WO2020077915A1 - 羟基酪醇及其衍生物在制备抗抑郁产品中的新应用 - Google Patents

羟基酪醇及其衍生物在制备抗抑郁产品中的新应用 Download PDF

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WO2020077915A1
WO2020077915A1 PCT/CN2019/073088 CN2019073088W WO2020077915A1 WO 2020077915 A1 WO2020077915 A1 WO 2020077915A1 CN 2019073088 W CN2019073088 W CN 2019073088W WO 2020077915 A1 WO2020077915 A1 WO 2020077915A1
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hydroxytyrosol
acid
depression
group
use according
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PCT/CN2019/073088
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English (en)
French (fr)
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凌沛学
刘飞
邵华荣
吴季栩
郭新艳
边玲
李帅广
程艳玲
张建强
张岱州
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山东省药学科学院
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Priority to JP2021520413A priority Critical patent/JP7352623B2/ja
Publication of WO2020077915A1 publication Critical patent/WO2020077915A1/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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to the new use of hydroxytyrosol.
  • Depression also known as depressive disorder, is a group of clinical symptom groups or states centered on self-experience in depressed mood, with persistent and significant spontaneous mood depression as the main clinical feature and the main type of mood disorder.
  • the main clinical symptoms are: low mood, out-of-group, out-of-group, physical discomfort, loss of appetite and sleep disturbances; some cases have obvious anxiety and motor agitation; in severe cases, mental symptoms such as hallucinations and delusions may occur.
  • the drugs for depression in the market include paroxetine, sertraline, fluvoxamine, and venlafaxine.
  • drugs for depression in the market include paroxetine, sertraline, fluvoxamine, and venlafaxine.
  • side effects of drugs such as drowsiness, constipation, gastrointestinal discomfort, respiratory depression, memory loss and Dependence, etc., it is of great significance to find and develop safer antidepressants.
  • Dopamine can be damaged in the nucleus accumbens and striatum, and when the level of dopamine decreases, depression symptoms such as lack of pleasure, anxiety, and loss of appetite will appear.
  • the level of dopamine in the brain may be one of the indicators of the severity of depression and the effect of treatment, so regulating the level of dopamine in the brain is of great significance for the treatment of depression.
  • Hydroxytyrosol (CtyHrosio, C 8 H 10 O 3 , CAS: 10597-60-1), also known as 3,4-dihydroxy phenylethanol (3,4-dihydroxy phenylethanol), is a hydrophilic and lipophilic natural Polyphenol compounds. At room temperature and low purity, it is yellow oily substance, and at high concentration, it is colorless oily substance. They are all fluid; they are mainly present in the form of oleuropein in the fruits and leaves of the olive family of the olive family. Due to the structure of catechol and phenethyl alcohol, hydroxytyrosol has strong antioxidant properties and has received extensive attention in recent years.
  • hydroxytyrosol has a strong antioxidant effect, has a good inhibitory and preventive effect on the occurrence and development of inflammation; it has a potential neuroprotective effect on dopaminergic cells, and can be used to treat Parkinson's and Alzheimer's synthesis Sign.
  • the prior art has disclosed a preparation method of hydroxytyrosol and its use in the manufacture of cartilage protection, prevention and treatment of osteoarthritis, blood lipid lowering, and treatment of macular eye disease products, but the use of hydroxytyrosol as a prevention and treatment of depression Not yet public.
  • the present invention provides a new use of hydroxytyrosol in the preparation of antidepressant products, which has the functions of preventing and treating depression and its complications, and preventing the recurrence of depression.
  • the present invention adopts the following technical solutions.
  • hydroxytyrosol and its derivatives in the preparation of products for the prevention and treatment of depression. It can be used to alleviate and improve the mental illness caused by psychological stress; it can be used to alleviate and improve various symptoms of depression, such as low mood, out of group, physical discomfort, loss of appetite and sleep disorders.
  • the hydroxytyrosol derivative is at least one selected from the group consisting of hydroxytyrosolate, hydroxytyrosol ester and hydroxytyrosol ether, and its structural formula is part or all of -OH in the compound represented by formula (I) Salts, esters or ethers with bases, acids, alcohols:
  • hydroxytyrosol derivatives can be converted into hydroxytyrosol by hydrolysis in the human body or animal body, producing the same or similar physiological activities.
  • the hydroxytyrosol salt is a physiologically acceptable salt formed by hydroxytyrosol and an inorganic or organic base.
  • alkali metal salts of hydroxytyrosol such as sodium and potassium salts
  • alkaline earth metal salts of hydroxytyrosol such as calcium and magnesium salts
  • ammonium salts and salts of hydroxytyrosol with nitrogen-containing organic bases.
  • the nitrogen-containing organic base includes but is not limited to trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, Dicyclohexylamine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, N, N′-dibenzylethylenediamine, procaine, amphetamine.
  • the hydroxytyrosol ester is a physiologically acceptable ester of hydroxytyrosol and an inorganic or organic acid;
  • the inorganic acid is selected from sulfuric acid, phosphoric acid, carbonic acid, and hydrochloric acid;
  • the organic acid is selected from formic acid, acetic acid, propionic acid, Butyric acid, maleic acid, oxalic acid, methanesulfonic acid, succinic acid or fatty acids.
  • the hydroxytyrosol ether includes hydroxytyrosol alkyl ether, hydroxytyrosol aryl ether and hydroxytyrosol glycoside.
  • the alkyl ether can be methyl, ethyl, n-propyl, n-butyl, n-hexyl, n-octyl, isopropyl or tert-butyl.
  • the aryl ether may be an aromatic ether containing carbon atoms, or a heteroaromatic ring ether containing nitrogen atoms, sulfur atoms, and oxygen atoms;
  • the hydroxytyrosol glycoside may be hydroxytyrosol glucoside, hydroxytyrosine Alcohol fructoside and so on.
  • the hydroxytyrosol and its derivatives may be derived from chemical synthesis, microbial fermentation, or animal and plant extraction, for example, from olive fruits, olive leaves, or other extracts containing hydroxytyrosol and its derivatives.
  • the product for preventing and treating depression can be medicine, food, functional food, special medical food or cosmetics.
  • the antidepressant product may further contain acceptable auxiliary materials for preparing medicines, foods, functional foods, special medical foods, or cosmetics.
  • acceptable auxiliary materials for preparing medicines, foods, functional foods, special medical foods, or cosmetics.
  • the product for preventing and treating depression can be in the form of oral, injection or external use.
  • the oral dosage form includes, but is not limited to, lozenges, tablets, capsules, and granules; it is preferably a buccal dosage form, such as a sublingual lozenge.
  • the injection dosage form includes, but is not limited to, injection solution and powder injection.
  • the external dosage form includes, but is not limited to, suppositories, aerosols, films, and patches; it is preferably a pharmaceutical form for lumens, such as a pharmaceutical form for nasal passages, which can absorb the medicine through the nasal mucosa.
  • the antidepressant foods include but are not limited to baked goods, condiments, beverages, alcohols, milk and dairy products, frozen drinks, soups, nutrition bars, spreads, dietary supplements, food or feed additives, functional foods.
