Topical pharmaceutical composition

Abstract

To provide a topical composition that comprises 3,5 Dihydroxy-4-isopropyl-trans-stilbene, which is sensitive to oxidation and photo-degradation, as an active ingredient, is both chemically and physically stable, delivers the active ingredient to the desired site of action in the epidermis and / or dermis, and does not irritate the skin in use.SOLUTION: The present invention provides topical pharmaceutical emulsion compositions comprising a therapeutically effective amount of 3,5-Dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, a water phase, a surfactant, and an antioxidant, and wherein the emulsion composition is homogeneous and / or the active ingredient is solubilized in the oil phase. The invention also relates to methods of treating a dermatological condition or disorder in a patient by administering the present compositions to the skin of the patient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to a topical pharmaceutical composition. [Background technology]

[0002] For pharmaceutical chemists, it is a challenge to prepare a topical pharmaceutical composition that is physically stable and in which the active ingredient is also known to be chemically stable. (i) Without irritating the skin, (ii) It may be particularly adapted to deliver an active ingredient onto or into the skin to treat a specific dermatological condition or disorder, (iii) Appearance is refined to ensure that the patient follows the prescribed prescription plan, (iv) Allow the active ingredient to penetrate the appropriate layer of the skin, engage with the desired target, and (v) Achieve local skin / epidermal delivery while minimizing systemic exposure. It is necessary to do so.

[0003] The desired active ingredient to be formulated in a physically and chemically stable topical composition is 3,5-dihydroxy-4-isopropyl-trans-stilbene having the following formula: [ka]

[0004] This compound is also known as 5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene-1,3-diol or 2-(1-methylethyl)-5-[(1E)-2-phenylethenyl]-1,3-benzenediol.

[0005] 3,5-Dihydroxy-4-isopropyl-trans-stilbene is thought to have been first disclosed as an antibiotic in Paul et al., Journal of Chemical Ecology 1981 7(3):589-597. Li et al., Applied and Environmental Microbiology 1995 61(12):4329-4333 also isolated the above compound, which was isolated from different bacterial strains and its antifungal activity was further shown. The antifungal activity of the above compound is also described in WO1995 / 003695 (Agro-Biotech Corporation). The above compound is further described in WO2001 / 042231 (Welichem Biotech Inc.) and U.S.Pat.No.7,868,047, and is described as being suitable for the treatment of various important dermatological conditions including psoriasis and inflammation. Example 3 of U.S.Pat.No.7,868,047 describes a cream formulation in which the active ingredient is manufactured with Galax Base. The applicant was unable to confirm the compendial notation or availability of a commercially available cream base called "Galax", and therefore its composition remains unknown.

[0006] 3,5-Dihydroxy-4-isopropyl-trans-stilbene is known to be sensitive to oxidation and photodegradation (see, for example, Gao et al., Journal of Polymer Research 2011 18:1,501-1,508). Therefore, in the art, there is still a need for topical compositions containing 3,5-dihydroxy-4-isopropyl-trans-stilbene that are chemically and physically stable, deliver the active ingredient to the desired site of action in the epidermis and / or dermis, and do not irritate the skin during use. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] [Figure 1] FIG. 1 shows the appearance of the heterogeneous emulsions that were characteristic of Formulations 2-14. [Figure 2] Figure 2 shows the appearance of the heterogeneous emulsion, which is a characteristic of Formulations 2 to 14, compared to the physically stable formulation characterized by Formulations 15 to 40. [Figure 3] Figure 3 shows the amounts of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered to the epidermis and dermis by Formulations 1, 12, 17, and 21 to 24. [Figure 4] Figure 4 shows the amounts of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered to the receiving solution over 15 hours by Formulations 1, 12, 17, and 21 to 24. [Figure 5] Figure 5 shows the amounts of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered to the dermis at 3, 6, 9, 12, and 15 hours by Formulations 12 and 21. [Figure 6] Figure 6 shows the amounts of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered to the receiving solution over 72 hours by Formulations 12 and 21. [Figure 7] Figure 7 shows the rates of change of mRNA Cyp1A1 in human ex vivo skin after Th17 stimulation by Formulations 12, 17, 21, and 22. [Figure 8] Figure 8 shows the amounts of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered to the skin of Göttingen minipigs after 7 days of repeated dosing. [Figure 9] Figure 9 shows the amounts of 3,5-dihydroxy-4-isopropyl-trans-stilbene in the plasma of Göttingen minipigs after 7 days of repeated dosing. As described herein, "Formulation 12 (2.0%)", which is used throughout including Figures 8 and 9, corresponds to Formulation 14. SUMMARY OF THE INVENTION

[0008] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and the active ingredient, wherein the emulsion composition is homogeneous.

[0009] In another embodiment, the active ingredient is solubilized in the oil phase of the emulsion composition. In another embodiment, if the oil phase contains mineral oil or petrolatum, a second oil phase component is present, and if the oil phase contains both mineral oil and petrolatum, a third oil phase component is present. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, at least a third oil phase component is present, which is an ester or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, a second oil phase component is present, which is an ester or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride.

[0010] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an effective amount of an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is homogeneous, and 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and if the oil phase contains mineral oil or petrolatum, a second oil phase component is present, and if the oil phase contains both mineral oil and petrolatum, a third oil phase component is present. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, there is at least a third oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is glycerin and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride.

[0011] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the active ingredient is solubilized in the oil phase of the emulsion composition. In another embodiment, the emulsion composition is homogeneous.

[0012] In another embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is homogeneous and / or the active ingredient is solubilized in the oil phase of the emulsion composition.

[0013] In another embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the average droplet size of the discontinuous phase is less than approximately 35 microns. In another embodiment, the average droplet size of the discontinuous phase is less than approximately 25 microns. In another embodiment, the average droplet size of the discontinuous phase is less than approximately 15 microns. In another embodiment, the average droplet size of the discontinuous phase is less than approximately 10 microns. In another embodiment, the average droplet size of the discontinuous phase is less than approximately 5 microns. In another embodiment, the average droplet size of the discontinuous phase is approximately 1 micron or less than approximately 1 micron. In another embodiment, the average droplet size of the discontinuous phase is approximately 0.05 to approximately 1 micron. In another embodiment, the average droplet size of the discontinuous phase is approximately 0.1 to approximately 0.75 microns. In another embodiment, the average droplet size of the discontinuous phase is approximately 0.5 microns.

[0014] In another embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the average particle size of the oil phase is less than about 10 microns, the emulsion composition is homogeneous, and / or the active ingredient is solubilized in the oil phase of the emulsion composition.

[0015] In another embodiment, the present invention provides a method for treating a dermatological condition or disorder in a patient requiring such treatment, comprising administering to the patient a topical pharmaceutical emulsion composition comprising an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is homogeneous. In another embodiment, the active ingredient is solubilized in the oil phase of the emulsion composition. In another embodiment, a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, there is at least a third oil phase component which is an ester or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is an ester or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride.

[0016] In another embodiment, the present invention provides a method for treating a dermatological condition or disorder in a patient requiring such treatment, the method comprising an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, at least a third oil phase component is present, comprising an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In one embodiment, the dermatological condition or disorder is an inflammatory dermatological condition or disorder. In another embodiment, the inflammatory dermatological condition or disorder is atopic dermatitis and / or psoriasis and / or acne.

[0017] In another embodiment, the present invention relates to the use in the treatment or prevention of a dermatological condition or disorder in a human patient of a topical pharmaceutical emulsion composition comprising an effective amount of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion is homogeneous.

[0018] In another embodiment, the present invention relates to the use of a topical pharmaceutical emulsion composition comprising an effective amount of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, at least a third oil phase component is present, which is an ester and / or an ester of glycerin, preferably an ester of glycerin such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride.

[0019] In another embodiment, the present invention relates to a topical pharmaceutical emulsion composition for use in the treatment or prevention of a dermatological condition or disorder in a human patient, comprising an effective amount of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains petrolatum in an amount of ≤3%, or ≤2%, or ≤1%. In another embodiment, if the oil phase contains both mineral oil and petrolatum, there is at least a third oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride.

[0020] In another embodiment, the present invention relates to a method for reducing irritation in the use of a topical pharmaceutical emulsion composition containing the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof to a patient requiring such use, the method comprising administering to the patient a pharmaceutical emulsion composition comprising an oil phase, an aqueous phase, a surfactant and an antioxidant, wherein 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains petrolatum in an amount of ≤3%, or ≤2%, or ≤1%. In another embodiment, if the oil phase contains both mineral oil and petrolatum, there is at least a third oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride.

[0021] In one embodiment, the emulsion composition of the present invention is compared to the emulsion composition of Formulation 1 or 12 (containing equivalent %w / w active ingredients).

[0022] In another embodiment, the present invention relates to a method for improving the retention time of an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, in the skin of a patient requiring it, the method comprising administering to the patient a pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is homogeneous.

[0023] In another embodiment, the present invention relates to a method for improving the residence time of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in the skin of a patient requiring it, the method comprising administering to the patient a pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, there is at least a third oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In one embodiment, the emulsion composition of the present invention is compared to the emulsion composition of Formulation 1 or 12 (containing equivalent %w / w active ingredients).

[0024] In another embodiment, the present invention relates to a method for improving the residence time of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in the skin of a patient requiring it, the method comprising administering to the patient a pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant and an antioxidant, wherein the emulsion is homogeneous and / or the active ingredient is solubilized in the oil phase. In another embodiment, the average droplet size of the discontinuous phase is about 5 microns or less. In another embodiment, the average droplet size of the discontinuous phase is about 1 micron or less.

[0025] In another embodiment, the present invention relates to a method for mitigating adverse reactions in a patient administered a composition comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, the method comprising administering to the patient a pharmaceutical emulsion composition comprising an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion is homogeneous and / or the active ingredient is solubilized in the oil phase. In another embodiment, the average droplet size of the discontinuous phase is about 5 microns or less. In another embodiment, the average droplet size of the discontinuous phase is about 1 micron or less.

[0026] In another embodiment, the present invention relates to a method for mitigating adverse effects in a patient administered a composition comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, the method comprising administering to the patient a pharmaceutical emulsion composition comprising an oil phase, an aqueous phase, a surfactant and an antioxidant, wherein 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, a second oil phase component is present if the oil phase comprises mineral oil or petrolatum, and a third oil phase component is present if the oil phase comprises both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, or ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, there is at least a third oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In one embodiment, the emulsion composition of the present invention is compared to the emulsion composition of formulation 1 or 12, or to an emulsion composition of a similar formulation containing equivalent active ingredients.

[0027] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and if the oil phase contains mineral oil, a second oil phase component other than petrolatum is present in the composition.

[0028] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and if the oil phase contains mineral oil, a second oil phase component other than petrolatum is present, or if the oil phase contains both mineral oil and petrolatum, at least a third oil phase component is present. In another embodiment, the oil phase is substantially free of mineral oil and / or petrolatum. [Modes for carrying out the invention]

[0029] In addition to producing physically and chemically stable pharmaceutical formulations, the present invention also provides pharmaceutical formulations that are non-irritating to the skin during administration and use, or less irritating than conventional formulations used in the development of active ingredients to date. Another aspect of the present invention is a formulation that not only has excellent skin penetration and excellent target engagement of appropriate receptors, but also has significant non-systemic exposure of the active ingredient to the patient during administration and use.

[0030] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is homogeneous. In one embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. In another embodiment, a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, ≤2%, or ≤1% petrolatum. In another embodiment, when the oil phase contains both mineral oil and petrolatum, there is at least a third oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, when the oil phase contains mineral oil, there is a second oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. The second and third oil phase components are used as cosolvents for the active ingredients in the oil phase of the emulsion composition. That is, the second and third oil phase components act as oil-miscible cosolvents.

[0031] In one embodiment, the active ingredient solubilized in the oil phase of the emulsion composition is present in an amount of ≥50% w / w, ≥60% w / w, ≥70% w / w, ≥80% w / w, 90% w / w, 95% w / w, or >98% w / w relative to the weight percent of the active ingredient. In a preferred embodiment, 95% w / w or 98% w / w of the active ingredient is solubilized in the oil phase of the emulsion to produce a homogeneous composition.

[0032] In another embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the aqueous phase of the emulsion composition. Since 3,5-dihydroxy-4-isopropyl-trans-stilbene is insoluble in water, a water-miscible organic solvent (i.e., a water-miscible cosolvent) can be used to solubilize the active ingredient in the aqueous phase of the emulsion. Preferably, the active ingredient solubilized in the aqueous phase of the emulsion composition is present in an amount of ≥10% w / w, or ≥20% w / w, or ≥30% w / w, or ≥40% w / w, or 50% w / w, or 60% w / w, or 70% w / w, or 80% w / w, or 90% w / w, or 95% w / w, relative to the weight percent of the active ingredient.

[0033] As used herein, the term "D90" means that 90% of the droplets have an oil droplet size diameter smaller than a certain size. Alternatively, the term "D90" is defined as 90% of the oil droplets being less than a few microns in size on a volume basis. In one embodiment, the average droplet size D90 of the discontinuous phase in the composition is less than 15 microns. In another embodiment, the average droplet size of the discontinuous phase according to the present invention has a D90 of less than 5 microns.

[0034] As used herein, the term "D50" means the median or 50th percentile of droplets smaller than a certain size. Alternatively, the term "D50" is defined as 50% of the oil droplets being less than a few microns in size, on a volume basis. In one embodiment, the D50 of the average droplet size of the discontinuous phase in the composition is less than 5 microns. In another embodiment, the average droplet size of the discontinuous phase according to the present invention has a D50 of less than 1 micron.

[0035] Methods for measuring the particle size distribution of oil droplets are known in the art. In one embodiment, the diameter distribution of oil droplet sizes in the composition according to the present invention can be measured using laser diffraction techniques. Suitable laser diffraction devices include, for example, the Sympatec HELOS / QUIXEL or the Malvern laser diffractometer available from Malvern Instruments, Malvern, UK.

[0036] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the average droplet size of the discontinuous phase is less than about 35 microns. In another embodiment, the average droplet size of the discontinuous phase is less than about 25 microns. In another embodiment, the average droplet size of the discontinuous phase is less than about 15 microns. In another embodiment, the average droplet size of the discontinuous phase is less than about 10 microns. In another embodiment, the average droplet size of the discontinuous phase is less than about 5 microns. In another embodiment, the average droplet size of the discontinuous phase is about 1 micron or less than about 1 micron. In another embodiment, the average droplet size of the discontinuous phase is about 0.05 to about 35 microns. In another embodiment, the average droplet size of the discontinuous phase is about 0.05 to about 5 microns. In another embodiment, the average droplet size of the discontinuous phase is about 0.05 to about 1 micron. In another embodiment, the average droplet size of the discontinuous phase is about 0.1 to about 0.75 microns.

[0037] In one embodiment, at least 90% of the droplets in the oil phase (e.g., discontinuous phase) of the oil-in-water emulsion have a droplet size of about 1 micron or less than 1 micron. In another embodiment, at least 95%, 97%, 98%, or 99% of the droplets are about 1 micron or less than 1 micron.

[0038] Alternatively, or at least additionally, at least about 75%, at least about 85%, or at least about 90% of the droplet sizes of the discontinuous phase oil in the oil-in-water emulsion have a size of less than about 10 microns, less than about 5 microns, less than about 1 micron, or less than about 0.75 microns. Any combination of the above percentages and droplet sizes can be used to define oil droplets in the composition of the present invention.

[0039] In one embodiment, the emulsion composition of the present invention preferably has at least one of the following properties: a D50 average droplet diameter of less than 1 micron when measured at 2 to 8°C; and / or when measured at 25°C and 60%RH; and / or when measured at 30°C for 6 months; or a D50 average droplet diameter of less than 1 micron when measured at 30°C for 6 months.

[0040] In another embodiment, a topical pharmaceutical emulsion composition comprising an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the average droplet size of the oil phase is less than approximately 5 microns, and the emulsion is optionally homogeneous. In another embodiment, the active substance is solubilized in the oil phase.

[0041] In another embodiment, a topical pharmaceutical emulsion composition comprising an active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the average droplet size of the oil phase is less than about 1 micron, and the emulsion is optionally homogeneous. In another embodiment, the active substance is solubilized in the oil phase.

[0042] As used herein, the terms “emulsion” and “oil-in-water emulsion” mean a colloidal dispersion in which liquid oil is dispersed as droplets (discrete phase, also known as discontinuous non-aqueous phase or discontinuous phase) in a continuous aqueous medium (also known as the continuous phase, continuous aqueous phase, or continuous phase) unless otherwise indicated or understood from the context in which they are used. In some embodiments, at least 50% (w / w) of the active ingredient is dissolved and remains in the emulsion. In some embodiments, at least 75% (w / w) of the active ingredient is dissolved and remains in the emulsion. In certain embodiments, as further described herein, more than 85% of the active ingredient is present in the discontinuous phase.

[0043] 3,5-dihydroxy-4-isopropyl-trans-stilbene In one embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is present in the emulsion composition in an amount of about 0.01% to about 5% by weight, for example, about 0.05% to about 2% by weight. In another embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is present in an amount of about 0.1% to about 1.0% by weight relative to the total weight of the composition. In one embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is present in an amount of about 0.25%, 0.30%, 0.40%, 0.50%, 0.75%, 1%, or 2% by weight relative to the total weight of the composition. In one embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is present in an amount of about 0.25% to about 0.50% by weight.

[0044] Oil phase The topical pharmaceutical emulsion composition of the present invention comprises an oil phase. Preferably, the oil phase comprises one or more oils and / or lipids.

[0045] Examples of oils and lipids include fatty acids, esters, glycerol esters, aliphatic alcohols, waxes, sterols, unsaponifiable matter, siloxanes, silanes, lanolin, hydrocarbons, essential oils, vegetable oils, mineral oils, animal oils and edible oils, and mixtures thereof.

[0046] In one embodiment, the oil and / or lipid is selected from the group consisting of esters and glycerol esters, and mixtures thereof. In another embodiment, the oil and / or lipid is at least a glycerol ester.

