from 5 nm to 100 nm. In particular, 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).

[235] The method comprises a step of adding the active agent. Preferably, the active agent is a hydrophilic active pharmaceutical ingredient.

[236] A hydrophilic compound, such as an amino acid, preferably a photosensitizer or a metabolic precursor, such as ALA, or / and a pharmaceutically acceptable salt thereof (such as ALA hydrochloride), may be added to the aqueous component before contact of the mixture obtained in step (a) with an aqueous component in step (b), such that the active agent may be non-covalently bound to the nanovesicles (in particular to the nanovesicle surface) in step (b).

[237] A hydrophilic compound, such as an amino acid, preferably a photosensitizer or a metabolic precursor, such as ALA, or / and a pharmaceutically acceptable salt thereof (such as ALA hydrochloride), may also be added to the nanoemulsion obtained in step (b), such that the active agent can be non-covalently bound to the nanovesicles (in particular to the nanovesicle surface).

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

[239] Yet another aspect of the present invention is a dispensing product or container product, comprising the formulation as Petition 870250088327, dated 09 / 29 / 2025, pages 290 / 333 54 / 84 described in the present invention. In the dispensing product or container product, the formulation of the present invention is provided in a container or dispenser. Suitable dispensers and containers are known to those skilled in the art. For example, the dispenser may be a compression tube comprising the formulation as described in the present invention. The compression tube may contain the gel formulation as described in the present invention. The dispenser may also be a metered-dose dispenser or a foam dispenser.

[240] The foam container or dispenser may comprise a propellant, wherein the propellant is provided for pressurizing the foam container or dispenser. 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.

[241] The dispensing product may be a foam dispensing product, comprising a foam dispenser as described in the present invention. The foam dispenser comprises a container, wherein said container comprises the formulation as described in the present invention, and a propellant. The propellant is provided to pressurize the foam dispenser. Any suitable propellant may be used as described in the present invention. A foam generating device is mounted in the container. In particular, the formulation is prepared as a foamable formulation.

[242] 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 disease Petition 870250088327, dated 09 / 29 / 2025, pages 291 / 333 55 / 84 dermatological is a dermatological disease or condition as described in the present invention.

[243] 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 the present invention.

[244] 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 neoplasms or precursors thereof; an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation, such as acne.

[245] Drugs containing ALA (and derivatives) stimulate the synthesis of fluorescent porphyrins that preferentially accumulate in cells / tissues with increased metabolic activity. This can be exploited in the photodynamic diagnostic method, which can be applied to neoplastic skin diseases, such as benign or malignant neoplasms or precursors thereof, 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 (e.g., 1-3 h). Subsequently, blue spectrum light is applied to induce red fluorescence of the accumulated porphyrins. The fluorescence can be detected by visual inspection or appropriate technical devices for qualitative or quantitative evaluation.

[246] The photodynamic diagnostic method may include: (i) administer the formulation comprising a photosensitizer or Petition 870250088327, dated 09 / 29 / 2025, pages 292 / 333 56 / 84 a metabolic precursor, such as 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 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.

[247] In step (i), the formulation can be incubated on the skin for, for example, 1 to 3 h.

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

[249] 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.

[250] Diagnosis according to the method described in the present invention can be performed for demarcation of tumor borders to assist in surgery, to evaluate treatment efficacy and / or evaluation of light-induced photobleaching for light dosimetry in therapy. Petition 870250088327, dated 09 / 29 / 2025, pages 293 / 333 57 / 84 photodynamic.

[251] An alternative aspect of the invention relates to a formulation as described in the first aspect of the invention, but comprising propylene glycol. The formulation of the alternative aspect may be free of, may be essentially free of, or may comprise less than an amount indicated, such as less than 1%, less than or equal to 0.99%, less than or equal to 0.95%, less than or equal to 0.9%, less than or equal to 0.8%, less than or equal to 0.7%, less than or equal to 0.6%, less than or equal to 0.5%.less than or equal to 0.4%, less than or equal to 0.3%, less than or equal to 0.2%, or less than or equal to 0.1% of a polyol, all polyols, or any number of polyols selected from the group consisting of glycerin, diglycerin, polyglycerin, diethylene 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.The formulation of the alternative aspect may be essentially free of a polyol or any number of polyols selected from the group consisting of glycerin, diglycerin, polyglycerin, diethylene 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.

[252] The invention also belongs to the following embodiments: 1. A formulation comprising (a) a nanoemulsion comprising: (i) at least one aqueous component; (ii) a carrier component comprising: Petition 870250088327, dated 09 / 29 / 2025, pp. 294 / 333 58 / 84 (1) at least one lipophilic component, (2) at least one surfactant and (3) at least one alcohol; and (b) an active agent comprising a carboxylic acid group, or a derivative, or salt of a carboxylic acid group, wherein the formulation comprises less than 1% w / w of propylene glycol or no propylene glycol.

[253] 2. The formulation of embodiment 1, in which the formulation comprises less than or equal to 0.9% w / w of propylene glycol or no propylene glycol.

[254] 3. The formulation of embodiment 1 or 2, preferably 2, in which the formulation essentially does not comprise any propylene glycol.

[255] 4. The formulation of any of the embodiments 1 to 3, preferably 3, in which the formulation does not comprise propylene glycol.

