WO2020233681A1 - 具有预防和治疗激素依赖性皮炎功效的生物多糖及其应用 - Google Patents

具有预防和治疗激素依赖性皮炎功效的生物多糖及其应用 Download PDF

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WO2020233681A1
WO2020233681A1 PCT/CN2020/091619 CN2020091619W WO2020233681A1 WO 2020233681 A1 WO2020233681 A1 WO 2020233681A1 CN 2020091619 W CN2020091619 W CN 2020091619W WO 2020233681 A1 WO2020233681 A1 WO 2020233681A1
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glucan
hormone
dependent dermatitis
skin
another preferred
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PCT/CN2020/091619
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English (en)
French (fr)
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郭宏亮
庄秀园
朱斌念
叶榛
吴佳迪
王轩
郭晓宇
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浙江立恩生物科技有限公司
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Priority to CN202080035862.1A priority Critical patent/CN113840613A/zh
Priority to US17/612,841 priority patent/US20220241319A1/en
Publication of WO2020233681A1 publication Critical patent/WO2020233681A1/zh

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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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof

Definitions

  • the present invention relates to the field of biotechnology, in particular to a biopolysaccharide with the effects of preventing and treating hormone-dependent dermatitis and its application.
  • Glucocorticoid is an extremely important type of regulatory molecule in the body. It plays an important role in regulating the development, growth, metabolism and immune function of the body. It is the most important regulator of stress response in the body and is also the most widely used clinically. And effective anti-inflammatory and immunosuppressive agents. In emergency or critical situations, glucocorticoids are often the first choice. They have anti-inflammatory, anti-toxic, anti-allergic, anti-shock, non-specific immune suppression and antipyretic effects, and can prevent and prevent immune inflammation and pathology. The occurrence of sexual immune response is effective for almost any type of allergic disease.
  • glucocorticoids have huge risks.
  • the common hormone-dependent dermatitis is caused by long-term incorrect use of topical drugs or cosmetics containing glucocorticoids.
  • the incidence of hormone-dependent dermatitis has been on the rise, and it is difficult to cure.
  • the commonly used treatment methods stay on moisturizing, anti-inflammatory, anti-allergic and anti-infective treatments.
  • the treatment cycle is long, the effect is poor, and it is easy to relapse, which brings double trauma to the patient's physiology and psychology.
  • the purpose of the present invention is to provide a medicine that can effectively treat hormone-dependent dermatitis.
  • Another object of the present invention is to provide a biopolysaccharide with the effects of preventing and treating hormone-dependent dermatitis and its application.
  • ⁇ -glucan for preparing a preparation or composition for preventing and/or treating hormone-dependent dermatitis.
  • the ⁇ -glucan is ⁇ -D-glucan.
  • the ⁇ -glucan is ⁇ -1,3-glucan, preferably ⁇ -1,3-glucan with ⁇ -1,6-branched.
  • l is an integer ⁇ 0, preferably 0-50, preferably 0-10, more preferably 0-3, more preferably 1-2, more preferably 1;
  • m is an integer ⁇ 0, more Preferably it is 0-19, preferably 0-4, more preferably 0-1, more preferably 0;
  • n is an integer ⁇ 3, preferably 30-60000, more preferably 100-10000 .
  • the degree of branching (DB) of the ⁇ -glucan is 0.02-0.8, preferably 0.1-0.5, preferably 0.2-0.4.
  • the ⁇ -glucan includes ⁇ -glucan having a three-helical structure.
  • the content of the ⁇ -glucan of the triple helix structure is 80%, 90%, 95%, based on the total molar amount of the ⁇ -glucan.
  • the ⁇ -1,3-backbone of the ⁇ -glucan is the main body of the triple helix structure.
  • the ⁇ -1,6-branches of the ⁇ -glucan are located outside the three-helix three-dimensional structure.
  • the molecular weight of the ⁇ -glucan is ⁇ 2kD, preferably 2kD-40000kD, more preferably 20kD-20000kD.
  • the molecular weight of the ⁇ -glucan may be 5kD-35000kD; 10kD-30000kD; 50kD-25000kD; 100kD-20000kD; 200kD-18000kD; 400kD-16000kD; 500kD-14000kD; 1000kD-12000kD; 2000kD-4000kD; 3000kD-5000kD; 4000kD-6000kD; 5000kD-7000kD; 6000kD-8000kD; 7000kD-9000kD; or 8000kD-10000kD.
  • the ⁇ -glucan is selected from the group consisting of Schizophyllum ⁇ -glucan, Lentinus edodes ⁇ -glucan, Sclerotium ⁇ -glucan, Grifola frondosa ⁇ -glucan Glycan, Pleurotus ostreatus, mushroom ⁇ -glucan, yeast ⁇ -glucan, oat ⁇ -glucan, or a combination thereof.
  • the ⁇ -glucan is Schizophyllum ⁇ -glucan.
  • the mushroom ⁇ -glucan has five ⁇ -1,3- main chains with two ⁇ -1,6-branches, and each branch has 1 glucose residue. -Based ⁇ -glucan.
  • the purity of the ⁇ -glucan is ⁇ 70%, preferably ⁇ 90%, more preferably ⁇ 95%, more preferably ⁇ 99%.
  • the ⁇ -glucan has good stability.
  • the ⁇ -glucan is in a solid or liquid form, such as ⁇ -glucan solid particles or powder, or a ⁇ -glucan aqueous solution.
  • the particle size of the ⁇ -glucan particles or powder is ⁇ 20 mm, preferably 0.001-10 mm, more preferably 0.01-5 mm, and more preferably 0.1-2 mm.
  • the ⁇ -glucan is completely water-soluble ⁇ -glucan.
  • the ⁇ -glucan (granule or powder) has good water solubility and/or natural solubility.
  • the solubility of the ⁇ -glucan (granule or powder) in water (100g) at 25°C is ⁇ 0.0001g, preferably 0.01-50g, more preferably 0.1-10g.
  • the solubility of the ⁇ -glucan (granule or powder) in water (100g) at 25°C may be 0.1-100g; 0.2-90g; 0.5-80g; 1-50g; or, The solubility can be 0.1-0.3g; 0.2-0.4g; 0.3-0.5g; 0.4-0.6g; 0.5-0.7g; 0.6-0.8g; 0.7-0.9g; 0.8-1g; or 1-3g; 2- 4g; 3-5g; 4-6g; 5-7g; 6-8g; 7-9g; 8-10g.
  • the ⁇ -glucan solution is a solution of ⁇ -glucan in water, that is, an aqueous solution of ⁇ -glucan.
  • the ⁇ -glucan (water) solution has a high viscosity; preferably, the ⁇ -glucan aqueous solution (at 25°C) with a mass concentration of 0.5% has a viscosity of ⁇ 40 mPa ⁇ s, more preferably The ground is 100-10000mPa ⁇ s, more preferably 500-2000mPa ⁇ s.
  • the viscosity of the beta-glucan aqueous solution (25°C) with a mass concentration of 0.5% may be 50-10000mPa ⁇ s; 100-9000mPa ⁇ s; 200-8000mPa ⁇ s; 300-7000mPa ⁇ s; 400-6000mPa ⁇ s; 450-5000mPa ⁇ s; 500-5000mPa ⁇ s; 550-4000mPa ⁇ s; 600-3000mPa ⁇ s; 650-2000mPa ⁇ s; 700-1500mPa ⁇ s.
  • the beta-glucan aqueous solution with a mass concentration of 1% has high clarity or high light transmittance, and the light transmittance of the beta-glucan aqueous solution with a mass concentration of 1% ⁇ 50%, preferably ⁇ 80%, preferably ⁇ 85%, more preferably ⁇ 95%;
  • the ⁇ -glucan solution has good stability.
  • the prevention and/or treatment of hormone-dependent dermatitis includes: preventing the formation or recurrence of hormone-dependent dermatitis, improving or alleviating symptoms of hormone-dependent dermatitis, accelerating the regression or healing of hormone-dependent dermatitis, and improving hormone Residual scars from dependent dermatitis, or to accelerate the regression of hormone-dependent dermatitis scars.
  • the prevention and/or treatment of hormone-dependent dermatitis is prevention of recurrence of hormone-dependent dermatitis.
  • the treatment of hormone-dependent dermatitis includes inhibiting the side effects of drugs for hormone-dependent dermatitis.
  • the ⁇ -glucan is used to inhibit the side effects of hormone-dependent dermatitis treatment drugs.
  • the side effects include inflammation, edema, burning, pain.
  • the “hormone-dependent dermatitis” refers to dermatitis caused by long-term and repeated improper external use of hormones.
  • the clinical manifestations include thinning of the epidermis and dermis, hypopigmentation or precipitation, exposing blood vessels, rosacea-like, and acne-like Dermatitis, folliculitis, are characterized by hormone dependence and rebound phenomenon, also known as hormone face.
  • hormone-dependent dermatitis symptoms include the following groups: skin itching, burning, pain, dryness, scaling, tightness, flushing of facial skin, repeated occurrence of erythema, papules, shrinkage and thinning of the skin , Telangiectasia, acne, rosacea-like changes, pigmentation or loss, facial skin atrophy, inflammatory pustules, etc.
  • the preparation or composition contains (a) ⁇ -glucan; and optionally (b) a pharmaceutically, cosmetically, or device-acceptable carrier or excipient.
  • the preparation or composition contains (a) Schizophyllum ⁇ -glucan; and optionally (b) a pharmaceutically, cosmetically, or device-acceptable carrier or excipient Agent.
  • the formulation or composition contains 0.0001-99wt%, preferably 0.001-90wt%, more preferably 0.01-50wt%, more preferably 0.05-10wt% of ⁇ -glucan, according to Based on the total weight of the formulation or composition.
  • the mass concentration of the ⁇ -glucan in the preparation or composition is ⁇ 1 ⁇ g/mL, specifically may be 1 ⁇ g/mL-200mg/mL, or 1 ⁇ g/mL-5mg/mL , Or 1 ⁇ g/mL-1mg/mL.
  • the preparation or composition is also used to enhance skin immunity or active defense function.
  • the preparation or composition is also used to prevent and/or treat skin and mucosal inflammation or other skin inflammatory diseases.
  • the dosage form of the composition or preparation is a solid dosage form, a semi-solid dosage form, or a liquid dosage form, such as a solution, gel, cream, emulsion, and the like.
  • the composition is a pharmaceutical composition or a cosmetic composition, preferably an external pharmaceutical dosage form.
  • the preparation is an external preparation or a transdermal preparation (such as an external solution, ointment, patch, etc.).
  • the preparation or composition includes cosmetics, foods, medical devices or drugs, and the specific cosmetics may be functional cosmetics.
  • a preparation comprising ⁇ -glucan.
  • the ⁇ -glucan is selected from the group consisting of Schizophyllum ⁇ -glucan, Lentinus edodes ⁇ -glucan, Sclerotium ⁇ -glucan, Grifola frondosa ⁇ -glucan Glycan, Pleurotus ostreatus, mushroom ⁇ -glucan, yeast ⁇ -glucan, oat ⁇ -glucan, or a combination thereof.
  • the ⁇ -glucan is Schizophyllum ⁇ -glucan.
  • the ⁇ -glucan is completely water-soluble ⁇ -glucan.
  • the preparation is Schizophyllum ⁇ -glucan, and the ⁇ -glucan has good water solubility, natural solubility and/or reconstitution.
  • the ⁇ -glucan in the preparation is in a solid form or a liquid form.
  • the formulation contains an aqueous solution of ⁇ -glucan, and the mass concentration of the ⁇ -glucan is 0.0001-50wt%, preferably 0.02-10wt%, more preferably 0.05-5wt% , Based on the total weight of the ⁇ -glucan aqueous solution.
  • the content of the aqueous solution of ⁇ -glucan in the formulation is ⁇ 80wt%, preferably ⁇ 90wt%, more preferably ⁇ 95wt%, more preferably ⁇ 99wt%, more preferably ⁇ 99.5wt %, based on the total weight of the formulation.
  • the ⁇ -glucan in the preparation has one or more characteristics selected from the following group:
  • the purity of the ⁇ -glucan is ⁇ 70%, preferably ⁇ 90%, more preferably ⁇ 95%, more preferably ⁇ 99%;
  • the ⁇ -glucan has good water solubility, resolubility and/or natural solubility
  • the solubility of the ⁇ -glucan (solid particles or powder) in water at 25°C is ⁇ 0.0001g/100g water, preferably 0.01-50g/100g water, more preferably 0.1g-10g/100g water;
  • the aqueous solution of ⁇ -glucan has high clarity or high light transmittance; preferably, the light transmittance of the aqueous solution of ⁇ -glucan with a mass concentration of 1% is ⁇ 50%, preferably ⁇ 80%, preferably ⁇ 85%, more preferably ⁇ 95%;
  • the ⁇ -glucan solution has a high viscosity; preferably, the ⁇ -glucan aqueous solution with a mass concentration of 0.5% (at 25° C.) has a viscosity ⁇ 40 mPa ⁇ s, more preferably 100-10000, more preferably 600-2000mPa ⁇ s;
  • the aqueous solution of ⁇ -glucan has good stability; and/or
  • the molecular weight of the ⁇ -glucan is ⁇ 2kD, preferably 2kD-40000kD, more preferably 20kD-20000kD.
  • the preparation contains (a) ⁇ -glucan; and (b) a pharmaceutically, cosmetically, or device-acceptable carrier or excipient.