[0047] In one embodiment, the oil phase contains fatty acids. Exemplary fatty acids include, but are not limited to, isostearic acid, oleic acid, stearic acid, linoleic acid, linolenic acid, myristic acid, palmitic acid, ricinoleic acid, and arachidic acid, as well as mixtures thereof.

[0048] In one embodiment, the oil phase contains an ester. Exemplary esters, though not particularly limited, include cococaprylic / capric acid, diethyl sebacate, diisopropyl adipate, diisopropyl dilinoleate, ethyl oleate, ethylhexyl hydroxystearate, glycol distearate, glycol stearate, hydroxyoctacosanyl hydroxystearate, isopropyl isostearate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, methyl glucose sesquistearate, methyl laurate, methyl salicylate, methyl stearate, myristyl lactate, octyl salicylate, oleyl oleate, PPG-20 methyl glucose ether distearate, propylene glycol diacetate, propylene glycol dicaprylate, propylene glycol monolaurate, propylene glycol monopalmitostearate, propylene glycol ricinoleate, triacetin distearate, and sucrose distearate, as well as mixtures thereof. In one embodiment, the ester is diethyl sebacate or diisopropyl adipate.

[0049] In one embodiment, the oil phase contains glycerin esters. Exemplary glycerin esters include, but are not limited to, caprylic / capric acid glyceride, caprylic / capric acid triglyceride, caprylic / capric acid / succinate triglyceride, capryl glucoside, cetearyl glucoside, cocoglyceride, decyl glucoside, lauryl glucoside, glyceryl citrate, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glyceryl ricinoleate, glyceryl stearate, mono and diglycerides, PEG-12 glyceryl laurate, PEG-120 glyceryl stearate, polyglyceryl-3 oleate, polyoxylglyceryl stearate, tallow glycerides and medium-chain triglycerides (MCTs), and mixtures thereof. In one embodiment, the oil phase of the emulsion contains medium-chain triglycerides. In one embodiment, the carbon length of the medium-chain triglycerides is C6~C 12 In another embodiment, the length of the carbon atoms in the medium-chain triglyceride is C6 to C8.

[0050] In one embodiment, the oil phase contains an aliphatic alcohol. Examples of aliphatic alcohols, though not limited to them, include caprylic alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, behenyl alcohol, lanolin alcohol, arachidyl alcohol, oleyl alcohol, palm alcohol, isocetyl alcohol, cetyl alcohol, and stearyl alcohol, and mixtures thereof. In one embodiment, the aliphatic alcohol is a mixture of cetyl alcohol and stearyl alcohol. Preferably, the ratio of cetyl alcohol to stearyl alcohol is about 2:1 to about 1:9.

[0051] In one embodiment, the oil phase includes wax. Exemplary waxes include beeswax, carnauba wax, dimethicone PEG-1 beeswax, dimethicone beeswax, lanolin wax, microcrystalline wax, white wax, candelilla wax, paraffin wax, emulsifying wax, PEG-8 beeswax, yellow wax, cetyl ester wax, shellac wax, and synthetic beeswax, as well as mixtures thereof.

[0052] In one embodiment, the oil phase contains sterols. Exemplary sterols include, but are not limited to, rapeseed (Brassica Campestris) sterols, C. 10 ~C 30 Examples include cholesterol / lanosterol esters, canolasterol, cholesterol, lanolin cholesterol, glycine sojasterol, PEG-20 phytosterols and phytosterols, and mixtures thereof.

[0053] In one embodiment, the oil phase comprises a siloxane and / or silane. Examples of siloxanes and silanes, but not limited to them, include dimethicone, cyclomethicone, simethicone, phenyldimethicone, cyclopentasiloxane, cyclotetrasiloxane, dimethylsiloxane and dimethicone crosspolymer, as well as mixtures thereof.

[0054] In one embodiment, the oil phase contains hydrocarbons. Examples of hydrocarbons, but not limited to, include dodecane, petrolatum, squalane, squalene, and paraffin, as well as mixtures thereof.

[0055] In one embodiment, the oil phase contains essential oils. Exemplary essential oils include, but are not limited to, primrose oil, rose oil, eucalyptus oil, borage oil, bergamot oil, chamomile oil, citronella oil, lavender oil, peppermint oil, pine oil, pine needle oil, spearmint oil, tea tree oil, and wintergreen oil, as well as mixtures thereof.

[0056] In one embodiment, the oil phase includes vegetable oil. Examples of vegetable oils, but are not limited to, almond oil, anise oil, canola oil, castor oil, coconut oil, corn oil, avocado oil, cottonseed oil, olive oil, palm kernel oil, peanut oil, sunflower oil, safflower oil, and soybean oil, as well as mixtures thereof.

[0057] In one embodiment, the oil phase may contain mineral oil. Examples of mineral oils include, but are not limited to, mineral oil and light mineral oil. When the oil phase contains mineral oil, another oil phase component is present in the formulation. In one embodiment, the second oil phase component is not petrolatum. In one embodiment, the second oil phase component is not a petrolatum derivative. In one embodiment, the emulsion composition contains an oil phase substantially free of mineral oil. In another embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase is substantially free of petrolatum derivatives. In another embodiment, the emulsion composition contains an oil phase substantially free of mineral oil and petrolatum. In another embodiment, the emulsion composition contains an oil phase substantially free of mineral oil, petrolatum, and petrolatum derivatives.

[0058] In one embodiment, the oil phase contains edible oil. Examples of edible oils, though not limited to them, include cinnamon oil, clove oil, lemon oil, and peppermint oil, as well as mixtures thereof.

[0059] In one embodiment, the oil phase of the emulsion contains an ester of glycerin, which is a medium-chain triglyceride (MCT). Preferably, the MCT is present in an amount of about 2% to about 30% by weight relative to the total weight of the composition, for example, about 2% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, or about 30% by weight relative to the total weight of the composition. In another embodiment, the oil phase of the emulsion contains an amount of MCT in an amount of about 5% to about 30% by weight relative to the total weight of the composition. In another embodiment, the oil phase of the emulsion contains an amount of MCT in an amount of about 5% to about 20% by weight relative to the total weight of the composition. In another embodiment, the MCT is present in an amount of about 10% by weight relative to the total weight of the composition.

[0060] In one embodiment, the oil phase contains oil and / or lipids in an amount of about 5% to about 45% by weight, for example, about 5% to about 35% by weight, relative to the total weight of the composition. In another embodiment, the oil phase contains oil and / or lipids in an amount of about 5% to about 25% by weight, relative to the total weight of the composition. In yet another embodiment, the oil phase contains oil and / or lipids in an amount of about 5% to about 15% by weight, relative to the total weight of the composition.

[0061] aqueous phase The topical pharmaceutical emulsion composition of the present invention comprises an aqueous phase containing water or a water phase. Preferably, water is present in the composition in an amount of about 25% to about 85% by weight relative to the total weight of the composition. In one embodiment, water is present in the composition in an amount of about 30% to about 80% by weight relative to the total weight of the composition. In another embodiment, water is present in an amount of about 55% to about 75% by weight relative to the total weight of the composition.

[0062] surfactants Topical pharmaceutical emulsion compositions contain surfactants. In one embodiment, the surfactant is a mixture of two or more surfactants. As used herein, a surfactant is a compound that reduces the surface tension between two liquids, or between a liquid and a solid. Surfactants can also act as detergents, wetting agents, emulsifiers, foaming agents, and dispersants. Furthermore, as used herein, an emulsifier corresponds to a surfactant.

[0063] Preferably, the surfactant is present in the composition in an amount of about 1% to about 20% by weight, for example, about 5% to about 15% by weight, relative to the total weight of the composition.

[0064] The hydrophilic / lipophilic balance (HLB) of a surfactant represents its affinity for water or oil. The HLB scale ranges from 1 (fully lipophilic) to 20 (fully hydrophilic), with 10 representing a state where both properties are balanced. Lipophilic surfactants tend to form water-in-oil (w / o) emulsions, while hydrophilic surfactants tend to form oil-in-water (o / w) emulsions. The HLB of a mixture of two surfactants is equal to the weighted average of the product of the weight fraction of surfactant A multiplied by its HLB value and the product of the weight fraction of surfactant B multiplied by its HLB value.

[0065] In one embodiment, the surfactant comprises one or more nonionic surfactants. In another embodiment, the surfactant comprises two or more nonionic surfactants, and the weighted average of the HLB values ​​of the two or more nonionic surfactants is about 10 to about 20. In yet another embodiment, the surfactant comprises two or more nonionic surfactants, and the weighted average of the HLB values ​​of the two or more nonionic surfactants is about 1 to about 10.

[0066] Suitable nonionic surfactants in the present invention are not particularly limited, but include ethoxylated aliphatic alcohol ethers, PEG castor oil, PEG esters, propylene glycol esters, glyceryl esters and derivatives, polymer ethers, sorbitan derivatives, aliphatic alcohols, emulsifying waxes, and mixtures thereof.

[0067] In one embodiment, the nonionic surfactant is an ethoxylated aliphatic alcohol ether. Examples of ethoxylated aliphatic alcohol ethers are, but are not limited to, Steareth-2, Steareth-10, Steareth-20, Steareth-21, Steareth-40, Steareth-100, Beheneth-10, Ceteareth-2, Ceteareth-3, Ceteareth-5, Ceteareth-6, Ceteareth-10, Ceteareth-12, Ceteareth-15, Ceteareth-20, Ceteareth-21, Ceteareth-22, Ceteareth-25, Ceteareth-30, Ceteareth-31, Ceteareth-32, Ceteareth-33, Ceteth-2, Ceteth Examples include C20-10, Ceteth-20, Ceteth-23, Choles-24, Isoceteth-20, Laureth-2, Laureth-3, Laureth-4, Laureth-5, Laureth-9, Laureth-10, Laureth-12, Laureth-15, Laureth-20, Laureth-21, Laureth-22, Laureth-23, Nonoxynol-9, Nonoxynol-15, Octoxynol-1, Octoxynol-9, Oleth-2, Oleth-5, Oleth-10, Oleth-20, C20-40 Pareth-24 and Trideceth-10, as well as mixtures thereof.

[0068] In one embodiment, the nonionic surfactant is PEG castor oil. Examples of PEG castor oils, though not particularly limited, include PEG-7 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-30 castor oil, PEG-33 castor oil, PEG-35 castor oil, PEG-36 castor oil, PEG-40 castor oil, PEG-40 hydrogenated castor oil, PEG-50 castor oil, PEG-54 hydrogenated castor oil, PEG-60 castor oil, and PEG-60 hydrogenated castor oil, as well as mixtures thereof.

[0069] In one embodiment, the nonionic surfactant is a PEG ester. Exemplary PEG esters include, but are not limited to, PEG-4 dilaurate, PEG-150 distearate, PEG-12 glyceryl laurate, PEG-120 glyceryl stearate, PEG-6 isostearate, PEG-4 laurate, PEG-8 laurate, PEG-20 methyl glucose sesquistearate, PEG-5 oleate, PEG-6 oleate, PEG-10 oleate, PEG-25 propylene glycol stearate, PEG-2 stearate, PEG-6 stearate, PEG-6-32 stearate, PEG-8 stearate, PEG-9 stearate, PEG-20 stearate, PEG-40 stearate, PEG-45 stearate, PEG-50 stearate, and PEG-100 stearate, as well as mixtures thereof.

[0070] In one embodiment, the nonionic surfactant is a propylene glycol ester. Examples of propylene glycol esters include, but are not limited to, propylene glycol laurate, propylene glycol palmitostearate, propylene glycol ricinoleate, and propylene glycol stearate, as well as mixtures thereof.

[0071] In one embodiment, the nonionic surfactant is a glyceryl ester or derivative. Exemplary glyceryl esters and derivatives include, but are not limited to, glyceryl behenate, glyceryl dibehenate, glyceryl dioleate, glyceryl distearate, glyceryl isostearate, glyceryl laurate, glyceryl linoleate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glyceryl ricinoleate, glyceryl stearate, PEG-23 glyceryl cocoate, PEG-6 caprylic / capric glycerate, PEG-7 glyceryl cocoate, polyglyceryl-10 distearate, polyglyceryl-2 diisostearate, polyglyceryl-3 subisostearate and polyglyceryl-6 diisostearate, PEG-12 glyceryl laurate, PEG-120 glyceryl stearate, and mixtures thereof.

[0072] In one embodiment, the nonionic surfactant is a polymer ether. Examples of polymer ethers, though not particularly limited, include poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 184, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338, and poloxamer 407, as well as mixtures thereof.

[0073] In one embodiment, the nonionic surfactant is a sorbitan derivative. Examples of similar sorbitan derivatives, but not limited to, include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, and sorbitan tristearate, as well as mixtures thereof.

[0074] In one embodiment, the nonionic surfactant is an aliphatic alcohol. Examples of aliphatic alcohols, but are not limited to, isostearyl alcohol, caprylyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, behenyl alcohol, lanolin alcohol, arachidyl alcohol, oleyl alcohol, palm alcohol, isocetyl alcohol, cetyl alcohol, stearyl alcohol, and cetearyl alcohol, as well as mixtures thereof. In one embodiment, the aliphatic alcohol is a mixture of cetyl alcohol and stearyl alcohol, also known as cetearyl alcohol (also known as cetostearyl alcohol).

[0075] In one embodiment, the nonionic surfactant is an emulsifying wax, for example, a nonionic emulsifying wax also known as emulsifying wax NF, or emulsifying wax BP. In one embodiment, the emulsifying wax is a mixture of cetearyl alcohol and polysorbate 60. In another embodiment, it is a patented mixture known as "Polawax NF" (trademark) (Croda Inc, Edison, NJ, USA).

[0076] In one embodiment, the surfactant comprises one or more ethoxylated aliphatic alcohol ethers. In another embodiment, the ethoxylated aliphatic alcohol ether is a mixture of steareth-2 and steareth-20.

[0077] In one embodiment, the surfactant comprises a mixture of an ethoxylated aliphatic alcohol ether and a sorbitan derivative. In another embodiment, the mixture of the ethoxylated aliphatic alcohol ether and the sorbitan derivative is a mixture of Steareth-2, Steareth-20, and polysorbate 80.

[0078] In one embodiment, if two surfactants are present in the formulation, each surfactant is present in an amount of about 0.5% to about 5% by weight relative to the total weight of the composition. In another embodiment, if three surfactants are present in the formulation, each surfactant is present in an amount of about 0.5% to about 5% by weight relative to the total weight of the composition. Similarly, if four or more surfactants are present, each is present in an amount of about 0.5% to about 5% by weight relative to the total weight of the composition.

[0079] In one embodiment, the surfactant comprises a mixture of an ethoxylated aliphatic alcohol ether and an emulsifying wax. In another embodiment, the surfactant comprises a mixture of an ethoxylated aliphatic alcohol ether, a sorbitan derivative, and an emulsifying wax. Preferably, the mixture of the ethoxylated aliphatic alcohol ether and the emulsifying wax is a mixture of Steareth-2, Steareth-20, and Polawax® NF. Preferably, the mixture of the ethoxylated aliphatic alcohol ether, a sorbitan derivative, and an emulsifying wax is a mixture of Steareth-2, Steareth-20, Polysorbate 80, and Polawax® NF. In an alternative embodiment, the surfactant comprises a mixture of an ethoxylated aliphatic alcohol ether and an aliphatic alcohol. Preferably, the mixture of the ethoxylated aliphatic alcohol ether and the aliphatic alcohol is a mixture of Steareth-2, Steareth-20, and cetearyl alcohol.

[0080] In another embodiment, the surfactant includes a mixture of an ethoxylated aliphatic alcohol ether, a sorbitan derivative, and an aliphatic alcohol. Preferably, the mixture of the ethoxylated aliphatic alcohol ether, sorbitan derivative, and aliphatic alcohol is a mixture of steareth-2, steareth-20, polysorbate 80, and cetearyl alcohol.

[0081] Antioxidant The topical pharmaceutical emulsion composition of the present invention contains an antioxidant. In one embodiment, the antioxidant is a mixture of two or more antioxidants.

[0082] Examples of antioxidants, though not limited to them, include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, propyl gallate, vitamin E TPGS, and tert-butylhydroquinone (TBHQ), as well as mixtures thereof. In one embodiment, the antioxidant is selected from the group consisting of butylated hydroxytoluene, propyl gallate, and tocopherol, as well as mixtures thereof.

[0083] In one embodiment, the antioxidant is butylated hydroxytoluene. In another embodiment, the antioxidant is propyl gallate. In yet another embodiment, the antioxidant is a mixture of butylated hydroxytoluene and propyl gallate.

[0084] In one embodiment, the antioxidant is used in combination with a chelating agent to inhibit or minimize metal-catalyzed reactions, such as those catalyzed by iron, nickel, copper, magnesium, calcium, zinc, or aluminum ions.

[0085] Preferably, the antioxidant is present in the composition in an amount of about 0.001% to about 5% by weight relative to the total weight of the composition. In one embodiment, the antioxidant is present in an amount of about 0.01% to 1% by weight, for example, about 0.05% or about 0.1% by weight relative to the total weight of the composition.

[0086] Dermatologically acceptable excipients The topical pharmaceutical emulsion composition of the present invention may further contain one or more additional dermatologically acceptable excipients. Examples of additional dermatologically acceptable excipients include, but are not limited to, pH adjusters, chelating agents, preservatives, cosolvents, penetration enhancers, wetting agents, thickeners or gelling agents or viscosity building agents, fragrances, colorants, and mixtures thereof.

[0087] In one embodiment, the additional dermatologically acceptable excipient is a preservative. In one embodiment, the additional dermatologically acceptable excipient is at least one co-solvent. In one embodiment, the additional dermatologically acceptable excipient is selected from the group consisting of pH adjusters, chelating agents, preservatives, and co-solvents, as well as mixtures thereof. In another embodiment, the additional dermatologically acceptable excipient includes a mixture of pH adjusters, chelating agents, preservatives, and co-solvents.

