WO2017016428A1 - 山竹果果壳萃取物用于制备治疗皮肤疾病的药物的用途 - Google Patents

山竹果果壳萃取物用于制备治疗皮肤疾病的药物的用途 Download PDF

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WO2017016428A1
WO2017016428A1 PCT/CN2016/090780 CN2016090780W WO2017016428A1 WO 2017016428 A1 WO2017016428 A1 WO 2017016428A1 CN 2016090780 W CN2016090780 W CN 2016090780W WO 2017016428 A1 WO2017016428 A1 WO 2017016428A1
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mangosteen
extract
shell
composition
husk
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PCT/CN2016/090780
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English (en)
French (fr)
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张嘉铭
蔡佩宜
陈谷政
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山酮新药开发股份有限公司
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Priority to DK16829794.3T priority Critical patent/DK3326637T3/da
Priority to ES16829794T priority patent/ES2880432T3/es
Priority to JP2018502248A priority patent/JP6836581B2/ja
Priority to US15/743,662 priority patent/US10383906B2/en
Priority to EP16829794.3A priority patent/EP3326637B1/en
Priority to PL16829794T priority patent/PL3326637T3/pl
Priority to DE212016000151.5U priority patent/DE212016000151U1/de
Publication of WO2017016428A1 publication Critical patent/WO2017016428A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to the use of a composition for the manufacture of a medicament for the treatment of skin diseases.
  • the skin is the largest organ in the human body.
  • the skin diseases are also numerous.
  • the skin diseases may be acute (lasting only a few minutes to several hours) or chronic conditions, which may affect individuals for days, months, years or even a lifetime.
  • Skin diseases may be It is a fungal, bacterial, or viral condition, or may be a non-infectious, immune response, such as an inflammatory response with or without an allergen, or may be an idiopathic disease.
  • the symptoms may be varied and may range from mild itching, redness and swelling to severe long pus and open pain, such as nociceptive ulceration, which may substantially affect the quality of an individual's life.
  • Skin diseases may be scarring, dermatitis, proliferative diseases or conditions, mast cell diseases or conditions, burns, contact with allergens and/or irritants, or inflammatory diseases or conditions, skin diseases including atopic dermatitis, large Pleural dermatosis, collagen disease, psoriasis, psoriasis, contact dermatitis, eczema, urticaria, rosacea, hypertrophic scarring, neoplasia, scleroderma, folliculitis, burns or skin mucinism .
  • Atopic dermatitis also known as atopic eczema
  • atopic eczema is a recurrent allergic skin disease, often associated with heredity, and is one of the most common skin diseases in infants and young children, accounting for 3 to 5% of the pediatric population. 60% of patients will develop symptoms within one year of age, and 30% of patients will develop between 1 and 5 years of age. About half of children with atopic dermatitis will have allergic rhinitis, asthma, allergic conjunctivitis, etc., which are called allergic children, or called atopic physique.
  • Psoriasis is a common chronic skin disease, also known as psoriasis. It is characterized by the appearance of papules of varying sizes, erythema, covered with silvery white scales, clear boundaries, and easy to occur on the scalp, the extremities and the back.
  • Folliculitis is a purulent inflammation that occurs when a bacterium invades the hair follicle. It occurs mostly in the head, neck, buttocks, genitals, perianal or other parts of the body, and is more likely to recur.
  • Contact dermatitis is an inflammatory reaction of skin mucous membranes due to exposure to foreign substances such as chemical fiber clothing, cosmetics, drugs, and the like. Its clinical features are sharp edges at the contact site, edematous erythema in the light, papules, leeches and even sputum in the heavier, and epidermis loosening or even necrosis in more severe cases.
  • the general treatment for skin diseases includes oral or topical preparations.
  • Steroid and antihistamine drugs are now widely used in the treatment of allergic diseases of atopic dermatitis, and in severe cases, immunosuppressive agents can be administered.
  • these methods only have a short-term therapeutic effect and are prone to adverse side effects such as skin atrophy, skin pigmentation, acne, osteoporosis, avascular necrosis, atherosclerosis, glaucoma, and tumor promotion. Growth and so on.
  • a novel therapeutic agent for symptomatic relief and treatment of atopic dermatitis which provides a powerful and long-lasting therapeutic effect and reduces side effects.
  • Mangosteen has been used in the field of breast cancer prevention and muscle-related diseases, as well as as a nutritional supplement and cosmetics for daily life, as well as for the treatment of acute hepatitis, liver fibrosis and prevention of cirrhosis (Taiwan Patent Notice) No. I411432).
  • Matsumoto et al. also studied the purification of ⁇ -mangostin, ⁇ -mangostin, ⁇ -mangostin, and methyl- ⁇ -mangostin from mangosteen husks, and studied the inhibition of this compound on various stages of the cell cycle. The effect shows that the compound has an anti-cell proliferation effect and an anti-tumor effect (Bioorg. Med. Chem. 2005, 13, 6064-6069).
  • the invention provides the use of a composition for the preparation of a pharmaceutical composition for the treatment of an immune disorder, an allergic condition or an inflammatory condition.
  • the invention provides the use of a composition for the manufacture of a medicament for the treatment of an autoimmune disease or allergy, wherein the composition comprises an effective amount of mangosteen husk extract.
  • the drug can also be used for topical or precise treatment purposes.
  • the invention further provides the use of a composition for the manufacture of a medicament for the treatment of an autoimmune disease or allergy, wherein the composition comprises an effective amount of mangosteen husk extract.
  • the mangosteen husk is extracted with a solvent selected from the group consisting of methanol, ethanol, n-propanol, 2-propanol, n-butanol, acetone, ethyl acetate and water.
  • a solvent selected from the group consisting of methanol, ethanol, n-propanol, 2-propanol, n-butanol, acetone, ethyl acetate and water. The group consisting of.
  • the mangosteen fruit shell extract is mangosteen fruit shell water extract and/or mangosteen fruit shell alcohol extract.
  • the mangosteen fruit shell refers to the part of the mangosteen fruit that has a softer inner shell and a harder outer shell.