[256] 5. The wording of any of embodiments 1 to 4, preferably 4, wherein the wording comprises none, essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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 from 2 to 5 carbon atoms.

[257] 6. The wording of any of the embodiments 1 to 5, preferably 5, wherein the wording comprises none, essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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 from 2 to 12 carbon atoms.

[258] 7. The formulation of any of the modalities 1 to 6, in which - at least one alcohol comprises at least three carbon atoms, preferably 3, 4 or 5 carbon atoms, plus Petition 870250088327, dated 09 / 29 / 2025, pp. 295 / 333 59 / 84 preferably at least one alcohol is selected from the group consisting of 1-propanol and 2-propanol and mixtures thereof; - at least one lipophilic component is selected from triglycerides and mixtures thereof, preferably wherein at least one lipophilic component is a caprylic and / or capric triglyceride or a mixture thereof; and / or - 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.

[259] 8. The formulation of any of the embodiments 1 to 7, comprising a total aqueous component in an amount of 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).

[260] 9. The formulation of any of embodiments 1 to 8, comprising (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 2% to 10% (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), more preferably from 1% to 5% (w / w) and even more preferably from 1% to 3%, based on the total weight of the nanoemulsion (a).

[261] 10. The formulation of any of the modalities 1 to 9, in which the active agent is a photosensitizer or a metabolic precursor thereof. Petition 870250088327, dated 09 / 29 / 2025, pp. 296 / 333 60 / 84

[262] 11. The formulation of any of the embodiments 1 to 10, in which the active agent is 5-aminolevulinic acid, a derivative, a precursor, a metabolite and / or a pharmaceutically acceptable salt thereof.

[263] 12. The formulation of any of the embodiments 1 to 11, in which the active agent is present in an amount from 0.1% to 25% (w / w), based on the total weight of the formulation.

[264] 13. The formulation of any of the embodiments 1 to 12, wherein the nanoemulsion comprises nanovesicles, wherein the nanovesicles have a size less than or equal to 500 nm, preferably less than or equal to 200 nm, more preferably in the range of 5 nm to 200 nm when (a) stored for one month, two months, three months, six months, twelve months or at least one month, at least two months, at least three months, at least six months or at least twelve months at 25 °C; and / or b) stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, thirty-six months or at least one month, at least two months, at least three months, at least six months or at least twelve months, at least eighteen months, at least twenty-four months, at least thirty months or at least thirty-six months at 2 to 8 °C.

[265] 14. The formulation of any of the modalities 1 to 13, characterized by a polydispersity index less than or equal to 0.4 when a) stored for one month, two months, three months, six months, twelve months or at least one month, at least two months, at least three months, at least six months or at least twelve months at 25 °C; and / or b) stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, thirty-six months or at least one month, at least two months, at least three months, for Petition 870250088327, dated 09 / 29 / 2025, pages 297 / 333 61 / 84 less six months or at least twelve months, at least eighteen months, at least twenty-four months, at least thirty months or at least thirty-six months at 2 to 8 °C.

[266] 15. The formulation of any of the embodiments 1 to 14, comprising at least one 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, guar gum, pectin, poly(ethylene oxide), polycarbophil, alginate, tragacanth gum, povidone, gelatin and mixtures thereof, more preferably wherein the gelling agent is selected from poloxamer, xanthan gum and mixtures thereof.

[267] 16. The formulation of any of the modalities 1 to 15, which is essentially free of parabens.

[268] 17. 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) an active agent comprising a carboxylic acid group, or a derivative, or salt of a carboxylic acid group, wherein the active agent is a photosensitizer or a metabolic precursor thereof; where the formulation essentially does not comprise any propylene glycol.

[269] 18. The formulation of modality 17, in which the active agent is an acid Petition 870250088327, dated 09 / 29 / 2025, pages 298 / 333 62 / 84 5-aminolevulinic acid, a derivative, a precursor, a metabolite and / or a pharmaceutically acceptable salt thereof.

[270] 19. 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) 5-aminolevulinic acid, a derivative, a precursor, a metabolite and / or a pharmaceutically acceptable salt thereof, wherein the formulation comprises less than 1% w / w of propylene glycol or no propylene glycol.

[271] 20. A method of treating a dermatological disease or condition, comprising administering an effective amount of the formulation of modality 10 to 12 to an individual who needs it.

[272] The invention also belongs to the following items: 1. A formulation comprising (a) a nanoemulsion, said emulsion 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) an active agent comprising a carboxylic acid group or a derivative, or salt of a carboxylic acid group, wherein the formulation comprises less than 1% w / w of propylene glycol, Petition 870250088327, dated 09 / 29 / 2025, pages 299 / 333 63 / 84 preferably less than or equal to 0.99%, 0.95% or 0.9% w / w of propylene glycol or no propylene glycol.

[273] 2. The formulation of item 1, in which the formulation does not essentially comprise any propylene glycol.

[274] 3. The wording of any of the above items, wherein the wording comprises none, essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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, preferably none, essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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 5 carbon atoms.

[275] 4. The wording of any of the above items, wherein the wording comprises none, essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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 5 carbon atoms, preferably none, essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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 12 carbon atoms.

