WO2021120972A1 - 一种治疗气血两虚症候的中药组合物及其制备方法和应用 - Google Patents

一种治疗气血两虚症候的中药组合物及其制备方法和应用 Download PDF

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WO2021120972A1
WO2021120972A1 PCT/CN2020/130097 CN2020130097W WO2021120972A1 WO 2021120972 A1 WO2021120972 A1 WO 2021120972A1 CN 2020130097 W CN2020130097 W CN 2020130097W WO 2021120972 A1 WO2021120972 A1 WO 2021120972A1
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chinese medicine
traditional chinese
blood
medicine composition
parts
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French (fr)
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周厚成
胡昌江
黄宇
仰莲
马彤
姜艳娇
张希
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四川新绿色药业科技发展有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/72—Rhamnaceae (Buckthorn family), e.g. buckthorn, chewstick or umbrella-tree
    • A61K36/725—Ziziphus, e.g. jujube
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A61K36/815—Lycium (desert-thorn)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction

Definitions

  • the invention relates to a traditional Chinese medicine composition for the treatment of deficiency of both qi and blood, and a preparation method and application thereof, in particular to a traditional Chinese medicine composition of Astragalus and Angelica for the treatment of deficiency of both qi and blood, and a preparation method and application thereof, belonging to Chinese medicine technology field.
  • Deficiency of both qi and blood refers to the syndrome of insufficient qi and blood loss, that is, a pathological state where qi deficiency and blood deficiency exist at the same time. It is often caused by long-term illness and injury of qi and blood. It can cause blood deficiency due to qi deficiency and inability to produce blood. It can also cause qi deficiency due to blood deficiency. The clinical manifestations of qi deficiency and blood deficiency coexist. Symptoms include lack of qi and laziness, fatigue, spontaneous sweating, dizziness, palpitations, insomnia, pale or chlorosis. The treatment is to supplement both qi and blood.
  • Fang uses Astragalus (one or two), Chinese angelica (wine wash, two money), and the top piece of glutinous rice. Take two cups of water, fry until one cup, and remove the slag. Take warm, hollow before eating. ". It has the functions of invigorating qi and promoting blood, and mainly treats the syndrome of blood deficiency and yang floating and fever.
  • patent literature In order to better adapt to the evolution of modern diseases, the existing patent literature also records a variety of pharmaceutical compositions for the treatment of symptoms of deficiency of both Qi and blood. On the basis of Danggui Buxue Decoction, it also increases the spleen and kidney, strengthens immunity, Adjust human body functions and other functions, such as: patent document CN106310209A (a traditional Chinese medicine preparation and preparation method for treating Qi and blood deficiency, 2017.01.11) and patent document CN101804155A (a method for tumor radiotherapy, chemotherapy and postoperative physical weakness caused by Drugs for deficiency of both qi and blood and preparation methods thereof, 2012.02.01) and so on.
  • patent document CN106310209A a traditional Chinese medicine preparation and preparation method for treating Qi and blood deficiency, 2017.01.11
  • patent document CN101804155A a method for tumor radiotherapy, chemotherapy and postoperative physical weakness caused by Drugs for deficiency of both qi and blood and preparation methods thereof, 2012.02.01
  • the purpose of the present invention is to provide a Chinese medicinal composition for the treatment of deficiency of both qi and blood, which is composed of five herbs of astragalus, angelica, jujube, medlar and tangerine peel or extracts thereof, and the combined use of astragalus and angelica for growth of yang and yin, Qi vigorous and blood, and supplemented with wolfberry, jujube and tangerine peel, the whole prescription has the effects of nourishing the liver and kidney, strengthening the spleen and regulating qi, strengthening the body, strengthening the body's immune function and strengthening the body's immune function. It is mainly suitable for work pressure People with low immune function caused by excessive fatigue, insufficient postpartum qi and blood, and cancer after radiotherapy and chemotherapy.
  • Another object of the present invention is to provide a preparation method of the traditional Chinese medicine composition, which can be used to prepare prescription granules and ointments.
  • Another object of the present invention is to provide the application of the traditional Chinese medicine composition in the preparation of medicines or health care products for the treatment of deficiency of both qi and blood.
  • the present invention is realized by the following technical scheme: a traditional Chinese medicine composition for the treatment of deficiency of both qi and blood, in parts by weight, comprising the following components: Astragalus or its extract 25 ⁇ 35, Angelica or its extract 5 ⁇ 7 parts, 8-12 parts of jujube or its extract, 5-10 parts of wolfberry or its extract, 5-8 parts of tangerine peel or its extract.
  • the traditional Chinese medicine composition includes at least the following active ingredients: mullein glucoside ⁇ 0.10 mg/g, astragaloside ⁇ 0.45 mg/g, ferulic acid ⁇ 0.05 mg/g, and wolfberry polysaccharide ⁇ 8.0 mg/g.
  • a preparation method of a traditional Chinese medicine composition for treating deficiency of both qi and blood includes the following steps:
  • step (2) Take 25 ⁇ 35 parts of Astragalus, 5 ⁇ 7 parts of Angelica, 8 ⁇ 12 parts of Jujube, 5 ⁇ 10 parts of Chinese wolfberry, and 5 ⁇ 8 parts of dried tangerine peel by weight, mix with water, heat and extract, then filter , Concentrate to obtain a concentrated solution, the concentrated solution is carried out according to step (2) or step (3);
  • the raw materials are soaked in water, heated to boiling, kept slightly boiling for 1.5-2h, then filtered, the filter residue is added with water, heated to boiling, kept slightly boiling for 1.5-2h, then filtered, and the two filtrates are combined and used concentrate.
  • the concentration includes: concentrating the combined filtrate at a vacuum degree of -0.085 ⁇ -0.065Mpa and a temperature of 60 ⁇ 80°C, and concentrating to a relative density of 1.05 ⁇ 1.15 to obtain a concentrated solution.
  • the concentrated liquid is mixed with auxiliary materials in a weight ratio of 1:0.1-1.0, and the auxiliary materials are selected from at least one of refined honey or xylitol, maltitol, maltitol liquid, and maltose.
  • the concentrated liquid is mixed with the auxiliary materials in a weight ratio of 5-10:1, and the auxiliary materials are selected from at least one of soluble starch and maltodextrin.
  • the present invention has the following advantages and beneficial effects:
  • the present invention proposes a Chinese medicinal composition composed of five herbs of astragalus, angelica, jujube, wolfberry, tangerine peel or extracts thereof.
  • the Chinese medicinal composition is based on the traditional classic prescription "Danggui Buxue Decoction" Combined with modern pharmacological research knowledge, supplemented with jujube, wolfberry, and dried tangerine peel, a traditional Chinese medicine has been developed that can effectively treat the syndrome of deficiency of both qi and blood, nourish the liver and kidney, strengthen the spleen and regulate qi, strengthen the body, strengthen the body and strengthen the body.
  • a composition in which the active ingredients of Verbasil isoflavone glucoside are not less than 0.10 mg/g, astragaloside IV is not less than 0.45 mg/g, ferulic acid is not less than 0.05 mg/g, and Lycium barbarum polysaccharide is not less than 8.0 mg/g. g. At the same time, good therapeutic effects have been achieved clinically.
  • the traditional Chinese medicine composition of the present invention utilizes jujube, wolfberry, tangerine peel and astragalus, angelica to make a reasonable compatibility, and adopts water extraction technology to obtain the extract, which can effectively improve the versicolor isoflavone glucoside and astragaloside IV in the traditional Chinese medicine composition.
  • the transfer rate of effective ingredients such as Astragalus and Angelica can fully exert the curative effect of Astragalus and Angelica in treating Qi and Blood Deficiency Syndrome, while ensuring drug safety.
  • the traditional Chinese medicine composition of the present invention can be used in the preparation of medicines or health products for the treatment of deficiency of both qi and blood, and has a wide range of applications. It can be used in health wines, health foods, health drinks, etc., and can promote immunity and relieve Fatigue effect. It is suitable for people with low immunity caused by high work pressure, excessive fatigue, and people with low immunity after childbirth, cancer radiotherapy and chemotherapy.
