WO2023065376A1 - 一种包含落新妇苷和/或其异构体的组合物在制备治疗银屑病的药物中的用途 - Google Patents
一种包含落新妇苷和/或其异构体的组合物在制备治疗银屑病的药物中的用途 Download PDFInfo
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- WO2023065376A1 WO2023065376A1 PCT/CN2021/126302 CN2021126302W WO2023065376A1 WO 2023065376 A1 WO2023065376 A1 WO 2023065376A1 CN 2021126302 W CN2021126302 W CN 2021126302W WO 2023065376 A1 WO2023065376 A1 WO 2023065376A1
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- Prior art keywords
- astilbin
- psoriasis
- pharmaceutical composition
- taxifolin
- resveratrol
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the invention belongs to the field of natural medicines, and in particular relates to a pharmaceutical composition for treating psoriasis containing astilbin and/or its isomers, as well as its preparation and application.
- Psoriasis commonly known as psoriasis
- psoriasis is a clinically common chronic, relapsing, inflammatory autoimmune skin disease mediated by T cells.
- the clinical manifestations are mainly erythema and hypertrophic white scales of different shapes and sizes on the skin, mostly on the limbs, head and back. Severe skin lesions can spread to the skin of the whole body, and high fever, pustules, and erythroderma appear
- Psoriasis is characterized by lymphocyte infiltration, abnormal proliferation of keratinocytes, and abnormal secretion of cytokines as the main pathological manifestations.
- Psoriasis is affected by many factors such as age, gender, race, geographical location, environment, etc.
- psoriasis The etiology of psoriasis is still unclear, and it can be activated by a variety of factors, such as trauma, infection, genetics, drugs, environmental factors, etc. Studies have shown that it is a disease caused by the interaction of multiple genes, immune system and environmental factors. complex diseases. The pathophysiological mechanism of psoriasis is very complex, and various treatment methods have more or less limitations. For mild psoriasis, local topical drugs are mainly used, such as calcipotriol, retinoic acid, topical glucocorticoids, leflunomide, etc., while moderate and severe psoriasis must be treated systematically.
- Drugs include methotrexate (the recommended first-line drug for moderate to severe plaque psoriasis), glucocorticoids, tacrolimus and other cytotoxic and immunosuppressive drugs. All can have serious toxic and side effects when slightly longer, so application is limited.
- Chinese patent application 201910056951.3 discloses the application of a combination of astilbin and organic acid in the treatment of psoriasis, but the patented technology of this invention involves the combination of astilbin and organic acid, but does not contain astilbin and resveratrol Polyphenol active ingredients such as retrol.
- the purpose of the present invention is to solve the deficiencies of the prior art, realize the development and utilization of natural products by modern drug research methods, and combine a large number of pharmacodynamic experimental screenings to provide a drug containing astilbin and/or A pharmaceutical composition for treating psoriasis or its isomers and polyphenols, as well as its preparation and use.
- the present invention provides a pharmaceutical composition for treating psoriasis, said pharmaceutical composition comprising astilbin and/or its isomers and polyphenols, wherein said astilbin and/or The weight ratio of its isomers to polyphenols is 10:1-1:10.
- the isomer of astilbin is selected from one or more of neoisoastilbin, isoastilbin or neoastilbin, and the polyphenol is selected from One or more of rhizoside or its isomers, taxifolin, naringenin, quercetin, resveratrol, the isomer of rhubarb is selected from the group consisting of isofigiriside, new One or more kinds of basaltin or new isobasaloside.
- the weight ratio of astilbin and/or its isomers to polyphenols is 9:1-1:9, 8:1-1:8, 7:1-1:7, 6:1-1:6 , 5:1-1:5, 4:1-1:4, 3:1-1:3 or 2:1-1:2.
- the pharmaceutical composition comprises astilbin and isoflavin; or, astilbin and resveratrol; or, astilbin and naringenin; or; Isoastrogrin and taxifolin; alternatively, astilbin, astilbin, and resveratrol; alternatively, astilbin, astilbin, and naringenin; alternatively, astilbin, isofragrin, and Taxifolin; or, neoastilbin, resveratrol, and taxifolin; or, neoisoastilbin, quercetin, and taxifolin.
- the present invention provides a pharmaceutical preparation for the treatment of psoriasis, which consists of a therapeutically effective amount of the pharmaceutical composition described in the first aspect above and a pharmaceutically acceptable carrier production.
- the pharmaceutical preparations are powders, tablets, capsules, granules, oral liquids, injections, creams or ointments.
- the pharmaceutical preparation is selected from tablets, capsules, granules, creams or ointments.
- the present invention provides the use of the pharmaceutical composition described in the first aspect above or the pharmaceutical preparation described in the second aspect above in the preparation of a medicament for treating psoriasis.
- the psoriasis is psoriasis vulgaris, erythrodermic psoriasis, articular psoriasis or pustular psoriasis, and the psoriasis is in an advanced stage , quiescent or extinction phase.
- the drug inhibits excessive proliferation of human epidermal keratinocytes, the drug reduces skin inflammation, reduces the degree of skin lesions, and relieves skin erythema, scales and infiltration.
- the present invention has the following beneficial effects:
- the present invention is a composition composed of natural products. These natural products have a synergistic effect in the treatment of psoriasis, and the drug effect is better than the original single component, and the combination ratio is further optimized to achieve A better efficacy.
- Astilbin The chemical name of Astilbin is (2R,3R)5,7,3′,4′-tetrahydroxydihydroflavonol-3-O- ⁇ -L-rhamnopyranoside.
- Astilbin widely exists in a variety of plants in nature. Astilbin can be isolated from 12 families, 15 genera and 26 species of plants worldwide, which can be used as raw materials for extracting astilbin.
- Astilbin has a wide range of pharmacological activities, such as anti-inflammatory, immune suppression, rejection, liver and kidney protection, anti-oxidation, analgesic, anti-edema, antibacterial, hypoglycemic and regulation of fat metabolism and other pharmacological activities.
