Topical formulations of diaselein or lein and their use

Abstract

To provide a topical pharmaceutical composition containing diacerein and / or its analogs, and also to provide a method for treating various diseases using the composition.SOLUTION: Provided is a topical pharmaceutical composition containing a therapeutically effective amount of a compound selected from the group consisting of diacerein, rhein, monoacetylrhein, and salts or esters or prodrugs thereof, and one or more pharmaceutically acceptable excipients, the composition being in the form of ointment, cream, or gel, and at least about 90 vol.% of the compound having a particle size of about 0.5 to about 35 μm.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 187,743, filed on July 1, 2015, which is hereby incorporated by reference in its entirety.

[0002] The present invention relates to a topical pharmaceutical composition containing diacerein and / or its analogs, and also to the use of this topical pharmaceutical composition in the treatment of various diseases or conditions.

Background Art

[0003] Chemically, Rhein is 9,10 - dihydro - 4,5 - dihydroxy - 9,10 - dioxo - 2 - anthracenecarboxylic acid having the structure of formula (I), and diacerein, one of its prodrugs, is 4,5 - bis(acetyloxy)9,10 - dihydro - 4,5 - dihydroxy - 9,10 - dioxo - 2 - anthracenecarboxylic acid having the structure of formula (II). Diacerein is completely converted to Rhein before reaching the systemic circulation and exerts its physiological functions in the body in the form of Rhein.

[0004] Formula (I)

[0005]

Chem.

[0006] Formula (II)

[0007]

Chem.

[0008] Diacelein is a widely used anti-inflammatory drug in the treatment of osteoarthritis and has been shown to inhibit interleukin-1 (IL-1) signaling. Currently, diacelein capsules are available in 50 mg potency and are marketed in various countries under different brand names, including Art 50® and Artrodar®. As disclosed in U.S. Patents 8,536,152 and 8,865,689, diacelein can be used as an adjunctive therapy for type II diabetes and has also been shown to be effective in lowering blood uric acid levels, and therefore can be used to treat hyperuricemia or hyperuricemia-related metabolic disorders. In addition, diacelein has been reported to have potential efficacy in the treatment of epidermolysis bullosa (Wally et al., Orphanet Journal of Rare Diseases, 2013, vol. 8, issue 69).

[0009] Diacelein can be administered orally, but it is not fully absorbed by the gastrointestinal tract, and its oral bioavailability is estimated to be around 40% to 60%. Incomplete absorption of diacelein can lead to undesirable side effects such as diarrhea or loose stools. In vitro and in vivo studies have shown that unabsorbed diacelein is metabolized to lein in the colon, which then induces a laxative effect.

[0010] Since such side effects can occur due to oral administration, parenteral diacelene compositions have been proposed to overcome these problems.

[0011] PCT International Application WO2009 / 133430 discloses topical compositions containing diacelene or lein, which may be in various forms, such as lotions, creams, ointments, pastes, gels, etc. However, these compositions are not intended for any particular disease, and therefore, from the context of this paper, it is not possible to determine which form is best suited to a particular type of disease being treated.

[0012] Wally et al. disclosed a cream diaselein formulation for epidermolysis bullosa (Wally et al., Orphanet Journal of Rare Diseases, 2013, vol. 8, issue 69). However, this paper does not clarify whether the formulation's properties have a therapeutic effect on epidermolysis bullosa, or how it does.

[0013] The precise properties of diaselein preparations are considered crucial for determining their therapeutic effects on various diseases. [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] U.S. Patent No. 8,536,152 [Patent Document 2] U.S. Patent No. 8,865,689 [Patent Document 3] International Application No. 2009 / 133430 [Non-patent literature]

[0015] [Non-Patent Document 1] Wally et al.,Orphanet Journal of Rare Diseases,2013,vol.8,issue 69 [Overview of the project] [Problems that the invention aims to solve]

[0016] Considering that the literature provides little information on the relationship between the physicochemical properties of diaselein / rain topical formulations and their therapeutic effects, the present invention provides topical formulations that are appropriately adapted to various diseases. [Means for solving the problem]

[0017] The present invention provides a topical composition comprising a therapeutically effective amount of a compound selected from the group consisting of diacerein, rhein, monoacetylrhein and salts or esters or prodrugs thereof, and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of an ointment, cream or gel, and at least about 90 volume % of the compound has a particle size of from about 0.5 to 35 μm.

