WO2016184290A1 - 人参提取物、人参皂苷、人参皂苷衍生物在制备治疗巨细胞病毒感染病症的药物或保健品中的应用 - Google Patents

人参提取物、人参皂苷、人参皂苷衍生物在制备治疗巨细胞病毒感染病症的药物或保健品中的应用 Download PDF

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WO2016184290A1
WO2016184290A1 PCT/CN2016/079844 CN2016079844W WO2016184290A1 WO 2016184290 A1 WO2016184290 A1 WO 2016184290A1 CN 2016079844 W CN2016079844 W CN 2016079844W WO 2016184290 A1 WO2016184290 A1 WO 2016184290A1
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ginseng
ginsenoside
extract
derivative
saponin
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English (en)
French (fr)
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富力
王凯乾
惠敏
李凡
樊宏宇
王硕
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Priority to KR1020177035967A priority Critical patent/KR101966425B1/ko
Priority to DK16795777.8T priority patent/DK3295950T3/da
Priority to JP2017559407A priority patent/JP6457661B2/ja
Priority to AU2016263260A priority patent/AU2016263260B2/en
Priority to RU2017143772A priority patent/RU2679903C1/ru
Priority to US15/574,238 priority patent/US10675317B2/en
Priority to ES16795777T priority patent/ES2856969T3/es
Priority to CA2985862A priority patent/CA2985862C/en
Priority to EP16795777.8A priority patent/EP3295950B1/en
Publication of WO2016184290A1 publication Critical patent/WO2016184290A1/zh
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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)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9068—Zingiber, e.g. garden ginger
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/20—Natural extracts
    • A23V2250/21—Plant extracts
    • A23V2250/2124—Ginseng

Definitions

  • the invention belongs to the field of medicine and relates to a medicine or health food for treating human cytomegalovirus infection, in particular to a medicine Chinese ginseng extract and a derivative thereof for treating cytomegalovirus infection medicine or health food.
  • HCMV Human Cytomegalovirus
  • HCMV Human Cytomegalovirus
  • HCMV also known as cell inclusion body virus
  • HCMV has a large intranuclear inclusion body due to the enlargement of infected cells.
  • HCMV belongs to the subfamily of beta herpesvirus and is about 200 nm in diameter. It is one of the largest animal viruses, has a 64 nm core containing viral DNA, and is outsourced with a 110 nm icosahedron. The intact granules are surrounded by a capsule which consists of at least 25 to 30 viral particles encoded by a protein or glycoprotein.
  • the genome of HCMv is about 235-240 kb in length and has a molecular weight of 150-160 ⁇ 10 3 kDa.
  • HCMV HCMV consists of two components (long, L) and short (s). Since the two components are different or inverted in the direction of interconnection, the structure of the DNA molecule has four isomers. Widely distributed, other animals can be infected, causing infections in various systems, mainly genitourinary, central nervous system and liver disorders, ranging from mild asymptomatic infections to severe defects or death.
  • the HCMV gene is structurally composed of three polypeptide segments encoding the specificity of the infected cells: an immediate early protein region, an early protein region, and a late protein, and the three proteins are immunogenic and temporal.
  • HCMv transcription-translation is regulated by itself and host cells.
  • the expression of immediate early genes and early genes is regulated by promoters.
  • the detection is more common in acute infection, and late gene transcription and translation are regulated by IE, E genes and proteins. It indicates that the virus is in an incubation period, and the virus assembly is mature, which is the late result of HCMV infection.
  • mtrI is located on the E fragment of HindIII at the left end of genome U of ADl69 strain, and is 588 bp long, which can transform NIH3T3 and primary mouse embryo cells.
  • mtrII is located on the Xbal/Bam HI EM fragment of HCMV Towne strain DNA. It is 980 bp long and can transform NIH3T3 and rat-2 cells.
  • the AD169 and TdCMv Tanaka strains of HCMV have corresponding regions and contain two isolated promoters. P1, P2, mtrII are present in all transformed cells and the tumor cells they form.
  • mtrIII is located on the Xbal/BamHI fragment and encodes a major immediate early protein with a molecular weight of 72 kD. This protein is involved in the anti-activation and autoregulation of the virus, and mtrIII is not present in transformed cells.
  • infections are divided into three types: 1 toxic infection; 2 latent infection; 3 cell transformation or latent carcinogenesis.
  • In vitro test of HCMv inoculation into human fibroblasts can form a cell line containing viral antigens and have the characteristics of transformed cells.
  • a specific fragment of HCMV-DNA is extracted and transfected into a cell, and some cells can be transformed into a chromosomal DNA by DNA, and transformed, and inoculated into athymic nude mice to produce a tumor.
  • HCMV IE transfected HPV immortalized human cervical epithelial cell line and found that HCMV integrated into the cell chromosome, synergistically promotes malignant transformation of cervical epithelial cells with HPV16, and forms tumors in nude mice, indicating HCMV Closely related to cervical cancer.
  • Lu Deyin and other HCMV inactivated by ultraviolet light were inoculated into the cervix of the mouse 3 times/week for 8 weeks. Results The precancerous lesion rate of cervical cancer in the HCMV group was 27.8% (23/83), and the cancer incidence rate was 20.5% (17/83).
  • CMV has a typical herpesvirus morphology, and its DNA structure is similar to HSV, but is 5% larger than HSV.
  • the virus is highly species-specific for host or cultured cells, and human cytomegalovirus (HCMV) can only infect humans and proliferate in human fibroblasts. The virus proliferates slowly in cell culture, and the replication cycle is long. It takes 30 to 40 days for the initial isolation and culture to appear cytopathic. It is characterized by a large cell swell, a large nuclear nucleus, and a large nucleus around the nucleus. Acid inclusion body. The cellular immune function of the body plays an important role in the occurrence and development of CMV infection.
  • CMV Cellular immunodeficiency
  • the body is infected with CMV and can produce specific antibodies and killer T lymphocytes to activate NM cells.
  • the limited CMV replication ability of the antibody has certain resistance to reinfection of the same strain, but it is not resistant to the activation of endogenous latent virus, and the exogenous infection of other different strains of CMV.
  • the specific antiviral effect can be exerted by specific killing T lymphocytes and antibody-dependent cytotoxic cells.
  • HCMV infection is extremely common in the human population and can cause a variety of diseases.
  • Adult infections are often caused by immunodeficiency or immunosuppression. Especially after organ transplantation, bone marrow transplantation, immunosuppressive therapy and malignant tumor patients receive radiotherapy and chemotherapy.
  • Extremely susceptible to HCMV infection The incidence of HCMV infection among AIDS patients is also high. Due to the prevalence of HCMV infection and its possible serious consequences, it is highly valued worldwide, and it is of great significance for the epidemiology, diagnostic techniques, treatment and prevention of HCMV infection and basic research on virology. Tumor patients after receiving chemotherapy or radiotherapy. The immune function is much lower than that of normal people.
  • the latent human cytomegalovirus (HCMV) is easy to reactivate and cause serious infection. It is an important infectious factor affecting the survival rate and quality of life of cancer patients.
  • Cytomegalovirus infection is a congenital or acquired infection caused by cytomegalovirus (CMV), a congenital or acquired infection caused by CMV.