  • the formulation contains 0.0001-99wt%, preferably 0.001-90wt%, more preferably 0.01-50wt%, more preferably 0.05-10wt% of ⁇ -glucan, based on the total of the formulation Weight meter.
  • the preparation further contains (c) a second active ingredient, which is an active ingredient different from the ⁇ -glucan for treating hormone-dependent dermatitis, or for treating skin mucosa Active ingredient for inflammation or other skin diseases.
  • a second active ingredient which is an active ingredient different from the ⁇ -glucan for treating hormone-dependent dermatitis, or for treating skin mucosa Active ingredient for inflammation or other skin diseases.
  • the active ingredient for treating hormone-dependent dermatitis is selected from the group consisting of moisturizers, skin barrier repair ingredients, topical non-hormonal immunosuppressants, antihistamines, antiallergics, antibacterial agents, and Antibiotics and the like, specifically, such as glycerin, allantoin, hyaluronic acid, polyglutamic acid, aloe gel, silicone oil, horse oil, lanolin, ceramide, epidermal growth factor, tacrolimus, pimecrolimus, Loratadine, ebastine, boric acid, benzalkonium chloride, erythromycin, etc., or a combination thereof.
  • the active ingredient for the treatment of hormone-dependent dermatitis is selected from the following group of traditional Chinese medicines and their extracts: clearing away heat and removing the surface, clearing away heat, removing dampness and detoxification, clearing heat, cooling blood, and detoxifying, promoting blood circulation, removing blood stasis and removing stagnation, Reconciling Chongren, dispelling wind and dehumidification, or a combination thereof; specifically, such as Atractylodes, Pinellia, Bupleurum, Tangerine Peel, Red Peony, Rhubarb, Rehmannia glutinosa, Poria, Licorice, Cassia twig, Coptis, Scutellaria, Centella asiatica, Turmeric , Honeysuckle, forsythia, peony root/bark, burdock seed, loquat leaf, dandelion, ginseng, mulberry white bark, yam, raw hawthorn, ebony, wild chrysanthemum
  • the active ingredient for treating skin and mucosal inflammation or other skin diseases is selected from the group consisting of antihistamines, antibiotics, antifungal drugs, hormones, immunosuppressants, vitamins, and vitamin A acid.
  • the preparation is used to prevent and/or treat hormone-dependent dermatitis.
  • composition product comprising:
  • a first pharmaceutical composition the first pharmaceutical composition containing (a) a first active ingredient, the first active ingredient being ⁇ -glucan; and (b) pharmaceutical, cosmetic, or Acceptable carriers or excipients for devices; and
  • a second pharmaceutical composition which is a medicine for treating hormone-dependent dermatitis, or a medicine for treating skin and mucosal inflammation or other skin diseases.
  • the first pharmaceutical composition contains 0.0001-99wt%, preferably 0.001-90wt%, more preferably 0.01-50wt%, more preferably 0.05-10wt% ⁇ -glucan, Based on the total weight of the first pharmaceutical composition.
  • the ⁇ -glucan is selected from the group consisting of Schizophyllum ⁇ -glucan, Lentinus edodes ⁇ -glucan, Sclerotium ⁇ -glucan, Grifola frondosa ⁇ -glucan Glycan, Pleurotus ostreatus, mushroom ⁇ -glucan, yeast ⁇ -glucan, oat ⁇ -glucan, or a combination thereof.
  • the ⁇ -glucan is ⁇ -glucan of Schizophyllum.
  • the hormone-dependent dermatitis treatment drug contains (a) a second active ingredient, and the second active ingredient is an active ingredient that is different from the ⁇ -glucan for treating hormone-dependent dermatitis; and (b) Pharmaceutically, cosmetically, or device-acceptable carriers or excipients.
  • the active ingredient for treating hormone-dependent dermatitis is selected from the group consisting of moisturizers, skin barrier repair ingredients, topical non-hormonal immunosuppressants, antihistamines, antiallergics, antibacterial agents, and Antibiotics and the like, specifically, such as glycerin, allantoin, hyaluronic acid, polyglutamic acid, aloe gel, silicone oil, horse oil, lanolin, ceramide, epidermal growth factor, tacrolimus, pimecrolimus, Loratadine, ebastine, boric acid, benzalkonium chloride, erythromycin, etc., or a combination thereof.
  • the hormone-dependent dermatitis treatment drug is selected from the following group of traditional Chinese medicines and their extracts: clearing away heat and removing the surface, clearing away heat, removing dampness and detoxification, clearing heat, cooling blood and detoxifying, promoting blood circulation, removing blood stasis and removing stagnation, and reconciling Chongren, dispelling wind and dampness, or a combination thereof; specifically, for example, Atractylodes macrocephala, Pinellia ternata, Bupleurum, Tangerine peel, Red peony root, Rhubarb, Rehmannia glutinosa, Poria, Licorice, Cassia twig, Coptis, Scutellaria, Centella asiatica, Turmeric, Honeysuckle, forsythia, peony root/bark, burdock seed, loquat leaf, dandelion, ginseng, mulberry white bark, yam, raw hawthorn, ebony, wild chrysanthemum,
  • the therapeutic drugs for skin and mucosal inflammation or other skin diseases are selected from the group consisting of antihistamines, antibiotics, antifungal drugs, hormones, immunosuppressants, vitamins, and vitamin A acids , Cleansers, protectants, antipruritic agents, cutin promoters, exfoliants, astringents, corrosive agents, antibacterial agents, antifungal agents, antiviral agents, insecticides, sunscreens, decolorants, or combinations thereof; specifically For example, chlorpheniramine, loratadine, astemizole, ranitidine, dexamethasone, methylprednisolone, nystatin, ketoconazole, clotrimazole, 5-fluorocytosine , Adapalene, tripterygium glycosides, chloroquine, iodine, calamine lotion, or combinations thereof.
  • first pharmaceutical composition and the second pharmaceutical composition are independent of each other, or combined into one.
  • composition product is used to treat and/or prevent hormone-dependent dermatitis.
  • the composition product is cosmetics or medicines.
  • the recurrence rate and side effects of treatment using the composition product are lower than the recurrence rate and side effects of treatment using the second drug composition alone.
  • the fourth aspect of the present invention provides a method for preventing and/or treating hormone-dependent dermatitis, including the steps of: (a) administering ⁇ -glucan to a subject in need.
  • the ⁇ -glucan is selected from the group consisting of Schizophyllum ⁇ -glucan, Lentinus edodes ⁇ -glucan, Sclerotium ⁇ -glucan, Grifola frondosa ⁇ -glucan Glycan, Pleurotus ostreatus, mushroom ⁇ -glucan, yeast ⁇ -glucan, oat ⁇ -glucan, or a combination thereof.
  • the ⁇ -glucan is Schizophyllum ⁇ -glucan.
  • the subject includes hormone-dependent dermatitis patients or normal people.
  • Figure 1 shows the Fourier transform infrared spectrum of the Schizophyllum ⁇ -glucan prepared in Example 1.
  • Figure 2 shows the stability comparison of ⁇ -glucan
  • the left bottle is a commercially available 1.0% oat ⁇ -glucan solution
  • the right bottle is 1.0% Schizophyllum ⁇ -glucan prepared by the present invention.
  • Figure 3 shows the depilatory area on the back of the guinea pig used in the experiment in Example 3.
  • Figure 4 shows the changes in skin inflammation in the model group of guinea pigs in Example 3 starting on the seventh day after stopping applying clobetasol propionate solution.
  • A, B, C, D, E, F, G, and H are the seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and fourteenth days of stopping hormone application.
  • Figure 5 shows the changes in skin inflammation of the guinea pigs in the positive drug treatment group in Example 3 and Example 4 starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 6 shows the changes in skin inflammation of the guinea pigs in the 0.2% Schizophyllum ⁇ -glucan treatment group in Example 3 and Example 4, starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 7 shows the changes in skin inflammation of the guinea pigs in the 0.1% Schizophyllum ⁇ -glucan treatment group in Example 3 and Example 4, starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 8 shows the changes in skin inflammation of the guinea pigs in the 0.05% Schizophyllum ⁇ -glucan treatment group in Example 3 and Example 4, starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 9 shows the changes in skin inflammation of the guinea pigs in the 0.02% Schizophyllum ⁇ -glucan treatment group in Example 3 and Example 4, starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 10 shows the changes in skin inflammation of the guinea pigs in the 0.2% soluble yeast ⁇ -glucan treatment group in Example 3 and Example 4, starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 11 shows the changes in skin inflammation of the guinea pigs in the 0.1% soluble yeast ⁇ -glucan treatment group in Example 3 and Example 4 starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 12 shows the changes in skin inflammation of the guinea pigs in the 0.05% soluble yeast ⁇ -glucan treatment group in Example 3 and Example 4, starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 13 shows the changes in skin inflammation of the guinea pigs in the 0.02% soluble yeast ⁇ -glucan treatment group in Example 3 and Example 4, starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 14 shows the changes in skin inflammation of the guinea pigs in the Schizophyllum ⁇ -glucan combined positive drug group in Example 3 and Example 4 starting on the seventh day after stopping the application of clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 15 shows the changes in skin inflammation of the guinea pigs in the soluble yeast ⁇ -glucan combined with positive drug group in Example 3 and Example 4, starting on the seventh day after stopping applying clobetasol propionate solution.
  • A is before treatment (the seventh day after stopping the application of hormones)
  • B, C, D, E, F, G, and H are the second, third, fourth, fifth, sixth, seventh, and eighth days of treatment, respectively.
  • Figure 16 shows the comparison of the effect of patient B in Example 6 before and after the trial of the Schizophyllum ⁇ -glucan product.
  • Figure 17 shows the comparison of the effect of patient C in Example 6 before and after the trial of the Schizophyllum ⁇ -glucan product.
  • Figure 18 shows the comparison of the effect of patient D in Example 6 before and after the trial of the Schizophyllum ⁇ -glucan product.
  • ⁇ -glucan especially ⁇ -glucan (such as Schizophyllum ⁇ -glucan) with natural solubility, high molecular weight and high viscosity, It can prevent and/or treat hormone-dependent dermatitis very effectively.
  • Schizophyllum ⁇ -glucan can significantly alleviate and improve hormone-dependent dermatitis, effectively control the occurrence of hormone-dependent dermatitis, and accelerate the healing and/or regression of hormone-dependent dermatitis.
  • Schizophyllum ⁇ -glucan can also enhance the skin's active defense function, activate the skin's natural immunity, antibacterial, anti-inflammatory and repair skin, treat or prevent skin mucosal inflammation or other skin inflammatory diseases.
  • the present invention has been completed.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “substantially consisting of” or “consisting of”.
  • the term "completely water-soluble” refers to the solid form of ⁇ -glucan, which can be completely dissolved in water into an aqueous solution of ⁇ -glucan, that is, the solubility of ⁇ -glucan in 100g of water at 25°C is ⁇ 0.0001g , Preferably 0.01-50g, more preferably 0.1g-10g.
  • the term "naturally soluble” refers to the property of ⁇ -glucan in its natural state to completely dissolve in water to form an aqueous solution.
  • the "natural ⁇ -glucan” refers to the ⁇ -glucan produced by natural methods (such as biological fermentation).
  • the ⁇ -glucan has not undergone any chemical modification and has not undergone any chemical modification. Physical and/or chemical and/or biological methods break their long-chain molecules to reduce their molecular mass.
  • the ⁇ -glucan of the present invention is a natural ⁇ -glucan.
  • hormone-dependent dermatitis refers to dermatitis caused by long-term and repeated improper external use of hormones.
  • the clinical manifestations include thinning of the epidermis and dermis, hypopigmentation, exposing blood vessels, rosacea, acne-like dermatitis, folliculitis, and It is characterized by hormone dependence and rebound phenomenon, also known as hormone face. specifically,
  • Thinning of epidermis and dermis local long-term topical hormones can reduce the formation of stratum corneum particles and become thinner.
  • the elastic changes of glycoproteins and proteoglycans in the dermis weaken the adhesion between collagen fibrils and decrease the synthesis of collagen. .
  • hypopigmentation and sedimentation As the number of layers in the stratum corneum decreases, the melanin that migrates to the keratinocytes decreases, causing hypopigmentation.
  • the pigmentation may be related to the activation of melanocyte regeneration pigment by glucocorticoid.
  • Exposure of blood vessels The weakening of the adhesion between the collagen fibers in the blood vessel wall can cause the blood vessels to widen, and the disappearance of dermal collagen causes the surface blood vessels to be exposed.
  • Rosacea-like and acne-like dermatitis In hormone-induced rosacea-like skin lesions, the density of Demodex hair follicles is significantly increased. Demodex mites block the hair follicle sebaceous gland outlet, causing inflammation or allergic reactions. Strong hormones can also make Hyperplasia of sebaceous glands leads to a characteristic rosacea-like rash. Hormones can degenerate and degenerate hair follicle epithelium, leading to blocked outlets, acne-like rashes, or aggravation of original acne.
  • Folliculitis Due to the immunosuppressive effect of hormones, local hair follicle infection and primary folliculitis can be aggravated.
  • Hormone dependence and rebound phenomenon The anti-inflammatory properties of hormones can inhibit the development of papules and relieve itching, vasoconstriction, and disappearance of erythema.
  • hormones cannot eliminate the cause of the disease. After stopping, it can often cause the original disease to aggravate, which can be manifested as Inflammatory edema, redness, burning sensation, discomfort and acute impetigo rebound phenomena. This phenomenon often occurs 2 to 10 days after stopping the hormone, and lasts for a few days or 3 weeks. Due to the rebound phenomenon, the patient continues to use external hormones, resulting in hormone dependence.