[0018] The present invention also provides a topical composition comprising a therapeutically effective amount of a compound selected from the group consisting of diacerein, rhein, monoacetylrhein and salts or esters or prodrugs thereof, and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of a gel, and at least about 90 volume % of the compound has a particle size of less than about 1 μm.

[0019] The present invention also provides a method of treating inflammatory and / or hyperproliferative and pruritic skin diseases, and diseases associated with epidermal barrier dysfunction including aged skin and epidermal blistering diseases, comprising administering to a subject in need of treatment an effective amount of the composition of the present invention.

[0020] The present invention also provides a method of treating hyperuricemia, metabolic disorders associated with hyperuricemia, osteoarthritis or type 2 diabetes, comprising administering to a subject in need of treatment an effective amount of the composition of the present invention.

[0021] In some embodiments, the treatment method of the present invention expressly excludes the administration of any other active substances for treating diseases treatable by the composition of the present invention. However, in some embodiments, the method of the present invention contemplates the administration of other active substances.

[0022] Preferably, the treatment method of the present invention results in effective treatment of the related diseases in at least one treated subject, preferably in a substantial number of treated subjects, more preferably in a majority of treated subjects.

[0023] Detailed technical and preferred embodiments implemented for the present invention are described in the following paragraphs, with accompanying drawings, for those skilled in the art, so that the features of the claimed invention may be fully understood. [Brief explanation of the drawing]

[0024] [Figure 1] This is a statistical bar graph showing the lein concentrations in the dermis and epidermis 8 hours after treatment with three test diacelein formulations (G1, C1, and O1, n=4). [Figure 2A] This is a plot of cumulative rain penetration (ng / cm2) from skin tissue into receiver solution against time for three test diacelein formulations (G1, C1, and O1, n=4). [Figure 2B] This is a plot of cumulative rain penetration (ng / cm2) from skin tissue into receiver solution against time for three test diacelein formulations (G1, C1, and O1, n=4). [Figure 3] This is a statistical bar graph showing the lein concentrations in the dermis and epidermis 8 hours after treatment with two test diaselein ointment formulations (O2 and O3, n=3). [Figure 4] This is a plot of cumulative rain penetration (ng / cm2) from skin tissue into receiver solution against time for two test diaserain ointment formulations (O2 and O3, n=3). [Figure 5] This is a statistical bar graph showing the lein concentrations in the dermis and epidermis 8 hours after treatment with the test diaselein ointment formulation (O3, n=3) or the comparison formulation (n=3). [Figure 6] This is a plot of cumulative rain penetration (ng / cm2) from skin tissue into the receiver solution against time for the test diaserain ointment formulation (O3, n=3) and the comparative formulation (n=3). [Modes for carrying out the invention]

[0025] As used herein, the term “therapeutic dose” refers to a quantity that relieves or reduces one or more symptoms of a disease.

[0026] As used herein, the term “diacelein or its analogues” refers to diacelein, lein, monoacetylrein, or any pharmaceutically acceptable salt or ester or prodrug thereof.

[0027] Unless otherwise specified herein, terms such as “a,” “an,” and “the” as used herein (particularly in the “Claims” below) are understood to include both singular and plural forms.

[0028] As mentioned above, topical administration of diacelein can prevent undesirable side effects of oral administration by avoiding the gastrointestinal route, which has limited tolerability, and by reducing the amount of diacelein entering the systemic circulation compared to oral administration. Furthermore, when using diacelein to treat skin diseases, it is advantageous that diacelein can easily penetrate the stratum corneum and reach the target site (e.g., the dermis or epidermis where skin damage may occur). At the same time, it is desirable that diacelein be retained in the skin for as long as possible to fully exert its function. Therefore, a delicate balance needs to be achieved so that, on the one hand, diacelein or lein penetrates rapidly into the target site, while on the other hand, it is possible to retain it in the target site for sustained exposure.

[0029] The inventors of the present invention have discovered that the form of a topical diacelein / rain composition and / or the particle size of the active ingredient contained in the composition play an important role in its penetration (or diffusion rate) and retention rate in the skin.

[0030] The present invention therefore provides a topical diacelein / lein pharmaceutical composition suitable for skin diseases and satisfying the above requirements. The topical pharmaceutical composition contains a therapeutically effective amount of a compound selected from the group consisting of diacelein, lein, monoacetylrein and its salts or esters or prodrugs, and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of an ointment, cream or gel, and at least about 90% by volume of the compound has a particle size of about 0.5 to 35 μm.