  • the mangosteen fruit shell extract is mangosteen fruit shell water extract; in another preferred embodiment, the mangosteen fruit shell shell extract is mangosteen fruit shell alcohol extract.
  • the mangosteen husk is a mangosteen shell and/or a mangosteen shell.
  • the mangosteen husk is a mangosteen shell.
  • the composition further comprises an excipient having a ratio of from 1% to 10% and still has therapeutic efficacy.
  • the mangosteen husk water extract can relieve itching and/or promote cell proliferation; in another preferred embodiment, the mangosteen husk alcohol extract can be anti-inflammatory and/or analgesic.
  • the mangosteen husk extract inhibits an increase in the immunoregulatory related hormones IL-7 and IL-10, but does not inhibit the inflammatory related cytokine IL-1 or TNF- ⁇ .
  • the mangosteen shell extract mainly inhibited the increase of IL-7 and IL-10, and also inhibited the increase of IL-15 and MCP-1;
  • the extract of mangosteen shell and shell mainly inhibited IL-7, The increase of IL-10 and IL-15 also inhibited the increase of MCP-1.
  • the composition further comprises an oil.
  • the composition of the present invention may be an oral or parenteral preparation, and the parenteral preparation may be an external preparation, which may be a cream, a cream, an ointment, a gel, or the like. Lotion or patch.
  • the mangosteen husk extract of the present invention comprises alpha-mangostin and gamma-mangostin.
  • the mangosteen husk water extract of the present invention comprises alpha-mangostin and gamma-mangostin.
  • the mangosteen husk alcohol extract of the present invention comprises alpha-mangostin and gamma-mangostin.
  • composition of the present invention can treat or inhibit atopic dermatitis by inhibiting immunomodulatory related hormones, rather than inhibiting inflammatory cytokines such as IL-1 or TNF ⁇ .
  • Skin diseases include, but are not limited to, atopic dermatitis, bullous skin disease, collagen disease, psoriasis, psoriasis, contact dermatitis, eczema, urticaria, rosacea, hypertrophic scarring, neoplasia, hard Skin disease, folliculitis, burns or hyperlipidemia of the skin.
  • allergy disorder means a disease, condition or condition that is allergic to a generally harmless substance.
  • the materials may be present in the environment (eg, indoor air pollutants and air allergens) or not from the environment (eg, those causing skin or food allergies). Allergens can enter the body in many ways, including through breathing, ingestion, skin contact or injections (including insect mites).
  • Many allergic conditions are associated with atopic physique that has a tendency to produce allergic antibodies to IgE. Because IgE can sensitize obese cells anywhere in the body, individuals with atopic physique often show disease in more than one organ.
  • an allergic condition includes any allergic reaction that occurs when re-exposed to a sensitizing allergen, which in turn causes release of an inflammatory mediator.
  • Allergic conditions include, but are not limited to, allergic rhinitis (eg, hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitis media, drug reactions, insect spasm, latex response, conjunctivitis, Urticaria, systemic allergic reactions and allergic reactions, atopic dermatitis, asthma and food allergies.
  • the extract of the present invention can be used for preventing or treating a patient suffering from an inflammatory condition.
  • inflammatory condition means a disease, condition or symptom characterized by inflammation of the body tissue or an inflammatory component. It includes local inflammation Should be inflamed with systemic.
  • inflammatory conditions include: transplant rejection, including skin graft rejection; chronic inflammatory conditions of the joint including arthritis, rheumatoid arthritis, osteoarthritis, and bone diseases associated with increased bone loss; inflammatory Intestinal diseases such as ileitis, ulcerative colitis, Barrett's syndrome and Crohn's disease; inflammatory lung disorders such as asthma, adult respiratory distress syndrome and chronic obstructive respiratory disease; ocular inflammatory disease , including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic gingival inflammatory conditions, including gingivitis and periodontitis; tuberculosis; Jatropha; kidney inflammatory disease, including uremia complications, renal glomerulonephritis and kidney disease; skin inflammatory conditions, including sclerodermatitis, psoriasis and eczema; central nervous system inflammatory diseases, including chronic demyelination of the nervous system Alzheimer's
  • "Treatment of an inflammatory condition&quot refers to the administration of a compound or composition of the invention to an individual having an inflammatory condition, a symptom with such condition, or an individual suffering from such a disease, in order to treat, slow, alter, affect or prevent the inflammation.
  • an "effective dose” is a dose that achieves an effective result when administered to an individual, or a dose that possesses the desired activity in vivo or in vitro.
  • effective clinical outcomes include a reduction in the extent or severity of symptoms associated with the disease or condition, and/or prolonging the life of the individual, and/or improving the quality of life of the individual, as compared to untreated.
  • the precise amount of compound administered to an individual will depend on the type and severity of the disease or condition, as well as the individual characteristics, such as the general health of the individual, age, sex, weight, and tolerance to the drug. It is also determined by the inflammatory condition, the autoimmune condition, the degree, severity and type of the allergic condition or the immunosuppressive effect sought. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.
  • the effective amount of mangosteen fruit husk extract is from 20 mg/kg to 200 mg/kg.
  • the present invention relates to extracts or pharmaceutical compositions that are particularly useful for immunosuppression, or for treating or preventing inflammation, immune disorders, and allergic conditions.
  • compositions of the present invention can be formulated into a variety of oral or parenteral formulations.
  • Oral preparation can be adjusted into Solid preparations such as powders, granules, troches, capsules and the like, or formulated into liquid preparations such as suspensions, emulsions, syrups and the like.
  • the parenteral preparation can be formulated into an external preparation such as a cream, an ointment, a gel, a lotion, a patch, or the like, or a sorbent, an aerosol, a suppository or the like.
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable excipient, and in particular may further comprise a predetermined solvent or oil, if desired, and may further comprise a dispersing agent.
  • solvent examples include, but are not limited to, water, ethanol, isopropanol, 1,3-butylene glycol, propylene glycol, glycerin and the like.
