Pressurized nanoemulsion

Abstract

This invention relates to the stabilization of oil-in-water nanoemulsions in pressurized vessels. The nanovesicles contained in the nanoemulsions are particularly stable in terms of vesicle size and vesicle size uniformity even after long-term storage at different temperatures.

Description

Technical Field

[0001] The present invention relates to the stabilization of oil-in-water nanoemulsions for pharmaceutical and cosmetic uses contained in a pressurized container. The nanovesicles are particularly stable with respect to vesicle size and vesicle size uniformity even after long-term storage at different temperatures.

Background Art

[0002] Liquid nanoemulsions can be stored in a container under pressure using a propellant. These pressurized nanoemulsions can be discharged as a foam or a spray depending on the shape of the dispenser head.

[0003] Foam formulations and spray formulations are suitable for topical treatment because they can easily spread uniformly over the skin or treatment area and can reach areas that are difficult to reach, such as wrinkles and skin folds. These are considered convenient media for the topical administration of active agents.

[0004] Generally, foam formulations and spray formulations are easier to apply, have a lower density, and are more likely to spread compared to other topical dosage forms. In particular, compared to ointments, or creams and lotions, foam requires very little mechanical shear force to spread the formulation on the skin. This is a great advantage when applying a drug to severely inflamed skin (for example, in the case of sunburn where rubbing the formulation on the skin may cause pain or further inflammation). Furthermore, even when applied to a hairy area such as the scalp, these formulations are decomposed relatively quickly and easily reach the stratum corneum through the hair shaft. In this regard, since they exhibit the same behavior as lotions and scalp application liquids, patient compliance is improved.

[0005] Foam is a colloidal system in which bubbles are suspended or dispersed in a liquid medium. Liquid foam usually requires a certain kind of stabilizer or foaming agent to prevent or delay the coalescence of bubbles. Foam (especially foam for cosmetic or pharmaceutical use) is a very complex and delicate system.

[0006] There are several types of topical foams, including water-based foams such as commercially available shaving foams; water-based alcohol foams; emulsion-based foams containing oil and water components; and oleic foams with a high oil content. In skin treatment, oil-containing foams are preferred because the oil contributes to skin protection and moisturizing, which can improve the therapeutic effect of the formulation. Typically, foams are manufactured using liquefied hydrocarbon gas propellants such as propane, butane, and isobutane, or hydrofluorocarbon propellants.

[0007] Nanoemulsions are homogeneous, transparent, and slightly opalescent dispersions of oil and water. These dispersions are colloidal. The dispersed particles or vesicles in such emulsions consist of lipid cores surrounded by a monolayer of at least one surfactant or emulsifier. Nanoemulsions are characterized by exhibiting a predominantly monodisperse particle or vesicle size distribution, with an average particle or vesicle diameter of less than 200 nm, often less than 100 nm, and a polydispersity index of less than 0.4.

[0008] Nanoemulsions are generally more thermodynamically stable than conventional emulsions and microemulsions, but are often unstable under stress conditions such as high temperatures or freezing conditions. Because nanoemulsions are metastable and their structure is often dependent on the manufacturing process, they are fragile systems and can be difficult to incorporate into pharmaceutical or cosmetic compositions that require long-term stability. When nanoemulsions become unstable, opacity, creaming, or phase separation can occur. On the other hand, because nanoemulsions have fine and homogeneous nanovesicles, droplets, or globules, they can exhibit good texture and functional properties, making them a desirable medium for pharmaceutical and cosmetic compositions and thus offering useful applications in skincare.

[0009] In pharmaceutical and cosmetic formulations, nanoemulsions are combined with surfactants such as 5-aminolevulinic acid.

[0010] 5-aminolevulinic acid (also referred to herein as "ALA" or "5-ALA") is a small bioamino acid with a molecular weight (as HCl salt) of 167.59 g / mol and is highly hydrophilic. That is, it is readily soluble in water, and its octanol-water partition coefficient (logP) is approximately -3. ALA is used as a prodrug in photodynamic therapy (PDT) to promote the synthesis of protoporphyrin IX in diseased tissue, and subsequently, when irradiated with light of the appropriate wavelength, induces a photodynamic effect.

[0011] Known formulations of ALA for topical skin administration are unstable in aqueous solutions (see Reinhold, Future Oncology, 2017 Nov;13(27):2413-2428, doi:10.2217 / fon-2017-0247). To date, nanoemulsions using ALA have been formulated as gels containing 10% of the active ingredient. Previous gel formulations showed stability for up to 36 months at refrigerated temperatures (2-8°C), but were sensitive to higher temperatures (above standard room temperature). Exposure to higher temperatures was tolerated for a short period of one week, without posing a risk of deterioration in the quality of the medicinal product for human use.

[0012] Prior art has not taught any nanoemulsion compositions that exhibit high stability, either on their own or in combination with active pharmaceutical or cosmetic ingredients, even under stress conditions (e.g., high temperature or freezing conditions). The stability of such nanoemulsion compositions is characterized by the small droplet (nanovesicle) size and the predominantly monodisperse population of nanovesicles. Surprisingly, the inventors have found that these two properties remain stable over long periods and even under stress conditions when nanoemulsions are stored in a pressurized container. The concentration of active agents in cosmetic and pharmaceutical compositions using nanoemulsions is also favorably affected by pressurized formulations. When not stored in a pressurized container, the stability of the same formulation is significantly reduced, especially under stress conditions. Even more surprisingly, the stability of pressurized nanoemulsions does not depend on the presence and / or concentration of gelling agents known as emulsion stabilizers.

[0013] As mentioned above, nanoemulsions tend to aggregate under certain conditions, such as exposure to extreme temperatures, which increases droplet size and impairs the quality of the nanoemulsion.

[0014] From these aspects, it is clear that designing and preparing pressurized nanoemulsion compositions that exhibit high stability in terms of droplet size distribution and vesicle size distribution under different storage temperatures, compared to nanoemulsions not stored in pressurized containers, is by no means trivial or simple, but requires considerable inventive activity. [Overview of the project]

[0015] A first aspect of the present invention relates to a formulation. The formulation comprises (a) a nanoemulsion and (b) a propellant. The nanoemulsion comprises (i) at least one aqueous component and (ii) a carrier component. The carrier component comprises (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol. The formulation is contained in a pressurized vessel. The formulation is essentially free of fatty alcohols as a foam adjuvant.

[0016] A second aspect of the present invention relates to a method for stabilizing a nanoemulsion. The method comprises the following steps: (a) providing a nanoemulsion; (b) introducing the nanoemulsion into a container; and (c) adding a propellant to the container and pressurizing the container. The nanoemulsion comprises (i) at least one aqueous component; and (ii) a carrier component. The carrier component comprises (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol.

[0017] A third aspect of the present invention relates to the use of a nanoemulsion for the preparation of a foam or spray. The use comprises the following steps: (a) providing a formulation containing a nanoemulsion; (b) introducing the formulation containing the nanoemulsion into a container; (c) adding a propellant to the container to pressurize the container; and (d) releasing a foam or spray from the pressurized container. The nanoemulsion comprises (i) at least one aqueous component; and (ii) a carrier component comprising (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol.

[0018] A fourth aspect of the present invention relates to a container or a dispenser product including a container. The container or dispenser product includes a formulation. The formulation includes a nanoemulsion and (b) a propellant. The nanoemulsion includes (i) at least one aqueous component and (ii) a carrier component. The carrier component includes (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol. The formulation is essentially free of fatty alcohols. The container further includes a propellant. The propellant is provided for pressurizing the container.

[0019] A fifth aspect of the present invention relates to a foam obtained from the formulation of the first aspect.

[0020] A sixth aspect of the present invention relates to cosmetic applications of the formulation of the first aspect or the foam of the fifth aspect.

[0021] A seventh aspect of the present invention relates to a formulation of the first aspect or a form of the fifth aspect for use in pharmaceuticals. [Modes for carrying out the invention]

[0022] Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methodologies, protocols, and reagents described herein and may be modified. Furthermore, it should be understood that the terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0023] Preferably, the terms used in this specification are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[0024] Throughout the description of this specification, several documents are cited. Each document cited in this specification (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.) is hereby incorporated by reference in its entirety, whether mentioned above or below.

[0025] The elements of the present invention will be described below. It should be understood that these elements are listed with specific embodiments, but can be combined in any way and in any number to form further embodiments. The examples and preferred embodiments described in various forms should not be construed as limiting the present invention to only the explicitly described embodiments. This specification is to be understood as supporting and encompassing explicitly described embodiments in combination with any number of disclosed and / or preferred elements. Furthermore, all permutations and combinations of all elements described in this application should be considered to be disclosed by the description of this application, unless otherwise indicated in the context.

[0026] Throughout this specification and the following claims, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", are to be interpreted as including the stated integer or step or group of integers or steps but not as excluding any other integer or step or group of integers or steps. As used in this specification and the appended claims, the singular forms "a", "an" and "the" include the plural unless the context clearly dictates otherwise.

[0027] Generally, in pharmaceutical technology, topical formulations are selected to accommodate the physicochemical properties of the API and to improve or modulate both the skin / body surface permeability and stability. Usually, APIs with clearly different properties, such as molecular weight or degree of lipophilicity, require significantly different formulations as the appropriate vehicle.

[0028] In a preferred embodiment, the formulations of the present invention combine the advantages of a foam and a nanoemulsion.

[0029] The formulations of the present invention comprise the following three phases: (I) An aqueous phase or aqueous component, (II) A lipid phase or carrier component, and (III) A gas phase (i.e., a propellant).

[0030] The aqueous and lipid phases together form a nanoemulsion. The nanoemulsion exists in liquid form. Thus, the formulations of the present invention can also be described as comprising: · A liquid element comprising or consisting of a nanoemulsion, and · A gas element.

[0031] In the context of the present invention, the term “liquid” refers to a low-viscosity formulation of one or more fluids in which other components are dissolved or dispersed. In the context of this specification, low viscosity refers to a viscosity of ≤8 Pa·s (Pascal-seconds), ≤6 Pa·s, ≤5 Pa·s, preferably ≤4 Pa·s, ≤3 Pa·s, more preferably ≤1.0 Pa·s, or ≤0.5 Pa·s.

[0032] Those skilled in the art will know of suitable methods for measuring viscosity. Preferably, viscosity is determined as described in the Examples section.

[0033] Examples of the present invention demonstrate that the stability of formulations containing nanovesicles can be improved when stored in a pressurized storage device. In particular, stability is improved when stored under stress conditions such as high temperatures (e.g., 40°C) or freeze-thaw cycles.

[0034] The presence of a gelling agent such as xanthan gum or poloxamer can further improve stability, particularly at high temperatures (e.g., 40°C), and / or when subjected to freeze-thaw cycles. Surprisingly, the data from this invention show that the size stability of nanovesicles depends on the interaction between the lipid content and the gelling agent in pressurized formulations. This is not true for formulations stored in conventional storage devices such as tubes or glass vials that do not form foam. In the formulations of this invention, the addition of poloxamer results in better nanovesicle size stability under stress conditions (e.g., 40°C) at high lipid content (e.g., 20%). On the other hand, at low lipid content (e.g., 10%), better stability under stress conditions (e.g., 40°C) is obtained without the addition of a gelling agent. The gelling agent poloxamer can have contradictory effects on nanovesicle stability depending on the lipid content of the nanoemulsion. Poloxamer improves stability at high lipid content (e.g., 20%), but this effect was not observed at low lipid content (e.g., 10%). The discovery of this unique interaction is unprecedented in our existing knowledge.

[0035] The data of the present invention demonstrate that a high lipid content (e.g., 15-20% w / w relative to nanovesicles) can improve the foam strength (characterized by disintegration time) of foams produced from formulations containing nanovesicles, as described herein.

[0036] In the formulation of the present invention, the presence of xanthan gum improves the stability of the nanovesicle size under stress conditions (e.g., 40°C) in a pressurized container.

[0037] Furthermore, the present invention demonstrates that the stability of formulations containing nanovesicles, in which the activator is dissolved in the aqueous phase or in the nanovesicles, can be improved when stored in a pressurized device compared to conventional storage devices such as glass vials. Stability refers to both or either the nanovesicle size and / or the chemical stability of the active ingredients. The inventors have found that stabilizing effects can be observed in nanoemulsions (and foams derived therefrom) carrying activators with significantly different properties. Two examples useful for understanding the range of properties in terms of molecular weight and hydrophilicity are 5-aminolevulinic acid hydrochloride, a hydrophilic compound with a molecular weight of 131 g / mol, and tacrolimus, a lipophilic compound with a molecular weight of 804 g / mol. These exemplary compounds do not limit the scope of the present invention, but encompass hydrophilic and lipophilic compounds with molecular weights in the range of about 100 g / mol to about 1000 g / mol.

[0038] An exemplary formulation of the present invention comprises ALA. The formulation comprising ALA can be prepared, for example, with a 10% lipid phase (or carrier component).

[0039] Another embodiment of the present invention relates to a formulation containing TC. The release of TC from the formulation and its subsequent penetration into the skin can be improved using a nanoemulsion formulation, particularly a nanoemulsion foam, having, for example, a 20% lipid phase (or carrier component). Because of its soft texture, it is easy to apply and comfortable to use, so the foam may be even more beneficial in combination with TC. This adds value when treating sensitive or inflamed skin, such as atopic dermatitis or similar conditions. Furthermore, nanoemulsion foam formulations in a pressurized container can stabilize TC even under stress conditions.

[0040] Another example of the present invention is a nanoemulsion formulation containing an API of betamethasone propionate (BMP), a high-potency topical corticosteroid. BMP can be used to treat inflammatory skin diseases. The molecular weight of BMP is 392.46 g / mol, and its logP is 1.14. The BMP nanoemulsion according to the present invention can contain 15% carrier component. Thus, it has properties between ALA and TC, further highlighting the versatility of the nanoemulsion formulation of the present invention.

[0041] A first aspect of the present invention relates to a formulation. The formulation includes: (a) a nanoemulsion, (i) at least one aqueous component; (ii) A carrier component, (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Carrier components including Nanoemulsions including, (b) Propellant. Here, the formulation is contained in a pressurized container. Furthermore, the formulation essentially does not contain fatty alcohols.

[0042] Furthermore, the formulation contained in a pressurized container is also called a "pressurized formulation," and the nanoemulsion contained in the formulation may also be called a "pressurized nanoemulsion."

[0043] In some embodiments, the formulation is a lotion, spray, foam, emulsion, nanoemulsion, gel, or cream. In some embodiments, the formulation contained in a pressurized container is a lotion, emulsion, nanoemulsion, gel, or cream. In some embodiments, the formulation contained in a pressurized container is a lotion. In the context of this specification, lotion means a low-viscosity topical formulation intended for application to the skin. In preferred embodiments, the formulation is a liquid as described above. The pressurized formulation is released from the pressurized container as a spray or foam. In preferred embodiments of any of the embodiments described herein, the formulation containing a nanoemulsion is a foaming formulation. In the context of this specification, the term “foaming” means that foam is produced when the formulation is released from the pressurized container through a suitable valve. Valves suitable for forming foam from a liquid formulation contained in a pressurized container are known to those skilled in the art. Relevant information regarding the generation of foam from liquid formulations contained in pressurized containers can be found, for example, in "Pharmazeutische Technologie" 9th edition, Rudolf Voigt (Deutscher Apotheker Verlag Stuttgart 2000).

[0044] In preferred embodiments of the formulations described in the present invention, the aqueous component includes or forms an aqueous phase.

[0045] In preferred embodiments of the formulations described in the present invention, the carrier component comprises or consists of nanovesicles. In other words, the nanoemulsion comprises nanovesicles. In some embodiments, the nanovesicles comprise at least one lipophilic component, at least one surfactant, and at least one alcohol.

[0046] In a preferred embodiment, the formulation is provided for topical use.

[0047] It has been reported that fatty alcohols act as foaming agents in pressurized formulations, particularly foaming formulations.

[0048] In this specification, the term “foaming agent” refers to compounds that can increase the foaming ability of a formulation and / or stabilize the foam. In particular, the term “foaming agent” refers to fatty acids and fatty alcohols having at least six carbon atoms.

[0049] A formulation according to a first aspect of the present invention is essentially free of fatty alcohols. Preferably, the formulation is essentially free of fatty alcohols and essentially free of fatty acids. More preferably, the formulation is essentially free of foaming agents.

[0050] In the context of this specification, the expression “essentially does not contain” means that the formulation does not contain the compound, or that it contains the compound in less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), less than 0.2% (w / w), less than 0.1% (w / w), less than 0.08% (w / w), less than 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w), or less than 0.01% (w / w) of the compound, based on the total weight of the formulation.

[0051] When a formulation is described as "essentially free of compound X," it is always preferable that the formulation "does not contain compound X."

[0052] In the context of this specification, the term “fatty alcohol” refers to an alcohol having at least six carbon atoms, and usually between six and twenty-eight carbon atoms. Fatty alcohols can be saturated or unsaturated, and unbranched or branched. Fatty alcohols are usually straight-chain primary alcohols. As used herein, the term “fatty alcohol” refers to fatty alcohols in their individual form and does not include esters containing fatty alcohols.

[0053] In the context of this specification, the term “fatty acid” refers to a carboxylic acid having an aliphatic chain of at least six carbon atoms, typically between six and 28 carbon atoms. Fatty acids can be saturated or unsaturated, and unbranched or branched. The majority of naturally occurring fatty acids have unbranched chains of carbon atoms. As used herein, the term “fatty acid” refers to fatty acids in their individual form and does not include esters containing fatty acids.

[0054] The formulation is either free of fatty alcohols (in their own form or, in other words, as isolated molecules) or contains less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), less than 0.2% (w / w), less than 0.1% (w / w), less than 0.08% (w / w), less than 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w), or less than 0.01% (w / w) of fatty alcohols (in their own form or, in other words, as isolated molecules), based on the total weight of the formulation.

[0055] In particular, the formulations either do not contain fatty acids and fatty alcohols (in their individual forms or, in other words, as isolated molecules) or contain less than 0.5%(w / w), less than 0.4%(w / w), less than 0.3%(w / w), less than 0.2%(w / w), less than 0.1%(w / w), less than 0.08%(w / w), less than 0.07%(w / w), less than 0.06%(w / w), less than 0.05%(w / w), less than 0.04%(w / w), less than 0.03%(w / w), less than 0.02%(w / w), or less than 0.01%(w / w) of fatty acids and fatty alcohols (in their individual forms or, in other words, as isolated molecules) based on the total weight of the formulation.

[0056] Preferably, the formulation contains no foaming agent, or contains less than 0.5% (w / w), less than 0.4% (w / w), less than 0.3% (w / w), less than 0.2% (w / w), less than 0.1% (w / w), less than 0.08% (w / w), less than 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w), or less than 0.01% (w / w) of foaming agent based on the total weight of the formulation.

[0057] Remarkably, the formulation of the present invention, when contained in a pressurized container, exhibits high foaming ability even in the absence of fatty alcohols or other foaming agents, and forms a stable (long-collapse-time) foam when released from the pressurized container.

[0058] In a preferred embodiment, the formulation of the first aspect of the present invention essentially does not contain an emollient selected from monoesters or diesters containing an alcohol and a carboxylic acid.

[0059] In the context of this specification, the term "monoester" refers to a molecule containing only one ester group, and the term "diester" refers to a molecule containing only two ester groups.

[0060] In the context of this specification, the term "emollient" refers to a compound that has a softening or hydrating effect when applied to the skin. Emollients can form a protective film on the skin to prevent moisture loss.

[0061] Examples of emollients include isostearate esters, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolinate, pentaerythrityl tetrastatecate, neopentyl glycol di(caprylate / caprate), isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanolate, octyl hydroxystearate, and sucrose esters of fatty acids. Further examples include isopropyl myristate and glyceryl monostearate.