[0088] In one embodiment, the emulsion is an oil-in-water emulsion. In another embodiment, the emulsion is a water-in-oil emulsion.

[0089] Preferably, the emulsion may be formulated as a cream. The cream may be an oil-in-water cream or a water-in-oil cream. In one particular embodiment, the cream is an oil-in-water cream.

[0090] In another embodiment, the emulsion may be formulated as a lotion. The lotion may be an oil-in-water lotion or a water-in-oil lotion.

[0091] pH adjuster The topical pharmaceutical emulsion composition of the present invention may further contain a pH adjuster.

[0092] In one embodiment, the pH adjuster is an acid, an acid salt, or a mixture thereof. Preferably, the acid is selected from the group consisting of lactic acid, acetic acid, maleic acid, succinic acid, citric acid, benzoic acid, boric acid, sorbic acid, tartaric acid, EDTA, phosphoric acid, nitric acid, sulfuric acid, and hydrochloric acid, as well as mixtures thereof.

[0093] In another embodiment, the pH adjuster is a buffer. Preferably, the buffer is selected from the group consisting of citrate / citric acid, acetate / acetic acid, phosphate / phosphoric acid, propionate / propionic acid, lactate / lactic acid, ammonium / ammonia, and edetate / edetic acid. In one embodiment, the pH adjuster is a buffer that is citrate / citric acid.

[0094] Preferably, the pH adjuster is present in the composition in an amount of about 0.01% to about 10% by weight relative to the total weight of the composition. In one embodiment, the pH of the composition is adjusted to about 4 to about 7, for example, about 4.5 to about 6.5, using the pH adjuster.

[0095] Chelating agents The topical pharmaceutical emulsion composition of the present invention may further contain a chelating agent. In one embodiment, the chelating agent is a mixture of two or more chelating agents. As described herein, the composition of the present invention may also contain a mixture of a chelating agent and an antioxidant, both of which act to inhibit or minimize oxidative degradation reactions in the composition.

[0096] Examples of chelating agents include, but are not limited to, citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, ethylenediaminetetraacetic acid (EDTA), phosphonates, salts thereof, and mixtures thereof. Ethylenediaminetetraacetic acid is also known as edetate.

[0097] In one embodiment, the chelating agent is EDTA or a salt thereof, such as a potassium salt, sodium salt, or calcium salt of EDTA. In one embodiment, the EDTA or salt thereof is disodium EDTA. In another embodiment, the chelating agent is citric acid. In yet another embodiment, the composition of the present invention comprises a mixture of the chelating agent and an antioxidant which is a mixture of EDTA or a salt thereof and propyl gallate. In yet another embodiment, the composition of the present invention comprises a mixture of the chelating agent and an antioxidant which is a mixture of EDTA or a salt thereof and BHT. In one embodiment, the composition of the present invention comprises a mixture of the chelating agent and an antioxidant which is a mixture of disodium EDTA and BHT.

[0098] In further embodiments, the composition comprises a mixture of a chelating agent and an antioxidant which is a mixture of citric acid and propyl gallate. In one embodiment, the composition of the present invention comprises a mixture of a chelating agent and an antioxidant which is a mixture of citric acid and BHT.

[0099] Preferably, the chelating agent is present in the composition in an amount of about 0.01% to about 1% by weight relative to the total weight of the composition. In one embodiment, the chelating agent is present in the composition in an amount of about 0.1% by weight relative to the total weight of the composition.

[0100] Preservatives The topical pharmaceutical emulsion composition of the present invention may further contain a preservative. In one embodiment, the preservative is a mixture of two or more preservatives.

[0101] Examples of preservatives include, but are not limited to, benzyl alcohol, imidazolidinyl urea, diazolidinyl urea, dichlorobenzyl alcohol, chlorooxylenol, methylparaben, ethylparaben, propylparaben, butylparaben, phenoxyethanol, sorbic acid, benzoic acid, salts thereof, and mixtures thereof.

[0102] In one embodiment, the preservative is selected from the group consisting of benzyl alcohol, phenoxyethanol, and benzoic acid, as well as mixtures thereof.

[0103] In one embodiment, the preservative is benzyl alcohol. In another embodiment, the preservative is phenoxyethanol. In yet another embodiment, the preservative is benzoic acid.

[0104] Preferably, the preservative is present in the composition in an amount of about 0.01% to about 2% by weight relative to the total weight of the composition. In one embodiment, the preservative is present in the composition in an amount of about 0.25% by weight relative to the total weight of the composition.

[0105] cosolvent The topical pharmaceutical emulsion composition may further contain a co-solvent. The function of the co-solvent is, if necessary, to help solubilize 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in the oil and / or aqueous phases of the emulsion composition. An oil-miscible co-solvent may be used to help solubilize the active ingredient in the oil phase, and a water-miscible co-solvent may be used to help solubilize the active ingredient in the aqueous phase. In one embodiment, the co-solvent is used to help solubilize the active ingredient in the oil phase of the composition.

[0106] In one embodiment, the cosolvent is a mixture of two or more cosolvents.

[0107] Examples of cosolvents include, but are not limited to, alcohols such as ethanol, isopropanol, t-butyl alcohol, amyl alcohol, benzyl alcohol, cyclohexanedimethanol, diacetone alcohol, hexyl alcohol, tetrahydrofurfuryl alcohol, and diethylene glycol monoethyl ether; carboxylic acids such as acetic acid or polycarboxylic acids; diols such as 1,2-hexanediol, butylene glycol, diethylene glycol, dipropylene glycol, ethylhexanediol, ethylene glycol, hexylene glycol, pentylene glycol, propylene glycol, propylene glycol monolaurate, tetraethylene glycol, triethylene glycol, tripropylene glycol, and polyethylene glycol; and polyols such as butanetriol, glycerol, and 1,2,6-hexanetriol.Butyl stearate, C12-15 alkyl benzoate, C12-15 alkyl lactate, caprylic / capric triglyceride, cetearyl ethyl hexanoate, cetearyl isononanoate, cetyl octanoate, cetyl palmithiate, cococaprylate, cocoglyceride, decyl oleate, dibutyl adipate, dicaprylyl carbonate, diethylhexyl adipate Diethylhexyl succinate, diisopropyl adipate, dioctyl malate, di-PPG-2 myreth-10 adipate, di-PPG-3 myristyl ether adipate, ethyl oleate, ethylhexyl cocoate, ethylhexyl hydroxystearate, ethylhexyl palmitate, ethylhexyl pelargonate, ethylhexyl stearate, hexyl laurate, hexyl decyl phosphate Examples include ureate, hexyldecyl stearate, isocetyl stearate, isocetyl stearoyl stearate, isodecyl oleate, isopropyl myristate, isopropyl palmitate, isostearyl neopentanoate, isotridecyl isononanoate, lauryl lactate, myristyl lactate, myristyl myristate, octyldodecyl stearoyl stearate, oleyl ethyl acetate, oleyl oleate, pentaerythrityl tetracaprylate / caprate, pentaerythrityl tetraisostearate, PPG-2 myristyl ether propionate, propylene glycol dicaprylate / caprylate, propylene glycol isostearate, propylheptyl caprylate, and stearyl octanoate dimethyl isosorbide and propylene carbonate.

[0108] In one embodiment, the cosolvent is propylene glycol. In another embodiment, the cosolvent is a mixture of propylene glycol and diethylene glycol monoethyl ether.

[0109] Preferably, the cosolvent is present in the composition in an amount of about 1% to about 30% by weight, for example, about 5% to about 20% by weight, relative to the total weight of the composition.

[0110] Penetration enhancer The topical pharmaceutical emulsion composition of the present invention may further contain a penetration enhancer. In one embodiment, the penetration enhancer is a mixture of two or more penetration enhancers. The cosolvents or mixtures of two or more cosolvents described herein may function as penetration enhancers.

[0111] Examples of penetration enhancers include, but are not limited to, fatty acids, fatty acid esters, aliphatic alcohols, pyrrolidones, sulfoxides, alcohols, diols and polyols, and mixtures thereof.

[0112] Examples of fatty acids include, but are not limited to, oleic acid, capric acid, hexanoic acid, lauric acid, linoleic acid, linolenic acid, propionic acid, and vaccenic acid, as well as mixtures thereof.

[0113] Examples of typical fatty acid esters include, but are not limited to, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl palmitate, isopropyl myristate, diethyl sebacate, sorbitan monopalmitate, sorbitan oleate, sorbitan dilaurate, sorbitan trioleate, propylene glycol monolaurate, and sucrose monolaurate, as well as mixtures thereof.

[0114] Examples of aliphatic alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol, decanol, tridecanol, lauryl alcohol, linolenyl alcohol, and oleyl alcohol, as well as mixtures thereof.

[0115] Examples of pyrrolidones include, but are not limited to, N-methylpyrrolidone, 2-pyrrolidone, and N-cyclohexyl-2-pyrrolidone, as well as mixtures thereof.

[0116] Examples of exemplary sulfoxides include, but are not limited to, dimethyl sulfoxide and decyl methyl sulfoxide, as well as mixtures thereof.

[0117] Examples of alcohols include, but are not limited to, lower (C1-C6) alcohols and diethylene glycol monoethyl ethers, as well as mixtures thereof.

[0118] Examples of diols include, but are not limited to, 1,2-hexanediol, butylene glycol, diethylene glycol, dipropylene glycol, ethylhexanediol, ethylene glycol, hexylene glycol, pentylene glycol, propylene glycol, propylene glycol monolaurate, tetraethylene glycol, triethylene glycol, tripropylene glycol, polyethylene glycol, and polypropylene glycol, as well as mixtures thereof.

[0119] Examples of polyols include, but are not limited to, butanetriols, glycerols, and 1,2,6-hexanetriols, as well as mixtures thereof.

[0120] Preferably, the penetration enhancer is present in the composition in an amount of about 0.5% to about 40% by weight relative to the total weight of the composition, for example, about 1% to about 20% by weight or about 5% to about 15% by weight.

[0121] Gelling agent The topical pharmaceutical composition of the present invention may further contain a gelling agent. In one embodiment, the gelling agent is a mixture of two or more gelling agents.

[0122] Examples of gelling agents include, but are not limited to, agar, alginates, arabinoxylan, carrageenan, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose, curdlan, gelatin, gellan, β-glucan, tragacanth gum, guar gum, acacia gum, locust bean gum, pectin, starch, carbomer, acrylate copolymer, silica, xanthan gum, salts thereof, or combinations or mixtures thereof.

[0123] Preferably, the gelling agent is present in the composition in an amount of about 0.1% to about 2% by weight relative to the total weight of the composition. In one embodiment, the gelling agent is present in the composition in an amount of about 0.2% to about 1% by weight relative to the total weight of the composition.

[0124] 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is administered to patients for dermatological diseases or disorders as a dermatologically acceptable formulation. These formulations include any of the various known excipients that allow for topical administration, spreading of the active ingredient to the affected area, rapid drying, and / or enhanced penetration. Examples of preferred formulations include solutions, emulsions, creams, ointments, gels, lotions, sprays, aerosols, foams, or suspensions.

[0125] aqueous solution In one embodiment, the dermatologically acceptable formulation is an aqueous solution. In this embodiment, the pharmaceutical composition contains water in an amount of about 50% to about 99.9% by weight, or about 70% to about 99.9% by weight. Preferably, the pH of the composition is adjusted to about 2 to about 6, preferably about 4 to about 6, for example, about 4.5 to about 5.5. The topical aqueous solution may also contain one or more of the following: cosolvents, humectants, chelating agents, antioxidants, preservatives, fragrances, colorants, or penetration enhancers, as described herein.

[0126] Water-based gel In one embodiment, the dermatologically acceptable formulation is an aqueous gel. In this embodiment, the pharmaceutical composition contains water in an amount of about 50% to about 99% by weight, for example, about 70% to about 99% by weight. Preferably, the pH of the composition is adjusted to about 2 to about 6, more specifically about 4 to about 6, or about 4.5 to about 5.5. Furthermore, in this embodiment, the pharmaceutical composition also includes a suitable gelling agent. The composition may further contain a cosolvent, a wetting agent, a chelating agent, an antioxidant, a preservative, a fragrance, a coloring agent, or a penetration enhancer, or a combination or mixture thereof.

[0127] Hydrated alcohol gel In one embodiment, the dermatologically acceptable formulation is an aqueous alcohol gel. The aqueous alcohol solution of the present invention can be thickened with a gelling agent to form an aqueous alcohol gel.

[0128] In one embodiment, the aqueous alcohol gel comprises water, a lower alcohol, and a suitable gelling agent. The composition may further contain one or more of the following: a cosolvent, a pH adjuster, a wetting agent, a chelating agent, an antioxidant, a preservative, a fragrance, a coloring agent, or a penetration enhancer.

[0129] Aqueous solution In one embodiment, a dermatologically acceptable formulation is an aqueous solution, i.e., a solution that is substantially water-free or contains no water. In one embodiment, the aqueous solution contains no water. In another embodiment, the aqueous solution contains substantially no water.

[0130] In one embodiment, the aqueous solution comprises an anhydrous vehicle. In one embodiment, the anhydrous vehicle comprises one or more solvents selected from the group consisting of lower (C1-C6) alcohols, diols, and polyols.

[0131] Preferably, the lower alcohol is selected from the group consisting of ethanol, propanol, isopropanol, n-butyl alcohol, and t-butyl alcohol, and mixtures thereof. In one embodiment, the lower alcohol is tanol. In another embodiment, the lower alcohol is a mixture of ethanol and one or more other lower alcohols.

[0132] Preferably, the diol is selected from the group consisting of 1,2-hexanediol, butylene glycol, diethylene glycol, dipropylene glycol, ethylhexanediol, ethylene glycol, hexylene glycol, pentylene glycol, propylene glycol, propylene glycol monolaurate, tetraethylene glycol, triethylene glycol, tripropylene glycol, and polyethylene glycol.

[0133] Preferably, the polyol is selected from the group consisting of butanetriol, glycerol, and 1,2,6-hexanetriol.

[0134] In one embodiment, the anhydrous vehicle comprises a mixture of ethanol and propylene glycol. In another embodiment, the anhydrous vehicle comprises a mixture of ethanol, propylene glycol, and polyethylene glycol. In yet another embodiment, the anhydrous vehicle is ethanol.

[0135] Preferably, the anhydrous vehicle is present in the composition in an amount of about 50% to about 99.5% by weight.

[0136] Anhydrous gel In one embodiment, the dermatologically acceptable formulation is an aqueous solution. The anhydrous solution can be thickened with a gelling agent to form an anhydrous gel. In one embodiment, the anhydrous gel comprises an anhydrous vehicle and a gelling agent. The anhydrous gel may further contain a cosolvent, a wetting agent, a chelating agent, an antioxidant, a preservative, a fragrance, a coloring agent, or a penetration enhancer, or a combination or mixture thereof.

[0137] Oily solution In one embodiment, a dermatologically acceptable formulation is formulated as an oily solution. The oily solution comprises oils and / or lipids as described herein.

[0138] In one embodiment, oils and / or lipids are present in an amount of about 70% to about 99.9% by weight. In another embodiment, oils and / or lipids are present in an amount of about 80% to about 99% by weight.

[0139] The oily solution may further contain a cosolvent, a wetting agent, a chelating agent, an antioxidant, a preservative, a fragrance, a colorant, or a penetration enhancer, or a combination or mixture thereof.

[0140] Oily gel In yet another embodiment, an oily solution is thickened with a gelling agent to form an oily gel.

[0141] In one embodiment, the oily gel comprises oil and / or lipids, as well as a gelling agent. Preferably, the oil and / or lipids are present in an amount of about 70% to about 99.9% by weight, for example, about 80% to about 99% by weight. The oily gel may further contain a cosolvent, a wetting agent, a chelating agent, an antioxidant, a preservative, a fragrance, a coloring agent, or a penetration enhancer, or a combination or mixture thereof.

[0142] cream In one embodiment, the dermatologically acceptable formulation is a cream. In one embodiment, the cream is an oil-in-water cream. Preferably, the oil-in-water cream comprises an oil phase, an aqueous phase, a surfactant, and an antioxidant.

[0143] In one embodiment, the pH of the composition is adjusted to about 2 to about 6, for example, about 4 to about 6. In another embodiment, the pH of the composition is adjusted to about 4.5 to about 5.5.

[0144] The composition may further contain a cosolvent, a wetting agent, a chelating agent, a preservative, a fragrance, a coloring agent, or a penetration enhancer, or a combination or mixture thereof.

[0145] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an oil phase containing about 5% to about 45% by weight of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, oil and / or lipid; an aqueous phase containing about 25% to about 85% by weight of water; a surfactant in an amount of about 1% to about 20% by weight; and an antioxidant in an amount of about 0.001% to about 5% by weight, wherein the emulsion composition is homogeneous, all percentages are relative to the weight of the final composition, and all totals equal 100% by weight.

[0146] In one embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. In another embodiment, a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, at least a third oil phase component is present, which is an ester and / or ester of glycerin, preferably a glycerin ester such as a medium-chain triglyceride.

[0147] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an oil phase containing about 5% to about 35% by weight of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, oil and / or lipids, an aqueous phase containing about 25% to about 85% by weight of water, a surfactant in about 1% to about 20% by weight, and an antioxidant in about 0.001% to about 5% by weight, wherein the emulsion composition is homogeneous, and the 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, all percentages are relative to the weight of the final composition, and all totals equal 100% by weight.

[0148] In another embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an oil phase containing about 5% to about 35% by weight of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, oil and / or lipids, an aqueous phase containing about 30% to about 80% by weight of water, a surfactant in an amount of about 5% to about 15% by weight, and an antioxidant in an amount of about 0.001% to about 5% by weight, wherein the emulsion composition is homogeneous, all percentages are relative to the weight of the final composition, and all totals equal 100% by weight. In another embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition.