[0031] In the context of this application, the particle size distribution is based on volume D values ​​(i.e., Dv values, e.g., Dv10, Dv50, and Dv90) which are commonly used to represent a range of particle sizes of a given sample.

[0032] Preferably, the composition is provided as an ointment or cream, more preferably as an ointment. Surprisingly, it has been found that ointment or cream formulations provide a higher retention rate and longer retention time on the skin compared to gel formulations.

[0033] In one embodiment, at least about 90% by volume of the compound in the composition has a particle size of about 1 to about 15 μm, preferably about 2 to about 5 μm. Preferably, the composition containing the compound having this particle size is in the form of an ointment or cream and, when administered to the skin of a subject, more than 90% of the compound, preferably substantially all of the compound, is retained in the skin for at least about 2 hours, more preferably about 4 hours, even more preferably about 6 hours, and most preferably about 8 hours after administration. The retention rate and retention time of the compound in the skin can be measured, for example, by a diffusion cell test. In this test, a diffusion cell device, which essentially consists of a piece of skin fixed between two forceps, is attached, and the formulation containing the compound is applied to one side (upper part) of the skin, and the compound concentration is measured at regular time intervals in the receiver part (bottom part) of the device (which may be a container filled with buffer in contact with the skin).

[0034] Furthermore, when administered to the skin of a subject, the concentration of the compound may be, for example, about 8 to 20 μg per gram of epidermal tissue and / or about 1 to 3 μg per gram of dermal tissue 8 hours after administration.

[0035] In another embodiment, at least about 90% by volume of the compounds in the composition have a particle size of about 10 to about 30 μm, preferably about 12 to about 25 μm. Preferably, the composition containing compounds having this particle size is in the form of an ointment or cream, more preferably an ointment, and when administered to the skin of a subject, more than 90% of the number of compounds, preferably substantially all of the compounds, remain on the skin for at least about 4 hours, more preferably about 6 hours, and most preferably about 8 hours after administration.

[0036] Furthermore, when administered to the skin of a subject, the concentration of the compound may be, for example, about 3 to about 6 μg per gram of epidermal tissue and / or about 0.2 to about 2 μg per gram of dermal tissue 8 hours after administration.

[0037] Topical pharmaceutical compositions having the above characteristics provide a good balance of penetration and retention and are therefore useful in the treatment of inflammatory and / or hyperproliferative and pruritic skin diseases selected from skin diseases such as atopic dermatitis, psoriasis, cystic psoriasis, rosacea, keloids, hyperplastic scars, acne, Netherton syndrome, or other pruritic skin diseases including nodular prurigo, unspecified itching in the elderly, and diseases involving impaired epidermal barrier function, including aging skin and epidermolysis bullosa. Preferably, the compositions are useful in the treatment of epidermolysis bullosa.

[0038] The present invention also relates to a method for treating inflammatory and / or hyperproliferative and pruritic skin diseases, as well as diseases involving epidermal barrier dysfunction, including senescent skin and epidermolysis bullosa, comprising administering an effective amount of the composition of the present invention to a subject in need of treatment.

[0039] The present invention further provides topical diacelein / lein pharmaceutical compositions useful in the treatment of hyperuricemia, hyperuricemia-related disorders (e.g., acute gout, chronic gout, gouty erythema, uric acid nephrolithiasis, gouty nephropathy, etc.), osteoarthritis, and type 2 diabetes. Unlike compositions used for the treatment of skin diseases, the compositions of the present invention allow the active compounds to easily penetrate the skin and enter the body relatively quickly in order to reach the systemic circulation and exert their functions within the body. The topical composition contains a therapeutically effective amount of a compound selected from the group consisting of diacelein, lein, monoacetylrein and its salts or esters or prodrugs, as well as one or more pharmaceutically acceptable excipients, wherein the composition is in the form of a gel, and at least about 90% by volume of the compound has a particle size of less than about 1 μm, and preferably greater than about 0.1 μm.

[0040] Preferably, when the composition is administered to the skin of a subject, the compound is released into the body from the skin within about 6 hours, more preferably within about 4 hours, and most preferably within about 2 hours after administration.