  • oils which 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-glyceride, di-glyceride, triglyceride, mineral oil, deep sea fish oil Squalene, jojoba oil, olive oil, evening primrose oil, Borage Oil, grape seed oil, coconut oil, sunflower oil, shea butter and any Groups of combinations, but not limited to them.
  • the solvent and the oil may be used singly or in any combination thereof.
  • useful dispersing agents may include, but are not limited to, lecithin, organic monoglycerides, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan stearate, and the like. These materials may also be used singly or in any combination thereof.
  • composition may further comprise additional ingredients such as antibacterials or preservatives.
  • the active ingredient can be used together with the composition as long as it has no adverse effect on the pharmaceutical activity of the composition of the present invention.
  • a moisturizer such as ceramide is usually used as a conventional atopic dermatitis agent, or a liquid component such as hydroxycortisol steroids, vitamin A derivatives such as palmitic acid vitamin A and/or fertility.
  • a phenol or the like can be used together with the composition.
  • a suitable external skin preparation can be used as a base material, and an aqueous solution, a nonaqueous solvent, a suspension, an emulsion or a lyophilized preparation or the like can be used, which is sterilized by a known method.
  • the dosage can be determined according to various factors such as the route of administration, age, sex, and the weight of the patient, the severity of the disease, and the form of the agent as an active ingredient.
  • composition of the invention may be a food or cosmetic composition
  • the composition may be prepared by the appropriate addition of at least one food nourishing or cosmetically acceptable carrier.
  • the food composition can be used or added to, for example, a health food.
  • a health food means a food product comprising a composition of the invention having an improved function compared to a general food product. Healthy foods can be prepared by adding the composition to a general food, or by encapsulation, pulverization or suspension.
  • the cosmetic composition may be added by itself or together with other cosmetic ingredients, or may be suitably used according to other known methods.
  • Cosmetics include aftershaves, lotions, creams, masks and make-up, but not limited to them.
  • the cosmetic composition can be formulated into various compositions such as gels, creams, ointments and the like.
  • the composition in the form of a gel, a cream and an ointment can be suitably prepared according to the form of the composition by a known method by adding a known softener, an emulsifier and a thickener or a raw material known in other techniques.
  • composition in the form of a gel can be prepared, for example, by adding a softening agent such as trimethylolpropane, polyethylene glycol, and glycerin, a solvent such as propylene glycol, ethanol, and isocetyl alcohol, and pure water.
  • a softening agent such as trimethylolpropane, polyethylene glycol, and glycerin
  • a solvent such as propylene glycol, ethanol, and isocetyl alcohol
  • composition in the form of a cream can be prepared, for example, by the addition of fatty alcohols such as stearyl alcohol, stigmasterol, behenyl alcohol, arachidyl alcohol, isostearyl alcohol and isocetyl alcohol; emulsifiers such as lipids , for example, lecithin, phosphatidylcholine, phosphatidylethanolamine, phospholipidic acid, phospholipid inositol and its derivatives, glyceryl stearate, sorbitan palmitate, sorbitan stearate, etc.; natural fat 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.; A solvent such as propylene glycol or the like; and pure water.
  • fatty alcohols such as stearyl alcohol, stigmasterol, behenyl alcohol, arachi
  • the preparation in the form of an ointment can be prepared, for example, by the addition of softening agents, emulsifiers and waxes, such as microcrystalline waxes, paraffin waxes, ceresins, beeswax, whale wax, petrolatum and the like.
  • the invention provides a method of using the composition to prepare an agent for treating or ameliorating atopic dermatitis.
  • treatment or alleviation is intended to mean the course or symptom of a disease that is stopped or delayed when the patient uses the agent.
  • Figure 1 Changes in body weight of mice in each group.
  • Figure 2 Changes in ear thickness in each group of mice.
  • Figure 3 Changes in ear weight of each group of mice.
  • Figure 4 Photographs of mouse ears in each group.
  • Figure 5 Sectional view of the ear tissue of each group of mice.
  • Figure 6 HPLC chromatogram of mangosteen fruit shell alcohol extract.
  • Example 1 Preparation of a pharmaceutical composition
  • mangosteen fruit shell dry the shell to 50% ⁇ 95%, extract with solvent (such as water or 10% ⁇ 95% alcohol), concentrate to obtain mangosteen fruit shell extract.
  • solvent such as water or 10% ⁇ 95% alcohol
  • the outer shell and the inner shell of the mangosteen fruit shell are separated, and the mango shell shell and the mangosteen shell shell are dried to 50% to 95%, respectively, and extracted with a solvent (such as water or 10% to 95% alcohol). Concentrated to obtain mangosteen fruit shell extract and mangosteen shell shell extract.
  • a solvent such as water or 10% to 95% alcohol
  • Alcohol and water extracts of mangosteen fruit husks, alcohol and water extracts of mangosteen husks and shells were made into creams or ointments of different concentrations.
  • test animals used 8-week-old BALB/c mice (purchased from Lesco Biotech) and weighed 25 to 28 g. They were quarantined by an animal house veterinarian for one week before entering the breeding room. Animals were divided into 9 groups, 3 in each group, for a total of 27.
  • the breeding room was set at a temperature of 21 ⁇ 2 ° C, a humidity of 30-70% and a 12-hour bright, 12-hour dark light cycle. Unlimited supply of feed and water.
  • TNCB 2-Chloro-1,3,5-trinitrobezene
  • the TNCB is administered on the same day as the test article, the TNCB is administered at least one hour apart from the test substance in order to reduce the interaction between the two.
  • the experimental design grouping is shown in the table below.
  • the 0.5%, 1%, 2%, 3%, and 5% mangosteen creams contained mangosteen extracts of 20 mg/kg, 40 mg/kg, 80 mg/kg, 120 mg/kg, and 200 mg/kg, respectively.
  • Mouse body weight changes and ear thickness were monitored twice a week. All experimental animals were bled before and after TNCB induction, before and at the time of sacrifice. The blood was centrifuged at 3,000 rpm for 30 minutes at 4 ° C, and serum was obtained, and the sample was stored.
