WO2022166283A1 - 醣类组合物作为医药组成物及其用途 - Google Patents

醣类组合物作为医药组成物及其用途 Download PDF

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WO2022166283A1
WO2022166283A1 PCT/CN2021/128375 CN2021128375W WO2022166283A1 WO 2022166283 A1 WO2022166283 A1 WO 2022166283A1 CN 2021128375 W CN2021128375 W CN 2021128375W WO 2022166283 A1 WO2022166283 A1 WO 2022166283A1
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dncb
group
administered
content
oral
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French (fr)
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吴彰哲
陈伯瑞
洪志骏
黄郁婷
伊波匡彦
友利诚
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株式会社麦德凯日本
麦德凯生科股份有限公司
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    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • 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

Definitions

  • the present invention relates to a saccharide composition as a pharmaceutical composition, and particularly relates to a pharmaceutical composition of a saccharide composition capable of maintaining skin, inhibiting skin allergy, inhibiting skin inflammation or improving atopic dermatitis.
  • Atopic dermatitis also known as atopic eczema
  • AD is an allergic skin disease.
  • the typical symptoms of atopic dermatitis are dry skin accompanied by severe itching and redness and other symptoms of skin irritation or skin inflammation.
  • prolonged scratching can lead to sleep deprivation, poor mental health, inability to concentrate, affect quality of life, and even worsen symptoms and increase the risk of bacterial skin infections.
  • the current drugs for the treatment of atopic dermatitis include steroids, antihistamines, immunosuppressants, etc., and steroids are the mainstay.
  • steroids can control the condition of dermatitis, long-term use can cause side effects such as skin atrophy, vasodilation, and impact on adrenaline secretion and growth.
  • the present invention is directed to a saccharide composition and a pharmaceutical composition, which can have the effects of maintaining skin, inhibiting skin allergy, inhibiting skin inflammation or improving atopic dermatitis.
  • the carbohydrate composition includes fucose, glucuronic acid, galactose, and arabinose. Based on the total weight of the saccharide composition, the content of fucose is 45.5% to 76% by weight, the content of glucuronic acid is 11% to 19% by weight, and the content of galactose is 4.5% to 14.5% by weight , the content of arabinose is 5.5% to 18% by weight.
  • the content of fucose is 49.5 wt % to 72.5 wt %, and the content of glucuronic acid is 11 wt % to 17.5 wt % %, the content of galactose is 6% to 14% by weight, and the content of arabinose is 8.5% to 16% by weight.
  • the content of fucose is 52% to 69% by weight, and the content of glucuronic acid is 11.5% to 17% by weight, based on the total weight of the saccharide composition.
  • the content of galactose is 6.5% to 13.5% by weight, and the content of arabinose is 9% to 15.5% by weight.
  • the above-mentioned saccharide composition is an oral preparation.
  • the dosage range of the saccharide composition in the above-mentioned oral formulation is 50 mg/kg to 800 mg/kg.
  • the above-mentioned saccharide composition is an external preparation.
  • the dosage range of the saccharide composition in the above-mentioned external preparation is 35 mg/mL to 70 mg/mL.
  • the above-mentioned saccharide composition is an external preparation and an oral preparation.
  • the dosage range of the saccharide composition in the above-mentioned external preparation is 35 mg/mL to 70 mg/mL, and the dosage range of the saccharide composition in the oral preparation is 50 mg /kg to 800mg/kg.
  • the use of the carbohydrate composition can be used to prepare a medicine for inhibiting skin allergy, inhibiting skin inflammation or improving atopic dermatitis.
  • the use of the carbohydrate composition can be used to prepare a health food or a skin care product.
  • the pharmaceutical composition includes the above-mentioned carbohydrate composition and additives.
  • the saccharide composition may include 45.5% to 76% by weight of fucose, 11% to 19% by weight of glucuronic acid , 4.5% to 14.5% by weight of galactose and 5.5% to 18% by weight of arabinose, so that the saccharide composition and the pharmaceutical composition containing the saccharide composition can maintain the skin, inhibit skin allergies, and inhibit skin inflammation. Or improve the effect of atopic dermatitis, and no side effects.
  • Figures 1A to 1B affect the cytotoxicity and nitric oxide production of the saccharide composition of the present example on RAW264.7 macrophages;
  • Figures 2A to 2C affect the degranulation, interleukin-4 and histamine of the carbohydrate composition of the present embodiment on P815 mast cells;
  • Fig. 3 is the experimental procedure of using the external preparation or/and oral preparation of the carbohydrate-containing composition of the present embodiment to treat mice with atopic dermatitis;
  • Fig. 4 is the influence of using the external preparation of this embodiment on the dermatitis score of atopic dermatitis mice;
  • Fig. 5 is the influence of using the external preparation of this embodiment on the subcutaneous lymph node of atopic dermatitis mice;
  • 6A to 6C are the effects of using the external preparation of this example on the skin thickness of mice with atopic dermatitis
  • 7A to 7B are the effects of using the topical preparation of this example on skin lesions in mice with atopic dermatitis
  • Fig. 8 is the effect of using the external preparation of this embodiment on IgE in mice with atopic dermatitis
  • Fig. 9 is the effect of using the oral preparation of this embodiment on the dermatitis score of atopic dermatitis mice;
  • Figure 10 shows the effect of using the oral formulation of this example on the subcutaneous lymph nodes of mice with atopic dermatitis
  • 11A to 11B show the effect of using the oral formulation of this example on the skin thickness of mice with atopic dermatitis
  • 13A to 13B are the effects of using the oral formulation of this example on cytokines in mice with atopic dermatitis
  • Figure 14 shows the effect of using the oral formulation of this example on IgE in mice with atopic dermatitis
  • Figure 15 is the effect of using the external preparation and oral preparation of this example simultaneously on the dermatitis score of mice with atopic dermatitis;
  • Figure 16 shows the effect of using the topical preparation and oral preparation of this example simultaneously on the subcutaneous lymph nodes of mice with atopic dermatitis
  • Figures 17A to 17B show the effects of simultaneous use of the topical preparation and oral preparation of this example on cytokines in mice with atopic dermatitis;
  • Fig. 18 shows the effect of simultaneous use of the external preparation and oral preparation of this example on IgE in mice with atopic dermatitis.
  • the saccharide composition of this embodiment can be substantially composed of fucose, glucuronic acid, galactose, arabinose, and other saccharides.
  • other carbohydrates may include, for example, but not limited to, glucose.
  • the content of fucose may be, for example, 45.5% to 76% by weight
  • the content of glucuronic acid may be, for example, 11% to 19% by weight
  • the content of galactose may be, for example, 11% to 19% by weight.
  • the content of arabinose may be, for example, 4.5 to 14.5% by weight
  • the content of arabinose may be, for example, 5.5 to 18% by weight
  • the content of other sugars may be, for example, 0 to 3.5% by weight, but not limit.
  • the content of fucose may be, for example, 49.5 to 72.5% by weight based on 100% by weight of the carbohydrate composition, and the content of glucuronic acid may be, for example, 49.5% to 72.5% by weight. It may be, for example, 11 to 17.5% by weight, the content of 6 galactose may be, for example, to 14% by weight, the content of arabinose may be, for example, 8.5 to 16% by weight, and the content of other sugars may be, for example, 0 wt% to 3.5 wt%, but not limited thereto.
  • the content of fucose may be, for example, 52% to 69% by weight, and the content of glucuronic acid may be, for example, 52% to 69% by weight. It can be, for example, 11.5% to 17% by weight, the content of galactose can be, for example, 6.5% to 13.5% by weight, the content of arabinose can be, for example, 9% to 15.5% by weight, and the content of other sugars can be, for example, 0 wt% to 3.5 wt%, but not limited thereto.
  • the saccharide composition may, for example, be derived from natural algal extracts or saccharide mixtures. Wherein, based on 100% by weight of the natural algae extract, the content of the carbohydrate composition may be, for example, greater than 95% by weight, but not limited thereto.
  • the natural algae extract can be, for example, brown algae extract, for example, the natural algae extract can be, for example, water cloud (Cladosiphon okamuranus or Okinawa mozuku) extract, but not limited to this .
  • the carbohydrate composition can be used as an external preparation.
  • the external preparation can be, for example, liquid, powder, granule, spray, ointment, cream, latex, gel or patch, but not limited thereto.
  • the effective dosage range of the carbohydrate composition in the external preparation may be, for example, 35 mg/mL to 70 mg/mL, but not limited thereto.
  • the content of the carbohydrate composition may be, for example, 70% by weight, and the content of the additive may be, for example, 30% by weight, but not limited thereto.
  • the additives in the external preparation may include olive oil and emulsifier, but not limited thereto.
  • the carbohydrate composition can also be an oral preparation.
  • the oral formulation refers to administration in oral form or may be suitable for oral administration.
  • Oral preparations can be, for example, capsules, lozenges, pills, granules, powders, drops and drop pills, but not limited thereto.
  • the effective dosage range of the carbohydrate composition in the oral formulation may be, for example, 50 mg/kg to 800 mg/kg, but not limited thereto.
  • the use of the saccharide composition can be, for example, for the preparation of medicines for inhibiting skin allergy, inhibiting skin inflammation or improving atopic dermatitis without side effects, but not limited thereto.
  • the saccharide composition can be further used as edible health food, smeared skin care product or pharmaceutical composition to maintain skin, inhibit skin allergy, inhibit skin inflammation or improve atopic dermatitis.
  • the saccharide composition of this embodiment does not cause side effects to users or patients.
  • the use of the carbohydrate composition in this embodiment can be, for example, for preparing a health food or skin care product that maintains the skin and has no side effects, but is not limited thereto;
  • the use of the pharmaceutical composition in this embodiment can be, for example, It is used to prepare a medicine for inhibiting skin allergy, inhibiting skin inflammation or improving atopic dermatitis without side effects, but not limited thereto.
  • the pharmaceutical composition of this embodiment may include a saccharide composition and additives.
  • the additives may include excipients, solvents, diluents, pigments, flavoring agents and/or thickeners, etc., as inactive ingredients in the pharmaceutical composition.
  • the additives are not particularly limited, and can be adjusted according to the type or dosage form of different pharmaceutical compositions.
  • the statistical analysis results in the following examples are all represented by letters in the corresponding figures. Wherein, the letters are, for example, a, b, c, d, e, f, etc., but not limited thereto.
  • the letters are, for example, a, b, c, d, e, f, etc., but not limited thereto.
  • the two groups in the diagram are marked with the same letter, it means that there is no significant difference between the two groups; on the contrary, when the two groups in the diagram are marked with different letters , it means that there is a significant difference between the two groups, and the p value is less than 0.05.
  • the first group is marked a
  • the second group is marked b
  • the third group is marked bc
  • the fourth group is marked c
  • the first group (ie a) and the second group (ie b) can be represented.
  • the saccharide composition is, for example, water cloud extract, for example, but not limited thereto. That is, in other embodiments, the saccharide composition may also be a saccharide mixture prepared and mixed by fucose, glucuronic acid, galactose, arabinose and other saccharides.
  • the preparation method of the water cloud extract includes the following steps, but not limited thereto: extracting the water cloud with hot water and hydrochloric acid (HCl) at a specific pH value, temperature and extraction time reaction; then, after centrifugation, ultrafiltration (ultrafiltration) and concentration, neutralization reaction with sodium hydroxide (NaOH) to a specific pH value; then, sterilization (sterilization) by ultra-high temperature heating method; At a specific temperature and rotation speed, spray drying is performed by an atomizer; then, a vibration sifter and an 80-mesh screening size are used for screening to obtain a water cloud extract.
  • HCl hydrochloric acid
  • Example 1 the composition and content of the saccharide compositions of Example 1, Example 2 and Example 3 were analyzed by means of nuclear magnetic resonance (NMR), and the analysis results are shown in Table 1 below.