[276] 5. The formulation of any of the above items, wherein at least one alcohol comprises at least three carbon atoms, preferably 3, 4 or 5 carbon atoms.

[277] 6. The formulation of any of the above items, in which the active agent is a photosensitizer or a metabolic precursor thereof.

[278] 7. The formulation of any of the above items, in which the active agent is present in an amount from 0.01% to 25% (w / w), preferably 0.1% to 25% (w / w), more preferably 1% to 25% (w / w), based on the total weight of the formulation. Petition 870250088327, dated 09 / 29 / 2025, pp. 300 / 333 64 / 84

[279] 8. The formulation of any of the above items, in which the active agent is 5-aminolevulinic acid, a derivative, a precursor, a metabolite and / or a pharmaceutically acceptable salt thereof.

[280] The formulation of item 8, in which 5-aminolevulinic acid, the derivative, the precursor, the metabolite thereof and / or the pharmaceutically acceptable salt thereof, is present in an amount from 0.01% to 25% (w / w), preferably 0.1% to 25% (w / w), more preferably 1% to 25% (w / w), based on the total weight of the formulation.

[281] 10. The wording of any of items 8 or 9, wherein the wording comprises an entity characterized by m / z = 246 in an amount less than or equal to 1.5%, 1.0% or 0.75% when stored for 3 months at 40 °C.

[282] 11. The wording of any of items 8 to 10, wherein the wording comprises an entity characterized by m / z = 246 in an amount less than or equal to 1.5%, 1.0%, 0.5% or 0.2% when stored for 6 months at 25 °C.

[283] 12. The formulation of any of the above items, where the formulation is a pharmaceutical formulation.

[284] 13. The formulation of any of the above items, where the formulation is for topical use and / or where the formulation is a lotion, a spray, a foam, an emulsion, a nanoemulsion, a gel or a cream.

[285] 14. The formulation of any of the above items, in which the active agent is dissolved in the aqueous phase and / or is able to interact with the surface of the nanovesicles.

[286] 15. The formulation of any of the above items, in which the active agent is a hydrophilic active agent.

[287] 16. The formulation of any of the above items, in which the Petition 870250088327, dated 09 / 29 / 2025, pp. 301 / 333 65 / 84 nanoemulsion comprises nanovesicles, wherein the nanovesicles have a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm when stored for one month at 40 °C.

[288] 17. The formulation of any of the preceding items, wherein the nanoemulsion comprises nanovesicles, wherein the nanovesicles have a size less than or equal to 500 nm, preferably in the range of 5 nm to 200 nm when stored for six months at 25 °C.

[289] 18. The formulation of any of the preceding items, in which the aqueous component is 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 80% to 95% (w / w).

[290] 19. The formulation of any of the above items, wherein the aqueous component comprises at least one pH buffering agent.

[291] 20. The formulation of item 19, in which the pH buffering agent is selected from the group consisting of citrate, phosphate, acetate and carbonate.

[292] 21. The wording of any of the above items, having a pH of 2 to 6.

[293] 22. The wording of any of the above items, having a pH of 2 to 4.

[294] 23. The formulation of any of the preceding items, in which at least one lipophilic component is selected from triglycerides and mixtures thereof.

[295] 24. The formulation of any of the above items, wherein at least one lipophilic component comprises a caprylic and / or capric triglyceride or a mixture thereof.

[296] 25. The wording of any of the above items, in which the Petition 870250088327, dated 09 / 29 / 2025, pp. 302 / 333 66 / 84 at least one lipophilic component is 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 10% (w / w), and more preferably from 0.5% to 8% (w / w) or 3% to 8% (w / w).

[297] 26. The formulation of any of the above items, wherein at least one surfactant comprises (a) a phospholipid, a lysophospholipid, a ceramide and / or a mixture thereof, and / or (b) a polyoxyethylene type surfactant.

[298] 27. The formulation of any of the above items, in which at least one surfactant comprises lecithin, preferably soy lecithin.

[299] 28. The nanoemulsion of item 27, in which the lecithin has a phosphatidylcholine content of at least 80% by weight.

[300] 29. The formulation of any of items 26 to 28, in which the phospholipid, lysophospholipid, ceramide and / or mixture thereof is present in an amount of 0.1% to 10% (w / w), based on the total weight of the nanoemulsion (a), preferably from 0.15% to 5% (w / w) and more preferably from 0.2% to 3% (w / w).

[301] 30. The formulation of any of items 26 to 29, in which the polyoxyethylene type surfactant comprises Polysorbate 80.

[302] 31. The formulation of any of items 26 to 30, in which the polyoxyethylene type surfactant is present in an amount of 0.1% to 10% (w / w), based on the total weight of the nanoemulsion (a), more preferably from 0.2% to 5% (w / w) and most preferably from 0.5% to 5% (w / w).

[303] 32. The formulation of any of the above items, in which at least one alcohol is selected from the group consisting of 1-propanol or Petition 870250088327, dated 09 / 29 / 2025, pp. 303 / 333 67 / 84 2-propanol and a mixture thereof.

[304] 33. The formulation of any of the preceding items, in which at least one alcohol is present in an amount of 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 2% (w / w).

[305] 34. The formulation of any of the above items, comprising at least one gelling agent.

[306] 35. The formulation of any of the preceding items, wherein 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.