[0149] In one embodiment, the composition may further contain one or more cosolvents present in the composition in an amount of about 1% to about 30% by weight relative to the total weight of the composition. In another embodiment, the composition may contain a preservative present in an amount of about 0.01% to about 2% by weight relative to the total weight of the composition. In another embodiment, the composition may further contain a chelating agent present in an amount of about 0.01% to about 1% by weight relative to the total weight of the composition. In another embodiment, the composition may further contain a pH adjusting agent present in an amount of about 0.01% to about 10% by weight relative to the total weight of the composition. In another embodiment, the oil phase may contain esters and / or glycerol esters, preferably medium-chain triglyceride (MCT) glycerol esters, present in an amount of about 2% to about 30% by weight relative to the total weight of the composition.

[0150] In another embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising an oil phase containing 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, oil and / or lipids in an amount of about 5% to about 35% by weight, an aqueous phase with water in an amount of about 30% to about 80% by weight, a surfactant in an amount of about 5% to about 15% by weight, a pH adjuster in an amount of about 0.001% to about 5% by weight, and a pH adjuster in an amount of about 0.01% to about 10% by weight, wherein the emulsion composition is homogeneous, all percentages are relative to the weight of the final composition, and all totals equal 100% by weight. In another embodiment, water is present in an amount of about 55% to about 75% by weight relative to the total weight of the composition. In another embodiment, oil and / or lipids are present in an amount of about 5% to about 25% by weight relative to the total weight of the composition. In another embodiment, oil and / or lipids are present in an amount of about 5% to about 15% by weight relative to the total weight of the composition. In one embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. In one embodiment, the composition may further contain one or more cosolvents present in the composition in an amount of about 1% to about 30% by weight relative to the total weight of the composition.

[0151] The present invention also provides pharmaceuticals comprising combinations of therapeutic agents for simultaneous, separate, or sequential use in the treatment of conditions in which administration of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is suggested.

[0152] In the context of this specification, the term “simultaneously” when referring to the simultaneous administration of related drugs means exactly the same thing, for example, in embodiments where the drugs are combined in a single preparation. In other embodiments, “simultaneously” may mean that one drug is administered sequentially for a short period, and “short period” means the duration during which the drugs are able to have their intended synergistic effect.

[0153] From the above-mentioned perspective, the present invention also relates to combination therapies, including simultaneous, co-administration, or sequential administration of a compound or pharmaceutical composition of the present invention with other active drugs or therapeutic agents, and such administrations are also determined by those skilled in the art.

[0154] In such a combination composition, the dosage form of the present invention contains each of the active drug components in an effective dose.

[0155] In another aspect, the present invention relates to a combination therapy in which a second therapeutic agent is administered before, simultaneously with, or after the administration of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, either in the same formulation or in a separate formulation, and the second therapeutic agent is administered by the same local route or not, for example, intravenously, intramuscularly, intraocularly, intravaginally, rectally, etc.

[0156] In other words, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof can be administered together, simultaneously, or sequentially to the administration site or the desired site of action in any order. The order of administration is not considered essential if, when administered topically, they are in contact at some point in time at the administration site or the desired site of action. While the presence of both on the same vehicle facilitates administration to the patient and may result in improved compliance, this is not essential for the purposes of the present invention.

[0157] In another embodiment, the topical pharmaceutical composition retains more than 90% of its original concentration of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof after being stored at 40°C for 3 months.

[0158] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion is homogeneous. In another embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. In yet another embodiment, the composition is an oil-in-water cream.

[0159] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, an antioxidant, and a preservative, wherein the emulsion composition is homogeneous. In another embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. In yet another embodiment, the composition is an oil-in-water cream.

[0160] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, an antioxidant, a preservative, and a cosolvent, wherein the emulsion composition is homogeneous. In another embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. In yet another embodiment, the composition is an oil-in-water cream.

[0161] In one embodiment, the present invention provides a topical pharmaceutical emulsion composition comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, an antioxidant, a preservative, a cosolvent, and a pH adjuster, wherein the emulsion is homogeneous. In another embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. In yet another embodiment, the composition is an oil-in-water cream.

[0162] In another embodiment, the present invention is i) 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof; ii) an oil phase containing oil and / or lipids; iii) an aqueous phase containing water; iv) Surfactants; v) Antioxidants; vi) pH adjuster; vii) Chelating agents; viii) Preservatives; and ix) Cosolvent The present invention provides a topical pharmaceutical emulsion composition containing a homogeneous emulsion.

[0163] Preferably, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition, and preferably the composition is an oil-in-water cream.

[0164] In one embodiment, if the oil phase contains mineral oil or petrolatum, a second oil phase component is present, and if the oil phase contains both mineral oil and petrolatum, a third oil phase component is also present. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, at least a third oil phase component is present, which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, a second oil phase component is present, which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride.

[0165] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof Oil phase containing oil and / or lipids, Aqueous phase containing water, Surfactants containing ethoxylated aliphatic alcohol ethers; The present invention provides a topical pharmaceutical emulsion composition containing a homogeneous emulsion.

[0166] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof Oil phase containing oil and / or lipids, Aqueous phase containing water, Surfactants containing ethoxylated aliphatic alcohol ethers, Antioxidants selected from the group consisting of butylated hydroxytoluene, propyl gallate, tocopherol, and mixtures thereof. The present invention provides a topical pharmaceutical emulsion composition containing a homogeneous emulsion.

[0167] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof Oil phase containing oil and / or lipids, Aqueous phase containing water, Surfactants containing ethoxylated aliphatic alcohol ethers, Antioxidants selected from the group consisting of butylated hydroxytoluene, propyl gallate, and tocopherol, and mixtures thereof, Chelating agents The present invention provides a topical pharmaceutical emulsion composition containing [a specific ingredient], wherein the emulsion is homogeneous.

[0168] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof Oil phase containing oil and / or lipids, Aqueous phase containing water, Surfactants containing ethoxylated aliphatic alcohol ethers, Antioxidants selected from the group consisting of butylated hydroxytoluene, propyl gallate, and tocopherol, and mixtures thereof, Chelating agents, A preservative selected from the group consisting of benzyl alcohol, phenoxyethanol, benzoic acid, and mixtures thereof. The present invention provides a topical pharmaceutical emulsion composition containing a homogeneous emulsion.

[0169] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof Oil phase containing oil and / or lipids, Aqueous phase containing water, Surfactants containing ethoxylated aliphatic alcohol ethers, Antioxidants selected from the group consisting of butylated hydroxytoluene, propyl gallate, and tocopherol, and mixtures thereof, Chelating agents, A preservative selected from the group consisting of benzyl alcohol, phenoxyethanol, and benzoic acid, and mixtures thereof. Cosolvent, and pH adjuster The present invention provides a topical pharmaceutical emulsion composition containing a homogeneous emulsion.

[0170] Preferably, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. Preferably, the composition is an oil-in-water cream. In one embodiment, if the oil phase contains mineral oil or petrolatum, a second oil phase component is present, and if the oil phase contains both mineral oil and petrolatum, a third oil phase component is present. In one embodiment, the oil phase is substantially free of petrolatum. In another embodiment, the oil phase contains ≤3%, ≤2%, or ≤1% petrolatum. In another embodiment, if the oil phase contains both mineral oil and petrolatum, at least a third oil phase component is present, which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride. In another embodiment, if the oil phase contains mineral oil, there is a second oil phase component which is an ester and / or glycerin ester, preferably a glycerin ester such as a medium-chain triglyceride.

[0171] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof An oil phase containing oils and / or lipids that are medium-chain triglycerides, Aqueous phase containing water, Surfactants containing ethoxylated aliphatic alcohol ethers, Butyrlated hydroxytoluene is an antioxidant. EDTA or its salts are chelating agents. Benzoic acid is a preservative. A cosolvent comprising a mixture of propylene glycol and diethylene glycol monoethyl ether, Citrate / citrate buffer is a pH adjuster. The present invention provides a topical pharmaceutical emulsion composition comprising a pH adjusted to approximately 4.5 to approximately 6.5, and the emulsion being homogeneous.

[0172] Preferably, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. Preferably, the composition is an oil-in-water cream.

[0173] In all compositions described herein, the amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof that may be present in the composition may range from about 0.25% to about 2% by weight of the composition. In one embodiment, the amount may be 0.25%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, or 2.0% by weight relative to the total weight of the composition. In another embodiment, the amount is about 0.25% to about 0.50% by weight relative to the total weight of the composition. In another embodiment, the amount is about 0.25% by weight relative to the total weight of the composition. In another embodiment, the amount is about 0.50% by weight relative to the total weight of the composition. In another embodiment, the amount is about 0.75% by weight relative to the total weight of the composition. In another embodiment, the amount is about 1.0% by weight relative to the total weight of the composition.

[0174] In yet another embodiment of the present invention, there are (a) an oil phase; (b) an aqueous / aqueous phase; (c) at least one cosolvent; (d) at least one surfactant; (e) an antioxidant; and (f) an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof. In one embodiment, the oil phase comprises mineral oil. In another embodiment, the oil phase comprises petrolatum. In yet another embodiment, the oil phase comprises both mineral oil and petrolatum. In yet another embodiment, the oil phase comprises mineral oil and / or petrolatum, each present independently in an amount greater than 3% w / w. In yet another embodiment, the oil phase comprises mineral oil and / or petrolatum, each present independently in an amount greater than 5% w / w. In yet another embodiment, the oil phase comprises mineral oil and / or petrolatum, each present independently in an amount greater than 10% w / w. In yet another embodiment, the oil phase comprises mineral oil and / or petrolatum, each present independently in an amount greater than 15% w / w. In another embodiment, the oil phase comprises any combination of mineral oil and / or petrolatum present in an amount exceeding 5% w / w. In another embodiment, the oil phase comprises any combination of mineral oil and / or petrolatum present in an amount exceeding 10% w / w. In another embodiment, the oil phase comprises any combination of mineral oil and / or petrolatum present in an amount exceeding 15% w / w. In another embodiment, the oil phase comprises any combination of mineral oil and / or petrolatum present in an amount exceeding 20% ​​w / w. In another embodiment, the oil phase comprises any combination of mineral oil and / or petrolatum present in an amount exceeding 25% w / w.

[0175] Not intended to be limited to this description, if the oil phase contains components that do not dissolve the active ingredient, such as mineral oil and / or petrolatum, as illustrated by formulations 1, 12 and 41-42 of this specification, the active ingredient is solubilized in a cosolvent such as propylene glycol and / or diethylene glycol monoethyl ether, but is not particularly limited. Subsequently, if the aqueous phase is added to the oil phase, the active ingredient may be soluble in both the aqueous phase and / or the oil phase, depending on where and to what extent the cosolvent is distributed into the system.

[0176] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof; An oil phase comprising at least one oil and / or lipid, which is mineral oil or petrolatum; Aqueous phase containing water; at least one cosolvent; and surfactants A topical pharmaceutical emulsion composition is provided, which in this embodiment optionally also comprises a suitable gelling agent, wetting agent, pH adjuster, chelating agent, preservative, fragrance agent, colorant, or penetration enhancer, or a combination or mixture thereof, all percentages relative to the weight of the final composition, and all totals equal 100% by weight.

[0177] Preferably, the composition is an oil-in-water cream. In one embodiment, the surfactant comprises an ethoxylated aliphatic alcohol ether. In another embodiment, the cosolvent comprises a mixture of propylene glycol and diethylene glycol monoethyl ether.

[0178] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof; An oil phase containing at least one oil and / or lipid, which is mineral oil or petrolatum, in an amount of about 5% to about 45% by weight; An aqueous phase containing water in an amount of approximately 50% to 99.9% by weight; At least one co-solvent in an amount of approximately 1% to 30% by weight; Surfactants in an amount of approximately 1% to 20% by weight; Antioxidant in an amount of approximately 0.001% to 5% by weight; The invention also provides topical pharmaceutical emulsion compositions comprising, optionally, a gelling agent, a wetting agent, a pH adjuster, a chelating agent, a preservative, a fragrance agent, a coloring agent, or a penetration enhancer, or a combination or mixture thereof, all percentages being relative to the weight of the final composition, and all totals equal 100% by weight.

[0179] In one embodiment, the surfactant comprises an ethoxylated aliphatic alcohol ether. In another embodiment, the cosolvent comprises a mixture of propylene glycol and diethylene glycol monoethyl ether.

[0180] In another embodiment, the antioxidant is selected from the group consisting of butylated hydroxytoluene, propyl gallate, and tocopherol, as well as mixtures thereof.

[0181] In another embodiment, the cosolvent includes a mixture of propylene glycol and diethylene glycol monoethyl ether.

[0182] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof; An oil phase comprising at least one oil and / or lipid, which is mineral oil or petrolatum; Aqueous phase containing water; At least one co-solvent; Surfactants; Antioxidants; and Chelating agents; and optionally include gelling agents, wetting agents, pH adjusters, preservatives, fragrances, colorants, or penetration enhancers, or combinations thereof or mixtures thereof, all percentages are relative to the weight % of the final composition, and all totals equal 100% by weight.

[0183] In another embodiment, the cosolvent includes a mixture of propylene glycol and diethylene glycol monoethyl ether.

[0184] In one embodiment, the surfactant includes an ethoxylated aliphatic alcohol ether.

[0185] In another embodiment, the antioxidant is selected from the group consisting of butylated hydroxytoluene, propyl gallate, and tocopherol, as well as mixtures thereof.

[0186] In another embodiment, the composition may further contain a chelating agent present in an amount of about 0.01% to about 1% by weight relative to the total weight of the composition. In one embodiment, the chelating agent is a mixture of two or more chelating agents.

[0187] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof; An oil phase comprising at least one oil and / or lipid, which is mineral oil or petrolatum; Aqueous phase containing water; At least one co-solvent; Surfactants; Antioxidant; Chelating agents; and Preservatives; The invention also provides topical pharmaceutical emulsion compositions comprising, optionally, a gelling agent, a wetting agent, a pH adjuster, a preservative, a fragrance agent, a coloring agent, or a penetration enhancer, or a combination or mixture thereof, all percentages being relative to the weight of the final composition, and all totals equal 100% by weight.

[0188] In one embodiment, the surfactant comprises an ethoxylated aliphatic alcohol ether. In another embodiment, two surfactants are present in the formulation. Preferably, when two surfactants are present, each surfactant is present in an amount of about 0.5% to about 5% by weight of the total weight of the composition. In another embodiment, three surfactants are present in the formulation. Preferably, when three surfactants are present, each surfactant is present in an amount of about 0.5% to about 5% by weight of the total weight of the composition. Similarly, when four or more surfactants are present, each is present in an amount of about 0.5% to about 5% by weight of the total weight of the composition.

[0189] In another embodiment, the antioxidant is selected from the group consisting of butylated hydroxytoluene, propyl gallate, and tocopherol, as well as mixtures thereof.

[0190] In another embodiment, the cosolvent includes a mixture of propylene glycol and diethylene glycol monoethyl ether.

[0191] In one embodiment, the chelating agent is EDTA or a salt thereof.

[0192] In another embodiment, the preservative is benzoic acid.

[0193] In another embodiment, the present invention is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof An oil phase comprising at least one oil and / or lipid, which is mineral oil or petrolatum. Aqueous phase containing water, Surfactants containing ethoxylated aliphatic alcohol ethers, Antioxidants, Chelating agents, Preservatives, Cosolvent, and Humectant The invention also provides topical pharmaceutical emulsion compositions comprising, optionally, a gelling agent, a wetting agent, a preservative, a fragrance agent, a coloring agent, or a penetration enhancer, or a combination or mixture thereof, all percentages being relative to the weight of the final composition, and all totals equal 100% by weight.

[0194] In one embodiment, the surfactant includes an ethoxylated aliphatic alcohol ether.

[0195] In another embodiment, the antioxidant is selected from the group consisting of butylated hydroxytoluene, propyl gallate, and tocopherol, as well as mixtures thereof.

[0196] In another embodiment, the preservative is selected from the group consisting of benzyl alcohol, phenoxyethanol, and benzoic acid, as well as mixtures thereof.

[0197] In another embodiment, the cosolvent includes a mixture of propylene glycol and diethylene glycol monoethyl ether.

[0198] In one embodiment, the chelating agent is EDTA or a salt thereof.

[0199] In another embodiment, the preservative is benzoic acid.

[0200] In another embodiment, the pH adjuster is a citrate / citrate buffer.

[0201] Alternatively, when discussed in terms of biological function, the term dose may be used. As used herein, dose is defined as the amount of drug product administered per unit body surface area, i.e., mg / cm². 2 The amount of active ingredient delivered to the skin layer (epidermis or dermis) is expressed in units of a skin section or cm². 2The amount can be expressed in nanograms (ng) or micrograms (μg) per unit. Alternatively, the amount of active ingredient delivered to the epidermis or dermis can be expressed as a percentage of the administered dose. The amount of active ingredient delivered to the receptor fluid can be expressed in ng or ng / cm³. 2 This can be expressed as the amount accumulated.

[0202] In one embodiment, the emulsion composition contains 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in a composition in which the in vitro measured skin penetration in humans is at least 0.01 to 10% of the active ingredient dose over about 1 to about 72 hours. In another embodiment, this period is about 2 to about 24 hours. In yet another embodiment, this period is about 1 to about 15 hours. The percentage of the active ingredient dose can be 0.01 to 10%, 0.01 to 5%, 0.01 to 3%, or 0.4 to 2.3% w / w.

[0203] In one embodiment, the emulsion composition contains 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in a composition in which the in vitro measured skin penetration in humans is at least 0.01 to 10% of the active ingredient dose over about 1 to about 72 hours. In another embodiment, this period is about 2 to about 24 hours. In yet another embodiment, this period is about 6 to about 15 hours. The percentage of the active ingredient dose may be 0.01 to 7.5%, 0.01 to 5%, 0.01 to 3%, or 0.3 to 1.7%. In an alternative embodiment, the dose is 1 to 2 μg / cm³. 2 For example, it is measured at a concentration of 0.5% w / v.