  • Example 1 Example 2 Example 3 Fucose (wt%) 68.9 52.3 61 Glucuronic acid (wt%) 11.8 16.2 16.6 Galactose (wt%) 6.8 13.1 8.6 Arabinose (wt%) 9.1 15.1 10.9 Other sugars (wt%) 3.4 3.3 2.9
  • Example 2 Effect of carbohydrate composition on cytotoxicity and nitric oxide production of RAW264.7 macrophages
  • the saccharide composition was formulated into different concentrations using a solvent, namely, the saccharide compositions with concentrations of 31.25 ⁇ g/mL, 62.5 ⁇ g/mL, 125 ⁇ g/mL, 250 ⁇ g/mL, 500 ⁇ g/mL, and 1000 ⁇ g/mL.
  • the solvent is, for example, phosphate buffered saline (phosphate buffered saline, PBS), but not limited thereto.
  • the method for evaluating the cytotoxicity of the carbohydrate composition on macrophages is, for example: after the drug treatment, the cells in each well are collected to count the number of cells respectively; The cell number of cells in the lipopolysaccharide group was regarded as 100% cell viability, and the cell numbers of cells in other groups were converted to the corresponding cell viability, thereby judging the effect of carbohydrate compositions on macrophages. Cytotoxicity, the results are shown in Figure 1A. As can be seen from the results in FIG. 1A , as the concentration of the added carbohydrate composition increased, there was no significant difference in the cell viability between different groups, and all were above 90%. Therefore, it can be shown that the carbohydrate composition does not cause cytotoxicity to macrophages.
  • the method for evaluating the production of nitric oxide is, for example: after drug treatment, pipette 50 ⁇ L of the supernatant to an ELISA plate, add 25 ⁇ L Griess reagent A and 25 ⁇ L Griess reagent B, and protect from light. After the reaction, the absorbance at 550 nm was tested, and the results are shown in Figure 1B.
  • the saccharide composition can suppress inflammation symptoms by inhibiting the production of nitric oxide stimulated by lipopolysaccharide.
  • Example 3 Degranulation, interleukin-4 and histamine effects of carbohydrate compositions on P815 mast cells
  • the saccharide composition was formulated into different concentrations using a solvent, ie, the saccharide compositions with concentrations of 75 ⁇ g/mL, 150 ⁇ g/mL, 300 ⁇ g/mL, and 600 ⁇ g/mL.
  • the solvent is, for example, PBS, but not limited thereto.
  • 1 ⁇ 106 P815 mast cells were cultured in each well of a 24-well plate; placed in a 37°C, 5% CO2 incubator for 1 hour to allow the cells to adhere Attached, please refer to FIG. 2A to FIG. 2C , sugar compositions of different concentrations are added according to groups, and 10 ⁇ g/mL mast cell degranulation agent (compound 48/80) is also added according to groups, wherein mast cells are degranulated.
  • the drug can induce degranulation of mast cells and release inflammatory mediators such as histamine to cause inflammatory symptoms; then, placed in an incubator and cultured for about 6 hours (ie, after drug treatment) , pipette the supernatant to the enzyme-linked immunosorbent assay plate to measure the content of interleukin-4 (IL-4) and histamine, the results are shown in Figure 2B and Figure 2C; then, using toluidine blue (toluidine blue) blue) to stain mast cells to observe the degranulation of mast cells, the results are shown in Figure 2A.
  • inflammatory mediators such as histamine to cause inflammatory symptoms
  • a drug such as Dermovate or an external preparation (eg, a cream) is applied to the affected part of the skin every day.
  • Blood collection was performed on days 0, 9, and 28 to monitor serum IgE levels.
  • the mice were sacrificed on day 28, and the blood, subcutaneous lymph nodes, skin, etc. of the mice were collected for subsequent analysis.
  • mice were divided into 5 groups, and each group had 5 mice, which were respectively the negative control group and the induction group. , positive control group, low-dose group and high-dose group.
  • the negative control group was the group that was not administered DNCB and topical preparations
  • the induction group was the group that was administered DNCB but not administered topical preparations
  • the positive control group was the group that was administered DNCB and diamolecine.
  • the group was the group administered with DNCB and the external preparation containing 35 mg/mL carbohydrate composition
  • the high-dose group was the group administered with DNCB and the external preparation containing 70 mg/mL carbohydrate composition.
  • DNCB is a commonly used composition for inducing animal models of atopic dermatitis.
  • Diamofu is a commercially available ointment or cream containing 0.05% by weight of clobetasol propionate (corticosteroid), which can be applied to the affected area and used to treat skin diseases such as atopic dermatitis.
  • Example 4 Effects of topical formulations on dermatitis scores in mice with atopic dermatitis
  • the severity of atopic dermatitis and the condition of skin recovery were judged by visual observation and dermatitis score.
  • the symptoms of skin allergy and skin inflammation caused by atopic dermatitis may include erythema/hemorrhage, scaring/dryness, edema, and excoriation/erosion (erosion).
  • the scoring scale is 0 to 3, with 0 indicating no symptoms, 1 indicating mild symptoms, 2 indicating moderate symptoms, and 3 indicating severe symptoms.
  • the mice of each group were scored by the atopic dermatitis scoring method on the 4th, 7th, 11th, 14th, 18th, 21st, 25th, and 28th day, and the results are shown in FIG. 4 .
  • the induction group administered with DNCB but not administered topical formulations had significantly higher scores and more severe skin allergies and skin inflammations. symptoms.
  • the positive control group administered with DNCB and diamorphine, the low-dose group administered with DNCB and the topical formulation containing the 35 mg/mL carbohydrate composition, and the group administered with The high-dose group administered with DNCB and a topical formulation containing a 70 mg/mL carbohydrate composition significantly reduced the scores and alleviated the symptoms of skin allergy and skin inflammation.
  • the low-dose group and high-dose group administered with DNCB and external preparations containing carbohydrate compositions had better effects to reduce the symptoms of skin allergy and skin inflammation . Therefore, it can be indicated that the external preparation of the carbohydrate-containing composition can be used to treat the lesions to suppress the symptoms of skin allergy and skin inflammation, thereby repairing the skin and improving or treating atopic dermatitis.
  • Example 5 Effects of topical preparations on subcutaneous lymph nodes in mice with atopic dermatitis
  • the induction group to which DNCB was administered but not the external preparation had significantly heavier subcutaneous lymph nodes compared to the negative control group to which neither DNCB nor the external preparation was administered.
  • the positive control group administered with DNCB and diamolox the low-dose group administered with DNCB and the topical formulation containing the 35 mg/mL carbohydrate composition
  • the The high-dose group administered with DNCB and the external preparation containing 70 mg/mL carbohydrate composition can significantly reduce the weight of subcutaneous lymph nodes. Therefore, it can be indicated that the external preparation containing the carbohydrate composition can be used to treat the lesions, so as to slow down the inflammation and enlargement of the subcutaneous lymph nodes, thereby improving or treating atopic dermatitis.
  • Example 6 Effects of topical formulations on skin thickness in mice with atopic dermatitis
  • Hematoxylin-eosin staining was performed on the skin tissue of each group of mice to observe and measure the thickness changes of the epidermis and dermis of the skin. Dewaxed with xylene and covered with water; then soaked the slides in blue Hematoxylin and stained for a few seconds; then rinsed with running water until the water flow was colorless, and then stained with red eosin (Eosin) for a few seconds; then with running water Rinse and let the slides dry, soak them in 70%, 90%, 100% ethanol and xylene respectively for dehydration; then after the slides are dry, they can be mounted and stored, and the staining results are shown in Figure 6A to Figure 6C .
  • 6B is the quantification result of the thickness of the epidermis layer in FIG. 6A
  • FIG. 6C is the quantification result of the thickness of the dermis layer in FIG. 6A .
  • the induction group administered with DNCB but not administered with the topical preparation can significantly increase the thickness of the epidermis and dermis layer. .
  • the positive control group administered with DNCB and diamolox, the low-dose group administered with DNCB and the topical formulation containing the 35 mg/mL carbohydrate composition, and the The high-dose group given DNCB and the external preparation containing 70 mg/mL carbohydrate composition can significantly reduce the thickness of the epidermal layer. Therefore, it can be indicated that the external preparation of the carbohydrate-containing composition can be targeted at the lesion to slow down the thickening of the epidermis.
  • Example 7 Effects of topical formulations on skin lesions in mice with atopic dermatitis
  • Giemsa staining was performed on the skin tissue of each group of mice to observe and measure the skin lesions. The steps were roughly as follows: before staining, the paraffin covering the tissue was removed; then, after the glass slide was covered with water , soak the glass slides in methanol for 5 minutes; after the glass slides are air-dried, put the glass slides in 20-fold diluted Giemsa stain; rinse with running water after 40 minutes until the water flow becomes colorless; after the glass slides are air-dried , soaked in 70%, 90%, 100% ethanol and xylene respectively for dehydration; then the slides can be mounted after drying, and the staining results are shown in Figures 7A to 7B. Among them, Fig. 7B is the quantification result of the eosinophilic granulocyte in Fig. 7A (as shown by the tip of the triangle in Fig. 7A).
  • the induction group administered with DNCB but not administered with the topical formulation can significantly increase the infiltration of eosinophilic granules in the dermis layer.
  • the positive control group administered with DNCB and diamolox, and the high-dose group administered with DNCB and the topical formulation containing 70 mg/mL carbohydrate composition can significantly significantly reduce the infiltration of eosinophilic granule globules into the dermis. Therefore, it can be indicated that the external preparation containing the carbohydrate composition can be treated for the lesion to reduce the infiltration of eosinophilic granular spheres into the dermis, thereby slowing down the situation of skin lesions.
  • Example 8 Effects of topical preparations on IgE in mice with atopic dermatitis
  • IgE immunoglobulin E
  • the following uses enzyme-linked immunosorbent assay (Enzyme-linked immunosorbent assay, ELISA assay) to analyze the blood collected from mice in each group on days 0, 9, and 28 to measure the IgE content in the blood.
  • the steps are roughly as follows: use the commercially available Mouse ELISA ready-set-go kit for analysis; first, immobilize 100 ⁇ L of capture antibody in the hole of the enzyme-linked immunosorbent assay plate (ELISA plate), seal it Place at 4°C to overnight; then, wash each well 3 times with more than 250 ⁇ L of Wash Buffer, add 200 ⁇ L of Blocking Buffer, and let it act for 1 hour at room temperature; then, according to the instructions, use 1X ELISA/ELISPOT to standardize The samples were serially diluted, and then 100 ⁇ L of different concentrations of the standard and 100 ⁇ L of the serum to be tested were added to different wells respectively; after 2 hours of reaction at room temperature, wash each well with more than 250 ⁇ L of Wash Buffer for 3-5 times; then
  • the induction group administered with DNCB, the positive control group administered with DNCB, the low dose group administered with DNCB, And the high-dose group administered with DNCB can significantly increase the content of IgE due to the induction of DNCB.
  • the induction group administered with DNCB but not the external preparation had significantly more IgE content than the negative control group not administered with DNCB.
  • the positive control group administered with DNCB and diamolox the low-dose group administered with DNCB and the topical formulation containing the 35 mg/mL carbohydrate composition
  • the The high-dose group of DNCB and external preparation containing 70 mg/mL carbohydrate composition can significantly reduce the IgE content.
  • the low-dose group administered with DNCB and the external preparation containing 35 mg/mL carbohydrate composition Compared with the positive control group administered with DNCB and diamolactine, the low-dose group administered with DNCB and the external preparation containing 35 mg/mL carbohydrate composition, and the low dose group administered with DNCB and the topical preparation containing 70 mg/mL carbohydrate composition
  • the high-dose group of the formulation could reduce the IgE content more significantly. Therefore, it can be indicated that the external preparation of the carbohydrate-containing composition can be treated at the lesion to reduce the IgE content, thereby improving or treating atopic dermatitis.
