Nanoemulsion without propylene glycol

Abstract

This invention relates to an oil-in-water nanoemulsion that is essentially free of propylene glycol. The nanovesicle formulation is particularly stable with respect to storage periods at different storage temperatures.

Description

Technical Field

[0001] The present invention relates to an external composition containing a water-in-oil nanoemulsion and an active ingredient, and the above composition essentially does not contain propylene glycol. This preparation has few impurities and by-products of the active ingredient over time, thus ensuring higher quality standards and improved preservability.

Background Art

[0002] Dispersion systems are colloidal systems, including micelles, liposomes, virosomes, emulsions, micro / nanoemulsions, suspensions, polymer solutions, etc. Emulsions or microemulsions are oil-in-water type, water-in-oil type, or intermediate phase dispersion systems, and often surfactants are dispersed as emulsifiers. Nanoemulsions are a subgroup of emulsions containing extremely fine water-in-oil dispersion systems. Nanoemulsions are highly homogeneous, transparent, or slightly milky white dispersion systems (or emulsions) of oil and water. The dispersed liquid droplets (liquids) or vesicles in such emulsions are composed of a lipid core surrounded by a monolayer of at least one surfactant or emulsifier. Nanoemulsions are characterized by an average particle diameter or vesicle diameter of less than 200 nm (often less than 100 nm) and a narrow and monodisperse distribution of particle diameter or vesicle diameter.

[0003] Nanoemulsions are more thermodynamically stable than conventional emulsions and are a preferred medium for pharmaceutical compositions that need to maintain long-term stability. Nanoemulsions are in a metastable state, and their structure often depends on the manufacturing process, so they are unstable systems, and it is difficult to incorporate them into pharmaceutical compositions that can be stored for a long time under various storage conditions. When destabilized, they may show non-uniformity, emulsification, or phase separation. However, due to their extremely fine droplet or spherical particle size, they may exhibit excellent texture and sensory properties, and thus useful applications in the skin care field are expected.

[0004] Nanoemulsions are generally produced by mechanically refining an oil phase into an aqueous phase in the presence of a surfactant. The ultra-miniature reduction of oily particles is often achieved by at least one pass through a high-pressure homogenizer or ultrasonic device.

[0005] Formulations containing nanoemulsions as a delivery medium for active ingredients often contain auxiliary agents such as organic molecules like propylene glycol and solvents. Propylene glycol is known to have beneficial properties such as penetration-enhancing and antiseptic effects (Carrer et al., Effect of propylene glycol on the skin penetration of drugs. Arch Dermatol Res 312, 337-352 (2020), https: / / doi.org / 10.1007 / s00403-019-02017-5, McGowan MA et al., Propylene Glycol in Contact Dermatitis: A Systematic Review. Dermatitis, 2018; 29(1):6-12, doi: 10.1097 / DER.0000000000000307). Furthermore, it is known to be an excellent solvent for other auxiliary agents and components, and an excellent emulsifier. However, there have been reports of allergic reactions to propylene glycol in patients with atopic dermatitis, and it is also known to be irritating to the eyes. Furthermore, it is a diol and, due to its nucleophilicity, may cause undesirable side reactions. For example, reactions with sorbitol and glycerol in the presence of cetirizine, which is a well-known anti-allergic compound, are known.

[0006] Propylene glycol is commonly used as a solvent for hydrophilic compounds. For example, parabens are only slightly soluble in water. In the preparation of aqueous formulations or formulations containing aqueous components, parabens need to be dissolved in a suitable solvent such as propylene glycol in order to be introduced into the aqueous phase.

[0007] 5-aminolevulinic acid (hereinafter also referred to as "ALA" or "5-ALA")ALA is a small, bio-derived amino acid with a molecular weight (as hydrochloride) of 167.59 g / mol and is highly hydrophilic. That is, it readily dissolves in water, and its octanol-water partition coefficient (logP) is approximately -3. ALA is used as a precursor in photodynamic therapy (PDT) to promote the synthesis of protoporphyrin IX in diseased tissue. Subsequently, photodynamic effects are induced by irradiation with light of an appropriate wavelength.

[0008] Known formulations of ALA for topical skin administration are unstable in aqueous solutions (Reinhold, Future Oncology, 2017 Nov;13(27):2413-2428, doi: 10.2217 / fon-2017-0247). Conventionally, nanoemulsions used in combination with ALA contained 10% active ingredient and were prepared as gel formulations. Conventional gel formulations showed stability for up to 36 months at refrigerated temperatures (2-8°C), but were vulnerable to higher temperatures (above standard room temperature). Exposure to higher temperatures was tolerable for a range of several weeks and did not pose a risk of compromising the quality as a human drug. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Carrer et al., Effect of propylene glycol on the skin penetration of drugs. Arch Dermatol Res 312, 337-352 (2020), https: / / doi.org / 10.1007 / s00403-019-02017-5 [Non-Patent Document 2] McGowan MA et al., Propylene Glycol in Contact Dermatitis: A Systematic Review. Dermatitis, 2018; 29(1):6-12, doi: 10.1097 / DER.0000000000000307 [Non-Patent Document 3] Reinhold, Future Oncology, 2017 Nov;13(27):2413-2428, doi: 10.2217 / fon-2017-0247 [Overview of the project]

[0010] A first aspect of the present invention is: (a)(i) at least one aqueous component, (ii)(1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol Carrier components containing Nanoemulsions containing, and (b) Activators containing a carboxylic acid group, or a derivative or salt of a carboxylic acid group A formulation containing, The present invention relates to a formulation which contains less than 1% by weight of propylene glycol or which does not contain propylene glycol.

[0011] Another aspect of the present invention relates to a formulation of the first aspect for use in a method for treating and / or preventing a skin disease or skin condition.

[0012] Another aspect of the present invention relates to a method for preparing a formulation described herein, the method comprising the steps of: (a) mixing at least one lipophilic component, at least one surfactant, and at least one alcohol having at least three carbon atoms; and (b) contacting the mixture obtained in step (a) with an aqueous component under conditions that enable the formation of a nanoemulsion, wherein the activator is added under conditions that enable the activator to interact with the surface of nanovesicles when dissolved in the aqueous phase. [Brief explanation of the drawing]

[0013] The present invention is further illustrated by the following drawings and embodiments. [Figure 1]The contents of known impurities (2-hydroxypropyl-δ-aminolevulinic acid, m / z: 190) and the impurity with m / z = 246 in Formulation 1 (containing propylene glycol) and Formulation 2 (propylene glycol-free) after storage at 25°C or 40°C for 6 months. [Figure 2] Chromatograms of known impurities (2-hydroxypropyl-δ-aminolevulinic acid; m / z: 190) and the impurity with m / z = 246 in Formulation 1 (containing propylene glycol) and Formulation 2 (propylene glycol-free) after storage at 40°C for 3 months. [Figure 3] The skin penetration amounts of Formulation 1 (containing propylene glycol) and Formulation 2 (propylene glycol-free) in human skin. (PpIX: protoporphyrin IX. Error bars indicate standard deviation.) [Figure 4] Franz cell (top: schematic diagram, bottom: photograph). [Figure 5] The 5-ALA release amounts from propylene glycol-containing Formulation 1 and propylene glycol-free Formulation 2 (after 2.5 hours, within the linear range of the Higuchi plot). (The displayed values are the average values of 6 experiments. The cumulative transport amount to the receptor chamber is expressed as μg per 1 cm² of membrane area versus the square root of time.)

Modes for Carrying Out the Invention

[0014] Before the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methodologies, protocols (or procedures) and reagents described herein, as these may be modified. Also, the terms used herein are for the purpose of describing particular embodiments only 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 one of ordinary skill in the art.

[0015] Preferably, the terms used herein follow the definitions set forth in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Koelbl, H. eds. (1995, Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[0016] Throughout the description of this specification, multiple documents are cited. Each document cited in this specification (including all patents, patent applications, scientific publications, manufacturer's specifications, instruction manuals, etc.), regardless of whether it is above or below, is hereby incorporated by reference in its entirety into this specification.

[0017] The components of the present invention will be described below. It should be understood that although these components are listed with specific embodiments, they may be combined in any way and in any number to form additional embodiments. The examples and preferred embodiments described in various forms should not be construed as limiting the invention to only the explicitly described embodiments. This specification should be understood to support and encompass both the explicitly described embodiments and embodiments that combine any number of the disclosed and / or preferred elements. Further, unless the context indicates otherwise, any permutation and combination of all the elements described in this application should be considered to be disclosed by the description of this application.

[0018] In this specification and the claims, unless the context clearly requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” should be understood to mean that they include the elements, steps, or groups of elements or steps described, but do not exclude any other elements, steps, or groups of elements or steps. In this specification and the appended claims, the singular forms “a,” “an,” and “the” should be interpreted as including the plural form unless the context clearly requires otherwise.

[0019] The preparation of topical medicinal gel formulations is an extremely complex process, requiring consideration of various aspects such as pH, solubility, polymorphism, applicability, and overall formulation stability. Furthermore, the active ingredient (API), excipients, interactions between all components, and the advantages and limitations of the manufacturing steps must also be considered. In oil-in-water nanoemulsion formulations, there are two distinct phases requiring stabilization and patient compatibility. One is typically a hydrophobic carrier component that stabilizes and releases the API, and the other is an aqueous component. These elements combine to form a complex formulation containing numerous components. However, the more components a composition contains, the higher the likelihood of problems and pitfalls during the formulation process. Examples include undesirable side reactions / interactions between components and deterioration of the impurity profile. Furthermore, after application to the skin, patients may experience allergic reactions or skin irritation to various components. Therefore, pharmaceutical compositions should contain only the necessary components, omitting as many auxiliary agents and additives as possible. Polyols, particularly propylene glycol, are a very common excipient in cosmetics, pharmaceuticals, and food products. It may be used as a solvent, humectant, preservative, or emulsifying stabilizer. One of its particularly attractive properties in topical pharmaceuticals is its ability to promote the penetration of active ingredients.

[0020] The prior art does not teach any pharmaceutical compositions comprising a nanoemulsion composition having an activator that does not contain propylene glycol and contains a carboxylic acid group or its derivative, or a pharmaceutically acceptable salt of a carboxylic acid group.

[0021] In this specification, "propylene glycol" refers to propane-1,2-diol (also known as 1,2-propanediol, α-propylene glycol, 1,2-dihydroxypropane, methyl ethyl glycol, and methyl ethylene glycol).

[0022] As mentioned above, nanoemulsions tend to aggregate under certain conditions, such as exposure to extreme temperature differences, which increases droplet size and impairs the quality of the nanoemulsion.

[0023] These aspects clearly indicate a strong desire for the design and preparation of compositions having high permeability and an improved impurity profile.

[0024] Examples of the present invention demonstrate that in pharmaceutical formulations containing active ingredients, particularly hydrophilic active ingredients and / or carboxylic acid groups or their derivatives, or pharmaceutically acceptable salts of carboxylic acids, omitting propylene glycol results in a better impurity profile compared to pharmaceutical formulations containing propylene glycol, without limiting the penetration properties of the topical pharmaceutical composition. Surprisingly, the omission of propylene glycol improves the penetration of the base. This is a non-obvious discovery for those skilled in the art.

[0025] In this specification, “activator” and “active ingredient” are used interchangeably. As used herein, “activator” includes pharmaceutical activators (also referred to herein as “pharmaceutical activators,” “active pharmaceutical ingredients,” or “APIs”) and cosmetic activators (also referred to herein as “cosmetic activators”). In this specification, a pharmaceutical active ingredient defines a chemical, biological, mineralogical, or other entity or component responsible for the therapeutic effect (pharmacological, physiological, physical, etc.) of a product. In this specification, a cosmetic active ingredient defines a chemical, biological, mineralogical, or other entity or component responsible for the cosmetic effect of a product. Active ingredients may be plant extracts. Active ingredients may exist as pharmaceutically acceptable salts. Active ingredients may exist as cosmetically acceptable salts.

[0026] In the following specifications, unless otherwise specified, the term "activator containing a carboxylic acid group" also refers to an activator containing a derivative of a carboxylic acid group or an activator containing a salt of a carboxylic acid group.

[0027] Preferably, the surfactant containing the carboxylic acid group is a hydrophilic surfactant. Preferably, the logP value of the hydrophilic surfactant is 1 or less, 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less, 0.1 or less, or a negative logP value. Here, P is the octane-water partition coefficient.

[0028] In this specification, "carboxylic acid group derivative" refers to a carboxylic acid group that has reacted with other chemical groups to form a compound, and in particular to a carboxylic acid group that has reacted with a hydroxyl group to form an ester.

[0029] While not intended to be constrained by theory, activators containing carboxylic acid groups may undergo nucleophilic reactions with propylene glycol, potentially forming undesirable products such as esters. Even if the activator contains carboxylic acid group derivatives in ester form, it may still undergo nucleophilic reactions with propylene glycol, for example via transesterification, potentially forming undesirable products such as esters. Therefore, omitting propylene glycol may reduce the generation of undesirable by-products.

[0030] In addition to the expected quenching of esters formed by 5-ALA and propylene glycol, this example demonstrates a remarkably significant reduction in the previously detected m / z=246 impurity in the propylene glycol-free 5-ALA gel formulation of the present invention. This reduction represents a meaningful improvement compared to formulations in the prior art. Firstly, this impurity is most likely to produce "off-spec" results in stability tests. Secondly, the amount of this impurity increases after high temperatures and long-term storage. As observed in the propylene glycol-free formulation of the present invention, the reduction of this impurity improves stability under stress conditions and allows for longer storage. Furthermore, unknown impurities can be harmful to patients because it is impossible to predict their metabolism and long-term effects on the human body.

