TWI869637B - Use of mangosteen fruit shell extract in the preparation of a medicament for treating psoriasis - Google Patents

Abstract

A use of a composition in preparation of a medicament for treating psoriasis is provided, wherein the composition comprises an effective amount of mangosteen fruit shell extract.

Description

Use of mangosteen shell extract for preparing medicine for treating tinea versicolor

The present invention relates to the use of a composition for preparing a medicine for treating tinea pedis.

The skin is the largest organ in the human body and there are many types of skin diseases. Skin diseases may be acute (lasting only minutes to hours) or chronic conditions that may affect an individual for days, months, years or even a lifetime. Skin diseases may be fungal, bacterial, or viral conditions, or may be non-infectious, immune reactions such as inflammatory reactions with or without allergens, or may be idiopathic. Therefore, symptoms may vary and may range from mild itching, redness and swelling to severe abscesses and open pains such as injurious ulcers. Skin diseases may substantially affect an individual's quality of life.

Pityriasis is a common chronic inflammatory skin disease that affects approximately 3% of the world's population. Pityriasis may be caused by a variety of factors, including genetic, epigenetic, environmental and lifestyle factors, involving innate and adaptive immune responses. Once the immune process is activated, more dendritic cells, macrophages and T cells will be recruited from the diseased skin and secrete more inflammatory mediators, which in turn promotes excessive epidermal proliferation and abnormal differentiation of keratinocytes, resulting in epidermal thickening and leading to pityriasis plaques.

Treatment of tinea pedis aims to stop the rapid growth of skin cells and remove scales. There are three commonly used treatments, topical treatments (creams and ointments), light therapy (phototherapy) and oral or injectable medications. Steroid medications are often used for topical treatments and oral or injectable medications, especially for the treatment of moderate to severe tinea pedis, however, long-term use or overuse of strong corticosteroids may lead to some unpleasant side effects.

Mangosteen has been studied and applied in the prevention of breast cancer and muscle-related diseases. It has also been developed as a nutritional supplement and cosmetic for daily life. It is also used to treat acute hepatitis, liver fibrosis and prevent cirrhosis.

Matsumoto et al. also studied the purification of α-mangostin, β-mangostin, γ-mangostin, and methyl-β-mangostin from mangosteen shells, and studied the inhibitory effects of the compounds on various stages of the cell cycle, showing that the compounds have anti-cell proliferation and anti-tumor effects (Bioorg.Med.Chem.2005,13,6064-6069).

The present invention provides a composition for use in preparing a pharmaceutical composition for treating skin diseases.

Specifically, the present invention provides a composition for preparing a drug for treating tinea pedis, wherein the composition comprises an effective dose of mangosteen shell extract. The drug can also be used for local treatment or precision treatment.

The present invention also provides a method for treating eczema in an individual, comprising administering a pharmaceutical composition comprising an effective dose of mangosteen shell extract.

The chloasma described in the present invention includes plaque chloasma, nail chloasma, guttate chloasma, inverse chloasma, purulent chloasma, erythrodermic chloasma and chloasma arthritis.

The mangosteen shell consists of a softer inner shell and a harder outer shell.

In a preferred embodiment, the mangosteen shell is extracted using a solvent, and the extraction solvent is selected from the group consisting of methanol, ethanol, n-propanol, 2-propanol, n-butanol, acetone, ethyl acetate and water.

In another preferred embodiment, the mangosteen shell extract is a mangosteen shell water extract and/or a mangosteen shell alcohol extract.

In a preferred embodiment, the mangosteen shell extract is a mangosteen shell water extract.

In another preferred embodiment, the mangosteen shell extract is a mangosteen shell alcohol extract.

In a preferred embodiment, the mangosteen shell is the outer shell/inner shell of the mangosteen shell and/or the whole shell of the mangosteen shell.

In another preferred embodiment, the mangosteen shell is the outer shell of the mangosteen shell.

In a preferred embodiment, the composition of the present invention can be an oral or parenteral preparation, the parenteral preparation can be an external preparation, the external preparation can be a cream, ointment, gel, lotion or patch.

In a preferred embodiment, the mangosteen shell extract of the present invention contains α-mangostin and γ-mangostin.

In another preferred embodiment, the mangosteen shell water extract of the present invention contains α-mangostin and γ-mangostin.

In another preferred embodiment, the mangosteen shell alcohol extract of the present invention contains α-mangostin and γ-mangostin.

The term "effective dose" as used herein refers to a dose that achieves an effective result when administered to an individual, or a dose that has the desired activity in vivo or in vitro. In the case of inflammatory diseases and autoimmune diseases, effective clinical results include a reduction in the degree or severity of symptoms associated with the disease or disease, and/or an extension of the life span of the individual, and/or an improvement in the quality of life of the individual, compared to no treatment. The exact amount of compound administered to an individual will depend on the type and severity of the disease or symptom and individual characteristics, such as the individual's general health, age, sex, weight, and tolerance to drugs. It will also depend on the degree, severity, and type of inflammatory diseases, autoimmune diseases, allergic diseases, or the immunosuppressive effect sought. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.