  • mice with atopic dermatitis were prepared in the same or similar manner as in Examples 4 to 8, and blood was collected and sacrificed at the same time point.
  • the difference between Examples 9 to 14 and Examples 4 to 8 is that on days 14 to 28, the oral formulations were tube-fed every day.
  • the mice were divided into 6 groups, namely the negative control group, the induction group, and the positive control group. , low-dose group, middle-dose group and high-dose group.
  • the negative control group was the group not administered DNCB and oral preparations
  • the induction group was the group administered DNCB but not oral preparations
  • the positive control group was the group administered DNCB and dexamethasone
  • the low dose group is the group administered with DNCB and the oral preparation containing 200mg/kg carbohydrate composition
  • the middle dose group is the group administered with DNCB and the oral preparation containing 400mg/kg carbohydrate composition
  • the high dose group was administered DNCB with an oral formulation containing 800 mg/kg of the saccharide composition.
  • dexamethasone is a commercially available synthetic corticosteroid, which can be used to treat skin diseases such as atopic dermatitis.
  • the induction group administered with DNCB but not administered the oral formulation had significantly higher scores and more severe skin irritation and skin inflammation. symptoms.
  • the positive control group administered with DNCB and dexamethasone the low-dose group administered with DNCB and the oral formulation containing 200 mg/kg carbohydrate composition, administered with The mid-dose group of DNCB and oral formulation containing 400 mg/kg carbohydrate composition and the high dose group administered DNCB and oral formulation containing 800 mg/kg carbohydrate composition significantly reduced scores and slowed skin irritation and skin inflammation symptoms. Therefore, it can be indicated that the oral preparation of the sugar-containing composition can suppress the symptoms of skin irritation and skin inflammation, thereby repairing the skin and improving or treating atopic dermatitis.
  • Example 10 Effects of oral formulations on subcutaneous lymph nodes in mice with atopic dermatitis
  • the weights of the subcutaneous lymph nodes of the mice in each group were measured in the same or similar manner as in Example 5, and the results are shown in FIG. 10 .
  • the induction group administered with DNCB but not the oral formulation had significantly heavier subcutaneous lymph nodes compared to the negative control group not administered DNCB and the oral formulation.
  • the positive control group administered DNCB and dexamethasone, and the high-dose group administered DNCB and the oral formulation containing 800 mg/kg carbohydrate composition had significantly higher doses than the induction group administered DNCB but not the oral formulation. Decreases the weight of subcutaneous lymph nodes. Therefore, it can be indicated that the oral preparation of the carbohydrate-containing composition can slow down the inflammation and enlargement of subcutaneous lymph nodes, thereby improving or treating atopic dermatitis.
  • Example 11 Effect of oral formulation on skin thickness in mice with atopic dermatitis
  • FIG. 11B is the quantification result of the thickness of the epidermis in FIG. 11A .
  • the induction group administered with DNCB but not administered with the oral formulation can significantly increase the thickness of the epidermis.
  • the positive control group administered with DNCB and dexamethasone the low-dose group administered with DNCB and the oral formulation containing 200 mg/kg carbohydrate composition, administered with The middle dose group of DNCB and the oral formulation containing 400 mg/kg carbohydrate composition, and the high dose group administered with DNCB and oral formulation containing 800 mg/kg carbohydrate composition significantly reduced the thickness of the epidermal layer. Therefore, it can be said that the oral formulation of the sugar-containing composition can slow down the thickening of the epidermis.
  • Example 12 Effects of oral formulations on skin lesions in mice with atopic dermatitis
  • FIG. 12B is the quantification result of the eosinophilic granule sphere in FIG. 12A (as shown by the tip of the triangle in FIG. 12A ).
  • the induction group administered with DNCB but not administered with the oral formulation can significantly increase the infiltration of eosinophilic granules in the dermis. .
  • the positive control group administered with DNCB and dexamethasone Compared with the induction group administered with DNCB but not administered the oral formulation, the positive control group administered with DNCB and dexamethasone, the low-dose group administered with DNCB and the oral formulation containing the 200 mg/kg carbohydrate composition, administered with The middle-dose group of DNCB and oral formulation containing 400 mg/kg carbohydrate composition, and the high-dose group administered DNCB and oral formulation containing 800 mg/kg carbohydrate composition can significantly reduce the infiltration of eosinophilic granular globules in the dermis middle. Therefore, it can be indicated that the oral formulation of the sugar-containing composition can reduce the infiltration of eosinophilic granular globules into the dermis, thereby slowing down the situation of skin lesions.
  • Example 13 Effects of oral formulations on cytokines in mice with atopic dermatitis
  • Example 8 With the same or similar method as Example 8, the commercially available ProcartaPlex Mouse Simplex kit and enzyme-linked immunosorbent assay were used to measure the interleukin-1 ⁇ (IL-1 ⁇ ), interleukin-1 ⁇ (IL-1 ⁇ ), interleukin- 4 (IL-4), Interleukin-5 (IL-5), Interleukin-6 (IL-6), Interleukin-13 (IL-13), Interleukin-22 (IL-22) , thymic stromal lymphopoietin (TSLP), interferon- ⁇ (INF- ⁇ ) and tumor necrosis factor- ⁇ (tumor necrosis factor- ⁇ , TNF- ⁇ ) content, the results are shown in Figure 13A and shown in Figure 13B.
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-4 interleukin- 4
  • IL-5 Interleukin-5
  • IL-6 Interleukin-6
  • IL-13 Interleukin-13
  • IL-22 Interleuk
  • IL-4, IL-5, IL-6, IL-13, IL-22 and TSLP in Figure 13A are cytokines (cytokine) related to helper T cells (T helper 2 cells, Th2), and Figure 13A The N.D. in it means NOT DETECTED.
  • INF- ⁇ , TNF- ⁇ and IL-1 ⁇ in FIG. 13B are cytokines associated with inflammation.
  • the induction group administered with DNCB but not administered with the oral formulation had significantly more IL-4, IL-5, IL- 6.
  • the content of IL-13, IL-22 and TSLP Compared with the induction group administered with DNCB but not the oral formulation, the low-dose group administered with DNCB and the oral formulation containing 200 mg/kg carbohydrate composition, administered DNCB and the oral formulation containing 400 mg/kg carbohydrate composition.
  • the middle-dose group of the formulation, and the high-dose group administered with DNCB and an oral formulation containing 800 mg/kg carbohydrate composition significantly reduced IL-4, IL-5, IL-6, IL-13, IL-22 and TSLP content.
  • the positive control group administered with DNCB and dexamethasone also significantly decreased the levels of IL-4, IL-5, IL-6, IL-13 and TSLP compared to the induction group administered with DNCB but not the oral formulation. content, but could not significantly reduce the content of IL-22.
  • the low-dose group administered with DNCB and the oral formulation containing 200 mg/kg carbohydrate composition compared with the positive control group administered with DNCB and dexamethasone, the low-dose group administered with DNCB and the oral formulation containing 200 mg/kg carbohydrate composition, the low-dose group administered with DNCB and the oral formulation containing 400 mg/kg carbohydrate composition, The middle-dose group of the oral formulation, and the high-dose group administered with DNCB and the oral formulation containing 800 mg/kg of the saccharide composition could more significantly reduce the content of IL-13. Compared with the positive control group administered with DNCB and dexamethasone, the high-dose group administered with DNCB and the oral formulation containing 800 mg/kg of the carbohydrate composition could more significantly reduce the content of IL-22.
  • the oral preparation of sugar-containing composition can reduce the content of cytokines IL-4, IL-5, IL-6, IL-13, IL-22 and TSLP related to helper T cells, thereby improving or treating Atopic dermatitis.
  • the positive control group administered with DNCB and dexamethasone Compared with the induction group administered with DNCB but not administered the oral formulation, the positive control group administered with DNCB and dexamethasone, the low-dose group administered with DNCB and the oral formulation containing 200 mg/kg carbohydrate composition, administered with The middle-dose group of DNCB and oral formulation containing 400 mg/kg carbohydrate composition, and the high-dose group administered with DNCB and oral formulation containing 800 mg/kg carbohydrate composition significantly reduced INF- ⁇ , TNF- ⁇ and IL-1 ⁇ content. Therefore, it can be indicated that the oral preparation of the carbohydrate-containing composition can reduce the content of the cytokines INF- ⁇ , TNF- ⁇ and IL-1 ⁇ associated with inflammation, thereby improving or treating atopic dermatitis. In addition, it can also be shown that the oral preparation of the saccharide-containing composition has the effect of regulating the allergic reaction of the systemic circulation.
  • Example 14 Effects of oral formulations on IgE in mice with atopic dermatitis
  • mice in each group was measured in the same or similar method as in Example 8, and the results are shown in FIG. 14 .
  • the induction group administered with DNCB but not the oral formulation had significantly more IgE content than the negative control group not administered DNCB and the oral formulation.
  • the positive control group administered DNCB and dexamethasone Compared to the induction group administered DNCB but not the oral formulation, the positive control group administered DNCB and dexamethasone, the middle dose group administered DNCB and the oral formulation containing 400 mg/kg carbohydrate composition, and the The high-dose group administered with DNCB and an oral formulation containing 800 mg/kg of the saccharide composition significantly reduced IgE content.
  • the middle-dose group administered with DNCB and the oral formulation containing 400 mg/kg carbohydrate composition Compared with the positive control group administered with DNCB and dexamethasone, the middle-dose group administered with DNCB and the oral formulation containing 400 mg/kg carbohydrate composition, and the oral formulation administered with DNCB and 800 mg/kg carbohydrate composition
  • the high-dose group of the formulation could reduce the IgE content more significantly. Therefore, it can be indicated that the oral preparation of the carbohydrate-containing composition can reduce the IgE content, thereby improving or treating atopic dermatitis.
  • the oral preparation of the saccharide-containing composition has the effect of regulating the allergic reaction of the systemic circulation.
  • mice with atopic dermatitis were prepared in the same or similar manner as in Examples 4 to 8, and blood was collected and sacrificed at the same time point.
  • the difference between Examples 15 to 18 and Examples 4 to 8 is that on days 14 to 28, the external preparations were smeared, the oral preparations were fed by tube, or the external preparations were applied and the oral preparation tubes were applied at the same time. Hello; blood was collected on days 9 and 28 to monitor serum IgE levels.
  • the negative control group was the group that was not administered DNCB and external preparations or oral preparations
  • the induction group was the group that was administered DNCB but not administered external preparations or oral preparations
  • the external use group was administered DNCB and containing 70 mg/mL.
  • the group of external preparations of carbohydrate compositions the oral group is the group administered with DNCB and the oral preparation containing 800mg/kg carbohydrate composition
  • the external oral group is administered with DNCB, containing 35mg/mL carbohydrate composition.
  • the topical oral group is the topical formulation with half the dose in the topical group (that is, the topical formulation containing 35 mg/mL carbohydrate composition) and the oral formulation in the oral group with half the dose (that is, containing 400 mg/kg) Oral preparation of carbohydrate composition) to treat mice with atopic dermatitis, in order to reduce drug abuse and achieve effective resource allocation in clinical application.
  • the topical oral group can also provide two methods of treatment at the same time: to adjust the allergic reaction of the systemic circulation, and to treat the lesions.
  • Example 15 Effects of simultaneous use of topical and oral formulations on dermatitis scores in mice with atopic dermatitis
  • the induction group administered with DNCB but not administered with topical or oral formulations had significantly higher scores and more severe Symptoms of skin allergies and skin inflammation.