[0062] In particular, the formulation according to the first aspect of the present invention is essentially free of diisopropyl adipate, isopropyl myristate, and glyceryl monostearate.

[0063] Another example of an emollient is petrolatum. In the context of this specification, the term “petrolatum” refers to a semi-solid mixture of hydrocarbons obtained from petroleum distillation. The hydrocarbons constituting petrolatum mainly consist of at least 25 carbon atoms. The CAS number for petrolatum is 8009-03-8. Preferably, the formulations of the first aspect of the present invention are essentially free of petrolatum.

[0064] In preferred embodiments, the formulations of the first aspect of the present invention are essentially free of a gelling agent or contain only a small amount of a gelling agent. If the formulations of the first aspect of the present invention contain a gelling agent, the gelling agent is included in an amount that does not affect gel formation. As described above, the formulations of the first aspect of the present invention include a liquid element (an element containing a nanoemulsion) and a gaseous element (a propellant). If the formulation contains a gelling agent, the gelling agent is included at a concentration of 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.5% or less, based on the total weight of the formulation. If the formulation contains poloxamer as a gelling agent, poloxamer is included at a concentration of 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or 0.5% or less, based on the total weight of the formulation. If the formulation contains xanthan gum as a gelling agent, xanthan gum is included at a concentration of 2% or less, 1% or less, or 0.5% or less, based on the total weight of the formulation.

[0065] In a preferred embodiment, the formulation of the first aspect of the present invention is essentially free of a gelling agent.

[0066] In the context of this specification, the term "gelling agent" refers to polymeric agents that can increase the viscosity of a formulation. Gelling agents include poloxamer, xanthan gum, bentonite, sodium carboxymethylcellulose, hydroxymethylcellulose, carbomer, hydroxypropylcellulose, gellan gum, guar gum, pectin, poly(ethylene) oxide, polycarbophil, alginic acid, tragacanth, povidone, and gelatin. Gelling agents that enhance the stability of nanoemulsion formulations are described.

[0067] Remarkably, the formulation of the present invention contained in a pressurized container is extremely stable with respect to nanovesicle size, even in the absence of a gelling agent or in the presence of only very low concentrations of a gelling agent.

[0068] In some embodiments, the formulation includes an activator. Herein, the terms “activator” and “active ingredient” are used interchangeably. The activator may be dissolved in the aqueous phase and interactable with the surface of the nanovesicles, and / or the activator may be dissolved in the core of the nanovesicles. Surprisingly, the formulations of the present invention, housed in a pressurized vessel, are remarkably stable with respect to the concentration of the activator, both in the absence of a gelling agent and in the presence of only very low concentrations of a gelling agent.

[0069] As used herein, “interactive with the surface of nanovesicles” includes the activator non-covalently bonding with nanovesicles, particularly the surface of 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 the activator interacts with the surface of nanovesicles, and the remainder dissolves in the aqueous phase.

[0070] The small size and high homogeneity of the nanovesicles impart cosmetic-advantaged properties that distinguish them from conventional emulsions: the nanoemulsions of the present invention are transparent and exhibit a novel texture. Furthermore, the nanoemulsions of the present invention are capable of more efficient delivery of surfactants, and are therefore of increasing importance in the fields of medicine and pharmaceuticals.

[0071] The formulations of the present invention, provided in a pressurized container, exhibit remarkable resistance to degradation over time under stress conditions with respect to API content and nanoemulsion vesicle size, compared to nanoemulsions stored in non-pressurized containers such as tubes or glass vials. The active ingredient content remains stable over long periods in the formulations of the present invention. In some embodiments, stability can be further improved if the formulation includes an auxiliary or gelling agent selected from polymer agents such as xanthan gum or poloxamer 407.

[0072] As used herein, “degradation over time” refers to changes, decomposition, and / or degradation of the formulation and / or activator that affect the chemical and physical stability during storage, particularly under stress conditions. Such physical or chemical changes due to storage may include, but are not limited to, Ostwald ripening, aggregation, or coalescence. These may cause changes in the size or polydispersity index of nanovesicles.

[0073] Furthermore, as used herein, “deterioration over time” also refers to changes, decomposition, and / or degradation of the activator that affect the chemical and physical stability during storage, particularly under stress conditions. Such physical or chemical changes due to storage may include, but are not limited to, a decrease in the concentration of the activator or an increase in impurities.

[0074] In this specification, “stress conditions” for storage refer to temperatures significantly above room temperature (e.g., 40°C) or significantly below commonly used storage temperatures (e.g., below 0°C (-15°C to -25°C, etc.)).

[0075] Examples of the present invention demonstrate that the pressurized nanoemulsion of the present invention yields unexpectedly stable nanovesicle sizes under a variety of conditions, including stress conditions.

[0076] As used herein, "nanovesicle emulsion" or "nanoemulsion" refers to an oil dispersion in water (oil-in-water dispersion, oil-in-water emulsion, O / W emulsion). Nanoemulsions are monophase, transparent, and can be slightly milky white. The nanoemulsions of the present invention can be colloidal. Dispersed vesicles in such emulsions may consist of lipid cores surrounded by a monolayer of at least one surfactant or emulsifier. The nanoemulsions of the present invention may be characterized by an average vesicle size of less than 500 nm, less than 200 nm, or less than 100 nm. The nanoemulsions of the present invention may have a mainly monodisperse vesicle size distribution, for example, a vesicle size distribution characterized by a polydispersity index of 0.4 or less or 0.3 or less.

[0077] As used herein, “nanovesicle,” “nano vesicle,” “lipid vesicle,” “oil droplet,” “liquid droplet,” and “oil sphere” are interchangeable and refer to small oil droplets in an oil-in-water emulsion. Lipid vesicles of average size (see above (e.g., less than 500 nm, less than 200 nm, less than 100 nm)) consist of a single layer of surfactant and a lipid core. In the present invention, nanovesicles can have a size of 500 nm or less, 300 nm or less, or 200 nm or less, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.

[0078] In this specification, the terms “nanoparticle” or “nano particle” are distinguished from “nanovesicle” and refer to solid particles not described herein. The formulations of the present invention may be formulations that are essentially nanoparticle-free. “Simply nanoparticle-free” means that the formulation contains 2% or less by weight of nanoparticles or 1% or less by weight of nanoparticles, or does not contain nanoparticles at all. Nanoparticles are mainly inorganic or polymeric solid particles and may have sizes less than 100 nm, less than 200 nm, or less than 500 nm. The size can be determined by the methods described herein. For example, the formulation may not essentially contain nanoparticles with a diameter of less than 100 nm as determined by dynamic light scattering.

[0079] As used herein, “topical use” of the formulations of the present invention refers to application to a specific location on or within the body (particularly the human body). This includes, but is not limited to, the administration of the formulation to a body surface such as the skin or mucous membranes. Topical use may be epicutaneous, meaning that the formulation is administered directly to the skin. Topical use may be for pharmaceutical or cosmetic purposes.

[0080] As used herein, “stability” of a formulation containing nanovesicles as described herein 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 found to be stable. Indicators known to those skilled in the art to represent the integrity of nanovesicles are, for example, the average size and polydispersity index, as determined by the dynamic light scattering method described herein. Nanovesicles produced according to the present invention may have a size of less than 200 nm, preferably less than 100 nm, more preferably less than 50 nm, and even more preferably less than 30 nm immediately after production. Examples of the present invention show that, when stored under stress conditions, the size of nanovesicles in an unstabilized comparative formulation may increase to more than 1000 nm or more than 1500 nm. In contrast, the size of nanovesicles in the formulation of the present invention contained in a pressurized vessel remains small. For example, the formulations described herein are stable if the nanovesicles, when stored under stress conditions as described herein, are 500 nm or less, 300 nm or less, or 200 nm or less, preferably in the range of 5 nm to 200 nm, and more preferably in the range of 5 nm to 100 nm.

[0081] Furthermore, "stability" may also refer to the absence of processes described above as deterioration over time, which can lead to a decrease in the functionality or quality of the pharmaceutical product. The pharmaceutical compositions described in this invention are pharmaceutically effective as long as the nanovesicle size is 500 nm or less, 300 nm or less, or 200 nm or less, preferably in the range of 5 nm to 200 nm, and more preferably in the range of 5 nm to 100 nm.

[0082] Furthermore, "stability" may also refer to the stable content of a pharmaceutical or cosmetic surfactant. For example, if at least 70%, at least 80%, or at least 90% of the surfactant content remains present when stored under stress conditions as described herein, the content of a pharmaceutical or cosmetic surfactant during storage is considered stable.

[0083] In the context of this specification, whenever a period is described as "one month, two months, three months," etc., it means that the embodiment includes a period of "at least one month, at least two months, at least three months," etc.

[0084] In the formulation of the present invention containing ALA, the ALA content is, (i) After being stored at 40°C for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, the amount may be at least 90%, or at least 95%, and / or (ii) After storage at 25°C for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, the content may be at least 95%, or at least 97%, and / or (iii) After storage at 5°C for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, at least 95%, at least 97%, or at least 99% That's fine.

[0085] In the present invention formulation containing TC, the TC content is: (i) at least 90% after storage at 40°C for one month, and / or (ii) After storage at 40°C for one or two months, the percentage may be at least 78%, or at least 80%, and / or (iii) After storage at 40°C for one, two, or three months, the content may be at least 71%, or at least 75%, and / or (iv) After storage at 25°C for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, the percentage may be at least 90%, at least 95%, at least 97%, or at least 99%, and / or (v) After storage at 25°C for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, the content may be at least 83%, or at least 88%, and / or (vi) After storage at 5°C for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, or 24 months, the percentage may be at least 90%, at least 95%, at least 97%, at least 99%, or 100%. (vii) After storage at 5°C for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, the percentage may be at least 90%, at least 95%, at least 97%, at least 99%, or 100%. (viii) After storage at 5°C for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, or 48 months, at least 90%, at least 95%, at least 97%, at least 99%, or 100% That's fine.

[0086] In the present invention, the formulation may be stable for at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, or at least 36 months at high temperatures (e.g., 40°C). In particular, the formulation of the present invention may be stable for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 24 months, at least 36 months, or at least 48 months at temperatures between 2°C and 25°C, for example, between 15°C and 25°C or about 5°C. In particular, the formulation of the present invention may be stable even after being subjected to one, two, three, four, five, or more freeze-thaw cycles.

[0087] The nanovesicles contained in the formulation of the present invention have a stable size. The size of the nanovesicles during preparation is as follows. Importantly, the size remains within the indicated range, especially after storage under stressful conditions such as high temperatures or freeze-thaw cycles.

[0088] The formulations of the present invention are homogeneous (primarily monodisperse), characterized by a polydispersity index of 0.4 or less. The formulations of the present invention have a stable polydispersity index. The polydispersity index at the time of preparation is 0.4 or less. Importantly, the polydispersity index remains 0.4 or less even after storage under stressful conditions, particularly high temperatures or freeze-thaw cycles. In preferred embodiments of any aspect of the present invention, the polydispersity index is 0.3 or less.

[0089] The nanovesicles in the formulation of the present invention may have a size of 500 nm or less or 300 nm or less, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm, when stored in a pressurized container at 40°C for 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 18 months, or 24 months.

[0090] The nanovesicles in the formulations of the present invention may have a size (or diameter) of 500 nm or less or 300 nm or less, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 150 nm, especially when subjected to at least one freeze-thaw cycle, preferably one, two, three, four, or five freeze-thaw cycles. In particular, the xanthanum-containing formulations described herein may contain nanovesicles having such sizes.

[0091] At least one freeze-thaw cycle may include storing the formulation independently at below -15°C, preferably -24°C, and thawing at room temperature (e.g., independently selected from 15°C to 25°C). The formulation may be stored for a period of time during which cooling is possible, for example, at least 10 minutes, up to 30 minutes, up to 1 hour, up to 2 hours, up to 6 hours, or up to 12 hours. The formulation may be stored for a period of time, for example, up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or longer.

[0092] The nanovesicles in the formulations of the present invention may have a size (or diameter) of 500 nm or less or 300 nm or less, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 150 nm, when stored in a pressurized container at a temperature below -15°C, preferably -24°C. The formulations may be stored for a period of time that allows for cooling, for example, at least 10 minutes, up to 30 minutes, up to 1 hour, up to 2 hours, up to 6 hours, or up to 12 hours. In particular, the xanthanum-containing formulations described herein may contain nanovesicles having this size.

[0093] The vesicle size or diameter of the nanovesicles described herein can be expressed as a Z-mean (also referred to as the "Z-mean"). The size distribution of nanovesicles can be characterized by a polydispersity index. These parameters are known to those skilled in the art and are widely used in the art to characterize particles or vesicles in emulsions, suspensions, and / or polymer solutions.

[0094] In the present invention, the Z-mean (e.g., in nanometer units) and / or polydispersity index of the nanovesicle formulation 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 art and is established as a laser-based measurement of nanoparticles, microparticles, nanovesicles, or microvesicles in emulsions, suspensions, and / or polymer solutions.

[0095] In the formulations described herein, the total aqueous component may be present in an amount of 50% to 99% (w / w), preferably 70% to 95% (w / w), and more preferably 75% to 95% (w / w), based on the total weight of the nanoemulsion (a).

[0096] The aqueous component may contain at least one pH buffer. Any suitable buffer may be used. Suitable buffers are known to those skilled in the art. For example, at least one pH buffer may be selected from the group consisting of citrates, phosphates, acetates, and carbonates.

[0097] The pH of the aqueous component may be in the range of 2 to 9. Preferably, the pH of the aqueous component can be in the range of 2 to 7 or 2 to 6, for example, 2, 3, 4, 5, or 6, and more preferably in the range of 3 to 6 or 4 to 6, for example, 3, 4, 5, or 6. The pH of the aqueous component can also be in the range of 7 to 9.

[0098] In the formulations described herein, at least one lipophilic component may be selected from triglycerides and mixtures thereof.

[0099] Preferably, at least one lipophilic component is a lipid, vegetable oil, synthetic oil, and / or animal oil. Suitable lipids according to the present invention are physiologically acceptable lipids such as ceramides, mono-, di-, and triacylglycerin (triglycerides). In particular, at least one lipophilic component is a triglyceride, especially C 8-10The triglycerides containing fatty acids, or mixtures thereof. More specifically, at least one lipophilic component is caprylic acid triglyceride and / or capric acid triglyceride, and / or mixtures thereof, particularly preferably miglyol (e.g., Miglyol 812 available from IOI Oleochemical) or myritol (e.g., Myritol 318 available from BASF). Suitable vegetable and animal oils include, for example, sunflower oil, soybean oil, peanut oil, rapeseed oil, fish oil, and / or cetaceum oil.

[0100] In the formulations described herein, at least one lipophilic component may be present in an amount of 0.1% to 30% (w / w), preferably 0.25% to 15% (w / w), preferably 0.25% to 10% (w / w), more preferably 0.5% to 8% (w / w), or 3% to 8% (w / w), based on the total weight of the nanoemulsion (a). Furthermore, it is preferable that at least one lipophilic component be present in an amount of 10% to 30% (w / w), and more preferably 15% to 30% or 20% to 30%, based on the total weight of the nanoemulsion (a).

[0101] In the formulations described herein, triglycerides or triglycerides may be present in an amount of 2% to 10% (w / w), preferably 3% to 8% (w / w), based on the total weight of the nanoemulsion (a).

[0102] In the formulations described herein, at least one surfactant may be any suitable surfactant known to those skilled in the art.

[0103] Surfactants, also known as surfactants or emulsifiers, are well known in the art and include any agents that bind oil and water in a composition to form an emulsion. Surfactants are amphiphilic, meaning they reduce the surface tension between two liquids. In emulsions, they are called emulsifiers, and they coat droplets to prevent them from adhering together. Emulsifiers can be expressed by their hydrophilic / lipophilic balance (HLB), which indicates their affinity for water or oil. Low HLB (e.g., HLB=1) refers to lipophilic emulsifiers, and high HLB (e.g., HLB=20) refers to hydrophilic emulsifiers. Generally, lipophilic emulsifiers are used in water-in-oil emulsions, and hydrophilic emulsifiers are used in oil-in-water emulsions. Those skilled in the art will identify which emulsifiers or mixtures thereof are suitable for the preferred medium and purpose of the composition. In certain emulsions, a combination of emulsifiers may be advantageous.

[0104] Suitable film-forming surfactants are phospholipids, lysophospholipids, ceramides, and / or mixtures thereof. Preferably, the phospholipids are lecithin or cephalin derived from soybeans or chicken eggs. More preferably, at least one surfactant is lecithin, most preferably soybean lecithin.

[0105] In the formulations described herein, phospholipids, lysophospholipids, ceramides and / or mixtures thereof may be present in an amount of 1% to 10% (w / w) based on the total weight of nanoemulsion (a), preferably in an amount of 1.25% to 5% (w / w), more preferably 1.5% to 4% (w / w), and most preferably 1.5% to 2% (w / w) based on the total weight of nanoemulsion (a).

[0106] In the formulations described herein, phospholipids, lysophospholipids, ceramides, and / or mixtures thereof may be present in amounts of 0.1% to 10% (w / w), preferably 0.15% to 5% (w / w), more preferably 0.2% to 3% (w / w) or 0.2% to 4% (w / w), and most preferably 0.2% to 0.4% (w / w), based on the total weight of the formulation.

[0107] 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., the phosphatidylcholine content, plays an important role with respect to the size of the nanoemulsion vesicles. The higher the phosphatidylcholine content of the lecithin, the smaller the size of the nanoemulsion vesicles.

[0108] As for O / W emulsion-forming surfactants, anionic, nonionic, cationic, and / or amphoteric surfactants are preferred, similar to block copolymers. Preferred anionic surfactants are soaps, alkylbenzene sulfons, alkanesulfons, alkyl sulfates, and / or alkyl ether sulfates. Preferred cationic surfactants are quaternary ammonium compounds, preferably those having one or two hydrophobic groups (e.g., cetyltrimethylammonium bromide and cetyltrimethylammonium chloride) and / or salts of long-chain primary amines. Preferred amphoteric surfactants are N-(acylamidoalkyl)betaines, alkylammonium phosphate compounds, N-alkyl-β-aminopropionates, and / or amine-N-oxides. A suitable copolymer building block is, for example, propylene oxide. In the present invention, nonionic surfactants are particularly preferred as O / W emulsion-forming surfactants.

[0109] In the formulations described herein, at least one surfactant may be any polyoxyethylene-type surfactant. Preferred nonionic surfactants may be selected from the group consisting of fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, alkyl polyglucosides, fatty acid glucamides, fatty acid polyglycol ethers, ethylene oxide-propylene oxide-block polymers, polyglycerol fatty acid esters, fatty acid alkanolamides, and (ethoxylated) sorbitan fatty acid esters (sorbitan). Particularly preferred ethoxylated sorbitan fatty acid esters are polyoxyethylene sorbitan monooleate, most preferably polysorbate 80.

[0110] At least one surfactant, such as a polyoxyethylene-type surfactant, may be present in an amount of 1% to 10% (w / w), preferably 2% to 10% (w / w), 2% to 8% (w / w), and more preferably 3% to 7% (w / w), based on the total weight of the nanoemulsion (a).

[0111] The formulation of the present invention may contain at least one hydrophilic surfactant, particularly polysorbate 80, having an HLB of 9 to 17, more preferably 12 to 16.