  • the traditional Chinese medicine composition for treating Qi and blood deficiency syndromes of the present invention uses 25-35 parts by weight of Astragalus or its extract, 5-7 parts by weight of Angelica or its extract, 8-12 parts by weight of Jujube or its extract, and Chinese wolfberry It is composed of 5-10 parts by weight of its extract and 5-8 parts by weight of tangerine peel or its extract.
  • the traditional Chinese medicine composition is through the mutual combination and compatibility of various drugs.
  • the traditional Chinese medicine composition can be an ointment or granular preparation of the traditional Chinese medicine composition, which is prepared by the following methods:
  • Astragalus remove impurities, separate the size, wash, moisten thoroughly, cut into thick slices (2 ⁇ 4mm), and dry (70 ⁇ 5°C).
  • Angelica Remove impurities, wash, moisturize, slice (1 ⁇ 2mm), dry at low temperature (55 ⁇ 5°C).
  • Chenpi remove impurities, spray with water, moisten thoroughly, cut into shreds, and dry (55 ⁇ 5°C).
  • the combined filtrate is stirred uniformly, and concentrated at a vacuum degree of -0.085 ⁇ -0.065Mpa and a temperature of 60 ⁇ 80°C, and concentrated to a relative density of 1.05 ⁇ 1.15 (60 ⁇ 80°C) to obtain a concentrated solution.
  • the auxiliary material may be at least one of refined honey or xylitol, maltitol, maltitol liquid, and maltose.
  • the method of refining honey is: putting the honey in a pot, heating it with a martial fire (100-120°C), then using a slow fire (70-90°C) after boiling, and removing floating foam and wax from time to time. Boil until the honey swells and foams and presents a light red luster, and the white silk is sticky but cannot be pulled by hand.
  • step (5) The same as the above steps (1) to (3), and then the concentrate is subjected to the operation of step (5).
  • the obtained concentrated liquid and auxiliary materials are mixed in a weight ratio of 5-10:1, stirred evenly, the mixture is freeze-dried or spray-dried, sieved to obtain a fine dry powder, and the fine dry powder is then squeezed, crushed, and granulated to make The required granules must have a moisture content of less than 6.5%.
  • the auxiliary material can be at least one of soluble starch and maltodextrin.
  • the traditional Chinese medicine composition can be used to prepare medicines or health products for treating Qi and blood deficiency syndrome.
  • the drugs can be administered in the form of tablets, dragees, gelatin capsules, injectable preparations, drinkable suspensions or disintegrable pastes.
  • the medicine may only be a Chinese medicine composition with an effective content, or a medicine composition containing the Chinese medicine composition.
  • the medicine may be formed by compounding an effective dose of the Chinese medicine composition with a pharmaceutically acceptable drug carrier. combination.
  • Health care products can be used as carriers in tea, wine, bee products, beverages, soups, fresh juices, medicated diets, etc., and use effective content of traditional Chinese medicine compositions as the functional part of them to treat the symptoms of deficiency of both qi and blood in the human body. Adjustment and improvement.
  • Examples 1 to 5 all relate to a traditional Chinese medicine composition ointment for treating Qi and blood deficiency syndrome.
  • Examples 6 to 10 all relate to a Chinese medicine composition granule for the treatment of deficiency of both qi and blood.
  • Verbasil glucoside (C 22 H 22 O 10 ) was determined for the Chinese medicine composition products involved in the foregoing Examples 1-10.
  • Chromatographic conditions and system suitability test use octadecylsilane-bonded silica gel as filler; use acetonitrile as mobile phase A, 0.2% formic acid solution as mobile phase B, and perform gradient elution as specified in Table 3;
  • the detection wavelength is 260nm.
  • the number of theoretical plates should not be less than 3000 based on the peak of mullein glucoside.
  • Preparation of the reference solution Take an appropriate amount of the Verbasil glucoside reference substance, accurately weigh it, and add methanol to make a solution containing 50 ⁇ g per 1 ml.
  • Preparation of test solution Take about 2g of the preparation, accurately weigh it into a 50ml volumetric flask, add water to dissolve it to the mark, shake well, filter, and get it.
  • Determination method accurately draw 10 ⁇ l each of the reference solution and the test solution, inject it into the liquid chromatograph, and determine it.
  • Determination of the content of decoction pieces of astragalus A total of three pieces of decoctions of astragalus were taken, and the content of decoction pieces of astragalus were determined according to the processing requirements of the 2015 edition of "Chinese Pharmacopoeia”. The determination method was determined by high performance liquid chromatography (General Principle 0512) and calculated The average value of Verbasil glucoside in three pieces of astragalus decoction.
  • the content of astragaloside IV (C 41 H 68 O 14 ) was determined for the Chinese medicine composition products involved in the foregoing Examples 1-10.
  • Preparation of reference substance solution Take an appropriate amount of astragaloside IV reference substance, accurately weigh it, and add 80% methanol to make a solution containing 0.5 mg per 1 ml.
  • test solution Take about 1.0g of this product, place it in a conical flask with a stopper, and accurately add 80% methanol containing 4% concentrated ammonia test solution (take 4ml of concentrated ammonia test solution, add 80% methanol to 100ml, Shake well) 50mL, tightly plugged, weighed, heated to reflux for 1 hour, let cool, and then weighed.
  • Determination method accurately draw 5 ⁇ l and 10 ⁇ l of the reference solution and 10-20 ⁇ l of the test solution respectively, inject into the liquid chromatograph, determine, and calculate with the logarithmic equation of the external standard two-point method to obtain.
  • Determination of the content of decoction pieces of astragalus A total of three pieces of decoctions of astragalus were taken, and the content of decoction pieces of astragalus were determined according to the processing requirements of the 2015 edition of "Chinese Pharmacopoeia”. The determination method was determined by high performance liquid chromatography (General Principle 0512) and calculated The average content of astragaloside IV in three astragalus decoction pieces.
  • the content of ferulic acid (C 10 H 10 O 4 ) was determined for the Chinese medicine composition products involved in the foregoing Examples 1-10.
  • Preparation of reference substance solution Take an appropriate amount of ferulic acid reference substance, accurately weigh it, place it in a brown measuring flask, add 70% methanol to make a solution containing 12 ⁇ g per 1ml, and get it.
  • Preparation of the test solution Take about 1g of the preparation, accurately weigh it, place it in a stoppered conical flask, add 20ml of 70% methanol tightly, weigh it, ultrasonically treat it for 30 minutes, let it cool, and then weigh it. , Use 70% methanol to make up the lost weight, shake well, stand still, take the supernatant and filter, and take the subsequent filtrate to get it.
  • Determination method accurately draw 10 ⁇ l each of the reference solution and the test solution, inject it into the liquid chromatograph, and determine it.
  • Determination of the content of decoction pieces of Angelica sinensis A total of three pieces of decoction pieces of Angelica sinensis were taken, and the content of the decoction pieces of Angelica sinensis were determined according to the processing requirements of the 2015 edition of "Chinese Pharmacopoeia”. The determination method was determined according to the high performance liquid chromatography (General Principle 0512) and calculated The average value of ferulic acid in three pieces of Angelica sinensis.
  • Lycium barbarum polysaccharide (C 6 H 12 O 6 ) was determined for the Chinese medicinal composition products involved in the foregoing Examples 1-10.
  • the specific measurement method is as follows:
  • Preparation of reference substance solution Take 25mg of anhydrous glucose reference substance, accurately weigh it, put it in a 250ml measuring flask, add an appropriate amount of water to dissolve, dilute to the mark, and shake well to obtain (each 1ml contains 0.1mg of anhydrous glucose).
  • Determination method Take about 0.5g of the preparation, accurately weigh it, add 100ml of 80% ethanol, heat to reflux for 1 hour, filter while hot, wash the filter residue and filter with 30ml of hot 80% ethanol, put the filter residue and filter paper in the flask, add water 150ml, heated to reflux for 2 hours.
  • Determination of the content of decoction pieces Three parts of wolfberry medicinal materials were taken for content determination. The determination method was determined by high performance liquid chromatography (General Principle 0512), and the average value of the content of wolfberry polysaccharides in the three parts of wolfberry medicinal materials was calculated.
  • the above-mentioned comparative examples 1 to 4 are specifically According to the research on the effect of the effective ingredients in the relevant prescriptions under different compatibility, to establish the content determination method in the traditional Chinese medicine composition, to determine the content of the effective ingredients such as the verbasil glucoside and astragaloside IV, and calculate the corresponding conversion rate at the same time.