[0041] The present invention also provides a method for treating hyperuricemia, hyperuricemia-related disorders (e.g., acute gout, chronic gout, gouty redness, uric acid nephrolithiasis, gouty nephropathy, etc.), osteoarthritis, and type 2 diabetes, comprising administering an effective amount of the composition of the present invention to a subject in need of treatment.

[0042] In some embodiments, the treatment method of the present invention explicitly excludes the administration of any other active substances to treat diseases treatable by the composition of the present invention. In some embodiments, however, the method of the present invention considers the administration of other active substances.

[0043] Preferably, the treatment method of the present invention results in effective treatment of the related disease in at least one treated subject, preferably in a substantial number of treated subjects, and more preferably in the majority of treated subjects.

[0044] The topical pharmaceutical composition of the present invention may contain, based on the total weight of the composition, preferably about 0.1% to about 10% by weight, more preferably about 0.1% to 5% by weight, and most preferably about 0.5% to about 2% by weight of the compound.

[0045] Pharmaceutically acceptable excipients in a composition may include antioxidants, gelling agents / hydrogel bases, pH adjusters / buffers, penetration enhancers, preservatives, chelating agents, wetting agents, surfactants, emulsifiers, thickeners, solvents, stabilizers, and the like. In this specification, the excipients / components in the present invention may have multiple functions; for example, one excipient may be used as a surfactant and / or a stabilizer and / or emulsifier.

[0046] Examples of antioxidants include, but are not limited to, one or more of the following: vitamin C, vitamin A and alpha-lipoic acid, ascorbyl palmitate, sodium pyrosulfite, butylhydroxyanisole (BHA), and butylhydroxytoluene (BHT).

[0047] Suitable gelling agents / hydrogel bases may include, but are not limited to, one or more of the following: guar gum, xanthan gum and carrageenan gum, guar gum modified to be anionic, nonionic, cationic and lipophilic, polyacrylic acid (e.g., carbomer), polymethacrylic acid, cellulose resin, polyethylene glycol, hydroxyalkylcellulose, carboxyalkylcellulose, and polyalkyleneamines.

[0048] Examples of pH adjusters / buffers include, but are not limited to, one or more of the following: sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, amino acids, aluminum glycinate, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, citric acid, etc.

[0049] Examples of penetration enhancers include diethylene glycol monoethyl ether, dimethyl sulfoxide, propylene glycol, isopropyl myristate (IPM), calcipotriene, cleansing agents, emollients, ethoxydiglycol, triacetin, propylene glycol, benzyl alcohol, sodium laureth sulfate, dimethyl isosorbide, isopropyl myristate, medium-chain triglyceride oil (MCT oil), menthol, isopropyl palmitate, isopropyl isostearate, propylene glycol monostearate, lecithin This includes, but is not limited to, one or more of the following: diisopropyl adipate, diethyl sebacate, oleic acid, ethyl oleate, urea, glyceryl oleate, caprylic / capric triglyceride, dicaprylic / propylene glycol dicaprate, laureth-4, oleth-2, oleth-20, propylene carbonate, nonoxynol-9,2-n-nonyl-1,3-dioxolane, C7-C14-hydrocarbyl-substituted 1,3-dioxolane, 1,3-dioxane or acetal, and nonoxynol-15.

[0050] The preservative may be one or more of the following, for example: sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, ethylenediaminetetraacetic acid (EDTA), parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, benzalkonium chloride, benzethonium chloride, phenol, phenylmercury(II) nitrate, thimerosal, methylparaben, ethylparaben, and / or propylparaben.

[0051] Examples of suitable solvents include, but are not limited to, one or more of the following: alcohol, castor oil, diisopropyl adipate, ethoxylated alcohol, ethyl alcohol, fatty citrate alcohol, glycerin, 1,2,6-hexanetriol, hexylene glycol, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, mineral oil, phosphoric acid, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1450, polyethylene glycol 8000, polyethylene glycol 1000 monocetyl ether, polyethylene glycol monostearate, polyethylene glycol monostearate 400, polyethylene glycol, polyoxyl 20 cetostearyl ether, polyoxypropylene 15-stearyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate, propylene carbonate, propylene glycol, pure water, SD alcohol 40, and saturated fatty acid triglycerides.