In a preferred embodiment, the effective dosage of the mangosteen shell extract of the present invention is 1% (w/w) to 10% (w/w); in the best embodiment, the effective dosage of the mangosteen shell extract is 1.25% (w/w) to 5% (w/w).

The pharmaceutical composition of the present invention can be formulated into various oral or parenteral preparations. Oral preparations can be formulated into solid preparations, such as powders, granules, tablets, capsules, etc., or formulated into liquid preparations, such as suspensions, emulsions, syrups, etc. Parenteral preparations can be formulated into external preparations, such as creams, ointments, gels, lotions, patches, etc., or inhalers, aerosols, suppositories, etc.

The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable excipient, in particular, may further contain a predetermined solvent or oil, and may further contain a dispersant if necessary.

Examples of solvents used in the present invention include but are not limited to water, ethanol, isopropanol, 1,3-butylene glycol, propylene glycol, glycerol, etc.

Examples of oils that can be used in the present invention are selected from the group consisting of corn oil, sesame oil, linseed oil, cottonseed oil, soybean oil, peanut oil, mono-glycerides, di-glycerides, tri-glycerides, mineral oils, deep-sea fish oil, squalene, jojoba oil, olive oil, evening primrose oil, borage oil, grape seed oil, coconut oil, sunflower seed oil, shea butter and any combination thereof, but are not limited thereto.

Solvents and oils may be used alone or in any combination.

Examples of useful dispersants may include lecithin, organic monoglycerides, behenyl alcohol fatty acid esters, polyoxyethylene fatty acid esters, sorbitan stearate, etc., but are not limited thereto. These raw materials may also be used alone or in any combination.

If desired, the composition may further comprise additional materials, such as antimicrobial agents or preservatives.

At the same time, known active ingredients can be used together with the composition as long as they do not have an adverse effect on the pharmaceutical activity of the composition of the present invention. For example, a skin cream such as ceramide is commonly used as a known atopic dermatitis agent, or a liquid component such as a steroid such as hydrocortisone, a vitamin A derivative such as vitamin A palmitate and/or tocopherol can be used together with the composition.

When the pharmaceutical composition is used as an external preparation, appropriate external preparations for skin use can be used as the basic raw materials. Aqueous solutions, non-aqueous solvents, suspensions, emulsions or freeze-dried preparations can all be used and sterilized according to known methods.

In the composition of the present invention that is actually administered or applied, the dosage can be determined according to various factors, such as the administration route, age, gender, and weight of the patient, the severity of the disease, and the dosage form of the active ingredient.

In the case where the composition of the present invention can be a food or cosmetic composition, the composition can be prepared by appropriately adding at least one food nourishing or cosmetically acceptable carrier.

The food composition can be used or added to, for example, health food. As used herein, the term "health food" means a food containing the composition of the present invention that has enhanced functions compared to general food. The health food can be prepared by adding the composition to general food, or by encapsulation, powderization or suspension.

The cosmetic composition can be added by itself or together with other cosmetic ingredients, or can be used appropriately according to other known methods. Cosmetics include aftershaves, lotions, creams, facial masks and makeup, but are not limited to them.

Cosmetic compositions can be formulated into various composition forms, such as gels, creams, ointments, etc. Compositions in the form of gels, creams and ointments can be appropriately prepared using known methods according to the form of the composition by adding known softeners, emulsifiers and thickeners or other raw materials known in the art.

The composition in the form of a gel can be prepared, for example, by adding a softener such as trimethylolpropane, polyethylene glycol and glycerin, a solvent such as propylene glycol, ethanol and isocetyl alcohol, and pure water.

The preparation of the composition in the form of a cream can be achieved, for example, by adding fatty alcohols, such as stearyl alcohol, myristyl alcohol, behenyl alcohol, arachidyl alcohol, isostearyl alcohol and isocetyl alcohol; emulsifiers, such as lipids, such as lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol and its derivatives, stearic acid glyceryl ester, sorbitan palmitate, sorbitan stearate, etc.; natural fats and oils, such as avocado oil, almond oil, babassu oil, borage oil, camellia oil, etc.; lipid compositions, such as ceramide, cholesterol, fatty acids, phytosphingosine, lecithin, etc.; solvents, such as propylene glycol, etc.; and pure water.

The preparation of the composition in the form of an ointment can be achieved, for example, by adding a softener, an emulsifier and a wax, such as microcrystalline wax, stone wax, ceresin, honey wax, whale wax, vaseline, etc.