  • the experimental group invited a number of female subjects who had syndromes of deficiency of both qi and blood through traditional Chinese medicine to participate in the clinical study.
  • Prescription 1 Astragalus 30g, Angelica 6g, Jujube 10g, Lycium barbarum 8g, Tangerine peel 6g (for prescription dosage refer to Example 4);
  • Prescription 2 Astragalus 30g, Angelica 6g (for prescription dosage refer to Comparative Example 1);
  • Prescription 3 Astragalus 30g, Chinese wolfberry 10g, Chinese yam 10g, Angelica 6g, Ginseng 15g, Amomum 5g, Zao kernel 6g, Mulberry 3g (for prescription dosage refer to Comparative Example 5);
  • Prescription 4 Rehmannia glutinosa, yam, wolfberry, cornus, achyranthes, dodder, rhodiola, tuckahoe, ginseng, cinnamon, eucommia, dipsacus, mulberry, red peony, white peony, roasted licorice, chuanxiong 5g each .
  • the subjects were divided into 4 groups, 5 people in each group, and they were taken according to the above prescription for 2 weeks, 1 dose per day, divided into 3 times. Observe the improvement of Qi and blood deficiency symptoms in each group, see Table 18 below.
  • the improvement is based on an average score of 5 points, of which 1-2 is average; 3-4 is good; 5 is basically cured.
  • prescription one and prescription two only use less medicinal prescriptions, which can still exert a better effect of nourishing blood and nourishing qi.
  • Prescription 1 Astragalus 30g, Angelica 6g, Jujube 10g, Lycium barbarum 8g, Tangerine peel 6g (for prescription dosage refer to Example 4);
  • Prescription 2 Astragalus 30g, Angelica 6g (for prescription dosage refer to Comparative Example 1);
  • Prescription 5 10g jujube, 10g wolfberry, 7g tangerine peel;
  • Prescription 6 Astragalus 30g, Angelica 6g, Jujube 10g, Lycium barbarum 10g, Tangerine peel 7g, Rehmannia root 6g, Yam 10g, Morus alba 6g.
  • each prescription was weighed 30 times the amount of each prescription according to the compatibility of the prescription, mixed and stirred evenly, added 12 times the prescription amount of water, decocted twice, 90 minutes each time, filtered, two times The filtrates were combined. The combined extracts are mixed and concentrated into a concentrated solution with a concentration of 1.2 to 1.5 g/mL of crude drug.
  • SOD and MDA content determination experiment A total of 50 Kunming mice, male, weighing 18-22g, were randomly divided into 5 groups, each with 10 mice, respectively, one prescription group, prescription group two, prescription group five, Six prescription groups and a blank control group.
  • the control group was given the same volume of distilled water for 30 days without interruption, and the weight of each mouse was weighed after 30 minutes of intragastric administration on the 30th day.
  • Blood was collected from mouse eyeballs. The whole blood was collected in a 1.5mL EP tube without anticoagulant, placed in a refrigerator at 4°C for 3h, and centrifuged at 3500r/min for 15min after blood clotting. The serum was collected and the blood was collected according to the SOD test box, The MDA test box detects the SOD activity ability and MDA content in the serum of each group of mice.
  • Zhishu Decoction and Zhizhu Pills both of which are combined with the Qi-invigorating Zhishi and Atractylodes Atractylodes which invigorate Qi and invigorate the spleen.
  • Zhishi is more important than Atractylodes.
  • Baizhu is heavier than that of Citrus aurantium, replenishing weight while eliminating, mainly replenishing, and is a pill, which has a slower effect and is suitable for spleen deficiency and qi stagnation. Stop this full proof of swelling in the chest.
  • Another example is Didang Decoction and Didang Pill.
  • the prescriptions are all composed of leeches, horsefly, rhubarb, and peach kernels.
  • Didang decoction is a decoction, which mainly treats the severe symptoms of scorching blood accumulation, body heat, low abdomen, and self-interested urination, which makes people go crazy or mad; while Didang pill is reduced by leech and horsefly, rhubarb is the same amount, and peach kernels Increased amount is made into pills, which are mainly used to treat the mild syndrome of blood accumulation under the scorch.
  • the body is hot, the abdomen is less full but not hard, the urine is self-interested, and there is no madness.
  • Astragalus, angelica, jujube, wolfberry, and dried tangerine peel can be used to invigorate qi and blood, and invigorate the spleen in the theoretical guidance of traditional Chinese medicine.
  • the compatibility ratio of the traditional Chinese medicine composition involved in this application is strictly based on the functional symptoms used, the dosage is accurate, and the curative effect is obvious.
  • the experimental group used the establishment of a composite anemia model and an animal model of anemia after chemotherapy to investigate its blood-enriching effect under different dosages.
  • Prescription 1 Astragalus 30g, Angelica 6g, Jujube 10g, Lycium barbarum 8g, Tangerine peel 6g (for prescription dosage refer to Example 4);
  • Prescription 7 Astragalus 10g, Angelica 10g, Jujube 5g, Lycium barbarum 5g, Tangerine peel 10g;
  • Prescription 8 Astragalus 12g, Angelica 6g, Jujube 20g, Lycium barbarum 20g, Tangerine peel 7g;
  • Modeling medicine Cyclophosphamide for injection (0.2ml/piece), produced by Shanxi Taisheng Pharmaceutical Co., Ltd. (National Medicine Standard H18010373).
  • EDTA-ka2 anticoagulant is provided by Boster Biotech Co., Ltd.
  • mice in the other groups were bled 0.4ml for 1-3 days, 0.3ml for 4-5 days, and 0.4ml for 6-7 days; Fasting every other day.
  • the modeling cycle is 12 days.
  • mice in the other groups were injected intraperitoneally with a dose of 200 mg/kg body weight per day on 1d and 3 days respectively; for 5 days and 7 days, a ring was injected intraperitoneally with a dose of 100 mg/kg body weight per day. Phosphoramide. A total of 4 injections. The modeling cycle is 14 days.
  • Each prescription was 30 times the amount according to the compatibility of the prescription, and each piece was weighed, mixed and stirred evenly, added 12 times the prescription amount of water, decocted twice for 90 minutes each time, filtered, and the two filtrates were combined.
  • the combined extracts are mixed and concentrated into a concentrated solution with a concentration of 1.2 to 1.5 g/mL of crude drug.
  • prescription 1, prescription 7, and prescription 8 can all reduce the weight loss trend of mice in the anemia model group to a certain extent. There is a significant advantage in body weight, and the data is statistically significant (P ⁇ 0.05).
  • the peripheral blood red blood cell count of the mice in the compound anemia model group was significantly decreased, which was statistically significant (P ⁇ 0.05).
  • the dose ratio of this group can significantly increase the peripheral blood of the mice. Red blood cell count; at the same time, compared with the normal group, the peripheral white red blood cell count of the mice in the chemotherapy anemia model group was significantly reduced, which was statistically significant (P ⁇ 0.05).
  • the dose ratio of this group can significantly increase the peripheral white blood cell count of the mice. The number of white and red blood cells.
  • the experimental results of the anemia model show that with 30g of astragalus, 6g of angelica, 10g of jujube, 8g of wolfberry, and 6g of tangerine peel (prescription 1), it has obvious advantages in improving the weight of mice and increasing the number of peripheral blood cells. Prove the accuracy and superiority of the dose ratio of this group of prescriptions.