  • CMV cytomegalovirus
  • CMV is a double-stranded DNA virus belonging to the herpes virus group, its morphology and other herpes. The virus is similar and has obvious species specificity to host or tissue culture cells. Human CMV can only be isolated and cultured in human embryonic fibroblasts.
  • HCMV infection is very widespread in the population.
  • the adult infection rate in China is over 95%.
  • Adult infections are mostly caused by immunodeficiency or immunosuppression.
  • organ transplantation bone marrow transplantation, immunosuppressive therapy and malignant tumor patients receive radiotherapy and chemotherapy.
  • Extremely susceptible to HCMV infection Most infected people have no clinical symptoms, but under certain conditions, multiple organs and systems can cause serious diseases.
  • the virus can invade the lungs, liver, kidney, salivary glands, other glands of the breast, as well as multinucleated white blood cells and lymphocytes. It can excrete viruses from saliva, milk, blood, urine, semen, and uterine secretions in a long-term or intermittent manner.
  • congenital infection pregnancy maternal HCMV infection can cause congenital infection through the placenta invasion of the fetus, a small number of premature birth, miscarriage, stillbirth or death. Children with jaundice, hepatosplenomegaly, thrombocytopenic purpura and hemolytic anemia. Surviving children often have permanent inferior intelligence, neuromuscular dyskinesia, deafness and choroidal retinitis.
  • the UVMV-inactivated HCMV can transform rodent embryonic fibroblasts.
  • the detection rate of HCMV DNA is high, and the HCMV antibody titer is also higher than that of normal people.
  • Virus particles are also found in the cell lines established by the above tumors, suggesting that HCMV and its Like the herpes virus, it has the potential to be carcinogenic.
  • the latent human cytomegalovirus (HCMV) is easy to reactivate and cause serious infection. It is an important infectious factor affecting the survival rate and quality of life of cancer patients.
  • HCMV-infected patients are mostly in a latent infection state; even if HCMV replicates in vivo, it is mostly asymptomatic infection.
  • ganciclovir has toxic side effects such as bone marrow suppression, so it can only be used cautiously in symptomatic infection.
  • Ganociclovir DHPG has the effect of preventing the spread of HCMV. If combined with high titer anti-HCMV immunoglobulin, it can reduce the mortality of HCMV pneumonia complications in bone marrow transplantation.
  • HCMV infection of ganciclobe-resistant guanosine can be selected with sodium phosphate, although it can permanently reduce the spread of HCMV, the effect is better than the former. difference.
  • the development of a live vaccine of HCMV virus abroad can induce the production of antibodies, but the carcinogenic potential of the vaccine is to be resolved.
  • Ginsenosides as the main active ingredient of ginseng, has been widely studied and used. Among them, ginseng extract and its derivatives are the most attractive. As the main active ingredient of ginseng, it has good safety and has been prepared. The anti-tumor oral preparation is applied to the clinic and is intensively studied as an injection.
  • the present inventors have extracted a ginseng extract and a derivative thereof, which are active ingredients for treating human cytomegalovirus infection, from a ginseng medicinal material through a large number of modern scientific researches, and using ginseng medicinal materials, and extracting ginseng extract and its derivatives and The corresponding pharmaceutical preparations were studied for pharmacodynamics and pharmacology of human cytomegalovirus infection.
  • the results showed that the pharmacological effects of ginseng extract and its derivatives were clear, and the treatment of human cytomegalovirus infection was strong, and the side effects were low and safe. High in sex, it can provide a highly effective and low-toxic drug for the treatment of human cytomegalovirus infection.
  • the primary object of the present invention is to provide a new use of ginseng extract, ginsenoside or ginsenoside derivative in the preparation of a medicament or health care product for treating a human cytomegalovirus infection disorder, in view of the above technical problems in the treatment of a human cytomegalovirus infection disorder.
  • Ginseng extract, ginseng saponin and ginsenoside derivative have the properties and effects of treating human cytomegalovirus infection.
  • an aspect of the present invention provides a use of a ginseng extract, a ginsenoside or a ginsenoside derivative for the preparation of a medicament or a health care product for treating a human cytomegalovirus infection disorder.
  • related diseases caused by human cytomegalovirus infection include diseases caused by infection of human cytomegalovirus in the treatment of cardiovascular and cerebrovascular diseases, tumors, burns, AIDS, organ transplantation or perinatal period.
  • the inventors found that the chemical constituents of ginseng Ginseng extract, ginsenoside, and ginsenoside derivatives have a strong therapeutic effect on human cytomegalovirus infection.
  • the drug consists of a ginseng extract, a ginsenoside or a ginsenoside derivative and a pharmaceutically acceptable carrier.
  • the ginseng extract is selected from the group consisting of a ginseng alcohol extract and a ginseng water extract;
  • the ginseng saponin is ginseng total saponin, ginseng diol saponin, 20(R)-ginsenoside rg3;
  • the ginsenoside derivative It is a 20(R)-ginsenoside rg3 derivative.
  • the ginsenoside rg3 derivative is 20(R)-ginsenoside Rg3 octadecanoate having the formula: C 86 H 144 O 21 ; the structural formula is as in formula (I):
  • the ginseng alcohol extract is prepared according to the following steps:
  • the soaking treatment time of step 1) is from 30 to 60 min, preferably 30 min.
  • the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1:10.
  • the extraction solvent is an ethanol solution having a volume percentage concentration of ⁇ 50%, preferably 50-75% ethanol solution.
  • the number of times of heat extraction in the step 2) is 2-3 times, preferably 3 times.
  • the ratio of the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1:8 during each heating extraction; the temperature for each heating extraction is 60-80 ° C, preferably 70 °C; heating extraction time is 0.5-2h, preferably 1h.
  • the concentration in the concentration treatment in the step 3) is 65-85 ° C, preferably 80 ° C; the concentrated density of the concentrated extract is 1.05-1.15, preferably 1.1; the temperature during the drying process is 70 -90 ° C, preferably 85 ° C.
  • the total ginsenoside content of the ginseng alcohol extract is 2-5% (the detection method is tested according to the national standard: GB/T19506-2009 Appendix B).
  • the ginseng water extract is prepared according to the following steps:
  • the soaking treatment time of step 1) is from 30 to 60 min, preferably 30 min.
  • the weight ratio of the ginseng medicinal material to the water is 1:8-12, preferably 1:10.
  • the number of decoction extractions in the step 2) is 2-3 times, preferably 3 times.
  • the weight ratio of the ginseng medicinal material to water is 1:8-12, preferably 1:8; the temperature of each decocting extraction is 90-100 ° C, preferably 90-95 ° C; heating extraction time is 0.5-2 h, preferably 1 h.
  • the concentration temperature in the concentration treatment in the step 3) is 70-95 ° C, preferably 80 ° C;
  • the concentrated density of the concentrated extract is 1.05-1.15, preferably 1.1;
  • the temperature during the drying process is 70 -95 ° C, preferably 85 ° C.
  • the total ginsenoside content of the ginseng water extract is 2-5% (the detection method is carried out according to the national standard: GB/T19506-2009 Appendix B).
