WO2016095087A1 - Utilisation de l'acide chlorogénique dans la préparation d'un médicament indiqué pour le traitement du vitiligo - Google Patents

Utilisation de l'acide chlorogénique dans la préparation d'un médicament indiqué pour le traitement du vitiligo Download PDF

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Publication number
WO2016095087A1
WO2016095087A1 PCT/CN2014/093854 CN2014093854W WO2016095087A1 WO 2016095087 A1 WO2016095087 A1 WO 2016095087A1 CN 2014093854 W CN2014093854 W CN 2014093854W WO 2016095087 A1 WO2016095087 A1 WO 2016095087A1
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WIPO (PCT)
Prior art keywords
chlorogenic acid
preparation
group
model
vitiligo
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PCT/CN2014/093854
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English (en)
Chinese (zh)
Inventor
张洁
朱丽娜
黄望
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四川九章生物科技有限公司
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Priority to PCT/CN2014/093854 priority Critical patent/WO2016095087A1/fr
Publication of WO2016095087A1 publication Critical patent/WO2016095087A1/fr

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • the present invention relates to the use of chlorogenic acid for the preparation of a medicament for the treatment of vitiligo.
  • Chlorogenic acid also known as coffee tannin, chemically known as 3-0-caffeoylquinic acid, is derived from caffeic acid and quinic acid.
  • Quinic acid consists of a carboxylic acid.
  • Chlorogenic acid is a product of aerobic respiration metabolism in plants. It is the main active ingredient in many Chinese herbal medicines and fruits and vegetables. It has many biological activities, such as cardiovascular protection, anti-oxidation, anti-ultraviolet and anti-radiation effects. Anti-mutagenic and anti-cancer effects, antibacterial effects, antiviral effects, lipid-lowering and hypoglycemic effects, immunomodulatory effects, etc. It has a wide range of applications in the fields of pharmaceutical, chemical and food.
  • the technical solution of the present invention is to provide the use of chlorogenic acid in the preparation of a medicament for treating vitiligo.
  • the invention provides the use of chlorogenic acid for the preparation of a medicament for treating vitiligo.
  • the drug is a drug for reducing the expression of TNF- ⁇ and IL-4 at the lesion.
  • the drug is a drug that promotes melanocyte production.
  • the medicament is prepared by adding chlorogenic acid as an active ingredient, adding a pharmaceutically acceptable adjuvant or an auxiliary component.
  • the preparation is an oral preparation, an injection preparation or a transdermal preparation for external use.
  • the preparation is used in a dose of 1-100 mg/kg. Further preferably, the preparation is administered in a dose of from 1 to 30 mg/kg.
  • the test of the invention shows that chlorogenic acid can improve the pathological changes of the vitiligo model, reduce the expression of TNF- ⁇ and IL-4 in the lesion, promote the formation of melanocytes, and provide a theoretical basis for the clinical treatment of vitiligo.
  • Example 1 In vivo pharmacodynamic study of chlorogenic acid in the treatment of vitiligo
  • Black guinea pig weighing 300-350g, male and female.
  • Black guinea pigs were taken, and the area of the back hair was shaved by electric razor by 5 cm ⁇ 5 cm.
  • the body weight was randomly divided into groups of 10, namely, the blank control group (equal volume saline), the model group (equal volume saline), and the positive control.
  • the group (methicillin tablets 2.8 mg/kg), the chlorogenic acid low dose group (15 mg/kg), the chlorogenic acid medium dose group (30 mg kg), and the chlorogenic acid high dose group (60 mg/kg).
  • the blank control group was applied with 0.05 ml of physiological saline in the depilated area, and the other groups were applied with 5% hydroquinone 0.5 ml in the depilatory area twice a day for 11 days to prepare a vitiligo guinea pig model. On the 11th day, each group was administered daily at a dose of 1 hour after the application of hydroquinone, once a day for 50 days.
  • the pigment distribution in the back skin of guinea pigs was visually observed.
  • Judgment criteria (3cm 2 as the observation unit in the center of the guinea pig medication site): the pigment in the test area (3cm 2 ) basically returned to normal; the pigment area in the test area was >50%; The area is ⁇ 50%; the difference is that the skin in the test area is pale or white spotted, and the total effective rate is superior.
  • Each group of guinea pigs were taken 1 cm ⁇ 1 cm, fixed with 10% formaldehyde, embedded in paraffin, sectioned, and melanin stained with ferrous sulfate (Lillie method) to observe the distribution of melanin in epidermal basal cells and spine cells and guinea pigs with melanin in hair follicles. number.
  • Ten high-power fields were observed for each specimen, and the average number of basal cells containing melanin particles per 100 epidermal basal cells was counted.
  • Degree classification means no melanin; " ⁇ ” means occasional melanin; "+” means 30% to 50% of melanin; "++” means 51% to 85% of melanin; "+++” means 85 More than % of melanin.
  • the color of the epidermis of the guinea pigs in the model group was pale and some hairs were whitish. The difference was significant compared with the normal group. After treatment with chlorogenic acid, the effect was obvious. The skin of the guinea pigs was gradually blackened. The color of each drug group was brownish black, which was closer to the normal group, and there was a small amount of pigmentation, which was significantly different from the positive control group. The results are shown in Table 1.