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Abstract

本发明公开了一种治疗气血两虚症候的中药组合物及其制备方法和应用，按重量分数计，包括黄芪或其提取物25～35份、当归或其提取物5～7份、大枣或其提取物8～12份、枸杞或其提取物5～10份、陈皮或其提取物5～8份，该原料组分经炮制、提取、浓缩、辅料混合后可分别制备得到中药组合物的膏剂或颗粒制剂，可在制备治疗气血两虚症候药物或保健品中的应用。全方共具滋补肝肾、健脾理气、益卫固表、扶正固本之效，从而增强机体免疫机能，主要适用于工作压力大，过度疲劳，产后气血不足，癌症放化疗后而造成的免疫功能低下人群。

Description

一种治疗气血两虚症候的中药组合物及其制备方法和应用 技术领域
本发明是一种治疗气血两虚症候的中药组合物及其制备方法和应用，具体涉及用于治疗气血两虚症候的黄芪当归的中药复方组合物及其制备方法和应用，属于中药技术领域。
背景技术
气血两虚是指气血均亏损不足的证候，即气虚和血虚同时存在的病理状态，多由久病不愈，气血两伤所致，可因气虚不能生血而致血虚，亦可因血虚而致气虚。临床表现气虚与血虚同时存在，症见少气懒言、神疲乏力、自汗、眩晕、心悸失眠、面色淡白或萎黄等。治当气血双补。
传统中医经典名方制剂“当归补血汤”始载于金·李东垣著《内外伤辨惑论》，原方描述：“治肌热、燥热，困渴引饮，目赤面红，昼夜不息，其脉洪大而虚，重按全无。《内经》曰：脉虚血虚。又云：血虚发热，证象白虎，惟脉不长实为辨耳，误服白虎汤必死。此病得之于饥困劳役。方用黄芪(一两)，当归(酒洗，二钱)，上件罳咀，都作一服，水二盏，煎至一盏，去渣。温服，空心食前”。具补气生血等功效，主治血虚阳浮发热证。现代医学研究例如：王燕平等在《中草药》(2002，33(2)：138-138)中记载的“在当归补血汤中不同组分对正常及血虚小鼠免疫功能的影响，以及宁炼等在《中国中药杂志》(2002，27(1)：50-53)中记载的“当归补血汤促进造血功能的成分及其作用的研究”，均证实其具有改善血液***功能，调节免疫力、保肝、抗氧化等作用，也可用于各种癌症病人术后调理。然而，当归补血汤仅具有补气生血作用，结合现代疾病免疫力低下症情况，其主要表现为体质虚弱、营养不良、精神萎靡、疲乏无力、食欲降低、睡眠障碍等。因此，当归补血汤仅解决体质虚弱、睡眠障碍、全身无力等症，但对于食少纳差、营养不良等上尚存在不足。
为更好的适应现代疾病的演变，现有专利文献还记载了多种治疗气血两虚症状的药物组合物，其在当归补血汤的基础上，还增加了益脾补肾、增强免疫力、调整人体功能等功效，例如：专利文献CN106310209A(一种治疗气血两虚的中药制剂及制备方法，2017.01.11)以及专利文献CN101804155A(一种用于肿瘤放、化疗以及术后体虚引起的气血两虚症药物及其制备方法，2012.02.01)等。从目前可以查阅到的专利文献中了解到，当前用于缓解疲劳、提高免疫力、化疗后补血益气的中药数不甚数，如黄芪、当归、续断、熟地黄、炒山药、枸杞子、女贞子、桑葚子、酒萸肉、阿胶、陈皮、牡丹皮、大枣等药材。查阅相关专利文献可知，目前市面上多数用于此方面的组方，均包含10到20余味中药，甚至更多。这些采用大 剂量的组方往往存在诸多问题：一，过多种类药材的使用，难以确认起效药味的作用机制，因此，对药材剂量以及毒性难以掌控；二，过多种类药材单纯由作用相似的药味而叠加，未考虑药物之间的配伍关系，并不利于疾病的治疗，《黄帝内经》、《伤寒杂病论》等经典中医古籍中，处方基本很难超出十味以上；三，过多种类药材的使用，还会造成资源浪费，不利于经济成本控制及中药的可持续发展。
发明内容
本发明的目的在于提供一种治疗气血两虚症候的中药组合物，采用黄芪、当归、大枣、枸杞、陈皮五味药或其提取物组成，通过黄芪与当归两者合用阳生阴长，气旺生血，同时，再辅以枸杞、大枣和陈皮，全方共具滋补肝肾、健脾理气、益卫固表、扶正固本之效，从而增强机体免疫机能，主要适用于工作压力大、过度疲劳、产后气血不足、癌症放化疗后而造成的免疫功能低下人群。
本发明的另一目的在于提供所述中药组合物的制备方法，可用于制备组方颗粒制剂和膏剂。
本发明的另一目的在提供所述中药组合物在制备治疗气血两虚症候药物或保健品中的应用。
本发明通过下述技术方案实现：一种治疗气血两虚症候的中药组合物，按重量份数计，包括以下组份：黄芪或其提取物25～35份、当归或其提取物5～7份、大枣或其提取物8～12份、枸杞或其提取物5～10份、陈皮或其提取物5～8份。
所述中药组合物中至少包括以下有效成分：毛蕊异黄酮葡萄糖苷≥0.10mg/g、黄芪甲苷≥0.45mg/g、阿魏酸≥0.05mg/g、枸杞多糖≥8.0mg/g。
一种治疗气血两虚症候的中药组合物的制备方法，包括以下步骤：
(1)按重量份数计，取黄芪25～35份、当归5～7份、大枣8～12份、枸杞5～10份、陈皮5～8份混合后加水，加热提取后，经过滤、浓缩制得浓缩液，浓缩液按步骤(2)或步骤(3)进行；
(2)将浓缩液与辅料混合，加热搅拌制得中药组合物的膏剂；
(3)将浓缩液与辅料混合，搅拌均匀后干燥得到细干粉，将细干粉挤压、破碎、制粒后得到中药组合物的颗粒剂。
所述步骤(1)中，原材料加水浸泡后，加热至沸腾，保持微沸1.5～2h后过滤，滤渣加水，加热至沸腾，保持微沸1.5～2h后过滤，将两次滤液合并后用于浓缩。
所述步骤(1)中，浓缩包括：将合并后的滤液在在真空度-0.085～-0.065Mpa，温度60～80℃范围下进行浓缩，浓缩至相对密度为1.05～1.15，得到浓缩液。
所述步骤(2)中，按1：0.1～1.0的重量比，将浓缩液与辅料混合，辅料选自炼制蜂蜜或木糖醇、麦芽糖醇、麦芽糖醇液、麦芽糖中的至少一种。
所述步骤(3)中，按5～10：1的重量比，将浓缩液与辅料混合，辅料选自可溶性淀粉、麦芽糊精中的至少一种。
一种根据权利要求1所述中药组合物在制备治疗气血两虚症候药物或保健品中的应用。
本发明与现有技术相比，具有以下优点及有益效果：
(1)本发明提出了一种以黄芪、当归、大枣、枸杞、陈皮五味药或其提取物组成的中药组合物，该中药组合物在传统经典名方制剂“当归补血汤”的基础上，结合现代药理研究知识，辅以大枣、枸杞、陈皮，开发出了一种能有效治疗气血两虚症候以及滋补肝肾、健脾理气、益卫固表、扶正固本之功效的中药组合物，其有效成分中，毛蕊异黄酮葡萄糖苷不低于0.10mg/g、黄芪甲苷不低于0.45mg/g、阿魏酸不低于0.05mg/g、枸杞多糖不低于8.0mg/g，同时，在临床上也取得了良好的治疗效果。
(2)本发明涉及的中药组合物利用大枣、枸杞、陈皮与黄芪、当归进行合理配伍，并采用水提工艺获取其提取物，能有效提高中药组合物中毛蕊异黄酮葡萄糖苷、黄芪甲苷等有效成分的转移率，充分发挥了黄芪、当归治疗气血两虚症候的疗效，同时确保用药安全。
(3)本发明涉及的中药组合物可应用于制备治疗气血两虚症候药物或保健品中使用，应用范围广，可用于保健酒、保健药膳、保健饮料等，具有促进免疫力提高，缓解疲劳作用。适用于工作压力大、过度疲劳导致的免疫力低下，及产后、癌症放化疗后免疫力低下等人群。
具体实施方式
下面将本发明的发明目的、技术方案和有益效果作进一步详细的说明。
应该指出，以下详细说明都是示例性的，旨在对所要求的本发明提供进一步的说明，除非另有说明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
我们知道，传统经典名方制剂“当归补血汤”中，使用黄芪(一两)、当归(酒洗，二钱)进行配伍，具有补气生血等功效，但经现代医学研究证明，该名方制剂在解决免疫力低下时，对食欲差、营养不良等问题的解决上尚存在不足。现有可查阅的专利文献虽然记载了多种治疗气血两虚症状的药物组合物，但其处方的配伍机制并不明确，难以为临床应用的治疗效果做出指导。以此为背景，我们需要找到的是一种可明确药物配伍机制、精准确定药物剂量和有效成分、确定药物疗效并应用于临床实践的一种中药组合物。