  • the products for preventing and treating depression can be used in combination with other antidepressant products to reduce the dosage of other products and reduce side effects. It can also be a compound preparation composed of hydroxytyrosol and its derivatives and other active ingredients, which has a synergistic effect and can improve the effect of treating depression and reduce side effects.
  • active ingredients are selected from but not limited to ingredients with antidepressant activity, such as sertraline hydrochloride, fluoxetine, paroxetine, citalopram, fluvoxamine, doxepin hydrochloride, selegiline, safinamide , Toloxadone; any sedative and hypnotic active ingredients, such as kwazepam, temazepam, sulazepam, ⁇ -aminobutyric acid; or any combination of ingredients with antioxidant activity, such as salidroside ; Hydroxysalidium glycosides, tyrosol; components with neurasthenia, such as gastrodin.
  • ingredients with antidepressant activity such as sertraline hydrochloride, fluoxetine, paroxetine, citalopram, fluvoxamine, doxepin hydrochloride, selegiline, safinamide , Toloxadone
  • any sedative and hypnotic active ingredients such as kwazepam, tema
  • the content of hydroxytyrosol and its derivatives is 0.01% -99.99%; preferably 0.05% -95%; more preferably 0.05% -65%; the% is 100% by volume Fractional content (w / v) or mass percentage content (w / w).
  • the percentage content in the oral product is 0.05% -60%; preferably 0.1% -40%.
  • the percentage content in the product for injection is 0.1% -95%; preferably 0.5% -50%.
  • the percentage content in external products is 0.1% -65%.
  • the present invention provides a new use of hydroxytyrosol and its derivatives for the preparation of antidepressant products, which can be used to prevent or treat depression and its complications, prevent the recurrence of depression, reduce the incidence of depression and improve patients with depression
  • the quality of life, combined with other antidepressant drugs, can reduce the side effects of other products.
  • the sublingual lozenges are prepared by conventional procedures.
  • the formula (made into 1000 tablets) is as follows:
  • wet granulation and tableting method weigh the prescribed amount of sucrose and microcrystalline cellulose, and then mix hydroxytyrosol and 10% starch slurry, add it as a binder to the soft material, pass a 20 mesh sieve, wet granules Dry at 70 °C for 1h, sift through 20 mesh sieve, add talcum powder and mix well, then press to obtain.
  • Soft capsules are prepared by conventional procedures, and the formula (made of 1000 capsules) is as follows:
  • the tablets are prepared through conventional procedures and the formula (made into 1000 tablets) is as follows:
  • the granules are prepared by conventional procedures.
  • the formula (1000 bags) is as follows:
  • Sodium bisulfite, sucrose and microcrystalline cellulose were mixed, and then hydroxytyrosol and starch slurry were mixed and added as a binder to make a soft material and passed through a 12 mesh nylon sieve.
  • the edible flavor that has passed through the 80 mesh sieve is mixed with the whole granules, and packed separately.
  • the injection solution (1000 pcs) is prepared through the conventional process, and the formula is as follows:
  • the injections (100 pcs) are prepared by conventional procedures, the formula is as follows:
  • the health drink is prepared through the conventional process, the formula is as follows:
  • the product formula of the present invention also adds an appropriate amount of citric acid and sucralose flavoring agent, and edible flavors.
  • the specific preparation process is in accordance with the food Routine operations in the field can be carried out.
  • the tablets are prepared through conventional procedures and the formula (made into 1000 tablets) is as follows:
  • Fluoxetine, powdered sugar, microcrystalline cellulose and sodium carboxymethyl starch were mixed, and then hydroxytyrosol and 10% starch slurry were mixed and added to make a soft material.
  • Wet granules were made through a 14 mesh nylon sieve at 45 ° C dry. The dried granules are sized through a 12-mesh nylon sieve, and then the granules are mixed with talc powder, and then passed through a 12-mesh nylon sieve. After passing the content test, the granules are compressed and obtained.
  • the preparation method is as follows:
  • the sublingual buccal tablets of hydroxytyrosol caproate are prepared by conventional procedures.
  • the formula (made into 1000 tablets) is as follows:
  • wet granulation and tableting method weigh the prescribed amount of sucrose and microcrystalline cellulose, and then mix hydroxytyrosol and 10% starch slurry, add it as a binder to the soft material, pass a 20 mesh sieve, wet granules Dry at 70 °C for 1h, sift through 20 mesh sieve, add talcum powder and mix well, then press to obtain.
  • Hydroxytyrosol and its derivatives were provided by Shandong College of Pharmaceutical Sciences. 70 ICR mice, weighing 18-22g, provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd., animal room temperature controlled at 20 °C -25 °C, relative humidity 45% -55%, 12h / 12h day and night, free water intake and diet .
  • model control group (0mg / kg / d)
  • hydroxytyrosol low-dose group (1mg / kg / d)
  • hydroxytyrosol medium-dose group (4mg / kg / d)
  • Hydroxytyrosol high-dose group (10mg / kg / d)
  • Example 8 group each tablet contains hydroxytyrosol 20mg, fluoxetine 5mg), fluoxetine group (3mg / kg / d), hydroxytyrosol Caproate group (4mg / kg / d).
  • each of the 6 test groups was gavaged with the sample once a day for 30 days with 0.1mL / 10g body weight; the model control group was gavaged with the corresponding solvent, and the gavage volume was 0.1mL / 10g body weight.
  • the tail of each group of mice was glued to the upper bracket of the hanging box (30 cm ⁇ 30 cm ⁇ 25 cm) with tape to make it upside down, the head About 5cm from the bottom of the box, two mice were hung at a time, separated by a partition.
  • the mouse struggled to overcome the abnormal posture, but the activity was intermittently immobile for a period of time, showing a state of disappointment.
  • the suspension time is 6min, and the cumulative immobility time of the suspended tail within 4min after the statistics (the immobile state means that the mouse stops struggling or has no activity), the results are shown in Table 1:
  • Example 8 group (4mg / kg / d hydroxytyrosol + 1mg / kg / d fluoxetine) compared with the hydroxytyrosol group (10mg / kg / d), there was no significant difference in the dangling time, And significantly better than hydroxytyrosol (4mg / kg / d) and fluoxetine group (3mg / kg / d), indicating that the combined use of the composition has a synergistic effect and helps to relieve the disease.
  • mice Hydroxytyrosol and its derivatives were provided by Shandong College of Pharmaceutical Sciences. 70 ICR mice, weighing 18-22g, provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd., animal room temperature controlled at 20 °C -25 °C, relative humidity 45% -55%, 12h / 12h day and night, free water intake and diet . After adapting to the environment for one week, the mouse depression model was injected intraperitoneally with corticosterone for 21 days. The success of the model was judged by observing the changes in animal behavior.
  • model control group (0mg / kg / d)
  • low-dose hydroxytyrosol group (1mg / kg / d)
  • medium-dose hydroxytyrosol group (4mg / kg / d)
  • Hydroxytyrosol high-dose group (10mg / kg / d)
  • Example 8 group each tablet contains hydroxytyrosol 20mg, fluoxetine 5mg), fluoxetine group (3mg / kg / d), hydroxytyrosol In the caproate group (4 mg / kg / d), 10 mice per group.
  • Each of the 7 test groups was given a sample by gavage once a day for 30 days, with an intragastric amount of 0.1 mL / 10g body weight; the model control group was gavaged with the corresponding solvent, with an intragastric amount of 0.1 mL / 10g body weight.
