Nanoemulsion formulation with improved tacrolimus stability and skin penetration

Abstract

The present invention relates to a composition containing an oil-in-water nanoemulsion and a highly lipophilic macrolide lactone, such as tacrolimus, as an activator, dissolved in the oil-in-water nanoemulsion. In this formulation, tacrolimus can be completely dissolved rather than suspended, resulting in improved stability in terms of active ingredient content, pH, particle size, and particle size uniformity.

Description

Technical Field

[0001] The present invention relates to a water-in-oil nanoemulsion and a composition containing a highly lipophilic macrolide lactone such as tacrolimus dissolved in the nanoemulsion as an active ingredient. In this formulation, tacrolimus is completely dissolved rather than suspended, and the stability is improved from the viewpoints of the active ingredient content, pH, particle size, and particle size uniformity.

Background Art

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

[0003] Nanoemulsions are generally more thermodynamically stable than conventional emulsions, but are often unstable under stress conditions such as high temperature and freezing. Nanoemulsions are in a metastable state, and their structure often depends on the manufacturing process, so it is complicated to prepare them as pharmaceutical compositions that can be stored for a long time under various storage conditions. When destabilized, they may become non-uniform milky white or show phase separation. On the other hand, nanoemulsions may exhibit excellent texture and functional properties due to their very fine droplet or spherical particle size, so useful applications in the skin care field can be expected.

[0004] Nanoemulsions are often produced by mechanically crushing an oil phase in an aqueous phase in the presence of a surfactant. The extremely small size of the oil globules is often obtained by passing them through a high-pressure homogenizer or ultrasonic device at least once.

[0005] Tacrolimus (hereinafter also referred to as "TC") is a macrolide lactone molecule extracted from the soil bacterium Streptomyces tsukubaensis. In the pharmaceutical field, it is positioned as a calcineurin inhibitor with immunosuppressive effects. It is used as a topical agent to treat skin diseases involving the immune system, such as atopic dermatitis and psoriasis. TC is a molecule with a molecular weight of 804.03 g / mol and exhibits extremely high lipophilicity (logP>3). This means that it has lipophilicity more than six orders of magnitude (1 million times) greater than that of ALA. Due to this extremely high lipophilicity, TC has been incorporated into mixtures of mineral oil, paraffin, propylene carbonate, white petrolatum, and white wax. TC in aqueous compositions is formulated as a suspension, and it has been known that it has low stability in aqueous formulations (approximately 3 months at room temperature, approximately 9 months at 5°C).

[0006] Liquid formulations of TC, primarily using water-based formulations (such as nanoemulsions), have not yet been commercialized as finished pharmaceutical products by pharmaceutical companies. This is likely because solubilization and stabilization of TC in the aforementioned formulation system remain challenges. When using topical formulations of TC as pharmaceuticals, two further challenges exist. One is its high lipophilicity, which may hinder release into the skin from lipid-based formulations. The other is its weak ability to distribute into the watery regions of the skin (such as living cells). [Overview of the Initiative]

[0007] A first aspect of the present invention relates to a formulation comprising: (a) a nanoemulsion comprising (i) at least one aqueous component, (ii) a carrier component comprising (1) at least one lipophilic component, (2) at least one surfactant, and (3) at least one alcohol, and (b) an activator, the activator being a highly lipophilic macrolide lactone.

[0008] Another aspect of the present invention relates to a formulation of the first aspect for pharmaceutical use.

[0009] Another aspect of the present invention relates to a formulation of the first aspect used in a method for treating or preventing skin diseases, ophthalmic diseases, autoimmune diseases or conditions, or for preventing organ rejection after transplantation. [Brief explanation of the drawing]

[0010] The present invention is further illustrated by the following drawings and embodiments. [Figure 1] Solubility of tacrolimus. Top row: Solubility test using tacrolimus (time point 0). From left to right: TC2 (1 mg TC / mL phosphate buffer solution), TC3 (20 mg TC / g lipid phase or carrier component), TC4 (2 mg TC / mL BF200 nanoemulsion), TC5 (1 mg TC / mL BF200 nanoemulsion). Bottom row: Solubility test of tacrolimus after storage at 5°C and 25°C for 6 months. From left to right: TC4 stored at 5°C, TC4 stored at 25°C, TC5 stored at 5°C, TC5 stored at 25°C. [Figure 2] Tacrolimus assays in nanoemulsion formulations with different nominal TC content (0.1%, 0.01%), stored at 2-8°C, 25°C, or 40°C. [Figure 3] Particle size in nanoemulsion formulations with different nominal TC content (0.1%, 0.01%), stored at 2-8°C, 25°C, and 40°C. [Figure 4] Polydispersion index (PDI) of formulations with different nominal TC content (0.1%, 0.01%) after storage at 2-8°C, 25°C, or 40°C. [Figure 5] In vitro release volume of tacrolimus after 2.6 hours from a nanoemulsion formulation compared to commercially available tacrolimus ointment (SUPAC-SS). [Figure 6] Epidermal permeability of nanoemulsion formulation compared to commercially available tacrolimus ointment. Some of the data shown in the figure are the results of integrated experiments. [Modes for carrying out the invention]

[0011] Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methodologies, protocols, and reagents described herein, as these may vary. Furthermore, it should be understood that the terms used herein are for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0012] Preferably, the terms used herein shall, as far as possible, follow the definitions set forth in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, HGW, Nagel, B. and Koelbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[0013] Throughout this specification, multiple sources are referenced. Each source referenced herein (including all patents, patent applications, scientific publications, manufacturer specifications, instruction manuals, etc.) is incorporated in its entirety by reference, whether above or below.

[0014] The components of the present invention are described below. These components are listed together with specific embodiments, but it should be understood that they may be combined in any way and in any number to form additional embodiments. The examples and preferred embodiments described in various ways should not be construed as limiting the invention to only the explicitly described embodiments. This specification should be understood to support and encompass embodiments that combine the explicitly described embodiments with any number of the disclosed elements and / or preferred elements. Furthermore, unless the context indicates otherwise, any permutation and combination of all elements described in this application should be considered as disclosed by the description of this application.

[0015] In this specification and subsequent claims, unless the context clearly requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” should be understood to imply the elements, steps, or groups of elements or steps described, but not to exclude other elements, steps, 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.

[0016] The formulation of pharmaceutical compositions is an extremely complex process, requiring consideration of various aspects such as pH, solubility, polymorphism, applicability, and the overall stability of the pharmaceutical composition. Furthermore, the active ingredient (API), additives, interactions between all components, and the advantages and limitations of the manufacturing process must be considered. In oil-in-water nanoemulsion formulations, there are two distinct phases where stabilization and patient suitability are required: one is a hydrophobic carrier component that typically acts as a carrier (responsible for stabilizing and releasing the API), and the other is an aqueous component. These elements work together to form a complex formulation containing numerous components. One particularly attractive property of oil-in-water nanoemulsion formulations is their ability to enhance the penetration of active ingredients.

[0017] The prior art describes an aqueous formulation of TC as a suspension, and its stability is short (about 3 months at room temperature and up to 9 months at 5°C).

[0018] The prior art does not teach an aqueous formulation that can solubilize tacrolimus, which is a highly lipophilic active agent. Furthermore, the prior art does not teach an aqueous formulation (solution or suspension) of tacrolimus having long-term stability exceeding 24 months.

[0019] As described above, nanoemulsions tend to coalesce under certain circumstances such as exposure to extreme temperature differences, which increases the droplet size and impairs the quality of the nanoemulsion.

