WO2023165399A1 - 一种补气养血中成药制剂及其制备方法 - Google Patents

一种补气养血中成药制剂及其制备方法 Download PDF

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WO2023165399A1
WO2023165399A1 PCT/CN2023/077732 CN2023077732W WO2023165399A1 WO 2023165399 A1 WO2023165399 A1 WO 2023165399A1 CN 2023077732 W CN2023077732 W CN 2023077732W WO 2023165399 A1 WO2023165399 A1 WO 2023165399A1
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preparation
chinese patent
patent medicine
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French (fr)
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江涛
曾利杰
温德源
曾晨
陈丽斯
苏锐辉
汤迎湛
王川易
彭红英
方毓新
梁铭基
唐冬兰
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广州白云山敬修堂药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/704—Polygonum, e.g. knotweed
    • 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
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • 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)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • 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)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/804—Rehmannia
    • 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
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8965—Asparagus, e.g. garden asparagus or asparagus fern
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8968—Ophiopogon (Lilyturf)
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • A61K2236/10—Preparation or pretreatment of starting material
    • A61K2236/15—Preparation or pretreatment of starting material involving mechanical treatment, e.g. chopping up, cutting or grinding
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of traditional Chinese medicine preparations, and in particular relates to a Chinese patent medicine preparation for invigorating qi and nourishing blood and a preparation method thereof.
  • Kangshou Wan is composed of Polygonum multiflorum, Rehmannia glutinosa, Digupi, Rehmannia glutinosa, Poria cocos, Radix asparagus, Ophiopogon japonicus, and ginseng.
  • the prescription comes from page 1252 of "Chinese Medical Dictionary” - “Shen's Zunsheng Prescription”
  • the "Pill for Prolonging Life and Prolonging Life” was proposed by Professor Luo Yuankai of Guangzhou University of Traditional Chinese Medicine, and developed into a small pill preparation by Guangzhou Baiyunshan Jingxiutang Pharmaceutical Co., Ltd., and named "Kangshou Pill”.
  • Kangshou Pills Ministry of Health Drug Standard Chinese Medicine Prescription Eleventh Volume WS3-B-2231-96
  • the preparation process of Kangshou Pills is as follows: take half of the prescription amount of Polygonum multiflorum, mix well with black bean juice, moisten thoroughly, dry it with licorice juice Mix well and dry; Digupi and Poria cocos are washed with white wine and dried; Rehmannia glutinosa and Dihuang are soaked in white wine overnight; Asparagus and Radix are soaked in white wine for 3 hours and dried separately; powder, sieved, mixed evenly, pilled with water, dried, coated with licorice toner, polished, and obtained.
  • Kangshou Pills have the functions of nourishing qi and blood, nourishing the lungs and kidneys, and can be used for deficiency of both qi and blood, and deficiency of essence and blood, which can cause frailty, mental fatigue, dizziness, forgetfulness, hyperhidrosis, dry cough with less phlegm, palpitations, shortness of breath, The waist and knees are sore and weak.
  • the usage and dosage of Kangshou pills are light salt water or honey water, 5g each time, 2-3 times a day.
  • Ultrafine pulverization technology has the characteristics of improving the physical and chemical properties of materials, strengthening the use effect of materials, and expanding the application range of materials.
  • the current superfine pulverization includes airflow superfine pulverization, rotary ball mill superfine pulverization, mechanical shear superfine pulverization, high-frequency vibration superfine pulverization and other superfine pulverization technologies.
  • the above-mentioned ultrafine pulverization technology is not effective for pulverizing Chinese medicinal materials with high sugar content and high toughness, resulting in problems such as large particle size and sticking of the finished product, and the heat generated during the pulverization process is likely to cause the loss and decomposition of medicinal ingredients.
  • the medicinal materials such as Polygonum multiflorum multiflorum, Rehmannia glutinosa, Radix Digupi and Rehmannia glutinosa in the prescription of Kangshou pills are all high in sugar content, multi-tenacity fiber, simply adopting superfine powder technology can not reach the purpose of the present invention.
  • the object of the present invention is to provide a Chinese patent medicine preparation for invigorating qi and nourishing blood and a preparation method thereof on the basis of Kangshou Wan.
  • the Chinese patent medicine preparation for invigorating qi and nourishing blood prepared by the preparation method of the invention improves the bioavailability of the medicine, increases the efficacy of the medicine, reduces the single dose of the patient, and thus improves the compliance of the patient to take the medicine.
  • the present invention provides a Chinese patent medicine preparation for invigorating qi and nourishing blood, which contains the following Chinese medicine raw materials in parts by weight: Polygonum multiflorum 69.5-278 parts, Rehmannia glutinosa 56.8-227 parts, Digupi 86-344 parts, Rehmannia glutinosa 51.8-207 parts, Poria cocos 86-344 parts, Asparagus 51.8-207 parts, Ophiopogon japonicus 51.8-207 parts, Ginseng 51.5-206 parts.
  • the Chinese patent medicine preparation is made of the following Chinese medicine raw materials in parts by weight: Polygonum multiflorum 69.5-278 parts, Rehmannia glutinosa 56.8-227 parts, Digupi 86-344 parts, Dihuang 51.8-207 parts, Poria cocos 86-344 parts , Asparagus 51.8-207 parts, Ophiopogon japonicus 51.8-207 parts, Ginseng 51.5-206 parts.
  • the Chinese patent medicine preparation includes the following Chinese medicine raw materials in parts by weight: 139 parts of Radix Polygoni Multiflori, 113.5 parts of Rehmannia glutinosa, 172 parts of Digupi, 103.5 parts of Rehmannia glutinosa, 172 parts of Poria cocos, 103.5 parts of winter, 103.5 parts of Ophiopogon japonicus, 103 parts of ginseng.
  • the Chinese patent medicine preparation is made of the following Chinese medicine raw materials in parts by weight: Polygonum multiflorum 139 parts, Rehmannia glutinosa 113.5 parts, Digupi 172 parts, Rehmannia glutinosa 103.5 parts, Poria cocos 172 parts, Asparagus 103.5 parts, Ophiopogon japonicus 103.5 parts, Ginseng 103 parts.