[0031] Furthermore, functional in vitro tests described in the examples revealed that the drug release and skin penetration properties of the formulation were not impaired under any circumstances, even when propylene glycol was omitted. Compared to a comparative formulation containing propylene glycol, the formulation of the present invention without propylene glycol showed improved ALA penetration. The formulation without propylene glycol exhibited non-inferior penetration properties compared to the formulation containing it. This finding is surprising because propylene glycol is widely known and used as a highly effective penetration enhancer in topical pharmaceutical formulations.

[0032] In in vitro release tests, the formulation of the present invention, which does not contain propylene glycol, released more 5-ALA than the comparative formulation containing propylene glycol. This result is surprising because the addition of polyols that do not evaporate upon application, particularly glycerol and propylene glycol, is expected to improve adhesion and thereby promote drug release.

[0033] The formulation of the present invention has two phases: (I) Aqueous phase or aqueous component, (II) Lipid carrier phase Includes.

[0034] A first aspect of the present invention is: (a)(i) at least one aqueous component, (ii)(1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol Carrier components containing Nanoemulsions containing, and (b) Activators containing a carboxylic acid group, or a derivative or salt of a carboxylic acid group A formulation containing, The present invention relates to a formulation which contains less than 1% by weight of propylene glycol or which does not contain propylene glycol.

[0035] In a preferred embodiment, the above-mentioned formulation is a pharmaceutical formulation.

[0036] In some embodiments, the formulation is a lotion, spray, foam, emulsion, nanoemulsion, gel, or cream. In some embodiments, the formulation is a lotion. In the context of this specification, a lotion is a low-viscosity topical formulation intended for application to the skin. Lotions have a higher water content than creams or gels and therefore have a lower viscosity. In some embodiments, the viscosity of the lotion is ≤8 Pa·s (Pascal-seconds), ≤6 Pa·s, ≤5 Pa·s, ≤4 Pa·s, ≤3 Pa·s, ≤1.0 Pa·s, or ≤0.5 Pa·s.

[0037] Those skilled in the art know appropriate methods for measuring viscosity. Preferably, viscosity is measured by the method described in the Examples section.

[0038] In a preferred embodiment, the above formulation is intended for external use.

[0039] In preferred embodiments of the formulations described in the present invention, the aqueous component comprises or forms an aqueous phase. Preferably, the activator is dissolved in the aqueous phase.

[0040] In preferred embodiments of the formulations described in the present invention, the carrier component comprises or consists of nanovesicles. Preferably, the activator has the ability to interact with the surface of the nanovesicles.

[0041] The activator may exist as a salt. Examples of activators existing as salts include 5-aminolevulinic acid hydrochloride and 5-aminolevulinic acid phosphate.

[0042] In a more preferred embodiment, the activator is dissolved in the aqueous phase and is capable of interacting with the nanovesicle surface. The activator preferably comprises a carboxylic acid group, a derivative of a carboxylic acid group, or a pharmaceutically acceptable salt of a carboxylic acid group.

[0043] Examples of activators containing derivatives of carboxylic acid groups include esters of 5-aminolevulinic acid such as methyl δ-aminolevulinic acid (MAL) and hexyl δ-aminolevulinic acid (HAL).

[0044] Examples of activators containing pharmaceutically acceptable salts of carboxylic acid group derivatives include methyl δ-aminolevulinic acid hydrochloride and hexyl δ-aminolevulinic acid hydrochloride.

[0045] In all embodiments described herein, the salt of the carboxylic acid group is preferably a pharmaceutically acceptable salt of the carboxylic acid group. As used herein, “having the ability to interact with the surface of nanovesicles” includes the active ingredient being non-covalently bonded to nanovesicles, particularly to 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 active ingredient interacts with the surface of nanovesicles, with the remainder dissolved in the aqueous phase.

[0046] In this specification, the expression "the formulation contains 0.9% by weight or less of propylene glycol" is intended to include embodiments in which the formulation does not contain propylene glycol in an essential manner.

[0047] In preferred embodiments, the formulation is essentially propylene glycol-free.

[0048] In this specification, the expressions "essentially free of compound X," "essentially containing compound X," or "essentially containing compound X" are used interchangeably with respect to formulations. In particular, these expressions specify that the formulation does not contain compound X, or contains less than 0.1% by weight (w / w), less than 0.08% by weight, less than 0.07% by weight, less than 0.06% by weight, less than 0.05% by weight, less than 0.04% by weight, less than 0.03% by weight, less than 0.02% by weight, or less than 0.01% by weight.

[0049] In this specification, the expression "the composition contains less than X% of compound X" means that embodiments in which the composition does not contain compound X are also included.

[0050] The formulation may contain propylene glycol in an amount of 0.99%, 0.95%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by weight or less, or may not contain it at all.

[0051] In particular, the above-mentioned formulation may contain propylene glycol in an amount of 0.7%, 0.5%, 0.3%, or 0.1% by weight or less.

[0052] More specifically, the above-mentioned formulation may contain 0.5%, 0.3%, or 0.1% by weight or less of propylene glycol.

[0053] More specifically, the above-mentioned formulation may contain 0.3% by weight or less, or 0.1% by weight or less, of propylene glycol.

[0054] In a preferred embodiment, the formulation does not contain propylene glycol.

[0055] In addition to containing either no or only trace amounts of propylene glycol as defined above, the formulation preferably contains less than 1% by weight, or 0.99, 0.95, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1% by weight or less of acyclic polyols having 2 to 3 (i.e., 3 or fewer) carbon atoms. Preferably, the formulation contains less than 1% by weight, or 0.99, 0.95, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1% by weight or less of 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., having 4, 5, 6, 7, 8, 9, or 10 or fewer carbon atoms, respectively), or 0.99, 0.95, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1% by weight or less of 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, respectively. More preferably, the above formulation does not contain, essentially does not contain, polyols having 2 to 9, 2 to 10, 2 to 11, or 2 to 12 carbon atoms (i.e., each having 4, 5, 6, 7, 8, 9, 10, 11, or 12 or fewer carbon atoms), or contains less than 1% by weight of polyols, or 0.99, 0.95, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1% by weight or less of polyols. More preferably, the formulation does not contain, essentially does not contain, atypically contains, atypically contains, less than 1% by weight, or contains 0.99, 0.95, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1% by weight or less of acyclic polyols having 2 to 15, 2 to 20, 2 to 25, or 2 to 30 carbon atoms (i.e., having 15, 20, 25, or 30 or less carbon atoms, respectively). More preferably, the formulation contains no acyclic polyol, is essentially free of acyclic polyol, contains less than 1% by weight of acyclic polyol, or contains 0.99, 0.95, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1% by weight or less of acyclic polyol.

[0056] In this specification, "acyclic polyol" means a polyol that does not contain a cyclic hydrocarbon moiety, particularly a cyclic sugar moiety. Acyclic polyols may be linear or branched. Acyclic polyols may be diols, triols, or may contain three or more OH groups.

[0057] In a preferred embodiment, the formulation of the present invention is free from, essentially free from, or contains 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, or 0.1% by weight of polyols having molecular weights 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.

[0058] The formulation of the present invention does not necessarily have to contain glycerin.

[0059] The formulation of the present invention does not necessarily have to contain diglycerin.

[0060] The formulation of the present invention does not necessarily have to contain polyglycerin.

[0061] The formulation of the present invention does not necessarily have to contain diethylene glycol.

[0062] The formulation of the present invention does not necessarily have to contain dipropylene glycol.

[0063] The formulation of the present invention does not necessarily have to contain butylene glycol.

[0064] The formulation of the present invention does not necessarily have to contain pentylene glycol.

[0065] The formulation of the present invention does not necessarily have to contain hexene glycol.

[0066] The formulation of the present invention does not necessarily have to contain 1,3-propanediol.

[0067] The formulation of the present invention does not necessarily have to contain 1,5-pentanediol.

[0068] The formulation of the present invention does not necessarily have to contain octane-1,2-diol in its essence.

[0069] The formulation of the present invention does not necessarily have to contain polyethylene glycol having 2 to 50 ethylene oxide groups.

[0070] The formulation of the present invention may be one that does not essentially contain sorbitol.

[0071] The formulations of the present invention do not necessarily have to contain monosaccharides and disaccharides such as sorbitol, mannitol, and mixtures thereof.

[0072] The formulation of the present invention may contain glycerin in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or it may not contain glycerin. The formulation may not contain parabens as described herein.

[0073] In particular, the formulation of the present invention may contain glycerin at a weight percentage of 0.7%, 0.5%, 0.3%, or 0.1% or less. This formulation may also be paraben-free as described herein.

[0074] More specifically, the formulation of the present invention may contain glycerin in an amount of 0.5%, 0.3%, or 0.1% or less by weight. This formulation does not have to contain parabens as described herein.

[0075] Most specifically, the formulation of the present invention may contain glycerin in an amount of 0.3% or less by weight, or 0.1% or less. This formulation is paraben-free as described herein.

[0076] The formulations of the present invention may contain 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2%, or 0.1% by weight or less of diglycerin, or they may not contain diglycerin. As described herein, these formulations may not contain parabens.

[0077] In particular, the formulations of the present invention may contain 0.7, 0.5, 0.3, or 0.1% by weight or less of diglycerin. As described herein, the formulations do not need to contain parabens.

[0078] More specifically, the formulation of the present invention may contain polyglycerin in an amount of 0.5%, 0.3%, or 0.1% or less by weight. This formulation does not have to contain parabens as described herein.

[0079] Most specifically, the formulation of the present invention may contain polyglycerin in an amount of 0.3% or less by weight, or 0.1% or less. This formulation does not have to contain parabens as described herein.

[0080] The formulations of the present invention may contain diethylene glycol in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or may not contain any at all. As described herein, the formulations may not contain parabens.

[0081] In particular, the formulation of the present invention may contain diethylene glycol in an amount of 0.7% by weight or less, 0.5% by weight or less, 0.3% by weight or less, or 0.1% by weight or less. As described herein, the formulation does not have to contain parabens.

[0082] More specifically, the formulation of the present invention may contain 0.5, 0.3, or 0.1% by weight or less of diethylene glycol. The formulation may also be paraben-free as described herein.

[0083] Most specifically, the formulations of the present invention may contain 0.3% or 0.1% by weight or less of diethylene glycol. These formulations are paraben-free as described herein.

[0084] The formulations of the present invention may contain dipropylene glycol in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or may not contain any at all. As described herein, the formulations may not contain parabens.

[0085] In particular, the formulation of the present invention may contain dipropylene glycol in an amount of 0.7%, 0.5%, 0.3%, or 0.1% or less by weight. This formulation does not need to contain parabens as described herein.

[0086] More specifically, the formulation of the present invention may contain dipropylene glycol in an amount of 0.5%, 0.3%, or 0.1% or less by weight. This formulation may also be paraben-free as described herein.

[0087] Most specifically, the formulation of the present invention may contain 0.3% or 0.1% or less of dipropylene glycol by weight. This formulation does not have to contain parabens as described herein.

[0088] The formulations of the present invention may contain butylene glycol in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or may not contain any at all. As described herein, the composition may not contain parabens.

[0089] In particular, the compositions of the present invention may contain 0.7% by weight or less, 0.5% by weight or less, 0.3% by weight or less, or 0.1% by weight or less of butylene glycol. As described herein, the compositions do not need to contain parabens.

[0090] More specifically, the formulation of the present invention may contain 0.5% by weight or less, 0.3% by weight or less, or 0.1% by weight or less of butylene glycol. This formulation may be paraben-free as described herein.

[0091] Most specifically, the formulation of the present invention may contain butylene glycol in an amount of 0.3% or less or 0.1% or less by weight. This formulation does not have to contain parabens as described herein.

[0092] The formulation of the present invention may contain hexylene glycol in an amount of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or it may not contain hexylene glycol. The formulation may not contain parabens as described herein.

[0093] In particular, the formulations of the present invention may contain 0.7, 0.5, 0.3, or 0.1% by weight or less of hexylene glycol. These formulations do not have to contain parabens as described herein.

[0094] More specifically, the formulation of the present invention may contain hexylene glycol in an amount of 0.5%, 0.3%, or 0.1% or less by weight. This formulation does not have to contain parabens as described herein.

[0095] Most specifically, the formulation of the present invention may contain hexylene glycol in an amount of 0.3% or less or 0.1% or less by weight. This formulation does not have to contain parabens as described herein.

[0096] The formulations of the present invention may contain 1,3-propanediol in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or may not contain it at all. As described herein, the formulations may be paraben-free.

[0097] In particular, the formulations of the present invention may contain 1,3-propanediol in an amount of 0.7%, 0.5%, 0.3%, or 0.1% or less by weight. As described herein, the formulations do not need to contain parabens.

[0098] More specifically, the formulations of the present invention may contain 1,3-propanediol in an amount of 0.5%, 0.3%, or 0.1% or less by weight. As described herein, the formulations do not need to contain parabens.

[0099] Most particularly, the formulation of the present invention may contain 1,3-propanediol in an amount of 0.3% or less or 0.1% or less by weight. This formulation does not have to contain parabens as described herein.

[0100] The formulations of the present invention may contain 1,5-pentanediol in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or may not contain any at all. As described herein, the formulations may not contain parabens.