[0112] At least one surfactant may be a sugar-based surfactant. Sugar-based surfactants are a group of nonionic surfactants in which a hydrophilic sugar is bonded to a hydrophobic tail. One common substance in this class is n-dodecyl-β-D-maltoside, a type of maltoside surfactant named for the maltose sugar unit used. An example of a pyranoside surfactant is n-octyl-β-D-thioglucopyranoside. This class uses pyranose as its sugar unit. Examples of glycoside surfactants include octyl glucoside, decyl glucoside, and lauryl glucoside. An example of a polysaccharide surfactant is digitonin.

[0113] Another very important group of sugar-based surfactants are Tween surfactants, the most well-known being Tween 20 (also referred to herein as polysorbate 20) and Tween 80 (also referred to herein as polysorbate 80). These surfactants are generally called polysorbate surfactants because they are based on sorbitan sugars. Three oligo(ethylene glycol) side groups of different lengths are bonded to the sugar, thereby increasing the hydrophilicity of the head group. This structure forms the core of all Tween surfactants. They differ in their hydrophobic tails, which are fatty acids esterified to four oligo(ethylene glycol) tails. In Tween 20, this fatty acid is lauric acid, and in Tween 80, it is oleic acid.

[0114] In some embodiments, at least one surfactant is selected from the group consisting of phospholipids, particularly phosphatidylcholine, lysophospholipids, ceramides, and / or mixtures 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 and a polyoxyethylene-type surfactant as surfactants. In some embodiments, the formulation comprises phosphatidylcholine and a polyoxyethylene-type surfactant as surfactants. In some embodiments, the formulation comprises phosphatidylcholine and polysorbate 80 as surfactants.

[0115] In the formulations described herein, at least one alcohol contains five or fewer carbon atoms and may independently have three to five or three to four carbon atoms. Particularly preferred alcohols having five carbon atoms are 1-pentanol and / or 4-methyl-2-pentanol. Preferred alcohols having four carbon atoms are 1-butyl alcohol, iso-butyl alcohol (2-methyl-1-propanol), tert-butyl alcohol (2-methyl-2-propanol), and / or sec-butyl alcohol (2-butanol).

[0116] Preferably, at least one alcohol has 3 to 5 carbon atoms, more preferably 3 carbon atoms, and is selected from the group consisting of 1-propanol or 2-propanol (isopropyl alcohol) and mixtures thereof. The preferred alcohol is 2-propanol.

[0117] In the formulations described herein, the alcohol may be present in an amount of 0.1% to 10% (w / w), preferably 0.5% to 5% (w / w), and more preferably 1% to 3% (w / w), based on the total weight of the nanoemulsion (a).

[0118] In the formulations described herein, the alcohol may be a C3-C5 alcohol present in an amount of 1% to 5% (w / w) based on the total weight of the nanoemulsion (a).

[0119] Any suitable propellant may be used in the formulations described herein. Suitable propellants and mixtures thereof are known to those skilled in the art. Preferably, the propellant is selected from propane, isobutane, n-butane, and mixtures thereof. More preferably, the propellant is a mixture of propane and isobutane. In particular, the propellant is provided for pressurizing the container in which the formulation of the present invention is supplied.

[0120] The formulations described herein may contain a gelling agent. The inventors have found that while the gelling agent in the formulations described herein is not necessary to obtain a stable formulation or to form a foam, it can further enhance the formulation's resistance to degradation over time. A suitable gelling agent may be used. Suitable gelling agents and mixtures thereof are known to those skilled in the art. In the formulations described herein, 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.

[0121] If the formulation of the present invention contains a gelling agent, the gelling agent is preferably selected from poloxamer, xanthan gum, and / or mixtures thereof.

[0122] If the formulation of the present invention contains a gelling agent, the gelling agent is particularly preferably a poloxamer.

[0123] If the formulation of the present invention contains a gelling agent, the gelling agent is particularly preferably xanthan gum.

[0124] Poloxamers are nonionic triblock copolymers containing a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) sandwiched between two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Commercially available poloxamers include poloxamer 407 and poloxamer 188. Poloxamer 407 may have an average molecular weight of approximately 12,600 daltons. Poloxamer 188 may have an average molecular weight of approximately 8,400 daltons. In the formulations described herein, the preferred poloxamer is poloxamer 407.

[0125] In the formulations described herein, the gelling agent may be present in an amount of 0.1% to 10% (w / w), preferably 0.25% to 5% (w / w), and more preferably 0.5% to 4% (w / w), based on the total weight of the formulation.

[0126] The nanovesicles in the formulation of the present invention containing a gelling agent may have a size (or diameter) of 500 nm or less or 300 nm or less, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 150 nm, after being subjected to at least one freeze-thaw cycle, preferably one, two, three, four, or five freeze-thaw cycles. The freeze-thaw cycle may be one of those described herein.

[0127] Nanovesicles in the formulation of the present invention, which contains at least one gelling agent, may have a size (or diameter) of 500 nm or less or 300 nm or less, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 150 nm, when stored in a pressurized container at -15°C to -25°C, preferably -24°C, for, for 4 days. The storage conditions are as described herein.

[0128] In one embodiment, in the formulation described herein, at least one lipophilic component is present in an amount of 0.1% to less than 15% (w / w), preferably 0.1% to less than 10% (w / w), preferably 0.25% to less than 10% (w / w), more preferably 0.5% to 8% (w / w) or 3% to 8% (w / w), based on the total weight of the nanoemulsion (a), and the formulation is essentially free of gelling agents. In particular, the formulation is free of gelling agents. In this embodiment, the formulation may not contain poloxamers such as poloxamer 407 and poloxamer 188. In this embodiment, the formulation may not contain xanthan gum. In this embodiment, the formulation may not contain xanthan gum and poloxamers (e.g., poloxamer 407 and poloxamer 188). The at least one lipophilic component is as described herein.

[0129] In another embodiment, the formulation described herein includes: (I) At least one lipophilic component is present in an amount of at least 10% to 30% (w / w), preferably at least 15% to 30% (w / w), and more preferably at least 20% to 30% (w / w), based on the total weight of the nanoemulsion (a). (II) The formulation contains a gelling agent in an amount of less than 10% based on the total weight of the formulation, in particular 0.1% to 10% (w / w), preferably 0.25% to 5% (w / w), and more preferably 0.5% to 4% (w / w), based on the total weight of the formulation. In particular, the gelling agent is a poloxamer such as poloxamer 407 and / or poloxamer 188, as described herein.

[0130] At least one lipophilic component is as described herein.

[0131] The formulations described herein may contain preservatives. Any suitable preservative may be used. Suitable preservatives are known to those skilled in the art. The preservative may be selected from benzoates, citric acid, EDTA, potassium sorbate, vitamin C and / or its derivatives, and any mixture thereof. The preservative is preferably sodium benzoate. Suitable aqueous mixtures of sodium benzoate and potassium sorbate are commercially available, for example, Euxyl® k712 preservative (Ashland).

[0132] The preservative may be present in the formulation described herein in an amount of 0.01% to 3% (w / w), preferably 0.2% to 2% (w / w) or 0.1% to 2% (w / w), more preferably 0.2% to 1.5% (w / w), based on the total weight of the formulation.

[0133] In particular, the formulations of the present invention are essentially paraben-free, and preferably paraben-free. The class of paraben compounds includes p-hydroxybenzoic acid and esters of p-hydroxybenzoic acid (also known as 4-hydroxybenzoic acid).

[0134] Parabens are only slightly soluble in water. In the preparation of aqueous formulations or formulations containing aqueous components, it is necessary to dissolve the parabens in a solvent suitable for introducing them into the aqueous phase. A suitable solvent is propylene glycol.

[0135] 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 methyl ethylene glycol).

[0136] In this invention, since the preparation of a paraben solution in propylene glycol is unnecessary, the formulation of this invention can be made without propylene glycol.

[0137] The formulation of the present invention may be essentially propylene glycol-free, and preferably propylene glycol-free.

[0138] The formulation of the present invention may be essentially free of propylene glycol and parabens, and preferably free of propylene glycol and parabens.

[0139] As defined above, the formulation is preferably free of propylene glycol, or contains only a small amount of propylene glycol, and is also preferably free of, essentially free of, or contains in amounts less than 0.9% w / w, less than 0.8% w / w, less than 0.7% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, or less than 0.1% w / w of acyclic polyols having 2 to 3 (i.e., 3 or less) carbon atoms. Preferably, the formulation does not contain, essentially does not contain, or contains acyclic polyols 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., 4 or fewer, 5 or fewer, 6 or fewer, 7 or fewer, 8 or fewer, 9 or fewer, or 10 or fewer carbon atoms, respectively), or contains them in amounts less than 0.9% w / w, less than 0.8% w / w, less than 0.7% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, or less than 0.1% w / w. More preferably, the formulation does not contain, essentially does not contain, or contains in amounts less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% (w / w) polyols 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, respectively. More preferably, the formulation does not contain, essentially does not contain, or contains in amounts less than 0.9% w / w, less than 0.8% w / w, less than 0.7% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, or less than 0.1% w / w acyclic polyols having 2 to 15, 2 to 20, 25, or 2 to 30 carbon atoms (i.e., having 15 or fewer, 20 or fewer, 25 or fewer, or 30 or fewer carbon atoms respectively).More preferably, the formulation does not contain, essentially does not contain, or contains in amounts less than 0.9% w / w, less than 0.8% w / w, less than 0.7% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, or less than 0.1% w / w polyols having 2 to 15, 2 to 20, 25, or 2 to 30 carbon atoms (i.e., having 15 or fewer, 20 or fewer, 25 or fewer, or 30 or fewer carbon atoms respectively). More preferably, the formulation is free from acyclic polyols, essentially free from them, or contains them in amounts less than 0.9% w / w, less than 0.8% w / w, less than 0.7% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, or less than 0.1% w / w.

[0140] In the context of this specification, “acyclic polyol” means a polyol that does not contain a cyclic hydrocarbon moiety, in particular a cyclic sugar moiety. Acyclic polyols may be linear or branched. Acyclic polyols may contain diols, triols, or more than three OH groups.

[0141] In a preferred embodiment, the formulation of the present invention does not contain, essentially does not contain, or contains in amounts less than 0.9% w / w, less than 0.8% w / w, less than 0.7% w / w, less than 0.6% w / w, less than 0.5% w / w, less than 0.4% w / w, less than 0.3% w / w, less than 0.2% w / w, or less than 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.

[0142] As used herein, the expressions “essentially free of compound X,” “essentially does not contain compound X,” or “essentially does not contain compound X” are interchangeable with respect to a formulation. In particular, unless otherwise defined, these expressions mean that the formulation does not contain compound X, or that it contains 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.

[0143] As used herein, the expression "a composition containing less than X% of compound X" means that embodiments include the composition being essentially free of compound X.

[0144] In this specification, "the formulation is essentially propylene glycol-free" or "the formulation is essentially propylene glycol-free" means that the formulation is essentially propylene glycol-free. In particular, the pharmaceutical formulation of the present invention is propylene glycol-free, i.e., the formulation does not contain propylene glycol.

[0145] The formulation of the present invention does not necessarily have to contain propylene glycol.

[0146] The formulation of the present invention does not necessarily need to contain glycerin.

[0147] The formulation of the present invention does not necessarily need to contain diglycerin.

[0148] The formulation of the present invention does not necessarily have to contain polyglycerin.

[0149] The formulation of the present invention does not necessarily have to contain diethylene glycol.

[0150] The formulation of the present invention does not necessarily have to contain dipropylene glycol.

[0151] The formulation of the present invention does not necessarily have to contain butylene glycol.

[0152] The formulation of the present invention does not necessarily have to contain pentylene glycol.

[0153] The formulation of the present invention does not necessarily have to contain hexylene glycol.

[0154] The formulation of the present invention does not necessarily have to contain 1,3-propanediol.

[0155] The formulation of the present invention does not necessarily have to contain 1,5-pentanediol.

[0156] The formulation of the present invention does not necessarily have to contain octane-1,2-diol.

[0157] The formulation of the present invention does not necessarily have to contain polyethylene glycol having 2 to 50 ethylene oxide groups.

[0158] The formulations of the present invention do not necessarily have to contain monosaccharides and disaccharides such as sorbitol, mannitol, and mixtures thereof.

[0159] The formulations of the present invention may contain propylene glycol in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain propylene glycol. As described herein, the formulations may not contain parabens.

[0160] In particular, the formulations of the present invention may contain 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w of propylene glycol. As described herein, the formulations may be paraben-free.

[0161] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of propylene glycol. As described herein, the formulation may be paraben-free.

[0162] More specifically, the formulation of the present invention may contain 0.3% w / w or 0.1% w / w or less of propylene glycol. As described herein, the formulation may be paraben-free.

[0163] In a preferred embodiment, the formulation of the present invention does not contain propylene glycol.

[0164] The formulation of the present invention may contain glycerin at a concentration of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain glycerin. As described herein, the formulation may not contain parabens.

[0165] In particular, the formulation of the present invention may contain glycerin at a concentration of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0166] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of glycerin. As described herein, the formulation may not contain parabens.

[0167] More specifically, the formulation of the present invention may contain 0.3% w / w or less of glycerin, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0168] The formulation of the present invention may contain diglycerin at a concentration of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain diglycerin. As described herein, the formulation may not contain parabens.

[0169] In particular, the formulation of the present invention may contain diglycerin at a concentration of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0170] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of diglycerin. As described herein, the formulation may not contain parabens.

[0171] More specifically, the formulation of the present invention may contain 0.3% w / w or less of diglycerin, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0172] The formulation of the present invention may contain polyglycerin in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain polyglycerin. As described herein, the formulation may not contain parabens.

[0173] In particular, the formulation of the present invention may contain polyglycerin at a concentration of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0174] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of polyglycerin. As described herein, the formulation may be paraben-free.

[0175] More specifically, the formulation of the present invention may contain 0.3% w / w or less of polyglycerin, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0176] The formulation of the present invention may contain diethylene glycol in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain diethylene glycol. As described herein, the formulation may not contain parabens.

[0177] In particular, the formulation of the present invention may contain diethylene glycol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may not contain parabens.

[0178] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of diethylene glycol. As described herein, the formulation may not contain parabens.

[0179] More specifically, the formulation of the present invention may contain 0.3% w / w or less, or 0.1% w / w or less, of diethylene glycol. As described herein, the formulation may not contain parabens.

[0180] The formulations of the present invention may contain dipropylene glycol in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain dipropylene glycol. As described herein, the formulations may not contain parabens.

[0181] In particular, the formulations of the present invention may contain dipropylene glycol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulations may be paraben-free.

[0182] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of dipropylene glycol. As described herein, the formulation may be paraben-free.

[0183] More specifically, the formulation of the present invention may contain 0.3% w / w or less, or 0.1% w / w or less, of dipropylene glycol. As described herein, the formulation may be paraben-free.

[0184] The formulation of the present invention may contain butylene glycol in an amount of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain butylene glycol. As described herein, the formulation may not contain parabens.

[0185] In particular, the formulations of the present invention may contain butylene glycol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulations may be paraben-free.

[0186] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of butylene glycol. As described herein, the formulation may be paraben-free.

[0187] More specifically, the formulation of the present invention may contain 0.3% w / w or less, or 0.1% w / w or less, of butylene glycol. As described herein, the formulation may be paraben-free.

[0188] The formulation of the present invention may contain pentylene glycol in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain pentylene glycol. As described herein, the formulation may not contain parabens.

[0189] In particular, the formulation of the present invention may contain pentylene glycol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0190] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of pentylene glycol. As described herein, the formulation may not contain parabens.

[0191] More specifically, the formulation of the present invention may contain 0.3% w / w or less, or 0.1% w / w or less, of pentylene glycol. As described herein, the formulation may be paraben-free.

[0192] The formulation of the present invention may contain hexylene glycol in an amount of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain hexylene glycol. As described herein, the formulation may not contain parabens.

[0193] In particular, the formulation of the present invention may contain hexylene glycol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0194] More specifically, the formulation of the present invention may contain 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less of hexylene glycol. As described herein, the formulation may be paraben-free.

[0195] More specifically, the formulation of the present invention may contain 0.3% w / w or less of hexylene glycol, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0196] The formulation of the present invention may contain 1,3-propanediol in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain 1,3-propanediol. As described herein, the formulation may not contain parabens.

[0197] In particular, the formulation of the present invention may contain 1,3-propanediol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0198] More specifically, the formulation of the present invention may contain 1,3-propanediol in an amount of 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may not contain parabens.

[0199] More specifically, the formulation of the present invention may contain 0.3% w / w or less of 1,3-propanediol, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0200] The formulation of the present invention may contain 1,5-pentanediol in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain 1,5-pentanediol. As described herein, the formulation may not contain parabens.

[0201] In particular, the formulation of the present invention may contain 1,5-pentanediol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0202] More specifically, the formulation of the present invention may contain 1,5-pentanediol in an amount of 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0203] More specifically, the formulation of the present invention may contain 0.3% w / w or less of 1,5-pentanediol, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0204] The formulation of the present invention may contain octane-1,2-diol in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain octane-1,2-diol. As described herein, the formulation may not contain parabens.

[0205] In particular, the formulation of the present invention may contain octane-1,2-diol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0206] More specifically, the formulation of the present invention may contain octane-1,2-diol in an amount of 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0207] More specifically, the formulation of the present invention may contain octane-1,2-diol in an amount of 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0208] The formulation of the present invention may contain polyethylene glycol in an amount of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain polyethylene glycol. The polyethylene glycol particularly has 2 to 50 ethylene oxide groups. As described herein, the formulation may not contain parabens.

[0209] In particular, the formulation of the present invention may contain polyethylene glycol having 2 to 50 ethylene oxide groups in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0210] More specifically, the formulation of the present invention may contain polyethylene glycol having 2 to 50 ethylene oxide groups in an amount of 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0211] More specifically, the formulation of the present invention may contain polyethylene glycol having 2 to 50 ethylene oxide groups in an amount of 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulation may be paraben-free.

[0212] The formulations of the present invention may contain monosaccharides and disaccharides such as sorbitol, mannitol, and mixtures thereof in amounts of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less. As described herein, the formulations may be paraben-free.

[0213] In particular, the formulations of the present invention may contain monosaccharides and disaccharides such as sorbitol, mannitol, and mixtures thereof in amounts of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less, or may not contain monosaccharides and disaccharides such as sorbitol, mannitol, and mixtures thereof. As described herein, the formulations may not contain parabens.

[0214] More specifically, the formulations of the present invention may contain monosaccharides and disaccharides such as sorbitol, mannitol, and mixtures thereof in amounts of 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulations may be paraben-free.

[0215] More specifically, the formulations of the present invention may contain monosaccharides and disaccharides such as sorbitol, mannitol, and mixtures thereof in an amount of 0.3% w / w or less, or 0.1% w / w or less. As described herein, the formulations may be paraben-free.

[0216] The formulations of the present invention may not contain, essentially not contain, or contain less than a predetermined amount such as less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1%. The formulations of the present invention may contain, but not essentially, one polyol selected from the group consisting of monosaccharides or disaccharides such as 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 glycol having 2 to 50 ethylene oxide groups, and sorbitol, mannitol, and mixtures thereof, or an optionally selected number of polyols, but may contain other polyols. The formulations of the present invention may not essentially contain linear or branched polyols. The formulations of the present invention may not essentially contain polyols having 2 to 30 carbon atoms, more preferably 2 to 20, even more preferably 2 to 10 or 2 to 8, and most preferably 2 to 6 or 2 to 3 carbon atoms.

[0217] In particular, the formulations of the present invention do not necessarily have to contain polyols having 2 to 8 or 2 to 6 carbon atoms.

[0218] The formulation of the present invention may contain a polyol in an amount of 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less, or may not contain a polyol. The polyol may be a polyol as described herein. As described herein, the formulation may not contain parabens.