[0020] From these aspects, it is clear that the design and formulation of compositions having high permeability and an improved impurity profile are highly desired.

[0021] As used herein, "active agent" and "active ingredient" are used interchangeably. As used herein, "active agent" includes pharmaceutical active agents (also referred to herein as "pharmaceutical active agents" or "pharmaceutical active ingredients", "API") and cosmetic active agents (also referred to herein as "cosmetic active agents"). As used herein, a pharmaceutical active ingredient defines a chemical, biological, mineral or other entity or component responsible for the therapeutic effect (pharmacological, physiological, physical effects, etc.) in a product. As used herein, a cosmetic active ingredient defines a chemical, biological, mineral or other entity or component responsible for the cosmetic effect in a product. The active ingredient may be a plant extract. The active agent may exist as a pharmaceutically acceptable salt. The active agent may exist as a cosmetically acceptable salt.

[0022] The formulations of the present invention have two phases: (i) an aqueous phase or aqueous component, (ii) a lipid phase or carrier component and include.

[0023] The 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 A formulation containing, The present invention relates to a formulation in which the activator is a highly lipophilic macrolide lactone.

[0024] In the context of this specification, the term "highly lipophilic" refers to a compound having a logP value of at least 3, where P is the octane-water partition coefficient.

[0025] Preferably, the activator has a logP value of 3 or higher, for example, 3.0 to 7.0 or 3.0 to 5.0.

[0026] In this specification, "macrolide lactone" refers to a compound containing or primarily comprising a macrocyclic lactone ring. One or more deoxy sugars may be bonded to the lactone ring. The macrolactone ring preferably contains at least one cyclic half acetal, one 1,2-dicarbonyl substructure, and one piperidine substructure. Preferably, the macrolactone ring contains two methoxy ligands at positions 14 and 16. Preferably, the macrolide lactone is not halogenated. Preferably, the activator has immunosuppressive properties.

[0027] Particularly preferred is the activator being tacrolimus, pimecrolimus, everolimus, or sirolimus, preferably tacrolimus, its derivatives, isomers, tautomers, precursors, metabolites, hydrates, and / or pharmaceutically acceptable salts.

[0028] Tacrolimus, also referred to herein as "TC," is identified by CAS number 104987-11-3 and has the following chemical formula: It contains the file JPEG2026511974000002.jpg5864.

[0029] Tacrolimus is a macrolide lactone molecule isolated from the soil bacterium Streptomyces tsukubaensis. In the pharmaceutical field, it is positioned as a calcineurin inhibitor with immunosuppressive effects. It is used topically to treat skin diseases involving the immune system, such as atopic dermatitis and psoriasis. TC is a molecule with a molecular weight of 804.03 g / mol and has extremely high lipophilicity (logP > 3). That is, it exhibits lipophilicity six orders of magnitude higher than 5-aminolevulinic acid (ALA). Due to this extremely high lipophilicity, TC has been incorporated into mixtures of mineral oil, paraffin, propylene carbonate, white petrolatum, and white wax. It has long been known that TC has low stability in aqueous formulations (approximately 90 days at room temperature), and TC formulations in mainly water-based semi-solid systems (such as emulsions) have not been used in pharmaceutical applications until now, probably because solubilization and stabilization of TC in such formulations are challenges. There are two challenges to the pharmaceutical use of TC. Firstly, it has high lipophilicity, which may hinder its release from lipid-based formulations into the skin. Secondly, it has poor distribution ability to the watery areas of the skin (such as living cells).

[0030] A precursor of TC is, for example, pre-tacrolimus, with the following chemical formula: It contains the file JPEG2026511974000003.jpg5963.

[0031] Sirolimus is identified by CAS number 53123-88-9 and has the following chemical formula: It contains the file JPEG2026511974000004.jpg5256.

[0032] A precursor of sirolimus is, for example, pre-sirolimus, which has the following chemical formula: It contains the file JPEG2026511974000005.jpg5256.

[0033] Pimecrolimus is identified by CAS number 137071-32-0. Everolimus is identified by CAS number 159351-69-6. In a preferred embodiment, the formulation is a pharmaceutical formulation.

[0034] 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, lotion refers to a low-viscosity topical formulation intended for application to the skin. Because lotions have a high water content, they have a lower viscosity than creams or gels. 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.

[0035] Those skilled in the art know appropriate methods for measuring viscosity. Preferably, viscosity is measured by the method described in the Examples section.

[0036] This formulation may be for external, ophthalmic, or systemic use. In a preferred embodiment, this formulation is for external use.

[0037] In preferred embodiments of the formulations described in the present invention, the aqueous component comprises or forms an aqueous phase.

[0038] In preferred embodiments of the formulations described in the present invention, the carrier component comprises or is composed of nanovesicles. The carrier component is also called the lipid phase of the nanoemulsion. Preferably, the activator is dissolved in the lipid phase of the nanovesicles; that is, the activator is dissolved in the lipid phase of the nanoemulsion.

[0039] The activator may exist as a salt, hydrate, or derivative. 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 can deliver active ingredients such as tacrolimus more efficiently, and are therefore becoming increasingly important in the medical and pharmaceutical fields.

[0040] In this specification, “aging” refers to alteration, decomposition, and / or deterioration of a formulation that affects its chemical and physical stability, particularly during storage under stressful conditions. Such physical or chemical changes due to storage include, but are not limited to, Ostwald aging, aggregation, coalescence, and / or crushing, which may cause changes in vesicle size or polydispersity index.

[0041] The inventors discovered that tacrolimus can be dissolved rather than suspended in the aqueous formulation of the present invention, which contains a nanoemulsion.

[0042] Furthermore, the inventors discovered that the formulation of the present invention is surprisingly stable and resistant to degradation over time. In particular, the formulation of the present invention remains stable in terms of TC content, particle size, and particle size distribution even after being stored for 24 months at, for example, 2 to 8°C.

[0043] In this specification, when a period is described as "one month, two months, three months," etc., this means that embodiments such as "at least one month, at least two months, at least three months" are included.

[0044] 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). Nanoemulsions are monophase and may be transparent and / or slightly milky white. The nanoemulsion of the present invention is 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 diameter 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.

[0045] 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. A lipid vesicle with an average size (see above, e.g., less than 500 nm, less than 200 nm, less than 100 nm) composed of a single layer of surfactant and a lipid core. In the present invention, the size of a nanovesicle 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.

[0046] In this specification, the term “nanoparticles” is distinguished from “nanopecicles” and refers to solid particles not described in this invention. The formulations of this 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 a size 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, formulations that are essentially nanoparticle-free, measured by dynamic light scattering, include those with a diameter of less than 100 nm.

[0047] In this specification, “topical use” or “topical treatment” of the formulations of the invention means application to a specific site of the body (especially the human body). This includes, but is not limited to, the administration of the formulation to a body surface such as the skin or mucous membranes. Topical use is transdermal, meaning that the formulation is administered directly to the skin. In particular, topical use is a pharmaceutical application.

[0048] In this specification, “systemic use” or “systemic treatment” of the formulation of the invention means an application in which the active agent is distributed throughout the body via the blood or lymphatic system, for example, after injection or oral ingestion.

[0049] In this specification, the “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 of less than 100 nm, preferably less than 50 nm, and more preferably in the range of 20 nm 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.

[0050] "Stability" may also refer to the absence of processes that lead to the 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.

[0051] Furthermore, "stability" may refer specifically to the stability of the content of the active ingredient, such as tacrolimus. The content of the active ingredient 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 active ingredient remains.