[0101] In particular, the formulations of the present invention may contain 1,5-pentanediol in an amount of 0.7%, 0.5%, 0.3%, or 0.1% or less by weight. As described herein, the formulations do not need to contain parabens.

[0102] More specifically, the formulation of the present invention may contain 0.5% by weight or less, 0.3% by weight or less, or 0.1% by weight or less of 1,5-pentanediol. This formulation may be paraben-free as described herein.

[0103] Most specifically, the formulation of the present invention may contain 0.3% by weight or less, or 0.1% by weight or less, of 1,5-pentanediol. This formulation does not have to contain parabens as described herein.

[0104] The formulations of the present invention may contain octane-1,2-diol in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or may not contain octane-1,2-diol. As described herein, the formulations may not contain parabens.

[0105] In particular, the formulations of the present invention may contain octane-1,2-diol in an amount of 0.7%, 0.5%, 0.3%, or 0.1% or less by weight. As described herein, the formulations do not need to contain parabens.

[0106] More specifically, the formulation of the present invention may contain octane-1,2-diol in an amount of 0.5%, 0.3%, or 0.1% or less by weight. This formulation does not need to contain parabens as described herein.

[0107] In particular, the formulation of the present invention may contain octane-1,2-diol in an amount of 0.3% by weight or less, or 0.1% by weight or less. This formulation may be paraben-free as described herein.

[0108] The formulation of the present invention may contain polyethylene glycol in amounts of 0.9% by weight or less, 0.8% by weight or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, or 0.1% by weight or less, and may not contain polyethylene glycol, particularly polyethylene glycol having 2 to 50 ethylene oxide groups, or polyethylene glycol. The formulation may not contain parabens as described herein.

[0109] In particular, the formulation of the present invention contains polyethylene glycol in an amount of 0.7%, 0.5%, 0.3%, or 0.1% or less by weight, and may particularly contain polyethylene glycol having 2 to 50 ethylene oxide groups. This formulation does not have to contain parabens as described herein.

[0110] More specifically, the formulation of the present invention may contain polyethylene glycol (particularly having 2 to 50 ethylene oxide groups) in an amount of 0.5%, 0.3%, or 0.1% or less by weight. This formulation does not need to contain parabens as described herein.

[0111] Most specifically, the formulations of the present invention may contain polyethylene glycol having 2 to 50 ethylene oxide groups in an amount of 0.3% or less or 0.1% or less by weight. The formulations may not contain parabens as described herein.

[0112] The formulations of the present invention may contain sorbitol in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or may not contain any sorbitol at all. As described herein, the formulations may not contain parabens.

[0113] In particular, the formulations of the present invention may contain 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less of sorbitol by weight, or may not contain sorbitol at all. The formulations may also not contain parabens as described herein.

[0114] More specifically, the formulation of the present invention may contain 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less of sorbitol by weight percentage, or it may not contain sorbitol. The formulation may not contain parabens as described herein.

[0115] Most specifically, the formulations of the present invention may contain 0.3%, 0.2%, or 0.1% or less of sorbitol by weight percentage, or may not contain sorbitol. The formulations may not contain parabens as described herein.

[0116] The formulations of the present invention contain monosaccharides and disaccharides (such as sorbitol, mannitol, and mixtures thereof) in amounts of 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or do not contain sugars such as sorbitol, mannitol, and mixtures thereof. The formulations may not contain parabens as described herein.

[0117] 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%, 0.5%, 0.3%, or 0.1% or less by weight. The formulations may also be paraben-free as described in the specification.

[0118] 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%, 0.3%, or 0.1% or less by weight. The formulations may not contain parabens as described herein.

[0119] In particular, the formulation of the present invention may contain monosaccharides and disaccharides such as sorbitol, mannitol, and mixtures thereof in an amount of 0.3% or less by weight, or 0.1% or less. This formulation may also be paraben-free as described herein.

[0120] The formulations of the present invention may contain, essentially not contain, or contain less than specified amounts (e.g., less than 1%, less than 0.99%, less than 0.95%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%) of the following components: glycerin, diglycerin, polyglycerin, diethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, pentylene glycol, hexalene glycol, 1,3-propanediol, 1,5-pentanediol, octane-1,2-diol, polyethylene glycol (especially those having 2 to 50 ethylene oxide groups), and polyols selected from the group consisting of monosaccharides or disaccharides such as sorbitol, mannitol, and mixtures thereof, all polyols, or any selected number of polyols in amounts less than 0.6%, less than 0.5%. The formulations of the present invention may not essentially contain polyols selected from 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, or mixtures thereof, but may contain other polyols. The formulations of the present invention may not essentially contain linear or branched but acyclic polyols. The formulations of the present invention are essentially free from polyols having 2 to 30, 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.

[0121] The above formulations may contain polyols in amounts of 0.99%, 0.95%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less by weight, or they may not contain polyols. The polyols may be those described herein.

[0122] The above-mentioned formulation may contain a polyol in an amount of 0.7%, 0.5%, 0.3%, or 0.1% or less by weight. The polyol may be any of the polyols described herein.

[0123] The above-mentioned formulation may contain a polyol in an amount of 0.5%, 0.3%, or 0.1% or less by weight. The polyol may be any of the polyols described herein.

[0124] The formulation may contain 0.3% by weight or less, or 0.1% by weight or less, of a polyol. The polyol may be any of the polyols described herein.

[0125] The formulation does not need to contain polyols.

[0126] The minute size and high homogeneity of nanovesicles impart superior properties that differ from conventional emulsions. The nanoemulsions and formulations containing nanoemulsions of the present invention are transparent. Furthermore, the nanoemulsions and formulations containing nanoemulsions of the present invention are gaining increasing importance in the medical and pharmaceutical fields because they can deliver active ingredients more efficiently.

[0127] In this specification, “degradation over time” refers to alteration, decomposition, and / or deterioration of a formulation that affects its chemical and physical stability during storage, particularly under stress conditions. Such physical or chemical changes due to storage include, but are not limited to, Ostwald ripening, aggregation, coalescence, and / or disruption, which may result in changes in vesicle size or polydispersity index. In this specification, “degradation over time” may include, for example, the formation of impurities after storage at 25°C or 40°C for six months. Typical impurities in formulations containing 5-aminolevulinic acid as the active ingredient include 2-hydroxypropyl-δ-aminolevulinic acid and impurities characterized by m / z=246.

[0128] The inventors discovered that the formulation of the present invention is remarkably stable and resistant to changes over time. In particular, the formulation of the present invention contains fewer impurities than conventional formulations, even after being stored for 6 months at, for example, 25°C or 40°C.

[0129] In this specification, "stress conditions" in storage refer to temperatures significantly exceeding room temperature (e.g., 40°C).

[0130] In this specification, "nanopecicle emulsion" or "nanoemulsion" refers to an oil dispersion in water (oil-in-water dispersion, oil-in-water emulsion, O / W emulsion). The nanoemulsion is monophase and may be transparent and / or slightly milky white. The nanoemulsion of the present invention may be a colloidal system containing dispersed nanovesicles consisting of a lipid core surrounded by at least one surfactant or emulsifier monolayer. The nanoemulsion of the present invention and formulations containing the nanoemulsion are characterized by having an average particle or nanovesicle size of less than 500 nm, less than 200 nm, or less than 100 nm. The nanoemulsion of the present invention and formulations containing the nanoemulsion have a narrow (homogeneous) nanovesicle size distribution, for example, characterized by a nanovesicle size distribution with a polydispersity index of 0.4 or less.

[0131] In this specification, "nanovesicle," "lipid vesicle," "oil droplet," "droplet," and "oil ball" are used interchangeably and refer to minute oil droplets in an oil-in-water emulsion. They are lipid vesicles of average size (see above, e.g., less than 500, 200, or 100 nm) and consist of a single layer of surfactant and a lipid core. In the present invention, the size of nanovesicles may be 500 nm or less, or 300 nm or less. Preferably, it is in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm.

[0132] In this specification, the term “nanoparticles” is distinguished from “nanopecicles” and refers to solid particles not described in this invention. The formulations of the present invention may be formulations that are essentially nanoparticle-free. “Essentially nanoparticle-free” means that the formulation contains nanoparticles at a weight percentage of 2% or less, 1% or less, or none at all. The nanoparticles are mainly inorganic, and the solid lipids or polymer solid particles may have sizes of less than 100 nm, less than 200 nm, or less than 500 nm. The particle size can be measured by the methods described herein. For example, when measured by dynamic light scattering, the formulation may be essentially nanoparticle-free with a diameter of less than 100 nm.

[0133] In this specification, “topical use” of the formulations of the invention means application to the body, in particular to specific parts of the human body. This includes, but is not limited to, the administration of the formulations to body surfaces such as skin and mucous membranes. Topical use is transdermal, meaning that the formulations are administered directly to the skin. In particular, topical use is a pharmaceutical use.

[0134] In this specification, “stability” of a formulation containing nanovesicles 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 deemed stable. An indicator well known to those skilled in the art for describing the integrity of nanovesicles is, for example, the size measured by the dynamic light scattering method described herein. Nanovesicles produced according to the present invention may have a size in the range of less than 100 nm, preferably less than 50 nm, and more preferably 20 to 30 nm immediately after production. For example, the formulation described herein is stable if the size (or diameter) of the nanovesicles in the formulation of the present invention is 500 nm or less, or 300 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.

[0135] "Stability" may also refer to the absence of processes that lead to loss of pharmaceutical functionality or quality due to the aging phenomena described above. The compositions described in the present invention are functional or pharmacologically functional as long as the vesicle size is 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.

[0136] Furthermore, “stability” may refer to the stability of the hydrophilic active compound, particularly the 5-ALA content. The 5-ALA content is considered stable if, during storage, for example, under the stress conditions described herein, at least 70%, at least 80%, or at least 90% of the activator content remains present.

[0137] In the formulation of the present invention, the 5-ALA content is (i) After storage at 40°C for 3 months, at least 95%, and / or (ii) After storage at 25°C for 3, 6, 9 or 12 months, at least 95% or at least 97%, and / or (iii) After storage at 5°C for 12, 18, 24 or 36 months, at least 95%, at least 97%, or at least 99% That's fine.

[0138] In this specification, "stability" of a composition also refers to a low impurity content, i.e., a small amount of impurities. For example, the formulation of the present invention is stable when stored at 40°C for 6 months and contains 1.5%, 1.0%, or 0.75% or less of a substance with m / z=246, or 0.5%, 0.4%, 0.3%, or 0.2% or less.

[0139] In the present invention, the formulation may be stable for at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 12 months at room temperature (e.g., 15-25°C). In particular, the formulation of the present invention may be stable for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 24 months, or at least 36 months at 2-8°C or about 5°C.

[0140] When the formulation of the present invention is stored at 40°C for one month, the nanovesicle size is 500 nm or less, or 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 150 nm.

[0141] When the formulation of the present invention is stored at 25°C for 6 months, the nanovesicle size may be 500 nm or less, or 300 nm or less, or 200 nm or less, preferably in the range of 5 nm to 200 nm.

[0142] The size or diameter of nanovesicles described herein may be expressed as the Z-mean (also known as the "z-mean"). The size distribution of nanovesicles is characterized by a polydispersity index. These parameters are well known to those skilled in the art and are widely used in the art to characterize particles or vesicles in emulsions, suspensions, and / or polymer solutions.

[0143] In the present invention, the size of nanovesicles (e.g., Z-mean value (nm)) and / or the heterogeneity of the nanovesicle formulation (characterized by the polydispersity index) can be determined by dynamic light scattering (also known as photon correlation spectroscopy (PCS) or quasi-elastic light scattering (QELS)). Dynamic light scattering is a widely known and established technique in the field for measuring the size of nanoparticles, microparticles, or vesicles in emulsions, suspensions, and / or polymer solutions using lasers.

[0144] In the formulations described herein, the total aqueous component may be present in an amount of 50% to 99% by weight (w / w) based on the total weight of the nanoemulsion (a). Preferably, it is 70% to 95% (w / w), more preferably 75% to 95% (w / w), or 80% to 95%.

[0145] In this specification, “weight ratio,” “weight / weight,” or “w / w” means the weight or mass concentration of an ingredient in the formulation described herein. The weight or mass of an ingredient is expressed as a percentage of a reference formulation. For example, the weight or mass of an ingredient may be expressed as a percentage of the total weight or total mass of the formulation of the present invention, or as a percentage of the total weight or total mass of nanoemulsion (a).

[0146] The aqueous component may contain at least one pH buffer. Any suitable buffer can be used. Suitable buffers are well 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.

[0147] The pH of the aqueous component can be in the range of 2 to 9. Preferably, the pH of the aqueous component can be in the range of 2 to 6, for example 2, 3, 4, 5, or 6, more preferably in the range of 4 to 6, for example 4, 5, or 6, or in the range of 2 to 4, for example 2, 3, or 4.

[0148] In the formulations described herein, at least one lipophilic component may be selected from triglycerides and mixtures thereof.

[0149] Preferably, at least one lipophilic component is a lipid, synthetic oil, vegetable oil, and / or animal oil. Suitable lipids according to the present invention are physiologically acceptable lipids such as ceramides, monoacylglycerins, diacylglycerins, and triacylglycerins (triglycerides). In particular, at least one lipophilic component is a triglyceride, preferably a triglyceride containing C8-10 fatty acids, or a mixture thereof. More specifically, at least one lipophilic component is caprylic acid and / or capric acid triglyceride and / or a mixture thereof, particularly preferably migliol (e.g., migliol 812 available from IOI Oleochemical) or mylitol (e.g., mylitol 318 available from BASF). Suitable examples of vegetable and animal oils include sunflower oil, soybean oil, peanut oil, rapeseed oil, fish oil, and / or whale oil.