  • the present invention provides the preparation method of the Chinese patent medicine preparation described in the first aspect above, characterized in that: comprising the following steps:
  • Rehmannia glutinosa and rehmannia glutinosa are soaked in white wine for 2-24 hours, and dried separately for later use;
  • step (6) adding and mixing the crude medicinal powder obtained in step (5) with a research aid, the research assistant accounting for 0%-2.0% of the weight of the coarse medicinal powder;
  • step (6) Place the mixed powder obtained in step (6) into liquid nitrogen for freezing treatment for 0.5h-4h;
  • step (7) placing the mixed powder obtained in step (7) at a low temperature of -10-0°C for superfine pulverization together to obtain a superfine powder mixed powder;
  • the Chinese patent medicine preparation for invigorating qi and nourishing blood is any common dosage form prepared from the mixed powder obtained in step (8) by using a conventional traditional Chinese medicine preparation method.
  • step (1), step (2), step (3) and step (4) are dried until the water content is less than 0.5% by weight.
  • the research aid is one or both of the pharmaceutical excipients silicon dioxide or magnesium stearate recorded in the "Chinese Pharmacopoeia" .
  • the research aid is 0.2%-1.0% of the weight of the coarse powder of the medicinal material silicon dioxide or 0.4%-2.0% of the weight of the coarse powder of the medicinal material or magnesium stearate of 0.2%-1.5% of the weight of the coarse powder of the medicinal material or 50% of the weight of the coarse powder of the medicinal material Silicone 50% Magnesium Stearate.
  • the research aid is 0.8% silicon dioxide by weight of coarse medicinal powder or 1.5% magnesium stearate by weight of coarse medicinal powder or 50% silicon dioxide and 50% magnesium stearate by weight 1.0% by weight of coarse medicinal powder.
  • step (7) the mixed powder obtained in step (6) is preliminarily pulverized and then placed in liquid nitrogen for freezing treatment for 2 hours.
  • the average particle size of the mixed powder is less than 35 ⁇ m, preferably 25-30 ⁇ m.
  • the dosage form is selected from tablet, powder, capsule, pill, granule, oral liquid, granule, drop pill, micropill, intramuscular injection lotions, drops or ointments.
  • the dosage form is selected from tablets, pills, granules or capsules.
  • the tablet is a sugar-coated tablet, a film-coated tablet or an enteric-coated tablet
  • the capsule is a soft capsule
  • the ointment is an ointment or a plaster.
  • rehmannia glutinosa and “rehmannia glutinosa” are contained, wherein “rehmannia glutinosa” is sweet and slightly warm, and can nourish blood, nourish kidney and nourish yin; “rehmannia glutinosa” (also known as “rehmannia glutinosa”) ") Sweet in taste and cool in nature, it has the effects of clearing heat, nourishing yin, strengthening heart and diuresis, and the combination of two medicines has the functions of nourishing blood, nourishing yin, nourishing kidney water, strengthening heart, diuresis and anti-allergic.
  • the present invention has the following beneficial effects:
  • the preparation method of the present invention solves the problem of relatively low bioavailability of the Chinese patent medicine Shoukang Pills currently used clinically by adding a specific type and amount of research aids and freezing treatment with liquid nitrogen in the process of processing the raw materials of traditional Chinese medicines. low problem.
  • the Chinese patent medicine preparation for invigorating qi and nourishing blood prepared by the preparation method of the present invention improves the bioavailability of the medicine, increases the efficacy of the medicine, reduces the single dosage of the patient, and thus improves the compliance of the patient to take the medicine.
  • Figure 1 The relationship between liquid nitrogen freezing time and ultrafine powder particle size.
  • Figure 2 Curve of the relationship between the amount of research aids added and the particle size of the superfine powder.
  • Figure 3 Cumulative dissolution curves of Shoukang Pills and Chinese patent medicine preparations for nourishing qi and nourishing blood.
  • test materials used in the following examples are commercially available products unless otherwise specified.
  • the mixed powder obtained above was placed in liquid nitrogen and frozen for 2 hours;
  • the mixed powder obtained above was placed in liquid nitrogen and frozen for 2 hours;
  • Embodiment 3 liquid nitrogen freezing time test
  • test samples were placed in liquid nitrogen for 0, 0.5, 1, 2, and 4 hours of freezing treatment, and placed in a low-temperature environment of 0-10°C for superfine pulverization. , Measure the particle size of its powder sample and analyze it.
  • FIG. 1 The effect of freezing time on the particle size of ultrafine powder is shown in Figure 1. It can be seen from Figure 1 that, under other conditions being the same, as the freezing time in liquid nitrogen increases, the particle size (D90) of the superfine powder decreases significantly, and the particle size (D90) changes greatly after freezing for 0.5h compared to 0h. After liquid nitrogen freezing, the interaction force between molecules in the coarse powder is reduced, and the material is brittle and easy to crush. However, when the freezing time reaches 2h to 4h, the particle size (D90) changes little, indicating that the intermolecular force has reached the optimum value at 2h of freezing, and the subsequent extension of the freezing time has little effect. Therefore, in actual production practice, 2 hours can be used as the best material freezing time.
  • Embodiment 4 research assistant addition test
  • the test product was mixed with silicon dioxide and stearic acid with a weight of 0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5 and 2.0% of the test product respectively.
  • silicon dioxide and stearic acid with a weight of 0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5 and 2.0% of the test product respectively.
  • Magnesium and 50% silicon dioxide 50% magnesium stearate mixed powder the mixed powder obtained above was placed in liquid nitrogen for 4 hours of freezing treatment; placed in a low temperature environment of 0-10 ° C for superfine pulverization, and the powder was measured The particle size of the sample is analyzed.
  • the effect of the addition amount of research aids on the particle size of ultrafine powder is shown in Figure 2.
  • the particle size (D90) of the superfine powder is significantly reduced.
  • Mutual adhesion between powders, reducing powder Increase the moisture absorption rate of the powder, reduce the saturated moisture absorption of the powder, and make the superfine powder easier to disperse and pulverize.
  • the particle size of the superfine powder obviously decreases; when the addition of silicon dioxide reaches 0.8%, the addition of magnesium stearate reaches 1.5%, and the addition of 50% silicon dioxide and 50% magnesium stearate reaches 1.0%.
  • the particle size of the micropowder reaches the optimum value, and the subsequent increase in the amount of research aids has no obvious effect on the particle size.
  • the preferred research aid is silicon dioxide with a weight of 0.2%-1.0% of the coarse powder of medicinal materials or magnesium stearate with a weight of 0.4%-2.0% of the coarse powder of medicinal materials or 50% silicon dioxide 50 with a weight of 0.2%-1.5% of the coarse powder of medicinal materials.
  • %Magnesium stearate Preferably, the added research aid is 0.8% by weight of coarse medicinal powder, silicon dioxide or 1.5% by weight of magnesium stearate or 1.0% by weight of coarse medicinal powder, 50% silicon dioxide and 50% magnesium stearate.