[0052] In the formulation of the present invention, the content of the active ingredient is (i) After storage at 40°C for one month, at least 90%, and / or (ii) After storage at 25°C for 3 or 6 months, at least 90%, and / or (iii) After storage at 2-8°C for 12, 18, or 24 months, at least 90% That's fine.

[0053] In the present invention, the activator of the present invention may be stable at 2 to 8°C or about 5°C for at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 24 months.

[0054] In the present invention, 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, or at least 24 months at 2 to 25°C, 2 to 8°C, 15 to 25°C, 25°C, or about 5°C.

[0055] When the formulation of the present invention is stored at 40°C for 3 months, 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 100 nm.

[0056] When the formulation of the present invention is stored at 25°C for 24 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 100 nm.

[0057] Preferably, (a) When stored at 2-25°C for 1 month, 2 months, 3 months, or 6 months, (b) When stored at 2-8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months, The activator content is 80% or more, preferably 85% or more, and more preferably 90% or more.

[0058] Preferably, the nanoemulsion contains nanovesicles. (a) If stored at 2-25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months, (b) When stored at 2-8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, The nanovesicles have a size of 500 nm or less, preferably 200 nm or less, and more preferably in the range of 5 nm to 100 nm.

[0059] Preferably, (a) If stored at 2-25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months, (b) When stored at 2-8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months, The polydispersity index of the formulation is 0.4 or less.

[0060] 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 the polydispersity index. These parameters are well known to those skilled in the art and are widely used in the art to characterize particles or vesicles in emulsions, suspensions and / or polymer solutions.

[0061] 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.

[0062] In the formulations described herein, the total aqueous component may be present in an amount of 50% (w / w) to 99% by weight, preferably 70% to 95% by weight, more preferably 75% to 95% by weight, or 80% to 95% by weight, based on the total weight of the nanoemulsion (a).

[0063] In this specification, “w / w” 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).

[0064] The aqueous component may contain at least one pH buffer. Any suitable buffer may 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.

[0065] The pH of the aqueous component may be in the range of 2 to 9. Preferably, the pH of the aqueous component may be in the range of 2 to 6, for example 2, 3, 4, 5 or 6, more preferably in the range of 3 to 6, for example 3, 4, 5 or 6, or in the range of 3 to 5, for example 3, 4 or 5. In other embodiments, the pH of the aqueous component may be in the range of 4 to 10, or in the range of 5 to 7, preferably about 7.4.

[0066] If the formulation is for topical or oral use, the pH of the formulation is 2 to 7, preferably 2 to 6, more preferably 3 to 5. If the formulation is for parenteral use or ophthalmic use, the pH of the formulation is 4 to 10, or 5 to 7, preferably about 7.4.

[0067] In the formulations described herein, at least one lipophilic component may be selected from triglycerides and mixtures thereof.

[0068] 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). Examples of suitable vegetable and animal oils include sunflower oil, soybean oil, peanut oil, rapeseed oil, fish oil, and / or whale oil.

[0069] In the formulations described herein, at least one lipophilic component may be present in an amount of 0.1% to 30% (by weight) based on the total weight of the nanoemulsion (a). Preferably, this amount is 0.25% to 15% (by weight), more preferably 0.25% to 10% (by weight), more preferably 0.5% to 8% by weight, or 3% to 8% by weight. It is also preferable that at least one lipophilic component be present in an amount of 10% to 30% by weight relative to the total weight of the nanoemulsion (a), more preferably 15% to 30%, or 10% to 20%.

[0070] In the formulations described herein, at least one surfactant may be any suitable surfactant well known to those skilled in the art.

[0071] Surfactants (also called surfactants or emulsifiers) are well known in the art and include all 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 terms of hydrophilic / lipophilic balance (HLB), which indicates their affinity for water or oil. Low HLB (e.g., HLB=1) refers to lipophilic emulsifiers, and high HLB (e.g., HLB=20) refers to hydrophilic emulsifiers. Generally, lipophilic emulsifiers are used in water-oil emulsions, and hydrophilic emulsifiers are used in water-in-oil emulsions. Those skilled in the art can identify preferred bases for a composition and emulsifiers or mixtures thereof that are suitable for the purpose. In certain emulsions, a combination of emulsifiers may be advantageous.

[0072] Suitable film-forming surfactants include phospholipids, lysophospholipids, ceramides, and / or mixtures thereof. Preferably, the phospholipids are lecithin or cephalin derived from soybeans or chicken eggs. At least one surfactant is preferably a phospholipid, more preferably lecithin, and most preferably soy lecithin.

[0073] In the formulations described herein, phospholipids, particularly phosphatidylcholine, lysophospholipids, ceramides and / or mixtures thereof, may be present in an amount of 0.1% to 10% (by weight) based on the total weight of the nanoemulsion (a). Preferably, 0.15% to 5% (by weight), more preferably 0.2% to 3% by weight or 0.2% to 4% by weight, and most preferably 2.5% to 4% by weight.

[0074] Preferably, the phosphatidylcholine content of the lecithin is at least 80% by weight, more preferably at least 90% by weight, and most preferably at least 94% by weight. The quality of the lecithin, i.e., its phosphatidylcholine content, plays a 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.

[0075] 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-alkyl-β-aminopropionates, alkylammonium phosphate compounds, and / or amine-N-oxides. Suitable copolymer building blocks include, for example, propylene oxide. In the present invention, nonionic surfactants are particularly preferred as O / W emulsion-forming surfactants.

[0076] In preferred embodiments, the surfactant is a polyoxyethylene-based surfactant. In the formulations described herein, at least one surfactant may be any polyoxyethylene-based surfactant. Suitable nonionic surfactants may be selected from the group consisting of fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, alkyl polyglucosides, fatty acid glucamides, fatty acid polyglycol ethers, ethylene oxide-propylene oxide-block polymers, polyglycerol fatty acid esters, fatty acid alkanolamides, and (ethoxylated) sorbitan fatty acid esters (sorbitan). Particularly preferred ethoxylated sorbitan fatty acid esters are polyoxyethylene sorbitan monooleate, most preferably Polysorbate 80.

[0077] At least one surfactant, such as a polyoxyethylene-based surfactant, is more preferably 0.2% to 5% by weight, most preferably 1% to 5% by weight, or 0.5% to 5% by weight, relative to the total weight of the nanoemulsion (a).

[0078] 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, particularly Polysorbate 80, and may form a nanoemulsion.

[0079] At least one surfactant may be a sugar-based surfactant. Sugar-based surfactants are a group of nonionic surfactants in which a hydrophobic tail is attached to a hydrophilic sugar. One representative substance of this class is n-dodecyl-β-D-maltoside, a type of maltoside surfactant named for the maltose sugar unit used. An example of a pyranoside surfactant is n-octyl-β-D-thioglucopyranoside. This class uses pyranose as the sugar unit. Examples of glycoside surfactants include octyl glucoside, decyl glucoside, and lauryl glucoside. An example of a polysaccharide surfactant is digitonin.

[0080] Another very important group of sugar-based surfactants is Tween surfactants. The most well-known are Tween 20 (also referred to as Polysorbate 20 in this paper) and Tween 80 (also referred to as Polysorbate 80 in this paper). These surfactants are based on sorbitan sugar and are therefore generally called polysorbate surfactants. Three oligo (ethylene glycol) side chains of different lengths are bonded to the sugar, increasing 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 four oligo (ethylene glycol) tails. In Tween 20, this fatty acid is lauric acid, and in Tween 80, it is oleic acid.