[307] 36. The formulation of item 34 or 35, in which the gelling agent is selected from poloxamer, xanthan gum and / or mixtures thereof.

[308] 37. The formulation of any of the preceding items, in which the gelling agent is present in an amount of 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 1% to 4% (w / w).

[309] 38. The wording of any of the above items, additionally including at least one preservative.

[310] 39. The formulation of item 38, in which the preservative is benzoate, preferably sodium benzoate.

[311] 40. The formulation of item 38 or 39, in which the preservative is present in an amount of 0.01% to 3% w / w, based on the total weight of the formulation, preferably from 0.2% to 2% (w / w), and more preferably from 0.2% to 1.5% (w / w). Petition 870250088327, dated 09 / 29 / 2025, pp. 304 / 333 68 / 84

[312] 41. The wording of any of the above items, which is essentially paraben-free.

[313] 42. The formulation of any of the preceding items, characterized by a polydispersity index less than or equal to 0.8, wherein the polydispersity index is determined by dynamic light scattering.

[314] 43. The formulation of any of items 1 to 42, comprising: (a) a nanovesicle emulsion comprising (i) an aqueous component, present in an amount of 70% to 95% w / w, based on the total weight of the nanoemulsion (a).

[315] (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% 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) 0.1 to 20% of a photosensitizer or a metabolic precursor thereof, preferably 5-aminolevulinic acid hydrochloride, based on the total weight of the formulation; (c) 0.1 to 2% of at least one preservative, based on the total weight of the formulation; and wherein the formulation essentially does not comprise propylene glycol, and wherein the formulation preferably has a pH of 2 to 4.

[316] 44. The formulation of any of the preceding items, supplied in a container, wherein the container further comprises a propellant, Petition 870250088327, dated 09 / 29 / 2025, pages 305 / 333 69 / 84 and in which the propellant is supplied to pressurize the container and / or to pressurize the formulation in the container.

[317] 45. The formulation of any of the above items, for use in medicine.

[318] 46. The formulation of any of the above items, for use in a method of treatment and / or prevention of a dermatological disease or condition in an individual.

[319] 47. The formulation of any of the preceding items, for use in a method of treatment and / or prevention of a dermatological disease or condition in an individual, wherein the treatment and / or prevention of the dermatological disease or condition comprises: (a) administering topically to the individual a pharmaceutically effective amount of the formulation of any of items 1 to 46, to a diseased or affected area and, optionally, to an area around the diseased or affected area of ​​skin, and (b) incubating the pharmaceutical formulation in 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 the deep tissue layer.

[320] 48. The formulation for use of item 47, additionally comprising the step: (c) irradiate the area of ​​skin where the formulation was administered with light.

[321] 49. The formulation for use of either of items 47 or 48, wherein the area around the diseased or affected area of ​​skin includes an area of ​​at least about 5 mm in width.

[322] 50. The formulation for use of any of items 46 to 49, where the dermatological disease or condition includes diseases or conditions of the skin, Petition 870250088327, dated 09 / 29 / 2025, pages 306 / 333 70 / 84 cutaneous or mucosal appendages.

[323] 51. The formulation for use of any of items 46 to 50, wherein the dermatological disease or condition is 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.

[324] 52. The formulation for use of item 51, 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.

[325] 53. The formulation for use of item 51, 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.

[326] 54. The formulation for use of item 51, in which the infectious dermatological disease or condition is selected from the group consisting of bacterial infections, viral infections, fungal infections, parasitic infections Petition 870250088327, dated 09 / 29 / 2025, pages 307 / 333 71 / 84 and combinations thereof.

[327] 55. The formulation for use of item 51, 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, systemic lupus erythematosus, lichen planus, morphea, scleroderma, epidermolysis bullosa, dermatomyositis, graft-versus-host syndrome.

[328] 56. The formulation for use of any of items 47 to 50, 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.

[329] 57. The formulation of any of the above items, for use in a photodynamic diagnostic method of a neoplastic and / or proliferative dermatological disease or condition, such as benign or malignant neoplasms or precursors thereof; an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation, such as acne.

[330] 58. A method for preparing the formulation of any of items 1 to 57, comprising the following steps: (a) mixing at least one lipophilic component, at least one surfactant and at least one alcohol having at least three carbon atoms, and (b) bringing the mixture obtained in step (a) into contact with an aqueous component, under conditions that allow the formation of a nanoemulsion, Petition 870250088327, dated 09 / 29 / 2025, pages 308 / 333 72 / 84 where the active agent is added under conditions that allow interactions of the active agent with the surface of the nanovesicles when dissolved in the aqueous phase.

[331] 59. The method in item 58, additionally comprising (i) adding a gelling agent and / or (ii) adding a preservative.

[332] 60. A dispensing product comprising the formulation of any of items 1 to 57.

[333] 61. A container comprising the formulation of any of items 1 to 57.

[334] 62. Use of the formulation according to any of items 1 to 57, for the manufacture of a medicament for the treatment and / or prevention of a dermatological disease or condition in an individual.

[335] 63. 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 of any of items 1 to 57.