  • the primary skin disease has been cured, and obvious erythema, papules, pustules, skin streak disappearance, desquamation and other dermatitis manifestations have appeared repeatedly.
  • ⁇ -glucan is a kind of natural polysaccharide. There are many kinds of ⁇ -glucan that can be found in the natural environment. It usually exists in the cell walls of special kinds of bacteria, yeasts and fungi (Ganoderma lucidum), and can also be found in The coating of higher plant seeds. There are two main production methods of ⁇ -glucan. One is to extract directly from grains such as oats or fruiting body fungi such as mushrooms; the other is to extract and process the fermentation broth through liquid fermentation of fungi or bacteria. Obtain ⁇ -glucan.
  • beta-glucan of the present invention and “biopolysaccharide of the present invention” are used interchangeably, and mainly refer to the beta-glucan described in the first aspect of the present invention.
  • Schizophyllum ⁇ -glucan Lentinus ⁇ -glucan, Sclerotium ⁇ -glucan, Grifola frondosa ⁇ -glucan, Pleurotus ostreatus, mushroom ⁇ -glucan, yeast ⁇ -Glucan, oat ⁇ -glucan, or a combination thereof; preferably Schizophyllum ⁇ -glucan.
  • Schizophyllum ⁇ -glucan refers to ⁇ -glucan derived from Schizophyllum.
  • the structure of the ⁇ -glucan is shown in Formula I.
  • the molecular weight of the ⁇ -glucan is ⁇ 2kD, preferably 2kD-40000kD, more preferably 20kD-20000kD.
  • the molecular weight of the ⁇ -glucan may be 5kD-35000kD; 10kD-30000kD; 50kD-25000kD; 100kD-20000kD; 200kD-18000kD; 400kD-16000kD; 500kD-14000kD; 1000kD-12000kD; 2000kD-4000kD; 3000kD-5000kD; 4000kD-6000kD; 5000kD-7000kD; 6000kD-8000kD; 7000kD-9000kD; or 8000kD-10000kD.
  • the purity of the ⁇ -glucan is ⁇ 70%, preferably ⁇ 90%, more preferably ⁇ 95%, more preferably ⁇ 99%.
  • the ⁇ -glucan has good stability.
  • the ⁇ -glucan is in a solid or liquid form, such as ⁇ -glucan solid particles or powder, or a ⁇ -glucan aqueous solution.
  • the particle size of the ⁇ -glucan particles or powder is ⁇ 20 mm, preferably 0.001-10 mm, more preferably 0.01-5 mm, and more preferably 0.1-2 mm.
  • the ⁇ -glucan (granule or powder) has good water solubility and/or natural solubility.
  • the solubility of the ⁇ -glucan (granule or powder) in water (100g) at 25°C is ⁇ 0.0001g, preferably 0.01-50g, more preferably 0.1-10g.
  • the solubility of the ⁇ -glucan (granule or powder) in water (100g) at 25°C may be 0.1-100g; 0.2-90g; 0.5-80g; 1-50g; or, The solubility can be 0.1-0.3g; 0.2-0.4g; 0.3-0.5g; 0.4-0.6g; 0.5-0.7g; 0.6-0.8g; 0.7-0.9g; 0.8-1g; or 1-3g; 2- 4g; 3-5g; 4-6g; 5-7g; 6-8g; 7-9g; 8-10g.
  • the ⁇ -glucan solution is a solution of ⁇ -glucan in water, that is, an aqueous solution of ⁇ -glucan.
  • the ⁇ -glucan (water) solution has a high viscosity; preferably, the ⁇ -glucan aqueous solution (at 25°C) with a mass concentration of 0.5% has a viscosity of ⁇ 40 mPa ⁇ s, more preferably The ground is 100-10000mPa ⁇ s, more preferably 500-2000mPa ⁇ s.
  • the viscosity of the beta-glucan aqueous solution (25°C) with a mass concentration of 0.5% may be 50-10000mPa ⁇ s; 100-9000mPa ⁇ s; 200-8000mPa ⁇ s; 300-7000mPa ⁇ s; 400-6000mPa ⁇ s; 450-5000mPa ⁇ s; 500-5000mPa ⁇ s; 550-4000mPa ⁇ s; 600-3000mPa ⁇ s; 650-2000mPa ⁇ s; 700-1500mPa ⁇ s.
  • the beta-glucan aqueous solution with a mass concentration of 1% has high clarity or high light transmittance, and the light transmittance of the beta-glucan aqueous solution with a mass concentration of 1% ⁇ 50%, preferably ⁇ 80%, preferably ⁇ 85%, more preferably ⁇ 95%;
  • the ⁇ -glucan solution has good stability.
  • the ⁇ -glucan is derived from higher plants or various bacteria and fungi.
  • the embodiment of the present invention specifically takes the fermentation product of Schizophyllum as an example, but is not limited thereto.
  • the ⁇ -glucan of the present invention is an effective component for preventing and treating hormone-dependent dermatitis.
  • ⁇ -glucan enhances the resistance of normal skin, thereby effectively preventing the infection of external pathogenic microorganisms; on the other hand, For skin inflammation caused by bacterial infections, ⁇ -glucan can prevent excessive inflammation and damage, and at the same time promote the repair of damaged skin.
  • the beta-glucan of the present invention also enhances the skin's active defense function, stimulates the basic cellular immune function, prevents excessive inflammation, has a two-way immune regulation function, and will not harm the skin of patients or cause them to develop drug resistance.
  • the present invention provides a preparation or composition for preventing and/or treating hormone-dependent dermatitis, said preparation or composition containing (a) ⁇ -glucan; and optionally (b) pharmacy, cosmetics Acceptable carriers or excipients on top, or devices.
  • the preparation or composition contains (a) Schizophyllum ⁇ -glucan; and optionally (b) a pharmaceutically, cosmetically, or device-acceptable carrier or excipient Agent.
  • the formulation or composition contains 0.0001-99wt%, preferably 0.001-90wt%, more preferably 0.01-50wt%, more preferably 0.05-10wt% of ⁇ -glucan (preferably Schizophyllum ⁇ -glucan), based on the total weight of the preparation or composition.
  • ⁇ -glucan preferably Schizophyllum ⁇ -glucan
  • the mass concentration of the ⁇ -glucan in the preparation or composition is ⁇ 1 ⁇ g/mL, specifically may be 1 ⁇ g/mL-200mg/mlL, or 1 ⁇ g/mL-5mg/mL , Or 1 ⁇ g/mL-1mg/mL.
  • the formulation contains an aqueous solution of Schizophyllum ⁇ -glucan, and the content of the aqueous solution of Schizophyllum ⁇ -glucan in the formulation is ⁇ 80wt%, preferably ⁇ 90wt%, more preferably ⁇ 95wt%, more preferably ⁇ 99wt%, more preferably ⁇ 99.5wt%, based on the total weight of the formulation.
  • the mass concentration of Schizophyllum ⁇ -glucan in the aqueous solution of Schizophyllum ⁇ -glucan is 0.0001-50wt%, preferably 0.02-10wt%, more preferably 0.05-5% by weight, based on the total weight of the aqueous solution of Schizophyllum ⁇ -glucan.
  • the present invention provides a preparation for preventing and/or treating hormone-dependent dermatitis, the preparation comprising: ⁇ -glucan, 1,3-butanediol, 1,3 -Propylene glycol, polyethylene glycol 400, glycerin, hyaluronic acid, deionized water.
  • the components of the formulation are as shown in Table 1:
  • the "active ingredient (first active ingredient)" in the formulation or composition of the present invention refers to the ⁇ -glucan (preferably Schizophyllum ⁇ -glucan) of the present invention.
  • composition of the present invention can be used to prevent and/or treat hormone-dependent dermatitis.
  • the "active ingredient (first active ingredient)", preparation and/or composition are also used to prevent and/or treat skin and mucosal inflammation or other skin inflammatory diseases.
  • the "second active ingredient” refers to an active ingredient that is different from the ⁇ -glucan in the present invention for treating hormone-dependent dermatitis, or an active ingredient for treating skin and mucosal inflammation or other skin diseases.
  • Safety and effective amount refers to: the amount of the active ingredient is sufficient to significantly improve the condition or symptoms without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably, 10-200 mg active ingredient/dose.
  • the "one dose” is a tablet or an injection.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity.
  • composition here means that the components in the composition can be blended with the active ingredients of the present invention and between them without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose
  • the ⁇ -glucan of the present invention can form a complex with macromolecular compounds or polymers through non-bonding interactions.
  • the ⁇ -glucan of the present invention can be connected to macromolecular compounds or polymers through chemical bonds.
  • the macromolecular compound may be a biological macromolecule such as high glycans, proteins, nucleic acids, polypeptides and the like.
  • the administration method of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include, but are not limited to: topical, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), etc.
  • Solid dosage forms include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient or carrier, such as sodium citrate or dicalcium phosphate, or mixed with one or more of the following ingredients:
  • Fillers or compatibilizers for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;
  • Binders for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;
  • Humectants for example, glycerin
  • Disintegrants for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • a slow solvent such as paraffin
  • wetting agents such as cetyl alcohol and glyceryl monostearate
  • Sorbent for example, kaolin
  • Lubricants for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
  • the dosage form may also contain buffering agents.
  • the solid dosage forms can also be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of active ingredients in such compositions may be released in a certain part of the digestive tract in a delayed manner.
  • coatings and shell materials such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of active ingredients in such compositions may be released in a certain part of the digestive tract in a delayed manner.
  • embedding components that can be used are polymeric substances and waxes.
  • Liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.
  • the composition may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • a safe and effective amount of the composition of the present invention is administered to a mammal (such as a human) in need of treatment, wherein the dosage when administered is the effective dosage considered pharmaceutically, for a 60 kg body weight,
  • the daily dosage is usually 1-10000 mg, preferably 10-2000 mg, and more preferably 20-1000 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • the present invention also provides a composite product, which includes:
  • a first pharmaceutical composition the first pharmaceutical composition containing (a) a first active ingredient, the first active ingredient being ⁇ -glucan; and (b) pharmaceutical, cosmetic, or Acceptable carriers or excipients for devices; and
  • a second pharmaceutical composition which is a hormone-dependent dermatitis treatment drug different from the first pharmaceutical composition, or a treatment drug for skin and mucosal inflammation or other skin diseases.
  • composition of the present invention can be administered alone or in combination with other therapeutic drugs (for example, formulated in the same pharmaceutical composition).
  • the pharmaceutical composition of the present invention can also be used in combination with other drugs known to treat or improve similar conditions.
  • the original drug administration mode and dosage remain unchanged, while the pharmaceutical composition of the present invention is used simultaneously or subsequently.
  • the drug combination also includes the use of the pharmaceutical composition of the present invention and one or more other known drugs in overlapping time periods.
  • the dose of the pharmaceutical composition of the present invention or a known drug may be lower than the dose when they are used alone.
  • the ⁇ -glucan (such as Schizophyllum ⁇ -glucan) of the present invention can prevent and/or treat hormone-dependent dermatitis very effectively.
  • the beta-glucan of the present invention has very low side effects in the treatment of hormone-dependent dermatitis, does not destroy the ecological balance of the skin surface flora, and does not harm the patient's skin or cause it to develop drug resistance.
  • the ⁇ -glucan of the present invention can be used not only to prevent and/or treat hormone-dependent dermatitis, but also to enhance the active defense function of the skin, stimulate the basic immune function of cells, and prevent excessive inflammation at the same time. It has a two-way immune regulation function. Antibacterial, anti-inflammatory and skin repair, prevention and/or treatment of skin and mucous membrane inflammation or other skin inflammatory diseases.
  • the ⁇ -glucan of the present invention is combined with other drugs for the treatment of hormone-dependent dermatitis, which can further enhance the preventive and/or therapeutic effects and has a synergistic effect.
  • the ⁇ -glucan (preferably Schizophyllum ⁇ -glucan) of the present invention is a biopolysaccharide of pure natural origin, which is completely soluble or naturally soluble, and has not undergone any chemical and/or physical modification or Retouch.
  • the ⁇ -glucan of the present invention completely retains the three-dimensional conformation of the triple helix, and has better activity for preventing and/or treating hormone-dependent dermatitis.
  • the ⁇ -glucan of the present invention has excellent stability and can coexist with most substances to maintain its activity. Therefore, it has a wide range of applications and can be used in combination with other hormone-dependent dermatitis treatment drugs or skin care products. It improves skin texture while treating hormone-dependent dermatitis.
  • This embodiment only takes ⁇ -glucan obtained by fermentation of Schizophyllum as an example, but is not limited to this.
  • the fermentation broth in the following examples was fermented with Schizophyllum commune Fr-1003, product catalog: 38548 TM , purchased from the American Model Collection Center [ATCC]), as follows:
  • Seed activation put potato starch 100g/L, glucose 40g/L, yeast extract 2g/L, yeast extract powder 2g/L, and water into a shaker bottle with a liquid volume of 1/3 , Take the plate mycelium obtained in step 1 to inoculate the shake flask, culture it with shaking at 160 rpm in a constant temperature shaker at 25° C. for 7 days as a seed solution;
  • Fermentation culture Glucose 50g/L, sucrose 50g/L, soybean powder (Shandong Zhaoyuan Wenji Food Co., Ltd.) 5g/L, yeast extract 2g/L, potassium dihydrogen phosphate 0.5g/L, seven Fermentation medium made of hydrated magnesium sulfate 0.5g/L, ammonium sulfate 0.5g/L, potassium nitrate 6g/L, and water was added to the fermentor and sterilized at 121°C for 15 minutes, and then the seed liquid obtained in step 2 was inoculated with the above fermentation In the tank, stirring 4Lpm aerated fermentation at a constant temperature of 300rpm at 25°C for 8 days to obtain a Schizophyllum fermentation broth.