  • each group of mice was placed in an open box (55cm ⁇ 55cm ⁇ 40cm) without a lid, and the bottom of the box was divided into small squares of 11cm ⁇ 11cm with a white line.
  • the four walls are made of black to make a good contrast with the mouse in the darker room.
  • the camera was fixed above the center of the room, and the spontaneous activity of the mice was measured by video recording.
  • mice After the model was built for 21 days, the moving distance and the number of upright times of the mice were measured. The mouse was placed in the middle of the bottom of the box and allowed to move freely to adapt to the environment for 5 minutes. Then it was measured for 5 minutes, and recorded and observed with the camera each time. Between the two experiments, each cell at the bottom of the box was wiped clean with 70% ethanol. Each measurement time is 4 o'clock in the afternoon, the room is stable at 25 °C -28 °C, and keep the room quiet. Record the spontaneous activity of the mouse: every time the mouse passes a small grid or spans 10cm, it is counted as a parallel point, and the mouse's forelimbs standing upright or touching the carton wall are recorded as standing upright. The results are shown in Table 2:
  • Example 8 group (4 mg / kg / d hydroxytyrosol + 1 mg / kg / d fluoxetine) compared with the hydroxytyrosol group (10 mg / kg / d), the number of parallel shifts and the number of upright times were not significant Difference, and significantly better than hydroxytyrosol (4mg / kg / d) and fluoxetine group (3mg / kg / d), indicating that the combined use of the composition has a synergistic effect and helps to relieve the disease.
  • Hydroxytyrosol and its derivatives were provided by Shandong College of Pharmaceutical Sciences. 70 SD rats, weighing 183-224g, provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd., animal room temperature controlled at 20 °C -25 °C, relative humidity 45% -55%, day and night 12h / 12h, free water and food .
  • model control group (0mg / kg / d)
  • hydroxytyrosol low-dose group (0.5mg / kg / d)
  • hydroxytyrosol medium-dose group (2mg / kg / d)
  • Hydroxytyrosol high dose group (6mg / kg / d)
  • Example 8 group each tablet contains hydroxytyrosol 20mg, fluoxetine 5mg), fluoxetine group (2mg / kg / d), hydroxytyrosol Alcohol hexanoate group (4mg / kg / d).
  • Modeling and administration The rats in the blank control group were fed and drank normally, without any stimulation, and were fed in 5 cages; the remaining rats will be constructed for 6 weeks of chronic unpredictable mild stimulation depression models (single cage feeding). Choose one type of stress every day, different stress sources are randomly distributed, and the same stress source should be applied at least 7 days apart. Except for 24 hours of continuous stress, stress is applied every day from 8:30 to 12:00. Stress methods include: night lighting 12h, squirrel cage tilt 45 °, cold water (4 °C -8 °C) swimming 5min, 45 °C hot water swimming 5min, behavior limit 1h, wet litter 24h, tail pinching 1min, water ban 24h, Fasting for 24 hours, overnight in crowded squirrel cages, etc.
  • the sugar water preference test and forced swimming results showed that compared with the model control group, the sugar water preference and swimming immobility of the administration group were significantly improved, and were positively correlated with the dose.
  • Example 8 group (2mg / kg / d hydroxytyrosol + 0.5mg / kg / d fluoxetine) compared with hydroxytyrosol group (6mg / kg / d), sugar water preference and swimming immobility time were not significant sexual difference, and significantly better than hydroxytyrosol (2mg / kg / d) and fluoxetine group (2mg / kg / d), indicating that the combination of the composition has a synergistic effect and helps to relieve the disease.
  • Example 14 Effect of hydroxytyrosol on the content of monoamine neurotransmitters in the brain of depressed rats
  • Hydroxytyrosol and its derivatives were provided by Shandong College of Pharmaceutical Sciences. 70 SD rats, weighing 183-224g, provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd., animal room temperature controlled at 20 °C -25 °C, relative humidity 45% -55%, day and night 12h / 12h, free water intake and diet .
  • model control group (0mg / kg / d)
  • hydroxytyrosol low-dose group (0.5mg / kg / d)
  • hydroxytyrosol medium-dose group (2mg / kg / d)
  • Hydroxytyrosol high dose group (6mg / kg / d)
  • Example 8 group each tablet contains hydroxytyrosol 20mg, fluoxetine 5mg), fluoxetine group (2mg / kg / d), hydroxytyrosol Alcohol caproate group (2mg / kg / d).
  • the administration group started administration, once a day for 4 weeks (the model was continued during administration), and the model control group was orally administered the corresponding vehicle.
  • the rats were anesthetized by intraperitoneal injection of 0.35mL / 100g, and the brain was quickly stripped.
  • On the ice tray separate the cerebellum and the surrounding tissue of the hematoma.
  • Weighing taking 400mg tissue into a tissue homogenizer, added 0.1mol / L perchloric acid (containing 0.05% EDTA-Na 2) 1mL , homogenized in an ice-water bath. After completion, transfer the homogenate into a 1.5mL centrifuge tube, centrifuge at 10000r / min for 10min at 4 °C, take the supernatant and store in -80 °C refrigerator.
  • NE norepinephrine
  • DA dopamine
  • HT serotonin
  • the monoamine neurotransmitters in the administration group were significantly improved, and were positively correlated with the dose of hydroxytyrosol administered.
  • Example 15 Pharmacokinetic characteristics of hydroxytyrosol sublingual lozenges, hydroxytyrosol tablets and hydroxytyrosol caproate sublingual lozenges
  • Hydroxytyrosol sublingual buccal tablets (20mg / tablet), hydroxytyrosol tablets (20mg / tablet) and hydroxytyrosol caproate sublingual buccal tablets (20mg / tablet) were provided by Shandong Provincial College of Pharmaceutical Sciences, and the preparation methods are as in the examples One, two and ten are shown. 18 Beagle dogs, half male and half female, weighing 8.0-12kg, provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd. Animal room temperature is controlled at 20 °C -25 °C, relative humidity 45% -55%, day and night 12h / 12h, free water intake and diet.
  • the doses are all 40mg / piece. Randomly divided into three groups A, B and C. After fasting for 12 hours, group A was given hydroxytyrosol sublingual lozenges, group B was given hydroxytyrosol tablets orally, and group C was given hydroxytyrosol caproate sublingual lozenges. Before and after administration, 0.083, 0.167, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10h, 12 hours of blood were taken from the saphenous vein of the hind limbs, and the blood was collected by heparin anticoagulation , Separate the plasma and store it in the refrigerator at -20 °C to be tested. Animals were fed uniformly 4 hours after administration.
  • the Begle dogs were given the second dose 7 days after the first dose, and were killed immediately after 1 hour and the brain was quickly stripped.
  • On the ice tray separate the cerebellum and the surrounding tissue of the hematoma, weigh it, take 500mg of brain tissue, put it in a tissue homogenizer, add 2.5mL of physiological saline, and homogenize in an ice water bath. After completion, transfer the homogenate into a 1.5mL centrifuge tube, centrifuge at 10000r / min for 10min at 4 °C, take the supernatant and store in -80 °C refrigerator.
  • hydroxytyrosol was analyzed by LC-MS / MS.