  • Serum was preserved at the time of sacrifice, and serum biochemical indicators (IL-1 ⁇ , IL-2, IL-4, were performed according to the manual of the MAGPIX analyzer (Millipore, USA) and the reagent MCYTOMAG analysis kit (Millipore, USA). Analysis of IL-3, IL-5, IL-7, IL-10, IL-12 (p40), IL-15, IL-17, MCP-1, RANTES, TNF- ⁇ ).
  • IL-7, IL-10, IL-15 and MCP-1 were significantly increased, while mangosteen fruit shell extracts inhibited the increase of the index.
  • Mangosteen fruit shell The extracts were inhibited by 111.7%, 77.1%, 100%, 24%, and 16.1%, respectively.
  • the inhibitory indexes of mangosteen shell extracts were 97.0%, 92.8%, 65.6%, 82.7%, and 27%, respectively.
  • the results showed that the mangosteen husk can inhibit the inhibition of atopic dermatitis by inhibiting immune-regulated hormones, rather than the inhibition of inflammatory cytokines related to IL-1 or TNF ⁇ .
  • the mode of action of similar sterol drugs can inhibit a part of the immune system and thus affect the atopic dermatitis.
  • the extract of mangosteen shell shell is significantly better than the shell shell extract can completely inhibit IL- 10 indicators, while IL-10 is a major cytokine in the formation of T H 2 pathway antibodies. Therefore, the mangosteen shell extract has a greater effect on atopic dermatitis than the mangosteen shell extract.
  • the mode of action of mangosteen fruit hulls is similar to steroid drugs, steroids can inhibit the production of IL-15 under the index of IL-15, while mangosteen shells have a significant effect. This evidence shows that mangosteen The effect of the shell extract is specific to steroids rather than to the overall immune system. It can be seen that the composition and mechanism of action of mangosteen shell shell extract and inner shell extract are not exactly the same.
  • composition of the present invention has a remarkable effect on atopic dermatitis.
  • the chemical fingerprints of mangosteen fruit shell alcohol extracts were analyzed by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the mangosteen extract of the mangosteen fruit extract 300mg ⁇ 1mg was placed in a 100mL quantitative bottle, and the volume was adjusted to 100mL with Diluent. After shaking for at least 60min by ultrasonic wave until completely dissolved, the temperature was allowed to stand at room temperature and the bottom was cooled.
  • HPLC High performance liquid chromatography
  • HPLC high performance liquid chromatography
  • the column column (COSMOSIL MS-II, 5 um, 4.6 x 250 mm, Waters) was maintained at 30 ° C during the analysis.