[336] 64. A photodynamic diagnostic method for a neoplastic and / or proliferative dermatological disease or condition, such as benign or malignant neoplasms or precursors thereof; an inflammatory dermatological disease or condition; and / or a condition associated with bacterial proliferation, such as acne, said method comprising (i) administering the formulation in accordance with any of items 1 to 57 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, Petition 870250088327, dated 09 / 29 / 2025, pp. 309 / 333 73 / 84 where increased 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.

[337] The present invention is further illustrated by the following figures and examples. Figure captions

[338] Figure 1: Content of known impurities (2-hydroxypropylaminolevulinate, m / z 190) and m / z 246 impurities in Formulation 1 (with propylene glycol) and Formulation 2 (without propylene glycol) after storage for 6 months at 25 °C or 40 °C.

[339] Figure 2: Chromatograms of known impurities (2-hydroxypropylδ-aminolevulinate; m / z 190) in / z 246 of impurity in Formulation 1 (with propylene glycol) and Formulation 2 (without propylene glycol) after storage for 3 months at 40 °C.

[340] Figure 3: Skin penetration of Formulation 1 (with propylene glycol) and Formulation 2 (without propylene glycol) in ex vivo human skin. PpIX: protoporphyrin IX. Error bars indicate standard deviation.

[341] Figure 4: Franz cell (above: diagram, below: photograph) Figure 5: Release of 5-ALA from Formulation 1 (with propylene glycol) and Formulation 2 (without propylene glycol) after 2.5 hours (linear interval of the Higuchi graph). The values ​​shown are the average values ​​of the sextuple experiment. Cumulative transport to the acceptor compartment is expressed as pg per cm² of membrane area as a function of the square root of time. Examples Petition 870250088327, dated 09 / 29 / 2025, pages 310 / 333 74 / 84 Example 1: Preparation of Nanoemulsions BF200, BF215 and BF220 Table 1: Lipophilic content of the nanoemulsions used in the Examples BF200 10% lipophilic content BF215 15% lipophilic content BF220 20% lipophilic content

[342] The qualitative and quantitative compositions of nanoemulsions BF200, BF215 and BF220 are presented in Table 2. 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 2.0-3.0 3.0-4.0 surfactant >90% phosphatidylcholine, for pharmaceutical use, USP 2 Polysorbate 80 (polyoxyethylene sorbitol monooleate) 3.4 4.5-5.5 6.0-7.0 surfactant Ph. Eur. 3 Caprylic / capric triglycerides 3.5 4.5-5.5 6.0-8.0 lipid core Ph. Eur. 4 Isopropyl alcohol 1.4 2.0-3.0 2.0-4.0 solvent Ph. Eur. Content (% w / w) ingredients 1 to 4 10.0 15.0 20.0 Phosphate buffer 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.

[343] The manufacturing process for 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)

[344] 10 mM phosphate buffer (1000 g), pH 6, was prepared, and the phosphate buffer was optionally 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 Petition 870250088327, dated 09 / 29 / 2025, pages 311 / 333 75 / 84 Ingredient Weight (g) Polysorbate 80 (polyoxyethylene sorbitol monooleate) 34 Caprylic / capric triglycerides 35 Isopropyl alcohol 14

[345] Soy lecithin (17 g) was weighed into a suitable container, isopropyl alcohol (14 g) was added, and the container 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 homogeneous and transparent 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).

[346] In all examples shown in the present invention, the BF200 nanoemulsion was used. Step 3: Nanoemulsion fabrication by mixing the aqueous component from Step 1 and the carrier from Step 2 to a lipid content of 10% (BF200)

[347] Manufacture 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 to 60 °C in a suitable container. Then, the carrier (concentrate) from Step 2 was heated to approximately 45 to 60 °C. Subsequently, the carrier was poured into the phosphate buffer under continuous stirring. Petition 870250088327, dated 09 / 29 / 2025, pages 312 / 333 76 / 84 with a propeller mixer, resulting in the formation of a stable trombe (or nozzle) with the largest possible diameter, without causing foaming or splashing. The resulting nanoemulsion was stirred for 15 minutes. Finally, the nanoemulsion was cooled to room temperature.

[348] In nanoemulsion BF215, 850 g of phosphate buffer (from Step 1) and 150 g of carrier were mixed. In nanoemulsion BF220, 800 g of phosphate buffer (from Step 1) and 200 g of carrier were mixed. Step 4: Preparation of the final formulation and primary packaging

[349] Optionally, the nanoemulsion can be sterilized by filtration.

[350] 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 pharmaceutical formulation, for example by adding water, a suitable buffer or an additional aqueous gel base with, for example, poloxamer 407 or xanthan gum.

[351] Pharmaceutical formulations with different nanoemulsions BF200, BF215 and BF220 were packaged in a conventional glass container or in a test tube of appropriate size, respectively. Example 2: Preparation of Gel Formulation 1, containing propylene glycol (comparative example) Step 1: Nanoemulsion Preparation

[352] The BF200 nanoemulsion is produced according to Example 1. Sodium benzoate, 5-ALA and propylene glycol were added under stirring to the BF200 nanoemulsion. Table 4: Composition of the Nanoemulsion, based on BF200 Nanoemulsion component per 287.35 mg of emulsion Petition 870250088327, dated 09 / 29 / 2025, pages 313 / 333 77 / 84 Nanoemulsion Component BF200 Soy Phosphatidylcholine 3.00 mg Polysorbate 80 6.00 mg Medium-chain triglycerides (Miglyol 812) 6.00 mg Isopropyl alcohol 2.50 mg Disodium phosphate dihydrate 0.03 mg Monosodium phosphate dihydrate 0.22 mg Purified water 157.25 mg 175.00 mg Components added to BF200 5-Aminolevulinic acid hydrochloride 100.000 mg Propylene glycol 10.000 mg Sodium benzoate 2.35 mg 112.350 mg 287.35 mg Step 2: Preparing a gel base with xanthan gum (XT).