  • Embodiment 5 Dissolution test
  • Chromatographic column Thermo ODS-2 HYPERSIL (250mm ⁇ 4.6mm, 5 ⁇ m, American Thermo Fisher Corporation); mobile phase: acetonitrile-water (volume ratio: 20:80); detection wavelength: 320nm; flow rate: 1.0m L /min; column temperature: 40°C; injection volume: 10 ⁇ L.
  • Thermo ODS-2 HYPERSIL 250mm ⁇ 4.6mm, 5 ⁇ m, American Thermo Fisher Corporation
  • mobile phase acetonitrile-water (volume ratio: 20:80); detection wavelength: 320nm; flow rate: 1.0m L /min; column temperature: 40°C; injection volume: 10 ⁇ L.
  • the content of 2,3,5,4'-tetrahydroxystilbene-2-O- ⁇ -D-glucoside in the present invention is increased by about 30%, indicating that the cell wall is Destroyed during the crushing process, the active ingredients can be released without penetrating the cell wall, the release speed and release amount are improved, and the original efficacy of the medicinal material can be maintained.
  • Embodiment 6 pharmacodynamic experiment
  • SPF-grade Kunming mice were purchased from Guangdong Medical Experimental Animal Center, animal production license number: SCXF (Guangdong) 2018-0002.
  • the sample of Kangshou Wan was provided by Guangzhou Baiyunshan Jingxiutang Pharmaceutical Co., Ltd. (batch number: B11013); a Chinese patent medicine preparation for invigorating qi and nourishing blood, prepared according to the method in Example 1; normal saline.
  • mice with a body weight of 18-22 grams, both male and female were randomly divided into three groups: the Kangshou pill administration group, the Qi and blood nourishing Chinese patent medicine preparation group and the normal saline control group, with 18 mice in each group.
  • the administration group was given 5 g/kg dose of Kangshou Pill or Chinese patent medicine preparation for invigorating qi and blood, and the control group was given 0.5 mL of normal saline with equal volume.
  • Table 1 The results are shown in Table 1.
  • the test shared 66 mice for 15 months, with an average body weight of 37.5g/mouse. They were randomly divided into three groups: Kangshou Pills administration group, Qi-nourishing Chinese patent medicine preparations administration group and normal saline control group. 22 in each group, both male and female.
  • the administration group was administered with 2.7g/kg of Kangshou Pill or Chinese patent medicine preparation for invigorating qi and nourishing blood, once a day, for 8 consecutive days.
  • the control group was given equal volume of normal saline 0.5mL/rat.
  • the memory was measured using the maze method.
  • mice were fasted for half a day, and the mice were taken through the maze twice to make them understand the way to the end of the maze, and then the memory of each mouse was measured.
  • the time required for the mice to walk from the entrance to the end of the maze was used as an indicator of memory. The shorter the time required, the better the memory.
  • the experimental results are shown in Table 2.
  • mice weighing 17-19 grams were randomly divided into three groups, 11 in each group, in the Kangshou Pill administration group, in the Qi and blood-invigorating Chinese patent medicine preparation group, and in the normal saline control group.
  • the administration group was administered with 5g/kg of Kangshou Pills or Chinese patent medicine preparations for nourishing qi and nourishing blood, once a day, for 8 consecutive days, and the control group was given 0.5mL normal saline with equal volume.
  • the endurance test adopts the method of swimming with weight until complete fatigue, that is, a copper wire ring equivalent to 5% of its own body weight is attached to the base of the tail of the mouse, and then it is put into a glass pool with a water temperature of 27°C to swim forcibly, and the record is recorded from the moment it enters the water until it sinks to the bottom
  • the time over 10s is the weight-bearing swimming time.
  • the effects of each group on the swimming time of the mice were observed, and the results are shown in Table 3.
  • Weight-bearing swimming time can truly reflect the animal's exercise endurance. It can be seen from the results in Table 3 that the weight-bearing swimming time of mice in the Chinese patent medicine preparation group for nourishing qi and blood was compared with that of the Kangshou Pill group, P ⁇ 0.01, and the difference was very significant. It is believed that the Chinese patent medicine preparation for nourishing qi and blood can enhance the swimming endurance of mice.
  • the test adopted the method of increasing the weight of the prostate and seminal vesicles.
  • a total of 39 male mice with a weight of 12-14 grams were randomly divided into three groups: the Kangshou Pill administration group, the Qi-nourishing and blood-invigorating Chinese patent medicine preparation group, and the normal saline control group. 13 rats in each of the Kangshou Pill administration group and the Qi-nourishing and blood-invigorating Chinese patent medicine preparation group, and 13 rats in the control group.
  • the control group was given equal-volume normal saline 0.4mL/one, once a day, for a total of 9 days.
  • the test was performed, and the weight of the prostate and seminal vesicles was weighed. The average weight of the prostate and seminal vesicles per 10g of body weight was used for comparison.
  • the test adopts the method of uterine weight gain.
  • a total of 33 female mice with a body weight of 12-14 g were randomly divided into three groups: the Kangshou Pill administration group, the Qi-nourishing and blood-invigorating Chinese patent medicine preparation group and the normal saline control group.
  • 11 rats in each group the administration group was administered with 6g/kg of Kangshou Pills or Chinese patent medicine preparations for invigorating qi and nourishing blood, and the control group was given 0.4mL normal saline with the same volume, once a day, for a total of 9 days.
  • the examination was performed, the uterus was taken out and weighed, and compared with the average uterine weight per 10g of body weight, the results are shown in Table 5.
  • mice of Kunming species aged 15 months, both male and female were randomly divided into three groups: Kangshou Pill administration group, Qi and blood nourishing Chinese patent medicine preparation group and normal saline control group, with 16 mice in each group.
  • the overall weight of the 3 groups is basically the same.
  • the administration method is divided into two stages, and the first stage is intragastric administration, that is, the mice in the administration group are divided into two stages: Do not use 3.3g/kg of Kangshou pills or Chinese patent medicine preparations for invigorating qi and nourishing blood, once a day, for 13 consecutive days, and the control group received 0.5mL of normal saline with the same volume; in the second stage of administration, the administration group Each mouse is fed with biscuits 2.5g (soaked in 100mg/mL of Kangshou pills) soaked in the medicinal solution of Kangshou pills, and its dose is 6g/kg, once a day, administered for 47 days altogether, and combined One-stage oral gavage for 13 days and a total of 60 days of administration.