[0052] Suitable stabilizers or surfactants may be one or more of the following, for example: ionic polysorbate surfactants, Tween 20, Tween 40, Tween 60, Tween 80, nonylphenol polyethylene glycol ether, (alkylphenol-hydroxypolyoxyethylene), poly(oxy-1,2-ethanediyl), α-(4-nonylphenol)-ω-hydroxy-, branched (i.e., Tergitol® NP-40 surfactant), nonylphenol polyethylene glycol ether mixture (i.e., Tergitol® NP-70 (70% aqueous solution) surfactant), phenoxypolyethoxyethanol and polymers thereof, for example, Triton®, Poloxamer®, Spans®, Tyloxapol®, various grades of Brij, sodium dodecyl sulfate, cetyl alcohol, stearic acid, polyoxyl stearate, etc.

[0053] Examples of chelating agents include, but are not limited to, antioxidants, citric acid, disodium edetate (EDTA), disodium calcium edetate, edetic acid, malic acid, maltol, pentetic acid, sodium edetate, and trisodium edetate.

[0054] Examples of wetting agents include, but are not limited to, glycerin, propylene glycol, sorbitol, polyethylene glycol, polysaccharides (e.g., fructose, glucose, maltose, etc.), corn syrup, polyols, urea and its derivatives, and natural honey. Preferred wetting agents are propylene glycol and glycerin.

[0055] Examples of thickening agents include, but are not limited to, stearic acid, cellulose polymers, carbomer polymers, carbomer derivatives, cellulose derivatives, polyvinyl alcohol, poloxamers, and polysaccharides.

[0056] Examples of oily bases for creams include, but are not limited to, vegetable oils (e.g., castor oil), white petrolatum, and mineral oil.

[0057] Examples of ointment bases include, but are not limited to, petrolatum, fatty oils, lanolin, petrolatum, glycerin, paraffin, poloxamer, polyethylene glycol, stearic acid, and beeswax. Examples of ointment base modifiers include, but are not limited to, mineral oil and liquid paraffin.

[0058] In one embodiment, the topical pharmaceutical composition of the present invention is in the form of a gel and contains about 0.1% to about 10% by weight of diacelene or an analogue thereof, about 0.1% to about 5% by weight of a hydrogel base, about 2% to about 50% by weight of a wetting agent, and about 0.1% to about 2.5% by weight of a stabilizer / surfactant.

[0059] In one embodiment, the topical pharmaceutical composition of the present invention is in the form of a cream and contains about 0.1% to about 10% by weight of diacelene or an analogue thereof, about 0.5% to about 25% by weight of a surfactant, about 0.5% to about 25% by weight of an oily base, about 2% to about 50% by weight of a wetting agent, and water.

[0060] In one embodiment, the topical pharmaceutical composition of the present invention is in the form of a cream and comprises part A and part B, wherein part A comprises about 0.1% to about 10% by weight of diacelene or an analogue thereof, about 1.5% to about 40% by weight of a thickener, about 1% to about 40% by weight of an oily base and about 0.4% to about 10% by weight of a surfactant, and part B comprises about 0.2% to about 5% by weight of a stabilizer, about 0.6% to about 15% by weight of a wetting agent and water.

[0061] In one embodiment, the topical pharmaceutical composition of the present invention is in the form of an ointment and contains 0.1% to about 10% by weight of diacelene or an analogue thereof, about 15% to about 99% by weight of an ointment base, about 0% to about 60% by weight of a base modifier, and about 0% to about 10% by weight of a surfactant.

[0062] Preferably, the topical pharmaceutical composition of the present invention is a once-daily or twice-daily composition. That is, it is suitable for administration once or twice daily to achieve the desired therapeutic effect.

[0063] The topical pharmaceutical compositions of the present invention have the following advantages. First, they can be administered directly to the site affected by dermatological subcutaneous lesions, avoiding the gastrointestinal route and significantly reducing systemic exposure. Second, they are easy to apply and therefore more convenient for patients. Third, these topical formulations are also preferable to oral formulations for patients with dysphagia or those who dislike the taste of medication. Fourth, they more easily achieve sustained exposure to the target site.

[0064] The present invention also relates to a method for treating inflammatory and / or hyperproliferative and pruritic skin diseases, as well as diseases involving impaired epidermal barrier function, including senescent skin and epidermolysis bullosa, comprising administering an effective amount of a topical pharmaceutical composition to a subject in need of treatment, wherein the composition comprises a therapeutically effective amount of a compound selected from the group consisting of diaselein, lein, monoacetylrein and its salts or esters or prodrugs, and one or more pharmaceutically acceptable excipients, wherein when the composition is administered to the skin of a subject, more than 90% (in number) of the compound is retained in the skin for at least about 2 hours, preferably at least about 4 hours, more preferably about 6 hours, and most preferably about 8 hours after administration.