  • step (2) Centrifuge the digestion solution obtained in step (1) at 4,000 rpm for 5 minutes, and take the supernatant; filter the supernatant with a 300 mesh filter cloth under negative pressure, and take the filtered clear solution for later use. liquid;
  • step (3) Heat the leaching clear liquor filtered in step (2) to 50°C, add 200 mesh wooden activated carbon and 8-16 mesh coconut shell activated carbon to it at the same time, the added volume of each type of activated carbon is the volume of the leaching clear liquid 1%.
  • step (4) Quickly mix the filtered clear liquid in step (4) with 95% edible ethanol (volume ratio is 1:3), and stir until the precipitate is obtained; then the precipitate is re-dissolved to the original volume, and then quickly Mix with 95% edible ethanol (volume ratio is 1:3), and stir until a precipitate is obtained;
  • step (6) Place the precipitate obtained in step (5) in a perforated tray, and use an electric oven to dry at 40°C until constant weight to obtain a dry product;
  • the light transmittance of the beta-glucan solution with a mass concentration of 0.5% at a wavelength of 600 nm can reach 90%, and the viscosity can reach more than 600 mPa ⁇ s at 40°C.
  • the position of the functional group is basically the same. As shown in Figure 1, the main functional group positions are:
  • test results of Fourier transform infrared spectroscopy show that the product obtained in this example is ⁇ -glucan.
  • Quantitative detection of ⁇ -glucan was performed on the dried product obtained in step (6) of the second part of the above-mentioned Example 1, according to the yeast ⁇ -glucan industry standard QBT 4572-2013.
  • the obtained dried ⁇ -glucan sample was ground to a diameter of about 1.0 mm.
  • the content of ⁇ -glucan in the product was 99.23%.
  • step (7) in the second part of Example 1 a 0.3%, 0.5%, 0.8%, 1.0% (mass to volume ratio) ⁇ -glucan aqueous solution was prepared, and the dynamic viscosity was measured at 25°C.
  • the results are shown in Table 3. As the content of ⁇ -glucan increases, the viscosity of each sample also increases, which are 472, 740, 2150 and 3100 mPa ⁇ s, respectively.
  • yeast ⁇ -glucan particles purchased from Wellmune
  • the dynamic viscosity was measured at 25°C.
  • the dynamic viscosity of the 1.0% yeast ⁇ -glucan suspension was 0 mPa ⁇ s (see Table 3).
  • step (7) of the second part of Example 1 prepare 0.3%, 0.5%, 0.8%, 1.0% (mass to volume ratio) ⁇ -glucan aqueous solutions, and measure the light transmittance of the solution at a wavelength of 600nm.
  • the result As shown in Table 3, the light transmittance of each sample is 96.5%, 93.1%, 87.5% and 81.1%, respectively.
  • the measurement method of the above light transmittance is as follows:
  • the light transmittance of the sample is measured at a wavelength of 600 nm.
  • step (7) of the second part of Example 1 prepare 0.5%, 0.8%, 1.0% (mass to volume ratio) ⁇ -glucan aqueous solutions, add preservatives, and place 24 at room temperature (not protected from light) Month, observe the stability of the solution, and check the dynamic viscosity and light transmittance of the solution.
  • the above-mentioned three solution states are very stable, and their viscosity and light transmittance have little change, and the light transmittance is even improved (see Figure 2 and Table 3).
  • a is commercially available dispersible yeast ⁇ -glucan particles (insoluble in water)
  • b is commercially available soluble yeast ⁇ -glucan powder.
  • Example 2 Hormone-dependent dermatitis treatment cream with ⁇ -glucan as its effective component
  • the samples obtained in formula 1 and formula 5 were mixed with commercial pimecrolimus cream (containing 1% pimecrolimus) at a ratio of 1:1 to prepare a combination of 0.1% ⁇ -glucan and 0.5% pimecrolimus medicine.
  • the Schizophyllum combined positive drug group ( Figure 14A-D) and the soluble yeast combined positive drug group ( Figure 15A-D) may be due to the side effects of the positive drug, and the degree of improvement of hormone-dependent dermatitis symptoms such as papules is better than that of the two ⁇ - Dextran was low when used alone, but side effects such as edema caused by positive drugs were significantly suppressed ( Figure 5, 14, 15, FH in each figure). After treatment with two glucan creams, the inflammation was effectively controlled.
  • Example 4 The preventive effect of ⁇ -glucan on the recurrence of hormone-dependent dermatitis
  • Example 3 when the hormone-dependent dermatitis is effectively controlled, continue to apply the therapeutic drugs in Table 5 twice a day to observe the preventive effect of ⁇ -glucan on the recurrence of hormone-dependent dermatitis.
  • the hormone-dependent dermatitis was cured after 1 to 3 recurrences (Figure 6-9, EH in each graph, Figure 10-13, EH in each graph), and No recurrence, the two ⁇ -glucans have varying degrees of preventive effects on the recurrence of hormone-dependent dermatitis.
  • the two kinds of ⁇ -glucans have preventive effects on the recurrence of hormone-dependent dermatitis, and can improve the side effects caused by positive drugs.
  • the effect of Schizophyllum ⁇ -glucan is better than that of soluble yeast ⁇ -glucan .
  • This example provides 7 kinds of skin care products such as anti-hormone-dependent dermatitis essence.
  • the formula of the anti-hormone-dependent dermatitis skin care products is shown in Table 6.
  • Example 6 A case analysis of the effect of beta-glucan in patients with hormone-dependent dermatitis
  • a 48-year-old female patient B used hormone-containing cosmetics for a long time, causing hormone-dependent dermatitis, facial skin redness, swelling, and itching, and she could no longer use any other skin care products.
  • the 5mg/mL Schizophyllum ⁇ -glucan prepared by the method in Example 1 is used for cleansing and skin care (5mg/mL Schizophyllum ⁇ -glucan, diluted 20 times with water, used to clean the skin; 5mg/mL mL of Schizophyllum ⁇ -glucan, diluted 5 times with water for daily skin care). After the trial for 11 days, the swelling of the face disappeared, no symptoms of itching, and the skin color returned to normal (Figure 16)