  • the first stage is intragastric administration, that is, the mice in the administration group are divided into two stages: Do not use 3.3g/kg of Kangshou pills or Chinese patent medicine preparations for invigorating qi and nourishing blood, once a day, for 13 consecutive days
  • both Kangshou pills and Chinese patent medicine preparations for invigorating qi and nourishing blood can enhance the ability of mice to withstand hypoxia under normal pressure, improve the maze memory of aged mice, enhance the swimming endurance of mice, enhance the activity of male and female sex hormones and The effect of prolonging the lifespan of aged mice. Therefore, it is believed that both Kangshou pills and Chinese patent medicine preparations for nourishing qi and blood have the effects of nourishing qi and nourishing blood, nourishing the lungs and kidneys, strengthening and prolonging life; more obvious.
  • Embodiment 7 safety test
  • SPF-grade Kunming mice were purchased from Guangdong Medical Experimental Animal Center, animal production license number: SCXF (Guangdong) 2018-0002.
  • mice of Kunming species both male and female, were randomly divided into three groups: silicon dioxide preparation group, magnesium stearate preparation group and normal saline control group. 7g/kg silicon dioxide preparation test product, magnesium stearate preparation test product, the corresponding volume of deionized water is poured into the control group, and the fixed time is given twice a day. Continuous observation for 14d. The body weight, behavior, diet and excretion of animals in each group were recorded. On the 14th day, the blood from the eyeball and the liver and kidney were collected from the mice, and the biochemical indicators were measured and observed by pathological staining.
  • mice The body weight, diet, behavior, excretion, and serum glucose, total protein, creatinine, and triglycerides of the mice after the administration were not significantly changed compared with those before the administration (P>0.05). Compared with the control group, there was no significant difference; liver and kidney pathological staining also showed no toxicological changes.
  • the above research results suggest that the preparations made by adding silicon dioxide or magnesium stearate to Chinese patent medicines for invigorating qi and nourishing blood have no effect under the conditions of this experiment. Acute toxicity.

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Abstract

一种补气养血中成药制剂及其制备方法，所述中成药制剂由以下重量份的中药原料制成：何首乌139、熟地黄113.5、地骨皮172、地黄103.5、茯苓172、天冬103.5、麦冬103.5、人参103；所述制备方法包括在对中药原料进行处理过程中添加特定种类和用量的助研剂以及液氮冷冻的步骤。

Description

一种补气养血中成药制剂及其制备方法
相关申请的交叉引用
本申请要求2022年03月02日提交的中国申请号2022102001906的权益。所述申请号20221020019067据此全文以引用方式并入本文。
技术领域
本发明属于中药制剂领域，具体涉及一种补气养血中成药制剂及其制备方法。
背景技术