  • a 10 L sample was injected into the HPLC system.
  • the detection wavelength was UV 240 nm for peak detection.
  • Figure 6 shows the HPLC fingerprinting analysis of mangosteen fruit shell alcohol extract. The results showed that the mangosteen fruit shell alcohol extract had the following HPLC peaks for retention time (Table 6).

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Abstract

一种组合物用于制备治疗皮肤疾病的药物的用途，该组合物包含有效剂量的山竹果果壳萃取物。

Description

[根据细则37.2由ISA制定的发明名称]　山竹果果壳萃取物用于制备治疗皮肤疾病的药物的用途 技术领域
本发明涉及一种组合物用于制备治疗皮肤疾病的药物的用途。
背景技术
皮肤是人体最大的器官，皮肤疾病也是种类众多，皮肤疾病可能为急性(持续仅数分钟至数小时)或慢性的状况，其可能影响个体数天、数月、数年甚至一生，皮肤疾病可能为真菌性的、细菌性的、或病毒性的病况，或可能为非-感染性的、免疫性的反应，例如带有或不带有过敏原的发炎反应，或可能为特发性病。因此，症状可能为各式各样且可能从温和的痒感、发红与肿胀至严重的长脓与开放性疼痛，例如伤害性的溃烂，皮肤疾病可能实质影响个体生活的质量。
皮肤疾病可能为结瘢、皮肤炎、增生性疾病或病况、肥大细胞疾病或病况、烧伤、与过敏原及/或刺激物接触、或发炎疾病或病况，皮肤疾病包括异位性皮肤炎、大疱性皮肤病、胶原性疾病、牛皮癣、牛皮癣性病灶、接触性皮肤炎、湿疹、荨麻疹、红斑痤疮、肥厚性结瘢、瘢瘤形成、硬皮病、毛囊炎、烧伤或皮肤黏蛋白增多症。
异位性皮肤炎又称为异位性湿疹，是一种反复发作的过敏性皮肤疾病，常与遗传有关，是婴幼儿最常见的皮肤疾病之一，约占小儿人口的3～5％，其中60％的病人会在一岁内发病，30％的病人则在1到5岁之间发病。罹患异位性皮肤炎的小朋友，约有一半会合并出现过敏性鼻炎、气喘、过敏性结膜炎等，也就是所谓的过敏儿，或称为异位性体质。
牛皮癣是一种常见的慢性皮肤病，又称银屑病。其特征是出现大小不等的丘疹，红斑，表面覆盖着银白色鳞屑，边界清楚，易发于头皮、四肢伸侧及背部。
毛囊炎为系菌侵入毛囊部位所发生的化脓性炎症。其多发于头部、颈部、臀部、阴部、肛周或身体其它部位，较易复发。
接触性皮炎是皮肤粘膜由于接触外界物质，如化纤衣着，化妆品、药物等等而发生的炎性反应。其临床特点为在接触部位发生边缘鲜明的损害，轻者为水肿性红斑，较重者有丘疹、水疙甚至大疤，更严重者则可有表皮松解，甚至坏死。
一般治疗皮肤疾病的方式包括口服或外用制剂。类固醇及抗组织胺药物现在被广泛地使用于治疗异位性皮肤炎的过敏性疾病，严重时可给予免疫抑制药剂。但是这些方式仅呈现短暂的治疗效果，而且容易产生不利的副作用，例如皮肤萎缩、皮肤色素脱落、青春痘、骨质疏松症、缺血性坏死(avascular necrosis)、动脉硬化症、青光眼、促肿瘤生长等。因 此，急需研发一种欲用于症状缓解及治疗异位性皮肤炎的新颖治疗药剂，且其可提供强而有力且持久的疗效并减少副作用。
山竹果已被研究应用于乳癌的预防及肌肉相关疾病等领域，也开发作为日常生活的营养补充剂及化妆品等，同时也有关于治疗急性肝炎、肝纤维化及预防肝硬化的用途(台湾专利公告号第I411432号)。
Matsumoto等人也研究由山竹果壳中纯化出α-山竹素(mangostin)、β-山竹素、γ-山竹素、及甲基-β-山竹素，并研究该化合物对细胞周期各阶段的抑制作用，显示该化合物具有抗细胞增殖效果及抗肿瘤效应(Bioorg.Med.Chem.2005,13,6064-6069)。
发明内容
本发明提供一种组合物用于制备治疗免疫病症、过敏病症或发炎病症的医药组合物的用途。
具体而言，本发明提供一种组合物用于制备治疗自体免疫疾病或过敏的药物的用途，其中该组合物包含一有效剂量的山竹果果壳萃取物。该药物也可用于局部治疗或精确治疗的用途。
本发明另提供一种组合物用于制备治疗自体免疫疾病或过敏的药物的用途，其中该组合物包含一有效剂量的山竹果果壳萃取物。
在一较佳实施例中，该山竹果果壳利用溶剂进行萃取，该萃取溶剂选自由甲醇、乙醇、n-丙醇、2-丙醇、n-丁醇、丙酮、乙酸乙酯及水所组成的群组。
在另一较佳实施例中，该山竹果果壳萃取物为山竹果果壳水萃取物及/或山竹果果壳酒精萃取物。
山竹果果壳指山竹果中果肉之外的部份，果壳包含质地较软的内壳以及质地较硬的外壳。
在一较佳实施例中，该山竹果果壳萃取物为山竹果果壳水萃取物；在另一较佳实施例中，该山竹果果壳外壳萃取物为山竹果果壳酒精萃取物。
在一较佳实施例中，该山竹果果壳为山竹果果壳外壳及/或山竹果果壳内壳。
在另一较佳实施例中，该山竹果果壳为山竹果果壳外壳。
在一较佳实施例中，该组合物另包含一赋形剂，该赋形剂比例为1％～10％，仍具有治疗功效。
在一较佳实施例中，该山竹果果壳水萃取物可止痒及/或促进细胞增生；在另一较佳实施例中，该山竹果果壳酒精萃取物可消炎及/或止痛。
在又一较佳实施例中，该山竹果果壳萃取物可抑制免疫调节相关激素IL-7、IL-10的增加，而非抑制发炎相关细胞激素IL-1或TNF-α。其中，该山竹果果壳外壳萃取物主要抑制IL-7、IL-10的增加，亦可抑制IL-15、MCP-1的增加；该山竹果果壳内壳萃取物主要抑制IL-7、IL-10、IL-15的增加，亦可抑制MCP-1的增加。
在一较佳实施例中，该组合物另包含一油类。
在一较佳实施例中，本发明的组合物可为口服或非经肠胃道制剂，该非经肠胃道制剂可为外用制剂，该外用制剂可为乳霜、乳膏、软膏、凝胶、洗剂或贴布。