[0219] The formulation of the present invention may contain a polyol in an amount of 0.7% w / w or less, 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. The polyol may be any polyol described herein. As described herein, the formulation may not contain parabens.

[0220] The formulation of the present invention may contain a polyol in an amount of 0.5% w / w or less, 0.3% w / w or less, or 0.1% w / w or less. The polyol may be any polyol described herein. As described herein, the formulation may not contain parabens.

[0221] The formulation of the present invention may contain a polyol in an amount of 0.3% w / w or less, or 0.1% w / w or less. The polyol may be any polyol described herein. As described herein, the formulation may be paraben-free.

[0222] The formulation of the present invention does not necessarily have to contain polyols.

[0223] The formulations of the present invention may be essentially free of the polyols and parabens described herein, and preferably, they may be free of the polyols and parabens described herein.

[0224] The formulations described herein may contain an activator. The activator may be present in an amount of 0.0001% w / w to 50% w / w based on the total weight of the formulation. In particular, the activator may be present in an amount of 0.001% w / w to 50% w / w based on the total weight of the formulation, an amount of 0.01% w / w to 30% w / w based on the total weight of the formulation, or an amount of 0.01% w / w to 10% w / w based on the total weight of the formulation.

[0225] In embodiments in which the formulation contains an activator, the activator is either tacrolimus or not tacrolimus.

[0226] Tacrolimus (also referred to herein as "TC") is a macrolide lactone molecule extracted from the soil bacterium Streptomyces tsukubaensis. In the pharmaceutical field, tacrolimus is described as a calcineurin inhibitor with immunosuppressive properties. Tacrolimus is used topically to treat immune-mediated skin diseases such as atopic dermatitis or psoriasis. TC has a molecular weight of 804.03 g / mol and is highly lipophilic (logP > 3), being six orders of magnitude more lipophilic than ALA. Due to its high lipophilicity, TC is formulated in mixtures of mineral oil, paraffin, propylene carbonate, white petrolatum, and white wax. It has been previously found that TC has poor stability in aqueous formulations (approximately 90 days at room temperature).

[0227] Liquid formulations of TC, primarily in water-based systems (such as nanoemulsions), have not yet reached the market as end-product drugs by pharmaceutical companies. This may be due to the challenges of solubilizing and stabilizing TC in such formulations. When using topical formulations of TC as pharmaceuticals, two further challenges exist. First, its high lipophilicity may inhibit its release from lipid-based formulations into the skin. Second, it has a weak ability to disperse into the watery compartments of the skin (such as living cells).

[0228] In preferred embodiments, the activator is not tacrolimus. In embodiments where the activator is not tacrolimus, the activator is another activator, such as 5-aminolevulinic acid.

[0229] In some embodiments, the activator is not a highly lipophilic macrolide lactone.

[0230] In some embodiments, the activator is a highly lipophilic macrolide lactone.

[0231] In some embodiments, the activator is not a macrolide lactone with a logP value of 3.0 or greater, where P is the octanol-water partition coefficient.

[0232] In some embodiments, the activator is a macrolide lactone having a logP value of 3.0 or greater, where P is the octanol-water partition coefficient.

[0233] In some embodiments, the activator is not tacrolimus, pimecrolimus, everolimus, or sirolimus, their derivatives, precursors, metabolites, hydrates, and / or pharmaceutically acceptable salts.

[0234] In some embodiments, the activator is tacrolimus, pimecrolimus, everolimus, or sirolimus, their derivatives, precursors, metabolites, hydrates, and / or pharmaceutically acceptable salts thereof.

[0235] In preferred embodiments, the activator is a bio-derived substance. In this specification, the term “bio-derived substance” means a substance produced or potentially produced by living organisms. For example, 5-aminolevulinic acid is a bio-derived substance produced by living organisms such as plants, algae, bacteria, fungi, and animals. 5-aminolevulinic acid can also be produced in vitro by chemical synthesis. Because 5-aminolevulinic acid can be produced by living organisms, it is a bio-derived substance in the context of this specification, whether produced by chemical synthesis or by living organisms.

[0236] In this specification, “activator” includes active pharmaceutical agents (also referred to herein as “pharmaceutical activators,” “pharmaceutical active ingredients,” or “APIs”) and active cosmetic agents (also referred to herein as “cosmetic activators”). As used herein, an active pharmaceutical agent is defined as a chemical, biological, mineralogical, or any other entity or component responsible for the therapeutic effect (pharmacological, physiological, physical, etc.) of a product. As used herein, an active cosmetic agent is defined as a chemical, biological, mineralogical, or any other entity or component responsible for the cosmetic effect of a product. Activators may also be plant extracts.

[0237] The formulations of the present invention provide a highly efficient delivery system for a wide variety of activators. The activators may be any agent suitable for pharmaceutical or cosmetic applications as described herein. Examples of useful activators include, but are not limited to, anti-infective agents, antibiotics, antibacterial agents, antifungal agents, antiviral agents, antiparasitic agents, steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory agents, immunosuppressants, immunomodulators, and immunomodulatory agents. This includes agents, hormones, vitamin A, vitamin A derivatives, vitamin B, vitamin B derivatives, vitamin C, vitamin C derivatives, vitamin D, vitamin D derivatives, vitamin E, vitamin E derivatives, vitamin F, vitamin F derivatives, vitamin K, vitamin K derivatives, wound healing agents, antiseptics, anesthetics, antiallergic agents, alpha-hydroxy acids, lactic acid, glycolic acid, beta-hydroxy acids, proteins, peptides, neuropeptides, allergens, immunogenic substances, haptens, oxidizing agents, antioxidants, dicarboxylic acids, azelaic acid, sebacic acid, adipic acid, fumaric acid, retinoids, antiproliferative agents, anticancer agents, photodynamic therapy agents, anti-wrinkle agents, radical scavengers, chemical sunscreens, metal oxides (e.g., titanium dioxide, zinc oxide, zirconium oxide, iron oxide, etc.), silicone oxides, anti-wrinkle agents, whitening agents, skin protectants, masking agents, anti-verrucous agents, and re-lipidating agents.

[0238] The activator may be a hydrophilic agent such as 5-aminolevulinic acid, which is soluble in the aqueous phase (or aqueous component) and can interact with the surface of the nanovesicle. Alternatively, the activator may be a hydrophobic agent such as diclofenac or tacrolimus, which is soluble in the lipid phase (or carrier component) and can thereby be incorporated into the lipid core of the nanovesicle.

[0239] Another aspect of the present invention relates to a pharmaceutical formulation of the first aspect described herein.

[0240] In the formulations described herein, particularly in pharmaceutical formulations, the activator may be a small organic molecule having a molecular weight of, for example, 50 to 2500 g / mol, preferably 100 to 1000 g / mol, more preferably 115 to 950 g / mol, and even more preferably 130 to 900 g / mol.

[0241] The activator may exist in the form of pharmaceutically and / or cosmetically acceptable salts, such as hydrochloride, phosphate, acetate, sodium salt, or sulfate. The activator may also exist in the form of pharmaceutically and / or cosmetically acceptable derivatives or analogs, such as esters, ethers, (methyl-)thioesters, (methyl-)thioethers, methoxy-substituted benzyl ethers, silyl ethers, sulfonates, sulfenates, sulfinates, (cyclic) carbonates, carbamates, cyclic acetals or ketals, (chiral) ketones, hydrazones, enamines, and enols. Such derivatives or protecting groups are known to those skilled in the art and are not limited to the groups described.

[0242] In particular, the formulation of the present invention may include or consist of the following: (a) a nanoemulsion, (i) Based on the total weight of the nanoemulsion (a), an aqueous component is present in an amount of 60-96% (w / w), preferably 70-95% (w / w), (ii) a nanovesicle, (1) 1-5% of at least one phospholipid based on the total weight of the nanoemulsion (a); (2) 2-10% of at least one polyoxyethylene-type surfactant based on the total weight of nanoemulsion (a); (3) 1-5% C3-C5 alcohol based on the total weight of nanoemulsion (a); and (4) 2-10% triglycerides based on the total weight of nanoemulsion (a) Nanovesicles and Nanoemulsions containing; (b) 0.0001 to 50%, preferably 0.001 to 30%, of pharmaceutically active organic molecules, wherein the organic molecules have a molecular weight of 100 to 1000 g / mol, preferably 115 to 950 g / mol, more preferably 130 to 900 g / mol. (c) Optionally, 0.5 to 4% of at least one gelling agent based on the total weight of the preparation, (d) Optionally, 0.1 to 2% of at least one preservative based on the total weight of the preparation, (e) Propellant.

[0243] If the activator is tacrolimus and / or a pharmaceutically acceptable analog or derivative thereof, tacrolimus may be present in an amount of 0.001 to 5% w / w based on the total weight of the formulation. In particular, tacrolimus may be present in an amount of 0.01 to 3% w / w based on the total weight of the formulation, 0.05 to 1% w / w based on the total weight of the formulation, or 0.01 to 1% based on the total weight of the formulation.

[0244] When the activator is tacrolimus, the formulation of the present invention may include or consist of the following: (a) a nanoemulsion, (i) Based on the total weight of the nanoemulsion (a), an aqueous component is present in an amount of 70-95% (w / w), (ii) a nanovesicle, (1) 1-5% of at least one phospholipid based on the total weight of the nanoemulsion (a); (2) 2-10% of at least one polyoxyethylene-type surfactant based on the total weight of nanoemulsion (a); (3) 1-5% C3-C5 alcohol based on the total weight of nanoemulsion (a); and (4) 2-10% triglycerides based on the total weight of nanoemulsion (a) Nanovesicles and Nanoemulsions containing; (b) 0.01–1% tacrolimus based on the total weight of the preparation; (c) Optionally, 0.5 to 4% of at least one gelling agent based on the total weight of the preparation; (d) optionally, 0.1 to 2% of at least one preservative based on the total weight of the preparation; and (e) Propellant.

[0245] In formulations containing calcineurin inhibitors such as pharmaceutically acceptable macrolide lactones, preferably tacrolimus and / or pharmaceutically acceptable analogs or derivatives thereof, an aqueous component, at least one phospholipid, at least one polyoxyethylene-type surfactant, a C3-C5 alcohol, a triglyceride, a gelling agent, at least one preservative, and a propellant may be independently selected and contained in accordance with the disclosure herein.

[0246] The activator may be a photosensitizer or metabolic photosensitizer precursor such as 5-aminolevulinic acid (hereinafter also referred to as "ALA" or "5-ALA"), its pharmaceutically acceptable salts, derivatives, precursors, and / or metabolites. A preferred salt of 5-aminolevulinic acid is 5-aminolevulinic acid hydrochloride.

[0247] 5-aminolevulinic acid has the following chemical structure: [ka]

[0248] 5-aminolevulinic acid and / or its pharmaceutically acceptable salts may be present in amounts of 0.1 to 30% w / w based on the total weight of the formulation. In particular, 5-aminolevulinic acid and / or its pharmaceutically acceptable salts, esters, or other pharmaceutically related derivatives (e.g., methylaminolevulinic acid or hexylaminolevulinic acid) may be present in amounts of 1 to 20% w / w based on the total weight of the formulation, or 1 to 10% w / w based on the total weight of the formulation.

[0249] The activator may be a nonsteroidal anti-inflammatory drug (NSAID) such as diclofenac, a pharmaceutically acceptable salt thereof, a derivative, a precursor, and / or metabolite.

[0250] Diclofenac has the following chemical structure: [ka]

[0251] Diclofenac and / or its pharmaceutically acceptable salts may be present in amounts of 0.01 to 30% w / w based on the total weight of the preparation. In particular, diclofenac and / or pharmaceutically acceptable salts, esters, or other pharmaceutically related derivatives may be present in amounts of 0.1 to 20% w / w based on the total weight of the preparation, or 0.1 to 10% w / w based on the total weight of the preparation.

[0252] Another aspect of the present invention relates to a formulation of the first aspect described herein, which is a cosmetic formulation.

[0253] In the cosmetic formulation of the present invention, the surfactant is a cosmetic surfactant. In particular, the cosmetic surfactant is selected from plant extracts, natural or synthetic moisturizers, natural or synthetic cleansing agents, natural or synthetic protective agents, natural or synthetic detergents, natural or synthetic antioxidants, natural or synthetic skin conditioning agents, and natural or synthetic vitamins.

[0254] Suitable plant extracts include, but are not limited to, extracts obtained from mahonia root, matricaria chamomile, camellia sinensis, salvia officinalis (common sage), Achillea millefolium, witch hazel, yeast, glycyrrhizinus glabra (licorice), shea tree (e.g., shea butter), vegetable oils containing squalane, avocado, and acmella oleracea (main component: spiranthol), as well as mixtures thereof. Preferably, salvia officinalis or mahonia. Plant extracts disclosed in Faccio, 2020, iScience (https: / / doi.org / 10.1016 / j.isci.2020.101358) (disclosure of which is incorporated herein by reference) are also suitable cosmetic ingredients in the formulations of the present invention.

[0255] Suitable cosmetic surfactants also include, but are not limited to, berberine (an alkaloid from Mahonia achyfolium, which can also be found in other plants) and α-(-)-bisabolol (a monocyclic sesquiterpene alcohol, which can be found in German chamomile).

[0256] The cosmetic formulations of the present invention can be used for moisturizing the skin, cleansing the skin, protecting from the sun (ultraviolet rays) or other external influences, assisting in maintaining the skin barrier function, beautifying the skin, reducing signs of skin aging, and as supplemental care for stressed or diseased skin.

[0257] In particular, the formulation according to the first aspect of the present invention may include or consist of the following: (a) a nanoemulsion, (i) Based on the total weight of the nanoemulsion (a), the aqueous component present in amounts of 70% w / w to 95% w / w; (ii) a nanovesicle, (1) 1-5% of at least one phospholipid based on the total weight of the nanoemulsion (a); (2) 2-10% of at least one polyoxyethylene-type surfactant based on the total weight of nanoemulsion (a); (3) 1-5% C3-C5 alcohol based on the total weight of nanoemulsion (a); and (4) 2-10% triglycerides based on the total weight of nanoemulsion (a) Nanovesicles and Nanoemulsions containing; (b) A photosensitizer or its metabolic precursor comprising 1 to 20% of the total weight of the formulation, preferably 5-aminolevulinic acid hydrochloride; (c) Optionally, 0.5 to 4% of at least one gelling agent based on the total weight of the preparation; (d) optionally, 0.1 to 2% of at least one preservative based on the total weight of the preparation; and (e) Propellant.

[0258] Formulations comprising 5-aminolevulinic acid and / or a pharmaceutically acceptable salt thereof, aqueous components may also contain, independently selected in accordance with the disclosure herein, at least one phospholipid, at least one polyoxyethylene-type surfactant, C3-C5 alcohol, triglycerides, gelling agents, at least one preservative, and propellants.

[0259] Furthermore, the present invention relates to nanovesicles including the following: (i) 16-19% w / w soy lecithin, (ii) Polysorbate 80 with a concentration of 32-36% w / w (iii) 32-36% w / w caprylic / capric triglyceride, (iv) 12-16% w / w isopropyl alcohol.

[0260] Preferred nanovesicles of the present invention include the following: (i) 17% w / w soy lecithin (ii) 34% w / w polysorbate 80 (iii) 35% w / w caprylic / capric triglyceride (iv) 14% w / w isopropyl alcohol.

[0261] The present invention also relates to a nanoemulsion comprising the following. (a) 1.6 to 3.6% w / w of soy lecithin (b) 3.3 to 6.9% w / w of polysorbate 80 (c) 3.3 to 7.0% w / w of caprylic / capric triglyceride (d) 1.3 to 2.9% w / w of isopropyl alcohol (e) An aqueous phosphate buffer added up to 100%, for example a 5 to 20 mM phosphate buffer, having a pH of 2 to 8, preferably pH 2 to 7, more preferably pH 3 to 6.

[0262] A preferred nanoemulsion of the present invention comprises the following: (a) 1.7% w / w of soy lecithin (b) 3.4% w / w of polysorbate 80 (c) 3.5% w / w of caprylic / capric triglyceride (d) 1.4% w / w of isopropyl alcohol (e) An aqueous 10 mM phosphate buffer having a pH of 6 added up to 100%.

[0263] As used herein, this formulation is referred to as "BF200". The BF200 nanoemulsion can be obtained by contacting a mixture of components (a) to (d) having a total amount of 10% w / w and an aqueous 10 mM phosphate buffer having a pH of 6 at 90% w / w under conditions that allow for the formation of a nanoemulsion, thereby forming a nanoemulsion. An exemplary method for manufacturing the BF200 formulation is described in Example 1.

[0264] Another preferred nanoemulsion of the present invention comprises the following: (a) 2 to 3% w / w of soy lecithin (b) 4.5 to 5.5% w / w of polysorbate 80 (c) 4.5 to 5.5% w / w of caprylic / capric triglyceride (d) 2 to 3% w / w of isopropyl alcohol (e) A pH 6 aqueous 10 mM phosphate buffer solution, added to 100%.

[0265] In this specification, this formulation is referred to as "BF215". BF215 nanoemulsion can be obtained by contacting a mixture of components (a) to (d) in a total amount of 15% w / w with 85% w / w pH 6 aqueous 10 mM phosphate buffer under conditions that enable nanoemulsion formation, thereby forming a nanoemulsion. An exemplary method for producing the BF215 formulation is described in Example 1.

[0266] Further preferred nanoemulsions of the present invention include: (a) 3-4% w / w soy lecithin (b) 6-7% w / w polysorbate 80 (c) 6-8% w / w caprylic / capric triglyceride (d) 2-4% w / w isopropyl alcohol (e) A pH 6 aqueous 10 mM phosphate buffer solution, added to 100%.

[0267] In this specification, this formulation is referred to as "BF220". BF220 nanoemulsion can be obtained by contacting a mixture of components (a) to (d) in a total amount of 20% w / w with 80% w / w pH 6 aqueous 10 mM phosphate buffer under conditions that enable nanoemulsion formation, thereby forming a nanoemulsion. An exemplary method for producing the BF220 formulation is described in Example 1.

[0268] Preferred formulations of the present invention include: (1) 17.5% of the nanoemulsion BF200 as described herein, (2) 0-4% w / w poloxamer 407 (3) 0.1-0.3% w / w sodium benzoate (4) 3% w / w 5-ALA hydrochloride (5) Water that has been added up to 100%.

[0269] The pH of this preparation may be between 2.5 and 3.5.

[0270] Another preferred formulation of the present invention includes: (1) 17.5% of the nanoemulsion BF200 as described herein, (2) 0-4% w / w poloxamer 407 (3) 0.1-0.3% w / w sodium benzoate (4) 3% w / w 5-ALA hydrochloride (5) Water that has been added up to 100%.

[0271] The pH of this preparation may be between 2.5 and 3.5.

[0272] Further preferred formulations of the present invention include: (1) 35% of the nanoemulsion BF200 described herein, (2) 2-4% w / w poloxamer 407 (3) 0.1-0.3% w / w sodium benzoate (4) 3% w / w 5-ALA hydrochloride (5) Water that has been added up to 100%.

[0273] The pH of this preparation may be between 2.5 and 3.5.

[0274] Further preferred formulations of the present invention include: (1) 18-20% of the nanoemulsion BF220 as described herein, (2) 0-4% w / w poloxamer 407 (3) 0.1-0.3% w / w sodium benzoate (4) 0.1-1% w / w citric acid (5) 0-1% w / w EDTA (6) 0-1% w / w α-tocopherol acetate (7) Tacrolimus at 0.03% w / w, 0.06% w / w, or 0.1% w / w (8) Water that has been added up to 100%.

[0275] The pH of this formulation may be 3.0 to 4.0.