本发明涉及的治疗气血两虚症候的中药组合物采用黄芪或其提取物25～35重量份、当归或其提取物5～7重量份、大枣或其提取物8～12重量份、枸杞或其提取物5～10重量份、陈 皮或其提取物5～8重量份配伍组成。该中药组合物通过各药物之间的相互组合和配伍，其有效成分中，毛蕊异黄酮葡萄糖苷≥0.10mg/g、黄芪甲苷≥0.45mg/g、阿魏酸≥0.05mg/g、枸杞多糖≥8.0mg/g。
该中药组合物可以是中药组合物的膏剂或颗粒制剂，分别采用以下方法制备得到：
中药组合物膏剂：
(1)炮制
分别按2015版《中国药典》饮片炮制要求，对黄芪、当归、陈皮、大枣进行炮制：
黄芪：除去杂质，大小分开，洗净，润透，切厚片(2～4mm)，干燥(70±5℃)。
当归：除去杂质，洗净，润透，切片(1～2mm)，低温干燥(55±5℃)。
大枣：除去杂质，去核。
陈皮：除去杂质，喷淋水，润透，切丝，干燥(55±5℃)。
(2)提取
按组方比例分别称取炮制后饮片、药材，加水12倍，浸泡30分钟后，加热至沸腾，保持微沸1.5～2h，滤液用200目滤筛过滤，滤液待用；滤渣加水12倍，加热至沸腾，保持微沸1.5～2h，滤液用200目滤筛过滤，滤液待用；将2次滤液合并。
(3)浓缩
将合并的滤液搅拌均匀，在真空度-0.085～-0.065Mpa，温度60～80℃范围下进行浓缩，浓缩至相对密度为1.05～1.15(60～80℃)，得到浓缩液。
(4)膏剂制备
将浓缩液与辅料按1：0.1～1.0的重量比例混合，加热搅拌均匀成膏状，达到相对密度为1.15～1.40(60～80℃)即可，将膏状物用容器灌装，置于灭菌罐中，在121℃下灭菌30分钟，制得中药组合物的膏剂成品。
该过程中，辅料可以是炼制蜂蜜或木糖醇、麦芽糖醇、麦芽糖醇液、麦芽糖中的至少一种。其中，炼制蜂蜜的方法是：将蜂蜜置于锅中，用武火(100～120℃)加热，沸腾后改用文火(70～90℃)，并不时捞出漂浮的泡沫及蜡质等，熬至蜜鼓起泡沫呈浅红色光泽，手捻有粘性但不能拉成长的白丝，即可。
中药组合物的颗粒剂：
同上述步骤(1)～(3)，然后将浓缩液进行步骤(5)的操作。
(5)颗粒剂制备
得到的浓缩液与辅料按5～10：1的重量比例混合，搅拌均匀，将混合物进行冷冻干燥或喷雾干燥，过筛后得到细干粉，细干粉再经挤压、破碎、整粒，制成所需颗粒剂，其 水分要求低于6.5％。
该过程中，辅料可以是可溶性淀粉、麦芽糊精中的至少一种。
本发明还提出了可将该中药组合物用于制备治疗气血两虚症候的药物或保健品。实际应用时，药物可以片剂、糖衣丸、明胶胶囊、可注射制剂、可饮用混悬剂或可崩解糊剂的方式进行给药治疗。在一个可能的实施例中，药物可以仅为有效含量的中药组合物，或者是含有该中药组合物的药物组合物，例如，将有效剂量的中药组合物与医药上接受的药物载体复合形成药物组合。保健品可以茶、酒、蜂制品、饮品、汤品、鲜汁、药膳等方式作为载体，利用有效含量的中药组合物作为其中的功效部分，用于对人体气血两虚症状等机能方面的调节和改善。
下面以几个典型实施例来列举说明本发明的具体实施方式，当然，本发明的保护范围并不局限于以下实施例。
实施例1～5：
实施例1～5均涉及一种治疗气血两虚症候的中药组合物膏剂。
按上述中药组合物膏剂的制备方法，其具体工艺参数条件参照下表1。
表1 中药组合物膏剂的制备工艺条件参数表
Figure PCTCN2020130097-appb-000001
Figure PCTCN2020130097-appb-000002
实施例6～10：
实施例6～10均涉及一种治疗治疗气血两虚症候的中药组合物颗粒剂。
按上述中药组合物颗粒剂的制备方法，其具体工艺参数条件参照下表2。
表2 中药组合物颗粒剂的制备工艺条件参数表
Figure PCTCN2020130097-appb-000003
Figure PCTCN2020130097-appb-000004
按下述试验(一)至试验(四)所述方法对实施例1～10中涉及的中药组合物产品的有效成分及其转移率进行测定，具体内容如下：
试验(一)：
对上述实施例1～10中涉及的中药组合物产品进行毛蕊异黄酮葡萄糖苷(C 22H 22O 10)含量测定。
按高效液相色谱法(通则0512)进行测定，具体测定方法如下：
色谱条件与***适用性试验：以十八烷基硅烷键合硅胶为填充剂；以乙腈为流动相A，以0.2％甲酸溶液为流动相B，按下表3中的规定进行梯度洗脱；检测波长为260nm。理论板数按毛蕊异黄酮葡萄糖苷峰计算应不低于3000。
表3 色谱条件参数
时间(分钟) 流动相A(％) 流动相B(％)
0～20 20～40 80～60
20～30 40 60
对照品溶液的制备：取毛蕊异黄酮葡萄糖苷对照品适量，精密称定，加甲醇制成每1ml含50μg的溶液，即得。
供试品溶液的制备：取制剂约2g，精密称定至50ml容量瓶中，加水溶解至刻度，摇匀，滤过，即得。
测定法：分别精密吸取对照品溶液与供试品溶液各10μl，注入液相色谱仪，测定，即得。
经测定，上述实施例1～10中中药组合物产品中毛蕊异黄酮葡萄糖苷含量如下表4所示。
表4 毛蕊异黄酮葡萄糖苷含量测定表
Figure PCTCN2020130097-appb-000005
饮片含量测定：取黄芪饮片，共三份，按2015版《中国药典》饮片炮制要求分别对炮制后的黄芪饮片进行含量测定，测定方法按高效液相色谱法(通则0512)进行测定，并计算三份黄芪饮片中毛蕊异黄酮葡萄糖苷含量的平均值。
毛蕊异黄酮葡萄糖苷转移率计算：已知黄芪药材中毛蕊异黄酮葡萄糖苷含量为A％，则毛蕊异黄酮葡萄糖苷的转移率＝液相测得的毛蕊异黄酮葡萄糖苷含量/A％×中药组合物产品中 黄芪用量×100％。
经计算，上述实施例1～10中中药组合物产品中毛蕊异黄酮葡萄糖苷的转化率如下表5所示。
表5 毛蕊异黄酮葡萄糖苷转化率测定表
Figure PCTCN2020130097-appb-000006
试验(二)：
对上述实施例1～10中涉及的中药组合物产品进行黄芪甲苷(C 41H 68O 14)含量测定。
按高效液相色谱法(通则0512)进行测定，具体测定方法如下：
色谱条件与***适用性试验：以十八烷基硅烷键合硅胶为填充剂；以乙腈-水(32：68)为流动相；蒸发光散射检测器检测。理论板数按黄芪甲苷峰计算应不低于4000。
对照品溶液的制备：取黄芪甲苷对照品适量，精密称定，加80％甲醇制成每1ml含0.5mg的溶液，即得。
供试品溶液的制备：取本品约1.0g，置具塞锥形瓶中，精密加入含4％浓氨试液的80％甲醇(取浓氨试液4ml，加80％甲醇至100ml，摇匀)50mL，密塞，称定重量，加热回流1小时，放冷，再称定重量，用含4％浓氨试液的80％甲醇补足减失的重量，摇匀，滤过，精密量取续滤液25ml，蒸干，残渣用80％甲醇溶解，转移至5ml量瓶中，加80％甲醇至刻度，摇匀，滤过，取续滤液，即得。
测定法：分别精密吸取对照品溶液5μl、10μl，供试品溶液10～20μl，注入液相色谱仪，测定，用外标两点法对数方程计算，即得。
经测定，上述实施例1～10中中药组合物产品中黄芪甲苷含量如下表6所示。
表6 黄芪甲苷含量测定表
Figure PCTCN2020130097-appb-000007
饮片含量测定：取黄芪饮片，共三份，按2015版《中国药典》饮片炮制要求分别对炮制后的黄芪饮片进行含量测定，测定方法按高效液相色谱法(通则0512)进行测定，并计算三 份黄芪饮片中黄芪甲苷含量的平均值。
黄芪甲苷转移率计算：已知黄芪药材中黄芪甲苷含量为A％，则黄芪甲苷的转移率＝液相测得的黄芪甲苷含量/A％×中药组合物产品中黄芪用量×100％。
经计算，上述实施例1～10中中药组合物产品中黄芪甲苷的转化率如下表7所示。
表7 黄芪甲苷转化率测定表
Figure PCTCN2020130097-appb-000008