- Astilbin isomers refer to the stereoisomerism of astilbin at the C-2 and C-3 positions, respectively (2R,3R): astilbin, (2S,3S): new astilbin, (2S,3R): Neoisoastilbin, (2R,3S): Isastilbin, four cis and trans isomers.
- the isomers of rhizoidin refer to the stereoisomerism of rhizoidin at the C-2 and C-3 positions, (2R, 3R): rhizoidin, (2S, 3S): new rhizoidin, (2S ,3R): Isofarginine, (2R,3S): New Isofarginine.
- Taxifolin molecular formula C 15 H 12 O 7 ; molecular weight: 304.25, and its chemical name is 3,3',4',5,7-pentahydroxydihydroflavone.
- Taxifolin is a bioflavonoid essence (belonging to vitamin P) extracted from the root of larch in the alpine zone. Taxifolin is an important natural antioxidant necessary for the human body. Taxifolin is found in yew, yellow fir, and larch, and there is also a very small amount in the mother tree and wild black cherry. Because Taxifolin has a special molecular structure of five phenolic hydroxyl groups, it can effectively remove free radicals and toxins in the human body.
- Taxifolin has anti-inflammatory, antibacterial, anti-radiation, anti-cancer, anti-virus, immune regulation, melanin removal, Improving microcirculation and other broad-spectrum biological and pharmacological activities, it is a precious raw material for the production of food, medicine, and health care products.
- the structural formula is:
- Quercetin molecular formula C 15 H 10 O 7 ; molecular weight: 302.236, and its chemical name is 3,3',4',5,7-pentahydroxyflavone.
- Quercetin is a flavonol compound, widely distributed in the plant kingdom, and its content is high in the stems and leaves of buckwheat, sea buckthorn, hawthorn, and onions. Quercetin is also found in many foods, such as onions, apples, and mangoes. wait.
- there are more than 100 kinds of medicinal plants (such as Huai Mi, oriental cypress leaves, galangal, coltsfoot, mulberry, notoginseng, ginkgo, elderberry, etc.) all contain this ingredient.
- Quercetin is a flavonoid alcohol compound with a variety of biological activities, which can resist free radicals, complex or capture free radicals to prevent lipid peroxidation in the body; can directly inhibit tumors, and effectively play an anti-cancer and anti-cancer role; It also has strong biological activity in terms of anti-inflammation, anti-allergy, and prevention of diabetic complications.
- quercetin also has the effects of lowering blood pressure, enhancing capillary resistance, reducing capillary fragility, lowering blood fat, expanding coronary arteries, and increasing coronary blood flow. It also has adjuvant therapeutic effects on patients with coronary heart disease and hypertension. Quercetin is non-toxic, therefore, it is of great significance to the treatment and prevention of cancer, aging, and cardiovascular diseases, and has great development value.
- the structural formula is:
- various active ingredients in the pharmaceutical composition of the present invention can be administered in the same pharmaceutical formulation, or can be administered in different pharmaceutical formulations.
- the dosage form of each active ingredient may be the same or different.
- various active ingredients may be administered simultaneously or sequentially.
- the dosage form of the pharmaceutical preparation of the present invention is powder, tablet, capsule, granule, oral liquid or injection.
- the dosage form of the present invention is a tablet or capsule.
- the "pharmaceutically acceptable carrier” of the present invention refers to conventional pharmaceutical carriers in the field of pharmaceutical preparations, selected from fillers, binders, disintegrants, lubricants, suspending agents, wetting agents, pigments , one or more of flavoring agents, solvents, and surfactants.
- the drug of the present invention can be prepared into various solid oral preparations, liquid oral preparations and the like.
- Pharmaceutically acceptable oral solid preparations include: powder, ordinary tablet, dispersible tablet, enteric-coated tablet, granule, capsule, drop pill, powder, etc.
- Oral liquid preparations include oral liquid, emulsion, etc.
- the medicament of the present invention can also be made into an injection.
- various natural product active ingredients of the present invention can be extracted and isolated from plants containing the active ingredients by conventional biological purification methods, or can be purchased from commercially available products.
- test materials used in the following examples are commercially available products unless otherwise specified.
- HaCaT cells are human immortalized keratinocytes, have similar proliferation and differentiation characteristics with keratinocytes, and are immortal, and have the same pathological characteristics as the excessive proliferation and abnormal differentiation of psoriatic keratinocytes Similarity, has been widely used in psoriasis research
- HaCaT cells were inoculated in the prepared DMEM medium at 4 ⁇ 10 4 /mL, and placed in 37°C, 5% CO 2 , saturated humidity cell culture Cultivated in a box. Cells adhere to the wall and grow to cover 80% of the bottom area of the culture flask.
- Retinoic acid was dissolved in DMSO to prepare a 125 ⁇ mol/L solution, astilbin, neoastilbin, citrus glucoside, taxifolin, resveratrol, naringenin, quercetin, astilbin + isoglucoside (5:1), astilbin + resveratrol (5:1), astilbin + naringenin (10:1), isoastilbin + taxifolin (10:1), flavonoid composition Group 1: astilbin + astilbin + resveratrol (5:1:1), astilbin + astilagin + naringenin (5:1:1), flavonoid composition group 2: isoflavone Neoastilbin + Isoflavatin + Taxifolin (5:1:1), Neoastilbin + Resveratrol + Taxifolin (10:1:1), Neoisoastilbin + Quercetin + Taxifolin (10:1:1) was dissolved
- the cells When the cells reached the logarithmic growth phase, they were digested and counted, inoculated in a 96-well plate at 4.0 ⁇ 104 cells/mL (the edge wells were filled with sterile PBS), 100 ⁇ L per well, and placed at 37°C, 5% CO 2. Cultivate in a CO 2 incubator with saturated humidity for 24 hours (overnight). After the cells adhered to the wall, various drugs of corresponding concentrations were added, and the cells were continued to be cultured in a CO 2 incubator until the required time for MTT detection.