  • the topical group administered with DNCB and the topical preparation containing 70 mg/mL carbohydrate composition, administered with DNCB and the topical preparation containing 800 mg/kg carbohydrate composition Compared with the induction group administered with DNCB but not administered with the topical preparation or oral preparation, the topical group administered with DNCB and the topical preparation containing 70 mg/mL carbohydrate composition, administered with DNCB and the topical preparation containing 800 mg/kg carbohydrate composition.
  • the oral group of oral preparations of 100 mg/kg, and the group administered with external oral administration could significantly reduce Score and reduce the symptoms of skin irritation and skin inflammation. Therefore, it can be said that the simultaneous use of the external preparation with half the dose and the oral preparation with half the dose can also suppress the symptoms of skin allergy and skin inflammation, thereby repairing the skin and improving or treating atopic dermatitis.
  • the effect of the topical oral administration group in suppressing the symptoms of skin allergy and skin inflammation is similar to the effect of the topical administration group or the oral administration group in suppressing the symptoms of skin allergy and skin inflammation, it can be expressed that the external preparation and the dosage of halved doses are used at the same time.
  • the halved oral formulation may have additive effects in suppressing the symptoms of skin irritation and skin inflammation.
  • Example 16 Effects of simultaneous use of topical and oral formulations on subcutaneous lymph nodes in mice with atopic dermatitis
  • the weights of the subcutaneous lymph nodes of the mice in each group were measured in the same or similar manner as in Example 5, and the results are shown in FIG. 16 .
  • the induction group to which DNCB was administered but not the external or oral formulation had heavier subcutaneous lymph nodes than the negative control group that was not administered DNCB and the external or oral formulation.
  • the oral group administered with DNCB and the oral formulation containing 800 mg/kg carbohydrate composition, and the topical oral group were administered.
  • the external preparation containing 35 mg/mL carbohydrate composition and the group of oral preparation containing 400 mg/kg carbohydrate composition significantly reduced the weight of subcutaneous lymph nodes.
  • the simultaneous use of the topical preparation with half the dose and the oral preparation with half the dose can also slow down the inflammation and enlargement of subcutaneous lymph nodes, thereby improving or treating atopic dermatitis.
  • the effect of the topical oral group in reducing inflammation and enlargement of subcutaneous lymph nodes is similar to that of the topical group or oral group in reducing inflammation and enlargement of subcutaneous lymph nodes, it can be expressed that the topical preparation with half the dose and the half dosage are used at the same time.
  • the oral formulations of the drug may have an additive effect in reducing inflammation and swelling of subcutaneous lymph nodes.
  • Example 17 Effects of simultaneous use of topical and oral formulations on cytokines in mice with atopic dermatitis
  • IL-4 interleukin-4
  • IL-5 interleukin- 5
  • IL-13 interleukin-13
  • IL-22 interleukin-22
  • IL-33 interleukin-33
  • TSLP thymic stromal lymphopoietin
  • IL-4, IL-5, IL-13, IL-22, IL-33 and TSLP in Figure 17A are cytokines related to helper T cells (Th2).
  • the induction group administered with DNCB but not administered with topical or oral formulation had significantly more IL-4, Contents of IL-5, IL-13, IL-22, IL-33 and TSLP.
  • the topical group administered with DNCB and the topical preparation containing 70 mg/mL carbohydrate composition, administered with DNCB and the topical preparation containing 800 mg/kg carbohydrate composition Compared with the induction group administered with DNCB but not administered with the topical preparation or oral preparation, the topical group administered with DNCB and the topical preparation containing 70 mg/mL carbohydrate composition, administered with DNCB and the topical preparation containing 800 mg/kg carbohydrate composition.
  • the oral group of oral preparations of 100 mg/kg, and the group administered with external oral administration could significantly reduce Contents of IL-4, IL-5, IL-22, IL-33 and TSLP.
  • the oral group administered with DNCB and the oral formulation containing 800 mg/kg carbohydrate composition, and the topical oral group were administered.
  • the external preparation containing 35 mg/mL carbohydrate composition and the oral preparation group containing 400 mg/kg carbohydrate composition also significantly reduced the content of IL-13. Therefore, it can be shown that the simultaneous use of a topical formulation with a half-dose dose and an oral formulation with a half-dose dose also reduces the cytokines IL-4, IL-5, IL-13, IL-22, IL-33, and T helper cells associated with The content of TSLP, and then improve or treat atopic dermatitis.
  • the effect of the topical oral group on reducing the content of cytokines related to helper T cells is similar to the effect of the topical group or the oral group on reducing the contents of cytokines related to helper T cells, it can be expressed that the simultaneous use of dose reduction Half the topical formulation and half the dose of the oral formulation may have an additive effect in reducing levels of helper T cell-related cytokines.
  • the oral group administered with DNCB and the oral preparation containing 800 mg/kg carbohydrate composition and the oral administration for external use were administered.
  • the group ie, the group including DNCB, the external preparation containing 35 mg/mL carbohydrate composition, and the oral preparation containing 400 mg/kg carbohydrate composition