试验(三)：
对上述实施例1～10中涉及的中药组合物产品进行阿魏酸(C 10H 10O 4)含量测定。
按高效液相色谱法(通则0512)进行测定，具体测定方法如下：
色谱条件与***适用性试验：以十八烷基硅烷键合硅胶为填充剂；以乙腈-0.085％磷酸溶液(17：83)为流动相；检测波长为316nm；柱温35℃。理论板数按阿魏酸峰计算应不低于5000。
对照品溶液的制备：取阿魏酸对照品适量，精密称定，置棕色量瓶中，加70％甲醇制成每1mI含12μg的溶液，即得。
供试品溶液的制备：取制剂约1g，精密称定，置具塞锥形瓶中，精密加入70％甲醇20ml，密塞，称定重量，超声处理30分钟，放冷，再称定重量，用70％甲醇补足减失的重量，摇匀，静置，取上清液滤过，取续滤液，即得。
测定法：分别精密吸取对照品溶液与供试品溶液各10μl，注入液相色谱仪，测定，即得。
经测定，上述实施例1～10中中药组合物产品中阿魏酸含量如下表8所示。
表8 阿魏酸含量测定表
Figure PCTCN2020130097-appb-000009
饮片含量测定：取当归饮片，共三份，按2015版《中国药典》饮片炮制要求分别对炮制后的当归饮片进行含量测定，测定方法按高效液相色谱法(通则0512)进行测定，并计算三份当归饮片中阿魏酸含量的平均值。
黄芪甲苷转移率计算：已知当归药材中阿魏酸含量为A％，则阿魏酸的转移率＝液相测得的阿魏酸含量/A％×中药组合物产品中当归用量×100％。
经计算，上述实施例1～10中中药组合物产品中阿魏酸的转化率如下表9所示。
表9 阿魏酸转化率测定表
Figure PCTCN2020130097-appb-000010
试验(四)：
对上述实施例1～10中涉及的中药组合物产品进行枸杞多糖(C 6H 12O 6)含量测定。
具体测定方法如下：
对照品溶液的制备：取无水葡萄糖对照品25mg，精密称定，置250ml量瓶中，加水适量溶解，稀释至刻度，摇匀，即得(每1ml中含无水葡萄糖0.1mg)。
标准曲线的制备：精密量取对照品溶液0.2ml、0.4ml、0.6ml、0.8ml、1.0ml，分别置具塞试管中，分别加水补至2.0ml，各精密加入5％苯酚溶液1ml，摇匀，迅速精密加入硫酸5ml，摇匀，放置10分钟，置40℃水浴中保温15分钟，取出，迅速冷却至室温，以相应的试剂为空白，照紫外-可见分光光度法(通则0401)，在490nm的波长处测定吸光度，以吸光度为纵坐标，浓度为横坐标，绘制标准曲线。
测定法：取制剂约0.5g，精密称定，加入80％乙醇100ml，加热回流1小时，趁热滤过，滤渣与滤器用热80％乙醇30ml分次洗涤，滤渣连同滤纸置烧瓶中，加水150ml，加热回流2小时。趁热滤过，用少量热水洗涤滤器，合并滤液与洗液，放冷，移至250ml量瓶中，用水稀释至刻度，摇匀，精密量取1ml，置具塞试管中，加水1.0ml，照标准曲线的制备项下的方法，自“各精密加入5％苯酚溶液1ml”起，依法测定吸光度，从标准曲线上读出供试品溶液中含葡萄糖的重量(mg)，计算，即得。
经测定，上述实施例1～10中中药组合物产品中枸杞多糖含量如下表10所示。
表10 枸杞多糖含量测定表
Figure PCTCN2020130097-appb-000011
饮片含量测定：取枸杞药材，共三份，进行含量测定，测定方法按高效液相色谱法(通则0512)进行测定，并计算三份枸杞药材中枸杞多糖含量的平均值。
黄芪甲苷转移率计算：已知枸杞药材中枸杞多糖含量为A％，则枸杞多糖的转移率＝液相测得的枸杞多糖含量/A％×中药组合物产品中枸杞用量×100％。
经计算，上述实施例1～10中中药组合物产品中枸杞多糖的转化率如下表11所示。
表11 枸杞多糖转化率测定表
Figure PCTCN2020130097-appb-000012
对比例1：
以黄芪30g、当归6g为处方，分别按实施例4、实施例8所述方法及其工艺条件制备中药膏剂和中药颗粒剂。
按相同方法测定该中药膏剂及中药颗粒剂中毛蕊异黄酮葡萄糖苷、黄芪甲苷以及阿魏酸的含量及其转化率，如下表12所示。
表12 含量及转化率测定表
Figure PCTCN2020130097-appb-000013
对比例2：
以黄芪30g、当归6g、陈皮7g为处方，分别按实施例4、实施例8所述方法及其工艺条件制备中药膏剂和中药颗粒剂。
按相同方法测定该中药膏剂及中药颗粒剂中毛蕊异黄酮葡萄糖苷、黄芪甲苷以及阿魏酸的含量及其转化率，如下表13所示。
表13 含量及转化率测定表
Figure PCTCN2020130097-appb-000014
对比例3：
以黄芪30g、大枣10g、枸杞10g为处方，分别按实施例4、实施例8所述方法及其工艺条件制备中药膏剂和中药颗粒剂。
按相同方法测定该中药膏剂及中药颗粒剂中毛蕊异黄酮葡萄糖苷、黄芪甲苷以及枸杞多糖的含量及其转化率，如下表14所示。
表14 含量及转化率测定表
Figure PCTCN2020130097-appb-000015
对比例4：
以黄芪30g、当归6g、枸杞10g为处方，分别按实施例5、实施例9所述方法及其工艺条件制备中药膏剂和中药颗粒剂。
按相同方法测定该中药膏剂及中药颗粒剂中毛蕊异黄酮葡萄糖苷、黄芪甲苷、阿魏酸以及枸杞多糖的含量及其转化率，如下表15所示。
表15 含量及转化率测定表
Figure PCTCN2020130097-appb-000016
对比例5：
以黄芪30g、枸杞子10g、山药10g、当归6g、人参15g、砂仁5g、枣仁6g、桑葚3g为处方，分别按实施例5、实施例9所述方法及其工艺条件制备中药膏剂和中药颗粒剂。
按相同方法测定该中药膏剂及中药颗粒剂中毛蕊异黄酮葡萄糖苷、黄芪甲苷、阿魏酸以及枸杞多糖的含量及其转化率，如下表16所示。
表16 含量及转化率测定表
Figure PCTCN2020130097-appb-000017
对比例4：
以熟地黄、山药、枸杞、山萸肉、牛膝、菟丝子、红景天、茯苓、人参、肉桂、杜仲、续断、桑寄生、赤芍、白芍、炙甘草、川芎各5g为处方，分别按实施例4、实施例8所述方法及其工艺条件制备中药膏剂和中药颗粒剂。
按相同方法测定该中药膏剂及中药颗粒剂中毛蕊异黄酮葡萄糖苷、黄芪甲苷、阿魏酸以及枸杞多糖的含量及其转化率，如下表17所示。
表17 含量及转化率测定表
Figure PCTCN2020130097-appb-000018
近年来，临床及学界对于中药配伍合理性、科学性重视度不断增强，分子生物技术、化学分析技术等现代科学技术也为中药合理配伍提供了指导。研究发现，按不同比例搭配的中药，化学成分含量有一定差异。同时因相关研究报道及专利中均有大量药物配伍起到补血益气，提高免疫力、缓解疲劳的作用，为进一步研究本发明涉及的中药组合物配伍的合理性，上述对比例1～4专门针对不同配伍下的相关组方进行有效成分影响的研究，以建立中药组合物中含量测定方法，分别测定其毛蕊异黄酮葡萄糖苷和黄芪甲苷等有效成分的含量，同时计算其相应转化率。
将上述测定的实施例1～10中涉及的中药组合物产品与对比例1～4中中药膏剂和中药颗粒剂的有效成分含量及转化率进行比较可以知道，采用黄芪、当归、大枣、枸杞、陈皮，五味药材进行配伍得到的处方产品中，单纯使用其中2味、3味均不能达到最佳的成分转移，实现药理作用，具体可通过以下实验研究予以证明。
(一)临床研究
实验组邀请多位经中医辨证为气血两虚证候的女性受试者参与，分别采用具有补血益气、缓解疲劳的中药配伍与本组方药味进行对比临床研究。
处方一：黄芪30g、当归6g、大枣10g、枸杞8g、陈皮6g(处方用量参照实施例4)；
处方二:黄芪30g、当归6g(处方用量参照对比例1)；
处方三：黄芪30g、枸杞子10g、山药10g、当归6g、人参15g、砂仁5g、枣仁6g、桑葚3g(处方用量参照对比例5)；
处方四：熟地黄、山药、枸杞、山萸肉、牛膝、菟丝子、红景天、茯苓、、人参、肉桂、杜仲、续断、桑寄生、赤芍、白芍、炙甘草、川芎各5g.