  • the ginseng total saponin is prepared according to the following steps:
  • the soaking treatment time of step 1) is from 30 to 60 min, preferably 30 min.
  • the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1:10.
  • the extraction solvent is an ethanol solution having a volume percentage concentration of ⁇ 50%, preferably 50-75% ethanol solution.
  • the number of times of heat extraction in the step 2) is 2-3 times, preferably 3 times.
  • the ratio of the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1:8 during each heating extraction; the temperature for each heating extraction is 60-80 ° C, preferably 70 °C; heating extraction time is 0.5-2h, preferably 1h.
  • the step 2) is to collect the ginseng extract for concentration treatment, and then to prepare the ginseng concentrate, and then perform the macroporous resin column separation treatment.
  • the ginseng concentrate obtained after the concentration treatment contains 1-3.5 g of crude ginseng per ml, which is equivalent to 1-3.5 g of crude drug/ml, preferably 2.5 g of crude drug/ml.
  • the macroporous resin column chromatography in the step 3) comprises the following sequential steps: 3A) injecting the ginseng extract into the macroporous resin column, followed by elution with water as an eluent; 3B) using volume percent The ethanol solution having a concentration of 30% to 50% was eluted as an eluent and the ethanol eluate was collected to obtain a ginseng resin eluate.
  • the ratio of the weight of the ginseng in the ginseng extract to the volume of the macroporous resin is 1:0.8-2.5, preferably 1:1.
  • the ratio of the column diameter of the macroporous resin column to the column height of the resin is 1:5-10, preferably 1: 5-7, further preferably 1:5.5-5.9.
  • the macroporous adsorption resin described in the step 3) is one selected from the group consisting of X-5, AB-8, NK-2, NKA-2, NK-9, D3520, D101, and WLD, preferably D101.
  • the ratio of the amount of water in step 3A) to the column volume of the macroporous resin column is 2-4:1, preferably 4:1; and the concentration of 30%-50% ethanol solution in step 3B)
  • the ratio of the amount to the column volume of the macroporous resin column is from 2 to 8:1, preferably from 4 to 8:1, further preferably from 8:1.
  • the volume percent concentration of the eluent ethanol solution in step 3B) is 50%.
  • the concentration in the concentration treatment in step 4) is 65-90 ° C, preferably 80 ° C; the temperature during the drying treatment is 75-95 ° C, preferably 85 ° C.
  • the total ginsenoside content of the ginseng is 20-50% (the detection method is carried out according to the national standard: GB/T19506-2009 Appendix B).
  • the ginseng glycol saponin is prepared according to the following steps:
  • the first eluate of the ginseng resin column is subjected to a second macroporous resin chromatography separation using a macroporous resin column, and the eluate is collected and combined to obtain a second eluate of the ginseng resin column;
  • the soaking treatment time of step 1) is from 30 to 60 min, preferably 30 min.
  • the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1:10.
  • the extraction solvent is an ethanol solution having a volume percentage concentration of ⁇ 50%, preferably 50-75% ethanol solution.
  • the number of times of heat extraction in the step 2) is 2-3 times, preferably 3 times.
  • the ratio of the weight ratio of the ginseng medicinal material to the extraction solvent is 1:8-12, preferably 1:8 during each heating extraction; the temperature for each heating extraction is 60-80 ° C, preferably 70 °C; heating extraction time is 0.5-2h, preferably 1h.
  • the method further comprises the step 2A) of concentrating the ginseng extract collected in the step 2) to prepare a ginseng concentrate, and then performing the first macroporous resin column chromatography separation treatment.
  • the ginseng concentrate obtained after the concentration treatment contains 1-3.5 g of crude ginseng per ml, which is equivalent to 1-3.5 g of crude drug/ml, preferably 2.5 g of crude drug/ml.
  • the first macroporous resin column chromatography treatment in the step 3) comprises the following sequential steps: 3A) injecting the ginseng extract into the macroporous resin column, followed by elution with water as an eluent; 3B) Use a 30%-50% ethanol solution as the eluent The elution was carried out and the ethanol eluate was collected to obtain a ginseng-macroporous resin first eluate.
  • the ratio of the weight of the ginseng in the ginseng extract to the volume of the macroporous resin is 1:0.8-2.5, preferably 1:1.
  • the ratio of the column diameter of the macroporous resin column to the column height of the resin is 1:5 to 10, preferably 1:5 to 7, more preferably 1:5.5 to 5.9.
  • the macroporous adsorption resin described in the step 3) is one selected from the group consisting of X-5, AB-8, NK-2, NKA-2, NK-9, D3520, D101, and WLD, preferably D101.
  • the ratio of the amount of water in the step 3A) to the column volume of the macroporous resin column is 2-4:1, preferably 4:1; and the amount of the ethanol solution having a concentration of 30-50% by volume in the 3B) is
  • the column volume ratio of the macroporous resin column is from 2 to 8:1, preferably from 4 to 8:1, further preferably from 8:1.
  • the volume percent concentration of the eluent ethanol solution in step 3B) is 50%.
  • the method further comprises: concentrating the first eluate of the ginseng resin collected in the step 3) to prepare a first concentrated liquid of the ginseng resin, and then performing the second macroporous resin column chromatography separation treatment.
  • the ginseng concentrate obtained after the concentration treatment contains 3.5-6 g of crude ginseng per ml, which is equivalent to 3.5-6 g of crude drug/ml, preferably 5.0 g of crude drug/ml.
  • the second macroporous resin column chromatography treatment in step 4) comprises the following sequential steps: 4A) injecting the first eluate of the ginseng resin column into the macroporous resin column, followed by a concentration percentage of 50 ⁇ 60% ethanol solution is eluted as eluent; 4B) elution with ethanol solution with 70-80% by volume concentration as eluent and collecting ethanol eluent to obtain second eluate of ginseng resin .
  • the ratio of the weight of the ginseng to the volume of the macroporous resin in the first eluate of the ginseng resin column is 1:0.8-2.5, preferably 1:1.
  • the ratio of the column diameter of the macroporous resin column to the column height of the resin is 1:5 to 10, preferably 1:5 to 7, more preferably 1:5.5 to 5.9.
  • the macroporous adsorption resin described in the step 4) selects one of HPD-200, D203, XAD-4, and HPD-100, preferably HPD-100.
  • the ratio of the amount of the ethanol solution having a volume percentage concentration of 50 to 60% in step 4A) to the column volume of the macroporous resin column is 2-4:1, preferably 4:1; the mass percentage concentration in step 4B)
  • the ratio of the amount of the 70 to 80% ethanol solution to the column volume of the macroporous resin column is from 2 to 8:1, preferably from 4 to 8:1, further preferably from 8:1.
  • the concentration temperature in the concentration treatment in the step 5) is 65-95 ° C, preferably 80 ° C; the temperature during the drying treatment is 70-95 ° C, preferably 85 ° C.
  • the ginseng glycol saponin content is 30-70%.
  • the detection method is carried out according to the national standard: GB/T19506-2009 Appendix B).
  • the content of the 20(R)-ginsenoside Rg3 is 1% to 98%; preferably 30 to 80%, and more preferably 60%.
  • the 20(R)-ginsenoside Rg3 content is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%.