  • the group could significantly increase the content of TGF- ⁇ 1. Therefore, it can be indicated that the use of the oral preparation alone, or the simultaneous use of the external preparation with half the dose and the oral preparation with half the dose can increase the content of TGF- ⁇ 1, thereby improving or treating atopic dermatitis.
  • TGF- ⁇ 1 since the effect of increasing the content of TGF- ⁇ 1 in the topical oral group is similar to that in the oral group, it can be expressed that the simultaneous use of the external preparation with a half-dose and the oral preparation with a half-dose increases the The content of TGF- ⁇ 1 may have an additive effect.
  • Example 18 Effects of simultaneous use of topical and oral formulations on IgE in mice with atopic dermatitis
  • mice in each group was measured in the same or similar method as in Example 8, and the results are shown in FIG. 18 .
  • the induction group administered with DNCB but not administered with the topical or oral formulation significantly had more of IgE content.
  • the topical group administered with DNCB and the topical preparation containing 70 mg/mL carbohydrate composition, administered with DNCB and the topical preparation containing 800 mg/kg carbohydrate composition Compared with the induction group administered with DNCB but not administered with the topical preparation or oral preparation, the topical group administered with DNCB and the topical preparation containing 70 mg/mL carbohydrate composition, administered with DNCB and the topical preparation containing 800 mg/kg carbohydrate composition.
  • the oral group of oral preparations of 100 mg/kg, and the group administered with external oral administration ie, the group including DNCB, the external preparation containing 35 mg/mL carbohydrate composition, and the oral preparation containing 400 mg/kg carbohydrate composition
  • the simultaneous use of a topical preparation with a half-dose and an oral preparation with a half-dose can also reduce the IgE content, thereby improving or treating atopic dermatitis.
  • the effect of the topical oral group on reducing IgE content is similar to the effect of the topical group or the oral group on reducing IgE content, it can be expressed that the simultaneous use of the topical preparation with half the dose and the oral preparation with half the dose can reduce the IgE content. Can have an additive effect.
  • the saccharide composition may include 45.5% to 76% by weight of fucose and 11% to 19% by weight of glucose uronic acid, 4.5% to 14.5% by weight of galactose, and 5.5% to 18% by weight of arabinose, so that the saccharide composition and the pharmaceutical composition containing the saccharide composition can inhibit the stimulation of lipopolysaccharide.
  • Nitric oxide inhibit the degranulation of mast cells, inhibit the production of IL-4 and histamine by mast cells due to degranulation, inhibit the symptoms of skin allergies and skin inflammation, reduce inflammation and swelling of subcutaneous lymph nodes, reduce epidermal thickening , Reduce the infiltration of eosinophilic granules in the dermis, reduce the content of IL-4, IL-5, IL-6, IL-13, IL-22, IL-33 and TSLP, reduce INF- ⁇ , TNF- ⁇ and IL -1 ⁇ content, increase TGF- ⁇ 1 content, reduce IgE content, and then have the effect of maintaining skin, inhibiting skin allergies, inhibiting skin inflammation or improving atopic dermatitis without side effects.

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Abstract

本发明提供一种醣类组合物作为医药组成物及其用途。醣类组合物，包括岩藻糖、葡萄糖醛酸、半乳糖以及阿拉伯糖。以醣类组合物的总重量计，岩藻糖的含量为45.5重量％至76重量％，葡萄糖醛酸的含量为11重量％至19重量％，半乳糖的含量为4.5重量％至14.5重量％，阿拉伯糖的含量为5.5重量％至18重量％。提供一种包括上述醣类组合物的医药组成物。本发明提供一种醣类组合物与医药组成物，可具有保养皮肤、抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎的效果。

Description

醣类组合物作为医药组成物及其用途 技术领域
本发明涉及一种醣类组合物作为医药组成物，且特别是涉及一种可保养皮肤、抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎的醣类组合物的医药组成物。
背景技术
异位性皮肤炎(atopic dermatitis，AD)，又称为异位性湿疹，是一种皮肤过敏性疾病。异位性皮肤炎的典型症状为皮肤干燥并伴随着严重的搔痒及红肿等皮肤过敏或皮肤发炎的症状。然而，长期抓痒会造成患者睡眠不足、精神不佳，进而导致注意力无法集中而影响生活品质，甚至会造成症状恶化并提高皮肤细菌感染的风险。
目前治疗异位性皮肤炎的药物包括类固醇、抗组织胺、免疫抑制剂等，且主要是以类固醇为主。然而，虽然类固醇可以控制皮肤炎的病情，但长期使用却会造成皮肤萎缩、血管扩张、影响肾上腺素分泌而影响生长等副作用。
发明内容
本发明是针对一种醣类组合物与医药组成物，其可具有保养皮肤、抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎的效果。
根据本发明的实施例，醣类组合物包括岩藻糖(fucose)、葡萄糖醛酸(glucuronic acid)、半乳糖(galactose)以及阿拉伯糖(arabinose)。以醣类组合物的总重量计，岩藻糖的含量为45.5重量％至76重量％，葡萄糖醛酸的含量为11重量％至19重量％，半乳糖的含量为4.5重量％至14.5重量％，阿拉伯糖的含量为5.5重量％至18重量％。
在根据本发明的实施例的醣类组合物中，以醣类组合物的总重量计，岩藻糖的含量为49.5重量％至72.5重量％，葡萄糖醛酸的含量为11重量％至17.5重量％，半乳糖的6含量为重量％至14重量％，阿拉伯糖的含量为8.5重量％至16重量％。
在根据本发明的实施例的醣类组合物中，以醣类组合物的总重量计，岩藻糖的含量为52重量％至69重量％，葡萄糖醛酸的含量为11.5重量％至17重量％，半乳糖的含量为6.5重量％至13.5重量％，阿拉伯糖的含量为9重量％至15.5重量％。
在根据本发明的实施例的醣类组合物中，上述的醣类组合物为口服制剂。
在根据本发明的实施例的醣类组合物中，上述的口服制剂中的醣类组合物的剂量范围为50mg/kg至800mg/kg。
在根据本发明的实施例的醣类组合物中，上述的醣类组合物为外用制剂。
在根据本发明的实施例的醣类组合物中，上述的外用制剂中的醣类组合物的剂量范围为35mg/mL至70mg/mL。
在根据本发明的实施例的醣类组合物中，上述的醣类组合物为外用制剂与口服制剂。
在根据本发明的实施例的醣类组合物中，上述的外用制剂中的醣类组合物的剂量范围为35mg/mL至70mg/mL，且口服制剂中的醣类组合物的剂量范围为50mg/kg至800mg/kg。
根据本发明的实施例，醣类组合物的用途可用于制备抑制皮肤过敏、抑制皮肤发炎或改 善异位性皮肤炎的药物。
根据本发明的实施例，醣类组合物的用途可用于制备保养皮肤的保健食品或保养品。
根据本发明的实施例，医药组成物包括上述的醣类组合物以及添加剂。
基于上述，在本发明的实施例的醣类组合物与医药组成物中，由于醣类组合物可包括45.5重量％至76重量％的岩藻糖、11重量％至19重量％的葡萄糖醛酸、4.5重量％至14.5重量％的半乳糖以及5.5重量％至18重量％阿拉伯糖，因而使得醣类组合物与含有醣类组合物的医药组成物具有可保养皮肤、抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎的效果，且无副作用。
为让本发明的上述特征和优点能更明显易懂，下文特举实施例，并配合所附附图作详细说明如下。
附图说明
包含附图以便进一步理解本发明，且附图并入本说明书中并构成本说明书的一部分。附图说明本发明的实施例，并与描述一起用于解释本发明的原理。
图1A至1B为本实施例的醣类组合物对RAW264.7巨噬细胞的细胞毒性以及一氧化氮产量的影响；
图2A至2C为本实施例的醣类组合物对P815肥大细胞的脱颗粒作用、介白素-4以及组织胺的影响；
图3为使用本实施例含醣类组合物的外用制剂或/和口服制剂来治疗异位性皮肤炎小鼠的实验流程；
图4为使用本实施例的外用制剂对异位性皮肤炎小鼠的皮肤炎评分的影响；
图5为使用本实施例的外用制剂对异位性皮肤炎小鼠的皮下淋巴结的影响；
图6A至6C为使用本实施例的外用制剂对异位性皮肤炎小鼠的皮肤厚度的影响；
图7A至7B为使用本实施例的外用制剂对异位性皮肤炎小鼠的皮肤病变的影响；
图8为使用本实施例的外用制剂对异位性皮肤炎小鼠的IgE的影响；
图9为使用本实施例的口服制剂对异位性皮肤炎小鼠的皮肤炎评分的影响；
图10为使用本实施例的口服制剂对异位性皮肤炎小鼠的皮下淋巴结的影响；
图11A至11B为使用本实施例的口服制剂对异位性皮肤炎小鼠的皮肤厚度的影响；
图12A至12B为使用本实施例的口服制剂对异位性皮肤炎小鼠的皮肤病变的影响；
图13A至13B为使用本实施例的口服制剂对异位性皮肤炎小鼠的细胞因子的影响；
图14为使用本实施例的口服制剂对异位性皮肤炎小鼠的IgE的影响；
图15为同时使用本实施例的外用制剂和口服制剂对异位性皮肤炎小鼠的皮肤炎评分的影响；
图16为同时使用本实施例的外用制剂和口服制剂对异位性皮肤炎小鼠的皮下淋巴结的影响；
图17A至17B为同时使用本实施例的外用制剂和口服制剂对异位性皮肤炎小鼠的细胞因子的影响；
图18为同时使用本实施例的外用制剂和口服制剂对异位性皮肤炎小鼠的IgE的影响。
附图标号说明
无。
具体实施方式
现将详细地参考本发明的示范性实施例，示范性实施例的实例说明于附图中。只要有可能，相同元件符号在附图和描述中用来表示相同或相似部分。