受试人分为4组，每组5个人，分别按上述处方服用2周，每日1剂，分3次服用。观 察各组气血双虚症状改善情况，参见下表18。
表18 不同处方气血双虚临床比较
组方名 头晕改善度 心悸气短改善度 面色改善度 经期异常改善度 总有效率
处方一 4 4 5 5 18
处方二 4 4 4 4 16
处方三 3 4 5 4 15
处方四 3 4 4 3 14
备注：改善度以平均分5分计，其中1-2分为一般；3-4分为良好；5分为基本治愈。
综上临床研究可知，相较于较大处方三、处方四，处方一和处方二仅采用较少药味的处方，仍能发挥较好的补血益气效果。同时由处方一和处方二比较，较仅采用黄芪、当归两味药，采用黄芪、当归、大枣、枸杞子、陈皮五味药组成的配方在改善气血双虚引起的系列症状上更为具备一定的优势。故可知以本组方组味的处方在气血双虚治疗上的临床效果明显。
(二)药理实验研究
为进一步证明本组方药味用药的精准性，实验组分别对本组方进行拆方、加味进行药理学实验比较。
处方一：黄芪30g、当归6g、大枣10g、枸杞8g、陈皮6g(处方用量参照实施例4)；
处方二：黄芪30g、当归6g(处方用量参照对比例1)；
处方五：大枣10g、枸杞10g、陈皮7g；
处方六：黄芪30g、当归6g、大枣10g、枸杞10g、陈皮7g、熟地6g、山药10g、桑寄生6g。
(1)小鼠抗疲劳实验
(1.1)实验动物
雄性昆明种小鼠,体重18～22g。
仪器及试剂：各处方浓缩液均由实验室制备；SOD试剂盒、MDA试剂盒均购自南京建成生物工程研究所。
各处方浓缩液制备：各处方分别按组方配伍情况以30倍量，分别称取各饮片，混合搅拌均匀，加入处方量12倍水，煎煮2次，每次90分钟，滤过，两次滤液合并。将合并所得的提取液混匀浓缩成浓缩液，浓度为含生药量1.2～1.5g/mL。
SOD、MDA含量测定实验：选取昆明种小鼠共50只，雄性，体重18～22g，随机分5组,每组各10只小鼠,分别为处方一组、处方二组、处方五组、处方六组以及空白对照组。采用灌胃给药的方式按体重给药,空白对照组给予同样体积的蒸馏水，不间断灌胃30d，在第 30天灌胃30min后，称量每只小鼠体重。通过小鼠眼球取血方式取血，所得全血用不加抗凝剂的1.5mLEP管收集，在4℃冰箱放置3h待血液凝固后以3500r/min离心15min，取血清，按SOD测试盒、MDA测试盒，分别检测各组小鼠血清中的SOD活性能力以及MDA含量。
分析方法：运用SPSS17.0软件和Excel分析处理数据，计算结果用(x±s)表示，各组间进行统计学分析，P<0.05表示具有统计学意义。
结果与分析：与空白对照组相比，处方五、处方六组小鼠血清中的MDA含量没有显著性差异(P>0.05)，但是整体给药组小鼠的MDA含量有下降的趋势；处方二、六组小鼠SOD活性能力与空白对照组相比显著性提高(P<0.05)，处方一组小鼠SOD活性能力与空白对照组相比显著性提高(P<0.01)，处方五组小鼠SOD活性能力与空白对照组相比没有显著性差异(P>0.05)，参见下表19。
表19 不同处方对小鼠SOD活性能力、MDA含量的影响比较(χ±s,n＝10)
组别 MDA含量nmol/ml SOD活性能力μ/ml
空白对照组 12.78±0.17 4.56±0.129
处方一组 10.15±0.3﹡ 5.76±0.62﹡﹡
处方二组 10.65±1.91﹡ 5.35±1.02﹡
处方五组 11.23±2.18 4.79±0.007
处方六组 10.98±1.02 5.03±0.741﹡
注：与空白对照组比较，﹡表示P<0.05，﹡﹡表示P<0.01。
由上述药理实验数据综合比较可知，本组方若进行拆方、加味后其效果都较本组方药味组成方剂在减少MDA含量以及提高SOD活性能力上效果较差，可一定程度上说明本处方用药的精确性。
(三)计量的选择。
“中药不传之秘在于用量”，理、法、方、药贯穿在中医医学辨证论治的全过程，而对于方药剂量的调配准确与否，则是其中相当关键的一个环节。方剂的组成既有严格的原则性,需遵循君、臣、佐、使的配伍的关系，同时又有极大的灵活性，许多时候由于药物剂量稍有变化，就使方剂的功用主治迥然有别。如古籍记载：枳术汤与枳术丸，两方皆是用行气之枳实配伍益气健脾之白术，枳术汤中枳实重于白术，消重于补，意在以消为主，适用于气滞水停心下坚满证；而枳术丸中白术量重于枳实，补重于消，以补为主，且为丸剂，作用更缓，适用于脾虚气滞食停这胸脘痞满证。又如如抵当汤与抵当丸，方中皆由水蛭、虻虫、大黄、桃仁四药组成。抵当汤为汤剂，主治下焦蓄血之重证，身热、少腹硬满， 小便自利，其人发狂或如狂；而抵当丸则是水蛭、虻虫减量，大黄同量，桃仁加量制成丸剂，主治下焦蓄血之轻证，其人身热，少腹满而不硬，小便自利，无狂。
黄芪、当归、大枣、枸杞、陈皮在中医药理论指导中，均可用于补气补血、益气健脾。但在剂量组成上，本申请涉及的中药组合物配伍比例严格根据所用功效病症进行配伍组成，剂量精准，疗效明显。为进一步验证其剂量上的优选，实验组采用建立复合贫血模型、化疗后贫血动物模型，对不同剂量下其补血作用进行考察。
处方一：黄芪30g、当归6g、大枣10g、枸杞8g、陈皮6g(处方用量参照实施例4)；
处方七：黄芪10g、当归10g、大枣5g、枸杞5g、陈皮10g；
处方八：黄芪12g、当归6g、大枣20g、枸杞20g、陈皮7g；
(1)实验材料
SPF级健康BALB/C小鼠，200只，雌雄各半，体重为18～22克。
造模药：注射用环磷酰胺(0.2ml/支)，由山西泰盛制药有限公司生产(国药准字H18010373)。EDTA-ka2抗凝剂由博士德牛物技术有限公司提供。
全自动多物种小动物血液分析仪(中国瑞普生医学仪器有限公司提供)。
(2)动物造模
①建立复合型失血性贫血动物模型：除正常组外，其余各组小鼠在造模1-3天放血0.4ml、4-5天放血0.3ml、6-7天放血0.4ml天；同时采取隔日禁食方法。造模周期为12天。
②建立化疗贫血动物模型：除正常组外，其余各组小鼠分别于1d、3d每日按200mg/kg体重剂量腹腔注射环磷酰胺；5d、7d每日按100mg/kg体重剂量腹腔注射环磷酰胺。共注射4次。造模周期为14天。
(3)不同处方制备方法
各处方分别按组方配伍情况以30倍量，分别称取各饮片，混合搅拌均匀，加入处方量12倍水，煎煮2次，每次90分钟，滤过，两次滤液合并。将合并所得的提取液混匀浓缩成浓缩液，浓度为含生药量1.2～1.5g/mL。
(4)检测指标
(4.1)一般情况观察：①日常行为表现：是否存在活动减少、行动迟缓、反应迟钝、进食减少、大便溏稀、毛色枯萎、扎堆等表现。②体重：体重是疾病发生与进展过程的重要体征之一。于实验前、造模后l周、2周各测小鼠体重1次，以观察饥饿、放血、化疗对小鼠体重影响。