[0150] In the formulations described herein, at least one lipophilic component may be present in an amount of 0.1% to 30% (weight%) based on the total weight of the nanoemulsion (a). Preferably, this amount is 0.25% to 15% (weight), more preferably 0.25% to 10% (weight), and more preferably 0.5% to 8% or 3% to 8% (weight). It is also preferable that at least one lipophilic component be present in an amount of 10% to 30% (weight%) relative to the total weight of the nanoemulsion (a), more preferably 15% to 30%, or 10% to 20%.

[0151] In the formulations described herein, the triglyceride may be present in an amount of 2% to 10% (by weight) based on the total weight of the nanoemulsion (a). Preferably, it is 3% to 8% (by weight).

[0152] In the formulations described herein, at least one surfactant may be any suitable surfactant well known to those skilled in the art.

[0153] Surfactants (also called surfactants or emulsifiers) are widely known in the art and include any agents that combine oil and water in a composition to form an emulsion. They reduce the surface tension of two liquids and are amphiphilic. In emulsions, they are called emulsifiers and coat droplets to prevent adhesion. Emulsifiers are expressed in hydrophilic / hydrophobic balance (HL(B)) and indicate their affinity for water or oil. Low HLB (e.g., HLB=1) refers to hydrophobic 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 preferred bases for a composition and emulsifiers or mixtures thereof suitable for the purpose. In certain emulsions, a combination of emulsifiers may be advantageous.

[0154] Suitable film-forming surfactants include phospholipids, lysophospholipids, ceramides, and / or mixtures thereof. Preferably, the phospholipid is lecithin or cephalin derived from soybeans or chicken eggs. More preferably, at least one surfactant is lecithin, most preferably soybean lecithin.

[0155] In the formulations described herein, phospholipids (particularly phosphatidylcholine), lysophosphatidylcholine, ceramides and / or mixtures thereof may be present in an amount of 0.1 to 10% by weight, preferably 0.15 to 5% by weight, more preferably 1 to 5% by weight, and even more preferably 0.2 to 3% by weight, based on the total weight of the nanoemulsion (a).

[0156] Preferably, the phosphatidylcholine content of the lecithin is at least 80%, more preferably at least 90%, and most preferably at least 94% by weight. The quality of the lecithin, i.e., its phosphatidylcholine content, plays a decisive role in the size of the nanoemulsion vesicles. The higher the phosphatidylcholine content of the lecithin, the smaller the vesicle size of the nanoemulsion.

[0157] Suitable O / W emulsion-forming surfactants include anionic, nonionic, cationic, and / or amphoteric surfactants, as well as block copolymers. Suitable anionic surfactants include soaps, alkylbenzene sulfons, alkanesulfons, alkyl sulfates, and / or alkyl ether sulfates. Suitable cationic surfactants include quaternary ammonium compounds having one or two hydrophobic groups (e.g., bromidocetyltrimethylammonium and cetyltrimethylammonium chloride) and / or salts of long-chain primary amines. Suitable amphoteric surfactants include N-(acylamidoalkyl)betaines, N-alkylβ-aminopropionates, alkylammonium phosphate compounds, and / or amine-N-oxides. An example of a suitable copolymer building block is propylene oxide. In the present invention, nonionic surfactants are particularly preferred as O / W emulsion-forming surfactants.

[0158] In the formulations described herein, at least one surfactant may be a polyoxyethylene surfactant. Suitable nonionic surfactants can 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.

[0159] At least one surfactant, such as a polyoxyethylene-based surfactant, is more preferably 2 to 10% by weight, even more preferably 0.2 to 5% by weight, and most preferably 1 to 5% by weight or 0.5 to 5% by weight, based on the total weight of the nanoemulsion (a).

[0160] The formulation of the present invention may contain at least one hydrophilic surfactant having an HLB of 9 to 17, more preferably 12 to 16, and especially Polysorbate 80, in order to form a nanoemulsion.

[0161] 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 representative substance of this class is n-dodecyl-β-D-maltoside, which is called a maltoside surfactant because the sugar unit used is maltose. An example of a pyranoside surfactant is n-octyl-β-D-thioglucopyranoside. This class uses pyranose as the sugar unit. Examples of glycoside surfactants include octyl glucoside, decyl glucoside, and lauryl glucoside. An example of a polysaccharide surfactant is digitonin.

[0162] Another very important group of sugar-based surfactants are Tween surfactants. The most well-known are 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 sugar. The three oligo(ethylene glycol) side chains attached to the sugar are of different lengths, which improves the hydrophilicity of the head. This structure forms the core of all Tween surfactants. The difference lies in the hydrophobic tail, which is a fatty acid esterified to the four oligo(ethylene glycol) tails. In Tween 20, this fatty acid is lauric acid, and in Tween 80, it is oleic acid.

[0163] 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 surfactant. In some embodiments, at least one surfactant is phosphatidylcholine. In some embodiments, the formulation comprises a phospholipid and a polyoxyethylene surfactant as surfactants. In some embodiments, the formulation comprises phosphatidylcholine and a polyoxyethylene surfactant as surfactants. In some embodiments, the formulation comprises phosphatidylcholine and Polysorbate 80 as surfactants.

[0164] In a preferred embodiment, at least one alcohol contains at least three carbon atoms.

[0165] In the formulations described herein, at least one alcohol preferably independently has 3 to 5 (i.e., 5 or less) or 3 to 4 (i.e., 4 or less) carbon atoms. At least one alcohol may be at least one monohydric alcohol. Particularly suitable 5-carbon alcohols are 1-pentanol and / or 4-methyl-2-pentanol. Suitable 4-carbon alcohols are 1-butyl alcohol, isobutyl alcohol (2-methyl-1-propanol), tert-butyl alcohol (2-methyl-2-propanol) and / or sec-butyl alcohol (2-butanol). The alcohol is not propylene glycol.

[0166] Preferably, at least one alcohol has three carbon atoms, i.e., it is selected from the group consisting of 1-propanol or 2-propanol (isopropanol) and mixtures thereof. The preferred alcohol is 2-propanol.

[0167] In the formulations described herein, alcohol may be present in an amount of 0.1% to 10% (by weight) based on the total weight of the nanoemulsion (a). Preferably, it is 1% to 5% (by weight) or 0.5% to 5% (by weight), and more preferably 1% to 2% (by weight).

[0168] The formulations described herein may contain a gelling agent. Any suitable gelling agent can be used. Suitable gelling agents and mixtures thereof are well 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.

[0169] The gelling agent is preferably selected from poloxamer, xanthan gum, and / or mixtures thereof.

[0170] It is also preferable that the gelling agent be xanthan gum.

[0171] It is also preferable that the gelling agent be poloxamer.

[0172] Poloxamers are nonionic ternary block copolymers having a hydrophobic polyoxypropylene (poly(propylene oxide)) chain in the center and hydrophilic polyoxyethylene (poly(ethylene oxide)) chains on both sides. Commercially available poloxamers include Poloxamer 407 and Poloxamer 188. The average molecular weight of Poloxamer 407 is approximately 12,600 daltons. The average molecular weight of Poloxamer 188 is approximately 8,400 daltons. In the formulations described herein, Poloxamer 407 is the preferred poloxamer.

[0173] In the formulations described herein, the gelling agent may be present in an amount of 0.1% to 10% by weight based on the total weight of the formulation. Preferably, it is 0.25% to 5% by weight, more preferably 0.5% to 4% by weight or 1% to 4% by weight.

[0174] The formulations described herein may contain preservatives. Any suitable preservative can be used. Suitable preservatives are well known to those skilled in the art. The preservative is selected from benzoic acid, citric acid, EDTA, potassium sorbate, vitamin C and / or its derivatives, and any mixture thereof, preferably sodium benzoate. Suitable aqueous mixtures of sodium benzoate and potassium sorbate are commercially available, for example, Euxyl® K 712 preservative (Ashland).

[0175] The preservatives described herein may be present in the formulation in an amount of 0.01% to 3% by weight, based on the total weight of the formulation. Preferably, this amount is 0.2 to 2% by weight or 0.1 to 2% by weight, and more preferably 0.2 to 1.5% by weight.

[0176] 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 esters and PHB esters (esters of p-hydroxybenzoic acid, also known as 4-hydroxybenzoic acid).

[0177] 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 suitable solvent to introduce them into the aqueous phase. Suitable solvents include polyols, particularly propylene glycol (1,2-propanediol). In the present invention, this preparation step of dissolving parabens in propylene glycol is unnecessary, so the formulations of the present invention do not need to contain a mixture of two or more polyols, such as polyols and / or propylene glycol.

[0178] The formulations of the present invention are essentially free of polyols and / or mixtures of two or more polyols, contain parabens, and preferably do not contain propylene glycol and parabens.

[0179] The formulation of the present invention can be a gel formulation. In this specification, "gel" refers to a biphasic elastic colloidal material incorporated into a solid phase, often in which the dispersion is composed of a gelling agent. Suitable gelling agents such as xanthan gum are described herein.

[0180] The formulations of the present invention may be provided filled in a container or dispenser. Suitable dispensers and containers are well known to those skilled in the art. For example, the dispenser may be a squeeze tube containing the formulations described herein. The squeeze tube may contain the gel formulations described herein. The dispenser may be a metering dispenser, a foam dispenser, or a spray dispenser.

[0181] The container or dispenser may contain a propellant provided for pressurizing the container or dispenser. Any suitable propellant can be used. Suitable propellants and mixtures thereof are well known to those skilled in the art. Preferably, the propellant is selected from propane, isobutane, n-butane, and mixtures thereof.

[0182] The formulation of the present invention can be prepared as an effervescent formulation.

[0183] The formulation of the present invention can be prepared as a pressurized formulation, in which case a propellant for pressurizing the formulation is provided. Any propellant described herein may be used.

[0184] The formulation of the present invention may be prepared as a pressurizable effervescent formulation. In this case, a propellant for pressurizing the formulation is provided. Any propellant described herein may be used.

[0185] The formulation of the present invention may be provided in a foam dispenser as described herein. The foam dispenser includes a container, the container containing the formulation and propellant as described herein. The propellant is provided to pressurize the foam dispenser. Any suitable propellant as described herein may be used. A foam generating device is attached to the container. In particular, the formulation is prepared as a foaming formulation.

[0186] The present invention also provides foam comprising the formulation of the present invention as described herein.

[0187] In preferred embodiments, the activator in the formulation of the present invention comprises at least one carboxylic acid group capable of undergoing an esterification reaction. Preferably, the activator is a low molecular weight containing a carboxylic acid group, with a molecular weight of 50 to 1000 g / mol, more preferably 50 to 900 g / mol, and most preferably 100 to 850 g / mol.

[0188] The active ingredient may be present in an amount of 0.001 to 50% by weight based on the total weight of the preparation. In particular, the active ingredient may be present in an amount of 0.01 to 30% by weight, or 0.1 to 25% by weight, 0.5 to 25% by weight, 1 to 25% by weight, or 5 to 25% by weight based on the total weight of the preparation.

[0189] In particular, the activator in the formulation of the present invention is a hydrophilic compound having one carboxylic acid group. The activator is a photosensitizer or its metabolic precursor, most preferably 5-aminolevulinic acid (also referred to herein as "ALA" or "5-ALA"), a pharmaceutically acceptable salt, derivative, precursor and / or metabolite. A preferred salt of 5-aminolevulinic acid is the hydrochloride salt. Another preferred salt is the phosphate salt.

[0190] 5-aminolevulinic acid has the following chemical structure: JPEG2026512858000002.jpg 2963 Molecular weight: 131.13 g / mol It holds.

[0191] 5-aminolevulinic acid is a hydrophilic substance and may interact with the nanovesicle surface when dissolved in the aqueous phase.

[0192] 5-aminolevulinic acid, pharmaceutically acceptable salts, derivatives, precursors, and / or metabolites may be present in amounts of 0.001 to 50% by weight based on the total weight of the preparation. In particular, 5-aminolevulinic acid, its pharmaceutically acceptable salts, derivatives, precursors, and / or metabolites may be present in amounts of 0.01 to 30% by weight, or 0.1 to 25% by weight, 0.5 to 25% by weight, 1% to 25% by weight, or 5% to 25% by weight based on the total weight of the preparation.

[0193] In particular, the formulation of the present invention (a)(i) an aqueous component present in an amount of 70 to 95% by weight relative to the total weight of the nanoemulsion (a), (ii)(1) Based on the total weight of the nanoemulsion (a), 1 to 5% by weight of at least one phospholipid, (2) Based on the total weight of the nanoemulsion (a), 2 to 10% by weight of at least one polyoxyethylene-based surfactant, (3) Based on the total weight of the nanoemulsion (a), 1 to 5% by weight of C3 to C5 alcohols, (4) Based on the total weight of the nanoemulsion (a), 2 to 10% by weight of triglycerides Nanovesicles containing Nanoemulsions containing (b) Based on the total weight of the formulation, 0.1 to 20% by weight of an activator, preferably an activator containing a carboxylic acid group, and (c) Based on the total weight of the formulation, at least one preservative in an amount of 0.1 to 2% by weight. It may include, or consist of, The aforementioned formulation does not contain propylene glycol in an essential manner. The formulation preferably has a pH of 2 to 4. Preferably, the formulation may contain two surfactants, and more preferably, soy lecithin and Polysorbate 80.