- the comparison of cell proliferation inhibition rates in each group can be seen in Table 1.
- the single components all showed different degrees of cell proliferation inhibition activity, which was significantly different from that of the blank control group (P ⁇ 0.01). Among them, astilbin had the best activity, and astilbin or its
- the cell proliferation inhibitory activity of the binary combination composed of the isomer and each single component in the polyphenol component is better than that of the single component, and is better than the activity of the positive control retinoic acid, which reflects the synergistic effect of the combination.
- the triple combination of astilbin or its isomers and polyphenol components had the best cell proliferation inhibitory activity, and the difference between the positive control group was statistically significant (P ⁇ 0.05), and the triple combinations showed similar Combination synergy, superior to single ingredients, and combined synergy of ternary compositions, superior to related binary compositions. It further shows that the composition of astilbin or its isomers and the polyphenol components can produce similar combined synergistic effects.
- mice were anesthetized by intraperitoneal injection of pentobarbital sodium (80mg/kg), their backs were depilated, their smooth skin about 2cm ⁇ 2cm was exposed, and they were reared in single cages.
- Isastilbin Isoflavin: Taxifolin (5:1:1), positive drug (tripterygium glycosides tablets) control group and blank control group, 10 rats in each group. .
- mice in the control group were smeared with petroleum jelly on their backs every day and gavaged with purified water, and the mice in the other groups were smeared with 42 mg of 5% imiquimod cream on their backs every day.
- the administration group was administered with purified water by intragastric administration, the flavonoid composition group 1, the flavonoid composition group 2, the astilbin group, the astilbin group, and the resveratrol group were administered with 25 mg/kg of the corresponding solution by intragastric administration of 0.2 mL/time. Twice/day, the positive control group was given 0.2 mL/time of 10 mg/kg Tripterygium wilfordii tablet solution by intragastric administration, twice/day. After 7 days of modeling, 80% of the mice showed redness, swelling or even skin lesions, that is, the modeling was successful. On the same day of modeling, the medicine was used for 7 consecutive days, and the materials were collected on the 8th day.
- the model control group has a significant difference (P ⁇ 0.01) from the normal control group.
- flavonoid composition 2 groups can effectively alleviate the mouse psoriasis-like lesions induced by imiquimod, improve pathological forms such as mouse ear swelling and skin lesions, and its PASI score decreased significantly (P ⁇ 0.01), of which The flavonoid composition group 1 and the flavonoid composition group 2 have the best drug effects, both of which are better than the single group and the positive control group.
- Rat tail scale lacks a granular layer due to normal keratinization of the epidermis, and its natural keratinization is similar to that of human psoriasis epidermis, so it can simulate the characteristics of psoriasis parakeratosis.
- This model can be used to evaluate the role of drugs in promoting the formation of granular layer, and it is believed that if the drug can promote the formation of rat tail granular layer, it may have anti-psoriasis effect.
- Flavonoid composition 1 group, flavonoid composition 2 group, astilbin group, orchidin group were given 25mg/kg corresponding solution by intragastric administration of 0.2mL/time, 2 times/day, and the blank control group was given the same volume of normal saline, continuously 14 days.
- mice were killed 24 hours after the last administration, and the back epidermis about 1.5 cm away from the base of the tail was taken for routine tissue sectioning, HE staining, and the cornified layer, granular layer, spiny cell layer, basal cell layer, and Changes in the dermis and hair follicles, and count the number of scales with granular layers among the 100 scales (those with granular layers arranged in rows on the epidermis of the scales between the two hair follicle openings are counted as having granular layers), to calculate the number of granular layers.
- the number of scales in the layer %.
- the experimental results show that the astilbin group, the astilbin group, the resveratrol group, the flavonoid composition 1 group, and the flavonoid composition 2 groups all have a significant promoting effect on the formation of the granular layer of the rat tail scales, and the scales of the granular layer The number increased significantly, indicating that astilbin group, radicin group, resveratrol group, flavonoid composition 1 group, and flavonoid composition 2 groups may have a therapeutic effect on the psoriasis model, and flavonoid composition 1 group and The therapeutic effect of flavonoid composition group 2 is better than that of single group.
- astilbin 15g of astilbin, 3g of astilbin; 75g of microcrystalline cellulose; 50mL of 95% ethanol; 15g of hydroxypropyl cellulose; 120mL of 25% starch slurry; Mesh sieve granules, compressed into tablets.
- astilbin 15g astilbin, 5g isoastilbin, 3g astilagin, 3g resveratrol; 20g dextrin; 10g lactose, 120mL 25% starch slurry; 20g powdered sugar; Mesh sieve whole grains, pack into bags.
- Neoisoastilbin 15g quercetin 3g, taxifolin 3g; glyceryl monostearate 10g, liquid paraffin 9g, white petrolatum 6g, azone 2g, Span-806g, sodium lauryl sulfate 2g, Glycerin 16g, purified water 50g; under the condition of 500r/min, dissolve in 80°C water bath, mix, stir for 15min, cool to room temperature, and ointment can be obtained.