  • hydroxytyrosol can enter the blood circulation to reach the peak faster through sublingual administration, and hydroxytyrosol can be enriched in the brain faster.
  • Hydroxytyrosol caproate can increase the plasma and brain tissue exposure levels of hydroxytyrosol, which is beneficial for hydroxytyrosol to enter the brain tissue through the blood-brain barrier to play the role of prevention and treatment of depression.

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Abstract

本发明提供了羟基酪醇及其衍生物在制备抗抑郁产品中的应用，属于生物医药领域。羟基酪醇衍生物选自羟基酪醇盐、羟基酪醇酯和羟基酪醇醚中的至少一种，可以来自化学合成、微生物发酵或动植物提取。所述预防和治疗抑郁症产品可以是药品、食品、功能性食品等。以羟基酪醇及其衍生物为活性成分制备的抗抑郁产品，具有预防和治疗抑郁症及预防抑郁症复发的作用，可用于降低抑郁症的发病率和改善抑郁症患者的生活质量。

Description

羟基酪醇及其衍生物在制备抗抑郁产品中的新应用 技术领域
本发明属于生物医药领域，具体涉及羟基酪醇的新用途。
背景技术
随着社会经济的不断发展，生活节奏的加快，社会竞争日益激烈，人们的心理压力逐渐增大，抑郁症发病率逐年上升。据世界卫生组织估计全世界抑郁症患病率约3％-5％，总计约1-2亿人。到2022年，抑郁症将成为发展中国家最严重的疾病负担。
抑郁症又称抑郁障碍，是一组以抑郁心境自我体验为中心的临床症状群或状态，以持久且显著的自发性心情低落为主要临床特征，是心境障碍的主要类型。临床病症主要有：情绪低落、不合群、离群、躯体不适、食欲不振及睡眠障碍；部分病例有明显的焦虑和运动性激越；严重者可出现幻觉、妄想等精神病性症状。抑郁症主要有以下几类：内源性抑郁症、反应性抑郁症、隐匿性抑郁症、以学习困难为特征的抑郁症、药物引起的继发性抑郁症、躯体疾病引起的继发性抑郁症、产后抑郁症等。目前，市场上治疗抑郁症的药物有帕罗西汀、舍曲林、氟伏沙明、文拉法辛，存在较多的药物副作用，如嗜睡、便秘、胃肠道不适、呼吸抑制、记忆力减退和依赖性等，寻找和开发更为安全的抗抑郁药具有重要意义。
目前，关于抑郁症发病机制的理论学说较多：单胺类神经递质学说，神经内分泌学说、神经可塑性学说等。其中，单胺类神经递质学说的研究最为广发和深入，其认为抑郁症发病与单胺类神经递质如5-羟色胺、去甲肾上腺素、多巴胺等神经递质水平下降有关。多巴胺是一种重要的儿茶酚胺类神经递质，用来帮助细胞传送脉冲的化学物质。这种脑内分泌物和人的情欲、感觉有关，可传递兴奋及开心的信息。伏隔核区和纹状体区多巴胺能受损，多巴胺水平降低，则会出现快感缺失、焦虑、食欲不振等抑郁症症状。脑内多巴胺水平可能是抑郁症严重程度和治疗效果指标之一，因而调节脑内多巴胺的水平对治疗抑郁症具有重要意义。
羟基酪醇(hydroxytyrosol，C 8H 10O 3，CAS：10597-60-1)，又称3,4-二羟基苯乙醇(3,4-dihydroxy phenylethanol)，是一种亲水亲脂的天然多酚化合物。常温低纯度时呈黄色油状物，高浓度时呈无色油状物，均有流动性；主要以橄榄苦苷的形式存在于橄榄科橄榄属的果实和树叶中，是橄榄油中的有效成分。由于具有邻苯二酚和苯乙醇的结构，羟基酪醇有很强的抗氧化性，近年来得到了广泛的关注。研究证明，羟基酪醇具有极强的抗氧化作用，对炎症的发生发展有着较好的抑制和预防疗效；对多巴胺能细胞具有潜在神经保护作用，能用于 治疗帕金森和阿尔兹海默综合征。现有技术已公开羟基酪醇的制备方法及其用于制造保护软骨、预防和治疗骨关节炎、降血脂、治疗黄斑眼病产品中的用途，但是，羟基酪醇作为预防和治疗抑郁症的用途还未见公开。
发明内容
针对现有技术中存在的问题，本发明提供一种羟基酪醇用于制备抗抑郁产品中的新用途，具有预防和治疗抑郁症及其并发症的病情，预防抑郁症复发的作用。
为实现上述目的，本发明采用如下技术方案。
羟基酪醇及其衍生物在制备预防和治疗抑郁症产品中的应用。可用于缓解和改善人在经受心理应激后引起的心理疾病病况；用于缓解和改善抑郁症中的各种病状，如：情绪低落、不合群、躯体不适、食欲不振及睡眠障碍等。
所述的羟基酪醇衍生物，选自羟基酪醇盐、羟基酪醇酯和羟基酪醇醚中的至少一种，其结构式为如式(Ⅰ)所示的化合物中部分或者全部的-OH与碱、酸、醇形成的盐、酯或醚：
Figure PCTCN2019073088-appb-000001
上述羟基酪醇衍生物在人体或者动物体内经水解可转变成羟基酪醇，产生相同或相近的生理活性。
所述羟基酪醇盐为羟基酪醇与无机或有机碱所形成的生理上可接受的盐。包括但不限于羟基酪醇的碱金属盐，如钠盐、钾盐；羟基酪醇的碱土金属盐，如钙盐、镁盐；铵盐；羟基酪醇与含氮有机碱形成的盐。所述含氮有机碱包括但不限于三甲胺、三乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二乙胺、二环己基胺、二苄基胺、N-苄基-β-苯乙基胺、N,N’-二苄基乙二胺、普鲁卡因(Procaine)、安非他明(Amphetamine)。
所述羟基酪醇酯为羟基酪醇与无机或有机酸形成生理上可接受的酯；所述无机酸选自硫酸、磷酸、碳酸、盐酸；所述有机酸选自甲酸、乙酸、丙酸、丁酸、马来酸、草酸、甲磺酸、琥珀酸或脂肪酸。
所述羟基酪醇醚包括羟基酪醇烷基醚、羟基酪醇芳基醚和羟基酪醇糖苷。所述的烷基醚可以是甲基、乙基、正丙基、正丁基、正己基、正辛基、异丙基或叔丁基。所述的芳基醚可以是含碳原子的芳香醚，也可以是含有氮原子、硫原子、氧原子的杂芳环醚；所述的羟基酪醇糖苷可以是羟基酪醇葡萄糖苷、羟基酪醇果糖苷等。
所述羟基酪醇及其衍生物可来自化学合成、微生物发酵或动植物提取，如，提取自橄榄果实、橄榄叶或其他含有羟基酪醇及其衍生物的提取物。