[0194] In this formulation, at least one phospholipid, at least one polyoxyethylene surfactant, a C3-C5 alcohol, a triglyceride, and at least one preservative may be independently selected in accordance with the disclosures described herein.

[0195] In particular, the formulation of the present invention (a)(i) an aqueous component present in an amount of 70 to 95% by weight relative to the total weight of the nanoemulsion (a), (ii)(1) Based on the total weight of the nanoemulsion (a), 1 to 5% by weight of at least one phospholipid, (2) Based on the total weight of the nanoemulsion (a), 2 to 10% by weight of at least one polyoxyethylene-based surfactant, (3) Based on the total weight of the nanoemulsion (a), 1 to 5% by weight of C3 to C5 alcohols, (4) Based on the total weight of the nanoemulsion (a), 2 to 10% by weight of triglycerides Nanovesicles containing Emulsion of nanovesicles containing (b) Based on the total weight of the formulation, 0.1 to 20% by weight of an activator, preferably a hydrophilic activator, preferably a photosensitizer or its metabolic precursor, most preferably 5-aminolevulinic acid hydrochloride, and (c) Based on the total weight of the formulation, at least one preservative in an amount of 0.1 to 2% by weight. It may include, or essentially consist of, The aforementioned formulation does not contain propylene glycol in an essential manner. The formulation preferably has a pH of 2 to 4.

[0196] Preferably, the formulation may contain two surfactants, more preferably soy lecithin and Polysorbate 80.

[0197] In this formulation, at least one phospholipid, at least one polyoxyethylene surfactant, a C3-C5 alcohol, a triglyceride, and at least one preservative may be independently selected in accordance with the disclosures described herein.

[0198] The present invention also, (i) Soy lecithin 16-19% by weight, (ii) Polysorbate 80 32~36% by weight, (iii) Caprylic / capric triglyceride 32-36% by weight, and (iv) Isopropanol 12-16% by weight This relates to nanovesicles that include, essentially consist of, or are composed of.

[0199] A preferred nanovesicle of the present invention is (i) Soy lecithin 17% by weight (ii) Polysorbate 80 34% by weight (iii) Caprylic / Capric Triglyceride 35% by weight (iv) Isopropanol 14% by weight Including, essentially consisting of, or composed of.

[0200] The present invention also, (a) Soy lecithin 1.6-3.6% by weight (b) Polysorbate 80 3.3~6.9% by weight (c) Caprylic / Capric Triglyceride 3.3-7.0% by weight (d) Isopropanol 1.3-2.9% by weight (e) A phosphate buffer solution, for example, 5-20 mM phosphate buffer solution, pH 2-8, preferably pH 2-7, more preferably pH 3-6, up to 100% This relates to nanoemulsions that include, essentially consist of, or are composed of.

[0201] The preferred nanoemulsion of the present invention is (a) Soy lecithin 1.7% by weight (b) Polysorbate 80 3.4% by weight (c) Caprylic / Capric Triglyceride 3.5% by weight (d) Isopropanol 1.4% by weight (e) Add 10 mM phosphate buffer solution, pH 6, to 100%. Including, essentially consisting of, or composed of.

[0202] This formulation will be referred to herein as "BF200". BF200 nanoemulsion is obtained by contacting a mixture of components (a) to (d) (10% by weight total) with a 10 mM phosphate buffer aqueous solution at pH 6 (90% by weight) under conditions that enable the formation of a nanoemulsion. An example of a method for producing the BF200 formulation is described in Example 1.

[0203] Another preferred nanoemulsion of the present invention essentially comprises or consists of: (a) Soy lecithin 2-3% by weight (b) Polysorbate 80 4.5~5.5% by weight (c) Caprylic / Capric Triglyceride 4.5-5.5% by weight (d) Isopropanol 2-3% by weight (e) Add 10 mM phosphate buffer solution (pH 6 or less) until 100% is reached. Including, essentially consisting of, or composed of.

[0204] This formulation is referred to as "BF215" in this specification. BF215 nanoemulsion is obtained by contacting a mixture of components (a) to (d) (15% by weight total) with a 10 mM phosphate buffer aqueous solution at pH 6 (85% by weight total) under conditions that enable nanoemulsion formation. An example of a method for producing the BF215 formulation is described in Example 1.

[0205] A further preferred nanoemulsion of the present invention essentially comprises or consists of: (a) Soy lecithin 3-4% by weight (b) Polysorbate 80 6~7% by weight (c) Caprylic / Capric Triglyceride 6-8% by weight (d) Isopropanol 2-4% by weight (e) Add 10 mM phosphate buffer solution, pH 6, to 100%. Including, essentially consisting of, or composed of.

[0206] This formulation is referred to herein as "BF220". BF220 nanoemulsion is obtained by contacting a mixture of components (a) to (d) (20% by weight total) with a 10 mM aqueous phosphate buffer solution (pH 6, 80% by weight) under conditions that enable nanoemulsion formation. An example of a method for producing the BF220 formulation is described in Example 1.

[0207] A preferred formulation of the present invention that is essentially free of propylene glycol is: (1) 17.5% by weight of the nanoemulsion BF200 described herein (2) Xanthan gum 2.9% by weight (3) 0.24% by weight of sodium benzoate, (4) 10% by weight of 5-ALA hydrochloride, and (5) Water, up to 100% It includes, essentially consists of, or consists of. The pH of this formulation may be 2 to 3. The method for preparing this formulation is described in Example 3.

[0208] Representative comparative formulations not included in the claims are: (1) 17.5% by weight of the nanoemulsion BF200 described herein, (2) 2.9% by weight xanthan (3) 1% by weight of propylene glycol, (4) 0.24% by weight of sodium benzoate, (5) 10% by weight of 5-ALA hydrochloride, and (6) Water, up to 100% It may contain, essentially consist of, or consist of. The pH of this formulation may be 2 to 3. The method for preparing this formulation is described in Example 2.

[0209] All definitions and embodiments described in the first aspect also apply to all other aspects described herein, where applicable.

[0210] Another aspect relates to formulations for pharmaceutical uses as described herein.

[0211] Another aspect relates to a formulation described herein used for a method of treating and / or preventing a skin disease or skin condition in a subject.

[0212] The treatment and / or prevention of skin diseases or skin conditions is (a) Topically administering to the subject a formulation containing a photosensitizer or its metabolic precursor (preferably 5-aminolevulinic acid, pharmaceutically acceptable salts, derivatives, precursors and / or metabolites as described herein) in a pharmacologically effective amount to the affected area or affected skin region and the area surrounding the affected area, and (b) If necessary, culture the formulation on the subject's skin, whether or not to occlude the skin area where the formulation was administered. Includes, The occlusion is preferably performed using low-density polyethylene or polyurethane film to facilitate penetration into the deep tissues.

[0213] The treatment and / or prevention of skin diseases or skin conditions is (a) administering to a subject a pharmaceutically effective amount topically to the lesion or affected skin area and optionally the surrounding area a formulation containing a photosensitizer or its metabolic precursor (preferably 5-aminolevulinic acid, pharmaceutically acceptable salts, derivatives, precursors and / or metabolites as described herein), and (b) If necessary, incubate the formulation on the subject's skin, whether or not to occlude the skin area to which the formulation was administered. (c) Irradiating the skin area where the formulation has been administered with light. It may further include, The aforementioned occlusion is preferably performed using low-density polyethylene or polyurethane film in order to promote penetration into the deep tissues.

[0214] The light spectrum used for irradiation in step (c) may be matched to the absorption spectrum of the fluorescent porphyrin. For example, the light spectrum may be matched to the absorption peak of protoporphyrin IX. In particular, the light used for irradiation in step (c) may include visible wavelengths in the range of 380 nm to 780 nm, preferably having an evenly distributed irradiance or having irradiance peaks around 410 nm and / or 505 nm and / or 542 nm and / or 575 nm and / or 635 nm. The wavelength spectrum essentially does not include radiation at wavelengths below 380 nm and / or above 780 nm. In particular, the light used for irradiation in step (c) may include visible wavelengths in the range of 380 to 440 nm and / or 580 to 650 nm. The light used for irradiation in step (c) may also have the ability to induce red fluorescence of further accumulated porphyrins.

[0215] The light used in step (c) is red light, blue light, green light and / or violet light, preferably red light and / or violet light, and more preferably (a) red light is 10 to 75 J / cm². 2 Preferably 25-45 J / cm² 2 This results in an irradiance of 1-30 J / cm² of violet light. 2 Preferably 5-15 J / cm² 2 It produces this level of irradiance.

[0216] The irradiation in step (c) can be carried out using sunlight and / or daylight, or an artificial light source having a wavelength spectrum similar to or identical to sunlight, and preferably with the same irradiance. Light having a wavelength spectrum similar to or identical to sunlight, and preferably with the same irradiance, may have a wavelength spectrum from 100 nm to 1000 nm, a wavelength spectrum from 380 nm to 780 nm, preferably with uniform irradiance across the entire wavelength range, or with a peak in irradiance around 410 nm and / or 505 nm and / or 635 nm, or a wavelength spectrum from 570 nm to 650 nm or 570 nm to 630 nm, and / or a wavelength spectrum from 380 nm to 440 nm. The artificial light may be provided by an LED. Suitable apparatus for providing artificial light are described, for example, in U.S. Patent No. 11235169(B1) and U.S. Patent No. 11219781(B2), the disclosures of which are incorporated herein by reference.

[0217] The surrounding area of ​​a skin lesion or affected area may include unaffected surrounding areas to ensure that the lesion or affected area is properly treated in the surrounding area. For example, the surrounding area of ​​a skin lesion or affected area may include an area with a width of at least approximately 5 mm.

[0218] The skin diseases or conditions treated with the formulations described herein may include, but are not limited to, diseases or conditions of the skin, skin appendages, or mucous membranes.

[0219] The skin diseases or conditions treated with the 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, neoplastic, proliferative, and / or inflammatory changes associated with solitary lesions or lesion areas.

[0220] The inflammatory skin diseases or conditions treated with the formulations described herein include 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.

[0221] The neoplastic and / or proliferative skin diseases or conditions to be treated with the formulations described herein are basal cell carcinoma (preferably superficial basal cell carcinoma or nodular basal cell carcinoma), squamous cell carcinoma (preferably Bowen's disease or invasive squamous cell carcinoma), vulvar intraepithelial neoplasia (VIN), cutaneous T-cell lymphoma, Merkel cell carcinoma; hemangiomas; nodular or subcutaneous carcinomas; field carcinogenesis; non-melanoma skin cancer in organ transplant recipients; and prevention of non-melanoma skin cancer in organ transplant recipients.

[0222] The infectious skin diseases or conditions treated with the formulations described herein may be selected from the group consisting of bacterial infections, viral infections, fungal infections, parasitic infections, and combinations thereof.

[0223] The autoimmune skin diseases or conditions, or skin manifestations of autoimmune conditions, treated with the formulations described herein may be selected from the group consisting of psoriasis, pemphigus, systemic lupus erythematosus, lichen planus, scleroderma, scleroderma, epidermolysis bullosa, dermatomyositis, and graft-versus-host disease.

[0224] Skin conditions or conditions treated with the formulations described herein include sweating disorders, pigmentation disorders (including depigmentation disorders such as vitiligo, albinism, and post-inflammatory depigmentation, and pigmentation disorders such as melasma), sun reactions (such as sunburn), skin aging, photosensitivity, and disorders of hair follicles and sebaceous glands (including hirsutism, alopecia, and male pattern baldness).

[0225] Pharmaceuticals described herein, in particular photosensitizers or their metabolic precursors, preferably 5-aminolevulinic acid, pharmaceutically acceptable salts thereof, derivatives, precursors and / or metabolites thereof, as described herein, are used in pharmaceutical compositions containing these by the methods described herein. These include neoplastic and / or proliferative skin diseases or conditions, such as benign or malignant neoplasms or their precursors; inflammatory skin diseases or conditions; and / or conditions associated with bacterial growth, such as acne.

[0226] The formulations described herein may be used to treat the diseases or conditions described herein, such as benign or malignant skin neoplasms or their precursors, inflammatory skin diseases or conditions such as atopic dermatitis, eczema, psoriasis, rosacea, and chronic wounds, and neoplastic and / or proliferative skin diseases or conditions, including conditions associated with bacterial growth such as acne.

[0227] Another aspect of the present invention involves 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 enable the formation of a nanoemulsion. Includes, The method for preparing the formulation described herein involves adding the activator under conditions that allow it to interact with the nanovesicle surface when dissolved in the aqueous phase.

[0228] In step (b), the conditions that enable the formation of the nanoemulsion include mixing both phases at an appropriate temperature and stirring to form nanovesicles. Those skilled in the art are familiar with the appropriate temperature and stirring conditions. The vesicle size obtained is 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. In particular, the nanoemulsion of the present invention by step (b) can be prepared without using high-energy methods well known to those skilled in the art. High-energy methods include high-pressure homogenization, microfluidization, and sonication (Prev Nutr Food Sci. 2019 Sep; 24(3): 225-234).

[0229] This method includes a step of adding an activator. Preferably, the activator is a hydrophilic pharmaceutical active ingredient.

[0230] Hydrophilic compounds such as amino acids, preferably photosensitizers or metabolic precursors such as ALA, or / or pharmaceutically acceptable salts thereof (e.g., ALA hydrochloride), can be added to the aqueous component before the mixture obtained in step (a) is brought into contact with the aqueous component in step (b). This allows the activator to bond non-covalently to the nanovesicles (especially the nanovesicle surface) in step (b).