  • the present invention finds for the first time that ⁇ -glucan has a significant effect of treating and preventing hormone-dependent dermatitis, especially the high-viscosity, high-molecular-weight Schizophyllum ⁇ -glucan prepared in Example 1 of the present invention.
  • the present invention finds that the therapeutic and preventive activity of ⁇ -glucan is related to the degree of branching, the amount of glucose in the side chain, the three-dimensional structure, and the molecular weight of the hormone-dependent dermatitis.
  • the non-branched biopolysaccharides have no activity in treating and preventing hormone-dependent dermatitis, or the effect is poor.
  • the degree of branching of yeast glucan is variable.
  • the main chain randomly extends side chains composed of ⁇ -1,6-glycosidic bonds.
  • the amount of glucose in the side chains is large and variable, and the number can be as high as hundreds.
  • Granular yeast glucan has long side chains and is easy to form a tight network structure, while soluble yeast ⁇ -glucan has undergone structural modification, and its original activity has been greatly affected. It is a treatment for hormone-dependent dermatitis And the preventive effect is not as good as Schizophyllum ⁇ -glucan.
  • Schizophyllum ⁇ -glucan has moderate branching, with only one glucose residue on the side chain, and high molecular weight. It has a larger and longer three-dimensional triple helix structure and has a good activity in the treatment and prevention of hormone-dependent dermatitis.

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Abstract

一种包含β-葡聚糖的组合物，用于预防和/或治疗激素依赖性皮炎、皮肤黏膜炎症或其他皮肤炎性疾病。

Description

具有预防和治疗激素依赖性皮炎功效的生物多糖及其应用 技术领域
本发明涉及生物技术领域，尤其涉及一种具有预防和治疗激素依赖性皮炎功效的生物多糖及其应用。
背景技术
糖皮质激素是机体内极为重要的一类调节分子，它对机体的发育、生长、代谢以及免疫功能等起着重要调节作用，是机体应激反应最重要的调节激素，也是临床上使用最为广泛而有效的抗炎和免疫抑制剂。在紧急或危重情况下，糖皮质激素往往为首选，具有抗炎、抗毒、抗过敏、抗休克、非特异性抑制免疫及退热作用等多种作用，可以防止和阻止免疫性炎症反应和病理性免疫反应的发生，对任何类型的变态反应性疾病几乎都有效。
然而，长期大量使用糖皮质激素存在巨大风险。目前常见的激素依赖性皮炎，正是由于长期不正确使用含糖皮质激素的外用药物或者化妆品导致的。近年来激素依赖性皮炎的发病上升趋势明显，且顽固难以治愈。目前常用的治疗手段停留在保湿、抗炎抗过敏和抗感染治疗上，治疗周期长，效果差，易复发，给患者的生理和心理带来双重创伤。
因此，本领域迫切需要开发一种能有效预防和治疗激素依赖性皮炎的药物。
发明内容
本发明的目的是提供一种能有效治疗激素依赖性皮炎的药物。
本发明的另一目的是提供一种具有预防和治疗激素依赖性皮炎功效的生物多糖及其应用。
本发明的第一方面，提供了一种β-葡聚糖的用途，用于制备一制剂或组合物，所述制剂或组合物用于预防和/或治疗激素依赖性皮炎。
在另一优选例中，所述β-葡聚糖为β-D-葡聚糖。
在另一优选例中，所述β-葡聚糖为β-1,3-葡聚糖，优选地，具有β-1,6-分支的β-1,3-葡聚糖。
在另一优选例中，所述β-葡聚糖的结构如式I所示，
Figure PCTCN2020091619-appb-000001
其中，l为≥0的整数，较佳地0-50，较佳地0-10，更佳地0-3，更佳地1-2，更佳地1；m为≥0的整数，较佳地为0-19，较佳地为0-4，更佳地为0-1，更佳地为0；n为≥3的整数，较佳地为30-60000，更佳地100-10000。
在另一优选例中，所述β-葡聚糖的分支度(DB)为0.02-0.8，较佳地0.1-0.5，较佳地0.2-0.4。
在另一优选例中，所述β-葡聚糖包括具有三螺旋立体结构的β-葡聚糖。
在另一优选例中，所述三螺旋立体结构的β-葡聚糖的含量为80％，90％，95％，按β-葡聚糖的总摩尔量计。
在另一优选例中，所述β-葡聚糖的β-1,3-主链为三螺旋立体结构的主体。
在另一优选例中，所述β-葡聚糖的β-1,6-分支位于三螺旋立体结构的外侧。
在另一优选例中，所述β-葡聚糖的分子量≥2kD，较佳地2kD-40000kD，更佳地20kD-20000kD。
在另一优选例中，所述β-葡聚糖的分子量可以为5kD-35000kD；10kD-30000kD；50kD-25000kD；100kD-20000kD；200kD-18000kD；400kD-16000kD；500kD-14000kD；1000kD-12000kD；2000kD-4000kD；3000kD-5000kD；4000kD-6000kD；5000kD-7000kD；6000kD-8000kD；7000kD-9000kD；或者8000kD-10000kD。
在另一优选例中，所述β-葡聚糖选自下组：裂褶菌β-葡聚糖、香菇β-葡聚糖、小核菌β-葡聚糖、灰树花β-葡聚糖、侧耳多糖、蘑菇β-葡聚糖、酵母β-葡聚糖、燕麦β-葡聚糖、或其组合。
在另一优选例中，所述β-葡聚糖为裂褶菌β-葡聚糖。
在另一优选例中，所述香菇β-葡聚糖为每5个β-1,3-的主链，带有2个β-1,6-的分支，且每个分支1个葡萄糖残基的β-葡聚糖。
在另一优选例中，所述β-葡聚糖的纯度≥70％，较佳地≥90％，更佳地≥95％，更佳地≥99％。
在另一优选例中，所述β-葡聚糖具有良好的稳定性。
在另一优选例中，所述β-葡聚糖呈固态形式或液态形式，如β-葡聚糖固体颗粒或粉末、或β-葡聚糖水溶液。
在另一优选例中，所述β-葡聚糖颗粒或粉末的粒径≤20mm，较佳地0.001-10mm，更佳地0.01-5mm，更佳地0.1-2mm。
在另一优选例中，所述β-葡聚糖为完全水溶的β-葡聚糖。
在另一优选例中，所述β-葡聚糖(颗粒或粉末)具有良好的水溶性和/或天然可溶性。
在另一优选例中，所述β-葡聚糖(颗粒或粉末)在25℃水(100g)中的溶解度≥0.0001g，较佳地0.01-50g，更佳地0.1-10g。
在另一优选例中，所述β-葡聚糖(颗粒或粉末)在25℃水(100g)中的溶解度可以为0.1-100g；0.2-90g；0.5-80g；1-50g；或者，所述溶解度可以为0.1-0.3g；0.2-0.4g；0.3-0.5g；0.4-0.6g；0.5-0.7g；0.6-0.8g；0.7-0.9g；0.8-1g；或者1-3g；2-4g；3-5g；4-6g；5-7g；6-8g；7-9g；8-10g。
在另一优选例中，所述β-葡聚糖溶液为β-葡聚糖在水中的溶液，即β-葡聚糖水溶液。
在另一优选例中，所述β-葡聚糖(水)溶液粘度大；较佳地，质量浓度为0.5％的β-葡聚糖水溶液(25℃时)粘度≥40mPa·s，更佳地100-10000mPa·s，更佳地500-2000mPa·s。
在另一优选例中，所述质量浓度为0.5％的β-葡聚糖水溶液(25℃)粘度可以为50-10000mPa·s；100-9000mPa·s；200-8000mPa·s；300-7000mPa·s；400-6000mPa·s；450-5000mPa·s；500-5000mPa·s；550-4000mPa·s；600-3000mPa·s；650-2000mPa·s；700-1500mPa·s。
在另一优选例中，所述质量浓度为1％的β-葡聚糖的水溶液具有高澄清度或高透光率，所述质量浓度为1％的β-葡聚糖水溶液的透光率≥50％，较佳地≥80％，较佳地≥85％，更佳地≥95％；
在另一优选例中，所述β-葡聚糖溶液具有良好的稳定性。
在另一优选例中，所述预防和/或治疗激素依赖性皮炎包括：预防激素依赖性皮炎的生成或复发、改善或缓解激素依赖性皮炎症状、加快激素依赖性皮炎消退或愈合、改善激素依赖性皮炎残留的疤痕、或加快激素依赖性皮炎疤痕的消退。
在另一优选例中，所述预防和/或治疗激素依赖性皮炎为预防激素依赖性皮炎的复发。
在另一优选例中，所述治疗激素依赖性皮炎包括抑制激素依赖性皮炎治疗药物的副作用。
在另一优选例中，所述的β-葡聚糖用于抑制激素依赖性皮炎治疗药物的副作用。
在另一优选例中，所述的副作用包括发炎、水肿灼热、疼痛、。
在另一优选例中，所述“激素依赖性皮炎”指因长期反复不当的外用激素引起的皮炎，临床表现以表皮和真皮变薄、色素减退或沉着、血管显露、酒渣样、痤疮样皮炎、毛囊炎、具有激素依赖和反跳现象为特点，又称激素脸。
在另一优选例中，所述激素依赖性皮炎症状包括下组：皮肤瘙痒、灼热、疼痛、干燥、脱屑、紧绷感，面部皮肤出现潮红，反复发生红斑、丘疹、皮肤委缩变薄、毛细血管扩张，痤疮泛发，酒渣鼻样改变，色素沉着或脱失，面部皮肤出现萎缩纹、毛囊炎性脓包等。
在另一优选例中，所述制剂或组合物含有(a)β-葡聚糖；以及任选的(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂。
在另一优选例中，所述制剂或组合物含有(a)裂褶菌β-葡聚糖；以及任选的(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂。
在另一优选例中，所述制剂或组合物含有0.0001-99wt％，较佳地0.001-90wt％，更佳地0.01-50wt％，更佳地0.05-10wt％的β-葡聚糖，按制剂或组合物的总重量计。
在另一优选例中，所述β-葡聚糖在所述制剂或组合物中的质量浓度为≥1μg/mL，具体可以为1μg/mL-200mg/mL，或者1μg/mL-5mg/mL，或者1μg/mL-1mg/mL。
在另一优选例中，所述制剂或组合物还用于增强皮肤免疫力或主动防御功能。
在另一优选例中，所述制剂或组合物还用于预防和/或治疗皮肤黏膜炎症或其他皮肤炎性疾病。
在另一优选例中，所述组合物或制剂的剂型为固体剂型、半固体剂型、或液体剂型，如溶液、凝胶、膏霜、乳液等。
在另一优选例中，所述组合物为药物组合物或化妆品组合物，较佳地为外用药物剂型。
在另一优选例中，所述制剂为外用制剂或透皮制剂(如外用溶液剂、软膏剂、贴剂等)。
在另一优选例中，所述制剂或组合物包括化妆品、食品、医疗器械或药品，具体化妆品可以为功效型化妆品。
本发明的第二方面，提供了一种制剂，所述制剂包含β-葡聚糖。
在另一优选例中，所述β-葡聚糖选自下组：裂褶菌β-葡聚糖、香菇β-葡聚糖、小核菌β-葡聚糖、灰树花β-葡聚糖、侧耳多糖、蘑菇β-葡聚糖、酵母β-葡聚糖、燕麦β-葡聚糖、或其组合。
在另一优选例中，所述β-葡聚糖为裂褶菌β-葡聚糖。
在另一优选例中，所述β-葡聚糖为完全水溶的β-葡聚糖。
在另一优选例中，所述制剂为裂褶菌β-葡聚糖，且所述β-葡聚糖具有良好的水溶性、天然可溶性和/或复溶性。
在另一优选例中，所述制剂中的β-葡聚糖呈固态形式或液体形式。
在另一优选例中，所述制剂中包含β-葡聚糖水溶液，所述β-葡聚糖的质量浓度为0.0001-50wt％，较佳地0.02-10wt％，更佳地0.05-5wt％，按β-葡聚糖水溶液的总重量计。
在另一优选例中，所述制剂中β-葡聚糖水溶液的含量≥80wt％，较佳地≥90wt％，更佳地≥95wt％，更佳地≥99wt％，更佳地≥99.5wt％，按制剂的总重量计。
在另一优选例中，所述制剂中的β-葡聚糖具有选自下组一个或多个特征：
(1)所述β-葡聚糖的纯度≥70％，较佳地≥90％，更佳地≥95％，更佳地≥99％；
(2)所述β-葡聚糖具有良好的水溶性、复溶性和/或天然可溶性；
(3)所述β-葡聚糖(固体颗粒或粉末)在25℃水中的溶解度≥0.0001g/100g水，较佳地0.01-50g/100g水，更佳地0.1g-10g/100g水；
(4)所述β-葡聚糖的水溶液具有高澄清度或高透光率；优选地，所述质量浓度为1％的β-葡聚糖水溶液的透光率≥50％，较佳地≥80％，较佳地≥85％，更佳地≥95％；
(5)所述β-葡聚糖溶液粘度大；优选地，质量浓度为0.5％的β-葡聚糖水溶液(25℃时)粘度≥40mPa·s，更佳地100-10000，更佳地600-2000mPa·s；
(6)所述β-葡聚糖的水溶液具有良好的稳定性；和/或
(7)所述β-葡聚糖的分子量≥2kD，较佳地2kD-40000kD，更佳地20kD-20000kD。
在另一优选例中，所述制剂含有(a)β-葡聚糖；以及(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂。
在另一优选例中，所述制剂含有0.0001-99wt％，较佳地0.001-90wt％，更佳地0.01-50wt％，更佳地0.05-10wt％的β-葡聚糖，按制剂的总重量计。