康寿丸由何首乌、熟地黄、地骨皮、地黄、茯苓、天冬、麦冬、人参组方而成，处方来源于《中国医学大辞典》第1252页——《沈氏尊生方》中的“延年益寿不老丹”，由广州中医药大学罗元恺教授提议，经广州白云山敬修堂药业股份有限公司研制成小丸制剂，并命名为“康寿丸”。康寿丸(卫生部药品标准中药成方制剂第十一册WS3-B-2231-96)的制备工艺为：取一半处方量的何首乌，用黑豆汁拌匀，润透，干燥后用甘草汁拌匀，干燥；地骨皮、茯苓用白酒洗后干燥；熟地黄、地黄用白酒浸润一夜；天冬、麦冬用白酒浸润3小时，分别干燥；前述七味与人参及剩余的何首乌粉碎成细粉，过筛，混匀，用水泛丸，干燥，用甘草碳粉包衣，打光，即得。康寿丸具有补气养血，润肺滋肾的功能，可用于气血两虚，精血不足可致的身体羸弱，神疲乏力，眩晕健忘，多汗，干咳少痰，心悸气促，腰膝酸软。康寿丸的用法与用量为淡盐水或蜜糖水送服，一次5g，一日2-3次。
常规的炮制加工粉碎方法不能有效破坏药材的细胞结构，影响中成药有效成分的溶出、释放和吸收。目前康寿丸存在生物利用度相对较低的问题，导致 单次服用剂量偏大，患者服用存在一定的难度，降低了患者服药的依从性。
超微粉碎技术具有改善物料的理化性质、强化物料的使用效果、扩大物料的应用范围等特点。目前的超微粉碎有气流式超微粉碎、旋转球磨式超微粉碎、机械剪切式超微粉碎、高频振动式超微粉碎等超微粉碎技术。但上述超微粉碎技术对于含有高糖分、韧性大的中药材粉碎效果不佳，造成成品粒度大、粘结等问题，且粉碎过程中产生的热量容易造成药效成分流失、分解。康寿丸处方中何首乌、熟地黄、地骨皮、地黄等药材均为高糖分、多韧性纤维，单纯采用超微粉技术不能达到本发明的目的。
发明内容
针对现有技术的不足，本发明的目的是在康寿丸的基础上，提供一种补气养血中成药制剂及其制备方法。采用本发明制备方法制备得到的补气养血中成药制剂提高药物生物利用度，增加药效，减少患者单次服用剂量，从而提高患者服药的依从性。
具体地，通过以下几个方面的技术方案实现了本发明：
在第一个方面中，本发明提供了一种补气养血中成药制剂，所述中成药制剂包含以下重量份的中药原料：何首乌69.5-278份、熟地黄56.8-227份、地骨皮86-344份、地黄51.8-207份、茯苓86-344份、天冬51.8-207份、麦冬51.8-207份、人参51.5-206份。
优选地，所述中成药制剂由以下重量份的中药原料制成：何首乌69.5-278份、熟地黄56.8-227份、地骨皮86-344份、地黄51.8-207份、茯苓86-344份、天冬51.8-207份、麦冬51.8-207份、人参51.5-206份。
作为可选的方式，在上述中成药制剂中，所述中成药制剂包含以下重量份的中药原料：何首乌139份、熟地黄113.5份、地骨皮172份、地黄103.5份、茯苓172份、天冬103.5份、麦冬103.5份、人参103份。
优选地，所述中成药制剂由以下重量份的中药原料制成：何首乌139份、 熟地黄113.5份、地骨皮172份、地黄103.5份、茯苓172份、天冬103.5份、麦冬103.5份、人参103份。
在第二个方面中，本发明提供了上述第一个方面所述的中成药制剂的制备方法，其特征在于：包括以下步骤：
(1)称取所述何首乌重量份的1/2-1，加入所取何首乌重量份1/3-1/5的黑豆汁拌匀，润透，干燥后加入所取何首乌重量份1/9-1/11的甘草汁拌匀，干燥备用；
(2)地骨皮、茯苓用白酒洗后干燥备用；
(3)熟地黄、地黄用白酒浸润2-24h，分别干燥备用；
(4)取天冬、麦冬用白酒浸润2-6h，分别干燥备用；
(5)取上述七味与人参及剩余何首乌，混合后用粉碎机粉碎并过24-50目药典筛，得药材粗粉；
(6)将步骤(5)所得药材粗粉加入助研剂并混合，所述助研剂占药材粗粉重量的0％-2.0％；
(7)将步骤(6)所得混合粉末置于液氮中冷冻处理0.5h-4h；
(8)将步骤(7)所得混合粉末置于-10-0℃的低温中共同进行超微粉碎，得超微粉混合粉末；
(9)所述补气养血中成药制剂是以步骤(8)所得混合粉末使用常规中药制剂方法制备成的任一种常用剂型。
作为可选的方式，在上述制备方法中，步骤(1)、步骤(2)、步骤(3)和步骤(4)中干燥处理至以重量百分比计含水量小于0.5％。
作为可选的方式，在上述制备方法中，在步骤(6)中，所述助研剂为《中国药典》收载的药用辅料二氧化硅或硬脂酸镁中的一种或两种。
优选地，助研剂为药材粗粉重量0.2％-1.0％的二氧化硅或药材粗粉重量0.4％-2.0％的硬脂酸镁或者药材粗粉重量0.2％-1.5％的50％二氧化硅50％硬脂酸镁。
更优选地，助研剂为药材粗粉重量0.8％的二氧化硅或药材粗粉重量1.5％的硬脂酸镁或药材粗粉重量1.0％的50％二氧化硅50％硬脂酸镁。
作为可选的方式，在上述制备方法中，在步骤(7)中，将步骤(6)所得混合粉末初步粉碎后置于液氮中冷冻处理2h。
作为可选的方式，在上述制备方法中，在步骤(8)中，混合粉末的平均粒径小于35μm，优选25-30μm。
作为可选的方式，在上述制备方法中，在步骤(9)中，所述剂型选自片剂、散剂、胶囊剂、丸剂、冲剂、口服液、颗粒剂、滴丸剂、微丸、肌注剂、滴注剂或膏剂。
优选地，在步骤(9)中，所述剂型选自片剂、丸剂、颗粒剂或胶囊剂。
优选地，在步骤(9)中，所述片剂为糖衣片剂、薄膜衣片剂或肠溶衣片剂，所述胶囊剂为软胶囊，所述膏剂为软膏剂或硬膏剂。
在本发明所述补气养血中成药制剂中，含有“熟地黄”和“地黄”，其中，“熟地黄”味甘微温，能补血滋肾养阴；“地黄”(又称”生地黄”)味甘性凉，有清热养阴强心利尿之作用，二药配合,共收养血滋阴补益肾水、强心利尿抗过敏等功能。
本发明相对于现有技术，具有以下有益效果：
本发明所述制备方法通过在对中药原料进行处理过程中添加特定种类和用量的助研剂以及液氮冷冻的冷冻处理的方法，解决了目前临床上使用的中成药寿康丸生物利用度相对较低的问题。采用本发明所述制备方法制备得到的补气养血中成药制剂提高了药物生物利用度，增加了药效，减少了患者单次服用剂量，从而提高了患者服药的依从性。
附图说明
图1：液氮冷冻时间与超微粉粒度关系曲线图。
图2：助研剂加入量与超微粉粒度关系曲线图。
图3：寿康丸和补气养血中成药制剂的累积溶出度曲线图。
具体实施方式
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
实施例1：
A.取何首乌139g、熟地黄113.5g、地骨皮172g、地黄103.5g、茯苓172g、天冬103.5g、麦冬103.5g、人参103g备用。
B.取上述何首乌69.5g，用黑豆汁17.4g拌匀，润透，干燥后用甘草汁7.0g拌匀，干燥；地骨皮、茯苓用白酒洗后干燥；熟地黄、地黄用白酒浸润24h；天冬、麦冬用白酒浸润6h，分别干燥；
上述处理后的七味与人参及剩余何首乌，混合后用粉碎机粉碎并过24目药典筛，得药材粗粉；
将上述所得药材粗粉加入重量为上述药材粗粉0.8％的二氧化硅并混合；
将上述所得混合粉末置于液氮中冷冻处理2h；
将上述所得药材粗粉置于0-10℃低温环境中共同进行超微粉碎，得超微粉混合粉末，使药粉平均粒径小于28μm；