[0231] Hydrophilic compounds such as amino acids, preferably photosensitizers or metabolic precursors such as ALA, and / or pharmaceutically acceptable salts (e.g., ALA hydrochloride) can also be added to the nanoemulsion obtained in step (b). This allows the activator to be non-covalently bonded to the nanovesicles (particularly the nanovesicle surface).

[0232] The method for preparing the pharmaceutical formulation of the present invention is: (i) Adding a gelling agent, and / or (ii) Adding preservatives It may also include the following.

[0233] Another aspect of the present invention is a dispenser product or container product containing the formulation described herein. In this dispenser product or container product, the formulation of the present invention is contained in a container or dispenser. Suitable dispensers and containers are well known to those skilled in the art. For example, the dispenser may be a squeeze tube containing the formulation described herein. The squeeze tube may contain the gel formulation described herein. The dispenser may also be a metering dispenser or a foam dispenser.

[0234] The container or foam dispenser may contain a propellant provided for pressurizing the container or foam dispenser. Any suitable propellant can be used. Suitable propellants and mixtures thereof are well known to those skilled in the art. Preferably, the propellant is selected from propane, isobutane, n-butane and mixtures thereof.

[0235] The dispenser products described herein are foam dispenser products, and include a foam dispenser. The foam dispenser includes a container, which contains the formulation and propellant described herein. The propellant is provided to pressurize the foam dispenser. Any suitable propellant described herein may be used. A foam generator is attached to the container. In particular, the formulation is prepared as a foaming formulation.

[0236] In yet another embodiment, the formulations of the present invention may be used to manufacture pharmaceuticals for the treatment and / or prevention of skin diseases or skin conditions in subjects. In particular, skin diseases are skin diseases or skin conditions described herein.

[0237] Another embodiment includes a method for treating and / or preventing a skin disease or skin condition in a subject. This method comprises administering to the subject a pharmacologically effective amount of the formulation described herein. In particular, the skin disease is a skin disease or skin condition described herein.

[0238] A further aspect of the present invention is a photodynamic diagnostic method for neoplastic and / or proliferative skin diseases or conditions, such as benign or malignant neoplasms or their precursor lesions, inflammatory skin diseases or conditions, and / or conditions associated with bacterial growth, such as acne.

[0239] ALA (and its derivatives)-containing agents promote the synthesis of fluorescent porphyrins, which preferentially accumulate in cells / tissues with increased metabolic activity. This property may be utilized in photodynamic diagnostic methods applicable to neoplastic skin diseases such as benign or malignant neoplasms or their precursors, inflammatory conditions, or conditions involving bacterial growth such as acne. In photodynamic diagnostics, the ALA (or its derivative)-containing formulation is applied to the skin area to be diagnosed and incubated for an appropriate time (e.g., 1-3 hours). Subsequently, blue spectral light is irradiated to induce red fluorescence from the accumulated porphyrins. This fluorescence can be detected by visual inspection or by appropriate technical equipment for qualitative and quantitative evaluation.

[0240] Photodynamic diagnostics are, (i) administering a formulation containing a photosensitizer or metabolic precursor (e.g., 5-aminolevulinic acid, pharmaceutically acceptable salts, derivatives, precursors and / or metabolites) to the skin area of ​​concern under conditions that enable the synthesis of fluorescent porphyrins 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 porphyrins. It may include, Increased porphyrin fluorescence indicates increased metabolic activity and is associated with neoplastic and / or proliferative skin diseases or conditions, inflammatory skin diseases or conditions, and / or conditions related to bacterial growth.

[0241] In step (i), the formulation may be cultured on the skin for, for example, 1 to 3 hours. vinegar

[0242] In step (ii), the skin may be irradiated with light capable of inducing the red fluorescence of the accumulated porphyrin. Appropriate irradiation conditions are described herein.

[0243] The diagnosis of neoplastic and / or proliferative skin diseases or conditions can be made by detecting increased fluorescence (e.g., compared to normal tissue and / or skin (e.g., a site adjacent to the suspected area)). Fluorescence detection can be performed by visual inspection or appropriate technical equipment for qualitative or quantitative evaluation.

[0244] Diagnostic methods described herein may be performed for the purpose of clarifying tumor boundaries for surgical assistance, evaluating therapeutic effects, and / or for photo-induced decolorization for photodose measurement in photodynamic therapy.

[0245] Another aspect of the present invention is that certain components are absent, essentially absent, or present in amounts less than specified (e.g., less than 1%, 0.99% or less, 0.95% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less). These include glycerin, diglycerin, polyglycerin, diethylene 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 sorbitan. The formulation contains 0.5% or less of any number of polyols selected from the group of polyols selected from monosaccharides or disaccharides such as sorbitol, mannitol, and mixtures thereof. The alternative formulation essentially does not contain glycerin, diglycerin, polyglycerin, diethylene glycol, dipropylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,3-propanediol, 1,5-pentanediol, octane-1,2-diol, polyethylene glycol (especially those having 2 to 50 ethylene oxide groups), and any number of polyols selected from monosaccharides or disaccharides such as sorbitol, mannitol, and mixtures thereof.

[0246] The present invention also relates to the following aspects. (Aspect 1) (a)(i) At least one aqueous component, (ii)(1) At least one lipophilic component, (2) At least one surfactant, and (3) At least one alcohol A carrier component containing [[ID=第十七条]]A nanoemulsion containing, and (b) An active agent containing a carboxylic acid group, or a derivative or salt of a carboxylic acid group A formulation containing, wherein The formulation contains less than 1% by weight of propylene glycol or does not contain propylene glycol. (Aspect 2) The formulation according to Aspect 1, wherein the formulation contains less than 0.9% by weight of propylene glycol or does not contain propylene glycol. (Aspect 3) The formulation according to Aspect 1 or 2, preferably Aspect 2, wherein the formulation essentially does not contain propylene glycol. (Aspect 4) The formulation according to any one of Aspects 1 to 3, preferably Aspect 3, wherein the formulation does not contain propylene glycol. (Aspect 5) The formulation according to any one of Aspects 1 to 4, preferably Aspect 4, wherein the formulation does not contain, essentially does not contain, contains less than 1% by weight, or 0.99%, 0.95%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by weight or less of an acyclic polyol having 2 to 5 carbon atoms. (Aspect 6) The formulation according to any one of Aspects 1 to 5, preferably Aspect 5, wherein the formulation has a content of a polyol having 2 to 12 carbon atoms of zero, essentially zero, less than 1%, or 0.99%, 0.95%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by weight. (Aspect 7) The at least one alcohol comprises at least three carbon atoms, preferably three, four, or five carbon atoms, and more preferably, the at least one alcohol is selected from the group consisting of 1-propanol, 2-propanol, and mixtures thereof; The at least one lipophilic component is selected from triglycerides and mixtures thereof, preferably the at least one lipophilic component is caprylic acid and / or capric acid triglyceride, or a mixture thereof; and / or The formulation according to any one of embodiments 1 to 6, 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-based surfactant. (Aspect 8) A formulation according to any one of aspects 1 to 7, having a total aqueous component of 50% to 99% by weight, preferably 70% to 95% by weight, more preferably 75% to 95% by weight, and even more preferably 80% to 90% by weight. (Aspect 9) (a) at least one lipophilic component in an amount of 0.1% to 30% by weight, preferably 0.25% to 15% by weight, more preferably 0.25% to 10% by weight, more preferably 2% to 10% by weight or 3% to 8% by weight, and / or (b) Based on the total weight of the nanoemulsion (a), at least one alcohol in an amount of 0.1% to 10% by weight, preferably 0.5% to 5% by weight, more preferably 1% to 5% by weight, and even more preferably 1% to 3% by weight. A preparation according to any one of embodiments 1 to 8, including the preparation described above. (Aspect 10) The formulation according to any one of aspects 1 to 9, wherein the activator is a photosensitizer or a metabolic precursor thereof. (Aspect 11) The formulation according to any one of aspects 1 to 10, wherein the activator is 5-aminolevulinic acid, its derivatives, precursors, metabolites, and / or pharmaceutically acceptable salts. (Aspect 12) The formulation according to any one of aspects 1 to 11, wherein the activator is present in an amount of 0.1% to 25% by weight based on the total weight of the formulation. (Aspect 13) The nanoemulsion contains nanovesicles, (a) If stored at 2-25°C for 1 month, 2 months, 3 months, 6 months, 12 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, or at least 12 months, and / or (b) When stored at 2-8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months, The formulation according to any one of embodiments 1 to 12, wherein the size of the nanovesicle is 500 nm or less, preferably 200 nm or less, and more preferably in the range of 5 nm to 200 nm. (Aspect 14) (a) Stored at 2-25°C for 1 month, 2 months, 3 months, 6 months, 12 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, and / or (b) When stored at 2-8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months, A formulation according to any one of embodiments 1 to 13, wherein the polydispersity index is 0.4 or less. (Aspect 15) A formulation according to any one of aspects 1 to 14, comprising at least one 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 (alginate), tragacanth, povidone, gelatin, and mixtures thereof, and more preferably the gelling agent being selected from poloxamer, xanthan gum, and mixtures thereof. (Aspect 16) A formulation according to any one of aspects 1 to 15, which is essentially paraben-free. (Aspect 17) (a)(i) at least one aqueous component, (ii)(1) at least one lipophilic component, (5) at least one surfactant, and (6) at least one alcohol Carrier components containing Nanoemulsions containing, and (b) Activators containing a carboxylic acid group, or a derivative or salt of a carboxylic acid group A formulation containing, The activator is a photosensitizer or its metabolic precursor, A formulation that is essentially free of propylene glycol. (Aspect 18) The formulation according to aspect 17, wherein the activator is 5-aminolevulinic acid, its derivatives, precursors, metabolites, and / or pharmaceutically acceptable salts. (Aspect 19) (a)(i) at least one aqueous component, (ii)(7) at least one lipophilic component, (8) at least one surfactant, and (9) at least one alcohol Carrier components containing Nanoemulsions containing, and (b) Activators containing a carboxylic acid group, or a derivative or salt of a carboxylic acid group A formulation comprising the formulation contains less than 1% by weight of propylene glycol or does not contain propylene glycol. (Aspect 20) A method for treating a skin disease or skin condition, comprising administering to a subject in need thereof an effective amount of the formulation according to Aspects 10 to 12.