在另一优选例中，所述制剂还含有(c)第二活性成分，所述第二活性成分为不同于所述β-葡聚糖的治疗激素依赖性皮炎的活性成分，或治疗皮肤黏膜炎症或其他皮肤疾病的活性成分。
在另一优选例中，所述治疗激素依赖性皮炎的活性成分选自下组：保湿剂、皮肤屏障修复成分、外用非激素类免疫抑制剂、抗组胺药、抗过敏药、抗菌剂以及抗生素等，具体地，例如甘油、尿囊素、透明质酸、聚谷氨酸、芦荟胶、硅油、马油、绵羊油、神经酰胺、表皮生长因子、他克莫司、吡美莫司、氯雷他定、依巴斯汀、硼酸、苯扎氯铵、红霉素等，或其组合。
在另一优选例中，所述治疗激素依赖性皮炎活性成分选自下组中药及其提取物：清热解表类、清热利湿解毒类、清热凉血解毒类、活血化瘀散结类、调和冲任类、祛风除湿、或其组合；具体地，例如白术、半夏、柴胡、陈皮、赤芍、大黄、地黄、茯苓、甘草、桂枝、黄连、黄芩、积雪草、姜黄、金银花、连翘、牡丹根/皮、牛蒡子、枇杷叶、蒲公英、人参、桑白皮、山药、生山楂、乌梅、野菊花、生薏苡仁、焦栀子、枳实、竹茹、羌活、独活、防风、秦艽、威灵仙、五加皮或其组合。
在另一优选例中，所述治疗皮肤黏膜炎症或其他皮肤疾病的活性成分选自下组：抗组胺类、抗生素类、抗真菌药、激素类、免疫抑制剂、维生素类、维生素A酸类、清洁剂、保护剂、止痒剂、角质促成剂、角质剥脱剂、收敛剂、腐蚀剂、抗菌剂、抗真菌剂、抗病毒剂、杀虫剂、遮光剂、脱色剂、或其组合；具体地，例如氯苯那敏、氯雷他定、阿司咪唑、雷尼替丁、地塞米松、甲基泼尼松龙、制霉菌素、酮康唑、克霉唑、5-氟胞嘧啶、阿达帕林、雷公藤多甙、氯喹、碘町、炉甘石洗剂、或其组合。
在另一优选例中，所述制剂用于预防和/或治疗激素依赖性皮炎。
本发明的第三方面，提供了一种组合物产品，所述组合物产品包括：
(1)第一药物组合物，所述第一药物组合物含有(a)第一活性成分，所述第一活性成分为β-葡聚糖；和(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂；以及
(2)第二药物组合物，所述第二药物组合物为激素依赖性皮炎治疗药物、或皮肤黏膜炎症或其他皮肤疾病的治疗药物。
在另一优选例中，所述第一药物组合物含有0.0001-99wt％，较佳地0.001-90wt％，更佳地0.01-50wt％，更佳地0.05-10wt％的β-葡聚糖，按第一药物组合物的总重量计。
在另一优选例中，所述β-葡聚糖选自下组：裂褶菌β-葡聚糖、香菇β-葡聚糖、小核菌β-葡聚糖、灰树花β-葡聚糖、侧耳多糖、蘑菇β-葡聚糖、酵母β-葡聚糖、燕麦β-葡聚糖、或其组合。
在另一优选例中，所述β-葡聚糖为裂褶菌的β-葡聚糖。
在另一优选例中，所述激素依赖性皮炎治疗药物含有(a)第二活性成分，所述第二活性成分为不同于所述β-葡聚糖的治疗激素依赖性皮炎活性成分；和(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂。
在另一优选例中，所述治疗激素依赖性皮炎的活性成分选自下组：保湿剂、皮肤屏障修复成分、外用非激素类免疫抑制剂、抗组胺药、抗过敏药、抗菌剂以及抗生素等，具体地，例如甘油、尿囊素、透明质酸、聚谷氨酸、芦荟胶、硅油、马油、绵羊油、神经酰胺、表皮生长因子、他克莫司、吡美莫司、氯雷他定、依巴斯汀、硼酸、苯扎氯铵、红霉素等，或其组合。
在另一优选例中，所述激素依赖性皮炎治疗药物选自下组中药及其提取物：清热解表类、清热利湿解毒类、清热凉血解毒类、活血化瘀散结类、调和冲任类、祛风除湿、或其组合；具体地，例如白术、半夏、柴胡、陈皮、赤芍、大黄、地黄、茯苓、甘草、桂枝、黄连、黄芩、积雪草、姜黄、金银花、连翘、牡丹根/皮、牛蒡子、枇杷叶、蒲公英、人参、桑白皮、山药、生山楂、乌梅、野菊花、生薏苡仁、焦栀子、枳实、竹茹、羌活、独活、防风、秦艽、威灵仙、五加皮或其组合。
在另一优选例中，所述皮肤黏膜炎症或其他皮肤疾病的治疗药物选自下组：抗组胺类、抗生素类、抗真菌药、激素类、免疫抑制剂、维生素类、维生素A酸类、清洁剂、保护剂、止痒剂、角质促成剂、角质剥脱剂、收敛剂、腐蚀剂、抗菌剂、抗真菌剂、抗病毒剂、杀虫剂、遮光剂、脱色剂、或其组合；具体地，例如氯苯那敏、氯雷他定、阿司咪唑、雷尼替丁、地塞米松、甲基泼尼松龙、制霉菌素、酮康唑、克霉唑、5-氟胞嘧啶、阿达帕林、雷公藤多甙、氯喹、碘町、炉甘石洗剂、或其组合。
在另一优选例中，所述第一药物组合物和第二药物组合物为各自独立的、或合二为一的。
在另一优选例中，所述组合物产品用于治疗和/或预防激素依赖性皮炎。
在另一优选例中，所述组合物产品为化妆品或药物。
在另一优选例中，使用所述组合物产品治疗的复发率和副作用低于单独使用第二药 物组合物治疗的复发率和副作用。
本发明的第四方面，提供了一种预防和/或治疗激素依赖性皮炎的方法，包括步骤：(a)给需要的对象施用β-葡聚糖。
在另一优选例中，所述β-葡聚糖选自下组：裂褶菌β-葡聚糖、香菇β-葡聚糖、小核菌β-葡聚糖、灰树花β-葡聚糖、侧耳多糖、蘑菇β-葡聚糖、酵母β-葡聚糖、燕麦β-葡聚糖、或其组合。
在另一优选例中，所述β-葡聚糖为裂褶菌β-葡聚糖。
在另一优选例中，所述的对象包括激素依赖性皮炎患者、或正常人群。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了实施例1中制备的裂褶菌β-葡聚糖的傅里叶变换红外光谱图。
图2显示了β-葡聚糖稳定性对比，左边一瓶为市售1.0％燕麦β-葡聚糖溶液，右边一瓶为本发明制备的1.0％裂褶菌β-葡聚糖。
图3显示了实施例3中用于实验的豚鼠背部脱毛区域。
图4显示了实施例3中模型组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A、B、C、D、E、F、G、H分别为停止涂激素第七、八、九、十、十一、十二、十三、十四天。
图5显示了实施例3、实施例4中阳性药物治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图6显示了实施例3、实施例4中0.2％裂褶菌β-葡聚糖治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图7显示了实施例3、实施例4中0.1％裂褶菌β-葡聚糖治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图8显示了实施例3、实施例4中0.05％裂褶菌β-葡聚糖治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图9显示了实施例3、实施例4中0.02％裂褶菌β-葡聚糖治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)， B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图10显示了实施例3、实施例4中0.2％可溶性酵母β-葡聚糖治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图11显示了实施例3、实施例4中0.1％可溶性酵母β-葡聚糖治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图12显示了实施例3、实施例4中0.05％可溶性酵母β-葡聚糖治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图13显示了实施例3、实施例4中0.02％可溶性酵母β-葡聚糖治疗组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图14显示了实施例3、实施例4中裂褶菌β-葡聚糖联合阳性药物组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图15显示了实施例3、实施例4中可溶性酵母β-葡聚糖联合阳性药物组豚鼠，在停止涂抹丙酸氯倍他索溶液的第七天开始，皮肤炎症的变化状况。A为治疗前(停止涂激素第七天)，B、C、D、E、F、G、H分别为治疗的第二、三、四、五、六、七、八天。
图16显示了实施例6中患者B在试用裂褶菌β-葡聚糖制品前后的效果比对。
图17显示了实施例6中患者C在试用裂褶菌β-葡聚糖制品前后的效果比对。
图18显示了实施例6中患者D在试用裂褶菌β-葡聚糖制品前后的效果比对。
具体实施方式
本发明人经过广泛而深入的研究，首次意外地发现，β-葡聚糖，尤其是具有天然可溶性、高分子量、高粘度的β-葡聚糖(如裂褶菌β-葡聚糖)，能够非常有效地预防和/或治疗激素依赖性皮炎。实验表明，裂褶菌β-葡聚糖有明显缓解和改善激素依赖性皮炎，有效控制激素依赖性皮炎的发生，加速激素依赖性皮炎愈合和/或消退的作用。同时裂褶菌β-葡聚糖还能增强皮肤主动防御功能，激活皮肤天然免疫，抗菌、消炎和修复皮肤，治疗或预防皮肤黏膜炎症或其他皮肤炎性疾病。在此基础上，完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变 动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“完全水溶”指所述固态形式的β-葡聚糖，可以在水中完全溶解成为β-葡聚糖水溶液，即在25℃100g水中β-葡聚糖的溶解度≥0.0001g，较佳地0.01-50g，更佳地0.1g-10g。
如本文所用，术语“天然可溶性”指天然状态的β-葡聚糖本身所具有的、在水中完全溶解形成水溶液的性质。所述“天然状态的β-葡聚糖”，是指使用天然方法生产得到(如生物发酵)的β-葡聚糖，所述β-葡聚糖没有经过任何化学改性、并且没有经过任何物理的和/或化学的和/或生物的方法将其长链分子打断而降低其分子质量。在另一优选例中，本发明β-葡聚糖为天然状态的β-葡聚糖。
激素依赖性皮炎
所述“激素依赖性皮炎”，是指因长期反复不当的外用激素引起的皮炎，临床表现以表皮和真皮变薄、色素减退沉着、血管显露、酒渣样、痤疮样皮炎、毛囊炎、具有激素依赖和反跳现象为特点，又称激素脸。具体地，
表皮与真皮变薄：局部长期外用激素，可导致角质层颗粒形成减少而变薄，真皮的糖蛋白和蛋白聚糖的弹性变化使胶原的原纤维间粘附力减弱，胶原合成减少而变薄。
色素减退、沉着：由于角质层的层数减少，迁移到角质形成细胞的黑素减少，引起色素减退。而色素沉着可能与糖皮质激素激活黑素细胞再生色素有关。
血管显露：由于血管壁的胶原纤维间粘附力减弱可导致血管变宽，真皮胶原的消失而导致表面的血管显露。
酒渣样、痤疮样皮炎：在激素诱导的酒渣鼻样皮损中，毛囊蠕形螨的密度显著增高，蠕形螨封闭毛囊皮脂腺出口，引起炎症反应或变态反应，强效激素还可使皮脂腺增生，导致特有的酒渣鼻样皮疹。激素能使毛囊上皮退化变性，导致出口被堵塞，出现痤疮样皮疹或使原有的痤疮加重。
毛囊炎：因激素的免疫抑制作用，可使局部毛囊发生感染和原发毛囊炎加重。
激素依赖和反跳现象：激素的抗炎特性，可抑制丘疹的发展和减轻瘙痒，血管收缩，红斑消失，然而激素不能消除疾病的病因，停用后常可引起原有疾病加重，可表现为炎性水肿，发红，烧灼感，不适感和急性的脓疱疹等反跳现象。该现象常常发生在停用激素后2～10天，并持续几天或3周左右。因反跳现象导致患者继续外用激素，而造成激素依赖。
激素依赖性皮炎的一般诊断方法有：
1.长期反复外用糖皮质激素>1月，用时可好，停药又发的现象。
2.原发性皮肤病已治愈，又反复出现明显的红斑，丘疹、脓疱、皮纹消失、脱屑等皮 炎表现。
3.多发于面部、外阴、皱褶部等皮肤薄嫩处。
4.长期用药后留下色素沉着(减退)、萎缩纹、毛细血管扩张、多毛、脓疱等症状，伴有刺痛、烧灼感。
β-葡聚糖
β-葡聚糖是一种天然多糖，在自然环境中可以找到相当多种类的β-葡聚糖，通常存在于特殊种类的细菌、酵母菌、真菌(灵芝)的细胞壁中，也可存在于高等植物种子的包被中。β-葡聚糖的生产方法主要有两种，其一是从燕麦等谷物或蘑菇等子实体真菌中直接提取；其二是通过真菌或细菌的液体发酵，经由对发酵液进行提取加工，以获得β-葡聚糖。
如本文所用，“本发明β-葡聚糖”、“本发明生物多糖”可互换使用，主要是指本发明第一方面所述的β-葡聚糖，所述β-葡聚糖选自下组：裂褶菌β-葡聚糖、香菇β-葡聚糖、小核菌β-葡聚糖、灰树花β-葡聚糖、侧耳多糖、蘑菇β-葡聚糖、酵母β-葡聚糖、燕麦β-葡聚糖、或其组合；优选地裂褶菌β-葡聚糖。
如本文所用，“裂褶菌β-葡聚糖”指来源于裂褶菌的β-葡聚糖。
在另一优选例中，所述β-葡聚糖的结构如式I所示。
在另一优选例中，所述β-葡聚糖的分子量≥2kD，较佳地2kD-40000kD，更佳地20kD-20000kD。
在另一优选例中，所述β-葡聚糖的分子量可以为5kD-35000kD；10kD-30000kD；50kD-25000kD；100kD-20000kD；200kD-18000kD；400kD-16000kD；500kD-14000kD；1000kD-12000kD；2000kD-4000kD；3000kD-5000kD；4000kD-6000kD；5000kD-7000kD；6000kD-8000kD；7000kD-9000kD；或者8000kD-10000kD。
在另一优选例中，所述β-葡聚糖的纯度≥70％，较佳地≥90％，更佳地≥95％，更佳地≥99％。
在另一优选例中，所述β-葡聚糖具有良好的稳定性。
在另一优选例中，所述β-葡聚糖呈固态形式或液态形式，如β-葡聚糖固体颗粒或粉末、或β-葡聚糖水溶液。
在另一优选例中，所述β-葡聚糖颗粒或粉末的粒径≤20mm，较佳地0.001-10mm，更佳地0.01-5mm，更佳地0.1-2mm。
在另一优选例中，所述β-葡聚糖(颗粒或粉末)具有良好的水溶性和/或天然可溶性。
在另一优选例中，所述β-葡聚糖(颗粒或粉末)在25℃水(100g)中的溶解度≥0.0001g，较佳地0.01-50g，更佳地0.1-10g。
在另一优选例中，所述β-葡聚糖(颗粒或粉末)在25℃水(100g)中的溶解度可以为0.1-100g；0.2-90g；0.5-80g；1-50g；或者，所述溶解度可以为0.1-0.3g；0.2-0.4g；0.3-0.5g；0.4-0.6g；0.5-0.7g；0.6-0.8g；0.7-0.9g；0.8-1g；或者1-3g；2-4g；3-5g；4-6g；5-7g；6-8g； 7-9g；8-10g。
在另一优选例中，所述β-葡聚糖溶液为β-葡聚糖在水中的溶液，即β-葡聚糖水溶液。
在另一优选例中，所述β-葡聚糖(水)溶液粘度大；较佳地，质量浓度为0.5％的β-葡聚糖水溶液(25℃时)粘度≥40mPa·s，更佳地100-10000mPa·s，更佳地500-2000mPa·s。