(4.2)外周血细胞计数：分别于造模期前、造模中、造模结束时，小鼠眼眶静脉取血60ul，加入带有EDTA-ka2固体抗凝剂的试管中，使血液充分与抗凝剂混合后，采用全自动血细胞计数仪检测。
(5)统计方法
运用SPSS17.0软件和Excel分析处理数据，计算结果用(x±s)表示，各组间进行统计学分析，P<0.05表示具有统计学意义。
(6)结果与分析
(6.1)不同剂量对实验性贫血模型小鼠一般状况影响
(6.1.1)对贫血模型小鼠行为的影响：复合贫血组在造模后第7天开始出现活动减少、喜扎堆、拱背、竖毛、毛不光洁等现象。化疗贫血组：在造模后的第9天开始出现活动减少、喜扎堆、拱背、竖毛、毛不光洁等现象。不同剂量各组小鼠经用药治疗l周后，上述症状都有不同程度的减轻。
(6.1.2)对贫血模型小鼠体重的影响：处方不同剂量对复合贫血、化疗贫血小鼠体重的影响，结果分别见表20、21。
表20 对复合贫血模型小鼠体重的影响(g，χ±s,n＝10)
组别 造模前 造模治疗1周 治疗2周
正常组 20.93±2.03 21.03±0.92 △ 21.32±0.37 △
模型组 21.39±1.18 20.36±1.01 ﹡ 17.69±1.21 ﹡
处方一组 21.06±0.85 21.23±0.36 21.30±0.72 ﹡△
处方七组 21.33±0.81 20.15±0.63 20.63±0.45 △
处方八组 21.15±0.92 20.80±0.25 20.90±0.56 △
注：与正常组比较 ﹡P<0.05；与模型组比较， △P<0.05。
表21 对化疗贫血模型小鼠体重的影响(g，χ±s,n＝10)
组别 造模前 造模治疗1周 治疗2周
正常组 21.13±1.69 21.22±0.79 △ 21.25±1.02 △
模型组 21.29±0.75 20.41±0.93 ﹡ 18.00±0.33 ﹡
处方一组 21.76±1.13 21.35±0.36 22.25±1.67 ﹡△
处方七组 21.13±1.58 20.53±2.73 20.60±1.92 △
处方八组 21.45±0.47 20.01±1.92 19.93±1.83 △
注：与正常组比较 ﹡P<0.05；与模型组比较， △P<0.05。
由上述实验数据可以知道，处方一、处方七、处方八一定程度上均能减缓贫血模型组小鼠体重的下降趋势，处方一即本申请组方的剂量下，在恢复贫血模型组小鼠体重上有明显优势，且数据具有统计学意义(P<0.05)。
(6.1.3)对贫血模型小鼠外周血的影响：复合贫血组以红细胞计数为评价指标，化疗贫血组以白细胞计数为评价指标，分别比较不同剂量配比下，在提升外周血细胞计数方面的最佳配比。结果见下表22。
表22 不同剂量配比对贫血模型外周血细胞的影响(χ±s,n＝10)
Figure PCTCN2020130097-appb-000019
注：与正常组比较 ﹡P<0.05；与模型组比较， △P<0.05。
由上述实验数据分析，与正常组比较，复合贫血模型组小鼠外周血红细胞计数明显下降，有统计学意义(P<0.05)，在以本组方剂量配比下，能明显提高小鼠外周血红细胞数；同时，与正常组比较，化疗贫血模型组小鼠外周白红细胞计数明显下降，有统计学意义(P<0.05)，在以本组方剂量配比下，能明显提升小鼠外周白红细胞数。
综上贫血模型的实验结果表明，以黄芪30g、当归6g、大枣10g、枸杞8g、陈皮6g为剂量(即处方一)下，其改善小鼠体重、提高外周血细胞数上均具有明显优势，证明本组方剂量配比的准确性和优势性。
以上所述，仅是本发明的较佳实施例，并非对本发明做任何形式上的限制，凡是依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化，均落入本发明的保护范围之内。

Claims (8)

  1. 一种治疗气血两虚症候的中药组合物，其特征在于：按重量份数计，包括以下组份：黄芪或其提取物25～35份、当归或其提取物5～7份、大枣或其提取物8～12份、枸杞或其提取物5～10份、陈皮或其提取物5～8份。
  2. 根据权利要求1所述的一种治疗气血两虚症候的中药组合物，其特征在于：所述中药组合物中至少包括以下有效成分：毛蕊异黄酮葡萄糖苷≥0.10mg/g、黄芪甲苷≥0.45mg/g、阿魏酸≥0.05mg/g、枸杞多糖≥8.0mg/g。
  3. 一种治疗气血两虚症候的中药组合物的制备方法，其特征在于：包括以下步骤：
    (1)按重量份数计，取黄芪25～35份、当归5～7份、大枣8～12份、枸杞5～10份、陈皮5～8份混合后加水，加热提取后，经过滤、浓缩制得浓缩液，浓缩液按步骤(2)或步骤(3)进行；
    (2)将浓缩液与辅料混合，加热搅拌制得中药组合物的膏剂；
    (3)将浓缩液与辅料混合，搅拌均匀后干燥得到细干粉，将细干粉挤压、破碎、制粒后得到中药组合物的颗粒剂。
  4. 根据权利要求3所述的一种治疗气血两虚症候的中药组合物的制备方法，其特征在于：所述步骤(1)中，原材料加水浸泡后，加热至沸腾，保持微沸1.5～2h后过滤，滤渣加水，加热至沸腾，保持微沸1.5～2h后过滤，将两次滤液合并后用于浓缩。
  5. 根据权利要求4所述的一种治疗气血两虚症候的中药组合物的制备方法，其特征在于：所述步骤(1)中，浓缩包括：将合并后的滤液在在真空度-0.085～-0.065Mpa，温度60～80℃范围下进行浓缩，浓缩至相对密度为1.05～1.15，得到浓缩液。
  6. 根据权利要求3所述的一种治疗气血两虚症候的中药组合物的制备方法，其特征在于：所述步骤(2)中，按1：0.1～1.0的重量比，将浓缩液与辅料混合，辅料选自炼制蜂蜜或木糖醇、麦芽糖醇、麦芽糖醇液、麦芽糖中的至少一种。
  7. 根据权利要求3所述的一种治疗气血两虚症候的中药组合物的制备方法，其特征在于：所述步骤(3)中，按5～10：1的重量比，将浓缩液与辅料混合，辅料选自可溶性淀粉、麦芽糊精中的至少一种。
  8. 一种根据权利要求1所述中药组合物在制备治疗气血两虚症候药物或保健品中的应用。
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CN117398400A (zh) * 2023-12-15 2024-01-16 吉林敖东集团力源制药股份有限公司 一种治疗贫血的药物组合物
CN117398400B (zh) * 2023-12-15 2024-03-15 吉林敖东集团力源制药股份有限公司 一种治疗贫血的药物组合物
CN117904034A (zh) * 2024-01-19 2024-04-19 杏林医学科技(江苏)有限公司 自体干细胞培养液及其在修复女性生殖器官凝胶上的应用

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