所述预防和治疗抑郁症产品，可以是药品、食品、功能性食品、特医食品或化妆品。
所述抗抑郁产品还可以包含制备药品、食品、功能性食品、特医食品或化妆品等可接受的辅料。如，填料、载体、乳化剂、赋形剂等。
所述预防和治疗抑郁症产品，可以为口服、注射或外用剂型。所述口服剂型包括但不限于含片、片剂、胶囊和颗粒剂；优选为含服剂型，如舌下含片。所述注射剂型包括但不限于注射液、粉针剂。所述外用剂型包括但不限于栓剂、气雾剂、膜剂、贴剂；优选为腔道用药剂型，如鼻腔用药剂型，可通过鼻粘膜吸收药剂。
所述抗抑郁食品包括但不限于焙烤食品、调味品、饮料类、酒类、乳与乳制品、冷冻饮品、汤、营养棒、涂抹物、膳食补充剂、食品或饲料添加剂、功能性食物。
所述预防和治疗抑郁症产品，可与其他抗抑郁产品联合应用，以降低其他产品的应用剂量，减少副作用。还可以是羟基酪醇及其衍生物与其他活性成分组成的复方制剂，具有协同增效作用，可以提高治疗抑郁的效果，降低副作用。
其他活性成分选自但不限于具有抗抑郁活性的成分，如盐酸舍曲林、氟西汀、帕罗西汀、西酞普兰、氟伏沙明、盐酸多塞平、司来吉兰、沙芬酰胺、托洛沙酮；具有镇静催眠活性的成分，如夸西泮、替马西泮、舒乐安定、γ-氨基丁酸中的任一种或组合；具有抗氧化活性的成分，如红景天苷；羟基红景天苷、酪醇；具有治疗神经衰弱作用的成分，如天麻素。
所述预防和治疗抑郁症产品中，羟基酪醇及其衍生物的含量为0.01％-99.99％；优选为0.05％-95％；更优选为0.05％-65％；所述％为质量体积百分含量(w/v)或质量百分含量(w/w)。
进一步的，在口服产品中的百分含量为0.05％-60％；优选为0.1％-40％。在注射用产品中的百分含量为0.1％-95％；优选为0.5％-50％。在外用产品中的百分含量为0.1％-65％。
本发明的有益效果为：
本发明提供了羟基酪醇及其衍生物用于制备抗抑郁产品的新用途，可用于预防或治疗抑郁症及其并发症病情，预防抑郁症复发，降低抑郁症的发病率和改善抑郁症患者的生活质量，与其他抗抑郁药品联用，可降低其他产品的副作用。
具体实施方式
下面结合实施例对本发明做进一步说明，但本发明不受下述实施例的限制。
实施例1 羟基酪醇舌下含片的制备
通过常规工序来制备舌下含片，配方(制成1000粒)如下：
Figure PCTCN2019073088-appb-000002
采用湿法制粒压片法，称取处方量的蔗糖和微晶纤维素混匀，再将羟基酪醇和10％淀粉浆混匀，作为粘合剂加入制软材，过20目筛，湿颗粒70℃干燥1h，20目筛整粒，加入滑石粉混匀，压片，即得。
实施例2 羟基酪醇软胶囊的制备
通过常规工序来制备软胶囊，配方(制成1000粒)如下：
Figure PCTCN2019073088-appb-000003
取处方量羟基酪醇，加植物油溶解，作为药液待用；另取甘油及水加热至70℃，搅拌溶化，加入明胶，搅拌2h后，出去上浮的泡沫，滤过。开启软胶囊机，打开左右胶盒及喷体加热，同时开启水泵循环和制冷。喷体设定43℃，左右胶盒设置60℃。预热完成后，调节俩侧制皮厚度均为0.70mm。胶皮调试好后，将药液加入料斗中，调节装量，压制软胶囊。将软胶囊清洗，晾干。
实施例3 羟基酪醇片剂的制备
通过常规工序来制备片剂，配方(制成1000片)，如下：
Figure PCTCN2019073088-appb-000004
将糖粉、微晶纤维素和羧甲基淀粉钠混匀，再将羟基酪醇和淀粉浆混匀作为粘合剂加入，制软材，过14目尼龙筛制湿颗粒，于45℃干燥，外加滑石粉，混匀后，过12目尼龙筛，颗粒经含量检测合格后，压片，即得。
实施例4 羟基酪醇颗粒剂的制备
通过常规工序来制备颗粒剂，配方(1000袋)如下：
Figure PCTCN2019073088-appb-000005
将亚硫酸氢钠、蔗糖和微晶纤维素混匀，再将羟基酪醇和淀粉浆混匀作为粘合剂加入，制软材，过12目尼龙筛。将已过80目筛的食用香精与整粒好的颗粒混合，分装，即得。
实施例5 羟基酪醇注射剂的制备
通过常规工序来制备注射液(1000支)，配方如下：
Figure PCTCN2019073088-appb-000006
在配制容器中，加入处方量80％的注射用水，通二氧化碳饱和，加羟基酪醇溶解后，加入预先配制好的依地酸二钠溶液和亚硫酸氢钠溶液，搅拌均匀，添加二氧化碳饱和的注射用水至足量，过滤除杂。在二氧化碳气流下分装，灌封，灭菌。
实施例6 羟基酪醇注射剂制备
通过常规工序来制备注射剂(100支)，配方如下：
Figure PCTCN2019073088-appb-000007
将维生素E溶于精制大豆油中，再加入羟基酪醇，均质，过滤除杂，灌注，灭菌，即得。
实施例7 保健饮料的制备
通过常规工序来制备保健饮料，配方如下：
Figure PCTCN2019073088-appb-000008
按照以上重量称取原料，以少量水溶解后，再补水至1000mL，灭菌、分装即得。其中，羟基酪醇和酪氨酸为主料，为进一步调节产品的风味和口感，本发明的产品配方中还添加了适量的柠檬酸和三氯蔗糖调味剂，以及食用香精，具体制备过程按照食品领域的常规操作进行即可。
实施例8 复方羟基酪醇片剂的制备
通过常规工序来制备片剂，配方(制成1000片)，如下：
Figure PCTCN2019073088-appb-000009
将氟西汀、糖粉、微晶纤维素和羧甲基淀粉钠混匀，再将羟基酪醇和10％淀粉浆混匀加入后制软材，过14目尼龙筛制湿颗粒，于45℃干燥。干颗粒过12目尼龙筛整粒，然后将此颗粒与滑石粉，混匀后，再过12目尼龙筛，颗粒经含量检测合格后，压片，即得。
实施例9 羟基酪醇己酸酯的制备
制备方法如下：
在2.3mL的吡啶中溶解1g羟基对羟苯基乙醇，用10mL甲苯稀释并在冰水浴中冷却。加入3mL己酰氯，生成固体。过夜，使混合物达到室温。把产物溶解在乙酸乙酯与水混合溶液中，保留有机相，除去水相。有机相依次用1.5mol/L的HCl溶液和4％的碳酸氢钠溶液洗涤，烘干水分，浓缩，即得羟基酪醇己酸酯，其氢谱表征为：
1H NMR(CDCl 3)δ7.0-6.8(m,3H)；4.40(t,2H,J＝7.1Hz)；2.90(t,2H,J＝6.8Hz)；2.22(t,2H,J＝7.3Hz)；2.23(t,2H,J＝7.3Hz)；2.25(t,2H,J＝7.4Hz)；1.35-2.32(m,6H)；1.56-1.25(m,12H),0.93-0.87(m,9H)；
化合物结构如下：