C.口服制剂：
上述所得超微粉混合粉末加入适量水，湿法泛丸，干燥；
用甘草炭粉包衣，打光，即得。
实施例2：
A.取何首乌139g、熟地黄113.5g、地骨皮172g、地黄103.5g、茯苓172g、 天冬103.5g、麦冬103.5g、人参103g备用。
B.取上述何首乌69.5g，用黑豆汁17.4g拌匀，润透，干燥后用甘草汁7.0g拌匀，干燥；地骨皮、茯苓用白酒洗后干燥；熟地黄、地黄用白酒浸润24h；天冬、麦冬用白酒浸润6h，分别干燥；
上述处理后的七味与人参及剩余何首乌，混合后用粉碎机粉碎并过50目药典筛，得药材粗粉；
将上述所得药材粗粉加入重量为上述药材粗粉1.5％的硬脂酸镁并混合；
将上述所得混合粉末置于液氮中冷冻处理2h；
将上述所得药材粗粉置于0-10℃低温环境中共同进行超微粉碎，得超微粉混合粉末，使药粉平均粒径小于28μm；
C.口服制剂：
上述所得超微粉混合粉末加入适量水，湿法制颗粒，干燥；
过筛，装入胶囊，即得。
实施例3：液氮冷冻时间试验
1.试验材料
取何首乌139g、熟地黄113.5g、地骨皮172g、地黄103.5g、茯苓172g、天冬103.5g、麦冬103.5g、人参103g备用。
取上述何首乌69.5g，用黑豆汁17.4g拌匀，润透，干燥后用甘草汁7.0g拌匀，干燥；地骨皮、茯苓用白酒洗后干燥；熟地黄、地黄用白酒浸润24h；天冬、麦冬用白酒浸润6h，分别干燥；上述处理后的七味与人参及剩余何首乌，混和后用粉碎机粉碎并过24目药典筛，所得药材粗粉加入重量为上述药材粗粉1.0％的二氧化硅并混合，作为供试品。
2.试验方法
在粉碎机机转速、药粉含水量相同的条件下，分别将供试品置于液氮中冷冻处理0、0.5、1、2、4h，置于0-10℃低温环境中共同进行超微粉碎，测得其粉体样品的粒度，并进行分析。
3.结论
冷冻时间对超微粉的粒度影响见图1。由图1可知，在其他条件相同的情况下，随着在液氮中冷冻的时间增长，超微粉的粒度(D90)明显减小，冷冻0.5h较0h粒径(D90)变化较大。经过液氮冷冻，粗粉中分子之间的相互作用力减小，物料具有脆性，易于粉碎。而当冷冻时间达到2h到4h时，粒径(D90)改变较小，说明冷冻2h时分子间作用力已经达到最佳值，后续继续加长冷冻时间影响不大。故在实际生产实践中可以2h作为最佳物料冷冻时间。
实施例4：助研剂加入量试验
1.试验材料
取何首乌139g、熟地黄113.5g、地骨皮172g、地黄103.5g、茯苓172g、天冬103.5g、麦冬103.5g、人参103g备用。
取上述何首乌69.5g，用黑豆汁17.4g拌匀，润透，干燥后用甘草汁7.0g拌匀，干燥；地骨皮、茯苓用白酒洗后干燥；熟地黄、地黄用白酒浸润24h；天冬、麦冬用白酒浸润6h，分别干燥；
上述处理后的七味与人参及剩余何首乌，混和后用粉碎机粉碎并过24目药典筛，得药材粗粉作为供试品。
2.试验方法
在粉碎机机转速、药粉含水量相同的条件下，分别将供试品中混入重量为供试品0、0.2、0.4、0.6、0.8、1.0、1.5、2.0％的二氧化硅、硬脂酸镁以及50％二氧化硅50％硬脂酸镁混合粉末，将上述所得混合粉末置于液氮中冷冻处理4h；置于0-10℃低温环境中共同进行超微粉碎，测得其粉体样品的粒度，并进行分析。
3.结论
助研剂加入量对超微粉的粒度影响见图2。由图2可知，在其他条件相同的情况下，随着助研剂的增加，超微粉的粒度(D90)明显减少，助研剂可减少超微粉在设备内壁粘附并聚集，减少多糖物质的粉体间的相互粘连，降低粉 体吸湿速率，减少粉体饱和吸湿量，使超微粉更易分散、粉碎。在加入助研剂后超微粉粒度明显降低；在二氧化硅加入量达到0.8％、硬脂酸镁加入量达到1.5％、50％二氧化硅50％硬脂酸镁加入量达到1.0％时超微粉粒度达到最佳值，后续继续增大助研剂加入量对粒度影响不明显。
优选助研剂为药材粗粉重量0.2％-1.0％的二氧化硅或药材粗粉重量0.4％-2.0％的硬脂酸镁或药材粗粉重量0.2％-1.5％的50％二氧化硅50％硬脂酸镁。优选地，加入助研剂为药材粗粉重量0.8％的二氧化硅或药材粗粉重量1.5％的硬脂酸镁或药材粗粉重量1.0％的50％二氧化硅50％硬脂酸镁。
实施例5：溶出度试验
1.仪器与试剂
万分之一电子天平(梅特勒托利多公司)；安捷伦1260高效液相色谱仪(配置四元泵、自动进样器、柱温箱和DAD检测器)，OpenLab CDS色谱工作站。2,3,5,4＇-四羟基二苯乙烯-2-O-β-D-葡萄糖苷购自中国食品药品检定研究院。乙腈为色谱纯，水为超纯水，其他试剂均为分析纯。康寿丸样品由广州白云山敬修堂药业股份有限公司提供(批号：B11013)；一种补气养血中成药制剂，按照实施例1的方法制备。
2.方法与结果
2.1.人工胃液的配制
取稀盐酸16.4mL，加水800mL与胃蛋白酶10g，摇匀后，加水稀释至1000mL，即得，检测pH值为1.8。
2.2.供试品溶液制备
分别取约含何首乌3g生药量的康寿丸或补气养血中成药制剂，按照《中国药典》2020版四部通则0931溶出度与释放度测定法的第二法(桨法)进行测定。以“2.1”项人工胃液为溶出介质，转速75r/min，温度(37.0±0.5)℃。分别在5、10、15、20、30、40、50、60min分别取样1mL并及时补充等温度等体积的溶出介质，用0.45μm微孔滤膜滤过后，续滤液即为供试品溶液。 2.3.对照品溶液制备
取2,3,5,4＇-四羟基二苯乙烯-2-O-β-D-葡萄糖苷对照品约6mg，精密称定，置100mL量瓶中，加甲醇5mL，溶解后，用溶出介质稀释至刻度，摇匀，作为对照品溶液。
2.4.色谱条件
色谱柱：Thermo ODS–2 HYPERSIL(250mm×4.6mm，5μm，美国赛默飞世尔公司)；流动相:乙腈–水(体积比为20：80)；检测波长：320nm；流量:1.0m L/min；柱温:40℃；进样体积:10μL。
2.5.溶出度测定
按“2.4”条下色谱条件，分别取供试品溶液和对照品溶液注入液相色谱仪，记录色谱图，按外标法以峰面积计算的累积溶出量并绘制溶出曲线，结果见图3。
3.结论
本发明与使用已有工艺制作的康寿丸相比，2,3,5,4＇-四羟基二苯乙烯-2-O-β-D-葡萄糖苷含量提高了约30％，说明细胞壁在粉碎过程中得到破坏，有效成分无需穿透细胞壁即可释放，释放速度和释放量得到提高，能维持药材原有的药效。
实施例6：药效学实验
1.实验材料
SPF级昆明种小白鼠，购自广东省医学实验动物中心，动物生产许可证号：SCXF(粤)2018-0002。康寿丸样品由广州白云山敬修堂药业股份有限公司提供(批号：B11013)；补气养血中成药制剂，按照实施例1的方法制备；生理盐水。
2.统计学处理
所有数据均输入EXCEL2010进行统计分析，在不同组别中，计算平均值±标准差进行方差分析，用t检验进行组间比较。
3.对小鼠常压耐缺氧试验