在另一优选例中，所述质量浓度为0.5％的β-葡聚糖水溶液(25℃)粘度可以为50-10000mPa·s；100-9000mPa·s；200-8000mPa·s；300-7000mPa·s；400-6000mPa·s；450-5000mPa·s；500-5000mPa·s；550-4000mPa·s；600-3000mPa·s；650-2000mPa·s；700-1500mPa·s。
在另一优选例中，所述质量浓度为1％的β-葡聚糖的水溶液具有高澄清度或高透光率，所述质量浓度为1％的β-葡聚糖水溶液的透光率≥50％，较佳地≥80％，较佳地≥85％，更佳地≥95％；
在另一优选例中，所述β-葡聚糖溶液具有良好的稳定性。
在另一优选例中，所述β-葡聚糖来源于高等植物或者各种细菌、真菌。
本发明的实施例具体以裂褶菌的发酵产物为例，但不限于此。
本发明β-葡聚糖是一种预防和治疗激素依赖性皮炎的功效成分，一方面是β-葡聚糖增强正常皮肤的抵御能力，从而有效预防外界病原微生物的侵染；另一方面，对于细菌感染等造成的皮肤炎症，β-葡聚糖可防止炎症过度而造成损伤，同时还能促进受损皮肤的修复。本发明β-葡聚糖还增强皮肤主动防御功能，激发细胞基础免疫功能，同时预防过度炎症，具有双向免疫调节功能，不会伤害患者皮肤或使其产生耐药性。
制剂或组合物
本发明提供一种用于预防和/或治疗激素依赖性皮炎的制剂或组合物，所述制剂或组合物含有(a)β-葡聚糖；以及任选的(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂。
在另一优选例中，所述制剂或组合物含有(a)裂褶菌β-葡聚糖；以及任选的(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂。
在另一优选例中，所述制剂或组合物含有0.0001-99wt％，较佳地0.001-90wt％，更佳地0.01-50wt％，更佳地0.05-10wt％的β-葡聚糖(优选地裂褶菌β-葡聚糖)，按制剂或组合物的总重量计。
在另一优选例中，所述β-葡聚糖在所述制剂或组合物中的质量浓度为≥1μg/mL，具体可以为1μg/mL-200mg/mlL，或者1μg/mL-5mg/mL，或者1μg/mL-1mg/mL。
在另一优选例中，所述制剂含有裂褶菌β-葡聚糖水溶液，所述制剂中裂褶菌β-葡聚糖水溶液的含量≥80wt％，较佳地≥90wt％，更佳地≥95wt％，更佳地≥99wt％，更佳地≥99.5wt％，按制剂的总重量计。
在另一优选例中，所述制剂中，裂褶菌β-葡聚糖水溶液中的裂褶菌β-葡聚糖的质量浓 度为0.0001-50wt％，较佳地0.02-10wt％，更佳地0.05-5wt％，按裂褶菌β-葡聚糖水溶液的总重量计。
在一个优选的实施方式中，本发明提供了一种用于预防和/或治疗激素依赖性皮炎的制剂，所述制剂包括：β-葡聚糖、1,3-丁二醇、1,3-丙二醇、聚乙二醇400、甘油、透明质酸、去离子水。
在另一优选例中，所述制剂的组分如表1所示：
表1具有预防和/或治疗激素依赖性皮炎功效的制剂
Figure PCTCN2020091619-appb-000002
本发明所述制剂或组合物中的“活性成分(第一活性成分)”是指本发明所述的β-葡聚糖(优选地裂褶菌β-葡聚糖)。
本发明所述的“活性成分(第一活性成分)”、制剂和/或组合物可用于预防和/或治疗激素依赖性皮炎。
在另一优选例中，所述“活性成分(第一活性成分)”、制剂和/或组合物还用于预防和/或治疗皮肤黏膜炎症或其他皮肤炎性疾病。
“第二活性成分”是指本发明中不同于所述β-葡聚糖的治疗激素依赖性皮炎的活性成分，或治疗皮肤黏膜炎症或其他皮肤疾病的活性成分。
“安全有效量”指的是：活性成分的量足以明显改善病情或症状，而不至于产生严重的副作用。
通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片或一支注射针剂。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。
药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物 油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020091619-appb-000003
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
在另一优选例中，本发明β-葡聚糖可与大分子化合物或高分子通过非键合作用形成复合物。
在另一优选例中，本发明β-葡聚糖可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括但不限于：外敷、口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中，活性成分与至少一种常规惰性赋形剂或载体混合，如柠檬酸钠或磷酸二钙，或与下述成分一种或多种混合：
(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；
(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；
(c)保湿剂，例如，甘油；
(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；
(e)缓溶剂，例如石蜡；
(f)吸收加速剂，例如，季胺化合物；
(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；
(h)吸附剂，例如，高岭土；和/或
(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。
胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨 醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
使用药物组合物时，是将安全有效量的本发明组合物施用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～10000mg，较佳地10～2000mg，更佳地20～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种组合物产品，所述组合物产品包括：
(1)第一药物组合物，所述第一药物组合物含有(a)第一活性成分，所述第一活性成分为β-葡聚糖；和(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂；以及
(2)第二药物组合物，所述第二药物组合物为不同于第一药物组合物的激素依赖性皮炎治疗药物、或皮肤黏膜炎症或其他皮肤疾病的治疗药物。
本发明组合物可以单独给药，或者与其他治疗药物联合给药(如配制在同一药物组合物中)。
本发明药物组合物也可以与已知的治疗或改进相似病状的其它药物联用。联合给药时，原来药物的给药方式和剂量保持不变，而同时或随后使用本发明药物组合物。药物联用也包括在重叠的时间段使用本发明药物组合物与其它一种或几种已知药物。当本发明药物组合物与其它一种或几种药物进行药物联用时，本发明药物组合物或已知药物的剂量可能比它们单独用药时的剂量较低。
本发明的主要优点包括：
(a)本发明β-葡聚糖(如裂褶菌β-葡聚糖)能够非常有效地预防和/或治疗激素依赖性皮炎。
(b)本发明β-葡聚糖治疗激素依赖性皮炎的副作用非常低，不破坏皮肤表面菌群生态平衡，不会伤害患者皮肤或使其产生耐药性。
(c)本发明β-葡聚糖不仅可以用于预防和/或治疗激素依赖性皮炎，还可增强皮肤主动防御功能，激发细胞基础免疫功能，同时预防过度炎症，具有双向免疫调节功能，可以抗菌、消炎和修复皮肤，预防和/或治疗皮肤黏膜炎症或其他皮肤炎性疾病。
(d)本发明β-葡聚糖与其他治疗激素依赖性皮炎药物结合，可以进一步增强预防和/或治疗效果，具有协同作用。
(e)本发明β-葡聚糖(优选地裂褶菌β-葡聚糖)为纯天然来源的生物多糖，具有完全可溶性或天然可溶性，并且未经过任何化学和/或物理的改性或修饰。
(f)本发明β-葡聚糖完整保留了三螺旋的三维构象，具有更好的预防和/或治疗激素依赖性皮炎活性。
(g)本发明β-葡聚糖具有极佳的稳定性，能够与大多数物质共存而保持其活性，因而应用领域广泛，可与其他激素依赖性皮炎治疗药物或者护肤品结合使用，在预防和治疗激素依赖性皮炎的同时，改善肤质。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
下述实施例中所使用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材料、试剂、设备等，如无特殊说明，均可从商业途径得到。
实施例1、β-葡聚糖的获得以及测定
本实施例仅以裂褶菌发酵获得的β-葡聚糖为例，但不限于此。
一、裂褶菌菌种发酵液的获得
下述实施例中的发酵液通过发酵裂褶菌菌种(裂褶菌Schizophyllum commune Fr—1003，产品目录：
Figure PCTCN2020091619-appb-000004
38548 TM，购于美国模式菌种收集中心[ATCC])，具体如下：
1、裂褶菌菌种活化：将马铃薯200g/L、葡萄糖30g/L、氯化钠10g/L、琼脂20g/L制成平板培养基，把裂褶菌菌种接种到该平板培养基上，于25℃恒温培养箱内培养7天得到平板菌丝体；
2、种子活化：将马铃薯淀粉100g/L、葡萄糖40g/L、酵母浸膏2g/L、酵母浸粉2g/L、水制成的液体培养基装入摇瓶，装液量为1/3，取步骤1所得的平板菌丝体接种该摇瓶，于25℃恒温摇床内160rpm震荡培养培养7天，作为种子液；
3、发酵培养：将葡萄糖50g/L、蔗糖50g/L、黄豆粉(山东招远市温计食品有限公司)5g/L、酵母浸粉2g/L、磷酸二氢钾0.5g/L、七水合硫酸镁0.5g/L、硫酸铵0.5g/L、硝酸钾6g/L和水制成的发酵培养基加入发酵罐中121℃灭菌15分钟，再将步骤2所得的种子液接种上述发酵罐中，25℃恒温300rpm搅拌4Lpm通气发酵培养8天，得到裂褶菌发酵液。
二、β-葡聚糖的分离纯化及β-葡聚糖溶液的制备
(1)将上述第一部分得到的裂褶菌发酵液与4倍体积的蒸馏水混合，60℃下浸煮8h，得到浸煮液；
(2)将步骤(1)得到的浸煮液在4,000rpm离心5min，取上清液；将上清液用300目的滤布负压过滤，取滤出清液待用，即为浸煮清液；
(3)将步骤(2)过滤后的浸煮清液加热至50℃，向其中同时加入200目的木质活性炭及8～16目的椰壳活性炭，每种活性炭的添加体积为浸煮清液体积的1％。于50℃，350rpm 条件下持续搅拌4h，冷却后待用，得到混合有活性炭的浸煮清液；再将混合有活性炭的浸煮清液依次使用300目滤布及SCP-321#滤板(孔径大小约1.5μm)进行负压抽滤，取过滤后的清液待用；
(4)将Solarbio脂肪酶(L8070，酶活力100～400U/mg)溶于生理磷酸盐缓冲液中，按10U/mL的酶用量，将脂肪酶溶液加入步骤(3)制备的滤液中，搅拌均匀后40℃酶解2h；再将Solarbio中性蛋白酶(Z8030，酶活力>60U/mg)溶于生理磷酸盐缓冲液中，按60U/mL的酶用量，将中性蛋白酶溶液加入上述酶解液中，搅拌均匀后，40℃酶解2h。酶解结束后90℃水浴加热30min，以灭酶活，再以SCP-321#滤板(孔径大小约1.5μm)进行负压抽滤，取过滤后的清液待用；
(5)将步骤(4)过滤后的清液快速与95％浓度的食用乙醇混合(体积比为1：3)，搅拌，直至得到析出物；再将析出物重新溶解至原体积，后快速与95％浓度的食用乙醇混合(体积比为1：3)，搅拌，直至得到析出物；
(6)将步骤(5)得到的析出物置于带孔托盘中，使用电热烘箱40℃烘干，直至恒重，得干燥产物；
(7)将上述步骤(6)得到的β-葡聚糖干燥物粉碎，称取粉碎物5g，溶解于1,000mL超纯水中，维持600rpm搅拌2h，直至β-葡聚糖充分溶解，得到β-葡聚糖溶液；将上述β-葡聚糖溶液使用5μm滤膜进行负压抽滤，并添加适量化妆品用防腐剂后，即可得到浓度为0.5％的高粘度、高透光率的β-葡聚糖溶液。
该质量浓度为0.5％的β-葡聚糖溶液在600nm波长(以分光光度计检测)下的透光率可以达到90％，40℃时粘度可达600mPa·s以上。
三、β-葡聚糖的鉴定与检测
1、β-葡聚糖的红外光谱鉴定
对上述0.5％的β-葡聚糖溶液进行鉴定，具体按照《中华人民共和国药典》(2010版)二部附录IV中方法C使用红外光谱法，将105℃烘干后的样品，使用傅里叶变换红外光谱仪进行全波长扫描。结果上述实施例1第二部分步骤(7)得到的0.5％溶液为β-葡聚糖溶液。
与酵母β-葡聚糖行业标准QBT 4572-2013中酵母β-葡聚糖的红外光谱图对比，官能团位置基本吻合。如图1所示，主要的官能团位置为：
1)3301cm -1附近有较强，较宽的吸收峰(糖类O-H键伸缩振动吸收峰)
2)2921cm -1附近有较弱的吸收峰(糖类C-H键伸缩振动吸收峰)
3)886cm -1附近有较弱的吸收峰(糖类β构型特征振动吸收峰)
4)1076cm -1附近有较强的吸收峰(糖类C-OH，C-O-C伸缩振动吸收峰)
傅里叶变换红外光谱测试结果表明，本实施例得到的产物为β-葡聚糖。
2、β-葡聚糖的含量检测
对上述实施例1第二部分步骤(6)得到的干燥产物进行β-葡聚糖定量检测，具体按照酵 母β-葡聚糖行业标准QBT 4572-2013中酵母β-葡聚糖含量测定方法，将得到的β-葡聚糖干燥物样品研磨至直径1.0mm左右后进行。结果产物中β-葡聚糖含量为99.23％。
3、β-葡聚糖溶液的激素检测
对上述0.5％的β-葡聚糖溶液进行48项激素测定，具体按照《化妆品安全技术规范》(2015年版)第四章2.4雌三醇等7种组分第一法高压液相色谱-二极管阵列检测器法和GB/T24800.2-2009化妆品中四十一种糖皮质激素的测定液相色谱/串联质谱法和薄层层析法进行。结果上述实施例1第二部分步骤(7)得到的0.5％β-葡聚糖溶液中，未检出上述激素(结果见表2)。
表2 48项激素测定
Figure PCTCN2020091619-appb-000005
Figure PCTCN2020091619-appb-000006
4、β-葡聚糖溶液的粘度测定
按照实施例1第二部分步骤(7)的方法，配制0.3％、0.5％、0.8％、1.0％(质量体积比)的β-葡聚糖水溶液，于25℃时分别检测动力粘度。结果详见表3，随着β-葡聚糖含量的提高，各样品的粘度也递增，分别为472、740、2150和3100mPa·s。