[0081] 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.

[0082] In some embodiments, at least one surfactant is phosphatidylcholine.

[0083] In some embodiments, the formulation contains 0.5% to 5% by weight, preferably 1% to 4% by weight, and more preferably 1.2% to 3.5% by weight of phosphatidylcholine.

[0084] In some embodiments, the formulation contains 0.1% to 10% by weight, preferably 0.15% to 5% by weight, and more preferably 0.25% to 4.5% by weight of phosphatidylcholine.

[0085] In a preferred embodiment, at least one alcohol contains at least three carbon atoms.

[0086] 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 alcohols having 5 carbon atoms are 1-pentanol and / or 4-methyl-2-pentanol. Suitable alcohols having 4 carbon atoms include 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. 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.

[0087] 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 0.5% to 5% (by weight), and more preferably 1% to 2% (by weight).

[0088] The formulations described herein may contain a gelling agent. Any suitable gelling agent may 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.

[0089] The gelling agent is preferably selected from poloxamer, xanthan gum, and / or mixtures thereof.

[0090] It is also preferable that the gelling agent be xanthan gum.

[0091] It is also preferable that the gelling agent be poloxamer.

[0092] 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 products 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, the preferred poloxamer is Poloxamer 407.

[0093] 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.

[0094] The formulations described herein may contain one or more preservatives. Any suitable preservative or a mixture thereof may be used. Suitable preservatives are well known to those skilled in the art. The preservative may be selected from benzoates, tocopherol or its derivatives and any mixture thereof, citric acid, EDTA, potassium sorbate, vitamin C and / or its derivatives and any mixture thereof, and the preservative is preferably sodium benzoate. Suitable aqueous mixtures of sodium benzoate and potassium sorbate are commercially available, for example, Euxyl® K 712 preservative (Ashland). These components may be part of the aqueous components and / or nanovesicles.

[0095] The preservative content in the formulations described herein is in the range of 0.01% to 10% by weight, 0.01% to 7% by weight, 0.01% to 5% by weight, or 0.01% to 3% by weight, preferably 0.2% to 2% by weight or 0.1% to 2% by weight, and more preferably 0.2% to 1.5% by weight.

[0096] The formulation of the present invention may be a gel formulation. Herein, "gel" refers to a two-phase elastic colloidal material in which a dispersion is incorporated into a solid phase composed of a gelling agent. Suitable gelling agents, such as xanthan gum, are described herein.

[0097] The formulations of the present invention may be provided filled in containers or dispensers. 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.

[0098] The container or dispenser may contain a propellant provided for pressurizing the container or dispenser. Any suitable propellant may 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.

[0099] In some embodiments, the formulation contains a propellant and is housed in a pressurized vessel. Remarkably, the formulation of the present invention, when contained in a pressurized container, exhibits high foaming ability and forms stable bubbles (with a long collapse time) when released from the pressurized container, even in the absence of fatty alcohols or other foaming aids.

[0100] Remarkably, the formulation of the present invention, when filled into a pressurized container, exhibits high stability with respect to nanovesicle size, even in the absence of a gelling agent or in the presence of only a low concentration of a gelling agent.

[0101] Remarkably, the formulation of the present invention, sealed in a pressurized container, is extremely stable in terms of the concentration of the active ingredient, even when no gelling agent is present or when only a low concentration of gelling agent is present.

[0102] The formulations of the present invention, when filled into pressurized vessels, exhibit remarkable resistance to changes over time under stress conditions with respect to API content and nanoemulsion vesicle size compared to other formulations. In this specification, “petrolatum” refers to a semi-solid mixture of hydrocarbons obtained from petroleum distillation. The hydrocarbons constituting petrolatum mainly consist of at least 25 carbon atoms. The CAS number for petrolatum is 8009-03-8. Preferably, formulations of the first aspect of the present invention are essentially petrolatum-free.

[0103] The formulation of the present invention may be prepared as an effervescent formulation.

[0104] The formulations of the present invention may be prepared as pressurized formulations, which are provided with a propellant for pressurizing the formulation. Any propellant described herein may be used.

[0105] The formulation of the present invention may be prepared as a pressurized foaming formulation. In this case, a propellant for pressurizing the formulation is provided. Any propellant described herein may be used.

[0106] The formulation of the present invention may be provided in a foaming dispenser as described herein. The foaming dispenser includes a container, the container containing the formulation and propellant as described herein. The propellant is provided to pressurize the foaming dispenser. Any suitable propellant as described herein may be used. A foaming device is attached to the container. In particular, the formulation is prepared as a foaming formulation. The foaming device may include a valve for dispensing and measuring the formulation and a push button for operating the valve. When the push button is operated, the formulation may be released and form a foam. Suitable dispensers are well known to those skilled in the art.

[0107] The formulation of the present invention may be provided in a spray dispenser as described herein. The spray dispenser comprises a container and the formulation and propellant described herein within the container. The propellant is provided to pressurize the spray dispenser. Any suitable propellant may be used as described herein. A spray generating device is attached to the container. In particular, the formulation is prepared as a sprayable formulation.

[0108] The present invention also provides a form comprising the formulation of the present invention, as described herein.

[0109] In a preferred embodiment, the activator in the formulation of the present invention is a highly lipophilic activator such as tacrolimus.

[0110] The activator may be contained in amounts of 0.001% to 25%, 20%, 15%, 10%, or 5% (by weight) based on the total weight of the formulation. In particular, the activator may be contained in amounts of 0.001% to 10%, 0.005% to 5%, or 0.01% to 0.5% (by weight) based on the total weight of the formulation.

[0111] In some embodiments, the formulation is a topical formulation, and the activator is present in an amount of 0.001 to 0.5% by weight, preferably 0.005 to 0.2% by weight, and more preferably 0.01 to 0.1% by weight, based on the total weight of the formulation. In some embodiments, the formulation is a systemic formulation, and the activator is present in an amount of 0.005 to 25% by weight, preferably 0.01 to 10% by weight, more preferably 0.01 to 5% by weight, and even more preferably 0.01 to 2% by weight, based on the total weight of the formulation. The systemic formulation may be an injectable formulation or an oral formulation. In some embodiments, the systemic formulation is diluted with a pharmaceutically acceptable buffer before injection to a final concentration of 0.01 to 1% by weight, based on the total weight of the formulation.

[0112] In some embodiments, the formulation is an ophthalmic formulation, particularly an eye drop, and the activator is present in an amount of 0.001 to 0.5% by weight, preferably 0.005 to 0.2% by weight, and more preferably 0.01 to 0.1% by weight, based on the total weight of the formulation.

[0113] In a preferred embodiment, the formulation of the present invention is essentially free of fatty alcohols. In the context of this specification, the expressions “essentially does not contain” or “essentially free” mean that the formulation contains none of the compound, or less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, less than 0.1% by weight, 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. Fatty alcohols have been reported to act as foaming agents. These are used in prior art formulations, particularly foaming formulations.

[0114] Preferably, the formulation is essentially free of fatty alcohols and essentially free of fatty acids. In this specification, “fatty alcohol” means an alcohol having at least six carbon atoms, and usually having between six and twenty-eight carbon atoms. Fatty alcohols may be saturated or unsaturated, and may have a linear or branched structure. Fatty alcohols are usually linear primary alcohols. As used herein, the term “fatty alcohol” refers to fatty alcohols in their standalone form and does not include esters containing fatty alcohols.