  • the chlorogenic acid 15mg/kg, 30mg/kg, 60mg/kg could significantly increase the skin melanin of the model guinea pig, and significantly increase the distribution of melanin in the epidermal basal cells and spine cells. And melanin in the hair follicles.
  • Table 4 The results are shown in Table 4.
  • chlorogenic acid can significantly increase the skin melanin of experimental vitiligo model guinea pigs, significantly increase the distribution of melanin in skin epidermal basal cells and spine cells, and can significantly increase the melanin in skin hair follicles, and the tyrosinase content in blood is also significant.
  • Increased sexuality and significantly improved blood rheology indicators indicating that chlorogenic acid can increase the melanin production in experimental guinea pig model skin, reduce skin melanin decomposition and improve blood circulation, and play a better therapeutic effect on vitiligo.
  • Example 2 Chlorogenic acid visceral coefficient and TNF- ⁇ in the lesion area of vitiligo in guinea pig model The effects of IL-10, IL-4 and IFN- ⁇ expression
  • Black guinea pig weighing 300-350g, male and female.
  • An experimental vitiligo guinea pig model was prepared using hydroquinone (hydroquinone). Take healthy black guinea pigs, male and female, shave the back hair area by 5cm ⁇ 5cm with an electric razor, apply 5% hydroquinone 0.5ml twice a day in the hair removal area, and apply for 50 days continuously to prepare a vitiligo guinea pig model.
  • hydroquinone hydroquinone
  • the above model guinea pigs were randomly divided into 5 groups: model group, positive group, chlorogenic acid low dose group (15 mg/kg), chlorogenic acid medium dose group (30 mg/kg), and chlorogenic acid high dose group (60 mg). /kg), 10 in each group; another 10 unmodeled guinea pigs were used as blank control group.
  • the guinea pigs of each drug group started to be administered on the 10th day of modeling, and the guinea pigs in the blank control group and the model group were given an equal volume of physiological saline for 50 days.
  • the guinea pigs were sacrificed, and the skin of the drug site was taken at a center of 1 cm ⁇ 1 cm, fixed in neutral formaldehyde, embedded in paraffin, and sectioned. The thymus and spleen of the guinea pig were weighed and the thymus coefficient was calculated.
  • the slices were conventionally dewaxed to water.
  • Heat-repairing antigen 0.01 M citrate buffer (pH 6.0), heat-burned in an electric furnace or microwave oven until boiling, slice immersion, and PBS was washed 1-2 times after cooling. 30% H 2 O 21 parts + 10 parts of distilled water were mixed, and the endogenous enzyme was inactivated at room temperature for 10 minutes. Wash in PBS for 5 minutes ⁇ 3 times. The normal goat immune serum was blocked, incubated at room temperature for 15 minutes, and the serum was decanted without washing. HMB45 antibody diluted 1:100 was added dropwise at 4 ° C overnight. Wash in PBS for 2 minutes ⁇ 3 times.
  • the horseradish enzyme-labeled streptavidin working solution was added dropwise and incubated at 37 ° C for 10 minutes. Wash in PBS for 5 minutes ⁇ 3 times. DAB color development, control reaction time under the microscope, 20s-80s, to satisfactory color development. Wash with distilled water to stop color development. Hematoxylin mildly counterstained, hydrochloric acid alcohol differentiated, rinsed back to blue for 1 minute. Dehydrated, transparent, and sealed. Microscopic observation.
  • Semi-quantitative scoring was performed based on the degree of staining and the percentage of stained cells.
  • Five high-power fields 200 ⁇ were randomly selected from each slice, and the scores were based on the number of positive cells. The score was: 0 points. ⁇ 25% stained cells; 1 point, 25%-50% stained cells; 2 points, 50%-75% stained cells; 3 points, >75% stained cells.
  • the staining degree was as follows: 0 points, no staining; 1 point, light yellow; 2 points, brownish yellow; 3 points of tan.
  • the staining degree is divided into the percentage of the stained cells to obtain the total score, and the score is divided into 4 grades according to the score: 0, negative (-); 2 points, weak positive (+); 3-4 points, positive (++) 5-6 points, strong positive (+++).
  • Statistics were performed using the rank sum test method (Kruskal-Wallis method).
  • the visceral coefficient of the thymus and spleen of the model group was significantly reduced, and the difference was significant compared with the blank control group.
  • the chlorogenic acid group could increase the thymus and spleen and organ coefficient of the model guinea pig, which was significantly different from the model group. It was shown that chlorogenic acid can enhance the immune function of model guinea pigs. See Table 5.
  • TNF- ⁇ positive cells were mainly distributed in the basal layer of the epidermis, spine layer and granular layer. A few positive cells were distributed in the superficial dermis. IL-4 positive cells were mainly distributed in the basal layer and spinous layer of the epidermis, and the control group showed weak positive expression.
  • the expression levels of TNF- ⁇ and IL-4 in the lesion group were significantly higher than those in the normal control group (P ⁇ 0.01).
  • the expression levels of TNF- ⁇ and IL-4 in the lesion group were significantly lower than those in the model group. The difference was significant (P ⁇ 0.01).
  • Chlorogenic acid can improve the pathological changes of vitiligo model, reduce the expression of TNF- ⁇ and IL-4 in skin lesions, promote the formation of melanocytes, and provide a theoretical basis for its clinical treatment of vitiligo.