  • the content of the 20(R)-ginsenoside Rg3 derivative is from 1% to 98%; preferably from 30% to 80%, more preferably 60%.
  • the 20(R)-ginsenoside Rg3 derivative content is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98% .
  • the total ginsenoside content of the ginseng alcohol extract is 2-5%; the total ginsenoside content of the ginseng water extract is 2-5%; and the total ginsenoside content of the ginseng total saponin is 20-50 %; the content of the panaxadiol saponin in the ginseng glycol saponin is 30-70%.
  • pharmaceutically acceptable carriers are generally approved by health care professionals for this purpose and as inactive ingredients of the agent.
  • a compilation of pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical excipients, 2nd edition, edited by A. Wade and PJ Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994) found in the reference book.
  • the carrier comprises an excipient such as starch, water or the like; a lubricant such as magnesium stearate or the like; a disintegrating agent such as microcrystalline cellulose; a filler such as lactose; and a binder, Such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives, flavoring agents, spices, etc.;
  • the medicament is in the form of a tablet, a capsule, a pill, a powder, a granule, a syrup, a solution, an emulsion, an injection, a spray, an aerosol, a gel, a cream, a tincture, a cataplasm, a rubber. It is in the form of a plaster or a plaster.
  • Another aspect of the present invention provides a medicament or a health care product comprising a ginseng extract, a ginsenoside or a ginsenoside derivative for treating a human cytomegalovirus infection.
  • the ginseng extract is selected from the group consisting of a ginseng alcohol extract and a ginseng water extract;
  • the ginseng saponin is ginseng total saponin, ginseng diol saponin, 20(R)-ginsenoside rg3;
  • the ginsenoside derivative is 20(R)-ginsenoside rg3 derivative.
  • the ginsenoside rg3 derivative is 20(R)-ginsenoside Rg3 octadecyl butyrate.
  • the content of the 20(R)-ginsenoside Rg3 is 1% to 98%; preferably 30 to 80%, and more preferably 60%.
  • the 20(R)-ginsenoside Rg3 content is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%.
  • the content of the 20(R)-ginsenoside Rg3 derivative is from 1% to 98%; preferably from 30% to 80%, more preferably 60%.
  • the 20(R)-ginsenoside Rg3 derivative content is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98% .
  • the total ginsenoside content of the ginseng alcohol extract is 2-5%; the total ginsenoside content of the ginseng water extract is 2-5%; and the total ginsenoside content of the ginseng total saponin is 20-50 %; the content of the panaxadiol saponin in the ginseng glycol saponin is 30-70%.
  • the ratio of the weight of the ginseng extract, ginsenoside or ginsenoside derivative to the total weight of the drug or health care product is from 0.01 to 10:100, preferably from 0.1 to 10:100, further preferably from 1 to 10:100.
  • the medicine or health care product further includes a bean bean root extract, a Xanthium extract, a Scutellaria barbata extract, a Sophora flavescens extract, a dandelion extract, a honeysuckle extract, a ginger extract, and a grape seed extract. , one or more of vitamin P extract, vitamin C and its derivatives, or vitamin E and its derivatives.
  • the medicament can be prepared into various dosage forms by methods well known in the art, such as tablets, capsules, pills, powders, granules, syrups, solutions, injections, sprays, aerosols, gels, creams. Agent, expectorant, cataplasm, rubber plaster or plaster.
  • the invention also provides a method of treating a human cytomegalovirus infection condition comprising administering to a subject a therapeutically effective amount of a ginseng extract, a ginsenoside or a ginsenoside derivative, wherein the therapeutically effective amount is 0.6 to 12 mg/kg.
  • d is preferably 1 to 6 mg/kg ⁇ d, and more preferably 1.5 to 3 mg/kg ⁇ d.
  • terapéuticaally effective amount as used herein, unless otherwise indicated, is the amount of the agent in need of an effective effect; the “therapeutically effective amount” is adjustable and variable, and is ultimately determined by the medical personnel, the factors considered including the route of administration. And the general nature of the formulation, the recipient's weight, age, etc., and the nature and severity of the condition being treated.
  • the present invention has the following distinct advantages:
  • the present invention excavates new medicinal value for ginseng extract, ginsenoside or ginsenoside derivative, and is used for treating diseases related to human cytomegalovirus infection, including cardiovascular and cerebrovascular diseases, organ transplantation Human cytomegalovirus infection in patients with perinatal, oncology, burns, AIDS, etc., especially in organ transplants, bone marrow transplants, immunosuppressive therapy, and malignant tumor patients receiving radiotherapy and chemotherapy. Or human cytomegalovirus infection in an immunosuppressed state. It can be prepared into a medicine or health food for treating human cytomegalovirus infection, thereby opening up a new field for the application of ginseng medicine.
  • the ginseng extract, ginseng saponin or ginsenoside derivative of the invention has strong pharmacological action, has remarkable efficacy for treating human cytomegalovirus infection, has quick effect, small toxic and side effects, good safety, and can be taken for a long time, and has good Medicinal prospects.
  • the raw materials of the invention have rich sources, low cost, safe clinical use, simple preparation process, can be made into various dosage forms, and have small dosage and convenient use, so it is easy to promote.
  • the invention can be used for preparing a medicament for treating human cytomegalovirus infection by using ginseng extract, ginsenoside or ginsenoside derivative active ingredient, and ginseng extract, ginsenoside or ginsenoside derivative and other active ingredients can be used (for example) And Soybean root extract, Xanthium extract, Scutellaria barbata extract, Sophora flavescens extract, dandelion extract, honeysuckle extract, ginger extract, grape seed extract, pomegranate extract, vitamin C and A derivative or a combination of vitamin E and its derivatives is used to prepare a combination drug for treating human cytomegalovirus infection.
  • the first heat extraction process is carried out after constant temperature extraction at a temperature of 70 ° C for 1 hour, followed by filtration to obtain a first extract and a first dregs; wherein the weight ratio of the human involved in the extraction solvent (ethanol solution) is 1:10. .
  • the weight ratio of the human participation in the extraction solvent is 1:10, except for 1:10-12; the soaking time is 30 minutes, and other soaking time ⁇ 30 min is suitable for the present invention.
  • the extraction solvent is 30-60 min; the extraction solvent is in addition to the ethanol solution having a volume percentage concentration of 70%, and other ethanol solutions having a volume percentage concentration of ⁇ 50% are suitable for use in the present invention, preferably an ethanol solution having a concentration of 50-75%, Water ethanol; an extraction temperature of 60-80 ° C and a heat extraction time of 0.5-2 h are suitable for use in the present invention.
  • the weight ratio of human participation in the extraction solvent is 1:10.
  • the extraction solvent used in the second and third extraction processes of the ginseng alcohol extract is used in addition to the ethanol solution having a volume percentage concentration of 70%, and other ethanol solutions having a volume percentage concentration ⁇ 50% are suitable for the present invention.
  • the number of times of heat extraction in the preparation process of the ginseng alcohol extract is 3 times, and the number of times of extraction is 2-3 times, which is suitable for the present invention.
  • the first, second and third extracts obtained by the three filtrations were combined and placed in a rotary evaporator to carry out evaporation concentration treatment at a temperature of 80 ° C to obtain an extract having a relative density of 1.1, which was then placed in an oven at 85 ° C. Dry to constant weight, that is, get ginseng alcohol extract.