[0115] In the context of this specification, the term “fatty acid” refers to a carboxylic acid having an aliphatic chain with at least six carbon atoms, and usually between six and 28 carbon atoms. Fatty acids are saturated or unsaturated, linear or branched. The majority of naturally occurring fatty acids have linear carbon chains. As used herein, the term “fatty acid” refers to fatty acids in their individual forms and does not include esters containing fatty acids.

[0116] In a preferred embodiment, the formulation either does not contain fatty alcohol (in its standalone form, i.e., as an isolated molecule) or contains less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, less than 0.1% by weight, 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 of fatty alcohol (in its standalone form, i.e., as an isolated molecule).

[0117] In particular, in preferred embodiments, the formulation either does not contain fatty acids and fatty alcohols (in their individual form, i.e., as isolated molecules) or contains less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, less than 0.1% by weight, 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 of fatty acids and fatty alcohols (in their individual form, i.e., as isolated molecules).

[0118] More preferably, the formulation is essentially free of foaming agents. In particular, the formulation is free of foaming agents or contains a foaming agent in amounts of less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, less than 0.1% by weight, 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.

[0119] In this specification, the term “foaming agent” relates to compounds that can increase the foaming ability of a formulation and / or stabilize the foam. In particular, the term “foaming agent” relates to fatty acids and fatty alcohols having at least six carbon atoms. In particular, the formulations of the present invention (a)(i) an aqueous component present in an amount of 70-95% by weight relative to the total weight of nanoemulsion (a), (ii) Based on the total weight of (1) nanoemulsion (a), 1 to 5% by weight of at least one phospholipid, (2) Based on the total weight of nanoemulsion (a), 2 to 10% by weight of at least one polyoxyethylene-based surfactant, (3) Based on the total weight of nanoemulsion (a), 1 to 5% by weight of C3-C5 alcohol, and (4) Based on the total weight of nanoemulsion (a), 2 to 10% by weight of triglycerides Nanovesicles containing Nanoemulsions containing (b) Based on the total weight of the formulation, 0.01 to 1% by weight of a highly lipophilic macrolide lactone or a combination thereof, (c) Based on the total weight of the formulation, at least one preservative in an amount of 0.1 to 10% by weight, preferably 0.1 to 5% by weight, more preferably 0.1 to 2% by weight, (d) Optionally, 0.1 to 30% by weight, preferably 0.1 to 20% by weight, and more preferably 0.1 to 10% by weight of at least one gelling agent based on the total weight of the formulation. This may include or consist of these, The pH of the formulation is preferably 2 to 7. Preferably, the formulation may contain two types of surfactants, and more preferably, soy lecithin and Polysorbate 80.

[0120] 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.

[0121] In particular, the formulation of the present invention (a)(i) an aqueous component present in an amount of 70-95% by weight relative to the total weight of nanoemulsion (a), (ii) Based on the total weight of (1) nanoemulsion (a), 1 to 5% by weight of at least one phospholipid, (2) Based on the total weight of nanoemulsion (a), 2 to 10% by weight of at least one polyoxyethylene-based surfactant, (3) Based on the total weight of nanoemulsion (a), 1 to 5% by weight of C3-C5 alcohol, and (4) Based on the total weight of nanoemulsion (a), 2 to 10% by weight of triglycerides Nanovesicles containing Emulsion of nanovesicles containing (b) Based on the total weight of the formulation, 0.01 to 1% by weight of a highly lipophilic macrolide lactone, preferably tacrolimus, (c) Based on the total weight of the formulation, at least one preservative in an amount of 0.1 to 10% by weight, preferably 0.1 to 5% by weight, more preferably 0.1 to 2% by weight, (d) Optionally, at least one gelling agent in an amount of 0.1 to 30% by weight, preferably 0.1 to 20% by weight, and more preferably 0.1 to 10% by weight, based on the total weight of the formulation. It may include, essentially consist of, or consist of The pH of the formulation is preferably 2 to 7. Preferably, the formulation may contain two types of surfactants, and more preferably, it may contain soy lecithin and Polysorbate 80.

[0122] 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. The formulation may also contain further components selected from EDTA, α-tocopheryl acetate, and citric acid. These components may be part of an aqueous component and / or a nanovesicle.

[0123] In a preferred embodiment, the formulation of the present invention is (a)(i) an aqueous component present in an amount of 70-95% by weight relative to the total weight of nanoemulsion (a), (ii) Based on the total weight of (1) nanoemulsion (a), 1 to 5% by weight of at least one phospholipid, (2) Based on the total weight of nanoemulsion (a), 2 to 10% by weight of at least one polyoxyethylene-based surfactant, (3) Based on the total weight of nanoemulsion (a), 1 to 5% by weight of C3-C5 alcohol, and (4) Based on the total weight of nanoemulsion (a), 2 to 10% by weight of triglycerides Nanovesicles containing Nanoemulsions containing (b) Based on the total weight of the formulation, 0.01 to 1% of a pharmaceutically acceptable highly lipophilic macrolide lactone, preferably a calcineurin inhibitor such as tacrolimus. (c) Optionally, 0.5 to 6% by weight of at least one gelling agent based on the total weight of the formulation. (d) Optionally, 0.1 to 2% by weight of at least one preservative, based on the total weight of the formulation, and (e) Propellant It may include or consist of, The formulation is contained in a pressurized container, a propellant is supplied to pressurize the container, and the pressurized formulation is provided.

[0124] The present invention also, (i) Soy lecithin 16-19% by weight (ii) Polysorbate 80 in 32-36% by weight (iii) Caprylic / capric triglyceride in a quantity of 32-36% by weight, (iv) Isopropanol 12-16% by weight relating to nanovesicles that include, essentially consist of, or consist of.

[0125] 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. It includes, essentially consists of, or consists of.

[0126] 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, a 5-100 mM phosphate buffer solution, pH 2-8, preferably pH 2-7, more preferably pH 2-5, up to 100% by weight. The present invention relates to nanoemulsions that include, essentially consist of, or consist of the following.

[0127] 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) Phosphate buffer solution (5 mM to 100 mM, preferably 10 mM to 50 mM), pH 6, up to 100% by weight It includes, essentially consists of, or consists of.

[0128] The above nanoemulsion is referred to herein as "BF200". The 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. One example of a method for producing the BF200 formulation is described in Example 1.

[0129] Another preferred nanoemulsion of the present invention is (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) up to 100% by weight. It includes, essentially consists of, or consists of.

[0130] This nanoemulsion is referred to herein as "BF215". The BF215 nanoemulsion can be 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. One example of a method for producing the BF215 formulation is described in Example 1.

[0131] Another preferred nanoemulsion essentially includes 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% by weight. It includes, essentially consists of, or consists of.

[0132] This nanoemulsion is referred to herein as "BF220". The BF220 nanoemulsion is obtained by contacting a mixture of components (a) to (d) (20% by weight total) with a 10 mM phosphate buffer aqueous solution (pH 6, 80% by weight) under conditions that enable the formation of a nanoemulsion. One example of a method for producing the BF220 formulation is described in Example 1.

[0133] All definitions and embodiments described in the first aspect also apply to all other aspects described herein, where applicable.

[0134] Yet another aspect of the present invention relates to formulations for pharmaceutical use as described herein.

[0135] Yet another aspect of the present invention relates to formulations for pharmaceutical use as described herein.

[0136] In yet another aspect, the present invention relates to a method for treating and / or preventing skin diseases, ophthalmic diseases, autoimmune diseases or conditions, or to a formulation described herein used for the prevention of organ rejection after transplantation.