[0276] Another preferred formulation of the present invention comprises the following: (1) 18 to 20% of the nanoemulsion BF200 described herein, (2) 0 to 4% w / w of poloxamer 407 (3) 0 to 1% of xanthan gum (4) 4 to 6% w / w of pentylene glycol (5) 0 to 2% w / w of an aqueous mixture of water, sodium benzoate, and sodium sorbate (e.g., Euxyl 712 K) (9) 0 to 1% w / w of α-tocopherol acetate (6) 0 to 1% w / w of fragrance (7) 0 to 1% w / w of D-panthenol (8) 10% of a propellant (a mixture of isobutane, n-butane, and propane) (9) 1 to 3% w / w of mahonia extract (10) Water added up to 100%.

[0277] The pH of this formulation may be 5.0 to 6.5.

[0278] The formulation of the first aspect of the present invention comprises the above-mentioned preferred formulation and further a propellant, and is contained in a pressurized container. The formulation of the first aspect of the present invention essentially does not contain fatty alcohol.

[0279] All terms defined with respect to the first aspect of the present invention are applicable when used with respect to other aspects of the present invention and have the same meaning unless otherwise defined specifically. Further, all embodiments specified for the first aspect of the present invention are also assumed for other aspects of the present invention where applicable.

[0280] Another aspect of the present invention is a formulation, which comprises the following. (a) A nanoemulsion, wherein (i) at least one aqueous component and; (ii) A carrier component, (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Includes carrier components; (iii) Optionally, an activator, (1) It dissolves in the aqueous phase and is capable of interacting with the surface of the nanovesicle, and / or (2) Dissolved in the lipid core of the nanovesicle, Activating agents and Nanoemulsions containing; (b) Optionally, a gelling agent. Here, the formulation is supplied to a container further containing a propellant. The propellant is supplied to pressurize the container. Nanoemulsion (a) is the nanoemulsion described herein. In contrast to the formulation of the first embodiment, in this formulation, the propellant is not defined as an essential component of the formulation. Instead, the formulation is defined in this way, and the propellant is supplied to pressurize the container in which the formulation is contained. In a preferred embodiment, the formulation of this embodiment is essentially free of fatty alcohols, and preferably essentially free of foaming agents. In a preferred embodiment, the formulation of this embodiment is essentially free of fatty alcohols, and preferably essentially free of foaming agents. Any gelling agent (b) is the gelling agent described herein. The propellant supplied to pressurize the container is the propellant described herein.

[0281] The container may be one of those described herein, and in particular may be a dispenser such as a foam dispenser or a spray dispenser, preferably a foam dispenser.

[0282] The formulation supplied in the container may be used as a pharmaceutical product. The medical use may be any medical use described herein, in particular the treatment and / or prevention of a dermatological disease or condition in a subject as described herein.

[0283] Another aspect of the present invention is a formulation, the formulation comprising the following: (a) a nanoemulsion, (i) at least one aqueous component; (ii) A carrier component, (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Includes carrier components; (iii) Optionally, an activator, (1) It dissolves in the aqueous phase and is capable of interacting with the surface of the nanovesicle, and / or (2) Dissolved in the lipid core of the nanovesicle, Activating agents and Nanoemulsions, (b) Optionally, a gelling agent. Here, the formulation is prepared as a pressurized formulation. A propellant is supplied to pressurize the formulation. Nanoemulsion (a) is the nanoemulsion described herein. In contrast to the formulation of the first embodiment, in this formulation, the propellant is not defined as an essential component of the formulation. Instead, the formulation is defined as described above, and the propellant is supplied to pressurize the formulation, thereby providing a pressurized formulation. In a preferred embodiment, the formulation of this embodiment is essentially free of fatty alcohols, and preferably essentially free of foaming agents. Any gelling agent (b) is the gelling agent described herein. The propellant supplied to pressurize the container is the propellant described herein.

[0284] Pressurized formulations may be used for medical purposes. Medical uses may be any medical use described herein, in particular the treatment and / or prevention of dermatological diseases or conditions in subjects as described herein.

[0285] Another aspect of the present invention relates to a formulation defined as a formulation of the first aspect of the present invention, but which may include a fatty alcohol or another foaming agent.

[0286] A second aspect of the present invention relates to a method for stabilizing a nanoemulsion. The method comprises the following steps: (a) providing a nanoemulsion comprising (i) at least one aqueous component; (ii) a carrier component comprising (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol; (b) introducing the nanoemulsion into a container; and (c) adding a propellant to the container and pressurizing the container.

[0287] This embodiment is based on the surprising finding that the stability of nanoemulsions can be significantly improved when they are stored in a pressurized container with a propellant compared to when they are stored in another container, such as a glass vial. The overall improvement in stability does not depend on the presence of a gelling agent. The improvement in stability is particularly pronounced under stress conditions such as storage at high temperatures.

[0288] Those skilled in the art will know of suitable methods for filling a container with a nanoemulsion or a formulation comprising a nanoemulsion and a propellant, and for obtaining a pressurized vessel containing the nanoemulsion or the formulation comprising a nanoemulsion and a propellant. In a preferred embodiment, the propellant is added to the container containing the nanoemulsion or the formulation comprising a nanoemulsion via a valve.

[0289] Furthermore, this method also provides stabilization of nanoemulsion formulations, i.e., formulations further comprising a nanoemulsion and an activator, and / or additional aqueous components such as water, a buffer, or a gelling agent. Therefore, in some embodiments, the method of the second embodiment is a method for stabilizing formulations containing a nanoemulsion. In embodiments in which the nanoemulsion formulation contains an activator, the activator is also stabilized. That is, the concentration of the activator is kept stable even under stress conditions.

[0290] In this second embodiment, the nanoemulsion is the nanoemulsion defined in relation to the first embodiment. In this second embodiment, the formulation containing the nanoemulsion corresponds to the formulation defined in relation to the first embodiment, but differs in that the formulation does not contain a propellant (a propellant is supplied in step (c)), and the formulation containing the nanoemulsion may contain a fatty alcohol or another foaming agent. In a preferred embodiment, the formulation containing the nanoemulsion is essentially free of fatty alcohols, and preferably essentially free of foaming agents. In a preferred embodiment, the formulation containing the nanoemulsion is essentially free of a gelling agent.

[0291] In a preferred embodiment, the nanovesicles contained in the nanoemulsion have a stable size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when stored in a pressurized container for 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months, or when stored at 4 to 40°C, 10 to 40°C, 20 to 40°C, 30 to 40°C, or 40°C. Preferably, the size is determined by dynamic light scattering.

[0292] In a preferred embodiment, the nanoemulsion is characterized by a stable polydispersity index of 0.4 or less and / or 0.3 or less when stored in a pressurized container for 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months at 4-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C. Preferably, the polydispersity index is determined by dynamic light scattering.

[0293] A third aspect of the present invention relates to the use of a nanoemulsion for the preparation of a foam, comprising the following steps: (a) providing a formulation comprising a nanoemulsion, wherein the nanoemulsion comprises (i) at least one aqueous component; (ii) a carrier component comprising: (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol; (b) introducing the formulation comprising the nanoemulsion into a container; (c) adding a propellant to the container to pressurize the container; and (d) releasing the foam from the pressurized container. The foam comprises the nanoemulsion.

[0294] This third aspect is based on the remarkable discovery that a stable foam can be prepared from a formulation containing a nanoemulsion housed in a pressurized vessel, even in the absence of fatty alcohols or other foaming agents.

[0295] The foam is characterized by high stability and a long decay time. For example, the decay time is at least 8 minutes, at least 9 minutes, or at least 10 minutes at temperatures below 40°C, e.g., 25°C or 36°C.

[0296] Furthermore, this third aspect is based on the surprising finding that when nanoemulsions are stored in a pressurized vessel with a propellant, the stability of the nanoemulsions can be significantly improved compared to storage in other containers such as glass vials, even in the absence of fatty alcohols or other foaming agents.

[0297] In embodiments where the nanoemulsion formulation contains an activator, the activator is also stabilized. That is, the concentration of the activator is kept stable even under stress conditions.

[0298] In this third embodiment, the nanoemulsion is the nanoemulsion defined in relation to the first embodiment. In this third embodiment, the formulation containing the nanoemulsion corresponds to the formulation defined in relation to the first embodiment, but differs in that the formulation does not contain a propellant (a propellant is supplied in step (c)), and the formulation containing the nanoemulsion may contain a fatty alcohol or another foaming agent. In a preferred embodiment, the formulation containing the nanoemulsion is essentially free of fatty alcohols and preferably essentially free of foaming agents. In a preferred embodiment, the formulation containing the nanoemulsion is essentially free of a gelling agent.

[0299] A further aspect of the present invention is a method for preparing a formulation according to the first aspect of the present invention, comprising the following steps: (a) Mixing at least one lipophilic component, at least one surfactant, and at least one alcohol. (b) Contact the mixture obtained in step (a) with an aqueous component under conditions that allow for the formation of a nanoemulsion. (c) Introducing the formulation obtained in step (c) into a container, and (d) Add propellant to the container and pressurize the container.

[0300] This method may include a step of adding an activator.

[0301] In step (b), conditions that enable the formation of the nanoemulsion may include mixing the two phases at a suitable temperature and stirring to form nanovesicles. Suitable temperatures and stirring conditions are known to those skilled in the art. Vesicle sizes of 500 nm or less or 300 nm or less, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm can be obtained. In particular, the preparation of the nanoemulsion of the present invention by step (b) can be done without using high-energy methods known in the art. High-energy methods include high-pressure homogenization, microfluidization, and sonication (Prev Nutr Food Sci. 2019 Sep;24(3):225-234).

[0302] In some embodiments, the container is incorporated into a dispenser, such as a foam dispenser or a spray dispenser, and is preferably incorporated into a foam dispenser. In other words, the container may be part of the dispenser.

[0303] The dispenser may be any suitable dispenser. Examples of foam dispensers and spray dispensers are shown in Figure 1. Suitable dispensers are known to those skilled in the art. The container may be any suitable pressurized container. Suitable containers are known to those skilled in the art.

[0304] The activator may be added in step (a), added to the aqueous component before contacting the mixture obtained in step (a) with the aqueous component in step (b), or added to the nanoemulsion obtained in step (b).

[0305] The conditions under which the activator dissolved in the aqueous phase can interact with the surface of the nanovesicle, and / or the conditions that allow the activator to dissolve into the lipid core of the nanovesicle, may depend on the hydrophilicity or lipophilicity of the activator.

[0306] A hydrophilic compound such as an amino acid, preferably a photosensitizer or metabolic precursor, e.g., ALA, or / a pharmaceutically acceptable salt thereof (e.g., ALA hydrochloride) or an acceptable derivative (e.g., methyl-ALA), can be added to the aqueous component before contacting the mixture obtained in step (a) with the aqueous component in step (b). This allows the activator to dissolve in the aqueous phase and interact with the nanovesicles (particularly the nanovesicle surface) in step (b).

[0307] Hydrophilic compounds such as amino acids, preferably photosensitizers or metabolic precursors such as ALA, or / or pharmaceutically acceptable salts thereof (such as ALA hydrochloride) or acceptable derivatives (such as methyl-ALA), can be added to the aqueous component before contacting the mixture obtained in step (a) with the aqueous component in step (b). This allows the activator to dissolve in the aqueous phase and interact with nanovesicles (especially the nanovesicle surface) in step (b).

[0308] A pharmaceutically acceptable lipophilic compound, such as a macrolide lactone, preferably a calcineurin inhibitor such as tacrolimus, and / or a pharmaceutically acceptable derivative, may be added in step (a) such that the activator dissolves in the lipid core of the nanovesicle.

[0309] A method for preparing the formulation of the present invention may further include: (i) Adding a gelling agent, and / or (ii) Adding preservatives.

[0310] A fourth aspect of the present invention relates to a container for containing a formulation, or a dispenser product comprising a container for containing a formulation. The formulation is a nanoemulsion comprising (i) at least one aqueous component; (ii) a carrier component comprising (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol; and (b) a propellant. The formulation is essentially free of emollients, essentially free of fatty alcohols, preferably essentially free of foaming agents, and / or essentially free of gelling agents. The container further comprises a propellant. The propellant is supplied to pressurize the container.

[0311] In a preferred embodiment, the dispenser is a foam dispenser or a spray dispenser, preferably a foam dispenser. The dispenser comprises a container containing the formulation and a pressurized propellant, and a foam-generating device attached to the container. The foam-generating device may include a valve for dispensing and administering the formulation, and a push button for activating the valve. Activating the push button allows the formulation to be released and foam to be formed. An example of a dispenser is shown in Figure 1. Suitable dispensers are known to those skilled in the art.

[0312] A fifth aspect of the present invention relates to a foam obtained from the formulation of the first aspect.

[0313] The foam comprises the formulation described herein. The foam is formed when the formulation is released from a suitable pressurizing device (e.g., a foam dispenser described herein).

[0314] Surprisingly, the inventors have found that the nanoemulsion foam obtained from the formulation of the present invention has a decay time of at least 10 minutes at room temperature without the use of any foaming agent, even after the formulation, contained in a pressurized container, has been subjected to stress conditions such as freeze-thaw cycles or storage at high temperatures (40°C). As used herein, decay time refers to the time it takes for the foam to decay to half of its initial volume upon release. The nanoemulsion foam described in the present invention is destroyed by sheer force without requiring any foaming agent to form a stable foam upon release. Furthermore, it has been found that when the lipophilic content is high (for example, with a 20% lipid content), the foam described in the present invention has a decay time of at least 8 minutes at 36°C (skin temperature). Preferably, the formulation of the present invention has a decay time of at least 8 minutes, or at least 10 minutes, at room temperature, for example, 20-25°C.

[0315] A sixth aspect of the present invention relates to cosmetic applications of the formulation of the first aspect or the foam of the fifth aspect.

[0316] In this embodiment, the formulation includes the cosmetic formulation described herein. A seventh aspect of the present invention relates to the formulation of the first embodiment or the form of the fifth embodiment for use in pharmaceuticals.

[0317] In a preferred embodiment, the formulation or foam is provided for use in methods for treating and / or preventing dermatological diseases or conditions in a subject.

[0318] Treatment and / or prevention of dermatological diseases or conditions may include: (a) administering a pharmaceutically effective amount of a formulation comprising a pharmaceutically acceptable macrolide lactone, preferably a calcineurin inhibitor such as tacrolimus, its derivatives, precursors, analogs, and / or metabolites, to a subject, topically to a diseased area or affected area and an area of ​​skin surrounding the diseased area or affected area, wherein the formulation forms a foam, and (b) Optionally, incubating the pharmaceutical formulation on the subject's skin with or without occlusion of the area of ​​skin to which the formulation has been administered, preferably with occlusion being carried out using a low-density polyethylene or polyurethane film to promote deep tissue penetration.

[0319] Furthermore, the treatment and / or prevention of dermatological diseases or conditions may include the following: (a) A pharmaceutically effective amount of a formulation comprising the photosensitizer or its metabolic precursor as described herein, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt thereof, a derivative, a precursor, and / or metabolite, to a subject, topically administered to the diseased area or affected area and optionally to the area of ​​the skin surrounding the diseased area or affected area, wherein the formulation forms a foam, and (b) Optionally, incubating the pharmaceutical formulation on the subject's skin with or without occlusion of the area of ​​skin to which the formulation has been administered, wherein the occlusion is preferably carried out using a low-density polyethylene or polyurethane film to facilitate penetration into deeper tissues.

[0320] Furthermore, the treatment and / or prevention of dermatological diseases or conditions may include the following: (a) A pharmaceutically effective amount of a formulation comprising the photosensitizer or its metabolic precursor as described herein, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt thereof, a derivative, a precursor, and / or metabolite, to a subject, topically administered to a diseased area or affected area of ​​the skin, and optionally to an area surrounding the diseased area or affected area, wherein the formulation forms a foam, and (b) Optionally, incubating the pharmaceutical formulation on the subject's skin with or without occlusion of the area of ​​skin to which the formulation has been administered, preferably with occlusion using a low-density polyethylene or polyurethane film to facilitate penetration into deep tissues, and (c) Irradiating the skin area where the formulation has been administered with light.

[0321] The light spectrum used for irradiation in step (c) may be consistent with the absorption spectrum of the fluorescent porphyrin. For example, the light spectrum may be consistent with the absorption peak of protoporphyrin IX. In particular, the light used for irradiation in step (c) may include any visible wavelengths in the range of 380 nm to 780 nm, preferably having equal irradiance throughout, or having irradiance peaks around 410 nm, 505 nm, 542 nm, 575 nm, and / or 635 nm. The wavelength spectrum may not essentially contain radiation with wavelengths less than 380 nm and / or greater than 780 nm. In particular, the light used for irradiation in step (c) may include any visible wavelengths in the range of 380 to 440 nm and / or 580 to 650 nm. Furthermore, the light used for irradiation in step (c) may be capable of inducing red fluorescence of the accumulated porphyrin.

[0322] 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, (a) the red light is 10 to 75 J / cm². 2 Preferably 25-45 J / cm² 2 This results in radiation exposure; and / or violet light, 1-30 J / cm². 2 Preferably 5-15 J / cm² 2 This results in radiation exposure.

[0323] The irradiation in step (c) may be carried out using artificial light, sunlight and / or daylight, or an artificial light source that emits light whose wavelength spectrum, preferably irradiance, is similar to or identical to that of sunlight. The light whose wavelength spectrum and preferably irradiance are similar to or identical to that of sunlight may preferably have an overall equal irradiance, or have a wavelength spectrum of 100 nm to 1000 nm, a wavelength spectrum of 380 nm to 780 nm, or a wavelength spectrum of 570 nm to 650 nm or 570 nm to 630 nm, and / or a wavelength spectrum of 380 nm to 440 nm, with irradiance peaks around 410 nm, 505 nm, and / or 635 nm. The artificial light may be provided by an LED. Suitable devices for providing artificial light are described, for example, in U.S. Patent No. 11235169B1 and U.S. Patent No. 11219781B2, the disclosures of which are incorporated herein by reference.

[0324] The area surrounding the diseased area or affected area of ​​the skin may include non-affected surrounding areas to ensure adequate treatment of the diseased area or affected area. For example, the area surrounding the diseased area or affected area of ​​the skin may include an area of ​​at least approximately 5 mm in width.

[0325] The dermatological diseases or conditions treated by the pharmaceutical formulations described herein may include, but are not limited to, diseases or conditions of the skin, skin appendages, or mucous membranes.

[0326] The dermatological diseases or conditions treated with the pharmaceutical formulations described herein may be selected from the group consisting of inflammatory, neoplastic, proliferative, infectious, and / or autoimmune diseases or conditions, and / or their skin manifestations, and / or diseases involving solitary lesions or lesional areas, neoplastic, proliferative, and / or inflammatory changes.

[0327] The inflammatory dermatological diseases or conditions treated with the pharmaceutical formulations described herein may be selected from the group consisting of dermatitis, contact dermatitis, acne, atopic dermatitis, eczema, pustular dermatitis, seborrheic dermatitis, perioral dermatitis, chronic wounds, urticaria, skin ulcers, rosacea, rash, drug eruption, toxic epidermal necrolysis; erythema multiforme, erythema nodosum, granuloma annulare, and other inflammatory skin conditions.

[0328] The neoplastic and / or proliferative dermatological diseases or conditions treated with the pharmaceutical formulations described herein may be selected from the group consisting of basal cell carcinoma, preferably superficial or nodular basal cell carcinoma; squamous cell carcinoma, preferably Morbus Bowen or invasive squamous cell carcinoma; vulvar intraepithelial neoplasia (VIN); cutaneous T-cell lymphoma; Merkel cell carcinoma; hemangioma; nodular or subcutaneous carcinomas; field cancerization; non-melanoma skin cancer in organ transplant recipients; and prevention of non-melanoma skin cancer in organ transplant recipients.