[353] A round-bottom flask was disinfected with isopropanol. Water was placed in the bowl and then xanthan gum was spread over it. The resulting base gel was placed in a suitable beaker. Table 5: Base gel composition Gel base component: 712.65 mg of gel base; Xanthan gum 28.50 mg (4.0%); Purified water 684.15 mg (96.0%). Step 3: Formulation Preparation 1.

[354] 28.74% of the nanoemulsion produced in step 1 (including 17.5% of the BF200 nanoemulsion) and 71.26% of the xanthan gel base produced in step 2 are mixed and homogenized, resulting in Formulation 1. Table 6: Formulation Components of Gel 1 (BF200 nanoemulsion, gel base, 5-ALA, propylene glycol), mg per g of gel Component Formulation 1 per 1 g of gel 5-Aminolevulinic acid hydrochloride 100.000 mg Xanthan gum 28.50 mg Soy phosphatidylcholine 3.00 mg Polysorbate 80 6.00 mg Petition 870250088327, dated 09 / 29 / 2025, pages 314 / 333 78 / 84 Component Formulation 1 Medium-chain triglycerides (Miglyol 812) 6.00 mg Isopropyl alcohol 2.50 mg Disodium phosphate dihydrate 0.03 mg Monosodium phosphate dihydrate 0.22 mg Propylene glycol 10.000 mg Sodium benzoate 2.350 mg Purified water 841.4 mg

[355] Formulation 1 was placed in a 2 g test tube. Example 3: Preparation of Propylene Glycol-Free Gel Formulation 2 Step 1: Nanoemulsion Preparation

[356] Nanoemulsion BF200 is produced according to Example 1. Sodium benzoate and 5-ALA were added under stirring to nanoemulsion BF200. Formulation 2 does not contain propylene glycol. In view of Formulation 1, propylene glycol was replaced by the corresponding amount of xanthan gel base (10 mg / g, 1%). Table 7: Composition of the BF200-based nanoemulsion Nanoemulsion Component per 277.35 mg of BF200 emulsion: Soy phosphatidylcholine 3.00 mg, Polysorbate 80 6.00 mg, Medium-chain triglycerides (Miglyol 812) 6.00 mg, Isopropyl alcohol 2.50 mg, Disodium phosphate dihydrate 0.03 mg, Monosodium phosphate dihydrate 0.22 mg, Purified water 157.25 mg, 175.00 mg. Components added to BF200: 5-Aminolevulinic acid hydrochloride 100.000 mg, Propylene glycol 0.000 mg, Sodium benzoate 2.350 mg, 102.350 mg, 277.35 mg. Step 2: Preparing a gel base with xanthan gum (XT).

[357] The gel base is produced as described in Step 2 of the Example. 1. Petition 870250088327, dated 09 / 29 / 2025, pages 315 / 333 79 / 84 Table 8: Base gel composition Gel base component: 722.65 mg of gel base; Xanthan gum 28.90 mg (4.0%); Purified water 693.75 mg (96.0%). Step 3: Formulation Preparation 2.

[358] 27.74% of the nanoemulsion produced in step 1 (including 17.5% of the BF200 nanoemulsion) and 72.26% of xanthan gel base produced in step 2 are mixed and homogenized, resulting in Formulation 2. Table 9: Components of gel formulation 2 (BF200 nanoemulsion, gel base, 5-ALA), mg per g of gel Component Formulation 2 per 1 g of gel 5-Aminolevulinic acid hydrochloride 100.000 mg Xanthan gum 28.90 mg Soy phosphatidylcholine 3.0 mg Polysorbate 80 6.00 mg Medium chain triglycerides (Miglyol 812) 6.00 mg Isopropyl alcohol 2.5 mg Disodium phosphate dihydrate 0.03 mg Monosodium phosphate dihydrate 0.22 mg Propylene glycol 0.000 mg Sodium benzoate 2.350 mg Purified water 851.000 mg

[359] Formulation 2 was placed in a 2 g test tube. Example 4: Determination of vesicle size and polydispersity index by dynamic light scattering.

[360] The size of the nanovesicles, expressed as average z-size (e.g., in nm), and the homogeneity of the nanovesicle formulations, expressed as polydispersity index, were determined by dynamic light scattering (sometimes called Photon Correlation Spectroscopy (PCS) or Quasi-Elastic Light Scattering (QELS)). The technique is well known in the state of the art and well established for determining the size of nano or Petition 870250088327, dated 09 / 29 / 2025, pages 316 / 333 80 / 84 microparticles or vesicles in emulsions, suspensions or polymer solutions were measured using a laser. Measurements were conducted with a Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, United Kingdom). The measurement was performed according to the manufacturer's instructions.