[0137] 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.

[0138] The skin diseases or conditions treated with the formulations described herein may be selected from a group consisting of inflammatory, neoplastic, proliferative, infectious, and / or autoimmune diseases or conditions, and / or their skin manifestations, and / or diseases associated with solitary lesions or lesional areas, neoplastic, proliferative, and / or inflammatory changes.

[0139] 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.

[0140] The aforementioned skin disease or condition may be an autoimmune skin disease or condition. The autoimmune skin disease or condition, or skin manifestation of an autoimmune condition, 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. Furthermore, the diseases or conditions treated with the formulations described herein are selected from organ rejection reactions following organ transplantation (such as heart, kidney, liver, or lung transplants).

[0141] The eye diseases or conditions treated with the formulations described herein may be selected from the group consisting of keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), dry eye, and corneal endothelial rejection after corneal transplantation.

[0142] In yet another aspect, the present invention relates to a method for preparing the formulations described herein, (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) A step of mixing an activator into the lipid phase, (c) A step of contacting the mixture obtained in step (a) with an aqueous component under conditions that enable the formation of a nanoemulsion. Includes.

[0143] In step (b), the conditions enabling the formation of the nanoemulsion include mixing of both phases at an appropriate temperature and a stirring method for forming nanovesicles. Those skilled in the art are familiar with appropriate temperatures and stirring conditions. Vesicle sizes of 500 nm or less or 300 nm or less can be obtained, 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).

[0144] The method of the present invention includes a step of adding a lipid-soluble surfactant until it is completely dissolved in the lipid phase. Preferably, the surfactant is tacrolimus.

[0145] The method for preparing the pharmaceutical formulation of the present invention is: (i) Addition of a gelling agent, and / or (ii) Addition of preservatives It may also include the following.

[0146] In yet another embodiment, the present invention is a dispenser product or container product containing the formulation described herein. In the 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 be a metering dispenser, a foam dispenser, or a spray dispenser.

[0147] The container or foam dispenser or spray dispenser may contain a propellant provided for pressurizing the container or foam dispenser or spray dispenser. Any suitable propellant may 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.

[0148] A dispenser product is a foam dispenser or spray dispenser product including a foam dispenser or spray dispenser as described herein, wherein the foam dispenser or spray dispenser includes a container, the container containing the formulation and propellant as described herein. The propellant is provided to pressurize the foam dispenser or spray dispenser. Any suitable propellant as described herein may be used. A foam generating device or spray generating device is attached to the container. In particular, the formulation is prepared as a foaming formulation.

[0149] In yet another embodiment, the formulation of the present invention may be used to manufacture pharmaceuticals for the local or systemic treatment and / or prevention of skin diseases, ophthalmic diseases, or autoimmune diseases or conditions in a subject, or for the prevention of organ rejection after transplantation.

[0150] Another embodiment is a method for treating and / or preventing a skin disease or condition in a subject. The 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 condition described herein.

[0151] This 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 Carrier components containing Nanoemulsions containing, and (b) Activators A formulation containing, The formulation wherein the activator is a highly lipophilic macrolide lactone, preferably tacrolimus. (Item 5) The formulation according to any one of the preceding paragraphs, wherein the at least one alcohol comprises at least three carbon atoms, preferably three, four, or five carbon atoms. (Item 7) The formulation according to any one of the preceding items, wherein the activator is present in an amount of 0.001 to 5% by weight, preferably 0.005 to 1% by weight, and more preferably 0.01 to 1.0% by weight, based on the total weight of the formulation. (Item 12) The preparation described in any one of the preceding paragraphs, wherein the preparation is a pharmaceutical preparation. (Item 13) The preparation described in either of the preceding paragraphs, wherein the preparation is for external use or oral use. (Item 14) The preparation according to any one of the preceding items, wherein the activator is dissolved in a carrier component. (Item 15) The formulation according to any one of the preceding items, wherein the logP value of the activator is 3 or greater. (Item 16) The formulation according to any one of the preceding items, wherein the nanoemulsion contains nanovesicles, and when stored at 40°C for one month, two months, or three months, the size of the nanovesicles is 500 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. (Item 17) The formulation according to any one of the preceding items, wherein the nanoemulsion contains nanovesicles, and when stored at 25°C for 6 months, 12 months, 18 months, or 24 months, the size of the nanovesicles is 500 nm or less, preferably in the range of 5 nm to 200 nm, more preferably in the range of 5 nm to 100 nm. (Item 18) The formulation according to any one of the preceding items, 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 the preceding paragraphs, wherein the aqueous component comprises at least one pH buffering agent. (Item 20) The formulation of item 19 above, wherein the pH buffer is selected from the group consisting of citrate, phosphate, acetate, and carbonate. (Item 21) A topical or oral preparation having a pH of 2 to 7, as described in any one of the preceding items. (Item 22) An injectable or ophthalmic preparation having a pH of 5 to 9, as described in any one of the preceding items. (Item 23) The formulation according to any one of the preceding paragraphs, wherein at least one lipophilic component is selected from triglycerides and mixtures thereof. (Item 24) A formulation according to any one of the preceding paragraphs, wherein 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 the preceding items, wherein 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 the preceding paragraphs, 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 the preceding paragraphs, wherein at least one surfactant comprises lecithin, preferably soy lecithin. (Item 28) A nanoemulsion of Item 27, wherein the phosphatidylcholine content of lecithin is at least 80% by weight. (Item 29) A formulation according to any one of Items 26 to 28, wherein phospholipids, lysophospholipids, ceramides and / or mixtures thereof are present in an amount of 0.1% to 10% by weight, preferably 0.15% to 5% by weight, more preferably 0.2% to 3% by weight, based on the total weight of the nanoemulsion (a). (Item 30) A polyoxyethylene surfactant is a formulation described in any one of items 26-29, containing 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 the preceding paragraphs, wherein 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 the preceding items, 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 preparation according to any one of the preceding paragraphs, comprising at least one gelling agent. (Item 35) A formulation according to any one of the preceding items, wherein the gelling agent is selected from 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. (Item 36) A formulation of Item 34 or 35, wherein the gelling agent is selected from poloxamer, xanthanum and / or a mixture thereof. (Item 37) The formulation according to any one of the preceding items, 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 preparation according to any one of the preceding items, further comprising at least one preservative. (Item 39) The formulation of Item 38, wherein the preservative is a benzoate, preferably sodium benzoate. (Item 40) A formulation of 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 preparation described in any one of the preceding paragraphs that is essentially free of parabens. (Item 42) A formulation according to any one of the preceding items, characterized in that 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 70-95% by weight relative to the total weight of nanoemulsion (a), (ii) Based on the total weight of (1) nanoemulsion (a), 1 to 5% by weight of at least one phospholipid, (2) Based on the total weight of nanoemulsion (a), 2 to 10% by weight of at least one polyoxyethylene-based surfactant, (3) Based on the total weight of nanoemulsion (a), 1 to 5% by weight of C3-C5 alcohol, and (4) Based on the total weight of nanoemulsion (a), 2 to 10% by weight of triglycerides Nanovesicles containing Emulsion of nanovesicles containing (b) Based on the total weight of the formulation, 0.01 to 1% by weight of a highly lipophilic macrolide lactone or a combination thereof, (c) Based on the total weight of the formulation, at least one preservative in an amount of 0.1 to 10% by weight. Includes, The formulation according to any one of items 1 to 42, wherein the formulation preferably has a pH of 2 to 7. (Item 44) The formulation according to any one of the preceding paragraphs, wherein the formulation is filled into a container, the container further comprising a propellant, the propellant being provided for pressurizing the container and / or pressurizing the formulation within the container. (Item 45) A preparation described in any one of the preceding paragraphs, which is used for pharmaceutical purposes. (Item 46) A preparation described in any one of the preceding paragraphs, used for local or systemic treatment and / or prevention of skin diseases, ophthalmic diseases, or autoimmune diseases or conditions in a subject, or for the prevention of organ rejection after transplantation. (Item 47) A formulation for use in item 46, for which the ophthalmic disease is selected from the group consisting of keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), dry eye, and corneal endothelial rejection after corneal transplantation. (Item 48) Skin diseases or skin conditions, including diseases or conditions of the skin, skin appendages or mucous membranes, formulations for use under Item 46. (Item 49) Formulations for use of Item 46 or 48, wherein the 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. (Item 50) Inflammatory skin diseases or conditions 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, formulations for use in item 49. (Item 51) A formulation for use in item 49 for autoimmune skin diseases or conditions, or skin manifestations of autoimmune conditions, selected from the group consisting of psoriasis, pemphigus, systemic lupus erythematosus, lichen planus, scleroderma, scleroderma, epidermolysis bullosa, dermatomyositis, and graft-versus-host disease. (Item 52) A dispenser product containing a formulation described in any one of items 1 to 51. (Item 53) A container containing a preparation described in any one of items 1 to 51. (Item 54) Using any one of the formulations described in Items 1 to 51 in the manufacture of a medicinal product for the treatment and / or prevention of a skin disease or condition in a subject. (Item 55) A method for treating and / or preventing a skin disease or skin condition in a subject, comprising administering to the subject a pharmacologically effective amount of a preparation described in any one of Items 1 to 57. [Examples]