共用体重18-22克小鼠54只，雌雄兼有，随机分成康寿丸给药组、补气养血中成药制剂给药组和生理盐水对照组3组，每组18只。给药组分别以5g/kg剂量的康寿丸或补气养血中成药制剂进行灌胃，对照组给等容量生理盐水0.5mL/只。灌胃1小时后，将小鼠放入预先加5g钠石灰的250mL磨口瓶中。每瓶一只，瓶口用凡士林涂封，以死亡为指标，记录存活时间，结果见表1。
表1小鼠常压耐缺氧试验
从表1看出，补气养血中成药制剂组小鼠的存活时间比康寿丸组明显延长(P＜0.01)，表明该药具有提高小鼠常压耐缺氧能力的作用。
4.对老年小鼠记忆力试验
试验共用15个月小鼠66只，平均体重为37.5g/只。随机分成康寿丸给药组、补气养血中成药制剂给药组和生理盐水对照组3组。每组22只，雌雄兼有。给药组分别以2.7g/kg的康寿丸或补气养血中成药制剂灌胃，每天一次，连续给药8天。对照组给等容量生理盐水0.5mL/只。记忆力测定采用迷宫法，记忆力测定前先禁食半天，带小鼠走迷宫2次，使其了解到达迷宫终点的途径，然后才测定每只小鼠的记忆力。以小鼠从迷宫入口处走到终点所需时间作为记忆力的指标，所需时间越短，表明记忆力越好，实验结果见表2。
表2老年小鼠记忆力试验
从表2可看出，补气养血中成药制剂组小鼠到达迷宫终点所需时间比康寿 丸组缩短(P＜0.05)，表明补气养血中成药制剂具有提高老年小鼠迷宫记忆力。
5.游泳耐力试验
取体重17-19克雄性小鼠33只，随机分成康寿丸给药组、补气养血中成药制剂给药组和生理盐水对照组3组，每组11只。给药组分别以5g/kg的康寿丸或补气养血中成药制剂灌胃，每天一次，连续给药8天，对照组给等容量生理盐水0.5mL/只。耐力试验采用负重游泳直至完全疲劳法，即先在小鼠尾根栓上相当自身体重5％的铜线环，然后将其放入水温27℃的玻璃水池中强迫游泳，记录其入水到沉入水底超过10s的时间，其时间为负重游泳时间，观察各组对小鼠游泳时间的影响，结果见表3。
表3游泳耐力试验
负重游泳时间可真实反映动物的运动耐力。表3结果看出，补气养血中成药制剂组小鼠负重游泳时间与康寿丸组比较P＜0.01，差异非常显著，认为补气养血中成药制剂具有增强小鼠游泳耐力的作用。
6.雄性激素活性试验
试验采用前列腺和精囊增重法，取雄性小鼠幼鼠体重12-14克共39只，随机分成康寿丸给药组、补气养血中成药制剂给药组和生理盐水对照组3组，康寿丸给药组、补气养血中成药制剂给药组各13只，对照组13只，给药组分别以6g/kg的康寿丸或补气养血中成药制剂灌胃，对照组给等容量生理盐水0.4mL/只，每天1次，共给药9天，于第10天杀检，称其前列腺和精囊重量，以每10g体重的平均前列腺和精囊重量进行比较，结果将表4。
表4雄性激素活性试验
从表4结果看出，补气养血中成药制剂组雄性小鼠每10g体重的前列腺和精囊重量与康寿丸组比较P＜0.01，差异非常显著，根据精囊、前列腺等副性器官的生长发育依赖雄性激素，认为补气养血中成药制剂具有增强雄性激素活性作用。
7.雌性激素活性试验
试验采用子宫增重法，取雌性小鼠幼鼠体重12-14g共33只，随机分成康寿丸给药组、补气养血中成药制剂给药组和生理盐水对照组3组，每组各11只，给药组分别以6g/kg的康寿丸或补气养血中成药制剂灌胃，对照组给等容量生理盐水0.4mL/只，每天1次，共给药9天，于第10天杀检，取出子宫称其重量，以每10g体重的平均子宫重量进行比较，结果见表5。
表5雌性激素活性试验
从表5结果看出，康寿丸组小鼠每10g体重的子宫重量与生理盐水对照组比较，P＜0.05，差异非常显著，根据子宫的生长发育依赖雄性激素，认为补气养血中成药制剂具有增强雌性激素活性作用。
8.老年小鼠寿命试验
试验共用15月龄的昆明种老年小鼠48只，雌雄兼有，随机分成康寿丸给药组、补气养血中成药制剂给药组和生理盐水对照组3组，每组16只，3组总体重量基本相等。给药方法分为两个阶段，第一阶段为灌胃，即给药组小鼠分 别以3.3g/kg的康寿丸或补气养血中成药制剂灌胃，每天1次，连续13天，对照组以等容量生理盐水0.5mL/只；第二阶段给药，给药组每只小鼠喂以浸泡过康寿丸药液的饼干2.5g(浸于100mg/mL的康寿丸药液中)其剂量为6g/kg，每天1次，共给药47天，合并第一阶段灌胃13天共给药60天。对照组除改为等容量生理盐水外，其他所有的试验条件均与给药组相同。改用逐日登记动物死亡只数的方法，计算每只小鼠寿命，两组动物数据经统计学处理，结果见表6。
表6老年小鼠寿命试验
从表6看出，补气养血中成药制剂平均寿命比康寿丸组小鼠延长25.9天，经统计学处理，P＜0.05，差异显著，并且一种补气养血中成药制剂组小鼠技能延长最低寿命，也能增加最高寿命，表明补气养血中成药制剂具有延长老年小鼠寿命的作用。
9.结论
上述实验结果表明，康寿丸及补气养血中成药制剂均具有增强小鼠常压耐缺氧能力、提高老年小鼠迷宫记忆力、增强小鼠游泳耐力、增强小鼠雄性和雌性性激素活性和延长老年小鼠寿命的作用。因此认为康寿丸及补气养血中成药制剂均具有补气养血，润肺滋肾、强壮、益寿的功效；且在上述实验中，补气养血中成药制剂比康寿丸效果更为明显。
实施例7：安全性试验
1.实验材料
SPF级昆明种小白鼠，购自广东省医学实验动物中心，动物生产许可证号：SCXF(粤)2018-0002。
2.统计学处理
所有数据均输入EXCEL2010进行统计分析，在不同组别中，计算平均值±标准差进行方差分析，用t检验进行组间比较。
3.供试品制备
取何首乌139g、熟地黄113.5g、地骨皮172g、地黄103.5g、茯苓172g、天冬103.5g、麦冬103.5g、人参103g备用。
取上述何首乌69.5g，用黑豆汁17.4g拌匀，润透，干燥后用甘草汁7.0g拌匀，干燥；地骨皮、茯苓用白酒洗后干燥；熟地黄、地黄用白酒浸润24h；天冬、麦冬用白酒浸润6h，分别干燥；
上述处理后的七味与人参及剩余何首乌，混和后用粉碎机粉碎并过24目药典筛，得药材粗粉。在粉碎机机转速、药粉含水量相同的条件下，分别混入重量为上述药材粗粉重量2.0％的二氧化硅或硬脂酸镁，将上述所得混合粉末置于液氮中冷冻处理4h；置于0-10℃低温环境中共同进行超微粉碎，分别制得二氧化硅制剂供试品、硬脂酸镁制剂供试品。
4.试验方法
试验共用昆明种老年小鼠48只，雌雄兼有，随机分成二氧化硅制剂组给药、硬脂酸镁制剂给药组和生理盐水对照组3组，给药组连续10d灌胃，分别给予7g/kg的二氧化硅制剂供试品、硬脂酸镁制剂供试品，对照组灌相应体积的去离子水，每天固定时间灌胃两次。连续观察14d。记录各组动物的体质量、行为、饮食及排泄情况。于第14天对小鼠进行眼球取血和肝肾取材，并进行生化指标测定和病理染色观察。
5.结论