[361] 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 5: Determination of impurities

[362] Qualitative and quantitative analysis of impurities was performed by LC-MS using positive electrospray ionization (ESI+). The scan change covered degradation products in a range of 100 to 2000 m / z. Example 6: Determination of viscosity

[363] Viscosity was measured by rotation (measurement geometry: cone / plate) with a constant shear rate of 90.0 s-1 at 20 °C. Example A Impurity content in a 5-ALA nanoemulsion gel (compared to a comparative formulation containing propylene glycol) after 6 months of storage.

[364] Formulation 1 (containing 1% propylene glycol) was prepared as described in Example 2. Formulation 1 (free of propylene glycol) was prepared as described in Example 3.

[365] 10 ml glass tubes containing Formulation 1 or Formulation 2 were stored for six months at 25 °C or 40 °C.

[366] Impurities were detected by mass spectrometry, as described in Example 5. Petition 870250088327, dated 09 / 29 / 2025, pp. 317 / 333 81 / 84

[367] The results are summarized in Figure 1. As expected, the 5-ALA ester and propylene glycol (2-hydroxypropyl A-aminolevulinate) is not present in Formulation 2 (without propylene glycol). An impurity with m / z = 246 was found in the comparative Formulation 1 (with propylene glycol) in an average amount of about 0.3% after storage at 25 °C and 1.2% after storage at 40 °C. Unexpectedly, the impurity was found in Formulation 2 (without propylene glycol) in an average amount of about 0.15% after storage at 25 °C and 0.6% after storage at 40 °C.

[368] This behavior is also illustrated in Figure 2. Chromatograms of known impurities (2-hydroxypropyl A-aminolevulinate; m / z 190) in / z 246 of impurity in Formulation 1 (with propylene glycol) and Formulation 2 (without propylene glycol) after storage for 3 months at 40 °C.

[369] Conclusion: A 5-ALA formulation, being free of propylene glycol, is safer / pharmaceutically more tolerable than a comparative 5-ALA formulation containing propylene glycol. Example B Ex vivo skin penetration study using human eyelid skin.

[370] Formulation 1 (with propylene glycol) was prepared as described in Example 2. Formulation 2 (without propylene glycol) was prepared as described in Example 3. Objective • Comparison of the skin penetration properties of Formulation 1 (with propylene glycol) and Formulation 2 (without propylene glycol) • Evaluate the amount of protoporphyrin IX (PpIX) in skin biopsy samples from fresh and vital skin after drug application. Experimental configuration Test material Petition 870250088327, dated 09 / 29 / 2025, pages 318 / 333 82 / 84 • Human upper eyelid skin from routine blepharoplasty (eyelid tightening) surgeries • Formulation 1 with propylene glycol (batch no. 166M, (1) in Figure 3) • Formulation 2 without propylene glycol (batch no. 111M, (2) in Figure 3) Methodology • Incubation of skin explants with the formulation for 0, 1, and 3 h • Cryosection, extraction of protoporphyrin IX from skin sections • Extraction of PpIX from tissues and fluorimetric analysis of PpIX content in lysates Results

[371] The results are summarized in Figure 3. • Averages of n=5 plotted as a function of time (incubation time) • PpIX concentrations increase with incubation time • Although propylene glycol is a well-known penetration enhancer, equivalent penetration results were obtained with the new Formulation 2 without propylene glycol compared to the comparative Formulation 1 with propylene glycol (the formulation without propylene glycol is not inferior to the formulation with propylene glycol). • The differences between the formulations at different times were not statistically significant (Mann-Whitney U test).

[372] Conclusion: A propylene glycol-free 5-ALA formulation that proves to be more stable than a comparative propylene glycol-containing 5-ALA formulation (Example 1) provides equivalent penetration efficacy. Example C In vitro release test of 5-aminolevulinic acid from Formulation 1 (with propylene glycol) and Formulation 2 (without propylene glycol)

[373] Formulation 1 (with propylene glycol) was prepared as Petition 870250088327, dated 09 / 29 / 2025, pages 319 / 333 83 / 84 described in Example 2 (Batch 166M). Formulation 2 (without propylene glycol) was prepared as described in Example 3 (Batch 110M). Objective • Development of a method and evaluation of in vitro release (according to the SUPAC-SS guideline (FDA, SUPAC, 1997)) of ALA from gel formulations (GMP GLP) Experimental configuration Test materials • Synthetic membranes (nylon, 0.20 µm) • IVRT (in vitro release test) with the so-called “Franz diffusion cell”, Figure 4 • Formulation 1 with propylene glycol (comparative gel) • Formulation 2 without propylene glycol Methodology • Analytical method for ALA quantification: HPLC-MS / MS Application, sampling and analysis of drugs • Application of a 300 mg ALA nanoemulsion on a nylon membrane (0.20 µm) • Incubation at 32 ± 1 °C and sampling at t = 20, 40, 60, 90, 120 and 150 min • n = 6 for each formulation (with / without propylene glycol) 0 12 Franz cells • HPLC-MS / MS for quantification of ALA in the receptor compartment Results

[374] The results are described in Figure 5: • Higuchi graph (Takeru Higuchi 1961: Rate of release of Petition 870250088327, dated 09 / 29 / 2025, pages 320 / 333 84 / 84 medicaments from ointment bases containing drugs in suspension (DOI: 10.1002 / jps.2600501018), cumulative transport of 5-ALA (in pg cm-2), against square root of time (in h-0.5). • The amount transported is greater for Formulation 2 without propylene glycol. • The standard deviations of the two curves completely overlap. • There is no significant difference between the two formulations tested. Statistical comparison of the slopes of the release curve: Table 10: Formulation 1 Formulation 2 90% confidence interval limits with propylene glycol without propylene glycol Lower limit 8th value (0.75) Upper limit 29th value (1.33) Significant difference Batch 166M K27033 Test item A Batch 110M K27080 Test item B 0.816 1.036 No • There is no significant difference between the two formulations tested. • The propylene glycol-free formulation should be considered at least as good as the propylene glycol formulation in terms of drug release.