  • the ginseng alcohol extract is a light brownish yellow powder with a special odor and is soluble in ethanol.
  • the ginseng total saponin content in the ginseng alcohol extract was measured by the national standard (GB/T19506-2009 Appendix B method, geographical indication product Jilin Changbai Mountain ginseng) method, containing 3% of total ginseng saponins.
  • the concentration temperature is 65-85 ° C, and the relative density of the concentrated extract is 1.05-1.15, which is suitable for the present invention; the temperature during drying is 70-90 ° C, which is suitable for the present invention. .
  • People in the ginseng alcohol extract prepared by the method of the invention The total saponin content is 2-5%.
  • the ginseng (300 g) and the extraction solvent tap water (3000 g) were placed in a multi-functional extraction tank of Chinese medicine, uniformly mixed, and subjected to soaking treatment, wherein the soaking time was 30 min; the weight ratio of human participation in extracting solvent water was 1: 10.
  • the immersion time ⁇ 30 min is suitable for the present invention, preferably 30-60 min; the weight ratio of the human involved in extracting the solvent water is 1:10, and the other is, for example, 1:8. -12 are all suitable for use in the present invention.
  • the multi-function extraction tank power supply is turned on, heated, and the ginseng medicinal material is subjected to the first decoction extraction treatment, and the mixture is filtered at a constant temperature of 95 ° C for 1 hour, and then filtered to obtain the first extraction liquid and the first medicinal residue;
  • the weight ratio of the ginseng medicinal material to the extraction solvent water is 1:10, and other ratios such as 1:8-12 are suitable for the present invention.
  • the extraction temperature of 90-100 ° C is suitable for the present invention, preferably 90-95 ° C; the heating extraction time 0.5-2 h is suitable for the present invention, preferably 1 h.
  • the number of times of heat extraction in the preparation process of the ginseng water extract is 3 times, and the number of times of extraction is 2-3 times, which is suitable for the present invention.
  • the first, second and third extracts obtained by the three filtrations were combined and placed in a rotary evaporator to carry out evaporation concentration treatment at a temperature of 80 ° C to obtain an extract having a relative density of 1.1, which was then placed in an oven at 85 ° C. Dry to constant weight, that is, get ginseng water extract.
  • the ginseng water extract is a light brownish yellow powder with a special odor and good water solubility.
  • the content of total ginsenosides in ginseng water extract was measured by the method of Appendix B of GB/T19506-2009, containing 2% of total ginsenosides.
  • the concentration temperature is 70-95 ° C, and the relative density of the concentrated extract is 1.05-1.15, which is suitable for the present invention; the drying temperature of 70-95 ° C is suitable for the present invention.
  • the ginseng aqueous extract prepared by the method of the present invention has a total ginsenoside content of 2-5%.
  • the first, second, and third extracts obtained by the three filtrations were combined, placed in a rotary evaporator, and concentrated at a temperature of 80 ° C to obtain a ginseng concentrate (120 ml), which corresponds to 2.5 g of a crude drug/ml of ginseng solution.
  • the concentration of the ginseng concentrate is equal to 2.5 g of the crude drug per ml of the concentrated solution, and the other concentrated solution per ml is equivalent to 1-3.5 g of the crude drug (ie, 1-3.5 g of the crude drug/ml). .
  • the ginseng concentrate is applied to a macroporous resin column for macroporous resin column separation treatment, wherein the macroporous adsorption resin selects D101 type macroporous adsorption resin, the volume of resin in the resin column (300 ml) and the weight of ginseng (dry weight)
  • the ratio is 1:1 (ie, if the ginseng weighs 1 kg, the volume of the macroporous resin is 1 L; if the dry weight of the medicinal material is 1 g, the volume of the macroporous resin is 1 ml), the supernatant after concentration is completely flowed into the resin
  • the column first wash with 4 column volumes of water, discard the eluent; then elute with 8 column volume of 50% by volume ethanol solution, collect the eluate to obtain ginseng-macroporous resin wash Deliquoring
  • the ratio of the weight of ginseng in the ginseng extract to the volume of the macroporous resin in the ginseng extract of the present invention is 1:0.8-2.5, which is suitable for the present invention; the macroporous adsorption resin is in addition to D101.
  • X-5, AB-8, NK-2, NKA-2, NK-9, D3520, D101, WLD are all suitable for the present invention;
  • the ratio of the amount of water to the column volume of the macroporous resin column in the water elution process 2-4:1 is suitable for the present invention; when the eluent is an ethanol solution, the volume percentage concentration of the ethanol solution is 30%-50% except for 50%; the amount of the ethanol solution is compared with the macroporous resin column.
  • a column volume ratio of 2-4:1 is suitable for use in the present invention.
  • the ginseng-macroporous resin eluent was placed in a rotary evaporator and concentrated under reduced pressure at a temperature of 80 ° C. The solvent was recovered, and the residue was concentrated and dried in a dry box at 85 ° C to obtain ginseng total saponin 2.6 g. .
  • the total ginsenoside of ginseng is a light brownish yellow powder with a special odor.
  • the content of total ginsenosides produced by the method of Appendix B of GB/T19506-2009 was measured, and 32% of ginseng total saponins were contained.
  • the concentration temperature of 65-90 ° C is suitable for the present invention; the drying temperature of 75-95 ° C is suitable for the present invention.
  • the total ginsenoside content of ginseng prepared by the method of the invention is 20-50%.
  • the ginseng-macroporous resin first eluent was concentrated in a rotary evaporator at a temperature of 80 ° C to obtain a ginseng-macroporous resin first concentrated solution (60 ml), which corresponds to 5.0 g of crude drug/ml of ginseng solution. ;
  • the ginseng-macroporous resin first concentrated solution is applied to a macroporous resin column for macroporous resin column separation treatment, wherein the macroporous adsorption resin selects HPD-100 type macroporous adsorption resin, and the volume of the resin in the resin column (
  • the ratio of 300ml) to the weight of ginseng (dry weight) is 1:1 (ie, if the weight of ginseng is 1kg, the volume of macroporous resin is 1L; if the dry weight of medicinal material is 1g, the volume of macroporous resin is 1ml), to be concentrated
  • the supernatant is completely flowed into the resin column, it is first washed with 4 times column volume of a 60% by volume ethanol solution, and the eluate is discarded; then 8 times column volume is used as a percentage by weight of 80% ethanol.
  • the solution was eluted and the eluate was collected to obtain a second eluate of ginseng-macroporous resin.
  • the concentration of the ginseng concentrate in the concentration treatment of the present invention is equivalent to 5.0 g of the crude drug per ml of the concentrated solution, and the other concentrated liquid per ml equivalent to 3.5-6 g of the crude drug (i.e., 3.5-6 g of the crude drug/ml) is also suitable for use in the present invention.
  • the ratio of the weight of the ginseng to the volume of the macroporous resin in the first concentrated liquid of the ginseng-macroporous resin in the first concentrated liquid of the ginseng-macroporous resin of the present invention is 1:0.8-2.5.