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  • Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de l'acide chlorogénique dans la préparation d'un médicament indiqué pour le traitement du vitiligo. Les essais cliniques ont permis de démontrer que l'acide chlorogénique améliore les changements pathologiques modèles du vitiligo, qu'il diminue l'expression de TNF et IL-4 au niveau de l'endothélium tout en stimulant la production de mélanocytes. Par ailleurs, les paramétrages cliniques pour le traitement du vitiligo ont permis de poser des bases théoriques.
PCT/CN2014/093854 2014-12-15 2014-12-15 Utilisation de l'acide chlorogénique dans la préparation d'un médicament indiqué pour le traitement du vitiligo WO2016095087A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2014/093854 WO2016095087A1 (fr) 2014-12-15 2014-12-15 Utilisation de l'acide chlorogénique dans la préparation d'un médicament indiqué pour le traitement du vitiligo

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PCT/CN2014/093854 WO2016095087A1 (fr) 2014-12-15 2014-12-15 Utilisation de l'acide chlorogénique dans la préparation d'un médicament indiqué pour le traitement du vitiligo

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09151130A (ja) * 1995-12-01 1997-06-10 Yakurigaku Chuo Kenkyusho:Kk 白毛症および白斑症治療薬
WO2012017551A1 (fr) * 2010-08-06 2012-02-09 Yuasa Makoto Agent thérapeutique pour des maladies
CN104434902A (zh) * 2014-12-15 2015-03-25 四川九章生物科技有限公司 绿原酸在制备治疗白癜风的药物中的用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09151130A (ja) * 1995-12-01 1997-06-10 Yakurigaku Chuo Kenkyusho:Kk 白毛症および白斑症治療薬
WO2012017551A1 (fr) * 2010-08-06 2012-02-09 Yuasa Makoto Agent thérapeutique pour des maladies
CN104434902A (zh) * 2014-12-15 2015-03-25 四川九章生物科技有限公司 绿原酸在制备治疗白癜风的药物中的用途

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