本实施例的醣类组合物实质上可由岩藻糖(fucose)、葡萄糖醛酸(glucuronic acid)、半乳糖(galactose)、阿拉伯糖(arabinose)以及其他醣类组成。其中，其他醣类可例如是包括葡萄糖(glucose)，但不以此为限。
在本实施例中，基于醣类组合物为100重量％，岩藻糖的含量可例如是45.5重量％至76重量％，葡萄糖醛酸的含量可例如是11重量％至19重量％，半乳糖的含量可例如是4.5重量％至14.5重量％，阿拉伯糖的含量可例如是5.5重量％至18重量％，且其他醣类的含量可例如是0重量％至3.5重量％，但不以此为限。
在一些实施例中，若是为了能较佳地改善异位性皮肤炎，基于醣类组合物为100重量％，岩藻糖的含量可例如是49.5重量％至72.5重量％，葡萄糖醛酸的含量可例如是11重量％至17.5重量％，半乳糖的6含量可例如是重量％至14重量％，阿拉伯糖的含量可例如是8.5重量％至16重量％，且其他醣类的含量可例如是0重量％至3.5重量％，但不以此为限。
在一些实施例中，若是为了能更佳地改善异位性皮肤炎，基于醣类组合物为100重量％，岩藻糖的含量可例如是52重量％至69重量％，葡萄糖醛酸的含量可例如是11.5重量％至17重量％，半乳糖的含量可例如是6.5重量％至13.5重量％，阿拉伯糖的含量可例如是9重量％至15.5重量％，且其他醣类的含量可例如是0重量％至3.5重量％，但不以此为限。
在本实施例中，醣类组合物可例如是来自天然藻类萃取物或醣类混合物。其中，基于天然藻类萃取物为100重量％，醣类组合物的含量可例如是大于95重量％，但不以此为限。在本实施例中，所述天然藻类萃取物可例如是褐藻萃取物，举例来说，所述天然藻类萃取物可例如是水云(Cladosiphon okamuranus或Okinawa mozuku)萃取物，但不以此为限。
在本实施例中，醣类组合物可以作为外用制剂。其中，外用制剂可例如是液剂、粉剂、颗粒剂、喷剂、软膏、乳膏、乳胶、凝胶或贴片，但不以此为限。在本实施例中，外用制剂中的醣类组合物的有效剂量范围可例如是35mg/mL至70mg/mL，但不以此为限。在本实施例中，基于外用制剂为100重量％，醣类组合物的含量可例如是70重量％，且添加剂的含量可例如是30重量％，但不以此为限。在本实施例中，外用制剂中的添加剂可包括橄榄油、乳化剂，但不以此为限。
在本实施例中，醣类组合物也可以为口服制剂。其中，口服制剂是指以口服形式施用或可适合于经口投予。口服制剂可例如是胶囊、锭剂、丸剂、颗粒剂、散剂、滴剂及滴丸剂，但不以此为限。在本实施例中，口服制剂中的醣类组合物的有效剂量范围可例如是50mg/kg至800mg/kg，但不以此为限。
在本实施例中，醣类组合物的用途可例如是用于制备抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎且无副作用的药物，但不以此为限。
在本实施例中，醣类组合物可进一步地作为食用的保健食品、涂抹的保养品或医药组成物，以用来保养皮肤、抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎。此外，本实施例的醣类组合物也不会对使用者或患者产生副作用。举例来说，本实施例的醣类组合物的用途 可例如是用于制备保养皮肤且无副作用的保健食品或保养品，但不以此为限；本实施例的医药组成物的用途可例如是用于制备抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎且无副作用的药物，但不以此为限。
本实施例的医药组成物可包括醣类组合物以及添加剂。其中，所述添加剂可包括赋型剂、溶剂、稀释剂、色素、矫味剂和/或增稠剂等，以作为所述医药组成物中的非活性成分。在本实施例中，所述添加剂并没有特别限制，且可以配合不同的医药组成物的型态或剂型来进行调整。
针对本发明实施例中的醣类组合物与医药组成物的应用与功效，将以下列实施例及配合的附图来作为举例说明。然而，下列的实施例及配合的附图仅是辅助说明，而并非用以限定本发明。
[实施例]
以下实施例中的统计分析结果皆以字母表示于对应的图示中。其中，字母例如是a、b、c、d、e、f等，但不以此为限。当图示中的两个组别之间标示有相同的字母时，则表示这两个组别之间没有显著性差异；反之，当图示中的两个组别之间标示有不同的字母时，则表示这两个组别之间有显著性差异，且p值小于0.05。举例来说，当第一组标示为a、第二组标示为b、第三组标示为bc且第四组标示为c时，可表示第一组(即a)与第二组(即b)之间有显著性差异、第二组(即b)与第三组(即bc)之间没有显著性差异、且第三组(即bc)与第四组(即c)之间没有显著性差异。
实施例1：醣类组合物的成份分析
首先，制备3个不同批次的醣类组合物，分别为实例1、实例2以及实例3。其中，醣类组合物例如是水云萃取物为例来进行说明，但不以此为限。也就是说，在其他实施例中，醣类组合物也可以是由岩藻糖、葡萄糖醛酸、半乳糖、阿拉伯糖以及其他醣类所调配混合而成的醣类混合物。
在本实施例中，水云萃取物的制备方法包括以下步骤，但不以此为限：在特定的pH值、温度以及萃取时间，以热水和氢氯酸(HCl)对水云进行萃取反应；接着，再经由离心、超过滤(ultrafiltration)以及浓缩后，以氢氧化纳(NaOH)进行中和反应至特定的pH值；接着，利用超高温加热法进行杀菌(sterilization)；接着，在特定的温度及转速，利用喷雾器(atomizer)进行喷雾干燥；接着，利用振动筛(vibration sifter)及80目的筛选尺寸进行筛选，以获得水云萃取物。
然后，利用核磁共振(NMR)的方法来分析实例1、实例2以及实例3的醣类组合物的组成成份及其含量，其分析结果如下表1所示。
表1
  实例1 实例2 实例3
岩藻糖(重量％) 68.9 52.3 61
葡萄糖醛酸(重量％) 11.8 16.2 16.6
半乳糖(重量％) 6.8 13.1 8.6
阿拉伯糖(重量％) 9.1 15.1 10.9
其他醣类(重量％) 3.4 3.3 2.9
实施例2：醣类组合物对RAW264.7巨噬细胞的细胞毒性以及一氧化氮产量的影响
首先，利用溶剂将醣类组合物配制成不同浓度，即浓度为31.25μg/mL、62.5μg/mL、125 μg/mL、250μg/mL、500μg/mL、1000μg/mL的醣类组合物。其中，溶剂例如是磷酸盐缓冲生理盐水(phosphate buffered saline，PBS)，但不以此为限。
然后，将2×105的RAW264.7巨噬细胞(macrophage)培养在96孔盘(96-well plate)的每个孔洞中；置于37℃、5％CO2的培养箱中培养30分钟以使细胞贴附后，请参照图1A至图1B，依组别加入不同浓度的醣类组合物，且同时也依组别加入1μg/mL脂多醣(LPS)，其中脂多醣可刺激或诱导巨噬细胞产生一氧化氮并引起发炎症状；接着，放置于培养箱并培养约24小时后(即药物处理后)，通过计算细胞的数量来评估醣类组合物对巨噬细胞的细胞毒性(cytotoxicity)，并通过测量亚硝酸盐的含量来评估一氧化氮的产量。其中，由于一氧化氮在空气中极不稳定，容易变成亚硝酸盐和硝酸盐，因此通过测量亚硝酸盐的含量来评估一氧化氮的含量。
具体来说，评估醣类组合物对巨噬细胞的细胞毒性的方法例如是：在药物处理后，收集每个孔洞中的细胞，以分别计算细胞数量；接着，以未加入醣类组合物与脂多醣的组别的细胞的细胞数量当作是100％的细胞存活率，分别将其他组别的细胞的细胞数量换算为对应的细胞存活率，借此判断醣类组合物对巨噬细胞的细胞毒性，其结果如图1A所示。由图1A的结果可知，随着添加的醣类组合物的浓度增加，不同组别之间的细胞存活率没有显著性差异(significant difference)，且大约都在90％以上。因此，可表示醣类组合物不会对巨噬细胞造成细胞毒性。
此外，评估一氧化氮的产量的方法例如是：在药物处理后，吸取50μL的上清液至酵素连结免疫吸附分析盘(ELISA plate)，再加入25μL Griess reagent A及25μL Griess reagent B，避光反应后测试550nm下的吸光值，其结果如图1B所示。
由图1B的结果可知，相较于未添加脂多醣的组别(负控制组，negative control)几乎没有产生一氧化氮的情形，添加脂多醣但未添加醣类组合物的组别(诱导组)则会产生约45μM的一氧化氮。相较于添加脂多醣但未添加醣类组合物的组别，同时添加脂多醣及醣类组合物(31.25μg/mL、62.5μg/mL、125μg/mL、250μg/mL、500μg/mL、1000μg/mL)的组别(实验组)则可显著地抑制一氧化氮的产生量。在同时添加脂多醣及醣类组合物的所有组别中，随着添加的醣类组合物的浓度增加，一氧化氮的产生量也更加显著地被抑制。因此，可表示醣类组合物可通过抑制因脂多醣刺激而产生的一氧化氮来抑制发炎症状。
实施例3：醣类组合物对P815肥大细胞的脱颗粒作用、介白素-4以及组织胺的影响
首先，利用溶剂将醣类组合物配制成不同浓度，即浓度为75μg/mL、150μg/mL、300μg/mL、600μg/mL的醣类组合物。其中，溶剂例如是PBS，但不以此为限。
然后，将1×106的P815肥大细胞(mast cell)培养在24孔盘(24-well plate)的每个孔洞中；置于37℃、5％CO2的培养箱中培养1小时以使细胞贴附后，请参照图2A至图2C，依组别加入不同浓度的醣类组合物，且同时也依组别加入10μg/mL肥大细胞脱颗粒剂(compound 48/80)，其中肥大细胞脱颗粒剂可诱导肥大细胞产生脱颗粒作用(degranulation)并释出组织胺(histamine)等发炎介质(inflammatory mediators)而引起发炎症状；接着，放置于培养箱并培养约6小时后(即药物处理后)，吸取上清液至酵素连结免疫吸附分析盘，以测量介白素-4(IL-4)以及组织胺的含量，其结果如图2B与图2C所示；接着，利用甲苯胺蓝(toluidine blue)来对肥大细胞进行染色，以观察肥大细胞的脱颗粒情形，其结果如图2A所示。
由图2A的结果可知，相较于未添加肥大细胞脱颗粒剂的组别(负控制组)，添加肥大细胞 脱颗粒剂但未添加醣类组合物的组别(诱导组)可观察到多个脱颗粒的情形，如图2A中的三角形的尖端所示。相较于添加肥大细胞脱颗粒剂但未添加醣类组合物的组别(诱导组)，同时添加肥大细胞脱颗粒剂及醣类组合物(75μg/mL、150μg/mL、300μg/mL、600μg/mL)的组别(实验组)可显著地减少脱颗粒的情形。在同时添加肥大细胞脱颗粒剂及醣类组合物的所有组别(实验组)中，随着添加的醣类组合物的浓度增加，脱颗粒的情形也更加显著地减少。因此，可表示醣类组合物可抑制肥大细胞的脱颗粒作用。
由图2B与图2C的结果可知，相较于未添加肥大细胞脱颗粒剂的组别(负控制组)，添加肥大细胞脱颗粒剂但未添加醣类组合物的组别(诱导组)可显著地增加IL-4与组织胺的含量。相较于添加肥大细胞脱颗粒剂但未添加醣类组合物的组别(诱导组)，同时添加肥大细胞脱颗粒剂及医药组成物(75μg/mL、150μg/mL、300μg/mL、600μg/mL)的组别(实验组)可显著地减少IL-4与组织胺的含量。在同时添加肥大细胞脱颗粒剂及醣类组合物的所有组别(实验组)中，随着添加的醣类组合物的浓度增加，IL-4与组织胺的含量也更加显著地减少。因此，可表示醣类组合物可抑制肥大细胞因脱颗粒作用而产生的IL-4和组织胺，进而抑制发炎症状。
[实施例4～8]使用含醣类组合物的外用制剂来治疗异位性皮肤炎小鼠
首先，请参照图3，以1-氯-2,4-二硝基苯(1-chloro-2,4-dinitrobenzene，DNCB)溶液作为诱导剂，并在第0、4天对6周龄的BALB/c雄性小鼠的背部皮肤施予(administer)1％DNCB，以使小鼠产生异位性皮肤炎等过敏或发炎的症状(致敏，sensitize)。接着，在第7、11、14、18、21、25天持续对小鼠施予0.2％DNCB，以持续激发(challenge)小鼠产生异位性皮肤炎等过敏或发炎的症状。然后，在第14～28天，每天将戴摩肤(Dermovate)或外用制剂(例如是乳膏)等药物涂抹于皮肤的患部。在第0、9、28天进行采血，以监控血清中的IgE含量。在第28天牺牲小鼠，并采集小鼠的血液、皮下淋巴结、皮肤等，以进行后续分析。
此外，在本实施例中，如图4、5、6A-6C、7A-7B以及8所示，将小鼠分为5组，且每组5只小鼠，分别为负控制组、诱导组、正控制组、低剂量组以及高剂量组。其中，负控制组为不施予DNCB与外用制剂的组别，诱导组为施予DNCB但不施予外用制剂的组别，正控制组为施予DNCB与戴摩肤的组别，低剂量组为施予DNCB与含35mg/mL醣类组合物的外用制剂的组别，高剂量组为施予DNCB与含70mg/mL醣类组合物的外用制剂的组别。其中，DNCB为诱导异位性皮肤炎的动物模式的常用组合物。戴摩肤为市售的软膏或乳膏，含有0.05重量％的clobetasol propionate(皮质类固醇)，可涂抹于患部并用来治疗异位性皮肤炎等皮肤病。
实施例4：外用制剂对异位性皮肤炎小鼠的皮肤炎评分的影响
首先，通过肉眼观察的方式以及异位性皮肤炎评分法(dermatitis score)来评分，以判断异位性皮肤炎的严重程度及皮肤恢复的情形。其中，异位性皮肤炎所造成的皮肤过敏与皮肤发炎的症状可包括红斑(erythema)/出血(hemorrhage)、搔痒(scaring)/干燥(dryness)、肿胀(edema)以及脱皮(excoriation)/糜烂(erosion)。评分标准为0～3分，0分表示没有症状、1分表示轻微症状、2分表示中度症状、且3分表示严重症状。接着，在第4、7、11、14、18、21、25、28天以异位性皮肤炎评分法对各组别的小鼠进行评分，其结果如图4所示。