  • HPD-100, other HPD-200, D203, XAD-4 are suitable for the present invention
  • 60% ethanol solution elution process 60% ethanol solution and macroporous resin
  • the column volume ratio of the column is 2-4:1 suitable for the present invention; in the 80% ethanol solution elution process, the ratio of the amount of the 80% ethanol solution to the column volume of the macroporous resin column is 2-4:1. Suitable for use in the present invention.
  • the second eluate of ginseng-macroporous resin was placed in a rotary evaporator and concentrated under reduced pressure at a temperature of 80 ° C.
  • the solvent was recovered, and the residue was concentrated and dried in a dry box at 85 ° C to obtain a ginseng diol.
  • Total saponins 0.7g.
  • the ginseng diol saponin is a pale yellow powder with a special odor. Good water solubility.
  • the content of the ginseng glycol saponin obtained by the high performance liquid chromatography method of Appendix VI of the Chinese Pharmacopoeia of 2010 was used, and the content of the ginseng diol saponin was 59%.
  • the concentration temperature of 65-95 ° C is suitable for the present invention; the drying temperature of 70-95 ° C is suitable for the present invention.
  • the content of the panaxadiol saponin in the ginseng glycol saponin prepared by the method of the present invention is 30-70%.
  • the ginseng alcohol extract and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng alcohol extract and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng alcohol extract and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng alcohol extract, the pea root extract, the vitamin C and the starch are uniformly mixed and then filled into capsules to make 10,000 tablets.
  • the ginseng water extract and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng water extract and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng water extract and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng water extract, the bean extract, the vitamin C and the starch are uniformly mixed and then filled into capsules to make 10,000 tablets.
  • the ginseng total saponin and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng total saponin and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng total saponin and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng total saponins, the peas root extract, the vitamin C and the starch are uniformly mixed and then filled into capsules to make 10,000 tablets.
  • the ginseng glycol saponin and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng glycol saponin and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng glycol saponin and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 pieces.
  • the ginseng diol saponins, the stalk root extract, the vitamin C and the starch are uniformly mixed and then filled into capsules to prepare 10,000 tablets.
  • the ginseng saponin rg3 and the starch are uniformly mixed, and then granulated.
  • the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 tablets.
  • the ginseng saponin rg3 and the starch are uniformly mixed, and then granulated.
  • the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 tablets.
  • the ginseng saponin rg3 and the starch are uniformly mixed, and then granulated.
  • the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 tablets.
  • the ginseng saponin rg3 the stalk root extract, the vitamin C and the starch are uniformly mixed and then filled into capsules to prepare 10,000 tablets.
  • Ginsenoside rg3, ginger extract, vitamin C and sucrose powder are mixed and made into granules and then bagged to make 10,000 bags.
  • the ginsenoside rg3 derivative and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 tablets.
  • the ginsenoside rg3 derivative and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 tablets.
  • the ginsenoside rg3 derivative and the starch are uniformly mixed, and then granulated, and the talc powder and magnesium stearate are added and uniformly mixed, and then pressed into 10,000 tablets.
  • the ginsenoside rg3 derivative, the mountain bean root extract, the vitamin C and the starch are uniformly mixed and then filled into capsules to prepare 10,000 tablets.
  • the ginsenoside rg3 derivative, the ginger extract, the vitamin C and the sucrose powder are uniformly mixed into granules and then bagged to make 10,000 bags.
  • Test Example 1 Effect of ginseng extract, ginsenoside and its derivatives on immune function of mice infected with HCMV infection
  • Kunming mice male and female, weighing 18-22 g, are provided by the Animal Center of Zhejiang University of Traditional Chinese Medicine, license number SCXK (Shanghai) 2008-00l6.
  • Virus and cells HCMVAD169 standard strain, human embryonic lung fibroblasts (HEL), provided by the Virus Room of Shandong Academy of Medical Sciences.
  • the cytomegalovirus monoclonal antibody (HCMVMcAb) was introduced from the Diagnostics Laboratory of the Chinese Academy of Preventive Medicine, and is an early antigen monoclonal antibody.
  • the ELISA enzyme-linked immunosorbent assay
  • the ELISA has a working titer of 1 ⁇ 10 -5 .
  • Ginseng alcohol extract light brownish yellow powder containing 3% of total ginseng ginseng, produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20120601;
  • Ginseng water extract light brownish yellow powder containing 2% ginseng total saponin, produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20120602;
  • Ginseng total saponin light brownish yellow powder containing 32% ginseng total saponin, produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20120502;
  • Panaxadiol saponin light yellow powder containing 59% ginseng glycol saponin, produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20120403;
  • Ginsenoside rg3 derivative (20(R)-ginsenoside Rg3 octadecyl butyrate); developed by Dalian Fusheng Natural Medicine Development Co., Ltd., high-performance liquid chromatography two detectors UV detector and evaporative light scattering detector area The purity of each method was 99.6%.
  • Positive control drug ganciclovir (specification: 250mg / support, Livzon Group Hubei Keyi Pharmaceutical Co., Ltd., batch number 020506), clinical daily dose of 45.5mg / kg body weight.
  • HCMVADl69 1.3 Introduction and proliferation of the virus standard strain HCMVADl69 was introduced in the poisonous species of the Chinese Academy of Preventive Medicine in October 1999.
  • the virus was dissolved in 1640 medium and inoculated on spare HEL cells at 37 °C. After 16h, the cells showed lesions, the cells swelled, the granules in the cytoplasm increased, some of the cells became round, and some cells fell off. With the prolongation of the culture time, the lesion range is expanded, and by 96 hours, the lesion can reach more than 90%.
  • the HEL culture supernatant with cytopathic lesions up to +++ ⁇ ++++ was discarded, washed gently with PBS 3 times, added with double distilled water, frozen and thawed at -20 °C for 3 times, and vigorously beaten, 4 °C 10000 r/min After centrifugation for 20 min, the supernatant was collected and obtained.
  • mice male and female, were pre-incubated for 1 week under experimental conditions. They were randomly divided into 21 groups according to gender and body weight: normal control group; model group; positive drug control group; high- and medium-weight ginseng alcohol extract Low-dose group; high, medium and low doses of ginseng water extract; high, medium and low dose groups of ginseng total saponins; high, medium and low dose groups of ginseng diol saponins; high, medium and low dose groups of ginsenoside rg3 ; high, medium and low dose groups of ginsenoside rg3 derivatives.
  • the positive control group was given ganciclovir (45.5 mg/kg/d), and the three groups of ginseng alcohol extract were given 0.012 mg/kg/d, 0.06 mg/kg/d, 0.3 mg/kg/d, respectively.
  • the three groups of ginseng water extract were given ginseng water extract 0.012mg/kg/d, 0.06mg/kg/d, 0.3mg/kg/d, and the ginseng total saponins were given ginseng total saponins 0.012mg/kg.
  • mice were HCMVl0 -3, 0.1ml / only, the normal control group was injected with 0.9% saline, 0.1ml / only, On the second day of the exposure, the intragastric administration was started according to the determined dose, and the drug
  • the index and spleen index are the weight (mg) of the thymus and spleen organs per 10 g of body weight.