Figure PCTCN2019073088-appb-000010
实施例10 羟基酪醇己酸酯舌下含片的制备
通过常规工序来制备羟基酪醇己酸酯舌下含片，配方(制成1000粒)如下：
Figure PCTCN2019073088-appb-000011
采用湿法制粒压片法，称取处方量的蔗糖和微晶纤维素混匀，再将羟基酪醇和10％淀粉浆混匀，作为粘合剂加入制软材，过20目筛，湿颗粒70℃干燥1h，20目筛整粒，加入滑石粉混匀，压片，即得。
实施例11 悬尾法获得性绝望抑郁模型试验
羟基酪醇及其衍生物由山东省药学科学院提供。ICR小鼠70只，体重18-22g，济南朋悦实验动物繁育有限公司提供，动物室温度控制在20℃-25℃，相对湿度45％-55％，昼夜12h/12h，自由摄水和饮食。适应环境一周后，进行随机分为7组：模型对照组(0mg/kg/d)、羟基酪醇低剂量组(1mg/kg/d)、羟基酪醇中剂量组(4mg/kg/d)、羟基酪醇高剂量组(10mg/kg/d)、实施例8组(每粒药片含羟基酪醇20mg，氟西汀5mg)、氟西汀组(3mg/kg/d)、羟基酪醇己酸酯组(4mg/kg/d)。6个试验组各组灌胃给样品，每天1次，连续30d，0.1mL/10g体重；模型对照组用相应的溶媒灌胃，灌胃量为0.1mL/10g体重。于末次给予样品2h后，将各组小鼠分别尾端(在距尾尖部2cm处)用胶布粘于悬尾箱(30cm×30cm×25cm)上部支架上，使其成倒挂状态，头部离箱底约5cm，一次悬挂2只小鼠，中间用隔板隔开。小鼠为了克服不正常***而挣扎活动，但活动一段时间出现间断性不动，显示失望状态。悬挂时间为6min，统计后4min内悬尾累计不动时间(不动状态即小鼠停止挣扎或无任何活动)，结果如表1所示：
表1 羟基酪醇对小鼠悬尾试验的影响(mean±SD，n＝10)
组别 给药剂量(mg//kg/d) 动物数(只) 悬尾不动时间(s)
模型对照组 0 10 101±7.01
羟基酪醇低剂量组 1 10 87±5.45*
羟基酪醇中剂量组 4 10 74±7.35*
羟基酪醇高剂量组 10 10 62±4.37*
实施例8组 4羟基酪醇+1氟西汀 10 61±5.83*
氟西汀组 3 10 70±6.28*
羟基酪醇己酸酯组 4 10 72±5.48*
注：与模型对照组相比，*P<0.05。
由表1可见，给药动物组悬尾不动时间和模型对照组比较，均有显著性差异。其中，羟基酪醇的给药剂量越多，小鼠悬尾不动时间呈剂量依赖性缩短。羟基酪醇中剂量组(4mg/kg/d)、羟基酪醇己酸酯组(4mg/kg/d)与氟西汀组(3mg/kg/d)比较均没有显著性差异，说明羟基酪醇及其己酸酯衍生物均具备有改善病情或辅助治疗抑郁症的的效果。同时，实施例8组(4mg/kg/d羟基酪醇+1mg/kg/d氟西汀)与羟基酪醇组(10mg/kg/d)比较，悬尾不动时间未见显著性差异，且显著优于羟基酪醇(4mg/kg/d)和氟西汀组(3mg/kg/d)，说明组合物的搭配使用具有协同增效作用，有助于病情的缓解。
实施例12 旷场实验
羟基酪醇及其衍生物由山东省药学科学院提供。ICR小鼠70只，体重18-22g，济南朋悦实验动物繁育有限公司提供，动物室温度控制在20℃-25℃，相对湿度45％-55％，昼夜12h/12h，自由摄水和饮食。适应环境一周后，小鼠抑郁模型用皮质酮腹腔注射21d，通过观察动物行为学改变判断模型的成功。造模成功后，进行随机分为7组：模型对照组(0mg/kg/d)、羟基酪醇低剂量组(1mg/kg/d)、羟基酪醇中剂量组(4mg/kg/d)、羟基酪醇高剂量组(10mg/kg/d)、实施例8组(每粒药片含羟基酪醇20mg，氟西汀5mg)、氟西汀组(3mg/kg/d)、羟基酪醇己酸酯组(4mg/kg/d)，每组10只小鼠。7个试验组各组灌胃给样品，每天1次，连续30d，灌胃量为0.1mL/10g体重；模型对照组用相应的溶媒灌胃，灌胃量为0.1mL/10g体重。于末次给予样品2h后，将各组小鼠分别单独放在没有盖子的敞箱内(55cm×55cm×40cm)，在箱子的底部用白线分成11cm×11cm大小的小方格，此箱底和四壁制成黑色以便在较暗的房间里与小白鼠想成很好的对比。用摄影机固定于房间中心的上方，小鼠的自发活动被摄像记录测定。在造模21d后测定小鼠的移动距离和直立次数，把小鼠放在箱子的底部中间，让其自由活动适应环境5min后，再进行测量5min，每次用摄像机记录和观察。两次实验之间，箱子底部的每一小格用70％的乙醇擦洗干净。每次的测量时间均为下午4点，室内稳定25℃-28℃，并保持室内安静。记录小鼠的自发活动：小鼠每 通过一个小格或跨越10cm分别被记做平行1分，同时小鼠的双前肢直立或接触纸箱壁被记录为直立1次。结果如表2所示：
表2 羟基酪醇对小鼠平行移动格数和直立次数的影响(mean±SD，n＝10)
组别 给药剂量(mg//kg/d) 动物数(只) 平行移动格数 直立次数
模型对照组 0 10 1±0.41 0±0
羟基酪醇低剂量组 1 10 10±1.28* 1±0.31*
羟基酪醇中剂量组 4 10 19±1.23* 2±0.28*
羟基酪醇高剂量组 10 10 37±3.19* 3±0.25*
实施例8组 4羟基酪醇+1氟西汀 10 35±2.74* 3±0.34*
氟西汀组 3 10 18±3.62* 2±0.49*
羟基酪醇己酸酯组 4 10 18±4.21* 2±0.18*
注：与对照组相比，*P<0.05。
由表2可见，给药动物组平行移动格数和直立次数与模型对照组相比均有显著性差异。其中，羟基酪醇的给药剂量越多，小鼠活动次数呈剂量依赖性增多，探索行为增多。羟基酪醇中剂量组(4mg/kg/d)、羟基酪醇己酸酯组(4mg/kg/d)与氟西汀组(3mg/kg/d)相比均没有显著性差异，说明羟基酪醇及其己酸酯衍生物均具备有改善病情，治疗抑郁症的的效果。同时，实施例8组(4mg/kg/d羟基酪醇+1mg/kg/d氟西汀)与羟基酪醇组(10mg/kg/d)比较，平行移动格数和直立次数未见显著性差异，且显著优于羟基酪醇(4mg/kg/d)和氟西汀组(3mg/kg/d)，说明组合物的搭配使用具有协同增效作用，有助于病情的缓解。
实施例13 大鼠慢性不可预知轻度应激抑郁模型
羟基酪醇及其衍生物由山东省药学科学院提供。SD大鼠70只，体重183-224g，济南朋悦实验动物繁育有限公司提供，动物室温度控制在20℃-25℃，相对湿度45％-55％，昼夜12h/12h，自由摄水和饮食。