取市售分散性(不溶于水)酵母β-葡聚糖颗粒(购自Wellmune公司)，准确称取2g，加入去离子水混合，并定容至200mL，得到质量体积比为1.0％的酵母β-葡聚糖混悬液，于25℃时检测动力粘度。结果该1.0％的酵母β-葡聚糖混悬液的动力粘度为0mPa·s(见表3)。
取市售可溶性酵母β-葡聚糖粉末(购自Wellmune公司)，准确称取2g，加入去离子水溶解，并定容至200mL，得到质量体积比为1.0％的酵母β-葡聚糖水溶液，于25℃时检测动力粘度。结果该1.0％的酵母β-葡聚糖水溶液的动力粘度为0mPa·s(见表3)。
上述动力粘度的测定方法如下：
(1)取200mL上述溶液样品，置于250mL烧杯中；
(2)将盛有上述溶液/混合液样品的烧杯置于水浴锅中，25℃保温1h；
(3)使用旋转粘度计，检测25℃下各样品的动力粘度。
5、β-葡聚糖溶液的透光率测定
按照实施例1第二部分步骤(7)的方法，配制0.3％、0.5％、0.8％、1.0％(质量体积比)的β-葡聚糖水溶液，于600nm波长处测定溶液透光率，结果如见表3所示，各样品的透光率分别为96.5％、93.1％、87.5％和81.1％。
取市售1.0％的燕麦β-葡聚糖溶液(购自Symrise公司)，于600nm波长处测定溶液透光率，结果透光率为59.7％(见表3)。
取市售分散性酵母β-葡聚糖颗粒，准确称取2g，加入去离子水混合，并定容至200mL，得到质量体积比为1.0％的酵母β-葡聚糖混悬液，于600nm波长处测定混悬液透光率，结果透光率仅为1.3％(见表3)。
取市售可溶性酵母β-葡聚糖粉末，准确称取2g，加入去离子水溶解，并定容至200mL，得到质量体积比为1.0％的酵母β-葡聚糖水溶液，于600nm波长处测定溶液透光率，结果透光率为68.4％(见表3)。
上述透光率的测定方法如下：
(1)取10mL上述溶液样品置于离心管中；
(2)1000rpm低速离心1min，以去除气泡(两种酵母β-葡聚糖溶液/悬液无气泡，未经离心处理)；
(3)小心取3mL至1cm玻璃比色皿内，避免气泡；
(4)使用分光光度计，以去离子水作为空白参照(去离子水的透光率为100％计)，于600nm波长处测定样品透光率。
6、β-葡聚糖溶液的稳定性测定
按照实施例1第二部分步骤(7)的方法，配制0.5％、0.8％、1.0％(质量体积比)的β-葡聚糖水溶液，加入防腐剂后，室温(未避光)放置24个月，观察溶液稳定性，并检测溶液动力粘度和透光率。结果，上述三种溶液状态均十分稳定，其粘度和透光率变化不大，其中透光率甚至有所提高(见图2、表3)。
取市售1.0％的燕麦β-葡聚糖溶液，室温(未避光)放置24个月，观察溶液稳定性，并检 测溶液动力粘度和透光率。结果，该1.0％的燕麦β-葡聚糖溶液状态十分不稳定，室温放置3个月后就有固形物析出，导致其粘度和透光率无法检测(见图2、表3)。
表3各种β-葡聚糖溶液动力粘度数据
Figure PCTCN2020091619-appb-000007
注：a为市售分散性酵母β-葡聚糖颗粒(不溶于水)，b为市售可溶性酵母β-葡聚糖粉末。
实施例2、以β-葡聚糖为功效成分的激素依赖性皮炎治疗乳膏
按照表4配方，配制用于治疗激素依赖性皮炎的乳膏。
表4以β-葡聚糖为功效成分的激素依赖性皮炎治疗乳膏配方
Figure PCTCN2020091619-appb-000008
其中配方1和配方5所得样品，与商用吡美莫司乳膏(含1％吡美莫司)以1:1混合，制备含量0.1％β-葡聚糖和0.5％吡美莫司的联合治疗药物。
实施例3、β-葡聚糖对激素依赖性皮炎的治疗作用
1、使用7-9周龄体重约300g的雌性豚鼠，适应性饲养一周，使其适应新环境，饲料、水自由摄取；
2、腹部注射水合氯醛麻醉后，背部除毛，暴露背部皮肤(图3)；
3、用棉签蘸取0.05％丙酸氯倍他索溶液，均匀外涂于裸露的背部皮肤，每天两次，连续15天后停止涂抹，每日观察皮肤，直至皮肤出现丘疹等皮炎，建立激素依赖性皮炎模型；
4、按照表5的分组，将阳性治疗药物(商用吡美莫司乳膏)和实施例2制备的10种乳膏(不同来源的β-葡聚糖、以及β-葡聚糖联合阳性治疗药物)，均匀涂在豚鼠背部激素依赖性皮炎部位，每日两次，每次0.1g/9cm 2；
5、每日拍照，观察激素依赖性皮炎治疗效果。
表5 β-葡聚糖对激素依赖性皮炎的治疗/预防复发作用实验分组
Figure PCTCN2020091619-appb-000009
结果发现，自激素停止涂抹的第七天开始，丙酸氯倍他索涂抹区域出现红色皮疹，且随着时间的延长，皮疹情况越来越严重(图4，停止涂抹第九、十、十一天、十四，由于背毛生长的原因，部分红色丘疹被毛发掩盖)，激素依赖性皮炎模型成功建立。
按照表5进行分组治疗后，发现各组药物及组合物，对于激素依赖性皮炎均具有治疗作用(图5～15)：
1)阳性药物组(图5A、B)效果体现最快，第二天就基本完全好转；
2)阳性药物组的红色丘疹虽然消失得最快，但是仔细观察发现，第四天该组皮肤就开始整体发红，随时阳性药物的连续涂抹，该组皮肤反而再次发生丘疹，并开始发炎水肿(图5D-H)。结果表明阳性药虽然起效快，但对皮肤具有较大的副作用；皮炎复发时，症状比首次发生时严重程度大幅增加；
3)两种β-葡聚糖对激素依赖性皮炎也有治疗作用。不同浓度的裂褶菌β-葡聚糖(图6-9，各图的A-D)和可溶性酵母β-葡聚糖(图10-13，各图的A-D)在治疗的第二天有不同程度的改善。至第四天，除0.02％裂褶菌β-葡聚糖组在脱毛时收到损伤外，大多数裂褶菌β-葡聚糖治疗组的红色丘疹基本褪去，而可溶性酵母β-葡聚糖只有0.2％组(图10)效果较为明显，其余浓度红色丘疹未完全消失。由此可见，裂褶菌β-葡聚糖对激素依赖性皮炎的治疗效果优于可溶性酵母β-葡聚糖。
4)裂褶菌β-葡聚糖(图6-9，各图的A-D)组和可溶性酵母β-葡聚糖(图10-13，各图的A-D)组，在连续治疗的首个四天，皮肤逐渐光洁，无水肿发炎。从第五天开始，这两组的激素依赖性皮炎复发(图6-9，各图的E、F，图10-13，各图的E、F)，再次有丘疹出现，但严重程度较首次发生时(图6-9，各图的A，图10-13，各图的A)明显降低。之后随着治疗的延续，丘疹再次改善。其中0.05％、0.1％和0.2％的裂褶菌β-葡聚糖治疗组，未再复发，0.02％的裂褶菌β-葡聚糖治疗组和各浓度的可溶性酵母β-葡聚糖，在复发1-2次后痊愈。
但裂褶菌联合阳性药物组(图14A-D)和可溶性酵母联合阳性药物组(图15A-D)，可能由于阳性药物的副作用，丘疹等激素依赖性皮炎症状的改善程度较两种β-葡聚糖单独使用时低，但阳性药物引起的水肿等副作用得到了明显的抑制(图5、14、15，各图的F-H)。之后使用两种葡聚糖乳膏进行治疗，炎症状况得到有效控制。
实施例4、β-葡聚糖对激素依赖性皮炎复发的预防作用
使用实施例3中的豚鼠，在其激素依赖性皮炎得到有效控制时，继续每日两次涂抹表5中的治疗药物，观察β-葡聚糖对激素依赖性皮炎复发的预防作用。
从图5的每日变化趋势可以看出，阳性药物吡美莫司对激素依赖性皮炎的复发不具有预防作用，且由于发生了严重的水肿等副作用，其炎症程度反而比首次发生时更严重(图5E-H)。
两种β-葡聚糖单独使用组，其激素依赖性皮炎在复发1～3次后，均得到痊愈(图6-9，各图的E-H，图10-13，各图的E-H)，且未再复发，两种β-葡聚糖对激素依赖性皮炎的复发具有不同程度的预防作用。
两种β-葡聚糖联合阳性药物组，在首次复发时，严重程度均比初发时更大(图14F，图15F)，且结合阳性药物单独使用组的数据，本实施例将这两组改为单独β-葡聚糖乳膏治疗。其中0.1％裂褶菌β-葡聚糖治疗组在反复发作两次后、0.1％可溶性酵母β-葡聚糖治疗组在反复发作三次后，激素依赖性皮炎得到有效控制。
两种β-葡聚糖对激素依赖性皮炎的复发，均具有预防作用，且能够改善阳性药物带来的副作用，其中裂褶菌β-葡聚糖的效果优于可溶性酵母β-葡聚糖。
实施例5、抗激素依赖性皮炎护肤品
本实施例提供了7种抗激素依赖性皮炎精华液等护肤品，所述抗激素依赖性皮炎护肤品的配方如表6所示。
表6以β-葡聚糖为主要功效成分的抗激素依赖性皮炎护肤品配方
Figure PCTCN2020091619-appb-000010
Figure PCTCN2020091619-appb-000011
将按照表6配制成的抗激素依赖性皮炎精华液等护肤品，于早晚洁面后直接涂抹于面部皮肤。平均每天使用2次，连续使用8周，并评价试用效果。
实施例6、激素依赖性皮炎患者试用β-葡聚糖效果个例分析
几例激素依赖性皮炎患者试用β-葡聚糖，也取得了意想不到的效果。
1)一例47岁女性患者A，长期使用含有激素的化妆品，造成激素依赖性皮炎，面部红肿破溃，并伴有感染。经三甲医院皮肤科治疗1年，并使用医院推荐的修复屏障的化妆品，感染状况得到控制，但面部红肿破溃未得到有效治疗。使用实施例5配方1制备的护肤精华液1个月，反馈红肿破溃得到控制，仅剩由于长期皮损造成的疤痕。
2)一例48岁女性患者B，长期使用含有激素的化妆品，造成激素依赖性皮炎，面部皮肤红肿，瘙痒，不能再使用其他任何护肤品。使用实施例1方法制备的5mg/mL裂褶菌β-葡聚糖，用于洁肤和护肤(5mg/mL裂褶菌β-葡聚糖，用水稀释20倍后用于清洁皮肤；5mg/mL裂褶菌β-葡聚糖，用水稀释5倍后用于日常护肤)。试用11天后，面部消肿，无瘙痒症状，且肤色恢复正常(图16)
3)1例10岁女孩患者C，严重依赖润唇膏，在连续每天多次(6-8次)使用润唇膏6个月后，由于家长未及时购买，自我感觉唇部灼热疼痛，再次使用唇膏后，上述症状消退。之后家长让其停用，1天后发现唇部红肿，上下唇均有丘疹样疙瘩，左下唇角有脓性丘疹(图17左)。使用按照实施例1方法制备的5mg/mL无菌裂褶菌β-葡聚糖(无防腐剂)，直接涂抹于唇部。为防止裂褶菌β-葡聚糖染菌，每天使用一支(25mL)。使用36h后，嘴唇红肿消退，同时唇上及嘴角丘疹消失(图17右)。半个月后，由于感觉唇部干燥及没有意 识到问题的严重性，再次使用润唇膏2天，在家长要求下停用后，唇部再次红肿、干裂。使用5mg/mL无菌裂褶菌β-葡聚糖和绵羊油后2日，唇部出现蜕皮现象。之后停用绵羊油，仅每日多次外涂5mg/mL无菌裂褶菌β-葡聚糖，2日后红肿消退。之后巩固使用裂褶菌β-葡聚糖1个月，未再次复发。
4)1例19岁女生D，唇炎患者，经常性(平均2-3个月)复发唇部红肿、脱皮、丘疹(图18)。经正规三甲医院皮肤科诊断后，口服醋酸尼泼松片和复方甘草酸苷片，并外用他克莫司软膏。该志愿者在使用上述药物的同时，使用按照实施例1方法制备的5mg/mL无菌裂褶菌β-葡聚糖(无防腐剂)，直接涂抹于唇部。为防止裂褶菌β-葡聚糖染菌，每天使用一支(25mL)。连续使用3天后红肿消退，连续使用1个月，嘴唇不再脱皮，连续使用两个月后停用。半年后回访，状态平稳，未再发生唇炎。
讨论
本发明首次发现，β-葡聚糖具有显著的治疗和预防激素依赖性皮炎的功效，尤其是本发明实施例1中制备的高粘度、高分子质量的裂褶菌β-葡聚糖。
本发明发现β-葡聚糖的治疗和预防激素依赖性皮炎活性与其分支度高低、侧链的葡萄糖数量、立体结构、分子量均有关系。无分支度的生物多糖没有治疗和预防激素依赖性皮炎的活性，或效果较差。
酵母葡聚糖的分支度不定，主链上随机延伸出由β-1,6-糖苷键构成的侧链，侧链的葡萄糖数量较大且不定，多的可高达上百个。颗粒性酵母葡聚糖侧链长度长，容易形成严密的网状结构，而可溶性酵母β-葡聚糖经历了结构的改性，原有活性受到了极大影响，对激素依赖性皮炎的治疗和预防效果不如裂褶菌β-葡聚糖。
裂褶菌β-葡聚糖分支度适中，侧链仅一个葡萄糖残基，同时分子质量高，具有较大较长的立体三螺旋结构，具有很好的治疗和预防激素依赖性皮炎活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (14)

  1. 一种β-葡聚糖的用途，其特征在于，用于制备一制剂或组合物，所述制剂或组合物用于预防和/或治疗激素依赖性皮炎。
  2. 如权利要求1所述的用途，其特征在于，所述β-葡聚糖为β-1,3-葡聚糖。
  3. 如权利要求1所述的用途，其特征在于，所述β-葡聚糖为具有β-1,6-分支的β-1,3-葡聚糖。
  4. 如权利要求1所述的用途，其特征在于，所述β-葡聚糖的结构如式I所示，
    Figure PCTCN2020091619-appb-100001
    其中，l为≥0的整数，较佳地0-50，较佳地0-10，更佳地0-3，更佳地1-2，更佳地1；m为≥0的整数，较佳地为0-19，较佳地为0-4，更佳地为0-1，更佳地为0；n为≥3的整数，较佳地为30-60000，更佳地100-10000。
  5. 如权利要求1所述的用途，其特征在于，所述β-葡聚糖的分支度为0.02-0.8，较佳地0.1-0.5，较佳地0.2-0.4。
  6. 如权利要求1所述的用途，其特征在于，所述β-葡聚糖的分子量≥2kD，较佳地2kD-40000kD，更佳地20kD-20000kD。
  7. 如权利要求1所述的用途，其特征在于，所述β-葡聚糖选自下组：裂褶菌β-葡聚糖、香菇β-葡聚糖、小核菌β-葡聚糖、灰树花β-葡聚糖、侧耳多糖、蘑菇β-葡聚糖、酵母β-葡聚糖、燕麦β-葡聚糖、或其组合。
  8. 如权利要求1所述的用途，其特征在于，所述预防和/或治疗激素依赖性皮炎包括：预防激素依赖性皮炎的生成、改善或缓解激素依赖性皮炎症状、或加快激素依赖性皮炎消退或愈合、或改善激素依赖性皮炎造成的疤痕、或加快激素依赖性皮炎造成疤痕的消退。
  9. 如权利要求1所述的用途，其特征在于，所述制剂或组合物还用于预防和/或治疗皮肤黏膜炎症或其他皮肤炎性疾病。
  10. 如权利要求1所述的用途，其特征在于，所述制剂或组合物含有(a)β-葡聚糖；以及任选的(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂。
  11. 一种制剂，其特征在于，所述制剂含有(a)β-葡聚糖；以及(b)药学上、化妆品学上、或器械类可接受的载体或赋形剂。
  12. 如权利要求11所述的制剂，其特征在于，所述制剂还含有(c)第二活性成分，所述第二活性成分为不同于所述β-葡聚糖的治疗激素依赖性皮炎的活性成分，或治疗皮肤黏 膜炎症或其他皮肤疾病的活性成分。
  13. 如权利要求11所述的制剂，其特征在于，所述制剂用于预防和/或治疗激素依赖性皮炎。
  14. 一种组合物产品，其特征在于，所述组合物产品包括：
    (1)第一药物组合物，所述第一药物组合物含有(a)第一活性成分，所述第一活性成分为β-葡聚糖；和(b)药学上可接受的载体；以及
    (2)第二药物组合物，所述第二药物组合物为激素依赖性皮炎治疗药物、或皮肤黏膜炎症或其他皮肤疾病的治疗药物。
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