[0329] The infectious skin diseases or conditions treated with the pharmaceutical formulations described herein may be selected from the group consisting of bacterial infections, viral infections, fungal infections, parasitic infections, and combinations thereof.

[0330] The autoimmune skin diseases or conditions, or skin symptoms of autoimmune states, treated with the pharmaceutical formulations described herein may be selected from the group consisting of psoriasis, pemphigus, systemic lupus erythematosus, lichen planus, morphea, scleroderma, epidermolysis bullosa, dermatomyositis, and graft-versus-host syndrome.

[0331] The dermatological diseases or conditions treated with the pharmaceutical formulations described herein may be selected from the group consisting of hyperpigmentation disorders, including hyperpigmentation disorders such as sweating disorders, vitiligo, albinism, and post-inflammatory hypopigmentation, as well as hyperpigmentation disorders such as melasma, sunburn and other reactions to sunlight, skin aging, photosensitivity, hirsutism, alopecia, and male pattern baldness, and other disorders of hair follicles and sebaceous glands.

[0332] The formulations described herein, in particular pharmaceutical compositions comprising the photosensitizer or its metabolic precursor, preferably 5-aminolevulinic acid, its pharmaceutically acceptable salts, derivatives, precursors and / or metabolites, may be used in photodynamic diagnostic methods for neoplastic and / or proliferative dermatological diseases or conditions, such as benign or malignant tumors or their precursors; inflammatory dermatological diseases or conditions; and / or conditions related to bacterial growth, such as acne.

[0333] The formulations described herein, in particular, (a) a photosensitizer or its metabolic precursor, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt thereof, a derivative, a precursor, and / or a metabolite, (b) pharmaceutically acceptable macrolide lactones, preferably calcineurin inhibitors such as tacrolimus, derivatives, precursors, and / or metabolites thereof. Pharmaceutical compositions containing the above may be used to treat diseases or conditions described herein, such as neoplastic and / or proliferative skin diseases or conditions, including benign or malignant skin tumors or their precursors; inflammatory skin diseases or conditions, including atopic dermatitis, eczema, psoriasis, rosacea or chronic wounds; and bacterial growth-related conditions, including acne.

[0334] A further aspect of the present invention is the use of the formulations of the present invention as described herein for the manufacture of a medicament for the treatment and / or prevention of a dermatological disease or condition in a subject. In particular, the skin disease is a skin disease or condition as described herein.

[0335] A further aspect of the present invention is a method for treating and / or preventing a dermatological disease or condition in a subject, the method comprising administering a pharmaceutically effective amount of the formulation described herein to the subject. In particular, the skin disease is a skin disease or condition described herein.

[0336] A further aspect of the present invention is a photodynamic diagnostic method for neoplastic and / or proliferative dermatological diseases or conditions such as benign or malignant tumors or their precursors; inflammatory dermatological diseases or conditions; and / or conditions related to bacterial growth such as acne.

[0337] Drugs containing ALA (and its derivatives) promote the synthesis of fluorescent porphyrins, which preferentially accumulate in cells / tissues with increased metabolic activity. This can be utilized in photodynamic diagnostic methods and applied to neoplastic diseases of the skin, such as benign or malignant tumors or their precursors, inflammatory conditions, or conditions associated with bacterial growth, such as acne. In photodynamic diagnostics, an ALA (or derivative)-containing formulation is applied to the skin site to be diagnosed and incubated for an appropriate time. Then, blue spectrum light is irradiated to induce red fluorescence from the accumulated porphyrins. The fluorescence can be detected by visual inspection or by appropriate technical devices for qualitative or quantitative evaluation.

[0338] Photodynamic diagnostic methods may include the following: (i) administering a formulation comprising the photosensitizer or its metabolic precursor as described herein, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt thereof, a derivative, a precursor and / or metabolite, to a skin area to be diagnosed under conditions that enable the synthesis of fluorescent porphyrin in cells and / or tissues, and (ii) Irradiate the skin area to which the formulation has been administered under conditions that induce fluorescence of accumulated porphyrin. Here, increased porphyrin fluorescence indicates increased metabolic activity and suggests neoplastic and / or proliferative dermatological diseases or conditions, inflammatory dermatological diseases or conditions, and / or conditions associated with bacterial growth.

[0339] In step (i), a photosensitizer or its metabolic precursor, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt thereof, its derivatives, precursors and / or metabolites, may be incubated on the skin for an appropriate period of time.

[0340] In step (ii), the skin can be irradiated with light capable of inducing the red fluorescence of the accumulated porphyrin. Suitable irradiation conditions are described herein.

[0341] The diagnosis of neoplastic and / or proliferative skin diseases or conditions may be made by detecting increased fluorescence (e.g., compared to healthy tissue and / or skin, e.g., tissue and / or skin adjacent to the suspected site). Fluorescence detection may be performed by visual inspection or by appropriate technical devices for qualitative or quantitative evaluation.

[0342] Diagnostic methods described herein may be performed for tumor boundary demarcation to assist surgery, evaluation of therapeutic effects, and / or evaluation of photo-guided photobleaching for photodose measurement in photodynamic therapy.

[0343] A further aspect of the present invention is a method for the cosmetic treatment and / or prevention of a dermatological condition in a subject, the method comprising administering an effective amount of the formulation described herein to the subject. In particular, cosmetic treatment and / or prevention may include moisturizing the skin, cleansing the skin, protecting the skin from the sun (ultraviolet rays) or other external influences, assisting in maintaining the skin's barrier function, beautifying the skin, reducing signs of skin aging, and supporting care for stressed or diseased skin.

[0344] The present invention also relates to the following embodiments: 1. A pharmaceutical preparation: (a) a nanoemulsion: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Carrier components including Nanoemulsions including and (b) Propellant Includes, The preparation is contained in a pressurized container. The formulation is one that is essentially free of fatty alcohols. 2. The formulation is the formulation according to Embodiment 1, wherein the formulation essentially does not contain fatty acids. 3. The formulation is the formulation according to Embodiment 1 or 2, preferably 2, which essentially does not contain a gelling agent. 4. The formulation is one of any three embodiments, preferably three, and is essentially free of an emollient selected from monoesters or diesters containing alcohols and fatty acids. 5. The formulation comprises a gelling agent, the gelling agent present in an amount of 0.1% (w / w) to 10% (w / w) based on the total weight of the formulation, according to either Embodiment 1 or 2, preferably Embodiment 2. 6. The formulation according to Embodiment 5, wherein the gelling agent is poloxamer, and poloxamer is present in an amount of 0.5% (w / w) to 4% (w / w) based on the total weight of the formulation. 7. The formulation according to Embodiment 6, wherein at least one lipophilic component is present in an amount of 10% (w / w) to 30% (w / w), preferably 15% (w / w) to 30% (w / w), and more preferably 20% (w / w) to 30% (w / w), based on the total weight of the nanoemulsion (a). 8. A formulation according to any one of Embodiments 1 to 7, wherein the nanoemulsion is a. When stored in a pressurized container at 2-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or b. The polydispersity index is 0.4 or less when stored in a pressurized container at 2-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months; and / or c. When stored in a pressurized container at 2-25°C, 10-25°C, 15-25°C, 2-8°C, 5°C, or 25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or d. When subjected to one, two, three, four, five or more freeze-thaw cycles, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or e. The polydispersity index is 0.4 or less when stored in a pressurized container at 2-25°C, 10-25°C, 15-25°C, 2-8°C, 5°C, or 25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months; and / or f. When stored in a pressurized container at 2-8°C or 5°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, or 48 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or g. The polydispersity index is 0.4 or less when stored in a pressurized container at 2-8°C or 5°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, or 48 months, and / or A formulation characterized in that, when subjected to one, two, three, four, five, or more freeze-thaw cycles, the polydispersity index is 0.4 or less. 9. A formulation according to any one of Embodiments 1 to 8, comprising an activator. 10. The formulation according to Embodiment 9, wherein the activator is 5-aminolevulinic acid, a pharmaceutically acceptable salt thereof, a derivative, a precursor and / or metabolite. 11. A formulation according to any one of Embodiments 1 to 10, • At least one lipophilic component is selected from triglycerides and mixtures thereof; At least one surfactant is selected from the group consisting of phospholipids, lysophospholipids, ceramides and / or mixtures thereof, and / or at least one surfactant is a polyoxyethylene-type surfactant; • At least one alcohol has 3 to 5 carbon atoms; and / or The propellant is propane, isobutane, n-butane, or a mixture thereof, in the formulation. A formulation according to any one of Embodiments 1 to 11, comprising 12.50% to 99% (w / w) of total aqueous components. 13. The formulation according to Embodiment 5, 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. 14. A method for stabilizing a nanoemulsion, the method comprising the following steps: (a) supplying a nanoemulsion, the nanoemulsion is (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Carrier components including To supply nanoemulsions containing; (b) introducing nanoemulsions into containers; and (c) Adding propellant to the container and pressurizing the container and / or the nanoemulsion inside the container. Methods that include... 15. The method according to Embodiment 14, wherein the nanoemulsion is a. When stored in a pressurized container at 2-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or b. The polydispersity index is 0.4 or less when stored in a pressurized container at 2-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months; and / or c. When stored in a pressurized container at 2-25°C, 10-25°C, 15-25°C, 2-8°C, 5°C, or 25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or d. When subjected to one, two, three, four, five or more freeze-thaw cycles, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or e. The polydispersity index is 0.4 or less when stored in a pressurized container at 2-25°C, 10-25°C, 15-25°C, 2-8°C, 5°C, or 25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months; and / or f. When stored in a pressurized container at 2-8°C or 5°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, or 48 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or g. The polydispersity index is 0.4 or less when stored in a pressurized container at 2-8°C or 5°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, or 48 months; and / or A method characterized in that the polydispersity index is 0.4 or less when subjected to one, two, three, four, five, or more freeze-thaw cycles. 16. Use of nanoemulsion for the preparation of foam or spray, the use is as follows: (a) To provide a formulation comprising a nanoemulsion, wherein the nanoemulsion is: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Carrier components including To provide a formulation containing a nanoemulsion; (b) Introducing a formulation containing nanoemulsion into a container; (c) Adding propellant to the container and pressurizing the container; and (d) Discharging foam or spray from a pressurized container Includes, use. 17. A container for containing the formulation described in any one of Embodiments 1 to 13, or a foam dispenser product or spray dispenser product including a container. 18. A foam obtained from any one of the formulations described in Embodiments 1 to 13. 19. Cosmetic use of a formulation according to any one embodiment of Embodiments 1 to 13. 20. A method for treating a dermatological disease or condition, comprising administering an effective amount of the formulation described in Embodiment 9 to a subject in need thereof.

[0345] Furthermore, the present invention also relates to the following items: 1. A pharmaceutical preparation, said preparation is: (a) a nanoemulsion: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol; Carrier components including Nanoemulsions including; and (b) Propellant Includes, The preparation is contained in a pressurized container. The formulation is one which is essentially free of fatty alcohols, preferably one which is essentially free of fatty alcohols and fatty acids. 2. The formulation is the formulation described in item 1, which essentially does not contain foaming agents. 3. The preparation is one of the preparations described in any of the above items, which essentially does not contain an emollient. 4. A formulation according to any of the above items, which essentially does not contain an emollient selected from monoesters or diesters of alcohol and fatty acids. 5. The formulation is one of the formulations described in any of the above items, which essentially does not contain a gelling agent. 6. A nanoemulsion is a formulation according to any of the above items, comprising a nanovesicle containing a carrier component. 7. The formulation according to item 6, wherein when stored in a pressurized container at 40°C for 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, or at least 36 months, the nanovesicles have a stable size of 500 nm or less, preferably in the range of 5 nm to 200 nm. 8. The formulation according to any of the above items, wherein the total aqueous component is present in an amount of 50% w / w to 99% w / w, preferably 70% (w / w) to 95% (w / w), and more preferably 75% (w / w) to 95% (w / w), based on the total weight of the nanoemulsion (a). 9. The formulation according to any one of the above items, wherein the aqueous component comprises at least one pH buffer, preferably at least one pH buffer selected from the group consisting of citrate, phosphate, acetate, and carbonate. 10. The formulation according to any one of the above items, wherein at least one lipophilic component is selected from triglycerides and mixtures thereof, preferably at least one lipophilic component is caprylic acid triglyceride and / or capric acid triglyceride, or a mixture thereof. 11. The formulation according to any one of the above items, wherein at least one lipophilic component is present in an amount of 0.1% (w / w) to 30% (w / w), preferably 0.25% (w / w) to 15% (w / w), preferably 0.25% (w / w) to 10% (w / w), more preferably 0.5% (w / w) to 8% (w / w), or 3% (w / w) to 8% (w / w), based on the total weight of the nanoemulsion (a). 12. A formulation according to any one of the above items, wherein at least one surfactant is selected from the group consisting of phospholipids, lysophospholipids, ceramides and / or mixtures thereof, and / or at least one surfactant is a polyoxyethylene-type surfactant. 13. The formulation according to any one of the above items, wherein at least one surfactant is lecithin, preferably soy lecithin, and preferably the lecithin has a phosphatidylcholine content of at least 80% by weight. 14. The formulation according to item 12, wherein phospholipids, lysophospholipids, ceramides and / or mixtures thereof are present in an amount of 1% (w / w) to 10% (w / w), preferably 1.25% (w / w) to 5% (w / w), more preferably 1.5% (w / w) to 4% (w / w), most preferably 1.5% (w / w) to 2% (w / w), based on the total weight of the nanoemulsion (a), or 0.1% (w / w) to 10% (w / w), preferably 0.15% (w / w) to 5% (w / w), more preferably 0.2% (w / w) to 3% (w / w) or 0.2% (w / w) to 4% (w / w), most preferably 0.2% (w / w) to 0.4% (w / w), based on the total weight of the formulation. 15. The formulation described in item 12, wherein the polyoxyethylene-type surfactant is polysorbate 80. 16. The formulation according to either item 12 or 15, wherein the polyoxyethylene-type surfactant is present in an amount of 1% (w / w) to 10% (w / w), more preferably 2% (w / w) to 8% (w / w), and most preferably 3% (w / w) to 7% (w / w), based on the total weight of the nanoemulsion (a). 17. A preparation according to any one of the above items, wherein at least one alcohol is selected from the group consisting of 1-propanol or 2-propanol and mixtures thereof. 18. The formulation according to any one of the above items, wherein the alcohol is present in an amount of 0.1% w / w to 10% w / w, preferably 0.5% (w / w) to 5% (w / w), more preferably 1% (w / w) to 3% (w / w), based on the total weight of the nanoemulsion (a). 19. The formulation according to any one of the above items, wherein the propellant is propane, isobutane, or n-butane or a mixture thereof, preferably the propellant is a mixture of propane and isobutane. 20. A preparation containing a gelling agent, as described in any one of items 1-4 or 6-19. 21. The formulation according to item 20, 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. 22. The formulation according to item 20 or 21, wherein the gelling agent is selected from poloxamer, xanthanum and / or mixtures thereof. 23. The formulation according to any one of items 20 to 22, wherein the gelling agent is present in an amount of 0.1% (w / w) to 10% (w / w), preferably 0.25% (w / w) to 5% (w / w), and more preferably 0.5% (w / w) to 4% (w / w), based on the total weight of the formulation. 24. The formulation according to any one of items 20 to 23, wherein the nanoemulsion comprises nanovesicles containing a carrier component, and the nanovesicles have a stable size of 300 nm or less, preferably in the range of 5 nm to 200 nm, when stored in a pressurized container at -15°C to -25°C, preferably -24°C for 4 days, and the size is determined by dynamic light scattering. 25. A formulation according to any one of the above items, comprising a preservative, preferably the preservative being selected from benzoates, citric acid, EDTA, and potassium sorbate, and preferably the preservative being sodium benzoate. 26. The formulation according to item 23 or 24, wherein the preservative is present in an amount of 0.01% w / w to 3% w / w, preferably 0.2% (w / w) to 2% (w / w) or 0.1% (w / w) to 2% (w / w), more preferably 0.2% (w / w) to 1.5% (w / w), based on the total weight of the formulation. 27. A preparation that is essentially paraben-free, as described in any one of the above items. A formulation according to any one of the above items, characterized by having a polydispersity index of less than or equal to either 0.4 or 0.3, wherein the polydispersity index is determined by dynamic light scattering. 29. The preparation described in any one of the above items, wherein the activator is present in an amount of 0.001% w / w to 50% w / w based on the total weight of the preparation. 30. A pharmaceutical preparation containing an active agent, as described in any one of items 1 to 29. 31. The formulation according to item 30, wherein the activator is a low molecular weight organic compound having a molecular weight of 100 to 1000 g / mol, preferably 115 to 950 g / mol, and more preferably 130 to 900 g / mol. 32. The formulations described in item 30 or 31, wherein the activator is not a pharmaceutically acceptable macrolide lactone. 33. The activator is the formulation described in item 32, not tacrolimus. 34. The formulation according to item 30 or 31, wherein the activator is a photosensitizer or its metabolic precursor, preferably 5-aminolevulinic acid, a pharmaceutically acceptable salt thereof, a derivative, a precursor and / or metabolite. 35. (a) A nanoemulsion, said nanoemulsion (i) Based on the total weight of the nanoemulsion (a), the aqueous component present in amounts of 70% w / w to 95% w / w; (ii) a nanovesicle, (1) 1-5% of at least one phospholipid based on the total weight of the nanoemulsion (a); (2) 3-7% of at least one polyoxyethylene-type surfactant based on the total weight of nanoemulsion (a); (3) 1-3% C3-C5 alcohol based on the total weight of nanoemulsion (a); and (4) 3-8% triglycerides based on the total weight of the nanoemulsion (a); Nanovesicles and Nanoemulsions containing; (b) 1 to 20% of the total weight of the formulation of a photosensitizer or its metabolic precursor, preferably 5-aminolevulinic acid hydrochloride; (c) Optionally, 0.5 to 4% of at least one gelling agent based on the total weight of the preparation; (d) optionally, 0.1 to 2% of at least one preservative based on the total weight of the preparation; and (e) Propellant The formulations described in item 34, including those listed in item 34. 36. A preparation for use in medicine, as described in any one of items 1 to 35. 37. A formulation described in any one of items 32-35 for use in methods of treating and / or preventing dermatological diseases or conditions in a subject. 38. Treatment and / or prevention of dermatological diseases or conditions: (a) A pharmaceutically effective amount of the preparation described in any one of items 32-35 is administered topically to the diseased area or affected area of ​​the skin, and to the area surrounding the diseased area or affected area, wherein the preparation is to be administered topically in the form of a foam. (b) Optionally, occlude the area of ​​skin to which the formulation has been administered, or incubate the formulation on the subject's skin without occlusion, preferably by using a low-density polyethylene or polyurethane film to promote deep tissue penetration; incubation Formulations for use as described in item 37, including those listed. 39. A preparation described in any one of items 34-35 for use in methods of treating and / or preventing dermatological diseases or conditions in a subject, The treatment and / or prevention of dermatological diseases or conditions, (a) A pharmaceutically effective amount of the preparation described in any one of items 33-34 is administered topically to the diseased area or affected area of ​​the skin, and optionally to the area surrounding the diseased area or affected area, wherein the preparation forms a foam and is administered topically. (b) Optionally, the area of ​​skin to which the formulation has been administered is occluded, or the formulation is incubated on the skin of the subject without occlusion, preferably using a low-density polyethylene or polyurethane film to promote deep tissue penetration; (c) Irradiating the skin area where the formulation was administered with light A formulation containing the above. 40. A formulation for use as described in any one of items 38-39, which includes an area of ​​skin disease or surrounding the affected area, with an area of ​​at least approximately 5 mm in width. 41. A dermatological disease or condition, including diseases or conditions of the skin, skin appendages, or mucous membranes, is a formulation for use as described in any one of items 37-40. 42. A formulation for use as described in any one of items 37-41, selected from the group consisting of inflammatory, neoplastic, proliferative, infectious and / or autoimmune diseases or conditions, and / or their skin manifestations, and / or diseases associated with solitary lesions or lesional areas, neoplastic, proliferative and / or inflammatory changes. 43. Inflammatory dermatological diseases or conditions, selected from the group consisting of dermatitis, contact dermatitis, acne, atopic dermatitis, eczema, pustular dermatitis, seborrheic dermatitis, perioral dermatitis, chronic wounds, urticaria, skin ulcers, rosacea, rash, drug eruption, toxic epidermal necrolysis; erythema multiforme, erythema nodosum, granuloma annulare, and other inflammatory skin conditions, formulations for use as described in item 42. 44. Formulations for use as described in item 42, selected from the group consisting of neoplastic and / or proliferative dermatological diseases or conditions, basal cell carcinoma, preferably superficial basal cell carcinoma or nodular basal cell carcinoma; squamous cell carcinoma, preferably Morbus-Bohen or invasive squamous cell carcinoma; vulvar intraepithelial neoplasia (VIN); cutaneous T-cell lymphoma; Merkel cell carcinoma; hemangioma; nodular or subcutaneous carcinoma; widespread carcinogenesis; non-melanoma skin cancer in organ transplant recipients; and prevention of non-melanoma skin cancer in organ transplant recipients. 45. Infectious skin chemical diseases or conditions, selected from the group consisting of bacterial infections, viral infections, fungal infections, parasitic infections, and combinations thereof, formulations for use as described in item 42. 46. ​​An autoimmune dermatological disease or condition, or a skin manifestation of an autoimmune condition, selected from the group consisting of psoriasis, pemphigus, systemic lupus erythematosus, lichen planus, morphea, scleroderma, epidermolysis bullosa, dermatomyositis, and graft-versus-host syndrome, for use as described in item 42. 47. A formulation for use as described in any one of items 37-46, selected from the group consisting of dermatological diseases or conditions including hyperpigmentation disorders such as sweating disorders, vitiligo, albinism and post-inflammatory hypopigmentation, as well as hyperpigmentation disorders such as melasma, reactions to sunlight such as sunburn, skin aging, photosensitivity, hirsutism, alopecia, and male pattern baldness, and other disorders of hair follicles and sebaceous glands. 48. Preparations described in any one of items 34-35 for use in photodynamic diagnostic methods for neoplastic and / or proliferative cutaneous chemical disorders or conditions, such as benign or malignant tumors or their precursors; inflammatory cutaneous chemical disorders or conditions; and / or conditions associated with bacterial growth, such as acne. 49. A cosmetic formulation, as described in any one of items 1 to 29. 50. The formulations described in item 49, wherein the surfactant is a cosmetic surfactant selected from plant extracts, natural or synthetic humectants, natural or synthetic cleansing agents, natural or synthetic protective agents, natural or synthetic detergents, natural or synthetic antioxidants, natural or synthetic skin conditioning agents, and natural or synthetic vitamins. 51. Use of the formulations described in item 49 or 50 for moisturizing the skin, cleansing the skin, protecting from the sun (ultraviolet rays) or other external influences, assisting in maintaining the skin's barrier function, beautifying the skin, reducing signs of skin aging, or as supportive care for stressed or diseased skin. 52. A method for preparing a preparation described in any one of items 1 to 50, the method 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. (b) Contact the mixture obtained in step (a) with an aqueous component under conditions that allow for the formation of a nanoemulsion. (c) Introducing the formulation obtained in step (c) into a dispenser or container, and (d) Adding propellant to the dispenser or container and pressurizing the dispenser or container. Methods that include... 53. (i) Adding an activator; (ii) Adding a gelling agent, and / or (iii) Adding preservatives The method described in item 52, further including the method described in item 52. 54. A container for containing a formulation, wherein the formulation comprises a nanoemulsion, and the nanoemulsion is: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Carrier components including Includes, The formulation is essentially free of emollients; and The container further contains propellant, which is supplied to pressurize the container. 55. A dispenser product comprising a container for containing a formulation, wherein the formulation comprises a nanoemulsion, and the nanoemulsion is: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Carrier components including Includes, The formulation essentially contains no foaming agents; and The container further contains propellant, which is provided to pressurize the container; this is a dispenser product. 56. Formulations and propellants are independently defined in any one of items 1 to 50, in the containers described in item 54 or the dispensers described in item 55. 57. A preparation, wherein the preparation is (a) a nanoemulsion: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one alcohol having at least three carbon atoms Carrier components, (iii) Optionally, an activator and Nanoemulsions, (b) Optionally, a gelling agent Includes, The formulation is supplied to a container further containing propellant, and the propellant is supplied to pressurize the container. 58. A preparation, said preparation is (a) a nanoemulsion: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one alcohol having at least three carbon atoms Carrier components, (iii) Optionally, activator Nanoemulsions, (b) Optionally, a gelling agent Includes, A formulation is a formulation prepared as a pressurized formulation, to which a propellant is supplied to pressurize the formulation. 59. The components of the formulation, in particular the nanoemulsion, gelling agent and propellant, are independently defined in any one of items 1 to 50, as described in item 57 or 58. 60. A preparation for use in medicine, as described in any one of items 57-59. 61. A formulation described in any one of items 57-59 for use in methods of treating and / or preventing dermatological diseases or conditions in a subject. 62. A form obtained from or containing a preparation described in any one of items 1-50 or 57-61. 63. Use of any one of the formulations described in items 1-29, 57, 58, and 59 as a cosmetic. 64. Use of any one of the preparations described in items 1-48, 57, 58, and 59 for the manufacture of a medicament for the treatment and / or prevention of a dermatological disease or condition in a subject. 65. A method for treating and / or preventing a dermatological disease or condition in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a preparation described in any one of items 1-48, 57, 58, and 59. 66. A photodynamic diagnostic method for neoplastic and / or proliferative dermatological diseases or conditions such as benign or malignant tumors or their precursors; inflammatory dermatological diseases or conditions; and / or conditions related to bacterial growth such as acne, wherein the method is (i) Administer the formulation described in item 34 or 35 to the skin area to be diagnosed under conditions in which fluorescent porphyrin can be synthesized in cells and / or tissues, and (ii) Irradiating the skin area to which the formulation has been administered under conditions that induce fluorescence of accumulated porphyrins. Includes, An increase in porphyrin fluorescence indicates increased metabolic activity and suggests neoplastic and / or proliferative dermatological diseases or conditions, inflammatory dermatological diseases or conditions, and / or conditions associated with bacterial growth. 67. A method for the cosmetic treatment and / or prevention of a dermatological condition in a subject, the method comprising administering to the subject an effective amount of a formulation described in any one of items 1-29, 49-51, and 57-59. 68. A method for stabilizing a nanoemulsion, the method comprising the following steps (a) supplying a nanoemulsion, the nanoemulsion being: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Carrier components including To supply nanoemulsions containing; (b) introducing nanoemulsions into containers; and (c) Adding propellant to the container and pressurizing the container. Methods that include... 69. The nanoemulsion contains nanovesicles containing a carrier component, and the nanovesicles have a stable size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when stored in a pressurized container at 4 to 40°C, 10 to 40°C, 20 to 40°C, 30 to 40°C, or 40°C for 1 month, 2 months, 3 months, or at least 1 month, at least 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, or at least 36 months; and / or The method according to item 68, wherein the nanoemulsion is characterized by a stable polydispersity index of 0.4 or less and / or 0.3 or less when stored in a pressurized container at 4-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, or at least 36 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months. 70. The method described in item 68 or 69, which is a method for stabilizing a formulation containing a nanoemulsion. 71. Formulations, nanoemulsions, and propellants are independently defined in any one of items 1 to 50, according to the method of item 70. 72. Use of nanoemulsions for the preparation of foams or sprays, the use is as follows: (a) To supply a formulation containing a nanoemulsion, wherein the nanoemulsion is: (i) at least one aqueous component; (ii) Carrier component: (1) at least one lipophilic component, (2) at least one surfactant, and (3) At least one type of alcohol Carrier components including Including supplying; (b) Introducing a formulation containing nanoemulsion into a container; (c) Adding propellant to the container and pressurizing the container; and (d) Discharging foam or spray from a pressurized container Includes, use. 73. Formulations containing nanoemulsions, nanoemulsions and propellants are used independently as defined in any one of items 1 to 50, as described in item 72. 74. The formulation according to item 30 or 31, wherein the activator is a pharmaceutically acceptable macrolide lactone, preferably a calcineurin inhibitor, most preferably tacrolimus, a pharmaceutically acceptable derivative, precursor, analog, and / or metabolite thereof.