  • the eyeballs were taken for blood collection, serum was collected, diluted 100 times with physiological saline, and 1 mL of diluted serum, 0.5 mL of 5% chicken red cell suspension and 0.5 mL of 10% complement (guinea pig serum) were mixed evenly.
  • the temperature was kept in the °C incubator for 30 min, and the reaction was stopped by setting the refrigerator at 0 °C for 30 min. After centrifugation, the supernatant was taken, and the colorimetric value (OD value) was measured at 540 nm of a spectrophotometer.
  • mice were randomly selected from each group for sampling. 40 minutes after the last administration, blood was taken from the eyeballs, and blood was collected using a centrifuge tube. After the blood was coagulated, it was centrifuged at high speed, centrifuged at 3000 r/min for 5 min, and serum was taken. The determination of IL-2 in serum was carried out in accordance with the ELISA kit instructions.
  • mice in the model group first developed symptoms of infection, such as piloerection, hemiplegia, systemic ataxia and weight loss. The mice began to die from 5 to 7 days, and only survived at 21 days. Only, indicating that the model is successful.
  • Panaxol alcohol extract, ginseng water extract, ginseng total saponin, ginseng diol saponin, 20(R)-ginsenoside Rg3, 20(R)-ginsenoside Rg3 derivative group have mild poisoning symptoms, less death, and body weight Good growth indicates that these drugs have a certain inhibitory effect on the virus and can increase the survival rate of mice to varying degrees.
  • the number of surviving animals in each group was statistically compared with the model group, and it was confirmed that the high-dose group was significantly different.
  • the middle and small dose groups also had some protective effects on mice infected with HCMV.
  • the number of ganciclovir animals, weight gain and symptom performance were similar to those of the high dose group.
  • the thymus and spleen are important immune organs, and their organ index can reflect the strength of the body's immune function to some extent.
  • the main function of the thymus is to produce T lymphocytes and secrete thymosin, which are mainly involved in cellular immunity; the spleen is rich in lymphocytes and macrophages. Its weight is related to its function and the number of immune cells therein, depending on the extent to which lymphocytes proliferate.
  • the spleen and thymus index results of this experiment are shown in Table 2.
  • ginseng alcohol extract ginseng water extract, ginseng total saponin, ginseng diol saponin, ginsenoside rg3, ginsenoside rg3 derivative have obvious weight gain effect on immune organs infected with HCMV mice, the weight of each experimental group It was also higher than the model group, especially the spleen index and thymus index of the ginsenoside rg3 and ginsenoside rg3 derivatives groups were significantly different from the model group.
  • ginseng extract, ginseng saponin and its derivatives can protect the thymus and spleen of HCMV-infected model mice, have antigen-like immunity, and can restore and promote spleen lymphocyte activity.
  • the immunomodulatory effect. Therefore, ginseng extract and its derivatives can be used to treat human cytomegalovirus infection.
  • IL-2 is interleukin-2 (IL-2), also known as T cell growth factor (TCRF).
  • TCRF T cell growth factor
  • T cells that have been activated by specific antigen or mitogenic factor; activate T cells and promote cytokine production; stimulate NK cell proliferation, enhance NK killing activity and produce cytokines, induce LAK cell production; promote B cells Proliferate and secrete antibodies; activate macrophages.
  • the experimental results of IL-2 levels in mouse serum are shown in Table 3.
  • the results in Table 3 showed that the IL-2 level of the model group was the lowest, which was significantly different from the normal control group (P ⁇ 0.01), indicating that the modeling was successful.
  • Ginseng alcohol extract, ginseng water extract, ginseng total saponin, ginseng glycol saponin, ginsenoside rg3, ginsenoside rg3 derivatives are higher than the model group, indicating ginseng alcohol extract, ginseng water extract, ginseng total saponin, Ginsenoside saponins, ginsenoside rg3, and ginsenoside rg3 derivatives have an effect on IL-2 levels in HCMV-infected mice; ginseng water extract, ginseng total saponins, ginseng glycol saponins, ginsenoside rg3, ginseng The IL-2 level of the saponin rg3 derivative group was superior to that of the positive drug control group.