[0247] The present invention also relates to the following items: (Item 1) (a) (i) At least one aqueous component, (ii) (1) At least one lipophilic component, (2) At least one surfactant, and (3) At least one alcohol A carrier component containing A nanoemulsion containing (b) An active agent containing a carboxylic acid group, or a derivative or salt of a carboxylic acid group A formulation containing the formulation contains less than 1% by weight, preferably 0.99% or less, 0.95% or less, or 0.9% or less of propylene glycol, or does not contain propylene glycol. (Item 2) The formulation according to Item 1, wherein the formulation essentially does not contain propylene glycol. (Item 3) The formulation according to Item 1 or 2, wherein the formulation does not contain, essentially does not contain, contains less than 1% by weight, or 0.99% by weight, 0.95% by weight, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0. % by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, or 0.1% by weight or less of an acyclic polyol having 2 to 3 carbon atoms, and preferably does not contain, essentially does not contain, contains less than 1% by weight, or 0.99% by weight, 0.95% by weight, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, or 0.1% by weight or less of an acyclic polyol having 2 to 5 carbon atoms. (Item 4) The formulation according to any one of Items 1 to 3, wherein the formulation does not contain, essentially does not contain, a cyclic polyol having 2 to 5 carbon atoms, and contains less than 1% by weight, or 0.99% by weight, 0.95% by weight, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, or 0.1% by weight or less of a cyclic polyol having 2 to 5 carbon atoms, and preferably does not contain, essentially does not contain, a polyol having 2 to 12 carbon atoms, and contains less than 1% by weight, or 0.99% by weight, 0.95% by weight, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, or 0.1% by weight or less of a polyol having 2 to 12 carbon atoms. (Item 5) The formulation according to any one of items 1 to 4, wherein the at least one alcohol comprises at least three carbon atoms, preferably three, four, or five carbon atoms. (Item 6) The formulation according to any one of items 1 to 5, wherein the activator is a photosensitizer or a metabolic precursor thereof. (Item 7) The formulation according to any one of items 1 to 6, wherein the activator is present in an amount of 0.01% to 25% by weight, preferably 0.1% to 25% by weight, and more preferably 1% to 25% by weight, based on the total weight of the formulation. (Item 8) The formulation according to any one of items 1 to 7, wherein the activator is 5-aminolevulinic acid, its derivatives, precursors, metabolites, and / or pharmaceutically acceptable salts. (Item 9) The formulation according to Item 8, wherein the 5-aminolevulinic acid, the derivatives, precursors, metabolites, and / or pharmaceutically acceptable salts thereof are present in an amount of 0.01% to 25% by weight, preferably 0.1% to 25% by weight, and more preferably 1% to 25% by weight, based on the total weight of the formulation. (Item 10) The preparation according to item 8 or 9, wherein when the preparation is stored at 40°C for 3 months, it contains a substance characterized by m / z=246 in an amount of 1.5% or less, 1.0% or less, or 0.75% or less. (Item 11) The preparation described in any one of items 8 to 10, wherein when the preparation is stored at 25°C for 6 months, it contains a substance characterized by m / z=246 in an amount of 1.5% or less, 1.0% or less, 0.5% or less, or 0.2% or less. (Item 12) A preparation described in any one of items 1 to 11, wherein the preparation is a pharmaceutical preparation. (Item 13) The formulation according to any one of items 1 to 12, wherein the formulation is for external use and / or the formulation is a lotion, spray, foam, emulsion, nanoemulsion, gel or cream. (Item 14) The formulation according to any one of items 1 to 13, wherein the activator is capable of dissolving in the aqueous phase and / or interacting with the surface of the nanovesicle. (Item 15) The formulation according to any one of items 1 to 14, wherein the activator is a hydrophilic active ingredient. (Item 16) The formulation according to any one of Items 1 to 15, wherein the nanoemulsion contains nanovesicles, and the nanovesicles have a size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when stored at 40°C for one month. (Item 17) The formulation according to any one of Items 1 to 16, wherein the nanoemulsion contains nanovesicles, and the nanovesicles have a size of 500 nm or less, preferably in the range of 5 nm to 200 nm, when stored at 25°C for 6 months. (Item 18) The formulation according to any one of items 1 to 17, wherein the aqueous component is present in an amount of 50% to 99% by weight, preferably 70% to 95% by weight, and more preferably 80% to 95% by weight, based on the total weight of the nanoemulsion (a). (Item 19) The formulation according to any one of items 1 to 18, wherein the aqueous component comprises at least one pH buffering agent. (Item 20) The formulation according to Item 19, wherein the pH buffer is selected from the group consisting of citrate, phosphate, acetate, and carbonate. (Item 21) A formulation described in any one of items 1 to 20, with a pH of 2 to 6. (Item 22) A formulation described in any one of items 1 to 21, with a pH of 2 to 4. (Item 23) The formulation according to any one of items 1 to 22, wherein the at least one lipophilic component is selected from triglycerides and mixtures thereof. (Item 24) The formulation according to any one of items 1 to 23, wherein the at least one lipophilic component comprises caprylic acid triglyceride and / or capric acid triglyceride, or a mixture thereof. (Item 25) The formulation according to any one of items 1 to 24, wherein the at least one lipophilic component is present in an amount of 0.1% to 30% by weight, preferably 0.25% to 10% by weight, more preferably 0.5% to 8% by weight or 3% to 8% by weight, based on the total weight of the nanoemulsion (a). (Item 26) The formulation according to any one of items 1 to 25, wherein the at least one surfactant comprises (a) a phospholipid, a lysophospholipid, a ceramide and / or a mixture thereof, and / or (b) a polyoxyethylene-based surfactant. (Item 27) The formulation according to any one of items 1 to 26, wherein the at least one surfactant comprises lecithin, preferably soy lecithin. (Item 28) The preparation according to Item 27, wherein the lecithin contains at least 80% by weight of phosphatidylcholine. (Item 29) The formulation according to any one of items 26 to 28, wherein the phospholipid, lysophospholipid, ceramide and / or mixture thereof is present in an amount of 0.1% to 10% by weight, preferably 0.15% to 5% by weight, and more preferably 0.2% to 3% by weight, based on the total weight of the nanoemulsion (a). (Item 30) The formulation according to any one of items 26 to 29, wherein the polyoxyethylene surfactant comprises Polysorbate 80. (Item 31) The formulation according to any one of items 26 to 30, wherein the polyoxyethylene surfactant is present in an amount of 0.1% to 10% by weight, more preferably 0.2% to 5% by weight, and most preferably 0.5% to 5% by weight, based on the total weight of the nanoemulsion (a). (Item 32) The preparation according to any one of items 1 to 31, wherein the at least one alcohol is selected from the group consisting of 1-propanol or 2-propanol and mixtures thereof. (Item 33) The formulation according to any one of items 1 to 32, wherein the at least one alcohol is present in an amount of 0.1% to 10% by weight, preferably 0.5% to 5% by weight, and more preferably 1% to 2% by weight, based on the total weight of the nanoemulsion (a). (Item 34) A formulation according to any one of items 1 to 33, comprising at least one gelling agent. (Item 35) A formulation according to any one of items 1 to 34, 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 (alginate), tragacanth, povidone, gelatin, and mixtures thereof. (Item 36) The formulation according to Item 34 or 35, wherein the gelling agent is selected from poloxamer, xanthan, and / or mixtures thereof. (Item 37) The formulation according to any one of items 1 to 36, wherein the gelling agent is present in an amount of 0.1% to 10% by weight, preferably 0.25% to 5% by weight, and more preferably 1% to 4% by weight, based on the total weight of the formulation. (Item 38) A formulation according to any one of items 1 to 37, further comprising at least one preservative. (Item 39) The formulation according to Item 38, wherein the preservative is a benzoate, preferably sodium benzoate. (Item 40) The formulation according to Item 38 or 39, wherein the preservative is present in an amount of 0.01% to 3% by weight, preferably 0.2% to 2% by weight, and more preferably 0.2% to 1.5% by weight, based on the total weight of the formulation. (Item 41) A formulation that is essentially paraben-free, as described in any one of items 1 to 40. (Item 42) A formulation described in any one of items 1 to 41, wherein the polydispersity index measured by dynamic light scattering is 0.8 or less. (Item 43) (a)(i) an aqueous component present in an amount of 70 to 95% by weight relative to the total weight of the nanoemulsion (a), (ii)(1) Based on the total weight of the nanoemulsion (a), 1 to 5% by weight of at least one phospholipid, (2) Based on the total weight of the nanoemulsion (a), 2 to 10% by weight of at least one polyoxyethylene-based surfactant, (3) Based on the total weight of the nanoemulsion (a), 1 to 5% by weight of C3 to C5 alcohols, (4) Based on the total weight of the nanoemulsion (a), 2 to 10% by weight of triglycerides Nanovesicles containing Emulsion of nanovesicles containing (b) Based on the total weight of the formulation, 0.1 to 20% by weight of the photosensitizer or its metabolic precursor, preferably 5-aminolevulinic acid hydrochloride, and (c) Based on the total weight of the formulation, at least one preservative in an amount of 0.1 to 2% by weight. A formulation containing, The aforementioned formulation does not contain propylene glycol in an essential manner. The formulation according to any one of items 1 to 42, wherein the formulation preferably has a pH of 2 to 4. (Item 44) The formulation according to any one of items 1 to 43, which is contained in a container, the container further comprising a propellant, the propellant being provided for pressurizing the container and / or pressurizing the formulation inside the container. (Item 45) A preparation used for pharmaceutical purposes, as described in any one of items 1 to 44. (Item 46) A preparation described in any one of items 1 to 45, used for the treatment and / or prevention of a skin disease or skin condition in a subject. (Item 47) A preparation described in any one of items 1 to 46 for use in a method of treating and / or preventing a skin disease or skin condition in a subject, wherein the treatment and / or prevention of the skin disease or skin condition is (a) Locally administer one of the formulations from item 1 to 46 in a pharmacologically effective amount to the affected area or site of the subject, and, if necessary, to the surrounding area of ​​the affected skin region, and (b) Culturing the formulation on the subject's skin, whether or not the skin area to which the formulation was administered is occluded. Includes, The formulation is characterized by occlusion, preferably using a low-density polyethylene or polyurethane film, to promote penetration into deep tissues. (Item 48) (c) A step of irradiating the skin area where the formulation has been administered with light. Formulations for use as described in item 47, further including the above. (Item 49) A formulation for use as described in any one of items 47-48, including an area surrounding the affected area of ​​skin or the area affected by the skin, having an area of ​​at least about 5 mm in width. (Item 50) Skin diseases or skin conditions include diseases or conditions of the skin, skin appendages or mucous membranes, and formulations for use as described in any one of items 46-49. (Item 51) A skin disease or skin condition is selected from the group consisting of inflammatory, neoplastic, proliferative, infectious, and / or autoimmune diseases or conditions and / or skin manifestations thereof and / or diseases, neoplastic, proliferative, and / or inflammatory changes associated with a solitary lesion or area of ​​lesion, as described in any one of items 46 to 50. (Item 52) The inflammatory skin disease or condition described above is a formulation for use as described in Item 51, selected from 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. (Item 53) Formulations for use as described in Item 51, selected from neoplastic and / or proliferative skin diseases or conditions, including basal cell carcinoma (preferably superficial basal cell carcinoma or nodular basal cell carcinoma), squamous cell carcinoma (preferably Bowen's disease or invasive squamous cell carcinoma), vulvar intraepithelial neoplasia (VIN), cutaneous T-cell lymphoma, Merkel cell carcinoma; hemangioma; nodular or subcutaneous carcinomatous disease; field carcinogenesis; non-melanoma skin cancer in organ transplant recipients; and prevention of non-melanoma skin cancer in organ transplant recipients. (Item 54) A formulation for use as described in Item 51, wherein the infectious skin disease or condition is selected from the group consisting of bacterial infection, viral infection, fungal infection, parasitic infection, and combinations thereof. (Item 55) A formulation for use as described in Item 51, wherein the autoimmune skin disease or condition, or skin manifestation of an autoimmune condition, is selected from the group consisting of psoriasis, pemphigus, systemic lupus erythematosus, lichen planus, scleroderma, scleroderma, epidermolysis bullosa, dermatomyositis, and graft-versus-host disease. (Item 56) The skin disease or condition is selected from the group consisting of sweating disorders, pigmentation disorders (including depigmentation such as vitiligo), albinism, and post-inflammatory depigmentation / pigmentation (such as melasma), sun reaction (such as sunburn), skin aging, photosensitivity, and hair follicle / sebaceous gland disorders (such as hirsutism, alopecia, and male pattern baldness), and is a preparation for use as described in any one of items 47 to 50. (Item 57) A preparation described in any one of items 1 to 56, used for photodynamic diagnostic methods of neoplastic and / or proliferative skin diseases or conditions, such as benign or malignant neoplasms or their precursor lesions, inflammatory skin diseases or conditions, and / or conditions associated with bacterial growth, such as acne. (Item 58) (a) A step of mixing at least one lipophilic component, at least one surfactant, and at least one alcohol having at least three carbon atoms, (b) The step of contacting the mixture obtained in step (a) with an aqueous component under conditions that enable the formation of a nanoemulsion. Includes, A method for preparing a formulation according to any one of items 1 to 57, wherein the activator is added under conditions that allow it to interact with the surface of the nanovesicle when dissolved in the aqueous phase. (Item 59) (i) Adding a gelling agent, and / or (ii) Adding preservatives The method described in item 58, further including the method described in item 58. (Item 60) A dispenser product containing a formulation described in any one of items 1 through 57. (Item 61) A container containing a preparation described in any one of items 1 through 57. (Item 62) Use of any one of the formulations described in items 1 to 57 for the manufacture of a medicinal product for the treatment and / or prevention of a skin disease or skin condition in a subject. (Item 63) A method for treating and / or preventing a skin disease or skin condition in a subject, the method comprising administering to the subject a pharmacologically effective amount of a formulation described in any one of items 1 to 57. (Item 64) A photodynamic diagnostic method for neoplastic and / or proliferative skin diseases or conditions, such as benign or malignant neoplasms or their precursor lesions, inflammatory skin diseases or conditions, and / or conditions related to bacterial growth such as acne, wherein the method is (i) Administering any of the formulations described in item 1 to 57 to the skin area to be diagnosed under conditions that enable the synthesis of fluorescent porphyrins in cells and / or tissues, and (ii) Irradiate the skin area where the formulation has been administered under conditions that induce fluorescence of accumulated porphyrin. Includes, Increased fluorescence of porphyrins indicates increased metabolic activity and serves as an indicator of neoplastic and / or proliferative skin diseases or conditions, inflammatory skin diseases or conditions, and / or conditions associated with bacterial growth, according to the method. [Examples]

[0248] (Example 1): Preparation of nanoemulsions BF200, BF215, and BF220 Table 2 shows the qualitative and quantitative compositions of nanoemulsions BF200, BF215, and BF220. (TIFF2026512858000003.tif32154) TIFF2026512858000004.tif91164

[0249] A typical batch-sized method for producing nanoemulsions consists of the following steps 1 to 4. Step 1 Preparation of 10 mM phosphate buffer (aqueous component) A 10 mM phosphate buffer (1000 g), pH 6, was prepared and sterilized by filtration using a sterile filter as needed.

[0250] Step 2 Preparation of carriers containing lipophilic components, surfactants, and alcohols. TIFF2026512858000005.tif53163 Soy lecithin (17 g) was weighed into a suitable container, isopropyl alcohol (14 g) was added, and the container was covered to prevent evaporation of the alcohol. The soy lecithin was dissolved at room temperature with continuous stirring 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 with a suitable stirrer, and stirring was continued until a homogeneous clear solution was obtained. This solution is the carrier phase contained in the nanoemulsion BF200, which contains all emulsifiers and lipid components. Following this procedure, BF215 and BF220 were prepared by adjusting the amounts of components (see Table 2).

[0251] In all the examples described herein, nanoemulsion BF200 was used.

[0252] Step 3 Manufacturing of nanoemulsions with a lipid content of 10% (BF200) (mixing the aqueous component from Step 1 with the carrier from Step 2) Emulsion preparation 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 45-60°C in a suitable container. Next, the carrier (concentrate) from Step 2 was heated to approximately 45-60°C. Then, the carrier was poured into the phosphate buffer under continuous stirring with a propeller mixer to form a stable trombe (or jet) of the largest possible diameter without causing foaming or splashing. The resulting nanoemulsion was stirred for 15 minutes. Finally, the nanoemulsion was cooled to room temperature.

[0253] For nanoemulsion BF215, 850g of phosphate buffer (derived from Step 1) and 150g of carrier were mixed. For nanoemulsion BF220, 800g of phosphate buffer (derived from Step 1) and 200g of carrier were mixed.