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Abstract
一种落新妇苷和/或其异构体的治疗银屑病的药物组合物及其制剂和用途,所述药物组合物还包含选自以下的多酚:黄杞苷或其异构体、花旗松素、柚皮素、槲皮素、白藜芦醇的一种或多种。该药物组合物对咪喹莫特诱导的银屑病样小鼠模型和小鼠尾部鳞片模型具有显著的治疗效果,其中在所述药物组合物中将落新妇苷和/或其异构体与多酚组合具有显著的协同增效作用,其效果优于单独使用落新妇苷,并且所述药物组合物安全无不良反应,在制备治疗银屑病的药物中具有广泛的应用前景,具有重要的社会效益和经济效益。
Description
相关申请的交叉引用
本申请要求2021年10月19日提交的中国申请号2021112176457的权益。所述申请号2021112176457据此全文以引用方式并入本文。
本发明属于天然药物领域,具体涉及一种包含落新妇苷和/或其异构体的治疗银屑病的药物组合物及其制剂和用途。
银屑病(Psoriasis)俗称牛皮癣,是一种临床上常见的由T细胞介导的慢性、复发性、炎症性自身免疫性皮肤病。临床表现主要为皮肤出现形状不一、大小不等的红斑和肥厚的白色鳞屑,多发于四肢、头部和背部,严重皮损可泛发于全身皮肤,并出现高热、脓疱、红皮病样改变以及全身大小关节病变,银屑病以淋巴细胞浸润、角质细胞异常增生、细胞因子分泌异常为主要病理表现。银屑病受年龄、性别、种族、地理位置、环境等多种因素的影响,世界各地不同人群的患病率差异较大,例如,与欧美地区相比,中国、日本等亚洲国家银屑病的患病率相对较低。我国发病率约为0.47%,患病人数约为650万。但据统计,我国银屑病的患病率呈现逐年上升的趋势,且多为青壮年。银屑病发病机制目前尚无定论,由遗传、免疫、感染及多种环境共同作用导致。虽然临床治疗方法较为广泛,但效果欠佳,疗程长,易反复,给患者的精神和身体造成重大压力和痛苦,严重影响其生活质量,同时也为我国的医疗保健系统造成沉重负担。可见,开展对银屑病治疗药物的研究具有重大科学意义和社会价值。
银屑病的病因目前尚不明确,其可以被多种因素所激活,如创伤、感染、遗传、药物、环境因素等,研究表明这是一种由多种基因、免疫系统和环境因素相互作用引起的复杂疾病。银屑病病理生理机制非常复杂,各种治疗方法都或多或少的存在一些局限性。对于轻度银屑病主要采用局部外用药物,如卡泊三醇、维甲酸、外用糖皮质激素、来氟米特等,而中度、重度银屑病则必须采用系统性治疗,常用的系统治疗药物有甲氨蝶呤(中重度斑块型银屑病的推荐一线用药)、糖皮质激素、他克莫司等细胞毒类和免疫抑制类药物,这类药大多数在剂量稍大、疗程稍长时均会有严重的毒副反应,因此应用受到限制。近年来,对于中度、重度银屑病患者也开始采用单克隆抗体和靶向药物全身给药, 如依那西普、阿达木单抗(抗TNF-α);苏金单抗(抗IL-17);乌司奴单抗(抗IL-12/IL-23),这些药物疗效非常好,但是价格极其昂贵,并不是我国工薪阶层的患者所能承受的,且存在导致感染和恶性肿瘤的风险,因此需要谨慎地权衡风险收益。并且,在临床使用过程中发现,有些患者对上述药物不产生应答,或者有些患者在使用上述药物一段时间后会产生耐受。
因此,仍迫切需求开发疗效显著、毒性较小、价格低廉的银屑病系统治疗用药。近年来,我国医学工作者用中医药治疗银屑病取得了丰硕成果,从天然来源寻找治疗银屑病的药物公认为是研发此类药物的有效途径。
有文献报道落新妇苷和白藜芦醇具有治疗银屑病作用(参见,例如,张春红等,落新妇苷对永生化人角质形成细胞HaCaT增殖、凋亡的影响及机制探讨[J].山东医药.2015,55(46):20-22;毛艳菲等,白藜芦醇纳米粒联合丝素凝胶治疗银屑病的实验研究[J].医药导报,2019,12,38(12):1590-1596)。经文献检索,暂未见将落新妇苷和多酚联用用于治疗银屑病且产生协同增效作用的相关研究报道。中国专利申请201910056951.3公开了一种落新妇苷与有机酸的组合物在治疗银屑病中的应用,但是此发明专利技术涉及落新妇苷与有机酸的组合,但不包含黄杞苷、白藜芦醇等多酚类活性成分。
发明内容
本发明的目的是为了解决现有技术的不足,实现采用现代药物研究方法对天然产物进行开发利用,结合大量药效学实验筛选,提供了一种包含具有协同增效作用的落新妇苷和/或其异构体和多酚的治疗银屑病的药物组合物及其制剂和用途。
具体地,通过以下几个方面的技术方案实现了本发明:
在第一个方面中,本发明提供了一种治疗银屑病的药物组合物,所述药物组合物包含落新妇苷和/或其异构体和多酚,其中所述落新妇苷和/或其异构体与多酚的重量比为10:1-1:10。
作为可选方式,在上述药物组合物中,所述银屑病是寻常型银屑病、红皮型银屑病、关节型银屑病或脓疱型银屑病,所述银屑病处于进行期、静止期或消退期。
作为可选方式,在上述药物组合物中,所述落新妇苷的异构体选自新异落新妇苷、异落新妇苷或新落新妇苷的一种或多种,所述多酚选自黄杞苷或其异构体、花旗松素、柚皮素、槲皮素、白藜芦醇的一种或多种,所述黄杞苷的异构体选自异黄杞苷、新黄杞苷或新异黄杞苷的一种或多种。