在一较佳实施例中，本发明的山竹果果壳萃取物包含α山竹素(α-mangostin)及γ山竹素(γ-mangostin)。
在另一较佳实施例中，本发明的山竹果果壳水萃取物包含α山竹素(α-mangostin)及γ山竹素(γ-mangostin)。
在又一较佳实施例中，本发明的山竹果果壳酒精萃取物包含α山竹素(α-mangostin)及γ山竹素(γ-mangostin)。
本发明的组合物可以透过抑制免疫调节相关激素以治疗或抑制异位性皮肤炎，而非透过抑制IL-1或TNFα等发炎相关细胞激素。
皮肤疾病包括但不限于异位性皮肤炎、大疱性皮肤病、胶原性疾病、牛皮癣、牛皮癣性病灶、接触性皮肤炎、湿疹、荨麻疹、红斑痤疮、肥厚性结瘢、瘢瘤形成、硬皮病、毛囊炎、烧伤或皮肤黏蛋白增多症。
本文中所用「过敏病症」一词，意指对一般无害物质起过敏反应的疾病、症状或病症。该些物质可存在于环境中(例如，室内空气污染物与空气过敏原)或非来自于环境(例如，该些引起皮肤或食物过敏者)。过敏原能通过许多的途径进入身体，包括通过呼吸、摄取、皮肤接触或注射(包括昆虫螫)。许多过敏病症与具有产生过敏抗体IgE倾向的异位性体质有关。因为IgE能敏化身体内任何处的肥胖细胞，异位性体质的个体经常在多于一种的器官表现出疾病。为了本发明的目的，过敏病症包括任何当再次暴露于敏化过敏原中所发生的过敏反应，其进而造成发炎媒介体的释放。过敏病症包括但不限定为：过敏性鼻炎(例如，花粉热)、窦炎(sinusitis)、鼻窦炎(rhinosinusitis)、慢性或复发性中耳炎、药物反应、昆虫螫伤反应、乳胶反应、结膜炎、荨麻疹、全身性过敏反应与类过敏反应、异位性皮肤炎、气喘以及食物过敏。
本发明萃取物能用于预防或治疗患有发炎病症的病患。本文中所用的「发炎病症」，意指以身体组织发炎或具有发炎成分为特征的疾病、病症或症状。其包括局部发炎反 应与全身性发炎。此等发炎病症的实例包括：移植排斥，包括皮肤移植体排斥；关节的慢性发炎病症，包括关节炎、类风湿性关节炎、骨性关节炎及与增加骨质流失有关的骨骼疾病；发炎性肠道疾病，例如回肠炎、溃疡性结肠炎、巴瑞特氏(Barrett’s)症候群与克隆氏症；发炎性肺部病症，例如气喘、成人呼吸窘迫症候群与慢性阻塞性呼吸道疾病；眼部发炎病症，包括角膜失养症、砂眼、盘尾丝虫病(onchocerciasis)、葡萄膜炎、交感性眼炎(sympathetic ophthalmitis)与眼内炎；慢性牙龈发炎病症，包括牙龈炎与牙周炎；肺结核；痲疯；肾脏发炎疾病，包括尿毒并发症、肾丝球肾炎与肾脏病变；皮肤发炎病症，包括硬皮病(sclerodermatitis)、牛皮癣与湿疹；中枢神经系统发炎疾病，包括神经系统的慢性脱髓鞘症、多发性硬化症、艾滋病相关的神经退化症与阿兹海默氏症(Alzheimer’s disease)、传染性脑膜炎、脑脊髓炎、帕金森氏症(Parkinson’s disease)、杭丁顿氏(Huntington’s)舞蹈症、肌萎缩侧索硬化症、与病毒或自体免疫性脑炎；自体免疫病症、免疫复合体血管炎、全身性狼疮与红斑；全身性红斑狼疮(SLE)；以及心脏发炎疾病，诸如心肌病变、缺血性心脏疾病(高胆固醇血症、动脉粥状硬化)；以及各种其它具显著发炎成分的疾病，包括子痫前症、慢性肝衰竭、脑与脊髓创伤、癌症。也可能有全身性的发炎例如革兰氏(Gram)阳性或革兰氏阴性休克、出血性或过敏性休克，或者对促炎细胞激素反应而由癌症化疗诱发的休克，例如与促炎细胞激素有关的休克。此休克例如能由用于癌症化疗的化疗药剂诱发。本文中「发炎病症之治疗」指对患有发炎病症、具此等病症的症候或可能罹患此等疾病的个体投予本发明化合物或组合物，以便治疗、减缓、改变、影响或预防该发炎病症、其症候或患病倾向。
「有效剂量」是投予至个体时达到有效结果的剂量，或者是，在体内或体外拥有所需活性的剂量。在发炎病症与自体免疫病症的情况中，与未治疗比较，有效的临床结果包括与疾病或病症有关的症候的程度或严重性减缓、及/或延长个体寿命、及/或提高个体生活质量。投予至个体的精确化合物量将视疾病或症状的类型与严重性以及个体特性来决定，个体特性例如个体的一般健康状况、年龄、性别、体重与对药物的耐受性。也根据发炎病症、自体免疫病症、过敏病症的程度、严重性与类型或所求免疫抑制效果来决定。熟悉本领域的技术人员依据该些及其它因素将能够决定适当的剂量。在一较佳实施例中，山竹果果壳萃取物的有效剂量为20mg/kg～200mg/kg。
本发明是关于对免疫抑制，或对治疗或预防炎症、免疫病症及过敏病症特别有用的萃取物或医药组合物。
本发明医药组合物可调配成各种口服或非经肠胃道制剂的型式。口服制剂可调配成 固体制剂，例如粉末、颗粒、锭剂、胶囊等，或调配成液体制剂，例如悬浮液、乳液、糖浆等。非经肠胃道制剂可被调配成外用制剂，例如乳霜、软膏、凝胶、洗剂、贴布等，或吸剂、气溶胶、栓剂等。
本发明医药组合物可包含医药上可接受赋形剂，尤其是可进一步包含预定的溶剂或油类，如果需要，并可进一步包含分散剂。
可用于本发明的溶剂的实例包括水、乙醇、异丙醇、1,3-丁二醇、丙二醇、甘油等，但不以此为限。
可用于本发明的油类的实例选自由玉米油、芝麻油、亚麻油、棉花籽油、大豆油、花生油、单-甘油酯、二-甘油酯、三-甘油酯、矿物油、深海鱼鲛油角鲨烯(Squalene)、荷荷巴油(jojoba oil)、橄榄油、月见草油、琉璃苣油(Borage Oil)、葡萄籽油、椰子油、葵花籽油、乳油木果脂及其任意组合所组成的群组，但不以此为限。
溶剂及油类可单独使用或使用其任何的组合。
有益的分散剂实例可包含卵磷脂、有机单甘油酯、山黎醇脂肪酸酯、聚氧乙烯脂肪酸酯、硬脂酸山梨醇酐酯等，但不以此为限。这些原料也可单独使用或使用其任何的组合。
若需要，组合物可进一步包含额外原料，例如抗菌剂或防腐剂。
同时，已知活性成分可与组合物同时使用，只要其在本发明组合物的医药活性上不具有反效果即可。例如，如神经酰胺(ceramide)的润肤霜通常作为习知异位性皮肤炎药剂，或液体成分、例如氢羟肾上腺皮质素的类固醇、维生素A衍生物，例如棕榈酸维生素A及/或生育酚等可与组合物一同使用。