灌药后的小鼠的体质量、饮食、行为、排泄情况以及血清葡萄糖、总蛋白、肌酐、甘油三酯测量值与灌药前相比均无明显改变(P>0.05)，给药两组与对照组相比无明显差异；肝、肾病理染色也未出现毒理改变。上述研究结果提示，在补气养血中成药中加入二氧化硅或硬脂酸镁制成的制剂在本实验条件下无 急性毒性。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。

Claims (10)

  1. 一种补气养血中成药制剂，其特征在于：所述中成药制剂包含以下重量份的中药原料：何首乌69.5-278份、熟地黄56.8-227份、地骨皮86-344份、地黄51.8-207份、茯苓86-344份、天冬51.8-207份、麦冬51.8-207份、人参51.5-206份。
  2. 根据权利要求1所述的中成药制剂，其特征在于：所述中成药制剂包含以下重量份的中药原料：何首乌139份、熟地黄113.5份、地骨皮172份、地黄103.5份、茯苓172份、天冬103.5份、麦冬103.5份、人参103份。
  3. 权利要求1或权利要求2所述的中成药制剂的制备方法，其特征在于：包括以下步骤：
    (1)称取所述何首乌重量份的1/2-1，加入所取何首乌重量份1/3-1/5的黑豆汁拌匀，润透，干燥后加入所取何首乌重量份1/9-1/11的甘草汁拌匀，干燥备用；
    (2)地骨皮、茯苓用白酒洗后干燥备用；
    (3)熟地黄、地黄用白酒浸润2-24h，分别干燥备用；
    (4)取天冬、麦冬用白酒浸润2-6h，分别干燥备用；
    (5)取上述七味与人参及剩余何首乌，混合后用粉碎机粉碎并过24-50目药典筛，得药材粗粉；
    (6)将步骤(5)所得药材粗粉加入助研剂并混合，所述助研剂占药材粗粉重量的0％-2.0％；
    (7)将步骤(6)所得混合粉末置于液氮中冷冻处理0.5h-4h；
    (8)将步骤(7)所得混合粉末置于-10-0℃的低温中共同进行超微粉碎，得超微粉混合粉末；
    (9)所述补气养血中成药制剂是以步骤(8)所得混合粉末使用常规中药制剂方法制备成的任一种常用剂型。
  4. 根据权利要求3所述的制备方法，其特征在于：步骤(1)、步骤(2)、 步骤(3)和步骤(4)中干燥处理至以重量百分比计含水量小于0.5％。
  5. 根据权利要求3或权利要求4所述的制备方法，其特征在于：在步骤(6)中，所述助研剂为《中国药典》收载的药用辅料二氧化硅或硬脂酸镁中的一种或两种。
  6. 根据权利要求3至5中任一项所述的制备方法，其特征在于：在步骤(7)中，将步骤(6)所得混合粉末初步粉碎后置于液氮中冷冻处理2h。
  7. 根据权利要求3至6中任一项所述的制备方法，其特征在于：在步骤(8)中，混合粉末的平均粒径小于35μm，优选25-30μm。
  8. 根据权利要求3至7中任一项所述的制备方法，其特征在于：在步骤(9)中，所述剂型选自片剂、散剂、胶囊剂、丸剂、冲剂、口服液、颗粒剂、滴丸剂、微丸、肌注剂、滴注剂或膏剂。
  9. 根据权利要求8所述的制备方法，其特征在于：在步骤(9)中，所述剂型选自片剂、丸剂、颗粒剂或胶囊剂。
  10. 根据权利要求8或权利要求9所述的制备方法，其特征在于：在步骤(9)中，所述片剂为糖衣片剂、薄膜衣片剂或肠溶衣片剂，所述胶囊剂为软胶囊，所述膏剂为软膏剂或硬膏剂。
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114558079A (zh) * 2022-03-02 2022-05-31 广州白云山敬修堂药业股份有限公司 一种补气养血中成药制剂及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1239674A (zh) * 1999-06-29 1999-12-29 张家宝 一种对前列腺具有保健作用的营养液
CN102362978B (zh) * 2011-10-21 2013-02-06 北京同仁堂天然药物有限公司 一种具有益肾填精、补气养血功效的中药组合物
CN108721564B (zh) * 2017-04-24 2021-09-17 四川省中医药科学院 一种治疗血小板减少症的药物组合物及其制备方法和用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114558079A (zh) * 2022-03-02 2022-05-31 广州白云山敬修堂药业股份有限公司 一种补气养血中成药制剂及其制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Chinese Dictionary of Clinical Drugs, Traditional Chinese Medicine Preparations, Volume 1", 31 August 2018, CHINA MEDICAL SCIENCE AND TECHNOLOGY PRESS, CN, ISBN: 978-7-5067-9693-4, article PENG, CHENG ET AL.: "Kang's Niuhuang Jiedu Tablets (pills)", pages: 1139 - 1145, XP009549357 *
"Drug Standards of the Ministry of Health of the People's Republic of China Volume 11 of Traditional Chinese Medicine Prescriptions", 31 December 1996, MINISTRY OF HEALTH OF THE PEOPLE'S REPUBLIC OF CHINA , CN, article CHINESE PHARMACOPOEIA COMMISSION: "KangShouWan", pages: 175, XP009549356 *
"NATIONAL HANDBOOK OF OTC DRUGS (2ND EDITION", 31 August 2004, PEOPLE'S MEDICAL PUBLISHING HOUSE, CN, ISBN: 7-117-06084-0, article WU, JINGSHI: "KangShouWan", pages: 508 - 509, XP009549354 *
"NEW CHINESE PATENT MEDICINE", 31 October 2019, HENAN SCIENCE AND TECHNOLOGY PRESS, CN, ISBN: 978-7-5349-9642-9, article SUN, SHIFA: "KangShouWan", pages: 513, XP009549358 *

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