适应环境一周后，进行随机分为7组：模型对照组(0mg/kg/d)、羟基酪醇低剂量组(0.5mg/kg/d)、羟基酪醇中剂量组(2mg/kg/d)、羟基酪醇高剂量组(6mg/kg/d)、实施例8组(每粒药片含羟基酪醇20mg，氟西汀5mg)、氟西汀组(2mg/kg/d)、羟基酪醇己酸酯组(4mg/kg/d)。造模及给药：空白对照组大鼠正常摄食饮水，不给予任何刺激，5只一笼饲养；其余大鼠将进行6周的慢性不可预知温和刺激抑郁模型的构建(单笼饲养)。每天选用应激方式的1种，不同的应激源随机分布，间隔至少7d应用相同的应激源。除了24h持续压力，应激在每天8:30-12:00实施。应激方式包括：夜间照明12h、鼠笼倾斜45°、冷水(4℃-8℃)游泳5min、45℃热水游泳5min、行为限制1h、潮湿垫料24h、夹尾1min、 禁水24h、禁食24h、拥挤鼠笼过夜等。慢性应激2周后，所有大鼠再进行一次强迫游泳实验和蔗糖偏好实验。然后，给药组开始给药，每天1次，连续给药4周(给药期间继续造模)，模型对照组口服给予相应溶媒，采用强迫游泳实验和蔗糖偏好实验评价药物对小鼠抑郁样行为的影响。
在糖水测试前先用2瓶水让动物适应48h，第一个24h，两瓶均装有等量1％(w/v)蔗糖水。第二个24h，1瓶装有1％糖水，另1瓶装有等量纯净水，并且在12h后调换两个水瓶的位置。随后动物禁水不禁食，24h后进行糖水/纯水消耗实验。每笼放一只大鼠，同时给予每只大鼠事先称重好的几乎等量的两瓶水：1瓶1％糖水，另1瓶纯净水。测试时间为2h，测试1h后双瓶位置互换。测试结束后再次对双瓶进行称重。每只小鼠的糖偏好＝[糖水消耗量/(白水消耗量+糖水消耗量)]×100％，结果如表3所示：
表3 羟基酪醇对大鼠的糖偏好和强迫游泳行为的影响(mean±SD，n＝10)
Figure PCTCN2019073088-appb-000012
注：与模型对照组相比，*P<0.05。
糖水偏好试验及强迫游泳结果显示，与模型对照组相比，给药组糖水偏好及游泳不动时间均有显著改善，并与剂量呈正相关。羟基酪醇中剂量组(2mg/kg/d)、羟基酪醇己酸酯组(2mg/kg/d)与氟西汀组(2mg/kg/d)相比没有显著性差异，说明羟基酪醇及其己酸酯衍生物具备有治疗或辅助治疗抑郁症的的效果。同时，实施例8组(2mg/kg/d羟基酪醇+0.5mg/kg/d氟西汀)与羟基酪醇组(6mg/kg/d)比较，糖水偏好及游泳不动时间未见显著性差异，且显著优于羟基酪醇(2mg/kg/d)和氟西汀组(2mg/kg/d)，说明组合物的搭配具有协同增效作用，有助于病情的缓解。
实施例14 羟基酪醇对抑郁症大鼠脑内单胺类神经递质含量的影响
羟基酪醇及其衍生物由山东省药学科学院提供。SD大鼠70只，体重183-224g，济南朋悦实验动物繁育有限公司提供，动物室温度控制在20℃-25℃，相对湿度45％-55％，昼夜12h/12h，自由摄水和饮食。
适应环境一周后，进行随机分为7组：模型对照组(0mg/kg/d)、羟基酪醇低剂量组(0.5mg/kg/d)、羟基酪醇中剂量组(2mg/kg/d)、羟基酪醇高剂量组(6mg/kg/d)、实施例8组(每粒药片含羟基酪醇20mg，氟西汀5mg)、氟西汀组(2mg/kg/d)、羟基酪醇己酸酯组(2mg/kg/d)。
造模方法同实施例13。
慢性应激2周后，给药组开始给药，每天1次，连续给药4周(给药期间继续造模)，模型对照组口服给予相应溶媒。给药结束后，按0.35mL/100g腹腔注射麻醉大鼠，迅速剥取大脑。在冰盘上，分离除去小脑和血肿周边组织。称重，取400mg组织，放入组织匀浆器中，加入0.1mol/L高氯酸(含0.05％EDTA-Na 2)1mL，在冰水浴下匀浆。完成后，将匀浆转移入1.5mL离心管中，在4℃条件下，10000r/min离心10min，取上清液置-80℃冰箱保存。
分别精密称取去甲肾上腺素(NE)、多巴胺(DA)和5-羟色胺(5-HT)标准品适量，用0.1mol/L高氯酸(内含0.1％半胱氨酸)溶液分别配成质量浓度为1mg/mL的标准储备液，分别将储备液稀释成NE浓度0.1、0.5、1.5、3、4.5μg/mL，DA浓度为0.2、1、2、4、5μg/mL，5-HT浓度为0.5、1、1.5、2、3μg/mL，作为各组分的标准品对照液。
采用HPLC进行检测，色谱条件：色谱柱选择CLC-ODS柱，色谱的流动相为pH＝2.5离子对试剂(十二烷基硫酸钠0.15g，EDTA-Na 2 0.028g，pH＝2.5-3硫酸溶液0.2mL，10％甲醇溶液400mL，蒸馏水定容至1000mL)；流速1.2mL/min；柱温40℃。荧光激发波长285nm，发射波长313nm，进样量20μL，以峰面积外标法定量。
表4 羟基酪醇对大鼠的脑内的单胺类神经递质含量的影响(mean±SD，n＝10)
组别 给药剂量(mg/kg/d) 动物数(只) NE(μg/g) DA(μg/g) 5-HT(μg/g)
模型对照组 0 10 223±64.45 273±58.29 389±65.19
羟基酪醇低剂量组 0.5 10 458±60.15* 398±56.17* 567±82.41*
羟基酪醇中剂量组 2 10 658±72.11* 516±55.02* 762±75.84*
羟基酪醇高剂量组 6 10 858±62.75* 637±54.91* 1003±84.32*
实施例8组 2羟基酪醇+0.5氟西汀 10 869±73.12* 625±76.90* 994±85.32*
氟西汀组 2 10 634±61.94* 523±72.58* 774±72.65*
羟基酪醇己酸酯组 2 10 662±73.52* 531±73.76* 754±849.47*
注：与模型对照组相比，*P<0.05。
由表4可见，与模型对照组相比，给药组单胺类神经递质均有显著提高，并与羟基酪醇给药剂量呈正相关。羟基酪醇中剂量组(2mg/kg/d)、羟基酪醇己酸酯组(2mg/kg/d)与氟西汀组(2mg/kg/d)相比没有显著性差异，说明羟基酪醇及其己酸酯衍生物均可提高抑郁症动物脑内单胺类神经递质的水平。同时，实施例8组(2mg/kg/d羟基酪醇+0.5mg/kg/d 氟西汀)与羟基酪醇组(6mg/kg/d)比较，脑内单胺类神经递质的水平未见显著性差异，且显著优于羟基酪醇(2mg/kg/d)和氟西汀组(2mg/kg/d)，说明组合物的搭配具有协同增效作用，有助于抑郁症病情的缓解。