[0204] As shown in Figure 3, formulation 17 delivered a higher relative amount of the active ingredient to the dermis compared to formulations 1 and 12. Conversely, as shown in Figure 4, formulation 17 delivered a relatively small amount into the receptor fluid. Formulations 1 and 12 were remarkably similar, with only minor changes in buffer composition and preservatives (Tables 1 and 4, respectively). Such similarities were confirmed by the in vitro human skin flux and dermal accumulation results, allowing for further data extrapolation of formulations to other formulations and formulation 12, and therefore to formulation 1.

[0205] The two formulations shown in Figures 5 and 6 have different amounts of the active ingredient (formulation 12 contains 0.5%, and formulation 21 contains 1%), but the same conclusion can be reached when normalization is applied. For example, formulation 21 also shows a higher relative amount in the dermis compared to the recipient fluid, which is measured as skin flow rate and accumulation and normalized to the administered dose. Accumulation represents how much of the active ingredient penetrates through the skin (500 ± 100 μm) and reaches the recipient fluid over a specific period of time. Skin flow rate represents the slope of the accumulation curve and the steady state (R) observed during the experiment. 2 It is characterized as a linear phase, also known as ≥0.99.

[0206] The amount of dermis at each time point (Figure 5) was converted from % of the administered dose to ng of the active ingredient, and the value was divided by the respective accumulation amount ng (Figure 6) at 3, 6, 9, 12, and 15 hours, indicating that Formulation 21 promoted targeted delivery to the dermis and reduced the amount of active ingredient penetrating into the receiving solution (the unbound active ingredient penetrated deeper than 500 ± 100 μm). The dermis / accumulation amount ratio (ng / ng) in the receiving solution of Formulation 21 ranged from 9038.0 and 12937 at 3 hours and 6 hours, respectively, to 909.3 and 1044.0 at 12 hours and 15 hours, respectively. For Formulation 12, the ratio ranged from 7870.2 to 1428.7 at 3 hours and 6 hours, respectively, to 215.7 and 233.93 at 12 hours and 15 hours, respectively, showing a significantly different profile. As observed in Figures 3 and 4, Formulation 21 showed good dose proportionality with different active ingredient strengths from 0.5% (Formulation 17) to 2.0% (Formulation 22). Therefore, the above-mentioned dermis / accumulation amount ratio is effective in demonstrating the superiority of Formulation 21 over Formulation 12, despite the different strengths (1.0% and 0.5%, respectively).

[0207] The lag period of the active ingredient in the formulation was in the range of 8 - 12 hours after administration. After this period, the active ingredient reached its steady state and showed a constant skin flux. To characterize the targeted delivery to the dermis observed for Formulation 21 compared to Formulation 12, the ratio of dermis (ng) / skin flux (ng * cm 2 / hr) was used as an additional parameter. From the data shown in Figure 6, the delivered skin fluxes (R 2 with slopes of ≧ 0.99) for Formulations 21 and 12 were 0.7251 ng * cm 2 / hr and 0.9935 ng * cm 2 / hr, respectively. Considering the different strengths of Formulations 21 and 12 (1.0% and 0.5%, respectively), the normalized skin flux values (skin flux divided by the active ingredient strength) were 0.7251 ng * cm 2 / hr and 1.987 ng * cm2 The value was / hr. Using these normalized skin flow values ​​and the dermal volume converted to ng (from Figure 6) that covers the steady state region (after 8 hours), we calculated dermis (ng) / normalized skin flow (ng) * cm 2 The ratio ( / hr) was calculated. Formulation 21 showed selective delivery of the active ingredient to the dermis at 9, 12, and 15 hours with ratios of 1599.5, 1132.6, and 3200.7, respectively. Formulation 12 showed a significantly different delivery profile at 9, 12, and 15 hours with ratios of 213.25, 108.57, and 117.73, respectively.

[0208] One embodiment of the present invention is a topical pharmaceutical emulsion composition comprising a therapeutically effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion is homogeneous, and the composition, when administered in vitro, exhibits a normalized skin flow rate (ng) (by activity intensity) when using freshly excised human abdominal skin. * cm 2 The ratio of steady-state dermal volume (ng) to ( / hr) is set to 1000-5000. In one embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition.

[0209] In another embodiment of the present invention, a homogeneous topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the composition, when administered to a human body not exceeding 35% of body surface area (BSA) skin, yields 30 ng * Less than h / mL, or 23.5 ng * Less than h / mL, or 16ng * This results in an area under the curve (AUC) of less than h / mL (AUC(0-tau)). In another embodiment, the amount does not exceed 30% BSA.

[0210] In one embodiment, the AUC is at a steady state. In another embodiment, the amount of body surface area (BSA) to which the drug is administered is less than 50%, in another embodiment, it is less than 35%, and in yet another embodiment, it is less than 30%. It is recognized that if the BSA is >10%, the AUC may increase accordingly.

[0211] As used herein, the term "AUC(0-last)" means the area under the plasma concentration-time curve from time 0 to the last measurable concentration, calculated by the log-linear trapezoidal method.

[0212] As used herein, the term "AUC(0-12)" means the area under the plasma concentration-time curve from time 0 to 12 hours, calculated by the log-linear trapezoidal method.

[0213] As used herein, the term "AUC(0-tau)" means the area under the plasma concentration-time curve from time 0 to the end of the dosing interval, calculated by the log-linear trapezoidal method.

[0214] In another embodiment of the present invention, a homogeneous topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the composition has a steady state of C max The amount of body surface area (BSA) to which the active ingredient (1% strength) is administered, resulting in the maximum plasma level of the drug, is 15-35%, and the concentration is less than 4 ng / ml. max And it produces an AUC (0-8h) of 16 ng.h / mL or less.

[0215] [Table 1]

[0216] [Table 2]

[0217] Atopic dermatitis is clinically evaluated based on historical characteristics, morphology, distribution of skin lesions, and associated clinical signs. Many formal criteria have been developed to aid in classification. At least 28 different criteria exist for measuring disease severity. The most commonly used are the SCORAD index, the Eczema Area and Severity Index (EASI), the Investigators Global Assessment (IGA), and the Six-Area, Six-Sign Atopic Dermatitis (SASSAD) severity score. For the purposes of this specification, either the IGA criteria or the EASI criteria will be used.

[0218] IGA is a static 5-point morphological assessment of overall disease severity determined by a physician, using clinical features such as erythema, infiltration, papulogenesis, exudation, and crusting as guidelines. The IGA is created without referring to previous IGA scores.

[0219] The IGA allows researchers to assess overall disease severity at a specific point in time and ranges from clear to very severe (0=clear, 1=nearly clear, 2=mild, 3=moderate, 4=severe; in very rare cases, a score of 5=very severe may be used). In the IGA, clinical features such as erythema, infiltration, papulogenesis, exudation, and crusting are used as indicators of overall severity. While the IGA may not be considered a valid outcome measure, it is used to validate other outcome scales as a "gold standard." Even when used in combination with other validation scales, the IGA itself does not become an independent and valid tool, but it is thought to correlate well with the EASI and is considered to have reasonable surface validity.

[0220] The EASI scoring system is a clinical method for assessing the severity of AD, taking into account the overall severity of erythema, infiltration / papule formation, epidermal exfoliation and lichenification, as well as the extent of BSA affected by AD. The four clinical signs are each scored on a 4-point scale (0 - 3) for each of four specific body areas (head and neck, upper limbs, lower limbs and trunk). EASI is also a static assessment created without reference to previous scores.

[0221] One embodiment of the present invention is a method for treating atopic dermatitis (AD) in a patient, comprising administering to the patient a topical pharmaceutical emulsion composition comprising an effective amount of active 3,5-dihydroxy- (4-isopropyl) trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant and an antioxidant, wherein the emulsion composition is homogeneous and the administration is carried out until the IGA score in the patient reaches clear (0) or almost clear (1), or until a two-step improvement is seen in the patient's IGA score. In one embodiment, the active ingredient is solubilized in the oil phase of the composition.

[0222] In one embodiment, the patient achieves clear (0) or almost clear (1) of the IGA score from baseline. In another embodiment, the patient achieves a two-step improvement from the baseline IGA score. For the purposes of this specification, the patient starts with an IGA score of 3 or more at baseline as a measure of the degree of severity.

[0223] In one embodiment, the time the patient remains without recurrence is, for example, 1 month or more, or 2 months or more, or 3 months or more after treatment. In one embodiment, the treatment unit is a treatment period of 28 weeks or less, or 21 weeks or less, or 16 weeks or less, or 12 weeks or less, or 8 weeks or less. In one embodiment of the present invention, the time to recurrence is not affected by the treatment period.

[0224] Another embodiment is a method of improving the body surface area (BSA)% of a person suffering from atopic dermatitis (AD), the method comprising administering to a patient a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, the emulsion composition being homogeneous, and the improvement in BSA% seen in the patient being about ≧10 - 29%, or >≧30 - 49%, or ≧50 - 69%, or ≧70 - 89%, or 90 - 100%.

[0225] Itching is the most frequent symptom of AD and potentially has the greatest impact on quality of life. In another embodiment, a method of reducing itching in a person suffering from atopic dermatitis (AD) comprising administering to a patient a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, the emulsion composition being homogeneous, and the time until itching is reduced and / or the BSA% affected by itching decreases from the baseline measurement. In one embodiment, the formulation of the present invention can be compared to Formulation 1 or Formulation 12.

[0226] One embodiment of the present invention is a method for obtaining an optimal dose for the treatment of atopic dermatitis in a patient, the method comprising administering a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant and an antioxidant to a patient in need thereof, wherein the emulsion is homogeneous, and the administration is continued until the patient's IGA score is clear or nearly clear, or until a two-step reduction in the IGA score is achieved. In one embodiment, the patient achieves a clear or nearly clear IGA score. In one embodiment, the treatment unit is a treatment period of 28 weeks or less, or 21 weeks or less, or 16 weeks or less, or 12 weeks or less. In one embodiment, the time to relapse after treatment is 3 months or more. In another embodiment, the time to relapse after treatment is 1 month or more. In another embodiment, the time to relapse after treatment is 3 months or more. In another embodiment, the time to relapse after treatment is 6 months or more. In one embodiment of the present invention, the time to recurrence is not affected by the duration of treatment.

[0227] Another embodiment of the present invention is a method for reducing the time to achieve improvement in a patient with atopic dermatitis to a clear or nearly clear IGA score of >50%, or to achieve a two-step reduction in the IGA score, the method comprising administering a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant to a patient in need thereof, wherein the emulsion composition is homogeneous. A suitable comparative formulation may be formulation 1 / 1a or 12 (%w / w of similar active ingredients). In one embodiment, the time to achieve a 50% reduction is 12 weeks. In another embodiment, the time to achieve a 50% reduction is 8 weeks.

[0228] In one embodiment, the daily dose of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is 10 mg to 100 mg. In another embodiment, the daily dose is 10 mg to 50 mg.

[0229] Psoriasis can be assessed in a similar manner. Of the many psoriasis assessment methods currently available, the Psoriis Area and Severity Index (PASI) and the Physician Global Assessment (PGA) are the most widely used. The PASI score is used to measure the severity and extent of psoriasis.

[0230] PASI examines four body regions: i) head and neck, ii) hands and arms, iii) chest, abdomen and back (torso), and iv) buttocks, thighs, and legs. Each region has a score indicating how much area is affected by psoriasis (region) and a score indicating how bad the psoriasis is (severity). The score for each region can range from 0 (no psoriasis) to 6 (all skin affected). A severity score for each region is obtained by adding scores for redness, thickness, and size, which are each rated from 0 to 4, up to a maximum score of 12. A PASI score > 10 generally suggests that the patient has moderate to severe plaque psoriasis.

[0231] The PGA standard for typical applications is a 7-level scale ranging from clear to severe. Severe: Extremely pronounced plaque elevation, extent, and / or erythema. Moderate to severe: Significant plaque elevation, extent, and / or erythema. Moderate: Moderate plaque elevation, extent, and / or erythema. Mild to moderate; intermediate between mild and moderate. Mild: Mild plaque elevation, spread, and / or erythema. Almost clear; somewhere between mild and clear. Clear. No signs of psoriasis.

[0232] One embodiment of the present invention is the percentage of patients who achieve a 50% or 75% reduction in their PASI score (PASI 50 or PASI 75) by using the topical emulsion compositions described herein. This may be a standalone clinical endpoint or in combination with patients whose PGA score reaches 0 or 1 (clear or near clear) at a defined time point, such as 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks of treatment. For the purposes of this specification, patients are most likely to start with a baseline PGA score of 4 or higher, for example, having moderate to severe plaque psoriasis, as a measure of severity.

[0233] One embodiment of the present invention is a method for obtaining an optimal dose for the treatment of psoriasis in a patient, the method comprising administering a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant and an antioxidant to a patient in need thereof, wherein the emulsion composition is homogeneous, and the administration is continued until the patient's PGA score is clear or nearly clear. In one embodiment, the treatment unit is a treatment period of 28 weeks or less, or 21 weeks or less, or 16 weeks or less, or 12 weeks or less. In one embodiment, the time to relapse after treatment is 3 months or more. In another embodiment, the time to relapse after treatment is 6 months or more. In one embodiment of the present invention, the time to relapse is not affected by the treatment period.

[0234] Another embodiment of the present invention is a method for reducing the time to achieve a clear or nearly clear PGA score >50% in a patient with psoriasis, or the time to achieve a two-step reduction in the PGA score, the method comprising administering a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant to a patient in need, wherein the emulsion composition is homogeneous. In one embodiment, the time to achieve a 50% reduction is 12 weeks. In another embodiment, the time to achieve a 50% reduction is 8 weeks. In one embodiment, the reduction in time can be compared to the administration of a suitable comparator such as formulation 1 / 1a or 12 (equivalent %w / w of active ingredients).

[0235] Alternatively, a method for reducing the PASI score by 50% or 75% in patients with psoriasis, the method comprising administering a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant and an antioxidant, to a patient in need thereof, wherein the emulsion composition is homogeneous.

[0236] In one embodiment, the treatment unit is a treatment period of 28 weeks or less, or 21 weeks or less, or 16 weeks or less, or 12 weeks or less. In one embodiment, the time to recurrence after treatment is 3 months or more. In another embodiment, the time to recurrence after treatment is 6 months or more. In one embodiment of the present invention, the time to recurrence is not affected by the treatment period. The comparative formulation may be formulation 1 / 1a. In one embodiment, the time to achieve a 50% reduction is 12 weeks. In another embodiment, the time to achieve a 50% reduction is 8 weeks.

[0237] Another embodiment is a method for reducing the time to achieve a clear or nearly clear PGA score >50% in a patient with psoriasis, or the time to achieve a two-step reduction in the PGA score and a reduction of PASI 50 or PASI 75, comprising administering to the patient a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant and a surfactant, wherein the emulsion composition is homogeneous. In one embodiment, the PASI score is PASI 75. In another embodiment, the patient achieves a clear or nearly clear PGA score.

[0238] Another embodiment is a method for improving the time to reach a PASI 50 or PASI 75 score in a person suffering from psoriasis, the method comprising administering to the person a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is homogeneous. In one embodiment, the time to reach PASI 50 is 16 weeks, or 12 weeks, or 8 weeks. In another embodiment, the time to reach PASI 70 is 16 weeks, or 12 weeks, or 8 weeks. Suitable comparative formulations may be formulations 1 / 1a or 12 (equivalent active ingredients %w / w).

[0239] According to one embodiment, the present invention provides a method for treating a patient's dermatological condition or disorder, the method comprising administering a topical pharmaceutical emulsion composition comprising an effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene, an oil phase, an aqueous phase, a surfactant, and an antioxidant to a patient in need thereof, wherein the emulsion composition is homogeneous. In another embodiment, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the oil phase of the emulsion composition. In another embodiment, a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum.

[0240] Another aspect of the present invention relates to the use in the manufacture of a pharmaceutical product for treating an inflammatory skin disease or disorder in a patient, comprising a topical pharmaceutical emulsion composition comprising an effective amount of an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is homogeneous. In one embodiment, the active ingredient is solubilized in the oil phase of the emulsion composition. In another embodiment, a second oil phase component is present if the oil phase contains mineral oil or petrolatum, and a third oil phase component is present if the oil phase contains both mineral oil and petrolatum. In one embodiment, the disease or disorder is atopic dermatitis, psoriasis, or acne.

[0241] The compositions of the present invention can be used topically in a veterinary or medical setting. It is recognized that the patient or subject may be an animal, or livestock such as mammals including horses, cattle, pigs, sheep, poultry, fish, cats, dogs, and zoo animals. In one embodiment, the patient is an animal. In another embodiment, the patient is a mammal. In another embodiment, the mammal is a human. In another embodiment, the human is an adult patient or a pediatric patient. In one embodiment, the pediatric patient is a child. In another embodiment, the pediatric patient is between 3 months and 2 years of age or older.

[0242] In one embodiment, the dermatological condition or disorder for which treatment is sought is an inflammatory skin disease, such as dermatitis (e.g., atopic dermatitis, contact dermatitis, eczematous dermatitis or seborrheic dermatitis), acne, chronic inflammatory skin diseases such as psoriasis, rosacea or skin aging.