On the other hand, the present invention provides a method for preparing a medicament for treating or relieving tinea pedis using the composition. As used herein, the term "treating or relieving" means stopping or delaying the course or symptoms of the disease when the patient uses the medicament.

Figure 1 shows the ear thickness of the right ear of IL-23 injected mice after the placebo was given, compared with the ear thickness of the left ear of mice injected with PBS only.

Figure 2 shows the efficacy of three ointment samples on xerosis. Figure 2A shows that all ointment samples did not cause any adverse effects; Figures 2B, 2C, and 2D show that the three ointment samples have the potential to treat xerosis. Abbreviation: W: whole fruit shell extract.

Figure 3 shows that all ointment samples significantly reduced epidermal thickening. Figure 3A shows the histology of ear tissue sections of PBS/IL-23 injected mice under H&E staining. Scale bar: 50μM; Figure 3B shows the measurement results of ear thickness in the upper (dorsal) layer of the ear. The results are shown as mean ± standard error (SEM), * indicates P <0.05, ** indicates P <0.01, *** indicates P <0.001; Statistical method: Student's T test; Abbreviation: W: whole fruit shell extract.

Figure 4 shows the efficacy of 5% endocarp extract and 5% exocarp extract. Figure 4A shows that both 5% endocarp extract and 5% exocarp extract showed potential for treating eczema, and 5% exocarp extract was more effective than 5% endocarp extract. Figures 4B and 4C show that 5% endocarp extract and 5% exocarp extract significantly reduced epidermal thickening. The results are presented as mean ± standard error (SEM), * indicates P < 0.05, *** indicates P <0.001; statistical method: Student's T test; abbreviations: W: whole endocarp extract; I: endocarp extract; O: exocarp extract.

The following embodiments are non-limiting and merely represent various aspects and features of the present invention.

Experimental example

Preparation of pharmaceutical compositions

Take the mangosteen shell, dry it to 50%~95%, extract it with a solvent (such as water or 10%~95% alcohol), and concentrate it to obtain the mangosteen shell extract.

Separate the outer shell and inner shell of the mangosteen shell, dry the outer shell and inner shell of the mangosteen shell to 50%~95% respectively, extract with a solvent (such as water or 10%~95% alcohol), and concentrate to obtain the outer shell extract and inner shell extract of mangosteen shell.

The alcohol and water extracts of mangosteen shell, and the alcohol and water extracts of the inner and outer shells of mangosteen shell are made into creams or ointments of different concentrations.

Establishment of IL-23-induced eczema mouse model

The present invention was conducted using male wild-type mice (C57BL/6) aged 8-11 weeks. All mice were anesthetized with 1%-3% isoflurane in 100% oxygen. To induce psoriasis-like pathogenesis, mice were injected with IL-23 in the right ear and control buffer (PBS) in the left ear as described above. Vector-free recombinant mouse IL-23 (1 μg in 10 μL; purchased from eBioscience, cat. No. 34-8231-85) was injected intradermally into the right ear using a 31-G needle. Injections were given every other day for 14 days to induce psoriasis-like disease. Sterile PBS was injected into the left ear of the mouse as a vector control.

Animal experiments

60 mice were used for animal experiments, including 48 mice induced by leprosy-like disease model and 12 non-induced mice. All mice were divided into two experiments, 30 mice in each experiment. Each experiment included 5 groups, Group 1 (6 mice induced by leprosy-like disease model + 1.25% whole fruit shell extract treatment), Group 2 (6 mice induced by leprosy-like disease model + 2.5% whole fruit shell extract treatment), Group 3 (6 mice induced by leprosy-like disease model + 5% whole fruit shell extract treatment), Group 4 (6 mice induced by leprosy-like disease model + placebo) and Group 5 (6 non-induced mice + PBS). The two experiments and group allocation are shown in Table 1.

Table 1

Sterile PBS was injected into the left ear of mice in Group 5 as a vehicle control. Placebo (Group 4) and three ointment samples (Groups 1 to 3) were applied daily at the injection site (40.25 mg/ ^cm2 per ear) from day 0 to day 13 of the experiment. All mice were euthanized on day 14. Ear thickness was measured every other day at the center of the ear using a pocket thickness gauge (Mitutoyo Corp.), and ear photographs were taken on days 0, 5, 9, and 14 (data not shown).

Hematoxylin-eosin staining (H&E staining) and measurement of epidermal thickness

At the end of the experiment, mice were euthanized and the injected ears were collected. Half of the ears were fixed with 10% formalin, embedded in paraffin, sectioned, and stained with H&E. The average epidermal thickness was determined by measuring the distance between the outermost surface of the epidermis and the dermal-epidermal junction at five randomly selected locations (excluding the stratum corneum) in each H&E-stained sample using Olympus cellSens Standard software.

result

The present invention tested the effects of three ointment samples on the IL-23-induced eczema mouse model. The right ear of the mice was injected with 1 μg of vector-free recombinant mouse IL-23 every other day for 14 days, and the left ear was injected with sterile PBS as a vector control group.