实施例15 羟基酪醇舌下含片、羟基酪醇片和羟基酪醇己酸酯舌下含片的药动学特征
羟基酪醇舌下含片(20mg/片)、羟基酪醇片(20mg/片)和羟基酪醇己酸酯舌下含片(20mg/片)由山东省药学科学院提供，制备方法如实施例一、二和十所示。Beagle犬18只，雌雄各半，体重8.0-12kg，济南朋悦实验动物繁育有限公司提供。动物室温度控制在20℃-25℃，相对湿度45％-55％，昼夜12h/12h，自由摄水和饮食。
给药剂量均为40mg/只。随机分为A、B和C三组，禁食12h后，A组给予羟基酪醇舌下含片，B组口服给予羟基酪醇片，C组给予羟基酪醇己酸酯舌下含片。分别于给药前及给药后0.083、0.167、0.25、0.5、1、1.5、2、3、4、6、8、10h共12个时间点于后肢隐静脉取血2mL，肝素抗凝收集血液，分离血浆并储存于-20℃冰箱保存待测。动物给药4h后统一进食。
上述Begle犬第一次给药7d后，进行第2次给药，给药1h时立即处死并迅速剥取脑。在冰盘上，分离除去小脑和血肿周边组织，称重，取500mg脑组织，放入组织匀浆器中，加入生理盐水2.5mL，在冰水浴下匀浆。完成后，将匀浆转移入1.5mL离心管中，在4℃条件下，10000r/min离心10min，取上清液置-80℃冰箱保存。
将血浆及脑组织匀浆样品在室温下解冻，取200μL置于1.5mL EP管中，加20μg/mL水杨苷(内标)对照品溶液10μL，涡旋混匀3min，加乙腈1mL，涡旋混匀3min，14800r/min离心12min，取上清液1mL，37℃氮气吹干，残渣加初始流动相120μL复溶，14800r/min离心15min，取上清液，进样测定。
采用LC-MS/MS对其中羟基酪醇含量进行分析。色谱柱：ACQUITY UPLC BEH C 18色谱柱(2.1mm×50mm，1.7μm)；色谱条件：流动相乙腈(A)-0.1％甲酸(B)，梯度洗脱(0-1min，95％B；1-3.5min，95％→5％B；3.5-5min，5％B；5-6min，5％→95％B；6-7.5min，95％B)；柱温：35℃；体积流量：0.3mL/min；进样量5μL；质谱条件：MRM多反应监测，电喷雾负离子源；毛细管电压2.5kV；提取电压3V；离子源温度120℃；脱溶剂气温度400℃；碰撞电压15V；锥孔电压30V；脱溶剂气体体积流量800L/h；羟基酪醇和水杨苷的选择检测离子质核比m/z分别为153.01→123.01、285.28→123.04。
方法学验证结果显示，本方法适用于生物样本中羟基酪醇的含量测定，线性范围为 5-1000ng/mL。所得羟基酪醇舌下含片、羟基酪醇片剂及羟基酪醇己酸酯Beagle犬体内的药动学参数如表5所示：
表5 Beagle犬血浆中羟基酪醇的药动学参数(mean±SD,n＝6)
Figure PCTCN2019073088-appb-000013
表6 给药1h后Beagle犬脑组织中羟基酪醇的浓度(mean±SD，n＝6)
Figure PCTCN2019073088-appb-000014
结果显示，与口服片剂比较，羟基酪醇经由舌下含服的给药方式能更快进入血液循环达到峰值，且羟基酪醇能更快富集于大脑。羟基酪醇己酸酯可提高羟基酪醇的血浆和脑组织暴露水平，有利于羟基酪醇透过血脑屏障进入脑组织发挥预防和治疗抑郁症的疗效。

Claims (11)

  1. 羟基酪醇及其衍生物在制备预防和治疗抑郁症产品中的应用；所述羟基酪醇衍生物的结构式为如式(Ⅰ)所示的化合物中部分或者全部的-OH与碱、酸、醇形成的盐、酯或醚：
    Figure PCTCN2019073088-appb-100001
    式(Ⅰ)。
  2. 根据权利要求1所述的应用，其特征在于，羟基酪醇盐选自羟基酪醇的碱金属盐，碱土金属盐，铵盐或羟基酪醇与含氮有机碱形成的盐。
  3. 根据权利要求2所述的应用，其特征在于，所述含氮有机碱选自三甲胺、三乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二乙胺、二环己基胺、二苄基胺、N-苄基-β-苯乙基胺、N,N’-二苄基乙二胺、普鲁卡因或安非他明。
  4. 根据权利要求1所述的应用，其特征在于，所述羟基酪醇酯为羟基酪醇与无机或有机酸形成生理上可接受的酯；所述无机酸优选自硫酸、磷酸、碳酸或盐酸；所述有机酸优选自甲酸、乙酸、丙酸、丁酸、马来酸、草酸、甲磺酸、琥珀酸或脂肪酸。
  5. 根据权利要求1所述的应用，其特征在于，所述羟基酪醇醚包括羟基酪醇烷基醚、羟基酪醇芳基醚和羟基酪醇糖苷。
  6. 如权利要求1所述的羟基酪醇及其衍生物可来自化学合成、微生物发酵或动植物提取；所述植物可以是橄榄果实、橄榄叶或其他含羟基酪醇或其衍生物的植物。
  7. 根据权利要求1所述的应用，其特征在于，所述预防和治疗抑郁症产品选自药品、食品、功能性食品或特医食品。
  8. 根据权利要求7所述的应用，其特征在于，所述预防和治疗抑郁症产品为口服、注射、外用药品；口服药品优选为舌下含服剂型；注射药品优选为注射剂；外用药品优选为鼻腔用药。
  9. 根据权利要求1所述的应用，其特征在于，羟基酪醇及其衍生物可以与其他活性成分组合成复方制剂。
  10. 根据权利要求9所述的应用，其特征在于，其他活性成分选自具有抗抑郁活性的成分；如盐酸舍曲林、氟西汀、帕罗西汀、西酞普兰、氟伏沙明、盐酸多塞平、司来吉兰、沙芬酰胺、托洛沙酮；具有镇静催眠活性的成分；如夸西泮、替马西泮、舒乐安定、γ-氨基丁酸中的任一种或组合；具有抗氧化活性的成分；如红景天苷；羟基红景天苷、酪醇；具有治疗神经衰弱作用的成分；如天麻素。
  11. 根据权利要求1-10任一所述的应用，其特征在于，所述预防和治疗抑郁症产品中，羟基 酪醇及其衍生物的含量为0.01％-99.99％；优选为0.05％-95％；更优选为0.05％-65％；所述％为质量体积百分含量(w/v)或质量百分含量(w/w)。
PCT/CN2019/073088 2018-10-17 2019-01-25 羟基酪醇及其衍生物在制备抗抑郁产品中的新应用 WO2020077915A1 (zh)

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