[375] Conclusion: A propylene glycol-free 5-ALA gel formulation that proves to be more stable than a comparative 5-ALA formulation containing propylene glycol (Example 1) provides an equivalent in vitro release profile. Petition 870250088327, dated 09 / 29 / 2025, pages 321 / 333

Claims

1 / 5 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) an active agent comprising a carboxylic acid group, or a derivative, or salt of a carboxylic acid group, wherein the formulation comprises less than 1% w / w of propylene glycol or no propylene glycol.

2. Formulation according to claim 1, characterized in that the formulation comprises less than or equal to 0.9% w / w of propylene glycol or no propylene glycol.

3. Formulation according to claim 1 or 2, characterized in that the formulation essentially does not comprise any propylene glycol.

4. Formulation according to any one of claims 1 to 3, characterized in that the formulation does not comprise propylene glycol.

5. Formulation, according to any one of claims 1 to 4, characterized in that the formulation comprises none, essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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 5 carbon atoms.

6. Formulation, according to any one of claims 1 to 5, characterized in that the formulation comprises none, Petition 870250088327, dated 09 / 29 / 2025, page 322 / 333 2 / 5 essentially none, less than 1%, or less than or equal to 0.99%, 0.95%, 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 12 carbon atoms.

7. Formulation, according to any one of claims 1 to 6, characterized in that at least one alcohol comprises at least three carbon atoms, preferably 3, 4 or 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.

8. Formulation, according to any one of claims 1 to 7, 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.

9. Formulation, according to any one of claims 1 to 8, 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.

10. Formulation, according to any one of claims 1 to 9, characterized in that it comprises a total aqueous component in an amount of 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).

11. Formulation, according to any one of claims 1 to 10, 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), Petition 870250088327, dated 09 / 29 / 2025, page 323 / 333 3 / 5 preferably from 0.25% to 10% (w / w), and more preferably from 2% to 10% (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), more preferably from 1% to 5% (w / w) and even more preferably from 1% to 3%, based on the total weight of the nanoemulsion (a).

12. Formulation, according to any one of claims 1 to 11, characterized in that the active agent is a hydrophilic active agent.

13. Formulation according to any one of claims 1 to 12, characterized in that the active agent is a photosensitizer or a metabolic precursor thereof.

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

15. Formulation, according to any one of claims 1 to 14, characterized in that the active agent is present in an amount from 0.1% to 25% (w / w), based on the total weight of the formulation.

16. Formulation, according to any one of claims 1 to 15, characterized in that the nanoemulsion comprises nanovesicles, wherein the nanovesicles have a size less than or equal to 500 nm, preferably less than or equal to 200 nm, more preferably in the range of 5 nm to 200 nm when a) stored for one month, two months, three months, six months, twelve months or at least one month, at least two months, at least three months, at least six months or at least twelve months at 25 °C; and / or b) stored for one month, two months, three months, six months, twelve months at 25 °C. Petition 870250088327, dated 29 / 09 / 2025, p. 324 / 333 4 / 5 months, eighteen months, twenty-four months, thirty months, thirty-six months or at least one month, at least two months, at least three months, at least six months or at least twelve months, at least eighteen months, at least twenty-four months, at least thirty months or at least thirty-six months at 2 to 8 °C.

17. Formulation, according to any one of claims 1 to 16, characterized by a polydispersity index less than or equal to 0.4 when a) stored for one month, two months, three months, six months, twelve months or at least one month, at least two months, at least three months, at least six months or at least twelve months at 2 to 25 °C; and / or b) stored for one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, thirty months, thirty-six months or at least one month, at least two months, at least three months, at least six months or at least twelve months, at least eighteen months, at least twenty-four months, at least thirty months or at least thirty-six months at 2 to 8 °C.

18. Formulation, according to any one of claims 1 to 17, characterized in that it comprises at least one 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, guar gum, pectin, poly(ethylene oxide), polycarbophil, alginate, tragacanth gum, povidone, gelatin and mixtures thereof, more preferably wherein the gelling agent is selected from poloxamer, xanthan gum and mixtures thereof.

19. Formulation, according to any one of claims 1 to 18, characterized in that it is essentially free of parabens. Petition 870250088327, dated 09 / 29 / 2025, pp. 325 / 333 5 / 5 20. Formulation, according to any one of claims 1 to 19, characterized in that it is for use in medicine, in particular for use in a method of treatment and / or prevention of a dermatological disease or condition. Petition 870250088327, dated 09 / 29 / 2025, pp. 326 / 333

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