Placebo and three ointment samples (40.25 mg/cm ² per ear) were applied to the injection site every day, and ear photos were taken on days 0, 5, 9, and 14. To examine the effect of the ointment samples on ear swelling, the present invention measured ear thickness every other day from day 3 to day 13, and the ear thickness of the right ear injected with IL-23 and given a placebo showed a significant change compared to the ear thickness of the left ear injected with PBS (Figure 1). The results showed that the present invention can successfully induce ear swelling in mice using IL-23 injection, which is one of the symptoms of tinea pedis.

On days 0 to 14 (Figure 2A), the ear thickness of the left ear injected with PBS showed no significant changes in all groups, indicating that all ointment samples did not cause any adverse effects.

Figures 2B-2D show the ear thickness of the right ear injected with IL-23 and given three doses of ointment samples. All groups significantly reduced ear swelling on day 5. Among them, the 5% whole fruit shell extract group reduced ear swelling for a long time from day 5 to day 9 and day 13.

The present invention performed histological analysis on ear sections taken from euthanized mice. The results of H&E staining revealed that the placebo group had characteristics of a chlamydia-like phenotype, such as epidermal thickening, epidermal reticular ridges protruding into the dermis, and many cells infiltrating into the inflamed area (Figure 3A). The group given the ointment sample had reduced epidermal thickness and slightly reduced cell infiltration.

The present invention measured the epidermal thickness of each mouse (Figure 3B). These results also indicated that the thickness of the placebo group increased significantly compared with the group using only PBS. In contrast to the results of the placebo group, all ointment samples, including 1.25% whole fruit shell extract, 2.5% whole fruit shell extract, and 5% whole fruit shell extract, significantly reduced epidermal thickness. And the results of H&E staining indicated that in the eczema-like mouse model, the ointment samples could significantly reduce epidermal thickness and slightly reduce the eczema-like phenotype in histological analysis.

It is noteworthy that all groups applying the ointment samples showed early therapeutic effects within 5 days, especially the group applying 5% whole fruit shell extract also showed a longer duration of ear thickness reduction.

To further evaluate which part has a significant effect on the treatment of eczema, 5% of the outer shell of mangosteen and 5% of the inner shell of mangosteen were used in the same experiment and compared with each group.

As shown in Figure 4A, both the endocarp extract and the exocarp extract showed potential effects on eczema. The results of ear thickness of the right ear injected with IL-23 and administered with 5% endocarp extract and 5% exocarp extract also showed that ear swelling was significantly reduced on the 5th day (Figures 4B and 4C). In particular, administration of 5% exocarp extract showed that the reduction in ear thickness lasted longer than administration of 5% endocarp extract.

All results showed that treatment with these ointment samples was able to reduce the symptoms caused by tinea pedis, and among them, the 5% whole fruit shell extract was able to reduce the thickness of the ear and last longer.

Although the present invention has been described and illustrated in sufficient detail so that a person skilled in the art can make and implement the present invention, various substitutions, modifications and improvements should be obvious without departing from the spirit and scope of the present invention.

It is readily understood by those skilled in the art that the present invention is well adapted to achieve the objects and advantages mentioned and those inherent therein. The cells, animals, and processes and methods for producing them represent only the best modes of implementation, are exemplary, and are not intended to limit the scope of the invention. Those skilled in the art will be able to conceive of modifications and other uses thereof, which are included within the spirit of the invention and are limited by the scope of the scope of the patent application.

Claims (7)

A composition for preparing a drug for treating tinea pedis, wherein the composition comprises an effective dose of mangosteen shell extract, wherein the composition is a topical preparation for skin application, wherein the effective dose is 1% w/w to 8% w/w, and the composition is continuously administered for 5 to 7 days. The use as described in claim 1, wherein the mangosteen shell extract is a mangosteen shell water extract and/or a mangosteen shell alcohol extract. The use as described in claim 1, wherein the mangosteen shell is the outer shell of the mangosteen shell and/or the inner shell of the mangosteen shell. The use as described in claim 1, wherein the mangosteen shell is the outer shell of the mangosteen shell. The use as described in claim 1, wherein the mangosteen shell extract includes α-mangostin and γ-mangostin. The use as described in claim 1, wherein the effective dose is 1% w/w to 5% w/w. The use as described in claim 1, wherein the tinea includes plaque tinea, nail tinea, guttate tinea, inverse tinea, purulent tinea, erythrodermic tinea and tinea arthritis.

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