[0065] The present invention also relates to a method for treating inflammatory and / or hyperproliferative and pruritic skin diseases, as well as diseases involving impaired epidermal barrier function, including senescent skin and epidermolysis bullosa, comprising administering an effective amount of a topical pharmaceutical composition to a subject in need of treatment, wherein the composition comprises a therapeutically effective amount of a compound selected from the group consisting of diaselein, lein, monoacetylrein and its salts or esters or prodrugs, and one or more pharmaceutically acceptable excipients, wherein when the composition is administered to the skin of a subject, the concentration of the compound may be, for example, about 8 to about 20 μg per gram of epidermal tissue and / or about 1 to about 3 μg per gram of dermal tissue, 8 hours after administration.

[0066] The present invention also relates to a method for treating inflammatory and / or hyperproliferative and pruritic skin diseases, as well as diseases involving impaired epidermal barrier function, including senescent skin and epidermolysis bullosa, comprising administering an effective amount of a topical pharmaceutical composition to a subject in need of treatment, wherein the composition comprises a therapeutically effective amount of a compound selected from the group consisting of diaselein, lein, monoacetylrein and its salts or esters or prodrugs, and one or more pharmaceutically acceptable excipients, wherein when the composition is administered to the skin of a subject, the concentration of the compound may be, for example, about 3 to about 6 μg per gram of epidermal tissue and / or about 0.2 to about 2 μg per gram of dermal tissue, 8 hours after administration.

[0067] The present invention further relates to a method for treating hyperuricemia, hyperuricemia-related disorders, osteoarthritis and type 2 diabetes, comprising administering an effective amount of a topical pharmaceutical composition to a subject in need of treatment, wherein the composition comprises a therapeutically effective amount of a compound selected from the group consisting of diaselein, lein, monoacetylrein and its salts or esters or prodrugs, and one or more pharmaceutically acceptable excipients, wherein when the composition is administered to the skin of the subject, the compounds are released from the skin into the body within about 6 hours, more preferably within about 4 hours, and most preferably within about 2 hours after administration.

[0068] The present invention will be further described below with reference to the following examples. However, these examples are provided solely for illustrative purposes and are not intended to limit the scope of the invention. [Examples]

[0069] [Preparation Examples] Preparation of a diacelene topical composition Seven diacelein topical compositions (G1, C1, C2, and O1 to O4) in three different forms (gel, cream, and ointment) were prepared according to Tables 1 to 4. The particle size (Dv90) of the compounds in each composition was measured using Mastersizer 2000 version 5.60. The excipients / components listed in the following table may have multiple functions; for example, one excipient may be used as a surfactant and / or stabilizer and / or emulsifier.

[0070] [Table 1]

[0071] [Table 2]

[0072] [Table 3]

[0073] [Table 4]

[0074] [Example 1] Diffusion cell test of topical diacelene composition Procedure: Mice were sacrificially killed by cervical dislocation. Full-thickness flank skin was taken and placed on a diffusion cell in contact with the receptor phase, which was PBS (pH 5.4) (37°C) containing 30% PEG 300. Buffer was introduced into the receiver compartment at a flow rate of 3 to 4 mL / hour. A 20 μl dose of 1% diacelein gel (formulation G1), 1% diacelein cream (formulations C1 and C2), or 1% diacelein ointment (formulations O1, O2, and O3) was added to the skin surface in the donor compartment. Receiver solutions were collected at 0, 1, 2, 4, 6, and 8 hours. Eight hours after treatment with the formulation, the skin was removed from the diffusion cell and the skin surface was carefully cleaned with three alcohol swabs (without tape removal). The epidermis was separated from the dermis using a surgical scalpel blade. Both the separated epidermis and dermis were weighed, finely chopped, and extracted twice with 0.5 ml of acetonitrile:acetic acid:water (60:0.1:40) by vigorously shaking for 1 hour. The skin extracts were then centrifuged at 14,500 rpm for 20 minutes. All procedures were performed under reduced light conditions. Both the skin extracts and receiver solutions were stored at -20°C until subjected to HPLC analysis of diacelein and lein concentrations (diacelein readily converts to lein during the experiment). Skin infiltration was calculated from the slope of the linear portion of the cumulative lein infiltration versus time curve. The results are summarized below.