[0346] The present invention is further illustrated by the following figures and embodiments. [Brief explanation of the drawing]

[0347] [Figure 1] An exemplary pressurized dispenser (or container) equipped with a spray head (center) or a foam dispenser valve (left), used for storing an exemplary formulation in an embodiment of the present invention. A glass vial (right) used for storing an exemplary non-pressurized comparative formulation in an embodiment of the present invention. [Figure 2] Comparison of nanoemulsion formulations with different lipophilic content and no gelling agents: Vesicle size over time at different temperatures. [Figure 3] Comparison of nanoemulsion formulations with different pH values ​​and no gelling agents: Vesicle size over time at different temperatures. [Figure 4] Comparison of nanoemulsion formulations with different lipophilic content, where XT=1%: vesicle size over time at different temperatures. [Figure 5] Comparison of nanoemulsion formulations with different lipophilic content, where XT = 0.5%: vesicle size over time at different temperatures. [Figure 6] Comparison of nanoemulsion formulations with different lipophilic content, where PX = 2%: Vesicle size over time at different temperatures. [Figure 7]Comparison of nanoemulsion formulations with different lipophilic content, where PX = 1%: Vesicle size over time at different temperatures. [Figure 8] Comparison of nanoemulsion formulations with different lipophilic content using xanthan gum as an antifreeze (frozen for 4 days, once). From left to right: BF200 XT=0.5% / 1.0% glass, BF200 XT=0.5% / 1.0% foam, BF215 XT=0.5% / 1.0% glass, BF215 XT=0.5% / 1.0% foam, BF220 XT=0.5% / 1.0% glass, BF220 XT=0.5% / 1.0% foam. [Figure 9] Comparison of nanoemulsion formulations with different lipophilic content using xanthan gum as an antifreeze agent (5 freeze-thaw cycles). From left to right: BF200 XT=1% glass, BF200 XT=1% foam, BF215 XT=1% glass, BF215 XT=1% foam, BF220 XT=1% glass, BF220 XT=1% foam. [Figure 10] Comparison of TC content over time in BF220 using PX=4% as a gelling agent at 5°C. [Figure 11] Comparison of ALA content over time in BF200 using PX=2% as a gelling agent at 5°C and 25°C. [Figure 12] Analysis of foam collapse times of nanoemulsions BF200 and BF220 listed in Table 2 at room temperature and 36°C.

[0348] Some of the data shown in the figure was obtained from pooled experiments. [Examples]

[0349] In the examples, vesicle size and API content, which indicate the stability of nanoemulsion formulations and depend on lipophilic content, pH, and gelling agent, were measured under various conditions (0°C, 25°C, 40°C, freeze-thaw cycle).

[0350] Example 1: Preparation of nanoemulsions BF200, BF215, and BF220, and nanoemulsion formulations

[0351] [Table 1]

[0352] Table 2 shows the qualitative and quantitative compositions of nanoemulsions BF200, BF215, and BF220.

[0353] [Table 2]

[0354] The formulation does not contain gelling agents such as poloxamer 407.

[0355] The manufacturing process for nanoemulsions in a typical batch size consists of the following steps 1-4:

[0356] Step 1: Preparation of 10 mM phosphate buffer (aqueous component) A 10 mM phosphate buffer solution at pH 6 (1000 g) was prepared and optionally sterilized by filtration through a sterile filter.

[0357] Step 2: Preparation of a carrier containing lipophilic components, surfactants, and alcohols.

[0358] [Table 3]

[0359] 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 by continuous stirring at room temperature using a suitable stirrer. Caprylic / capric triglyceride (35 g) and polysorbate 80 (34 g) were weighed and added to the soy lecithin solution. The mixture was stirred at room temperature using a suitable stirrer until a homogeneous, clear solution was obtained. This solution is the carrier phase contained in nanoemulsion BF200, which contains all the emulsifiers and lipid components. BF215 and BF220 were prepared by adjusting the amounts of components according to this procedure (see Table 2).

[0360] Step 3: Production of a 10% lipid content nanoemulsion (BF200) by mixing the aqueous component from Step 1 with the carrier from Step 2. Preparation 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 containing the phosphate buffer was heated to approximately 45°C to 60°C in a suitable container. Next, the carrier (concentrate) from Step 2 was heated to approximately 45°C to 60°C. Then, the carrier was injected into the phosphate buffer under continuous stirring with a propeller mixer to form a stable trombe (or jet) of the maximum possible diameter without causing foaming or sputtering. The resulting nanoemulsion was stirred for approximately 15 minutes. Finally, the nanoemulsion was cooled to room temperature.

[0361] For nanoemulsion BF215, 850g of phosphate buffer (from step 1) and 150g of carrier were mixed. For nanoemulsion BF220, 800g of phosphate buffer (from step 1) and 200g of carrier were mixed.

[0362] In the following examples, the terms “nanoemulsion BF200,” “nanoemulsion BF215,” and “nanoemulsion BF220” are used to refer to the nanoemulsions prepared according to steps 1 to 3.

[0363] Nanoemulsions BF200, BF215, and BF220 were used in Examples A and G.

[0364] Step 4: Preparation of the final nanoemulsion formulation and primary packaging Optionally, the nanoemulsion was sterilized by filtration using a sterile filter and filled into 100 ml sterile glass bottles under a laminar flow hood.

[0365] Depending on the purpose of the nanoemulsion, auxiliary agents and / or excipients and / or active ingredients may be added (in appropriate steps according to this specification), and / or the nanoemulsion may be diluted in a manner that yields a suitable "nanoemulsion formulation." For example, water, a suitable buffer, or an aqueous gel base having poloxamer 407 or xanthan gum may be added.

[0366] In the following examples, the terms “nanoemulsion formulation BF200,” “nanoemulsion formulation BF215,” and “nanoemulsion formulation BF220” are used to refer to the nanoemulsion formulations prepared according to steps 1 to 4.

[0367] The abbreviations "BF200," "BF215," and "BF220" are used for both (stock) nanoemulsions and nanoemulsion formulations.

[0368] Nanoemulsions or nanoemulsion formulations were filled into conventional glass vials ("BF200 glass vials," "BF215 glass vials," and "BF220 glass vials") or foam dispensers ("pressurized BF200," "pressurized BF215," and "BF220") pressurized with a mixture of propane, isobutane, and n-butane. Typical examples of dispensers (pressurized containers) and glass vials are shown in Figure 1.

[0369] Example 2: Preparation of nanoemulsions BF200, BF215, and BF220 at pH 3 or 5 Nanoemulsions of BF200, BF215, and BF220 are prepared according to steps 1-3 of Example 1, except that a phosphate buffer with an appropriate pH is used in step 3 (preparation of the nanoemulsion by mixing the aqueous component of step 1 with the carrier of step 2). Other acids other than phosphoric acid and its salts can also be used for pH adjustment. If necessary, the pH may be further adjusted by adding an appropriate acid, salt, or buffer.

[0370] Nanoemulsions of BF200, BF215, and BF220 were filled into conventional glass vials ("BF200 pH=3 glass", "BF200 pH=5 glass", "BF215 pH=3 glass", "BF220 pH=3 glass") or foam dispensers ("BF200 pH=3 foam", "BF200 pH=5 foam", "BF215 pH=3 foam", "BF220 pH=3 foam") as described in Example 1.

[0371] The nanoemulsion described in this example was used in Example B.

[0372] Example 3: Preparation of nanoemulsion formulations BF200, BF215, and BF220 containing 0.5% (w / w) or 1% (w / w) xanthan gum. The nanoemulsion formulations BF200, BF215, and BF220 are prepared according to Example 1, by adding an appropriate amount of aqueous gel base containing xanthan gum in step 4.

[0373] The formulations were filled into conventional glass vials ("BF200 XT=0.5% glass", "BF215 XT=0.5% glass", "BF220 XT=0.5% glass") or foam dispensers ("BF200 XT=0.5% foam", "BF215 XT=0.5% foam", and "BF220 XT=0.5% foam") as described in Example 1.

[0374] The formulations were filled into conventional glass vials ("BF200 XT=1.0 glass", "BF215 XT=1.0% glass", "BF220 XT=1.0% glass") or foam dispensers ("BF200 XT=1.0% foam", "BF215 XT=1.0% foam", and "BF220 XT=1.0% foam") as described in Example 1.

[0375] The nanoemulsion formulation described in this example was used in Examples C, D, G, and H.

[0376] Example 4: Preparation of nanoemulsion formulations BF200, BF215, and BF220 containing 1% (w / w) or 2% (w / w) poloxamer 407 (PX) The nanoemulsion formulation is prepared according to Example 1, by adding an appropriate amount of aqueous gel base containing poloxamer 407 in step 4.

[0377] The formulations were filled into conventional glass vials ("BF200 PX=2.0% % glass", "BF215 PX=2.0% % glass", "BF220 PX=2.0% % glass") or foam dispensers ("BF200 PX=2.0% % foam", "BF215 PX=2.0% % foam", and "BF220 PX=2.0% % foam") as described in Example 1.

[0378] As described herein, nanoemulsion formulations of BF200 PX=2.0% glass, BF215 PX=2.0% glass, BF220 PX=2.0% glass, BF200 PX=2.0% foam, BF215 PX=2.0% foam, and BF220 PX=2.0% foam were used in Example E.

[0379] The formulations were filled into conventional glass vials ("BF200 PX=1.0% % glass", "BF215 PX=1.0% % glass", "BF220 PX=1.0% % glass") or foam dispensers ("BF200 PX=1.0% % foam", "BF215 PX=1.0% % foam", and "BF220 PX=1.0% % foam") as described in Example 1.

[0380] As described herein, nanoemulsion formulations of BF200 PX=1.0% glass, BF215 PX=1.0% glass, BF220 PX=1.0% glass, BF200 PX=1.0% foam, BF215 PX=1.0% foam, and BF220 PX=1.0% foam were used in Example F.

[0381] Example 5: Preparation of nanoemulsion formulation BF200 containing 3% 5-aminolevulinic acid and 2% poloxamer 407 Following Example 1, a formulation was prepared in step 4 by adding an appropriate amount of aqueous gel base containing poloxamer 407. 3% of 5-ALA was added.

[0382] The nanoemulsion formulation described in this example was used in Example I.

[0383] Example 6: Preparation of nanoemulsion formulation BF220 containing 0.1% tacrolimus (TC) and 4% poloxamer 407. According to Example 1, a formulation was prepared in step 4 by adding an appropriate amount of aqueous gel base containing poloxamer 407. 0.1% of TC was added.

[0384] The nanoemulsion formulation described in this example was used in Example J.

[0385] Example 7: Measurement of vesicle size and polydispersity index by dynamic light scattering method The size and polydispersity index of nanoemulsion formulations, expressed as the z-mean size (e.g., nm), were determined by dynamic light scattering (sometimes referred to as photon correlation spectroscopy (PCS) or quasi-elastic light scattering (QELS)). This technique is well-known in the art and is an established method for laser measurement of the size of nanoparticles, microparticles, or vesicles in emulsions, suspensions, or polymer solutions. For foam samples, analysis was performed after foam collapse. Measurements were performed using a Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK). Measurements were performed according to the manufacturer's instructions.