[0243] In some aspects, the dermatological condition or disorder is selected from the group for the treatment of skin diseases, wherein the skin diseases include persistent inflammation, skin disorders of cell kinetics and differentiation (e.g., psoriasis, psoriatic arthritis, exfoliative dermatitis, pityriasis rosea, lichen planus, lichen nitidus or porokeratosis); skin disorders of dermal junctions, vesicular and bullous disorders (e.g., pemphigus, bullous pemphigoid, acquired epidermolysis bullosa, or pustular rash on the palms or soles); skin disorders of epidermal appendages and related disorders (e.g., hair disorders, nails, rosacea, perioral dermatitis or milia syndrome); skin disorders such as tumors of the epidermis and appendages (e.g., squamous cell carcinoma, basal cell carcinoma, keratoacanthoma, benign epithelial tumor or Merkel cell carcinoma); melanocyte disorders (e.g., pigmentation disorders, vitiligo, melanopenia and melanocytosis, melanocytic nevi or melanoma); skin disorders of dermal inflammatory and neoplastic disorders (e.g., persistent nodular erythema, eosinophils, granuloma faciale, pyoderma gangrenosum, malignant atrophic papulosis, dermal and soft tissue fibrous damage, or Kaposi's sarcoma); disorders of the subcutaneous tissue (e.g., panniculitis or lipodystrophy); skin disorders related to altered reactive skin changes (e.g., urticaria, angioedema, graft-versus-host disease, allergic contact, autoeczematization dermatitis, atopic dermatitis or seborrheic dermatitis); changes in the skin due to mechanical and physical factors (e.g., burns, radiation dermatitis, calabar swellings or scleroderma); photodamage (e.g., acute and chronic UV radiation or photosensitization); or skin disorders due to microbial agents (e.g., leprosy, Lyme borreliosis, onychomycosis, tinea pedis, rubella, measles, herpes simplex, EBV (Epstein-Barr virus), HPV (human papillomavirus) (e.g., HPV6 and 7), warts or prions).

[0244] In one embodiment, the inflammatory disorder is selected from the group consisting of psoriasis, as well as atopic dermatitis and acne. In one embodiment, the dermatological condition or disorder is psoriasis. In another embodiment, the dermatological condition or disorder is atopic dermatitis. In yet another embodiment, the dermatological condition or disorder is acne.

[0245] definition The terms “therapeutically effective dose” or “effective dose” as used herein mean an amount of the active ingredient sufficient to produce a therapeutic effect upon administration, for example, an amount that, when repeatedly administered to the affected area over a period of time, causes improvement or change in the condition to be treated. The effective dose varies depending on the specific condition being treated, the severity of the condition, the duration of treatment, the stage of progression of the condition, the affected body surface area of ​​the clinical condition, and the specific components of the composition. The effective dose of the active ingredient for the treatment of a condition or disorder can be determined by standard clinical methods. The appropriate amount in any given case is readily apparent to those skilled in the art or can be determined by routine experimentation. The composition is generally administered topically to the affected area, i.e., topically to the skin area where the clinical abnormality appears.

[0246] Concentration, volume, solubility, and other numerical data may be expressed herein in the form of ranges. Such range formats are for convenience and brevity only and should be interpreted flexibly to include all numbers and subranges, as if each individual number and subrange within the range were explicitly stated, rather than only the numbers explicitly stated as limits of the range. All numbers representing volumes, percentages, or proportions, and other numerical values ​​used herein, should be understood in all cases as being modified by the term "approximately."

[0247] For example, the concentration range of 0.1–5 ng / ml should be interpreted to include not only the explicitly stated concentration limits of 0.1 ng / ml and 5 ng / ml, but also individual concentrations such as 0.2 ng / ml, 0.8 ng / ml, 1.0 ng / ml, 2.2 ng / ml, and 3.6 ng / mol, as well as subranges such as 0.3–2.5 ng / ml and 1.8–3.2 ng / ml. This interpretation should apply regardless of the range width or the described characteristics.

[0248] As used herein, the terms “administering” and “administration” mean any method of delivering a pharmaceutical emulsion composition to a patient in a manner that provides a desired therapeutic effect in an effective medical practice.

[0249] As used herein, “topical” administration of a pharmaceutical emulsion composition means application and diffusion to the stratum corneum, including administration to psoriatic lesions and damaged skin.

[0250] As used herein, in in vitro skin penetration studies, the term “epidermis” includes the stratum corneum and tissues or layers up to the basement membrane, isolated by thermal separation treatment.

[0251] As used herein, in in vitro skin penetration studies using skin samples with a thickness of 500 microns (+ / -100 microns), the term "epidermis" refers to the upper / surface layer obtained by thermal separation treatment, and the term "dermis" refers to the lower layer (after washing / tape removal treatment).

[0252] The terms “treatment” or “treating” a dermatological condition or disorder encompass alleviation of at least one symptom, reduction of its severity, or delay, prevention, or inhibition of its progression. Treatment does not necessarily mean that the condition or disorder is completely cured. Pharmaceutical emulsion compositions useful herein only need to reduce the severity of a condition or disorder, reduce the severity of associated symptoms, improve the patient’s quality of life, or delay, prevent, or inhibit the onset of symptoms or disorder. Treatment does not need to be effective to have clinical utility in the medical and pharmaceutical fields for all members of a population, for example, a population of patients with atopic dermatitis.

[0253] The term "pharmaceutically acceptable salt" means a salt that is safe and effective for topical use in patients and possesses the desired pharmaceutically active properties. Such salts include those formed when acidic protons are substituted with metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions).

[0254] The terms “pharmaceutically acceptable” and “dermatologically acceptable” mean that they are approved by a regulatory authority or listed in a pharmacopoeia or other generally accepted guidelines for use in animals, particularly humans.

[0255] As used herein, the term “skin penetration” means the diffusion of 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof through the stratum corneum, as well as into the epidermis and / or dermis of the skin.

[0256] As used herein, “patient” includes human patients, including adults, teenagers, and children (e.g., pediatric patients). Pediatric patients may include teenagers under the age of 18. In this specification, a child is under the age of 12.

[0257] As used herein, “solubilize” means dissolving in a particular phase in an amount of ≥50% w / w, or ≥60% w / w, or ≥70% w / w, or ≥80% w / w, or ≥90% w / w, or ≥95% w / w, relative to the weight % of the final composition being prepared.

[0258] As used herein, "homogeneous" means that one phase is uniformly dispersed in the other phase. In the case of an o / w emulsion, this means the uniform dispersion of the oil phase in the aqueous phase.

[0259] Any concentration range, percentage range, or ratio range described herein is understood to include any integer concentration, percentage, or ratio within that range, as well as fractions such as one-tenth and one-hundredth of an integer, unless otherwise specified.

[0260] Unless otherwise specified, all percentages are relative to the weight percentage of the final composition being prepared, and all totals equal 100% by weight.

[0261] As used herein, the terms “a” and “an” should be understood to mean “one or more” of the components described. Those skilled in the art will see that, unless otherwise indicated, the use of the singular form includes the plural form.

[0262] Throughout this application, the word “comprising” is used in descriptions of various embodiments, but in some specific examples, embodiments may be described alternatively using the words “consisting essentially of” or “consisting of.”

[0263] "Substantially free" of a specific ingredient means that the composition contains less than approximately 1% by weight of that ingredient. "Free" of a specific ingredient means that the composition does not contain that ingredient.

[0264] Because the biological profile, or the pK / pD of 3,5-dihydroxy-4-isopropyl-trans-stilbene or its pharmaceutically acceptable salt, depends on the absence of degradation products and the delivery of the active ingredient in an effective amount to the appropriate layer of skin, the compositions described herein provide patients with novel drug therapeutic options for various inflammatory skin conditions.

[0265] Other terms used herein are intended to be defined by their well-known meanings in the art. The following examples are illustrative of the invention and do not limit the scope of the invention. The following examples illustrate the invention. These examples do not limit the scope of the invention, but rather are intended to provide guidance to those skilled in the art for preparing and using the compounds, compositions and methods of the invention.

[0266] While specific embodiments of the present invention are described, those skilled in the art will understand that various changes and modifications can be made without departing from the spirit and scope of the invention. [Examples]

[0267] Example 1: Preparation of a cream containing 0.5 w / w 3,5-dihydroxy-4-isopropyl-trans-stilbene The following cream compositions were prepared. [Table 3]

[0268] Due to the chemical degradation of the active ingredient observed in the stability tests of the above-mentioned formulation, an alternative formulation was prepared using antioxidants and alternative preservatives and buffering systems. Alternatively, Crodex was used. TM to Polawax TM It can also be replaced with this. See Examples 2-4 below.

[0269] Example 2: Preparation of a cream composition containing 0.5% w / w 3,5-dihydroxy-4-isopropyl-trans-stilbene Next, the following cream composition was prepared. [Table 4]

[0270] Example 3: Further cream composition containing 0.5% w / w 3,5-dihydroxy-4-isopropyl-trans-stilbene [Table 5]

[0271] Example 4: Further cream composition containing 0.5% w / w 3,5-dihydroxy-4-isopropyl-trans-stilbene Based on the findings from Examples 2 and 3, formulations 10-14 were selected for further development. Formulations 10-14 are identical to each other except for the presence of different concentrations of the active ingredient (ranging from 0% to 2% w / w), with the water content adjusted accordingly. [Table 6]

[0272] Example 5: Preparation Method The cream compositions described in Examples 1 to 4 were prepared using the following general method.

[0273] Oil phase: 1. Add the oil phase components (e.g., white petrolatum, mineral oil, steareth-2, and steareth-20) to a container of appropriate size, begin mixing, and heat to 70-80°C. 2. When the oil phase reaches 70-80°C, add Polawax TM Slowly add Crodex or (if applicable) cetearyl alcohol. Mix until all materials are melted / dissolved and the oil phase is homogeneous.

[0274] Active phase: 3. Add the active phase components (e.g., propylene glycol and diethylene glycol monoethyl ether) to a separate container of appropriate size. Heat to 50-60°C while mixing. 4. Once the above temperature is reached, slowly add the active ingredient to the active phase while mixing. Maintain the temperature at 50-60°C and mix until homogeneous, free of insoluble particles, and the active phase has a uniform appearance.

[0275] Water phase: 5. Add the aqueous phase components (e.g., water and buffer) to the main mixing vessel. Begin mixing and heat to 70-80°C. Mix until all materials are completely dissolved and the aqueous phase has a homogeneous appearance.

[0276] Emulsification: 6. Once the aqueous and oil phases are free of insoluble particles and have a homogeneous appearance at 70-80°C, the oil phase is slowly transferred under vacuum to the main container containing the aqueous phase. The oil phase container is scraped off and transferred to the main container. 7. Once transfer and scraping are complete, maintain the mixer settings and mix for 5-10 minutes while keeping the product temperature at 70-80°C. Ensure the product has a homogeneous appearance. 8. Once homogenized, maintain the mixing and cool to 50-60°C. 9. When the temperature of the product and active phase reaches 50-60°C, increase the mixing and slowly transfer the active phase to the main container under vacuum. Use the reserve propylene glycol to scrape and rinse the active phase container and transfer it to the main container. 10. Once transfer and scraping are complete, maintain the product temperature at 50-60°C, increase the vacuum, and maintain the mixer settings, mixing for 5-10 minutes. Ensure the product has a homogeneous appearance. 11. Once mixing is complete, maintain the mixture and cool the batch to 30°C (25-35°C). 12. Once the above temperature is reached, reduce the mixing and cool the batch to <25°C. 13. Once the product temperature reaches <25°C, mix at high speed for 15 minutes. Maintain the product temperature at <25°C. 14. Once mixing is complete, reduce the mixing speed and ensure the product has a homogeneous appearance. If necessary, cool the product to <25°C before beginning to discharge the product. 15. Once the product is homogenized and the temperature is <25°C, take a sample as needed and transfer it to a suitable storage container.

[0277] An alternative process, in which the aqueous phase is added to the oil phase (i.e., the opposite of the above process), yielded a product with an unsatisfactory physical appearance and poor chemical stability.

[0278] Example 6 - Chemical and Physical Stability Samples of formulations 2-5 were stored at 25°C, 30°C, and 40°C for 3 months and subjected to visual analysis. Formulations 2-4 showed no discoloration or physical separation over the 3-month period. However, formulation 5 showed signs of heterogeneity.

[0279] The samples were also subjected to chemical stability analysis by HPLC using the following conditions: Zorbax Bonus reversed-phase column: 150 × 4.6 mm, 3.5 mm particle size with 4.0 mm guard frit. Column temperature: 25℃ Autosampler temperature: Ambient conditions Flow rate: 1.0ml / min Injection volume: 15μl Detection: 235nm Runtime: 50 minutes Mobile phase A: 0.1%TFA in water Mobile phase B: Acetonitrile

[0280] [Table 7]

[0281] Formulations 2-5 met the chemical stability specifications when stored for up to 3 months under standard ICH conditions. Formulations 6-9 showed similar chemical and physical stability. Based on these findings, formulations 10-14 were selected for further development. However, during the process development of formulations 10-14, microscopic analysis revealed heterogeneity in the emulsion structure of these formulations and the presence of waxy material. The heterogeneous emulsion is shown in Figure 1 and was determined to be dependent on the concentration of the active ingredient. In other words, no such findings were observed in formulation 10 (placebo), and an increase in the degree of heterogeneity was observed as the concentration of the active ingredient increased.

[0282] To identify which semi-solid component is responsible for the formation of heterogeneous emulsions, experiments were conducted by systematically substituting each semi-solid component as follows. [Table 8]

[0283] Formulations without petrolatum were observed to have a homogeneous emulsion. Further characterization was performed using hot-stage optical microscopy, XRD, IR microscopy, and fluorescence microscopy. These methods confirmed that the wax-like substance contained petrolatum and that its concentration was a function of the concentration of the active ingredient present. These observations suggested that the petrolatum was not sufficiently emulsified, and that the active ingredient was not solubilized in either the aqueous or oil phase of the emulsion.

[0284] Example 7: Development of a final physically and chemically stable cream formulation containing 0.5% w / w 3,5-dihydroxy-4-isopropyl-trans-stilbene for clinical development. The solubility of the active ingredient in different solvents was measured. The active ingredient was observed to have good solubility in medium-chain triglycerides (MCTs) selected to replace white petrolatum and mineral oil in the oil phase of the emulsion composition. The following formulations were prepared using 5%, 10%, 15%, and 20% MCTs (formulations 15-18). Two formulations (formulations 19 and 20) were also prepared by substituting Polawax (a proprietary blend of cetostearyl alcohol and emulsifier) ​​with cetostearyl alcohol and additional emulsifiers.

[0285] [Table 9]

[0286] Formulations 15-20 were subjected to microscopic analysis. All six formulations were homogeneous, with a dispersed oil phase having small particle sizes, and a homogeneous emulsion was observed. Figure 2 shows the difference in appearance between a formulation with 10% MCT in the oil phase and a formulation with a larger amount of white petrolatum and mineral oil in the oil phase. While not intended to be theoretically restrictive, it is thought that the amphiphilic nature of the active ingredient may destabilize the emulsion, especially if an appropriate solvent is not selected. It is thought that a more stable emulsion can be obtained by using a suitable solvent for the active ingredient in the oil phase.

[0287] Formulation 17 (0.5% active ingredient) was prepared along with equivalent formulations containing 1%, 2% (formulations 21 and 22, respectively), and 3% (formulation 26) of the active ingredient. Alternative formulations were also prepared (formulations 23 and 24) in which 7.2% Polawax was replaced with 5.90% cetostearyl alcohol to increase the surfactant content. A variant of Formulation 17 containing 0.1% of the active ingredient is shown as Formulation 25. Formulation 17 met all chemical and physical stability specifications when stored for up to 6 months under standard ICH conditions. Thus, one embodiment of the present invention is a pharmaceutical emulsion composition that is chemically and physically stable when stored for up to 6 months under standard ICH conditions, comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof as the active ingredient, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the active ingredient is solubilized in the oil phase of the emulsion composition. Another embodiment of the present invention is a pharmaceutical emulsion composition comprising an active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is homogeneous, and is chemically and physically stable when stored for up to 6 months under standard ICH conditions. In another embodiment, the active ingredient is solubilized in the oil phase of the emulsion composition. In another embodiment, the average droplet size of the discontinuous phase is 1 micron or less.

[0288] Additional formulations, such as formulations 27-29, were also manufactured with a change in the co-solvent. These data suggest that propylene glycol or Transcutol are not necessary for the physical stability of the formulations, and therefore, opportunities arise for using alternative solvents for the solubilization of the active ingredients used.

[0289] The formulations are shown in Table 8 below. [Table 10]

[0290] Example 8 - Method for preparing the final formulation The cream composition described in Example 7 was prepared using the following general method.

[0291] Oil phase: 1. Place the oil phase components (e.g., MCT, Polawax) in a container of appropriate size. TM Add benzoic acid, BHT, propylene glycol, diethylene glycol monoethyl ether, polysorbate 80, steareth-2, steareth-20, and the active ingredient, and continue mixing until the active ingredient is dissolved and the phase has a uniform appearance.

[0292] Water phase: 2. Add the aqueous phase components (e.g., water and sodium citrate, citric acid and disodium EDTA) to the main mixing vessel. Begin mixing and heat to 70-80°C. Mix until all materials are completely dissolved and the aqueous phase has a homogeneous appearance.

[0293] Emulsification: 3. Once the aqueous and oil phases are free of insoluble particles and have a homogeneous appearance at 70-80°C, the oil phase is slowly transferred under vacuum to the main container containing the aqueous phase. The oil phase container is scraped off and transferred to the main container. 4. Once transfer and scraping are complete, maintain the mixer settings and mix for 5-10 minutes while keeping the product temperature at 70-80°C. Ensure the product has a homogeneous appearance. 5. Transfer the batch to a holding container and allow it to cool.

[0294] Therefore, another embodiment of the present invention is: i) Mixing and heating the oil phase components and the active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, until dissolved; ii) A step of mixing until the aqueous phase components are completely dissolved. A method for producing an emulsion composition comprising, The oil phase component from step (i) and the aqueous phase component from step (ii) are added and mixed until the appearance is homogeneous. In one embodiment, the resulting emulsion composition is homogeneous. In another embodiment, the active ingredient is solubilized in the oil phase. In another embodiment, the average droplet size of the discontinuous phase is about 35 microns or less. In another embodiment, the average droplet size of the discontinuous phase is less than about 25 microns. In another embodiment, the average droplet size of the discontinuous phase is less than about 15 microns. In another embodiment, the average droplet size of the discontinuous phase is less than about 10 microns. In another embodiment, the average droplet size of the discontinuous phase is less than about 5 microns. In another embodiment, the average droplet size of the discontinuous phase is about 1 micron or less than about 1 micron. In another embodiment, the average droplet size of the discontinuous phase is about 0.5 microns. In another embodiment, the average droplet size of the discontinuous phase is about 0.05 to about 35 microns. In another embodiment, the average droplet size of the discontinuous phase is about 0.05 to about 5 microns. In another embodiment, the average droplet size of the discontinuous phase is about 0.05 to about 1 micron. In another embodiment, the average droplet size of the discontinuous phase is approximately 0.1 to approximately 0.75 microns. In another embodiment, the average droplet size of the discontinuous phase is approximately 0.05 to approximately 35 microns. In another embodiment, the average droplet size (D50) of the discontinuous phase is less than 5 microns. In another embodiment, the average droplet size (D50) of the discontinuous phase is less than 1 micron.