所述落新妇苷和/或其异构体与多酚的重量比为9:1-1:9、8:1-1:8、7: 1-1:7、6:1-1:6、5:1-1:5、4:1-1:4、3:1-1:3或2:1-1:2。
作为可选方式,在上述药物组合物中,所述药物组合物包含落新妇苷和异黄杞苷;或者,落新妇苷和白藜芦醇;或者,落新妇苷和柚皮素;或者;异落新妇苷和花旗松素;或者,落新妇苷、黄杞苷和白藜芦醇;或者,落新妇苷、黄杞苷和柚皮素;或者,异落新妇苷、异黄杞苷和花旗松素;或者,新落新妇苷、白藜芦醇和花旗松素;或者,新异落新妇苷、槲皮素和花旗松素。
作为可选方式,在上述药物组合物中,所述药物组合物以重量比计包含落新妇苷:异黄杞苷=5:1;或者,落新妇苷:白藜芦醇=5:1;或者,落新妇苷:柚皮素=10:1;或者,异落新妇苷:花旗松素=10:1;或者,落新妇苷:黄杞苷:白藜芦醇=5:1:1;或者,落新妇苷:黄杞苷:柚皮素=5:1:1;或者,异落新妇苷:异黄杞苷:花旗松素=5:1:1;或者,新落新妇苷:白藜芦醇:花旗松素=10:1:1;或者,新异落新妇苷:槲皮素:花旗松素=10:1:1。
在第二个方面中,本发明提供了一种用于治疗银屑病的药物制剂,所述药物制剂由治疗有效量的上述第一个方面所述的药物组合物和药学上可接受的载体制成。
作为可选方式,在上述药物制剂中,所述药物制剂为粉剂、片剂、胶囊剂、颗粒剂、口服液、注射剂、乳膏剂或软膏剂。
优选地,所述药物制剂选自片剂、胶囊剂、颗粒剂、乳膏剂或软膏剂。
在第三个方面中,本发明提供了上述第一个方面所述的药物组合物或者上述第二个方面所述的药物制剂在制备治疗银屑病的药物中的用途。
作为可选方式,在上述用途中,所述银屑病是寻常型银屑病、红皮型银屑病、关节型银屑病或脓疱型银屑病,所述银屑病处于进行期、静止期或消退期。
作为可选方式,在上述用途中,所述药物抑制人表皮角质形成细胞过度增殖,所述药物减轻皮肤炎症反应,降低皮损程度,缓解皮肤红斑、鳞屑和浸润。
本发明相对于现有技术,具有以下有益效果:
(1)本发明是由天然产物组合而成的组合物,这些天然产物之间在治疗银屑病方面具有协同增效作用,药效优于原单一成分,并且进一步优化了组合配比,实现了更好药效。
(2)与现有技术相比,本发明为多个天然产物组合而成的组合物,相较目前已上市的药物,其具有多靶点发挥药效的特点,增强药理作用和临床疗效,降低毒副作用。
(3)与现有技术相比,本发明为多个天然产物组合而成的组合物,与中药提取物相较,组合物中化学成分明确,可使药品质量标准的制订和生产质量的控制更加具有针对性,药品质量稳定可控,同时便于各种剂型制备和制剂水 平提高等。
本发明人在对落新妇苷和/或其异构体治疗银屑病药理机制的深入研究中,通过大量筛选,首次发现通过将落新妇苷和/或其异构体与多酚联合使用,在治疗银屑病方面具有显著的协同增效作用。在此基础上完成了本发明。
为了便于本领域技术人员的理解,下面对本发明中涉及的各种主要活性成分进行描述。
落新妇苷和黄杞苷均属于二氢黄酮醇苷类化合物,结构如下图所示:
落新妇苷(Astilbin)的化学名为(2R,3R)5,7,3′,4′-四羟基二氢黄酮醇-3-O-α-L-吡喃鼠李糖苷。落新妇苷广泛存在于自然界多种植物中,世界范围内有12科15属26种植物中均可分离出落新妇苷,均可作为提取落新妇苷的原料药材。落新妇苷药理活性广泛,具有抗炎、抑制免疫、抑制排异反应、保肝护肾、抗氧化、镇痛、抗水肿、抗菌,降血糖及调节脂肪代谢等多种药理活性。
黄杞苷(Engelitin)的化学名为(2R,3R)5,7,4′-三羟基二氢黄酮醇-3-O-α-L-吡喃鼠李糖苷。黄杞苷也广泛存在于自然界多种植物中,具有抗炎、抗癌、抗氧化、治疗骨质疏松、保肝、治疗慢性肾损伤、抗糖尿病、降尿酸等多种药理活性。
落新妇苷异构体是指落新妇苷在C-2和C-3位上存在立体异构现象,分别有(2R,3R):落新妇苷、(2S,3S):新落新妇苷、(2S,3R):新异落新妇苷、(2R,3S):异落新妇苷,四种顺、反异构体。
黄杞苷异构体是指黄杞苷在C-2和C-3位上存在立体异构现象,(2R,3R):黄杞苷、(2S,3S):新黄杞苷、(2S,3R):异黄杞苷、(2R,3S):新异黄杞苷。
花旗松素(Taxifolin),分子式C
15H
12O
7;分子量:304.25,其化学名称为3,3',4',5,7-五羟基二氢黄酮。花旗松素是从高寒带落叶松根部提取的生物类黄酮精华物质(属于维生素P)。花旗松素是人体必需的一种重要的天然抗氧化剂。花旗松素在紫杉、黄杉、落叶松中有发现,纹母树、野黑樱中也有极少量存在。由于花旗松素拥有五个酚羟基的特殊分子结构,可有效去除人体内 的自由基与毒素,因此花旗松素具有消炎、抗菌、抗辐射、抗癌、抗病毒、调节免疫力、清除黑色素、改善微循环等广谱的生物活性和药理活性,是食品、药品、保健品生产的珍贵原料。结构式为:
槲皮素(Quercetin),分子式C
15H
10O