[0075] [Influence of morphology on permeability and retention] transparency As shown in Figure 1, the gel-diacerein formulation (G1) penetrates the stratum corneum better than the cream and ointment formulations (C1 and O1). Eight hours after administration, the lein concentration per gram of epidermis was 204.0 μg for G1, 16.1 μg for C1, and 31.2 μg for O1, while the lein concentration per gram of dermis was 11.9 μg for G1, 2.53 μg for C1, and 3.14 μg for O1.

[0076] retention As shown in Figures 2A and 2B, Rain penetrated the skin tissue and was released into the receiver solution after 1 hour for the gel formulation (G1) and after 2 hours for the cream formulation (C1). However, for the ointment formulation (O1), Rain did not penetrate the skin tissue and did not enter the receiver solution until after 4 hours, indicating that the ointment formulation had a higher retention rate and longer retention time than the gel and cream formulations.

[0077] The results indicate that diaselein / rain has higher penetration into the stratum corneum in the gel formulation compared to the cream or ointment formulation, and that the ointment formulation has a longer retention time at the skin target site compared to the cream or gel formulation. The gel formulation has the shortest retention time at the skin target site among the three formulations.

[0078] [Effect of particle size on permeability and retention] Figure 3 shows that the ointment formulation with smaller particle size (O2) penetrated faster than the formulation with larger particle size (O3). Eight hours after administration, the lein concentration per gram of epidermis was 10.7 μg for O2 and 4.8 μg for O3, while the lein concentration per gram of dermis was 1.6 μg for O2 and 0.7 μg for O3.

[0079] Figure 4 shows that ointment formulation O2 released rain after 4 hours, while ointment formulation O3 did not release rain after 8 hours or even longer. Ointment formulation O3 showed similar compound concentrations in the skin layer but had a longer retention time compared to O2.

[0080] [Example 2] Comparative Examples Wally et al. disclose a cream formulation containing 1% diacelene in the commonly used care cream ultraphil® (Wally et al., Orphanet Journal of Rare Diseases, 2013, vol.8, issue 69). A comparative study was conducted between this cream formulation (comparative formulation) and the ointment formulation O3 of the present invention. The results are shown in Figures 5 and 6.

[0081] As shown in Figure 5, the ointment formulation O3 penetrated more deeply into the stratum corneum than the comparative formulation, demonstrating higher retention in the skin layer. Furthermore, as shown in Figure 6, while the laine in the comparative formulation penetrated the skin tissue and was detectable in the receiver solution after 4 hours, the laine in the O3 formulation did not penetrate the skin tissue and enter the receiver solution until after 6 hours.

[0082] The results revealed that the O3 formulation had higher penetration into the stratum corneum, a higher retention rate, and a longer retention time than the comparative formulation, demonstrating that the O3 formulation maintained a higher drug concentration in the skin layer.

[0083] The above disclosure relates to the detailed technical content and inventive features of the present invention. Those skilled in the art can make various modifications and substitutions based on the above-mentioned disclosures and proposals of the present invention without departing from their features. Nevertheless, such modifications and substitutions are not fully disclosed in the above description, but are substantially covered in the following appended claims.

Claims

1. A topical pharmaceutical composition for use in the treatment of epidermolysis bullosa, comprising a therapeutically effective amount of a compound selected from the group consisting of diaselein, lein, monoacetylrein and salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of an ointment, and at least about 90 volume percent of the compound has a particle size of about 10 to about 30 μm, and the composition comprises, based on the total weight of the composition, about 0.1% to about 10% by weight of the compound, about 15% to about 99% by weight of white petrolatum, about 16% to about 60% by weight of mineral oil, and about 0.5% to about 10% by weight of cetyl alcohol.

2. The composition according to claim 1, wherein at least about 90 volume percent of the compound has a particle size of about 12 to about 25 μm.

3. The composition according to claim 1, wherein the compound is present in an amount of about 0.1% to 5.0% by weight of the entire composition.

4. The composition according to claim 1, wherein the compound is present in an amount of about 0.5% to about 2.0% by weight of the entire composition.

5. The composition according to claim 1, administered once or twice a day.

6. The use of the composition according to claim 1 in the manufacture of a pharmaceutical for the treatment of epidermolysis bullosa, wherein an effective amount of the composition is administered to a subject requiring treatment.

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