[0295] Another embodiment is, i) Mixing and heating the oil phase components and the active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, until dissolved; ii) A step of mixing until the aqueous phase components are completely dissolved. A method for producing an emulsion composition comprising, The oil phase component from step (i) and the aqueous phase component from step (ii) are added and mixed until the appearance is homogeneous, and the emulsion is homogeneous, with an optional average droplet size (D50) of the oil / discontinuous phase being less than 5 microns.

[0296] Example 9: Further cream composition containing 1.0% w / w of 3,5-dihydroxy-4-isopropyl-trans-stilbene To aid in identifying the semi-solid components that cause heterogeneous emulsion formation, petrolatum was retained in the formulations, and further experiments were conducted by removing the mineral oil in the oil phase of the emulsion composition and replacing it with medium-chain triglycerides (MCTs) (see Table 9). Generally, the variables for formulations 30-32 are the percentage of petrolatum and the corresponding water content. Formulations 33 and 37 showed low content petrolatum (4% and 2%) and 10% MCT. Formulation 34 showed both MCT and mineral oil. Formulations 35 and 36 showed low content mineral oil and petrolatum along with MCT, and finally, formulations 38 and 39 showed low content mineral oil and petrolatum without MCT. Heterogeneous emulsion properties were observed in formulations 34-37 with varying amounts. Formulations containing low levels of petrolatum exhibited stable but heterogeneous emulsion properties with currently unknown active ingredients. In particular, mineral oil could be added to the formulation in combination with MCT.

[0297] [Table 11]

[0298] It should be noted that Example 3 of US Patent No. 7,868,047 contains the active substance in a “Galax” cream base, which does not appear to be a confidential or commercially available base. A commercially available product called “Glaxal” cream base, containing water, petrolatum, cetearyl alcohol, paraffin solution, cerealeth-20, sodium phosphate, and p-chloro-m-cresol, is available from WellSpring Pharmaceuticals, Fla., USA.

[0299] Using Example 3 as a guide, two formulations were prepared using WellSpring's Glaxal substrate. The active ingredient, 3,5-dihydroxy-4-isopropyl-trans-stilbene, was dissolved in ethanol and then added to the Glaxal substrate while mixing. Mixing was continued for 15 minutes until the formulation appeared homogeneous, and then it was analyzed under a microscope.

[0300] Formulation 41 containing 1% of the active ingredient and Formulation 42 containing 2% of the active ingredient were prepared with the following compositions. [Table 12]

[0301] As is evident from microscopic observation, the droplet diameter / particle size increased immediately upon addition of the active ingredient to the substrate, and this diameter depended on the amount of the added active ingredient. This was similar to the observations seen in formulations similar to formulation 12, which contains both mineral oil and petrolatum.

[0302] Example 10: Effect of a cream composition containing 3,5-dihydroxy-4-isopropyl-trans-stilbene on skin penetration properties The purpose of this study was to measure the in vitro skin penetration of 3,5-dihydroxy-4-isopropyl-trans-stilbene.

[0303] In particular, formulations 17 and 21-24 were tested for their ability to deliver the active ingredient to the epidermis and dermis, and compared with formulations 1 and 12.

[0304] In short, formulations 1, 12, 17, and 21-24 containing 3,5-dihydroxy-4-isopropyl-trans-stilbene were evaluated using a skin penetration assay. This test was designed to determine drug penetration into the epidermis, dermis, and receptor fluid. Skin was harvested from freshly excised human abdominal skin in a thickness of 500 ± 100 μm, placed in a flow-through diffusion cell using a donor block, and measured at 1.0 cm. 2 A leak-proof seal was attached, exposing the surface area. The diffusion cell was connected to a multi-channel pump using PBS at a flow rate of approximately 0.6 mL / hour. Each cell was then equilibrated in a heated manifold to ensure a skin surface temperature of 32°C (at least 30 minutes before administration). The test substance was administered at a dose of 10 μl per skin section (10 mg of test substance / cm³). 2The test substance was administered via ) to two separate donors to capture inter-individual variability, and intra-individual variability was captured using at least seven skin sections per donor. Fifteen hours after administration, the skin surface was wiped with a cotton swab, and tape removal was performed three times to remove any remaining test substance. The washed skin was thermally separated at the epidermal and dermal junction. The skin layers were placed in separate homogenization containers, and the drugs were extracted. Extraction of the active ingredient from separate test substances helped to evaluate the efficiency of the extraction solvent. Based on the recovered drug concentrations, skin penetration into the epidermis and dermis as a percentage of the administered dose was calculated. 3,5-Dihydroxy-4-isopropyl-trans-stilbene was detected by liquid chromatography / mass spectrometry.

[0305] Figure 3 shows the epidermis from formulations 1, 12, 17, and 21-24, and the amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered to the epidermis (15 hours after application).

[0306] Error bars represent the standard error of the mean (SEM) of 8 to 14 replicates per formulation (4 skin donors). Note: The dosing area of ​​the diffusion cell is 1 cm². 2 Therefore, the amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene shown in Figure 3 is μg / cm³. 2 It represents.

[0307] By comparing 0.5% w / w 3,5-dihydroxy-4-isopropyl-trans-stilbene formulations, it was observed that the amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered into the epidermis was similar for formulations 17, 12, and 1. However, formulation 17 delivered approximately three times more 3,5-dihydroxy-4-isopropyl-trans-stilbene to the dermis compared to formulations 12 and 1. Furthermore, data from formulations 17, 21, and 22 showed dose-dependent delivery of the active ingredient. Similarly, data from formulations 23 and 24 showed dose-dependent delivery of the active ingredient.

[0308] The amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered to the receptor fluid over 15 hours appeared to be inversely correlated, with formulation 17 showing 2 to 4 times less than formulations 12 and 1. Similar to the amount delivered to the skin layers (epidermis and dermis), data from formulations 17, 21, and 22 observed that the active ingredient was delivered to the receptor fluid in a dose-dependent manner. Similarly, data from formulations 23 and 24 also showed that the active ingredient was delivered to the receptor fluid in a dose-dependent manner.

[0309] Example 11: Effect of a cream composition containing 3,5-dihydroxy-4-isopropyl-trans-stilbene on skin accumulation Previous studies have shown that formulation 17 delivers a larger amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene to the dermis while distributing a smaller amount to the receptor compared to formulation 12. To further investigate this observation, we conducted tests in human ex vivo skin, measuring skin levels every 3 hours (0–15 hours) and after 24 hours, and comparing them to the concentrations measured in the receptor.

[0310] Formulations 12 and 21, each containing 0.5% and 1.0% 3,5-dihydroxy-4-isopropyl-trans-stilbene, respectively, were evaluated using an ex vivo human skin penetration assay. This assay was designed to determine drug penetration into the epidermis, dermis, and receptor fluid, and involved further sampling for skin accumulation. Skin was harvested from freshly excised human abdominal skin in a thickness of 500 ± 100 μm, placed in a flow-through diffusion cell using a donor block, and measured at 1.0 cm². 2 A leak-proof seal was attached, exposing the surface area. The diffusion cell was connected to a multi-channel pump using PBS at a flow rate of approximately 0.6 ml / hour. To maintain skin integrity and prevent bacterial growth, the recipient solution for the 72-hour test contained 1% antibiotic-antifungal agent. Each cell was then equilibrated in a heated manifold to ensure a skin surface temperature of 32°C (at least 30 minutes before administration). The test substance was administered at a dose of 10 μl per skin section (10 mg of test substance / cm³). 2The test substance was administered via ) to two separate donors to capture inter-individual variability, and intra-individual variability was captured using at least seven skin sections per donor. To measure the penetration of the active ingredient into the skin, the recipient fluid was collected every hour for 72 hours. At 3, 6, 9, 12, and 15 hours post-administration, the skin surface was wiped with a cotton swab, and the tape was removed three times to remove any remaining test substance that was thought not to have penetrated the skin. The washed skin was thermally separated at the epidermal and dermal junctions. The skin layers were placed in separate homogenization containers, and the drugs were extracted using an Omni bead homogenizer. Based on the recovered drug concentrations, skin penetration into the epidermis and dermis as a percentage of the administered dose was calculated. 3,5-Dihydroxy-4-isopropyl-trans-stilbene was detected using the liquid chromatography / mass spectrometry method described above.

[0311] Formulation 21 resulted in a higher concentration of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered to the dermis compared to Formulation 12, showing a similar trend to that observed above. See Figure 5. The increased tendency for dermal accumulation or tissue retention with Formulation 21 appeared 3 hours after administration and continued for 15 hours post-administration.

[0312] Because the skin began to lose its integrity, potentially leading to inaccurate measurements of the active ingredients, tissue analysis (epidermis and dermis) was not considered at later time points (i.e., more than 15 hours).

[0313] A similar inverse correlation was observed for the amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene delivered into the receptor fluid, with formulation 21 showing 1.4 times less than formulation 12 (Figure 6). This trend of reduced delivery to the receptor fluid was consistent throughout the entire 72-hour administration period, as both formulations appeared to reach a steady state after 12 hours (delayed phase). Despite formulation 21 (1% w / w) having twice the concentration of the active ingredient as formulation 12 (0.5% w / w), formulation 21 was unable to deliver a comparable amount into the receptor fluid. This result suggests that formulation 21 can alter tissue retention, preventing the active ingredient from distributing from the skin to the receptor fluid.

[0314] In one embodiment of the present invention, the above-described formulation is used, which allows the patient to be exposed to less systemic exposure of the active ingredient during use. In another embodiment, the frequency of administration to the affected area may be less frequent than previously assumed. The compositions of the present invention may be administered to the affected area at doses represented by any of the embodiments herein, twice daily, once daily, once every other day, twice weekly, three times weekly, or once weekly. In another embodiment, treatment may be administered in two stages, namely an initial administration frequency such as once or twice daily, followed by a maintenance stage such as every other day, twice weekly, three times weekly, or once weekly.

[0315] Example 12: Biological activity of a cream composition containing 3,5-dihydroxy-4-isopropyl-trans-stilbene in ex vivo human skin Target profiling revealed that 3,5-dihydroxy-4-isopropyl-trans-stilbene is an activator of the AhR pathway in human colon adenocarcinoma. BioMAP®, a system that can provide physiologically relevant insights into compounds before long-term, expensive animal or clinical studies, confirmed that AhR may be a primary target of 3,5-dihydroxy-4-isopropyl-trans-stilbene. 3,5-dihydroxy-4-isopropyl-trans-stilbene has also been shown to induce the expression of the AhR target gene, cypla1, in early human keratinocytes and human or rodent leukocytes. A model using freshly excised human skin is being developed to explore the intrinsic efficacy (i.e., target engagement) of the active ingredient. This model will allow for the administration of topical formulations to explore the pharmacodynamic activity of the skin. In this study, the CyplA1-induced biological activity of formulations 17, 21, and 22 was compared with formulation 12 to that of formulation 12.

[0316] Tissue culture using static cells A 750 μm sample was taken from freshly excised healthy human skin and washed with an antibiotic / antifungal solution prepared as 1% GIBCO® antibiotic-antifungal agent (100x) and 0.1% gentamicin in 1x Dulbecco's phosphate-buffered saline. A 12 mm diameter biopsy sample was cut using a disposable biopsy punch and washed with the antibiotic / antifungal solution for 5-10 minutes. The skin biopsy sample was placed in an autoclaved 2 ml receptor capacity container with a 7 mm (0.38 cm) diameter. 2The receptor chamber was placed in uncoated static cells and secured with a metal clamp and donor chamber to prevent leaks. The receptor chamber was filled with cornification media using a Pasteur pipette to dispense into the sampling port. The static cells were then placed in a humidified incubator at 37°C. On day 1, the test material was topically applied (to exposed / dry epidermis). After 24 hours (day 0), the medium in the receptor chamber was activated with an activation cocktail designed to stimulate skin-resident immunocompetent cells. After 24 hours (day 1), the tissue was removed, finely chopped into pieces less than 1 × 1 × 1 mm, and stored in 10 × volume RNA later containing 300 μl of RNeasy Lysis Buffer supplemented with 1% 2-β-mercaptoethanol for RNA isolation.

[0317] Keratinization culture medium The culture medium contains 237 ml of Dulbecco's Modified Eagle Medium (DMEM), 237 ml of Ham's F-12 medium, 1 ml of 90 mM adenine, 1 ml of 0.94 M CaCl, 1 ml of 10 nM triiodothyronine, 1 ml of insulin-transferrin-selenium-ethanolamine (ITS-X) (100x), 5 ml of antibiotic-antifungal agent (100x), 10 ml of fetal bovine serum (FBS), 5 ml of GlutaMAX® supplement, and 0.1 ml of 50 mg / ml gentamicin.

[0318] Activation CocktailThe ex vivo human skin target engagement model was originally developed to mimic the pro-inflammatory state of lesional psoriatic skin. This model is described in Smith et al., PLOS ONE, DOI:10.1371 / journal.pone.0147979; Feb 12, 2016, and is referred to herein as the sRICA (Skin Resident Immune Cell Activation) assay. Thus, skin resident immune cells are activated in situ in combination with 1 μg / ml purified NA / LE mouse anti-human CD3 antibody, 2 μg / ml CD28 antibody, 1 μg / ml anti-human IFN-γ antibody, 1 μg / ml anti-human IL-4 antibody, and 10 ng / ml recombinant human (rh)IL-1b / IL-1F2, 10 ng / ml rhIL-6 (R&D Systems), 1 ng / ml rhTGF-b1, and rhIL-21. All components are incorporated into a single mixture with the keratinizing medium (i.e., an activation cocktail).

[0319] RNA isolation and quantificationApproximately 40 mg of finely chopped tissue was added to homogenization tubes containing 2.8 mm and 1.4 mm ceramic beads. The tissue was homogenized using a high-throughput bead mill homogenizer by ice crushing for 10 cycles at 6300 rpm for 30 seconds each, followed by 2 minutes of ice crushing. 490 μl of water containing 10 μl of proteinase K was added to the homogenate, and digestion was carried out at 55°C for 15 minutes. The digested tissue was spun down at 10,000 × g for 3 minutes to form a cell debris pellet, and the supernatant was used for RNA isolation using Qiagen's Mini RNA Isolation Kit. Total RNA was quantified using Nanodrop 2000. RNA (1.4 μg) isolated from skin tissue was used as a template in a 20 μl PCR volume using the Invitrogen SuperScript VILO cDNA Synthesis Kit to prepare a cDNA template. cDNA was diluted 1:25 for subsequent qPCR using specific TaqMan probes for each gene to be quantified. A Life Technologies AVii7 PCR instrument was used for 40 qPCR amplification cycles. The RNA level of Cypla1 relative expression was calculated using the delta-delta CT formula and normalized to untreated skin sections.

[0320] Formulations 17, 21, and 22, as well as formulation 12, demonstrated the biological activity of 3,5-dihydroxy-4-isopropyl-trans-stilbene in human skin, indirectly measured by CyplA1 mRNA. There were no differences in biological activity among these formulations. The lack of dose-response for formulations 17, 21, and 22 suggests that this upregulation reached the maximum or plateau achievable in formulations containing 0.5% or less of 3,5-dihydroxy-4-isopropyl-trans-stilbene. These data confirm that the concentrations quantified in the in vitro skin penetration test are biologically available and capable of engaging targets in human skin. It was found that this assay does not yield statistically significant differences between formulations and / or concentrations of the active substance within the formulations.

[0321] Example 13: Systemic exposure and skin concentration of 3,5-dihydroxy-4-isopropyl-trans-stilbene after 7 days of topical administration to Göttingen minipig To assess tissue concentrations and systemic exposure, toxicological studies were conducted in Göttingen miniature pigs by repeatedly administering 3,5-dihydroxy-4-isopropyl-trans-stilbene topically over 7 days. To compare systemic exposure to local skin tissue levels, tissue biopsies were collected, sectioned, and analyzed for the active ingredient, and compared with plasma concentrations on days 1 and 7. A similar methodology for skin biopsies in miniature pigs is described in Mitra A, et al., Use of Minipig Skin Biopsy Models an Innovative Tool to Design Topical Formulation to Achieve Desired Pharmacokinetics in Humans. J Pharm Sci. 2015, Feb 17.

[0322] Formulation 22 (2% active ingredient) and Formulation 12 (2.0%, e.g., Formulation 14) were administered to the non-abrasive skin of miniature pigs (3 males / group) at a dose of 2% per day (approximately 23 hours) for 7 consecutive days. The skin administration sites in these groups accounted for 10% of the total surface area. The dose was 2 g / kg / day, as determined by formulation feasibility studies conducted before the start of administration (for each of the above dose groups, the preferred vehicle was administered to 10% of the total surface area of ​​the first miniature pig for approximately 23 hours). Hair was removed from the back and flanks of each animal on days 1, 7, and 14 of the study, and as needed during the study. The administration sites were semi-occluded with gauze patches held in place with tape and tubular mesh. At the end of the exposure period, the net and patch were removed, and all sites were wiped with warm reverse osmosis treated water and cotton gauze.

[0323] The following endpoints / parameters were evaluated: clinical observation, skin irritation (scored using the Draize method for body weight, and macroscopic and microscopic observations (treated and untreated skin)). Toxicological evaluations were performed on concentrations in plasma and skin collected on days 1 and 7.