7;分子量:302.236,其化学名称为3,3',4',5,7-五羟基黄酮。槲皮素属黄酮醇类化合物,植物界分布广泛,其中在荞麦的杆和叶、沙棘、山楂、洋葱中含量较高,槲皮素在许多食物中也均有发现,如洋葱、苹果、芒果等。另外,约有100多种药用植物(如槐米、侧柏叶、高良姜、款冬花、桑寄生、三七、银杏、接骨木等)中均含有此成分。槲皮素是具有多种生物活性的黄酮醇类化合物,能对抗自由基,络合或捕获自由基防止机体脂质过氧化反应;能够直接抑制肿瘤,有效发挥防癌抗癌作用;在抗菌、抗炎、抗过敏、防止糖尿病并发症方面也有较强的生物活性。此外,槲皮素还有降低血压、增强毛细血管抵抗力、减少毛细血管脆性、降血脂、扩张冠状动脉,增加冠脉血流量等作用,对冠心病及高血压患者也有辅助治疗作用。槲皮素无毒性,因此,对癌症、衰老、心血管疾病的治疗和预防有重要意义,具有较大的开发价值。结构式为:
柚皮素(Naringenin),分子式C
15H
12O
5;分子量:272.25,其化学名称为4',5,7-三羟基二氢黄酮。柚皮素属二氢黄酮类化合物,存在于多种草药和水果中,包括葡萄柚,佛手柑,酸橙,酸樱桃以及豆类,具有抗菌、抗炎、清除自由基、抗氧化、止咳祛痰、降血脂、抗癌抗肿瘤、解痉和利胆、预防和治疗肝病、抑制血小板凝结、抗粥样动脉硬化等作用,可被广泛地应用于医药、食品等领域。结构式为:
白藜芦醇(Resveratrol),分子式C
14H
12O
3;分子量:228.25,其化学名称为3,4',5-三羟基-1,2-二苯基乙烯(3,4',5-芪三酚)。白藜芦醇是一种非黄酮类多酚有机化合物,是许多植物受到刺激时产生的一种抗毒素。白藜芦醇主要存在于葡萄属、蓼属、花生属、藜芦属等21个科、31个属的至少72种植物中,其中包括虎杖、决明、桑树等常见的药用植物,以及葡萄、花生等农作物。 天然白藜芦醇的主要来源植物是虎杖和葡萄。白藜芦醇有抗氧化、抗炎、抗喘、抗癌、抗菌免疫调节、及心血管保护等作用。结构式为:
如本文所用,本发明药物组合物中的各种活性成分可以在同一药物制剂中施用,也可以在不同药物制剂中施用。在不同药物制剂中施用的情况下,各种活性成分的剂型可以是相同的,也可以是不同的。并且,各种活性成分可以同时或顺序施用。
如本文所用,本发明药物制剂的剂型为粉剂、片剂、胶囊剂、颗粒剂、口服液或注射剂。优选地,本发明的剂型为片剂或胶囊剂。
如本文所用,本发明的“药学上可接受的载体”是指药物制剂领域常规的药物载体,选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、色素、矫味剂、溶剂、表面活性剂中的一种或几种。
本发明所述填充剂包括但不限于淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等;所述润滑剂包括但不限于硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙姆等;所述粘合剂包括但不限于水、乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮等;所述崩解剂包括但不限于淀粉泡腾混合物即碳酸氢钠和枸橼酸、酒石酸、低取代羟丙基纤维素等;所述助悬剂包括但不限于多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等;所述溶剂包括但不限于水、平衡的盐溶液等。
优选地,可以将本发明的药物制成各种固体口服制剂、液体口服制剂等。药剂学可接受的口服剂固体制剂有:粉剂、普通片剂、分散片、肠溶片、颗粒剂、胶囊剂、滴丸、散剂等,口服液体制剂有口服液、乳剂等。或者,也可以将本发明的药物制成注射剂。
上述各种剂型可以根据药物制剂领域的常规工艺制备而成。
如本文所用,本发明的各种天然产物活性成分可以采用常规生物提纯方法从含有该活性成分的植物中提取分离得到,也可以购自市售产品。
在上文所述的医药用途中,对于各种活性成分的给药时间、给药次数和给药频率等等,需要根据病情的具体诊断结果而定,这在本领域技术人员掌握的技术范围之内。例如,将对小鼠或大鼠的治疗方案应用于人体上,所有药物对人的有效剂量可以通过该药物对小鼠或大鼠的有效剂量进行换算,这对于本领域的普通技术人员而言也是容易实现的。
下面参照具体的实施例对本发明做进一步说明。应当理解,此处所描述的具体实施例仅用于解释本发明,并不用于限定本发明的范围。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为市售产品。
除非另外说明,否则本发明中涉及的百分比和份数均为重量百分比和重量份数。
效果实施例:
1.细胞实验
细胞的培养:HaCaT细胞(HaCaT细胞是人永生化角质形成细胞,与角质形成细胞具有相似的增殖、分化特性,且具有永生性,与银屑病角质形成细胞过度增殖和异常分化的病理特征具有相似性,已广泛用于银屑病的研究),将HaCaT细胞以4×10
4/mL接种于配制好的DMEM培养基中,并放入37℃,5%CO