由图4的结果可知，相较于不施予DNCB与外用制剂的负控制组，施予DNCB但不施予外用制剂的诱导组显著地具有较高的分数以及较严重的皮肤过敏与皮肤发炎的症状。相较于施予DNCB但不施予外用制剂的诱导组，施予DNCB与戴摩肤的正控制组、施予DNCB与含35mg/mL醣类组合物的外用制剂的低剂量组、以及施予DNCB与含70mg/mL醣类组合物的 外用制剂的高剂量组可显著地降低分数并减缓皮肤过敏与皮肤发炎的症状。相较于施予DNCB与戴摩肤的正控制组，施予DNCB与含醣类组合物的外用制剂的低剂量组与高剂量组具有较佳地的效果来减缓皮肤过敏与皮肤发炎的症状。因此，可表示含醣类组合物的外用制剂可针对病灶处进行处理，以抑制皮肤过敏与皮肤发炎的症状，进而修复皮肤并改善或治疗异位性皮肤炎。
实施例5：外用制剂对异位性皮肤炎小鼠的皮下淋巴结的影响
由于异位性皮肤炎常会造成皮下淋巴结发炎，进而导致有皮下淋巴结肿大的情形，因此，以下通过测量各组别的小鼠的皮下淋巴结的重量来判断异位性皮肤炎的严重程度，其结果如图5所示。
由图5的结果可知，相较于不施予DNCB与外用制剂的负控制组，施予DNCB但不施予外用制剂的诱导组显著地具有较重的皮下淋巴结。相较于施予DNCB但不施予外用制剂的诱导组，施予DNCB与戴摩肤的正控制组、施予DNCB与含35mg/mL醣类组合物的外用制剂的低剂量组、以及施予DNCB与含70mg/mL醣类组合物的外用制剂的高剂量组可显著地降低皮下淋巴结的重量。因此，可表示含醣类组合物的外用制剂可针对病灶处进行处理，以减缓皮下淋巴结发炎及肿大的情形，进而改善或治疗异位性皮肤炎。
实施例6：外用制剂对异位性皮肤炎小鼠的皮肤厚度的影响
对各组别的小鼠的皮肤组织进行苏木素-伊红染色(H&E stain)，以观察并测量皮肤的表皮层与真皮层的厚度变化，其步骤大致如下：染色前先将包埋组织的石蜡以二甲苯脱蜡覆水；接着将玻片浸泡于蓝色的苏木素(Hematoxylin)并进行染色数秒；接着以流水冲洗至水流无色，再以红色的伊红(Eosin)进行染色数秒；接着以流水冲洗并待玻片干后，分别浸泡于70％、90％、100％乙醇及二甲苯以进行脱水；接着待玻片干后即可封片保存，其染色结果如图6A至图6C所示。其中，图6B为图6A中的表皮层的厚度的量化结果，且图6C为图6A中的真皮层的厚度的量化结果。
由图6A至图6C的结果可知，相较于不施予DNCB与外用制剂的负控制组，施予DNCB但不施予外用制剂的诱导组可显著地使表皮层与真皮层的厚度增厚。相较于施予DNCB但不施予外用制剂的诱导组，施予DNCB与戴摩肤的正控制组、施予DNCB与含35mg/mL醣类组合物的外用制剂的低剂量组、以及施予DNCB与含70mg/mL醣类组合物的外用制剂的高剂量组可显著地减少表皮层的厚度。因此，可表示含醣类组合物的外用制剂可针对病灶处进行处理，以减缓表皮层增厚的情形。
实施例7：外用制剂对异位性皮肤炎小鼠的皮肤病变的影响
对各组别的小鼠的皮肤组织进行吉姆萨染色(Giemsa stain)，以观察并测量皮肤病变的情形，其步骤大致如下：染色前将包覆组织的石蜡脱去；接着使玻片覆水后，将玻片浸泡于甲醇以固定5分钟；待玻片风干后，将玻片放入20倍稀释的吉姆萨染剂中；40分钟后用流水冲洗至水流呈无色；待玻片风干后，分别浸泡70％、90％、100％乙醇及二甲苯以进行脱水；接着玻片干后即可封片保存，其染色结果如图7A至图7B所示。其中，图7B为图7A中的嗜酸性颗粒球(eosinophilic granulocyte)(如图7A中的三角形的尖端所示)的量化结果。
由图7A至图7B的结果可知，相较于不施予DNCB与外用制剂的负控制组，施予DNCB但不施予外用制剂的诱导组可显著地增加嗜酸性颗粒球浸润于真皮层中。相较于施予DNCB但不施予外用制剂的诱导组，施予DNCB与戴摩肤的正控制组、以及施予DNCB与含70mg/mL 醣类组合物的外用制剂的高剂量组可显著地减少嗜酸性颗粒球浸润于真皮层中。因此，可表示含醣类组合物的外用制剂可针对病灶处进行处理，以减少嗜酸性颗粒球浸润于真皮层，进而减缓皮肤病变的情形。
实施例8：外用制剂对异位性皮肤炎小鼠的IgE的影响
由于异位性皮肤炎可通过过度分泌的免疫球蛋白E(Immunoglobulin E，IgE)来使肥大细胞产生脱颗粒作用，进而导致有释出组织胺、嗜酸性颗粒球浸润、皮下淋巴结肿大等皮肤过敏与皮肤发炎的症状，因此，以下通过测量各组别的小鼠的IgE含量来判断异位性皮肤炎的严重程度。
以下使用酵素连结免疫吸附分析法(Enzyme-linked immunosorbent assay，ELISA assay)来对各组别的小鼠于第0、9、28天所收集的血液进行分析，以测量血液中的IgE含量，其步骤大致如下：利用市售的Mouse ELISA ready-set-go kit来进行分析；首先，将100μL捕获抗体(capture antibody)固定于酵素连结免疫吸附分析盘(ELISA plate)的孔洞中，将其密封后放置于4℃至隔夜；接着，以大于250μL的Wash Buffer对每个孔洞清洗3次后，加入200μL的Blocking Buffer，并于室温下作用1小时；而后，依据说明书以1X的ELISA/ELISPOT对标准品进行连续稀释，再分别将100μL的不同浓度的标准品以及100μL的待测血清分别加入至不同的孔洞；于室温下反应2小时后，以大于250μL的Wash Buffer对每个孔洞清洗3-5次；接着，加入100μL的侦测抗体(Detection antibody)并于室温下反应1小时后，再以大于250μL的Wash Buffer对每个孔洞清洗3-5次；接着，加入100μL的Avidin-HRP，并于室温下反应30分钟；接着，以大于250μL的Wash Buffer对每个孔洞清洗5-7次，再加入100μL的1X TMB溶液；于室温避光下反应15分钟后，加入50μL的Stop Solution，并于波长450nm测其吸光值，其结果如图8所示。
由图8中的第9天的结果可知，相较于不施予DNCB与外用制剂的负控制组，施予DNCB的诱导组、施予DNCB的正控制组、施予DNCB的低剂量组、以及施予DNCB的高剂量组皆可因DNCB的诱导而显著地增加IgE的含量。
由图8中的第28天的结果可知，相较于不施予DNCB的负控制组，施予DNCB但不施予外用制剂的诱导组显著地具有较多的IgE含量。相较于施予DNCB但不施予外用制剂的诱导组，施予DNCB与戴摩肤的正控制组、施予DNCB与含35mg/mL醣类组合物的外用制剂的低剂量组、以及施予DNCB与含70mg/mL醣类组合物的外用制剂的高剂量组可显著地降低IgE含量。相较于施予DNCB与戴摩肤的正控制组，施予DNCB与含35mg/mL醣类组合物的外用制剂的低剂量组、以及施予DNCB与含70mg/mL醣类组合物的外用制剂的高剂量组可更加显著地降低IgE含量。因此，可表示含醣类组合物的外用制剂可针对病灶处进行处理，以减少IgE含量，进而改善或治疗异位性皮肤炎。
[实施例9～14]使用含醣类组合物的口服制剂来治疗异位性皮肤炎小鼠
首先，请参照图3，以与实施例4～8相同或类似的方法制备异位性皮肤炎小鼠，并在相同的时间点进行采血及牺牲。然而，实施例9～14与实施例4～8的差异在于：在第14～28天，每天以口服制剂进行管喂。此外，在本实施例中，如图9、10、11A-11B、12A-12B、13A-13B以及14所示，将小鼠分为6组，分别为负控制组、诱导组、正控制组、低剂量组、中剂量组以及高剂量组。其中，负控制组为不施予DNCB与口服制剂的组别，诱导组为施予DNCB但不施予口服制剂的组别，正控制组为施予DNCB与地塞米松(dexamethasone)的组别，低剂量 组为施予DNCB与含200mg/kg醣类组合物的口服制剂的组别，中剂量组为施予DNCB与含400mg/kg醣类组合物的口服制剂的组别，高剂量组为施予DNCB与含800mg/kg醣类组合物的口服制剂的组别。其中，地塞米松为市售的人工合成的皮质类固醇，可用来治疗异位性皮肤炎等皮肤病。
实施例9：口服制剂对异位性皮肤炎小鼠的皮肤炎评分的影响
以与实施例4相同或类似的方法判断各组别的小鼠的异位性皮肤炎的严重程度及皮肤恢复的情形，其结果如图9所示。
由图9的结果可知，相较于不施予DNCB与口服制剂的负控制组，施予DNCB但不施予口服制剂的诱导组显著地具有较高的分数以及较严重的皮肤过敏与皮肤发炎的症状。相较于施予DNCB但不施予口服制剂的诱导组，施予DNCB与地塞米松的正控制组、施予DNCB与含200mg/kg醣类组合物的口服制剂的低剂量组、施予DNCB与含400mg/kg醣类组合物的口服制剂的中剂量组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可显著地降低分数并减缓皮肤过敏与皮肤发炎的症状。因此，可表示含醣类组合物的口服制剂可抑制皮肤过敏与皮肤发炎的症状，进而修复皮肤并改善或治疗异位性皮肤炎。
实施例10：口服制剂对异位性皮肤炎小鼠的皮下淋巴结的影响
以与实施例5相同或类似的方法测量各组别的小鼠的皮下淋巴结的重量，其结果如图10所示。
由图10的结果可知，相较于不施予DNCB与口服制剂的负控制组，施予DNCB但不施予口服制剂的诱导组显著地具有较重的皮下淋巴结。相较于施予DNCB但不施予口服制剂的诱导组，施予DNCB与地塞米松的正控制组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可显著地降低皮下淋巴结的重量。因此，可表示含醣类组合物的口服制剂可减缓皮下淋巴结发炎及肿大的情形，进而改善或治疗异位性皮肤炎。
实施例11：口服制剂对异位性皮肤炎小鼠的皮肤厚度的影响
以与实施例6相同或类似的方法观察并测量各组别的小鼠的皮肤的表皮层与真皮层的厚度变化，其结果如图11A与图11B所示。其中，图11B为图11A中的表皮层的厚度的量化结果。
由图11A与图11B的结果可知，相较于不施予DNCB与口服制剂的负控制组，施予DNCB但不施予口服制剂的诱导组可显著地使表皮层的厚度增厚。相较于施予DNCB但不施予口服制剂的诱导组，施予DNCB与地塞米松的正控制组、施予DNCB与含200mg/kg醣类组合物的口服制剂的低剂量组、施予DNCB与含400mg/kg醣类组合物的口服制剂的中剂量组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可显著地减少表皮层的厚度。因此，可表示含醣类组合物的口服制剂可减缓表皮层增厚的情形。
实施例12：口服制剂对异位性皮肤炎小鼠的皮肤病变的影响
以与实施例7相同或类似的方法观察并测量各组别的小鼠的皮肤病变的情形，其结果如图12A与图12B所示。其中，图12B为图12A中的嗜酸性颗粒球(如图12A中的三角形的尖端所示)的量化结果。
由图12A与图12B的结果可知，相较于不施予DNCB与口服制剂的负控制组，施予DNCB但不施予口服制剂的诱导组可显著地增加嗜酸性颗粒球浸润于真皮层中。相较于施予DNCB但不施予口服制剂的诱导组，施予DNCB与地塞米松的正控制组、施予DNCB与含200mg/kg 醣类组合物的口服制剂的低剂量组、施予DNCB与含400mg/kg醣类组合物的口服制剂的中剂量组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可显著地减少嗜酸性颗粒球浸润于真皮层中。因此，可表示含醣类组合物的口服制剂可减少嗜酸性颗粒球浸润于真皮层，进而减缓皮肤病变的情形。
实施例13：口服制剂对异位性皮肤炎小鼠的细胞因子的影响
以与实施例8相同或类似的方法，以市售的ProcartaPlex Mouse Simplex kit以及酵素连结免疫吸附分析法来测量各组别的小鼠的介白素-1β(IL-1β)、介白素-4(IL-4)、介白素-5(IL-5)、介白素-6(IL-6)、介白素-13(IL-13)、介白素-22(IL-22)、胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin，TSLP)、干扰素-γ(INF-γ)以及肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)的含量，其结果如图13A与图13B所示。其中，图13A中的IL-4、IL-5、IL-6、IL-13、IL-22以及TSLP为与辅助T细胞(T helper 2 cell，Th2)相关的细胞因子(cytokine)，且图中的N.D.是指未检测到(NOT DETECTED)。图13B中的INF-γ、TNF-α以及IL-1β为与发炎相关的细胞因子。
由图13A的结果可知，相较于不施予DNCB与口服制剂的负控制组，施予DNCB但不施予口服制剂的诱导组显著地具有较多的IL-4、IL-5、IL-6、IL-13、IL-22以及TSLP的含量。相较于施予DNCB但不施予口服制剂的诱导组，施予DNCB与含200mg/kg醣类组合物的口服制剂的低剂量组、施予DNCB与含400mg/kg醣类组合物的口服制剂的中剂量组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可显著地降低IL-4、IL-5、IL-6、IL-13、IL-22以及TSLP的含量。相较于施予DNCB但不施予口服制剂的诱导组，施予DNCB与地塞米松的正控制组也可显著地降低IL-4、IL-5、IL-6、IL-13以及TSLP的含量，但不可显著降低IL-22的含量。
此外，相较于施予DNCB与地塞米松的正控制组，施予DNCB与含200mg/kg醣类组合物的口服制剂的低剂量组、施予DNCB与含400mg/kg醣类组合物的口服制剂的中剂量组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可更加显著地降低IL-13的含量。相较于施予DNCB与地塞米松的正控制组，施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可更加显著地降低IL-22的含量。在施予DNCB与口服制剂的所有组别中，随着口服制剂中的醣类组合物的浓度增加，抑制IL-6的效果更明显。因此，可表示含醣类组合物的口服制剂可减少与辅助T细胞相关的细胞因子IL-4、IL-5、IL-6、IL-13、IL-22以及TSLP的含量，进而改善或治疗异位性皮肤炎。