[0324] On day 7, the miniature pigs were euthanized, and the skin surface was cleaned using a combination of several washing steps, including a mild detergent, solvent, shaving, and tape removal, to ensure that any remaining preparation was removed from the skin surface. The skin was then excised, and the epidermal side of the skin was placed on a clean surface. A skin biopsy (8 mm) was taken from the administration area, placed in a freezing tube, and immediately frozen until analysis. While freezing, the subcutaneous tissue was removed using a razor blade, and the upper part of the sample (epidermis and upper dermis, 0-500 μm section) was cut from the dermis. Thus, the epidermis refers to the upper part of the skin sample consisting of the stratum corneum, epidermis, and upper dermis (approximately 500 μm), while the dermis refers to the deeper dermis (approximately 1500 μm, meaning a cut from the mid-dermis to the subcutaneous fat). Next, epidermal and dermal sections were weighed and homogenized in 1 ml of a 75:25 water:acetonitrile solution containing 0.1% formic acid. The homogenates were further treated with protein precipitation using a 100% acetonitrile solution containing 0.1% formic acid and an internal standard (5 ng / ml). The supernatant of the protein precipitate was passed through an Ostro 96-well plate to remove phospholipids.

[0325] Formulation 22 resulted in higher skin accumulation of 3,5-dihydroxy-4-isopropyl-trans-stilbene in the region above 500 μm and below 1500 μm compared to Formulation 12 (containing 2% of the active ingredient, also referred to herein as Formulation 14). Increased skin loading was observed on day 1 and persisted after 7 days of repeated administration. This data suggests that Formulation 22 has the ability to alter the skin microenvironment after a single dose, and that this effect can be maintained over longer periods of treatment.

[0326] Surprisingly, systemic exposure, as measured by AUC on days 1 and 7, was lower with formulation 22 compared to formulation 12 (2% active ingredient, e.g., formulation 14). Plasma concentrations are thought to decrease further with formulation 22 by day 7, with levels estimated to be approximately 2.5 times lower with formulation 22 compared to formulation 12 (2% active ingredient, e.g., formulation 14). This data correlates with observations in in vitro human skin penetration studies, where formulation 22 delivered lower concentrations of 3,5-dihydroxy-4-isopropyl-trans-stilbene to the recipient fluid and showed higher skin accumulation. The combination of these data suggests that formulation 22 can deliver a higher tissue volume to the target site while minimizing systemic exposure.

[0327] Based on in vitro skin permeability flow rates and human data, the predicted human AUC is 50 ng * Less than h / mL, or 42.5 ng * The expected C is less than h / mL. max This is 15 ng / ml or 12.5 ng / ml.

[0328] [Table 13]

[0329] Based on in vivo data from miniature pigs and human data, the predicted human AUC is 30.0 ng. * Less than h / mL, or 23.5 ng * It is expected to be less than h / mL. Based on in vivo data from miniature pigs and human data, the predicted C max The expected levels are less than 15 ng / ml or less than 11.3 ng / ml.

[0330] Based on limited human data, the human AUC (0-8 hours) is 16.0 ng. * <h / mL or 14ng * <h / mL or 11ng *It is expected to be less than h / mL. max The expected levels are less than 5 ng / ml, or less than 4 ng / ml, or less than 3 ng / ml.

[0331] [Table 14]

[0332] Example 14: Systemic exposure and skin concentration of 3,5-dihydroxy-4-isopropyl-trans-stilbene after 28 days of topical administration to Gottingen minipigs. Seven-day topical administration of 3,5-dihydroxy-4-isopropyl-trans-stilbene in formulation 22 resulted in significant concentrations of 3,5-dihydroxy-4-isopropyl-trans-stilbene in the skin of Göttingen miniature pigs. Systemic levels in this study decreased from day 1 to day 7, suggesting that formulation 22 can deliver higher tissue doses to the target site while minimizing systemic exposure. To determine if this trend persists over longer administration periods, repeated topical administrations of 3,5-dihydroxy-4-isopropyl-trans-stilbene over 28 days were performed to evaluate tissue concentrations, skin toxicity, skin irritation, and the toxicological kinetics of formulation 22.

[0333] The formulation was administered topically to the dorsal skin (~10% of the total surface area) of Göttingen miniature pigs (3 sexes / groups) twice daily (10 ± 1 hour intervals) for 28 days, and the skin toxicity and skin irritation of 3,5-dihydroxy-4-isopropyl-trans-stilbene were measured. The initial daily dose was 0, 10, 20, or 60 mg / kg / day of the dosage formulation at 1 g / kg / dose (2 g / kg / day) (concentrations of 0, 0.5, 1.0, and 3.0% w / w, respectively). After administering the dose on each administration day, the injection site was occluded for approximately 20 ± 1.5 hours from the first dose, and then gently washed before administering the next dose.

[0334] [Table 15]

[0335] On days 1 and 28, 3,5-dihydroxy-4-isopropyl-trans-stilbene could not be quantified in plasma at doses of 5 and 10 mg / kg / dose (10 and 20 mg / kg / day), except at two time points on day 28 (3 and 24 hours after the first dose), and at a single concentration value at each time point for females at 5 mg / kg / dose (10 mg / kg / day). At a dose of 30 mg / kg / dose (60 mg / kg / day), 3,5-dihydroxy-4-isopropyl-trans-stilbene was quantifiable in plasma up to 3 hours after administration on days 1 and 28 (either the first or second dose).

[0336] T max The values ​​were at a dose level of 60 mg / kg / day, and were in the range of 1 to 3 hours after administration (either the first or second dose) on days 1 and 28. max The values ​​ranged from 0.306 to 1.81 ng / ml in males and females. Generally, AUC 0-t The results could not be reported because most of the concentration values ​​were below the limit of quantification.

[0337] Concentrations of 3,5-dihydroxy-4-isopropyl-trans-stilbene were generally higher in the epidermis / upper dermis than in the subdermis in both males and females. The highest concentrations in the skin of individual animals at necropsy, sex-average, were in the 60 mg / kg / day group, at 8265 ng / g in the epidermis / epithelium and 1830 ng / g in the subdermis. Comparison of plasma and skin concentrations could not be evaluated because the 24-hour plasma concentration on day 28 was below the limit of quantification.

[0338] All animals survived until scheduled autopsy. Based on skin evaluation at the administration site, there was no skin irritation associated with the test substance. There was no systemic toxicity based on cardiovascular (ECG) and ophthalmic evaluation, body weight, food consumption, clinicopathology, and postmortem evaluation (organ weight, macroscopic and microscopic pathology). Therefore, one embodiment of the present invention is a pharmaceutical composition comprising 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, which is non-irritating or reduced-irritation compared to formulations having composition 1 or 12 (containing equivalent %w / w active ingredients).

[0339] In conclusion, no skin irritation or systemic toxicity occurred after topical administration (animal study) of 3,5-dihydroxy-4-isopropyl-trans-stilbene at doses of 0 (vehicle), 0.5, 1.0, and 3.0% w / w in the formulations of the present invention shown in Example 7 (10, 20 mg / kg / day) and Example 8 (60 mg / kg / day, respectively) to approximately 10% of the total surface area of ​​miniature pigs (n=3 / sex / group) twice daily for 28 days. Therefore, the highest dose tested, 3% (w / w) or 60 mg / kg / day, resulted in no observed adverse effects (NOAEL) for skin irritation or systemic toxicity. 3,5-dihydroxy-4-isopropyl-trans-stilbene achieved a peak mean concentration of 8265 ng / g in the skin (epidermis / upper dermis) of the 60 mg / kg / day group, although systemic exposure was relatively low or below the limit of quantification in all treatment groups.

[0340] All publications cited herein, including but not limited to patents and patent applications, are specifically and individually indicated so as to be incorporated herein by reference as if each individual publication were a complete reference.

[0341] The above description fully discloses the present invention, including its preferred embodiments. Modifications and improvements to the embodiments specifically disclosed herein are within the scope of the appended claims. Without further detail, those skilled in the art will be able to make the most of the present invention using the above description. Accordingly, the examples herein should be construed as merely illustrative and not limiting the scope of the invention. Embodiments of the present invention for which exclusive characteristics or disclaimers are claimed are defined as follows: The present invention includes, for example, the following embodiments. [Section 1] A topical pharmaceutical emulsion composition, The active ingredient is 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, along with an oil phase, an aqueous phase, a surfactant, and an antioxidant. The composition wherein the composition is homogeneous. [Section 2] The topical composition according to claim 1, wherein if the oil phase contains mineral oil or petrolatum, a second oil phase component is present, and if the oil phase contains both mineral oil and petrolatum, a third oil phase component is present. [Section 3] The emulsion composition according to claim 1 or 2, wherein the oil phase is substantially free of petrolatum or contains petrolatum in an amount of ≤3%, ≤2%, or ≤1%. [Section 4] The emulsion composition according to any one of claims 1 to 3, wherein the active ingredient is present in an amount of about 0.05% to about 2% by weight relative to the total weight of the composition. [Section 5] The emulsion composition according to any one of claims 1 to 4, wherein the antioxidant is selected from the group consisting of propyl gallate, butylated hydroxytoluene, and tocopherol. [Clause 6] The emulsion composition according to any one of claims 1 to 5, wherein the oil phase comprises at least one oil and / or lipid which is an ester and / or glycerin ester. [Section 7] The emulsion composition according to claim 6, wherein the glycerin ester is a medium-chain triglyceride. [Section 8] The emulsion composition according to any one of claims 1 to 7, wherein the surfactant is a nonionic surfactant. [Section 9] The emulsion composition according to claim 1 or 8, wherein the surfactant is selected from the group consisting of ethoxylated aliphatic alcohol ethers, PEG castor oil, PEG esters, propylene glycol esters, glyceryl esters and derivatives, polymer ethers, sorbitan derivatives, aliphatic alcohols and emulsifying waxes, and mixtures thereof. [Section 10] The emulsion composition according to claim 9, wherein the surfactant comprises at least one ethoxylated aliphatic alcohol ether. [Section 11] The emulsion composition according to claim 10, wherein the ethoxylated aliphatic alcohol ether is a mixture of steareth-2 and steareth-20. [Section 12] The emulsion composition according to any one of claims 1 to 11, wherein the surfactant comprises a mixture of an ethoxylated aliphatic alcohol ether and a sorbitan derivative. [Section 13] The emulsion composition according to claim 12, wherein the mixture of the ethoxylated aliphatic alcohol ether and the sorbitan derivative is a mixture of steareth-2, steareth-20, and polysorbate 80. [Section 14] The emulsion composition according to any one of claims 1 to 13, wherein the surfactant is a mixture of an ethoxylated aliphatic alcohol ether, a sorbitan derivative, and an aliphatic alcohol. [Section 15] The emulsion composition according to claim 14, wherein the mixture of the ethoxylated aliphatic alcohol ether, sorbitan derivative, and aliphatic alcohol is a mixture of steareth-2, steareth-20, polysorbate 80, and cetearyl alcohol. [Section 16] The emulsion composition according to any one of claims 1 to 15, wherein the surfactant is a mixture of an ethoxylated aliphatic alcohol ether, a sorbitan derivative, and a nonionic emulsifying wax. [Section 17] The emulsion composition according to claim 16, wherein the mixture of the ethoxylated aliphatic alcohol ether, sorbitan derivative, and emulsifying wax is a mixture of steareth-2, steareth-20, polysorbate 80, and emulsifying wax NF. [Section 18] The emulsion composition according to any one of claims 1 to 17, wherein the composition is an oil-in-water emulsion. [Section 19] An emulsion composition according to any one of claims 1 to 18, further comprising a preservative, a pH adjuster, a chelating agent, and a cosolvent. [Section 20] The emulsion composition according to any one of claims 1 to 19, wherein the composition is an oil-in-water cream. [Section 21] An emulsion according to any one of items 1 to 20, wherein the average droplet size of the discontinuous phase is approximately 5 microns or less. [Section 22] A composition according to any one of items 1 to 21, for use in the treatment or prevention of dermatological conditions or disorders in human patients. [Section 23] A method for treating an inflammatory disease or disorder in a patient, The method comprising administering a topical pharmaceutical emulsion composition described in any one of items 1 to 21 to a patient in need thereof. [Section 24] The method according to paragraph 23, wherein the disease or disorder is psoriasis, atopic dermatitis, or acne. [Section 25] Use of a topical pharmaceutical emulsion composition comprising a homogeneous composition containing the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, for the manufacture of a pharmaceutical for the treatment or prevention of inflammatory skin diseases or disorders in patients. [Section 26] The method or use according to any one of claims 23 to 25, wherein individual doses of the composition administered to the affected area may occur twice a day, once a day, once every other day, twice a week, three times a week, or once a week. [Section 27] A method for reducing irritation in the use of a topical pharmaceutical emulsion composition comprising the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof to a patient requiring such use, the method comprising administering a homogeneous emulsion composition comprising the active ingredient, an oil phase, an aqueous phase, a surfactant and an antioxidant to the patient, wherein the emulsion composition is optionally compared to formulation 1 or 12. [Section 28] A method for improving the residence time of a composition comprising the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in the skin of a patient requiring such use, wherein the method comprises administering to the patient a homogeneous emulsion composition comprising the active ingredient, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is optionally compared to formulation 1 or 12. [Section 29] A method for reducing adverse effects in a patient administered a composition comprising the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, wherein the method comprises administering to the patient a homogeneous emulsion composition comprising the active ingredient, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the emulsion composition is optionally compared to formulation 1 or 12. [Section 30] A pharmaceutical composition for topical administration comprising the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the composition is homogeneous and presents at a dose of 23.5 ng upon administration to human skin. * The composition that produces an AUC(0-tau) of less than h / ml. [Section 31] The aforementioned AUC is 16.0ng * The composition according to item 29, wherein the concentration is less than h / mL. [Section 32] A pharmaceutical composition for topical administration comprising the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the composition is homogeneous and, upon administration to human skin, does not reach a maximum plasma level (C) of less than 11.3 ng / mL. max The composition that produces ) [Section 33] The aforementioned maximum plasma level (C max The composition according to item 32, wherein the concentration is less than 4 ng / ml. [Section 34] A pharmaceutical composition for topical administration comprising the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, an oil phase, an aqueous phase, a surfactant, and an antioxidant, wherein the composition is homogeneous and the normalized skin flow rate (ng) (by activity strength) when using freshly excised human abdominal skin is obtained. * cm 2 The composition is administered in an in vitro system such that the ratio of dermal volume (ng) measured at a steady state to ( / hr) is between 1000 and 5000.

Claims

1. A homogeneous oil-in-water emulsion composition for use in a method to improve the residence time of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof in the skin of a patient requiring such treatment, the method comprising topically administering the composition to the patient's skin up to twice daily. The aforementioned composition, The active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, in an amount of 0.5% to 2% by weight based on the total weight of the composition. A first oil phase comprising medium-chain triglycerides with carbon lengths of C6 to C12 in an amount of 2% to 30% by weight relative to the total weight of the composition, wherein the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is solubilized in the first oil phase, and the first oil phase is free from mineral oil or petrolatum. Optionally, a second oil phase selected from the group consisting of mineral oil, petrolatum, and combinations thereof, Here, the first oil phase and, if present, the second oil phase, together, are present in an amount of 5% to 25% by weight relative to the total weight of the composition. Amount of aqueous phase: 30% to 80% by weight relative to the total weight of the composition A nonionic surfactant in an amount of 5% to 15% by weight relative to the total weight of the composition, wherein the nonionic surfactant is an emulsifying wax, and Antioxidant in an amount of 0.01% to 1% by weight relative to the total weight of the composition Includes, The oil-in-water emulsion composition has an average droplet size of 0.1 to 0.75 microns and an improved residence time on the skin.

2. The composition according to claim 1, wherein the improved residence time is measured as in vitro skin flux, and the ratio of the dermal volume of 3,5-dihydroxy-4-isopropyl-trans-stilbene measured at a steady state to the normalized skin flux is 1,000 to 5,000.

3. The composition according to claim 1, wherein the improved residence time appears 3 hours after administration and continues for 15 hours.

4. The composition according to claim 1, wherein the homogeneous oil-in-water emulsion composition further comprises one or more additional surfactants.

5. The composition according to claim 1, wherein the homogeneous oil-in-water emulsion composition does not contain a second oil phase.

6. The composition according to claim 1, wherein a second oil phase is present, and the second oil phase contains petrolatum in an amount of ≤3%.

7. The improved residence time is 50 ng * A homogeneous oil-in-water emulsion composition according to claim 1, as indicated by the area under the curve (AUC) of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof less than h / mL.

8. The improved residence time was 42.5 ng * The composition according to claim 7, wherein the AUC of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is less than h / mL.

9. The improved residence time is 30 ng * The composition according to claim 7, wherein the AUC of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is less than h / mL.

10. The improved residence time was 23.5 ng * The composition according to claim 7, wherein the AUC of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof is less than h / mL.

11. The improved residence time was 16 ng * The composition according to claim 7, as indicated by the AUC (0-8 hours) of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof less than h / mL.

12. The improved residence time was 14 ng * The composition according to claim 7, as indicated by the AUC (0-8 hours) of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof less than h / mL.

13. The improved residence time is 11 ng * The composition according to claim 7, as indicated by the AUC (0-8 hours) of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof less than h / mL.

14. The improved residence time of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof less than 15 ng / ml ｍａｘ A homogeneous oil-in-water emulsion composition according to claim 1, as shown by [the relevant figure].

15. The improved residence time is C of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt thereof, which is less than 12.5 ng / ml ｍａｘ The composition according to claim 14, as shown by

16. The improved residence time is less than 11.3 ng / ml of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt of C ｍａｘ The composition according to claim 14, as shown by [representation].

17. The improved residence time is less than 5 ng / ml of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt of C ｍａｘ The composition according to claim 14, as shown by [representation].

18. The improved residence time is less than 4 ng / ml of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt of C ｍａｘ The composition according to claim 14, as shown by [representation].

19. The improved residence time is less than 3 ng / ml of the active ingredient 3,5-dihydroxy-4-isopropyl-trans-stilbene or a pharmaceutically acceptable salt of C ｍａｘ The composition according to claim 14, as shown by [representation].

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