[0152] (Example 1): Preparation of nanoemulsions BF200, BF215, and BF220 Table 2 shows the qualitative and quantitative compositions of nanoemulsions BF200, BF215, and BF220. (TIFF2026511974000006.tif32154) TIFF2026511974000007.tif86158

[0153] The manufacturing process for nanoemulsions in a typical batch size consists of the following steps 1-4. Step 1 Preparation of phosphate buffer (aqueous component) A phosphate buffer solution (1000g) was prepared and sterilized as necessary.

[0154] Step 2 Preparation of a carrier component (lipid phase) containing lipophilic components, surfactants, and alcohols. TIFF2026511974000008.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).

[0155] In all the examples described herein, nanoemulsion BF200 was used.

[0156] Step 3 Manufacturing of nanoemulsions with a lipid content of 10% (BF200) (mixing of aqueous component in Step 1 and carrier in Step 2) An emulsion was prepared 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.

[0157] 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.

[0158] Step 4 Preparation of the final formulation and primary packaging. If necessary, the nanoemulsion may be sterilized. Depending on the purpose of the nanoemulsion, adjuvants and / or excipients and / or active ingredients (in appropriate steps as described) may be added, and / or the nanoemulsion may be diluted to obtain a suitable formulation. For example, water, a suitable buffer, or an additional aqueous gel base containing Poloxamer 407 or xanthan gum may be added.

[0159] (Example 2): Preparation of a nanoemulsion formulation (BF220) containing 0.1% or 0.01% tacrolimus (TC) and 4% Poloxamer 407. A formulation was prepared according to Example 1, and an appropriate amount of aqueous gel base containing Poloxamer 407 was added in step 4. 0.1% or 0.01% of TC was added to the lipophilic component in step 2 of Example 1.

[0160] (Example 3): Measurement of solubility properties of tacrolimus in nanoemulsion formulations Tacrolimus was dissolved by mechanical means (stirring). Complete dissolution of the substance was determined by visual observation. Complete dissolution was defined as a clear solution without any signs of turbidity or precipitation. A pure solvent was used as the standard.

[0161] (Example 4): Measurement of vesicle size and polydispersity index by dynamic light scattering method The size of the nanovesicles (z-mean size, e.g., in nm) 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.

[0162] The Zetasizer Nano ZS features an optical system with a 633nm green laser and a 173° scattering detector angle for size measurement. Although the instrument is capable of measurements under vacuum, vacuum was not applied to the sample in this embodiment for size and uniformity measurements.

[0163] (Example 5): In vitro release of tacrolimus formulation using nanoemulsion and tacrolimus ointment (SUPAC-SS) The in vitro release method is based on an open diffusion cell system such as the Franz cell system. A cylindrical glass Franz cell forms a diffusion chamber with an upper and lower section, between which a synthetic membrane (e.g., EMD Millipore MF Membrane, 0.025 μm) is clamped. The lower section (approximately 7 mL) is filled with a receiving medium (ethanol / water = 75:25 vol%) and maintained at approximately 32°C. At this temperature, the active pharmaceutical ingredient exhibits sufficient solubility. The receiving medium is agitated (approximately 400 rpm) to ensure the distribution and dissolution of the API. The diffusion area of ​​the membrane is approximately 1.8 cm². 2The membrane diameter was 25 mm. High-efficiency liquid chromatography (HPLC-UV) assays were used to monitor the diffusion and permeation of tacrolimus from the topical formulation to the membrane (for up to 2.6 hours).

[0164] (Example 6): Epidermal permeability of nanoemulsion formulation compared with commercially available tacrolimus ointment A 0.1% tacrolimus-containing nanoemulsion formulation and a conventional 0.1% ointment were compared using a stratified assay on ex vivo facial skin to evaluate tacrolimus deposition. Drug penetration into human skin during routine facial cosmetic surgery was investigated using an established ex vivo model. Penetration tests were performed using the following procedure: I. Skin sampling: Samples were taken from blepharoplasty (upper and lower eyelids) and facelift (cheeks / around the ears). II. Sample preparation: (a) A single non-occlusive skin application was performed on an ex vivo skin sample with a diameter of 6 mm. (b) Approximately 28.3 mg (100 mg / cm³) of the test substance 2 ) Application (c) After incubation in a humid environment of approximately 37°C and 5% CO2, the test solution was washed with 70% ethanol. Freezed at -80°C in cryopreservation solution. (d) Frozen sections 10 μm thick were prepared at 2-8°C. (e) Tacrolimus was extracted using ACN at approximately 20°C for 24 hours under conditions of 450 rpm, and then centrifuged at 20°C. III. Measurement of tacrolimus content by high-performance liquid chromatography (HPLC-UV).

[0165] (Example 7): Measurement of viscosity 90.0s at 20℃ -1 The viscosity was measured using a rotational viscometer (measurement shape: cone / plate) with a constant shear rate.

[0166] (Example A) Changes in tacrolimus (TC) content over time in BF220 using PX=4% as a gelling agent (under various temperature conditions) Nanoemulsion formulations BF220 TC=0.1% and BF220 TC=0.01% were prepared according to the method described in Example 2. The nanoemulsion formulations were stored at 2-8°C, 25°C, and 40°C. The TC content was measured at the start (0) and at each point in time during the 24-month storage period. The results are shown in Figure 2. Conclusion: 2-8°C: This formulation (Example 2) maintains API (TC) content better than conventional aqueous formulations. The TC in the Example 2 formulation was confirmed to be stable even after 24 months of storage at 2-8°C. At 40°C, the TC in the Example 2 formulation is stable for at least 1 month.