当使用医药组合物作为外用制剂时，可使用适当外用皮肤制剂作为基础原料，使用水性溶液、非水性溶剂、悬浮液、乳液或冻干制剂等，其依已知方法消毒。
在实际上被投与或施用的本发明组合物中，剂量可根据各种因素决定，例如投与路径、年龄、性别、及病患体重、与疾病严重性及作为活性成分的药剂型式。
在本发明组合物可为食品或化妆品组合物的情况，可通过适当添加至少一种食品滋养或美容可接受性载剂而制备该组合物。
食品组合物可用于或添加于例如健康食品。如本文中所使用，“健康食品”一词表示一种与一般食品相较下具有增进功能的含本发明组合物的食品。健康食品可通过添加该组合物至一般食品而制备，或藉由胶囊化、粉末化或悬浮液化制备。
化妆品组合物可以其本身或与其它化妆品成分一同添加，或可根据其它已知方法适当使用。化妆品包括须后水(aftershaves)、化妆水、乳霜、面膜及彩妆，但不以此为限。
化妆品组合物可调配成各种组合物形式，例如凝胶、乳霜、软膏等。凝胶、乳霜及软膏形式的组合物可根据组合物的形式使用已知方法，通过添加已知软化剂、乳化剂及增稠剂或其它技术中已知的原料而适当地制备。
凝胶形式的组合物例如可通过添加例如三甲基醇丙烷、聚乙二醇及甘油的软化剂、例如丙二醇、乙醇及异鲸蜡醇的溶剂、及纯水制备。
乳霜形式的组合物的制备例如可通过添加脂肪醇，例如硬脂醇、荳蔻醇、山嵛醇(behenyl alcohol)、花生醇、异十八醇及异鲸蜡醇；乳化剂，例如脂类，例如卵磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂丝胺酸、磷酸脂肌醇及其衍生物、硬脂酸甘油酯、棕榈酸山梨醇酯、硬脂酸山梨醇酯等；天然脂肪及油类，例如酪梨油、杏仁油、巴巴树油(babassu oil)、琉璃苣油、山茶花油等；脂质组合物，例如神经酰胺、胆固醇、脂肪酸、植物鞘胺醇、卵磷脂等；溶剂，例如丙二醇等；及纯水。
软膏形式的组合物的制备可例如通过添加软化剂、乳化剂及蜡，例如微晶蜡、石蜡、地蜡(ceresin)、蜜蜡、鲸蜡、凡士林等。
另一方面，本发明提供一种使用该组合物制备用于治疗或缓解异位性皮肤炎的药剂的方法。如本文中所使用，「治疗或缓解」一词意当病患使用药剂时，指停止或延迟疾病的病程或症状。
附图说明
图1：各组小鼠的体重变化。
图2：各组小鼠耳朵厚度变化。
图3：各组小鼠耳朵重量变化。
图4：各组小鼠耳朵照片。
图5：各组小鼠耳朵组织切片图。
图6：山竹果果壳酒精萃取物HPLC图谱。
具体实施方式
实施例1：制备医药组合物
取山竹果果壳，将果壳干燥至50％～95％，以溶剂(如水或10％～95％的酒精)进行萃取，浓缩取得山竹果果壳萃取物。
将山竹果果壳的外壳及内壳分离，分别将山竹果果壳外壳及山竹果果壳内壳干燥至50％～95％，以溶剂(如水或10％～95％的酒精)进行萃取，浓缩取得山竹果果壳外壳萃取物及山竹果果壳内壳萃取物。
分别将山竹果果壳的酒精及水萃取物、山竹果果壳内、外壳的酒精及水萃取物制成不同浓度的乳膏或软膏。
实施例2：动物试验
试验动物使用8周龄大的BALB/c小鼠(购自乐斯科生物科技公司)，体重为25～28g，进入饲育室之前先由动物房兽医师检疫一星期。将动物分为9组，每组3只，共27只。饲育房间设定温度为21±2℃，湿度为30-70％及12小时亮、12小时暗的光照循环。饲料与水无限制供应。
动物试验采用2-氯-1,3,5-三硝基苯(2-Chloro-1,3,5-trinitrobezene，TNCB)诱导小鼠形成异位性皮肤炎模式，以丙酮做为溶剂配制浓度1％的TNCB，在给测试物前一周涂抹于小鼠耳朵上(1次/2天，体积为4ml/kg)进行诱导。一周后开始给予测试物(1次/1天)，给予体积为4ml/kg，并且持续以TNCB诱导小鼠(1次/2天)。另外，同时给与软膏测试物及口服测试物的组别，其口服剂量为60mg/kg，体积为10ml/kg。如遇TNCB与测试物同一天给予时，为减少两者间相互影响，TNCB与测试物给予时间至少间隔1小时以上。试验设计分组如下表所示。0.5％、1％、2％、3％、5％的山竹果乳膏分别含有20mg/kg、40mg/kg、80mg/kg、120mg/kg、200mg/kg的山竹果果壳萃取物。
表1、异位性皮肤炎的动物试验设计
Figure PCTCN2016090780-appb-000001
PO：口服给予
每周监测小鼠的体重变化及耳朵厚度两次。所有实验动物分别在TNCB诱导前、诱导后给测试物前及牺牲时进行采血。血液经4℃，3000rpm离心30分钟后取得血清后保存样品。
所有动物在给测试物后第3周结束时牺牲，取下小鼠耳朵照相后置于10％福尔马林 溶液中保存，用于病理切片观察。病理观察采用HE染色(委托国家动物中心执行组织病理分析)。
数据以平均值±标准误差(SEM)表示，并以Student’s t-test来比较各处理组间的差异性。星号表示具有显著性差异，以*表示p<0.05；以**表示p<0.01；以***表示p<0.001。
试验结果
体重：TNCB诱导小鼠形成异位性皮肤炎后，在给测试物后第一周可能因为不适感导致小鼠体重些微下降外，整体而言体重并无明显统计上差异(图1)。
耳朵厚度变化：小鼠诱导后给予不同剂量的测试物软膏后，可观察到随测试物剂量增加小鼠耳朵肿胀程度(厚度)降低，并可观察到给予正控制组药物(1％醋酸氢化可体松(Hydrocortisone acetate))及高剂量测试物(5％)的组别与模型组相比分别有52.7％及47.3％的抑制率(p<0.01)，(表2，图2)。
表2、实验组耳朵厚度及耳朵重的抑制率(％)
Figure PCTCN2016090780-appb-000002
牺牲后耳朵重量变化：在实验结束后取下小鼠耳朵并且秤重可观察到，随测试物的剂量增加，小鼠耳朵重量逐渐减少。而在给予正控制组药物(1％醋酸氢化可体松)及高剂量测试物(5％)的组别与模型组相比分别可观察到82.4％及69.5％的抑制率(p<0.01)，另外2％及3％的测试物也分别有28.2％与28.9％的抑制率(p<0.05)，(表2，图3)。