2,饱和湿度的细胞培养箱中培养。细胞贴壁生长,增长至覆盖培养瓶底面积的80%时开始传代,传代时倒出原先的培养液,用PBS洗2次,0.25%胰蛋白酶消化2min,弃去胰酶,静置,继续消化致细胞皱缩、变圆,逐渐从培养瓶脱落时,加入新的DMEM培养基吹打细胞,计数后将一定浓度的细胞转入新的培养皿中,添加7mL培养基。复苏HaCaT细胞株,配制完全生长培养基(90%DMEM+10%FBS)汇合度达到80%左右传代,取出培养基,用无钙镁PBS洗两遍,加入1mL胰蛋白酶-EDTA溶液。让培养瓶在37℃下放置5min左右,直到细胞分离。加入3倍于胰酶量的新鲜培养基吹打并收集到15mL离心管,以1200r/min,离心5min,弃上清,再用新鲜培养基重悬细胞,并洗涤2次,最后1mL培养基重悬细胞并计数,进行扩大培养,传代培养比例是1:3。培养条件:37℃,空气95%,5%CO
2。
维甲酸用DMSO溶解配制成125μmol/L溶液,落新妇苷、新落新妇苷、黄杞苷、花旗松素、白藜芦醇、柚皮素、槲皮素、落新妇苷+异黄杞苷(5:1)、落新妇苷+白藜芦醇(5:1)、落新妇苷+柚皮素(10:1)、异落新妇苷+花旗松素(10:1)、黄酮组合物1组:落新妇苷+黄杞苷+白藜芦醇(5:1:1)、落新妇苷+黄杞苷+柚皮素(5:1:1)、黄酮组合物2组:异落新妇苷+异黄杞苷+花旗松素(5:1:1)、新落新妇苷+白藜芦醇+花旗松素(10:1:1)、新异落新妇苷+槲皮素+花旗松素(10:1:1)用DMSO溶解配制成100μmol/L溶液。
待细胞生长达对数生长期时,经消化后计数,以4.0×10
4个/mL接种于96孔板(边缘孔用无菌PBS填充),每孔100μL,置于37℃、5%CO
2、饱和湿度的CO
2培养箱培养24h(过夜)。待细胞贴壁后,加入相应浓度的各药物, 继续放入CO
2培养箱培养至所需时间,进行MTT检测。向96孔板细胞培养物每孔加入MTT(5g/L)20μL/孔,继续孵育4h,小心吸掉上清,加DMSO 100μL/孔,振荡10min,使结晶充分溶解,用酶标仪在492nm波长处测各孔的吸光度值。
表1:各组细胞增殖抑制率比较(x±s)
注释:与空白组比较,
#P<0.01;与阳性对照组比较,*P<0.05。
各组细胞增殖抑制率比较可见表1,单一成分均显示不同程度的细胞增殖抑制活性,与空白对照组比较具有显著差异(P<0.01),其中落新妇苷活性最好,落新妇苷或其异构体与多酚组分中各单一成分组成的二元组合的分细胞增殖抑制活性均优于单一成分,并且优于阳性对照维甲酸的活性,体现了组合增效作用。
落新妇苷或其异构体与多酚组分中成分组成三元组合分细胞增殖抑制活性最好,并且阳性对照组差异有统计学意义(P<0.05),三元组合物均显示相似的组合增效作用,优于单一成分,并且三元组合物的组合增效作用优于相关二元组合物。进一步表明落新妇苷或其异构体与多酚组分钟各成分所构成的组合物均产生相似的组合增效作用。
2.动物实验
2.1咪喹莫特诱导的小鼠银屑病样模型:
实验前,60只18-22g Balb/c雄性小鼠戊巴比妥钠腹腔注射麻醉(80mg/kg),背部去毛,裸露约2cm×2cm大小光滑皮肤,单笼饲养。随机分为 落新妇苷组,黄杞苷组,白藜芦醇组,黄酮组合物1组:落新妇苷:黄杞苷:白藜芦醇(5:1:1),黄酮组合物2组:异落新妇苷:异黄杞苷:花旗松素(5:1:1),阳性药(雷公藤多苷片)对照组和空白对照组,每组10只。。
对照组小鼠每日在背部涂抹凡士林,纯净水灌胃处理,其余各组小鼠背部每日涂抹5%咪喹莫特乳膏42mg。给药组给予纯净水灌胃,黄酮组合物1组,黄酮组合物2组,落新妇苷组,黄杞苷组,白藜芦醇组分别给予25mg/kg相应溶液灌胃0.2mL/次,2次/日,阳性对照组给予10mg/kg雷公藤多昔片溶液灌胃0.2mL/次,2次/日。造模7天后,80%小鼠出现红肿甚至皮损现象,即造模成功。造模当天药,连续7日,于第8日取材。
实验结果:与正常对照组比较,模型对照组耳部红肿、皮损严重,还覆盖部分鳞屑,对皮损严重程度(psoriasis area and severity index,PASI)进行评分。红斑、鳞屑及浸润增厚程度各为0-4(0,无;1,轻度;2,中度;3,重度;4,极重度),将3种评分累计得到总评分,结果见表2。
表2:本发明组合物对银屑病样小鼠皮损变化程度的影响(x±s,n=10)
注释:与空白组比较,
##P<0.01;与模型组比较,**P<0.01。
实验结论:由表2可见,模型对照组与正常对照组具有显著差异(P<0.01),与模型对照组比较,落新妇苷组,黄杞苷组,白藜芦醇组,黄酮组合物1组,黄酮组合物2组均可有效缓解咪喹莫特诱导的小鼠银屑病样病变,改善小鼠耳部红肿和皮损等病理形态,其PASI评分显著下降(P<0.01),其中黄酮组合物1组和黄酮组合物2组药效最佳,均优于单一组分组以及阳性对照组。
2.2小鼠尾部鳞片模型:
小鼠尾部鳞片模型:鼠尾鳞片因表皮正常角化缺乏颗粒层,其天然的角化形成与人类银屑病表皮相似,故可模拟银屑病角化不全的特点。可利用此模型评价了药物促进颗粒层形成的作用,认为药物如能促进鼠尾颗粒层形成,则可能具有抗银屑病作用。
取体重为18-22g Balb/c小鼠60只,雌雄各半。随机分为落新妇苷组,黄杞苷组,白藜芦醇组,黄酮组合物1组(落新妇苷:黄杞苷:白藜芦醇=5:1:1),黄酮组合物2组(异落新妇苷:异黄杞苷:花旗松素=5:1:1),阳性药对照组 和空白对照组,每组10只。黄酮组合物1组,黄酮组合物2组,落新妇苷组,黄杞苷组分别给予25mg/kg相应溶液灌胃0.2mL/次,2次/日,空白对照组给予同体积生理盐水,连续14天。末次给药24小时后处死小鼠,取距尾根约1.5cm的背部表皮,进行常规组织切片,HE染色,光学显微镜下观察鼠尾皮肤角化层、颗粒层、棘细胞层、基底细胞层、真皮层和毛囊等变化,并计数100个鳞片中有颗粒层形成的鳞片数(凡两个毛囊口之间的鳞片表皮有排列成行的颗粒层者计为有颗粒层形成),以计算有颗粒层的鳞片数%。