[0167] (Example B) Particle size and particle size distribution over time in BF220 using PX=4% as a gelling agent (under various temperature conditions) Nanoemulsion formulations BF220 TC=0.1% and BF220 TC=0.01% were prepared in the same manner as in Example 2. The nanoemulsion formulations were stored at 2-8°C, 25°C, and 40°C. Particle size, particle size distribution, and pH were measured at the start of storage (time 0) and at each point during the 24-month storage period. The results are shown in Figures 3 and 4. Conclusion: At 2-25°C, the formulation containing API(TC) (Example 2) was confirmed to be stable for storage for at least 24 months at 2-25°C. At 40°C, the formulation was stable for at least 3 months.

[0168] (Example C) In vitro release study of nanoemulsion formulation and tacrolimus ointment (SUPAC-SS) Both test formulations, when applied topically, released significantly higher concentrations of tacrolimus, which was then able to penetrate and enter the skin. The properties of the nanoemulsion formulation contribute to more effective tacrolimus release than ointments, where tacrolimus diffusion is further inhibited.

[0169] Using a release test method for tacrolimus nanoemulsions, no tacrolimus was released from reference ointments containing 0.1% and 0.03% tacrolimus. From the test formulation containing nanoemulsion BF220 and 0.03% tacrolimus, 28.39% of the applied amount of tacrolimus was released. From the test formulation containing nanoemulsion BF220 and 0.1% tacrolimus, 42.81% of the applied amount of tacrolimus was released. The data are shown in Figure 5.

[0170] (Example D) Solubility of tacrolimus in nanoemulsion formulations The samples were prepared as described in Example D. The compounds were dissolved in 10 mM phosphate buffer (TC2) at the specified concentrations (see table below). For samples TC3, TC4, and TC5, the lipid phase (intermediate) of nanoemulsion BF200 was used as the solvent. In the first step, tacrolimus was dissolved in the lipid phase, and then the aqueous phase and the lipid phase (containing tacrolimus) were mixed to prepare the nanoemulsion. Samples TC4 and TC5 were stored at 5°C and 25°C for 6 months. The results of the solubility tests at time points 0 and 6 months are shown in Figure 1 and Table 4. TIFF2026511974000009.tif61161 Conclusion: Tacrolimus is highly soluble in aqueous nanoemulsions (water content of at least 90%) at a concentration of at least 2 mg / mL.

[0171] (Example E) Epidermal permeability of nanoemulsion formulation compared to commercially available tacrolimus ointment The results showed that tacrolimus from a conventional lipophilic ointment containing 0.1% tacrolimus primarily remained on the skin surface, likely due to its formulation characteristics, with no epidermal penetration observed. On the other hand, the 0.1% tacrolimus-containing nanoemulsion formulation (BF220) demonstrated that tacrolimus deposition into deeper skin layers was achievable. This result is consistent with the results of Example C.

[0172] After 24 hours of incubation, differences were observed in the deposition profiles of samples treated with 0.1% tacrolimus-containing nanoemulsion (BF220) and samples treated with 0.1% tacrolimus-containing conventional lipophilic ointment. After treatment with 0.1% tacrolimus-containing nanoemulsion (BF220), the amount of tacrolimus was distributed very uniformly across all three skin layers, and tended to accumulate towards the deeper dermis. On the other hand, in the case of treatment with 0.1% tacrolimus-containing conventional lipophilic ointment, the highest concentration of tacrolimus was observed in the uppermost layer of the skin, and the concentration decreased rapidly with increasing layer depth. The data are shown in Figure 6.

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) Activating agents A formulation containing, The formulation wherein the activator is a highly lipophilic macrolide lactone.

2. The formulation according to claim 1, wherein the logP value of the macrolide lactone is 3 or higher.

3. The formulation according to claim 1 or 2, wherein the activator is dissolved in the carrier component of the nanoemulsion.

4. The formulation according to any one of claims 1 to 3, wherein the activator is Tacrolimus, Pipecuronium, Everolimus, or Silolimus, preferably Tacrolimus, its derivatives, isomers, tautomers, precursors, metabolites, hydrates, and / or pharmaceutically acceptable salts.

5. The formulation according to any one of claims 1 to 4, wherein the activator is present in an amount of 0.001 to 25% by weight, preferably 0.005 to 1% by weight, and most preferably 0.01 to 1% by weight, based on the total weight of the formulation.

6. The formulation according to any one of claims 1 to 5, wherein the aqueous component is present in an amount of 70 to 95% by weight, more preferably 80 to 95% by weight, based on the total weight of the nanoemulsion.

7. The formulation according to any one of claims 1 to 6, wherein the total amount of aqueous components is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% by weight, preferably 50 to 99% by weight, 70 to 95% by weight, more preferably 75 to 95% by weight, and even more preferably 80 to 90% by weight, based on the total weight of the formulation.

8. (a) The at least one alcohol comprises at least three carbon atoms, preferably three, four, or five carbon atoms, and preferably the at least one alcohol is selected from the group consisting of 1-propanol, 2-propanol, and mixtures thereof. (b) The at least one lipophilic component is selected from triglycerides and mixtures thereof, preferably the at least one lipophilic component is caprylic and / or capric triglyceride, or a mixture thereof, and / or (c) The formulation according to any one of claims 1 to 7, wherein the at least one surfactant is selected from phospholipids, lysophospholipids, ceramides and / or mixtures thereof, and / or the at least one surfactant is a polyoxyethylene surfactant.

9. The formulation according to any one of claims 1 to 8, wherein the at least one surfactant is phosphatidylcholine.

10. The formulation according to any one of claims 1 to 9, wherein the formulation contains 0.5 to 5% by weight, preferably 1 to 4% by weight, and more preferably 1.2 to 3.5% by weight of phosphatidylcholine.

11. The formulation according to any one of claims 1 to 10, wherein the formulation comprises a propellant and is contained in a pressurized container.

12. The formulation according to any one of claims 1 to 11, wherein the formulation essentially does not contain fatty alcohol.

13. The formulation according to any one of claims 1 to 12, wherein the formulation essentially does not contain a emollient selected from a monoester or diester containing an alcohol and a fatty acid.

14. A formulation according to any one of claims 1 to 13, comprising at least one gelling agent.

15. (a) When stored at 2-25°C for 1 month, 2 months, 3 months, or 6 months, (b) When stored at 2-8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months, The formulation according to any one of claims 1 to 14, wherein the activator is present in an amount of 80% or more, preferably 85% or more, and more preferably 90% or more.

16. The nanoemulsion contains nanovesicles, (a) When stored at 2-25°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months, (b) When stored at 2-8°C for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 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 100 nm.

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

18. The preparation according to any one of claims 1 to 17, wherein the preparation is a topical preparation, an ophthalmic preparation, a parenteral preparation, or an oral preparation.

19. The formulation according to any one of claims 1 to 18, wherein the formulation is a lotion, spray, foam, emulsion, nanoemulsion, gel, or cream.

20. A pharmaceutical preparation according to any one of claims 1 to 19, for use in medical applications.

21. A preparation according to any one of claims 1 to 20, for use in a method for treating or preventing a skin disease, an ophthalmic disease, or an autoimmune disease or condition, or for preventing organ rejection after transplantation.

22. A container containing a formulation, or a foam dispenser or spray dispenser product containing a container, wherein the formulation is (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 including, (iii) Active ingredients Includes a nanoemulsion containing The aforementioned active ingredient is a highly lipophilic macrolide lactone. A foam dispenser or spray dispenser product comprising a container or container, wherein the container further comprises a propellant, the propellant being provided for pressurizing the container.

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