[0386] The Zetasizer Nano ZS features an optical system with a 633nm green laser and a 173° scattering detector angle for size measurement. Although this instrument can be used under vacuum, in this case, a vacuum was not applied to the sample for size and homogeneity measurements.

[0387] Example 8: Measurement of viscosity The viscosity is 90.0 s at 20°C. -1 Measurements were taken by rotation (measurement shape: cone / plate) at a constant shear rate.

[0388] Example A Comparison of nanoemulsions with different lipophilicity content and no gelling agents: Vesicle size and polydispersity index over time at different temperatures. Nanoemulsions BF200, BF215, and BF220 were prepared as described in Example 1. The nanoemulsions were stored at 25°C for 36 months or at 40°C for 12 months. The size of the nanovesicles was measured by dynamic light scattering as described in Example 7, at 0 (start point) and at various points during the storage period. The results are shown in Figure 2 and Table 4.

[0389] [Table 4]

[0390] Compared to conventional storage in glass vials, where degradation is much faster under phase separation, vesicle size is extremely stable when nanoemulsions (without gelling agents) are stored in a pressurized container under ambient temperature conditions (25°C) and stress conditions (40°C). Conclusion: Pressurized containers are extremely advantageous for storage under ambient temperature and stress conditions.

[0391] Example B Comparison of nanoemulsions with different pH values ​​and no gelling agents: Vesicle size over time at different temperatures Nanoemulsions of BF200 pH=3 glass, BF200 pH=5 glass, BF200 pH=3 foam, BF200 pH=5 foam, BF215 pH=3 glass, BF220 pH=3 glass, BF215 pH=3 foam, and BF220 pH=3 foam were prepared as described in Example 2. The nanoemulsions were stored at 25°C for 36 months or at 40°C for up to 36 months. The size of the nanovesicles was measured by dynamic light scattering as described in Example 7, at 0 (start time) and at various points during the storage period. The results are shown in Figure 3 and Table 5.

[0392] [Table 5]

[0393] In glass vials, the combination of acidic pH and high temperature (e.g., 40°C) impairs the stability of vesicle size in nanoemulsions (phase separation) after 12 months of storage. When a pressurized container was used as the storage unit, a vesicle size of less than 190 nm was maintained for 12 months at 40°C. • Formulations stored in a pressurized container at pH 5 maintained a vesicle size of less than 133 nm for 36 months at 40°C. In glass vials, the combination of acidic pH and ambient temperature (e.g., 25°C) impairs the stability of vesicle size in nanoemulsions (phase separation) after 18 months of storage. When a pressurized container was used as the storage unit, a vesicle size of less than 116 nm was maintained for 36 months at 25°C. Conclusion: Pressurized containers are highly advantageous for storing nanoemulsions with pH 3 or pH 5 at ambient temperature and high temperatures (e.g., 25°C and 40°C).

[0394] Example C Comparison of nanoemulsion formulations with different lipophilic content, where xanthan gum (XT) = 1%: Vesicle size over time at different temperatures. Nanoemulsion formulations of BF200 XT=1.0% glass, BF215 XT=1.0% glass, BF220 XT=1.0% glass, BF200 XT=1.0% foam, BF215 XT=1.0% foam, and BF220 XT=1.0% foam were prepared as described in Example 3. The nanoemulsion formulations were stored at 25°C for 36 months or at 40°C for 12 months. The size of the nanovesicles was measured by dynamic light scattering as described in Example 7, at 0 (start time) and at various points during the storage period. The results are shown in Figure 4.

[0395] • In glass vials, high temperatures (e.g., 40°C) impair the stability of vesicle size in nanoemulsions after 12 months of storage (phase separation). When a pressurized container was used as the storage unit, a vesicle size of less than 315 nm was maintained for 12 months at 40°C. • In glass vials, the stability of vesicle size in nanoemulsions is compromised (phase separation) after 18 months of storage due to ambient temperature (e.g., 25°C). When a pressurized container was used as the storage unit, a vesicle size of less than 107 nm was maintained for 36 months at 25°C. Conclusion: Pressurized containers are highly advantageous for storing nanoemulsion formulations containing xanthan gum as a gelling agent at room temperature (25°C) and high temperatures (e.g., 40°C). XT=1% shows a stabilizing effect under standard conditions (glass vials) and low temperatures (5°C), especially in nanoemulsion formulations with high lipophilicity content (BF215, BF220).

[0396] Example D Comparison of nanoemulsion formulations with different lipophilic content, where XT = 0.5%: Vesicle size over time at different temperatures. Nanoemulsion formulations of BF200 XT=0.5% glass, BF215 XT=0.5% glass, BF220 XT=0.5% glass, BF200 XT=0.5% foam, BF215 XT=0.5% foam, and BF220 XT=0.5% foam were prepared as described in Example 3. The nanoemulsion formulations were stored at 25°C for 36 months or at 40°C for 12 months. The size of the nanovesicles was measured by dynamic light scattering as described in Example 7, at 0 (start time) and at various points during the storage period. The results are shown in Figure 5.

[0397] • In glass vials, high temperatures (e.g., 40°C) impair the stability of vesicle size in nanoemulsions after 12 months of storage (phase separation). When a pressurized container was used as the storage unit, the vesicle size was maintained at less than 250 nm for 12 months at 40°C. • In glass vials, the stability of vesicle size in nanoemulsions is compromised (phase separation) after 18 months of storage due to ambient temperature (e.g., 25°C). When a pressurized container was used as the storage unit, the vesicle size remained below 115 nm for 36 months at 25°C. Conclusion: Pressurized containers are highly advantageous for storing nanoemulsion formulations containing xanthan gum as a gelling agent at room temperature (25°C) and high temperatures (e.g., 40°C).

[0398] Example E Comparison of nanoemulsion formulations with different lipophilic content, where poloxamer 407 (PX) = 2%: Vesicle size over time at different temperatures. Nanoemulsion formulations of BF200 PX=2.0% glass, BF215 PX=2.0% glass, BF220 PX=2.0% glass, BF200 PX=2.0% foam, BF215 PX=2.0% foam, and BF220 PX=2.0% foam were prepared as described in Example 4. The nanoemulsion formulations were stored at 25°C for 36 months or at 40°C for 12 months. The size of the nanovesicles was measured by dynamic light scattering as described in Example 7, at 0 (start time) and at various points during the storage period. The results are shown in Figure 6.

[0399] Under all conditions, the vesicle size after 12 months of storage was less than 160 nm (40°C) or 110 nm (25°C), and the stabilizing effect of 2% poloxamer 407 in a pressurized container was observed, similar to that of conventional storage units (glass vials). Conclusion: Poloxamer 407 stabilizes nanoemulsions stored in pressurized containers and glass vials at 25°C for 36 months. Poloxamer 407 stabilizes nanoemulsions stored in pressurized containers and glass vials at 40°C for 18 months.

[0400] Example F Comparison of nanoemulsion formulations with different lipophilic content, where poloxamer 407 (PX) = 1%: Vesicle size over time at different temperatures. Nanoemulsion formulations of BF200 PX=1.0% glass, BF215 PX=1.0% glass, BF220 PX=1.0% glass, BF200 PX=1.0% foam, BF215 PX=1.0% foam, and BF220 PX=1.0% foam were prepared as described in Example 4. The nanoemulsion formulations were stored at 25°C for 36 months or at 40°C for 12 months. The size of the nanovesicles was measured by dynamic light scattering as described in Example 7, at 0 (start time) and at various points during the storage period. The results are shown in Figure 7.

[0401] When stored at 40°C for 12 months, the vesicle size increased to 234-541 nm in glass vials with high lipid content (BF215, BF220). In samples stored in pressurized containers, the vesicle size remained below 160 nm. After 36 months, the vesicle size remained below 121 nm (at 25°C). In glass vials, it increased to 144 nm with high lipid content (BF220). Conclusion: PX=1% shows a stabilizing effect at ambient temperature (25°C). This effect is enhanced by the pressurized vessel closure system. The pressurized vessel closure system improves stability at 40°C.

[0402] Example G Comparison of nanoemulsion formulations with different lipophilic content, containing xanthan gum as an antifreeze agent. Nanoemulsion formulations of BF200 XT=0% glass (=BF200 glass), BF215 XT=0% glass (=BF215 glass), BF220 XT=0% glass (=BF220 glass), BF200 XT=0% foam (=BF200 foam), BF215 XT=0% foam (=BF215 foam), and BF220 XT=0% foam (=BF220 foam) were prepared as described in Example 1.

[0403] Nanoemulsion formulations of BF200 XT=0.5% glass, BF215 XT=0.5% glass, BF220 XT=0.5% glass, BF200 XT=0.5% foam, BF215 XT=0.5% foam, and BF220 XT=0.5% foam were prepared as described in Example 3.

[0404] Nanoemulsion formulations of BF200 XT=1.0% glass, BF215 XT=1.0% glass, BF220 XT=1.0% glass, BF200 XT=1.0% foam, BF215 XT=1.0% foam, and BF220 XT=1.0% foam were prepared as described in Example 3.

[0405] The formulation was stored at -24°C for 4 days and then thawed (one freeze-thaw cycle). Vesicle size was measured as described in Example 7. The results are shown in Figure 8 and Table 6.

[0406] [Table 6]

[0407] • Nanoemulsion formulations containing xanthan gum are better protected under freezing conditions (compared to conventional storage units, i.e., glass vials) when stored in a pressurized container. • When xanthan gum is not present (XT=0%), these characteristics are not observed. Conclusion: For example, xanthan gum can ensure adequate freeze protection in pressurized containers. The combination of xanthan gum and pressurized containers is superior to "unpressurized" conditions, such as conventional storage in glass vials.

[0408] Example H Comparison of nanoemulsion formulations with different lipophilic content, containing xanthan gum as an antifreeze agent. Nanoemulsion formulations of BF200 XT=1.0% glass, BF215 XT=1.0% glass, BF220 XT=1.0% glass, BF200 XT=1.0% foam, BF215 XT=1.0% foam, and BF220 XT=1.0% foam are prepared as described in Example 3.

[0409] Other nanoemulsions were not prepared based on the results of Example G.

[0410] The formulation was subjected to five freeze-thaw cycles. In each cycle, the nanoemulsion was frozen at -24°C and then thawed at room temperature. After the final thawing, the vesicle size was measured as described in Example 7. The results are shown in Figure 9 and Table 7.

[0411] [Table 7]

[0412] Under all tested conditions, improved stability was observed in the nanovesicle formulation stored in a pressurized container after five freeze-thaw cycles. The formulation contained a gelling agent, such as xanthan gum, as an antifreeze. The combination of xanthan gum and a pressurized container proved superior to conventional "non-pressurized" conditions, such as storage in glass vials.

[0413] Example I Comparison of 5-aminolevulinic acid (ALA,5-ALA) content over time at different temperatures in BF200 containing PX=2% as a gelling agent. Nanoemulsion formulations of BF200 PX=2% glass and BF200 PX=2% foam were prepared as described in Example 5. The nanoemulsion formulations were stored at 25°C and 2–8°C. ALA content was measured at 0 (start time) and at various points during the 36-month storage period. The results are shown in Figure 11.

[0414] Conclusion: Under all conditions: Pressurized containers suitably retain API(5-ALA) content better than conventional storage units (e.g., glass vials). The ALA content after 36 months of storage at 2–25°C was at least 90%.

[0415] Example J Comparison of tacrolimus (TC) content over time at different temperatures in BF220 containing PX=4% as a gelling agent. Nanoemulsion formulations of BF220 TC=0.1% glass and BF220 TC=0.1% foam were prepared as described in Example 6. The nanoemulsion formulations were stored at 2–8°C and 25°C. The TC content was measured at various points in time, from 0 (start) to 48 months of storage. The results are shown in Figure 10.

[0416] Conclusion: At 2–8°C and 25°C: Pressurized containers suitably retain API(TC) content better than conventional storage units (e.g., glass vials). Formulations stored in pressurized containers were confirmed to be stable for at least 48 months at 2–8°C (5°C) and 6 months at 25°C. The TC content after 48 months at 2–8°C or 6 months at 25°C was at least 95%.

Claims

1. A pharmaceutical preparation, wherein the preparation is: (a) Nanoemulsion, (i) with at least one aqueous component; (ii) A carrier component, wherein the carrier component is: (1) At least one lipophilic component, (2) at least one surfactant, and (3) at least one type of alcohol The carrier component includes and The nanoemulsion comprising; and (b) Propellant Includes, The aforementioned preparation is housed in a pressurized container, The aforementioned formulation is a formulation that is essentially free of fatty alcohols.

2. The formulation according to claim 1, wherein the formulation essentially does not contain an emollient selected from monoesters or diesters containing alcohol and fatty acids.

3. The formulation according to claim 1 or 2, wherein the formulation is essentially free of a gelling agent.

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

5. The formulation according to any one of claims 1 to 4, wherein the at least one surfactant is selected from the group consisting of phospholipids, lysophospholipids, ceramides and / or mixtures thereof, and / or the at least one surfactant is a polyoxyethylene-type surfactant.

6. The formulation according to any one of claims 1 to 5, wherein the at least one alcohol has 3 to 5 carbon atoms, and more preferably the at least one alcohol is selected from the group consisting of 1-propanol, 2-propanol, and mixtures thereof.

7. The formulation according to any one of claims 1 to 6, wherein the propellant is propane, isobutane, or n-butane, or a mixture thereof.

8. A formulation according to any one of claims 1 to 7, comprising a total aqueous component in an amount of 50% to 99% (w / w), preferably 70% to 95% (w / w), more preferably 75% to 95% (w / w), and even more preferably 80% to 90% (w / w).

9. Based on the total weight of the nanoemulsion (a), (a) at least one lipophilic component in an amount of 0.1% to 30% (w / w), preferably 0.25% to 15% (w / w), preferably 0.25% to 10% (w / w), more preferably 0.5% to 8% (w / w) or 3% to 8% (w / w); and / or (b) At least one of the alcohols in an amount of 0.1% to 10% (w / w), preferably 0.5% to 5% (w / w), and more preferably 1% to 3% (w / w). A formulation according to any one of claims 1 to 8, including the formulation described in any one of claims 1 to 8.

10. A formulation according to any one of claims 1, 2, or 4 to 9, comprising a gelling agent, preferably the gelling agent being 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, more preferably the gelling agent being selected from poloxamer, xanthan gum, and mixtures thereof, in particular, the gelling agent being present in an amount of 0.1% to 10% (w / w), preferably 0.25% to 5% (w / w), more preferably 0.5% to 4% (w / w), based on the total weight of the formulation.

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

12. The aforementioned nanoemulsion is a. The pressurized container contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when stored at 2 to 40°C, 10 to 40°C, 20 to 40°C, 30 to 40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, or 12 months; and / or b. The pressurized container is characterized in that, when stored at 2-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, or 12 months, the polydispersity index is 0.4 or less; and / or c. The pressurized container contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when stored at 2 to 25°C, 10 to 25°C, 15 to 25°C, 2 to 8°C, 5°C, or 25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months; and / or d. Containing nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when subjected to one, two, three, four, five, or more freeze-thaw cycles; and / or e. The polydispersity index is 0.4 or less when stored in the pressurized container at 2-25°C, 10-25°C, 15-25°C, 2-8°C, 5°C, or 25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months; and / or f. The pressurized container contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when stored at 2 to 8°C or 5°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months; and / or g. The polydispersity index is 0.4 or less when stored in the pressurized container at 2 to 8°C or 5°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months; and / or h. The formulation according to any one of claims 1 to 11, characterized in that the polydispersity index is 0.4 or less when subjected to one, two, three, four, five, or more freeze-thaw cycles.

13. The activator preferably contains a biological substance, more preferably... 5-aminolevulinic acid, its pharmaceutically acceptable salts, derivatives, precursors and / or metabolites, or • Diclofenac, its pharmaceutically acceptable salts, derivatives, precursors and / or metabolites A formulation according to any one of claims 1 to 12, comprising:

14. A formulation according to any one of claims 1 to 13, comprising 5-aminolevulinic acid, a pharmaceutically acceptable salt thereof, a derivative, a precursor, and / or a metabolite thereof.

15. A method for stabilizing a nanoemulsion, the method comprising the following steps: (a) To provide a nanoemulsion, wherein the nanoemulsion is: (i) with at least one aqueous component; (ii) A carrier component, wherein the carrier component is: (1) At least one lipophilic component, (2) at least one surfactant, and (3) at least one type of alcohol The carrier component includes and To provide the nanoemulsion containing the above; (b) introducing the nanoemulsion into a container; and (c) Adding a propellant to the container to pressurize the container and / or the nanoemulsion inside the container. Methods that include...

16. The method according to claim 15, wherein the nanoemulsion is a nanoemulsion formulation containing an activator.

17. The aforementioned nanoemulsion is a. When stored in the pressurized container at 2-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, or 12 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or b. The polydispersity index is 0.4 or less when stored in the pressurized container at 2-40°C, 10-40°C, 20-40°C, 30-40°C, or 40°C for 1 month, 2 months, 3 months, 6 months, or 12 months; and / or c. When stored in the pressurized container at 2-25°C, 10-25°C, 15-25°C, 2-8°C, 5°C, or 25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or d. Containing nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when subjected to one, two, three, four, five, or more freeze-thaw cycles; and / or e. The polydispersity index is 0.4 or less when stored in the pressurized container at 2-25°C, 10-25°C, 15-25°C, 2-8°C, 5°C, or 25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months; and / or f. When stored in the pressurized container at 2 to 8°C or 5°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, it contains nanovesicles having a size of 500 nm or less, preferably in the range of 5 nm to 200 nm; and / or g. The polydispersity index is 0.4 or less when stored in the pressurized container at 2-8°C or 5°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months; and / or h. The method according to claim 16, characterized in that the polydispersity index is 0.4 or less when subjected to one, two, three, four, five, or more freeze-thaw cycles.

18. The use of a nanoemulsion for the preparation of a foam or spray, wherein the use is as follows: (a) To provide a formulation comprising a nanoemulsion, wherein the nanoemulsion is: (i) with at least one aqueous component; (ii) A carrier component, wherein the carrier component is: (1) At least one lipophilic component, (2) at least one surfactant, and (3) at least one type of alcohol The carrier component includes and To provide a formulation that includes the above; (b) Introducing the formulation containing the nanoemulsion into a container; (c) Adding propellant to the container and pressurizing the container; and (d) Discharging foam or spray from the pressurized container. Includes, use.

19. The use of the formulation according to claim 18, comprising an activator.

20. A container containing a formulation, or a foam dispenser or spray dispenser containing a container containing a formulation, wherein the formulation comprises a nanoemulsion, and the nanoemulsion is: (i) with at least one aqueous component; (ii) A carrier component, wherein the carrier component is: (1) At least one lipophilic component, (2) at least one surfactant, and (3) at least one type of alcohol The carrier component includes and Includes, The aforementioned preparation is essentially free of fatty alcohols; The container further comprises a propellant, which is provided for pressurizing the container, in a container, foam dispenser, or spray dispenser product.

21. The formulation comprises an activator, and is a container, foam dispenser, or spray dispenser product according to claim 20.

22. A foam or spray obtained from the formulation according to any one of claims 1 to 14.

23. Cosmetic use of the formulation according to any one of claims 1 to 14, or the foam or spray according to claim 22.

24. A formulation according to claim 13 or 14, or a foam or spray according to claim 22, for use in pharmaceuticals, preferably for use in methods for treating and / or preventing dermatological diseases or conditions.

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