表3:各组小鼠尾部鳞片表皮颗粒层形成的比较(x±s,n=10)
注释:与空白对照组比较,
△△P<0.01。
由表3可见,给药组与空白对照组具有显著差异(P<0.01),其中,黄酮组合物1组和黄酮组合物2组有颗粒层的鳞片数比例最多,与阳性对照雷公藤多苷片组相当。实验结果表明,落新妇苷组,黄杞苷组,白藜芦醇组,黄酮组合物1组,黄酮组合物2组均对鼠尾鳞片表皮颗粒层形成有明显的促进作用,颗粒层的鳞片数显著增多,说明落新妇苷组,黄杞苷组,白藜芦醇组,黄酮组合物1组,黄酮组合物2组均可能对银屑病模型有治疗作用,而且黄酮组合物1组和黄酮组合物2组治疗效果优于单一组分组。
此外,在上述动物实验中,未观察到本发明药物组合物存在明显的不良反应,实验动物对其具有良好的耐受性。
制剂实施例:
实施例1:
落新妇苷15g,黄杞苷3g;微晶纤维素75g;95%乙醇50mL;羟丙基纤维素15g;25%淀粉浆120mL;硬酸镁5g,制粒,50℃真空干燥,30-100目筛整粒,压成片剂。
实施例2:
落新妇苷15g,黄杞苷3g,白藜芦醇3g;微晶纤维素75g;95%乙醇50mL;羟丙基纤维素15g;20%淀粉浆120mL;硬酸镁5g,制粒,50℃真空干燥,60-100目筛整粒,灌胶囊。
实施例3:
落新妇苷15g,异落新妇苷5g,黄杞苷3g,白藜芦醇3g;糊精20g;乳糖10g,25%淀粉浆120mL;糖粉20g;100目筛制粒,50℃干燥,14目筛整粒,分装成袋。
实施例4:
新异落新妇苷15g,槲皮素3g,花旗松素3g;单硬脂酸甘油酯10g,液状石蜡9g,白凡士林6g、氮酮2g,司盘-806g,十二烷基硫酸钠2g,甘油16g,纯化水50g;在500r/min条件下,80℃水浴溶解,混合,搅拌15min,冷却至室温,即可得软膏。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (10)
- 一种治疗银屑病的药物组合物,其特征在于:所述药物组合物包含落新妇苷和/或其异构体和多酚,其中所述落新妇苷和/或其异构体与多酚的重量比为10:1-1:10。
- 根据权利要求1所述的药物组合物,其特征在于:所述银屑病是寻常型银屑病、红皮型银屑病、关节型银屑病或脓疱型银屑病,所述银屑病处于进行期、静止期或消退期。
- 根据权利要求1或权利要求2所述的药物组合物,其特征在于:所述落新妇苷的异构体选自新异落新妇苷、异落新妇苷或新落新妇苷的一种或多种,所述多酚选自黄杞苷或其异构体、花旗松素、柚皮素、槲皮素、白藜芦醇的一种或多种,所述黄杞苷的异构体选自异黄杞苷、新黄杞苷或新异黄杞苷的一种或多种,所述落新妇苷和/或其异构体与多酚的重量比为9:1-1:9、8:1-1:8、7:1-1:7、6:1-1:6、5:1-1:5、4:1-1:4、3:1-1:3或2:1-1:2。
- 根据权利要求1至3中任一项所述的药物组合物,其特征在于:所述药物组合物包含落新妇苷和异黄杞苷;或者,落新妇苷和白藜芦醇;或者,落新妇苷和柚皮素;或者;异落新妇苷和花旗松素;或者,落新妇苷、黄杞苷和白藜芦醇;或者,落新妇苷、黄杞苷和柚皮素;或者,异落新妇苷、异黄杞苷和花旗松素;或者,新落新妇苷、白藜芦醇和花旗松素;或者,新异落新妇苷、槲皮素和花旗松素。
- 根据权利要求1至4中任一项所述的药物组合物,其特征在于:所述药物组合物以重量比计包含落新妇苷:异黄杞苷=5:1;或者,落新妇苷:白藜芦醇=5:1;或者,落新妇苷:柚皮素=10:1;或者,异落新妇苷:花旗松素=10:1;或者,落新妇苷:黄杞苷:白藜芦醇=5:1:1;或者,落新妇苷:黄杞苷:柚皮素=5:1:1;或者,异落新妇苷:异黄杞苷:花旗松素=5:1:1;或者,新落新妇苷:白藜芦醇:花旗松素=10:1:1;或者,新异落新妇苷:槲皮素:花旗松素=10:1:1。
- 一种用于治疗银屑病的药物制剂,其特征在于:所述药物制剂由治疗有效量的权利要求1至5中任一项所述的药物组合物和药学上可接受的载体制成。
- 根据权利要求6所述的药物制剂,其特征在于:所述药物制剂为粉剂、片剂、胶囊剂、颗粒剂、口服液、注射剂、乳膏剂或软膏剂。
- 权利要求1至5中任一项所述的药物组合物或者权利要求6或权利要求7所述的药物制剂在制备治疗银屑病的药物中的用途。
- 根据权利要求8所述的用途,其特征在于:所述银屑病是寻常型银屑 病、红皮型银屑病、关节型银屑病或脓疱型银屑病,所述银屑病处于进行期、静止期或消退期。
- 根据权利要求8或权利要求9所述的用途,其特征在于:所述药物抑制人表皮角质形成细胞过度增殖,所述药物减轻皮肤炎症反应,降低皮损程度,缓解皮肤红斑、鳞屑和浸润。
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