[0254] Step 4 Preparation of the final formulation and primary packaging. If necessary, the nanoemulsion may be sterilized by filtration. Depending on the purpose of the nanoemulsion, the nanoemulsion may be diluted by adding auxiliary agents and / or excipients and / or active ingredients (in appropriate steps as described above) and / or by adding, for example, water, a suitable buffer, or an additional aqueous gel base containing Poloxamer 407 or xanthan gum, in order to obtain a suitable pharmaceutical formulation.

[0255] Formulations using different nanoemulsions BF200, BF215, and BF220 were each filled into conventional glass containers or squeeze tubes of appropriate sizes.

[0256] (Example 2): Preparation of Propylene Glycol-Containing Gel Formulation 1 (Comparative Example) Step 1 Preparation of nanoemulsions Nanoemulsion BF200 was prepared according to Example 1. Sodium benzoate, 5-ALA, and propylene glycol were added to nanoemulsion BF200 under stirring. TIFF2026512858000006.tif102162

[0257] Step 2 Preparation of gel base using xanthan gum (XT) A round-bottom flask was disinfected with isopropanol. Water was added to the flask, and xanthan gum was dispersed on top. The resulting base gel was transferred to a suitable beaker. TIFF2026512858000007.tif34162

[0258] Step 3 Preparation of Formulation 1 28.74% of the nanoemulsion prepared in Step 1 (containing 17.5% BF200 nanoemulsion) and 71.26% of the xanthan gel base prepared in Step 2 are mixed and homogenized to obtain Formulation 1. Formulation 1 (TIFF2026512858000008.tif92161) was filled into a 2g squeeze tube.

[0259] (Example 3): Preparation of Propylene Glycol-Free Gel Formulation 2 Step 1 Preparation of nanoemulsions Nanoemulsion BF200 was prepared according to Example 1. Sodium benzoate and 5-ALA were added to nanoemulsion BF200 under stirring. Formulation 2 does not contain propylene glycol. For Formulation 1, propylene glycol was replaced with a corresponding amount of xanthan gel base (10 mg / g, 1%). TIFF2026512858000009.tif95165

[0260] Step 2 Preparation of a gel base using xanthan gum (XT). The gel base was prepared by the method described in step 2 of Example 1. TIFF2026512858000010.tif36155

[0261] Step 3 Preparation of formulation 2. 27.74% of the nanoemulsion produced in Step 1 (including 17.5% of nanoemulsion BF200) and 72.26% of the xanthan gel base produced in Step 2 are mixed and homogenized to obtain Formulation 2. Formulation 2 was filled into a 2g squeeze tube. (TIFF2026512858000011.tif93157)

[0262] (Example 4): Measurement of vesicle size and polydispersity index by dynamic light scattering method The size of nanovesicles, expressed as the z-mean size (e.g., in nanometers), and the uniformity of the nanovesicle formulation, expressed as the polydispersity index, were measured by dynamic light scattering (also known as photon correlation spectroscopy (PCS) or quasi-elastic light scattering (QELS)). This technique is well-known and established in the art for measuring the size of nanoparticles, microparticles, or vesicles in emulsions, suspensions, or polymer solutions using lasers. Measurements were performed using a Zetasizer Nano ZS (Malvern Instruments, Malvern, Worcestershire, UK). Measurements were performed according to the manufacturer's instructions.

[0263] The Zetasizer Nano ZS features an optical system with a 633nm green laser and a 173° scattering detector angle for particle size measurement. Although this instrument is capable of measurements under vacuum, vacuum was not applied to the sample during particle size and uniformity measurements in this study.

[0264] (Example 5): Determination of impurities Qualitative and quantitative analysis of impurities was performed by LC-MS using positive electrospray ionization (ESI+). The scan range covered 100–2000 m / z, corresponding to the decomposition products.

[0265] (Example 6): Viscosity measurement Viscosity was measured by rotation (measurement method: cone / plate) at a constant shear rate of 90.0 / second at 20°C.

[0266] (Example A) Impurity content in 5-ALA nanoemulsion gel after 6 months of storage (compared to a comparative formulation containing propylene glycol) Formulation 1 (containing 1% propylene glycol) was prepared by the method described in Example 2. Formulation 1 (without propylene glycol) was prepared by the method described in Example 3. 10 mL glass vials filled with either Formulation 1 or Formulation 2 were stored at 25°C or 40°C for 6 months. Impurities were detected by mass spectrometry using the method described in Example 5.

[0267] The results are shown in Figure 1. As expected, the ester of 5-ALA and propylene glycol (2-hydroxypropyl-δ-aminolevulinic acid) was not present in formulation 2, which does not contain propylene glycol. In comparative formulation 1 (containing propylene glycol), an impurity with m / z=246 was detected at an average amount of approximately 0.3% after storage at 25°C and at an average amount of approximately 1.2% after storage at 40°C. Unexpectedly, this impurity was also found to be present in formulation 2, which does not contain propylene glycol, at an average amount of approximately 0.15% after storage at 25°C and at an average amount of 0.6% after storage at 40°C.

[0268] This behavior is also shown in Figure 2. Chromatograms of known impurities (2-hydroxypropyl-δ-aminolevulinic acid; m / z=190) and impurities m / z=246 in Formulation 1 (containing propylene glycol) and Formulation 2 (not containing propylene glycol) after storage at 40°C for 3 months. Conclusion: 5-ALA formulations without propylene glycol are safer and more pharmacologically tolerable than comparatory 5-ALA formulations containing propylene glycol.

[0269] (Example B) ex vivo skin penetration test using human eyelid skin Formulation 1 (containing propylene glycol) was prepared by the method described in Example 2. Formulation 2 (not containing propylene glycol) was prepared by the method described in Example 3. the purpose Comparison of skin penetration characteristics of Formulation 1 (containing propylene glycol) and Formulation 2 (not containing propylene glycol) Evaluation of protoporphyrin IX (PpIX) levels in skin biopsy samples from fresh living skin samples after drug application. Experimental Procedure Test materials Human upper eyelid skin harvested from routine blepharoplasty (eyelid tightening) procedures. Propylene glycol-containing formulation 1 (batch number 166M, (1) in Figure 3) Propylene glycol-free formulation 2 (batch number 111M, (2) in Figure 3) method Skin tissue samples were cultured with each preparation for 0 hours, 1 hour, and 3 hours. Frozen section preparation, protoporphyrin IX extraction from skin sections. PpIX extraction from tissue and fluorescence analysis of PpIX content in the lysis solution. result The results are shown in Figure 3. Plot the average value of n=5 against (culture) time. PpIX concentration increases with the progression of culture time. Propylene glycol is a well-known penetration enhancer, but the novel formulation 2, which does not contain propylene glycol, achieved penetration results equivalent to those of comparative formulation 1, which contains propylene glycol (the formulation without propylene glycol is not inferior to the formulation containing propylene glycol). The differences between formulations at different time points were not statistically significant (Mann-Whitney U test). Conclusion: The propylene glycol-free 5-ALA formulation was found to be more stable and exhibit equivalent penetration effects than the comparative 5-ALA formulation containing propylene glycol (Example 1).

[0270] (Example C) In vitro release test of 5-aminolevulinic acid from Formulation 1 (containing propylene glycol) and Formulation 2 (not containing propylene glycol) Formulation 1 (containing propylene glycol) was prepared by the method described in Example 2 (batch 166M). Formulation 2 (not containing propylene glycol) was prepared by the method described in Example 3 (batch 110M). the purpose Development and evaluation of methods for in vitro release of ALA from gel formulations (in accordance with SUPAC-SS guidelines (FDA, SUPAC, 1997)) (GMP GLP) Experimental Procedure Test materials Synthetic film (Nylon, 0.20 μm) IVRT (in vitro release test) using a so-called "Franz diffusion cell," Figure 4. Propylene glycol-containing formulation 1 (comparative gel) Propylene glycol-free formulation 2 method Analytical methods for ALA quantification: HPLC-MS / MS Drug application, sampling, and analysis 300 mg ALA nanoemulsion was coated onto a nylon film (0.20 μm). The cells were cultured at 32±1℃ and sampled at t=20, 40, 60, 90, 120, and 150 minutes. Number of samples n=6 for each formulation (containing / not containing propylene glycol): 12 Franz cells ALA quantification in the receptor compartment: HPLC-MS / MS result The results are shown in Figure 5: Higuchi plot (Takeru Higuchi 1961: "Rate of release of medicaments from ointment bases containing drugs in suspension" (DOI: 10.1002 / jps.2600501018)), cumulative transport of 5-ALA (μg cm³) -2 ) to the square root of time (h -0.5 ) Plot. Formulation 2, which does not contain propylene glycol, has a higher transport volume. The standard deviations of the two curves completely overlap. There was no significant difference between the two formulations tested.

[0271] Statistical comparison of the slopes of emission curves: No significant difference was observed between the two formulations tested (TIFF2026512858000012.tif48165). Formulations that do not contain propylene glycol are considered to have the same or better efficacy as formulations containing propylene glycol in terms of drug release. Conclusion: The propylene glycol-free 5-ALA gel formulation is more stable and exhibits a comparable in vitro release profile than the comparative 5-ALA formulation containing propylene glycol (Example 1).

Claims

1. (a) (i) at least one aqueous component, (ii) (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol Carrier components containing Nanoemulsions containing, and (b) Activators containing a carboxylic acid group, or a derivative or salt of a carboxylic acid group A formulation containing, A formulation wherein the formulation contains less than 1% by weight of propylene glycol, or does not contain propylene glycol.

2. The formulation according to claim 1, wherein the formulation contains less than 0.9% by weight of propylene glycol, or does not contain propylene glycol.

3. The formulation according to claim 1 or 2, wherein the formulation essentially does not contain propylene glycol.

4. The formulation according to any one of claims 1 to 3, wherein the formulation does not contain propylene glycol.

5. The formulation according to any one of claims 1 to 4, wherein the formulation does not contain, essentially does not contain, an acyclic polyol having 2 to 5 carbon atoms, and contains less than 1% by weight, or 0.99% by weight, 0.95% by weight, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, or 0.1% by weight or less of an acyclic polyol having 2 to 5 carbon atoms.

6. The formulation according to any one of claims 1 to 5, wherein the formulation does not contain, essentially does not contain, a polyol having 2 to 12 carbon atoms, and contains less than 1% by weight, or 0.99% by weight, 0.95% by weight, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, or 0.1% by weight or less of a polyol having 2 to 12 carbon atoms.

7. The formulation according to any one of claims 1 to 6, wherein the at least one alcohol comprises at least three carbon atoms, preferably three, four, or five carbon atoms, and more preferably, the at least one alcohol is selected from the group consisting of 1-propanol, 2-propanol, and mixtures thereof.

8. The formulation according to any one of claims 1 to 7, wherein the at least one lipophilic component is selected from triglycerides and mixtures thereof, preferably the at least one lipophilic component is caprylic acid and / or capric acid triglyceride, or a mixture thereof.

9. The formulation according to any one of claims 1 to 8, 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-based surfactant.

10. A formulation according to any one of claims 1 to 9, having a total aqueous component of 50% to 99% by weight, preferably 70% to 95% by weight, more preferably 75% to 95% by weight, and even more preferably 80% to 90% by weight.

11. (a) 0.1% to 30% by weight, preferably 0.25% to 15% by weight, more preferably 0.25% to 10% by weight, more preferably 2% to 10% by weight or 3% to 8% by weight of the lipophilic component, and / or (b) Based on the total weight of the nanoemulsion (a), at least one alcohol in an amount of 0.1% to 10% by weight, preferably 0.5% to 5% by weight, more preferably 1% to 5% by weight, and even more preferably 1% to 3% by weight. A formulation according to any one of claims 1 to 10, comprising:

12. The formulation according to any one of claims 1 to 11, wherein the activator is a hydrophilic activator.

13. The formulation according to any one of claims 1 to 12, wherein the activator is a photosensitizer or a metabolic precursor thereof.

14. The formulation according to any one of claims 1 to 13, wherein the activator is 5-aminolevulinic acid, its derivatives, precursors, metabolites, and / or pharmaceutically acceptable salts.

15. The formulation according to any one of claims 1 to 14, wherein the activator is present in an amount of 0.1% to 25% by weight based on the total weight of the formulation.

16. The nanoemulsion contains nanovesicles, (a) When stored at 2–25°C for 1 month, 2 months, 3 months, 6 months, 12 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, or at least 12 months, and / or (b) When stored at 2–8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months, The formulation according to any one of claims 1 to 15, wherein the size of the nanovesicle is 500 nm or less, preferably 200 nm or less, and more preferably in the range of 5 nm to 200 nm.

17. (a) When stored at 2–25°C for 1 month, 2 months, 3 months, 6 months, 12 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, and / or (b) When stored at 2–8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, or at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months, A formulation according to any one of claims 1 to 16, wherein the polydispersity index is 0.4 or less.

18. A formulation according to any one of claims 1 to 17, comprising at least one 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 (alginate), tragacanth, povidone, gelatin, and mixtures thereof, and more preferably the gelling agent being selected from poloxamer, xanthan gum, and mixtures thereof.

19. A formulation according to any one of claims 1 to 18, which is essentially paraben-free.

20. The preparation according to any one of the claims in the preceding paragraph, used for pharmaceutical purposes, particularly for methods of treating and / or preventing skin diseases or skin conditions, according to any one of claims 1 to 19.

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