牺牲后耳朵外观：在1实验结束后取下小鼠耳朵观察其外观，也可发现给予正控制组药物(1％醋酸氢化可体松)及高剂量(5％)的组别，耳朵轮廓完整，表面皮屑及粗糙感亦较轻微(图4)。
组织病理分析：依据国家实验动物中心病理切片结果，将TNCB诱导的慢性活动性皮肤炎(Chronic-active Dermatitis)病变的严重度分成五级：极微(1级)、轻度(2级)、中度(3级)、中度严重(4级)及极度严重(5级)。结果显示溶剂控制组、0.5％及2％ 病变平均严重度为4.67级；1％及2％+PO 60mg/kg组别病变平均严重度为5级；3％平均严重度为4.33级；正控制组药物(1％醋酸氢化可体松)平均严重度3级，而5％组别平均严重度则为2.67级(表3、图5)。
表3、实验组耳朵组织病理评分表
Figure PCTCN2016090780-appb-000003
山竹果果壳内、外壳萃取物分析：依据国家实验动物中心病理切片结果，将TNCB诱导的慢性活动性皮肤炎(Chronic-active Dermatitis)病变的严重度分成五级：极微(1级)、轻度(2级)、中度(3级)、中度严重(4级)及极度严重(5级)。结果显示外壳效果较内壳效果更佳(表4)。
表4、实验组耳朵厚度及耳朵重的抑制率(％)
抑制率(％) 1％醋酸氢化可体松 山竹果外壳(4％) 山竹果内壳(4％)
耳朵重 68.91 54.62 36.047
耳朵厚度 50.75 40.04 24.84
实施例3：血清分析
小鼠牺牲时保留血清，使用MAGPIX分析仪(Millipore,USA)及试剂MCYTOMAG分析试剂盒(Millipore,USA)，依据其操作手册进行血清中生化指标(IL-1β、IL-2、IL-4、IL-3、IL-5、IL-7、IL-10、IL-12(p40)、IL-15、IL-17、MCP-1、RANTES、TNF-α)的分析。
异位性皮肤炎模式中，分析其IL-7、IL-10、IL-15及MCP-1有显著的增加，而山竹果果壳萃取物皆可抑制其指标的上升，山竹果果壳外壳萃取物分别抑制111.7％、77.1％、100％、24％、16.1％。山竹果果壳内壳萃取物分别抑制指标为97.0％、92.8％、65.6％、82.7％、27％。结果呈现山竹果果壳可以透过抑制免疫调节相关激素以抑制异位性皮肤炎，而非IL-1或TNFα发炎相关细胞激素的抑制。如同类固醇药物作用模式，可以抑制一部分免疫系统，进而对异位性皮肤炎产生作用，而在IL-10指标下，山竹果壳外壳萃取物显著优于果壳内壳萃取物可完全抑制IL-10指标，而IL-10是TH2路径抗体形成重要的细胞激素。因此山竹果壳外壳萃取物在异位性皮肤炎的作用大于山竹果果壳内壳萃取物。另外，虽然山竹果果壳的作用模式类似类固醇药物，但在IL-15的指标项下，类固醇可以抑制IL-15的产 生，而山竹果果壳外壳则为显著作用，此证据显示，山竹果果壳外壳萃取物的作用较类固醇为专一，而非作用于整体免疫系统。由此可知，山竹果果壳外壳萃取物与内壳萃取物两者的组成与作用机制并不完全相同。
表5、血清各项指标抑制率
Figure PCTCN2016090780-appb-000004
由以上实施例的结果可知，本发明的组合物对异位性皮肤炎具有显著的疗效。
实施例4：山竹果果壳酒精萃取物的高效液相层析法分析
利用高效液相色层析法(HPLC)分析山竹果果壳酒精萃取物的化学指纹图谱。秤取山竹果果壳酒精萃取物300mg±1mg置入100mL定量瓶中，以稀释液(Diluent)定容至100mL后，以超音波振荡至少60min直至完全溶解后，室温静置回温，将底部油状物摇混均匀后，自100mL定量瓶取出2mL溶液转置入20mL定量瓶中，以稀释液(Diluent)定容至20mL后，以0.45μm PVDF滤膜过滤。
利用装配PDA检测器及自动配样器的AGILENT/1100系列HPLC系统，进行高效液相色层析法(HPLC)分析。层析管柱(COSMOSIL MS-II,5um,4.6x 250mm,Waters)在分析过程中管柱温度维持在30℃。将10L样品注入HPLC系统。利用乙腈-水-0.2％磷酸洗脱液系统(ACN/H2O＝72/28(v/v),w/0.2％H3PO4)以1.0ml/min的流速进行化学指纹图谱分析，测定波长为UV 240nm进行峰值检测。图6显示，山竹果果壳酒精萃取物的HPLC化学指纹图谱分析。结果显示，山竹果果壳酒精萃取物具有以下滞留时间的HPLC波峰(表6)。
表6、山竹果果壳酒精萃取物HPLC图谱波峰列表
波峰数 滞留时间(分钟)
1 5.53
2 6.22
3 12.48
4 14.24
5 16.29
6 20.04
7 24.41

Claims (10)

  1. 一种组合物用于制备治疗异位性皮肤炎的药物的用途，其中该组合物包含一有效剂量的山竹果果壳萃取物。
  2. 如权利要求1所述的用途，其中该山竹果果壳萃取物为山竹果果壳水萃取物及/或山竹果果壳酒精萃取物。
  3. 如权利要求1所述的用途，其中该山竹果果壳为山竹果果壳外壳及/或山竹果果壳内壳。
  4. 如权利要求1所述的用途，其中该山竹果果壳为山竹果果壳外壳。
  5. 如权利要求1所述的用途，其中该山竹果果壳萃取物包含α山竹素(α-mangostin)及γ山竹素(γ-mangostin)。
  6. 如权利要求1所述的用途，其中组合物另包含一赋形剂，该赋形剂比例为1％～10％。
  7. 如权利要求1所述的用途，其中该组合物能够抑制IL-7、IL-10、IL-15或MCP-1的增加。
  8. 如权利要求1所述的用途，其中该组合物为非经肠胃道制剂。
  9. 如权利要求1所述的用途，其中该非经肠胃道制剂为外用制剂。
  10. 如权利要求1所述的用途，其中该有效剂量为20mg/kg～200mg/kg。
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