由图13B的结果可知，相较于不施予DNCB与口服制剂的负控制组，施予DNCB但不施予口服制剂的诱导组显著地具有较多的INF-γ、TNF-α以及IL-1β的含量。相较于施予DNCB但不施予口服制剂的诱导组，施予DNCB与地塞米松的正控制组、施予DNCB与含200mg/kg醣类组合物的口服制剂的低剂量组、施予DNCB与含400mg/kg醣类组合物的口服制剂的中剂量组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可显著地降低INF-γ、TNF-α以及IL-1β的含量。因此，可表示含醣类组合物的口服制剂可减少与发炎相关的细胞因子INF-γ、TNF-α以及IL-1β的含量，进而改善或治疗异位性皮肤炎。此外，也可表示含醣类组合物的口服制剂可具有对全身性体循环的过敏反应进行调节的效果。
实施例14：口服制剂对异位性皮肤炎小鼠的IgE的影响
以与实施例8相同或类似的方法测量各组别的小鼠的IgE含量，其结果如图14所示。
由图14中的第9天的结果可知，相较于不施予DNCB的负控制组，施予DNCB的诱导组、施予DNCB的正控制组、施予DNCB的低剂量组、施予DNCB的中剂量组、以及施予DNCB的高剂量组皆可因DNCB的诱导而显著地增加IgE的含量。
由图14中的第28天的结果可知，相较于不施予DNCB与口服制剂的负控制组，施予DNCB但不施予口服制剂的诱导组显著地具有较多的IgE含量。相较于施予DNCB但不施予口服制剂的诱导组，施予DNCB与地塞米松的正控制组、施予DNCB与含400mg/kg醣类组合物的口服制剂的中剂量组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可显著地降低IgE含量。相较于施予DNCB与地塞米松的正控制组，施予DNCB与含400mg/kg醣类组合物的口服制剂的中剂量组、以及施予DNCB与含800mg/kg醣类组合物的口服制剂的高剂量组可更加显著地降低IgE含量。因此，可表示含醣类组合物的口服制剂可减少IgE含量，进而改善或治疗异位性皮肤炎。此外，也可表示含醣类组合物的口服制剂可具有对全身性体循环的过敏反应进行调节的效果。
[实施例15～18]同时使用含醣类组合物的外用制剂和含醣类组合物的口服制剂来治疗异位性皮肤炎小鼠
首先，请参照图3，以与实施例4～8相同或类似的方法制备异位性皮肤炎小鼠，并在相同的时间点进行采血及牺牲。然而，实施例15～18与实施例4～8的差异在于：在第14～28天，每天依组别以外用制剂进行涂抹、口服制剂进行管喂、或同时以外用制剂涂抹和口服制剂管喂；在第9、28天进行采血，以监控血清中的IgE含量。此外，在本实施例中，如图15、16、17A-17B以及18所示，将小鼠分为5组，分别为负控制组、诱导组、外用组、口服组以及外用口服组。其中，负控制组为不施予DNCB与外用制剂或口服制剂的组别，诱导组为施予DNCB但不施予外用制剂或口服制剂的组别，外用组为施予DNCB与含70mg/mL醣类组合物的外用制剂的组别，口服组为施予DNCB与含800mg/kg醣类组合物的口服制剂的组别，外用口服组为施予DNCB、含35mg/mL醣类组合物的外用制剂以及含400mg/kg醣类组合物的口服制剂的组别。也就是说，外用口服组是以外用组中减半剂量的外用制剂(即，含35mg/mL醣类组合物的外用制剂)搭配口服组中减半剂量的口服制剂(即，含400mg/kg醣类组合物的口服制剂)来治疗异位性皮肤炎小鼠，以期望在临床应用上可以减少药物的滥用，以达到有效的资源分配。此外，外用口服组也可同时提供两种方式来进行治疗：对全身性体循环的过敏反应进行调节，并针对病灶处进行处理。
实施例15：同时使用外用制剂和口服制剂对异位性皮肤炎小鼠的皮肤炎评分的影响
以与实施例4相同或类似的方法，在第7、14、21、28天判断各组别的小鼠的异位性皮肤炎的严重程度及皮肤恢复的情形，其结果如图15所示。
由图15的结果可知，相较于不施予DNCB与外用制剂或口服制剂的负控制组，施予DNCB但不施予外用制剂或口服制剂的诱导组显著地具有较高的分数以及较严重的皮肤过敏与皮肤发炎的症状。相较于施予DNCB但不施予外用制剂或口服制剂的诱导组，施予DNCB与含70mg/mL醣类组合物的外用制剂的外用组、施予DNCB与含800mg/kg醣类组合物的口服制剂的口服组、以及施予外用口服组(即，包括DNCB、含35mg/mL醣类组合物的外用制剂以及含400mg/kg醣类组合物的口服制剂的组别)可显著地降低分数并减缓皮肤过敏与皮肤发炎的症状。因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂也可抑制皮肤过敏与皮肤发炎的症状，进而修复皮肤并改善或治疗异位性皮肤炎。此外，由于外用口服组在抑 制皮肤过敏与皮肤发炎的症状的效果相似于外用组或口服组在抑制皮肤过敏与皮肤发炎的症状的效果，因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂在抑制皮肤过敏与皮肤发炎的症状上可具有相加作用(additive effects)。
实施例16：同时使用外用制剂和口服制剂对异位性皮肤炎小鼠的皮下淋巴结的影响
以与实施例5相同或类似的方法测量各组别的小鼠的皮下淋巴结的重量，其结果如图16所示。
由图16的结果可知，相较于不施予DNCB与外用制剂或口服制剂的负控制组，施予DNCB但不施予外用制剂或口服制剂的诱导组具有较重的皮下淋巴结。相较于施予DNCB但不施予外用制剂或口服制剂的诱导组，施予DNCB与含800mg/kg醣类组合物的口服制剂的口服组、以及施予外用口服组(即，包括DNCB、含35mg/mL醣类组合物的外用制剂以及含400mg/kg醣类组合物的口服制剂的组别)可显著地降低皮下淋巴结的重量。因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂也可减缓皮下淋巴结发炎及肿大的情形，进而改善或治疗异位性皮肤炎。此外，由于外用口服组在减缓皮下淋巴结发炎及肿大的效果相似于外用组或口服组在减缓皮下淋巴结发炎及肿大的效果，因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂在减缓皮下淋巴结发炎及肿大上可具有相加作用。
实施例17：同时使用外用制剂和口服制剂对异位性皮肤炎小鼠的细胞因子的影响
以与实施例8相同或类似的方法，以市售的ProcartaPlex Mouse Simplex kit以及酵素连结免疫吸附分析法来测量各组别的小鼠的介白素-4(IL-4)、介白素-5(IL-5)、介白素-13(IL-13)、介白素-22(IL-22)、介白素-33(IL-33)、胸腺基质淋巴细胞生成素(TSLP)以及转化生长因子-β1(transforming Growth Factor-β1，TGF-β1)的含量，其结果如图17A与图17B所示。其中，图17A中的IL-4、IL-5、IL-13、IL-22、IL-33以及TSLP为与辅助T细胞(Th2)相关的细胞因子。
由图17A的结果可知，相较于不施予DNCB与外用制剂或口服制剂的负控制组，施予DNCB但不施予外用制剂或口服制剂的诱导组显著地具有较多的IL-4、IL-5、IL-13、IL-22、IL-33以及TSLP的含量。相较于施予DNCB但不施予外用制剂或口服制剂的诱导组，施予DNCB与含70mg/mL醣类组合物的外用制剂的外用组、施予DNCB与含800mg/kg醣类组合物的口服制剂的口服组、以及施予外用口服组(即，包括DNCB、含35mg/mL醣类组合物的外用制剂以及含400mg/kg醣类组合物的口服制剂的组别)可显著地降低IL-4、IL-5、IL-22、IL-33以及TSLP的含量。相较于施予DNCB但不施予外用制剂或口服制剂的诱导组，施予DNCB与含800mg/kg醣类组合物的口服制剂的口服组、以及施予外用口服组(即，包括DNCB、含35mg/mL醣类组合物的外用制剂以及含400mg/kg醣类组合物的口服制剂的组别)也可显著地降低IL-13的含量。因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂也可减少与辅助T细胞相关的细胞因子IL-4、IL-5、IL-13、IL-22、IL-33以及TSLP的含量，进而改善或治疗异位性皮肤炎。此外，由于外用口服组在减少与辅助T细胞相关的细胞因子的含量的效果相似于外用组或口服组在减少与辅助T细胞相关的细胞因子的含量的效果，因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂在减少与辅助T细胞相关的细胞因子的含量上可具有相加作用。
由图17B的结果可知，相较于施予DNCB但不施予外用制剂或口服制剂的诱导组，施予DNCB与含800mg/kg醣类组合物的口服制剂的口服组、以及施予外用口服组(即，包括DNCB、含35mg/mL醣类组合物的外用制剂以及含400mg/kg醣类组合物的口服制剂的组别)可显著地 增加TGF-β1的含量。因此，可表示单独使用口服制剂、或同时使用剂量减半的外用制剂和剂量减半的口服制剂可增加TGF-β1的含量，进而改善或治疗异位性皮肤炎。此外，由于外用口服组在增加TGF-β1的含量的效果相似于口服组在增加TGF-β1的含量的效果，因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂在增加TGF-β1的含量上可具有相加作用。
实施例18：同时使用外用制剂和口服制剂对异位性皮肤炎小鼠的IgE的影响
以与实施例8相同或类似的方法测量各组别的小鼠的IgE含量，其结果如图18所示。
由图18中的第14天的结果可知，相较于不施予DNCB的负控制组，施予DNCB的诱导组、施予DNCB的外用组、施予DNCB的口服组、以及施予DNCB的外用口服组皆可因DNCB的诱导而显著地增加IgE的含量。
由图18中的第28天的结果可知，相较于不施予DNCB与外用制剂或口服制剂的负控制组，施予DNCB但不施予外用制剂或口服制剂的诱导组显著地具有较多的IgE含量。相较于施予DNCB但不施予外用制剂或口服制剂的诱导组，施予DNCB与含70mg/mL醣类组合物的外用制剂的外用组、施予DNCB与含800mg/kg醣类组合物的口服制剂的口服组、以及施予外用口服组(即，包括DNCB、含35mg/mL醣类组合物的外用制剂以及含400mg/kg醣类组合物的口服制剂的组别)可显著地降低IgE含量。因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂也可减少IgE含量，进而改善或治疗异位性皮肤炎。此外，由于外用口服组在减少IgE含量的效果相似于外用组或口服组在减少IgE含量的效果，因此，可表示同时使用剂量减半的外用制剂和剂量减半的口服制剂在减少IgE含量上可具有相加作用。
综上所述，在本发明的实施例的醣类组合物与医药组成物中，由于醣类组合物可包括45.5重量％至76重量％的岩藻糖、11重量％至19重量％的葡萄糖醛酸、4.5重量％至14.5重量％的半乳糖以及5.5重量％至18重量％阿拉伯糖，因而使得醣类组合物与含有醣类组合物的医药组成物可抑制因脂多醣刺激而产生的一氧化氮、抑制肥大细胞的脱颗粒作用、抑制肥大细胞因脱颗粒作用而产生的IL-4和组织胺、抑制皮肤过敏与皮肤发炎的症状、减缓皮下淋巴结发炎及肿大、减缓表皮层增厚、减少嗜酸性颗粒球浸润于真皮层、减少IL-4、IL-5、IL-6、IL-13、IL-22、IL-33以及TSLP的含量、减少INF-γ、TNF-α以及IL-1β的含量、增加TGF-β1的含量、减少IgE的含量，进而具有可保养皮肤、抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎的效果，且无副作用。
虽然本发明已以实施例揭示如上，然其并非用以限定本发明，任何本领域的普通技术人员，在不脱离本发明的精神和范围内，当可作些许的更动与润饰，故本发明的保护范围当视后附的申请专利范围所界定者为准。

Claims (12)

  1. 一种醣类组合物，其特征在于，包括：
    岩藻糖；
    葡萄糖醛酸；
    半乳糖；以及
    阿拉伯糖，
    其中以所述醣类组合物的总重量计，所述岩藻糖的含量为45.5重量％至76重量％，所述葡萄糖醛酸的含量为11重量％至19重量％，所述半乳糖的含量为4.5重量％至14.5重量％，所述阿拉伯糖的含量为5.5重量％至18重量％。
  2. 根据权利要求1所述的醣类组合物，其特征在于，以所述醣类组合物的总重量计，所述岩藻糖的含量为49.5重量％至72.5重量％，所述葡萄糖醛酸的含量为11重量％至17.5重量％，所述半乳糖的6含量为重量％至14重量％，所述阿拉伯糖的含量为8.5重量％至16重量％。
  3. 根据权利要求1所述的醣类组合物，其特征在于，以所述醣类组合物的总重量计，所述岩藻糖的含量为52重量％至69重量％，所述葡萄糖醛酸的含量为11.5重量％至17重量％，所述半乳糖的含量为6.5重量％至13.5重量％，所述阿拉伯糖的含量为9重量％至15.5重量％。
  4. 根据权利要求1所述的醣类组合物，其特征在于，所述醣类组合物为口服制剂。
  5. 根据权利要求4所述的醣类组合物，其特征在于，所述口服制剂中的所述醣类组合物的剂量范围为50mg/kg至800mg/kg。
  6. 根据权利要求1所述的醣类组合物，其特征在于，所述醣类组合物为外用制剂。
  7. 根据权利要求6所述的醣类组合物，其特征在于，所述外用制剂中的所述醣类组合物的剂量范围为35mg/mL至70mg/mL。
  8. 根据权利要求1所述的醣类组合物，其特征在于，所述醣类组合物为外用制剂与口服制剂。
  9. 根据权利要求8所述的醣类组合物，其特征在于，所述外用制剂中的所述醣类组合物的剂量范围为35mg/mL至70mg/mL，且所述口服制剂中的所述醣类组合物的剂量范围为50mg/kg至800mg/kg。
  10. 一种根据权利要求1所述的醣类组合物的用途，其特征在于，用于制备抑制皮肤过敏、抑制皮肤发炎或改善异位性皮肤炎的药物。
  11. 一种根据权利要求1所述的醣类组合物的用途，其特征在于，用于制备保养皮肤的保健食品或保养品。
  12. 一种医药组成物，其特征在于，包括：
    如权利要求1所述的醣类组合物；以及
    添加剂。
PCT/CN2021/128375 2021-02-08 2021-11-03 醣类组合物作为医药组成物及其用途 WO2022166283A1 (zh)

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