  • ginseng alcohol extract, ginseng water extract, ginseng total saponin, panaxadiol saponin, ginsenoside rg3 and ginsenoside rg3 derivatives all have an effect on the serum hemolysin antibody of HCMV-infected mice.
  • the numerical values are significantly different from the model group.
  • the serum hemolysin antibody levels of the ginseng water extract, the ginseng total saponin, the ginseng diol saponin, the ginsenoside rg3, and the ginsenoside rg3 derivative group were superior to the positive drug control group.
  • the ginseng water extract, ginseng total saponin, ginseng diol saponin, ginsenoside rg3, ginsenoside rg3 derivative group have stronger therapeutic effect on HCMV-infected mice than positive drugs.

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Abstract

一种人参提取物、人参皂苷、人参皂苷衍生物在制备用于治疗人类巨细胞病毒感染相关疾病药物中的应用。所述相关疾病包括患者在罹患心脑血管疾病、器官移植，围产期，肿瘤，烧伤，艾滋病等疾病的治疗过程中被人类巨细胞病毒感染。试验证明，人参提取物、人参皂苷、人参皂苷衍生物治疗人类巨细胞病毒感染的疾病中疗效显著，见效快、毒副作用小，是一种安全、高效、稳定、制备工艺简单的治疗人类巨细胞病毒感染药物或保健品，适于工业化生产，易于推广。为治疗人类巨细胞病毒感染提供了一种新的药物来源。

Description

人参提取物、人参皂苷、人参皂苷衍生物在制备治疗巨细胞病毒感染病症的药物或保健品中的应用 技术领域
本发明属于医药领域，涉及一种治疗人类巨细胞病毒感染的药物或保健食品，特别涉及一种中药人参提取物及其衍生物在治疗巨细胞病毒感染药物或保健食品中的应用。
背景技术
人类巨细胞病毒(human Cytomegalovirus,HCMV)亦称细胞包涵体病毒，由于感染的细胞肿大，并具有巨大的核内包涵体，故名。HCMV属于β疱疹病毒亚科，直径约200nm，是最大的动物病毒之一，具有一个64nm的、含有病毒DNA的内核，外包以110nm的20面体。完整的颗粒由一囊膜包裹，此囊至少由25～30个病毒颗粒所编码的蛋白质或糖蛋白组成BJ。HCMv的基因组长约235～240kb，分子量150～160×103kDa，线性双链DNA，属于DNA病毒。HCMV由长(long，L)和短(short，s)两种成分或节段组成。由于两种成分在相互连接处的方向不同或倒置，使DNA分子的结构有4种同质异构体。分布广泛，其他动物皆可遭受感染，引起以生殖泌尿系统，中枢神经系统和肝脏疾患为主的各系统感染，从轻微无症状感染直到严重缺陷或死亡。
HCMV基因结构上含有编码3种感染细胞特异性的多肽区段：即刻早期蛋白区、早期蛋白区、晚期蛋白，3种蛋白具有免疫原性和时相性。HCMv转录一翻译受自身与宿主细胞的调控，即刻早期基因和早期基因的表达受启动子的调控，其检出多见于急性感染，晚期基因转录和翻译受IE、E基因和蛋白调控，其检出标志着病毒处于潜伏期，病毒装配成熟，是HCMV感染的后期结果。HCMV基因组上有3个诱导细胞转化的形态转化区，即mtrI、mtrⅡ、mtrⅢ。mtrI位于ADl69株基因组U左侧末端的HindⅢ的E片段上，长588bp，可转化NIH3T3、原代鼠胚细胞。mtrⅡ位于HCMV Towne株DNA的Xbal/Bam HI EM片段上，长980bp，可转化NIH3T3、rat-2细胞，HCMV的ADl69、TdCMv Tanaka株上有其相对应的区域，并含有2个分离的启动子P1、P2，所有转化细胞及其形成的肿瘤细胞中均存在mtrⅡ。mtrⅢ位于Xbal/BamHI片段上，可编码分子量为72kD的主要即刻早期蛋白，该蛋白与病毒的反激活及自身调控有关，mtrⅢ不存在在转化细胞中。
从细胞水平来看，感染分为3种：①产毒性感染；②潜伏感染；③细胞转化或潜伏致癌。体外试验HCMv接种到人纤维母细胞后，可形成含病毒抗原的细胞株，并有转化细胞的特点。将HCMV-DNA的特定片段提取出来转染细胞，部分细胞可通过DNA整合到细胞染色体DNA，而发生转化，接种到无胸腺的裸鼠上产生肿瘤。刘朝奇等应用HCMV IE转染建立的HPV永生化的人宫颈上皮细胞系，结果发现HCMV整合到细胞染色体中，协同HPV16促进宫颈上皮细胞恶性转化，在裸鼠中形成肿瘤，说明了HCMV 与宫颈癌的关系密切。鲁德银等利用紫外线灭活的HCMV接种到小鼠宫颈部，3次/周，共8周。结果HCMV组宫颈癌前病变率为27.8％(23/83)，癌发生率为20.5％(17/83)。
CMV具有典型的疱疹病毒形态，其DNA结构也与HSV相似，但比HSV大5％。本病毒对宿主或培养细胞有高度的种特异性，人巨细胞病毒(HCMV)只能感染人，及在人纤维细胞中增殖。病毒在细胞培养中增殖缓慢，复制周期长，初次分离培养需30～40天才出现细胞病变，其特点是细胞肿大变园，核变大，核内出现周围绕有一轮“晕”的大型嗜酸性包涵体。机体的细胞免疫功能对CMV感染的发生和发展起重要作用，细胞免疫缺陷者，可导致严重的和长期的CMV感染，并使机体的细胞免疫进一步受到抑制，如杀伤性T细胞活力下降，NK细胞功能减低等。机体原发感染CMV后能产生特异性抗体和杀伤性T淋巴细胞，激活NM细胞。抗体有限CMV复制能力，对相同毒株再感染有一定抵抗力，但不能抵抗内源性潜伏病毒的活化，及CMV其他不同毒株的外源性感染。而通过特异性杀性T淋巴细胞和抗体依赖细胞毒性细胞能发挥最大的抗病毒作用。
HCMV在人群中感染极为普遍，能引起多种疾病的发生。成人感染则多发于免疫缺陷或免疫抑制状态下。尤其多处于器官移植、骨髓移植而接受免疫抑制剂治疗及恶性肿瘤患者接受放疗和化疗后。极易受HCMV感染。艾滋病患者HCMV感染发病者也很高。由于HCMV感染的普遍性及其可能造成严重后果，因而在全世界范围内受到高度重视，对HCMV感染的流行病学、诊断技术、治疗与预防以及有关病毒学基础研究均有非常重要的意义。肿瘤患者在接受化疗或放疗后。免疫功能大大低于正常人，潜伏的人巨细胞病毒(HCMV)易重新激活而导致严重感染.是影响肿瘤患者生存率和生活质量的重要感染因素。
巨细胞病毒感染症是由巨细胞病毒(CMV)引起的先天性或后天性感染，由CMV引起的先天性或后天性感染，CMV是双链DNA病毒，属于疱疹病毒群，其形态与其他疱疹病毒相似，对宿主或组织培养细胞有明显的种属特异性，人类CMV仅能在人胚纤维母细胞中分离、培养。
HCMV在人群中感染非常广泛，我国成人感染率达95％以上，成人感染多发于免疫缺陷或免疫抑制状态下。尤其多处于器官移植、骨髓移植而接受免疫抑制剂治疗及恶性肿瘤患者接受放疗和化疗后。极易受HCMV感染。多数感染者无临床症状，但在一定条件下侵袭多个器官和系统可产生严重疾病。病毒可侵入肺、肝、肾、唾液腺、乳腺其他腺体，以及多核白细胞和淋巴细胞，可长期或间隙地自唾液、乳汗血液、尿液、精液、子宫分泌物多处排出病毒。通常口腔，生殖道，胎盘，输血或器官移植等多途径传播。
(一)先天性感染妊娠母体HCMV感染可通过胎盘侵袭胎儿引起先天性感染，少数造成早产、流产、死产或生后死亡。患儿可发生黄疸，肝脾肿大，血小板减少性紫斑及溶血性贫血。存活儿童常遗留永久必性智力低下，神经肌肉运动障碍，耳聋和脉络视网膜炎等。
(二)围产期感染产妇泌尿道和宫颈排出HCMV，则分娩时婴儿经产道可被感染，多数和症状轻微或无临床症状的亚临床床感染，有的有轻微呼吸道障碍或肝功能损伤。
(三)儿童及成人感染通过吸乳、接吻、性接触、输血等感染、通常为亚临床型，有的也能导致嗜异 性抗体阴性单核细胞增多症。由于妊娠，接受免疫抑制治疗，器官移植，肿瘤等因素激活潜伏在单核细胞、淋巴细胞中病毒，引起单核细胞增多症、肝炎、间质性肺炎、视网膜炎、脑炎等。
(四)细胞转化和可能致癌作用经紫外线灭活的HCMV可转化啮齿类动物胚胎纤椎母细胞。在某些肿瘤如宫颈癌、结肠癌、前列腺癌、Kaposis肉瘤中HCMV DNA检出率高，HCMV抗体滴度亦高于正常人，在上述肿瘤建立的细胞株中还发现病毒颗粒，提示HCMV与其疱疹病毒一样，具有潜在致癌的可能性。肿瘤患者在接受化疗或放疗后。免疫功能大大低于正常人，潜伏的人巨细胞病毒(HCMV)易重新激活而导致严重感染.是影响肿瘤患者生存率和生活质量的重要感染因素。
由于HCMV感染患者大多处于潜伏感染状态；即使HCMV在体内复制活动，也多为无症状性感染。目前又无有效、安全的抗HCMV药物，故对HCMV感染的治疗，仍限于症状性感染时的对症处理；更昔洛韦因有骨髓抑制等毒副作用，因此只能在症状性感染时谨慎使用。丙氧鸟苷(ganciclovirDHPG)有防止HCMV扩散作用。如与高滴度抗HCMV免疫球蛋白合用，可降低骨髓移植的HCMV肺炎并发症死亡率，如果耐丙氧鸟苷的HCMV感染可选用磷甲酸钠，虽能持久地减少HCMV扩散，但效果比前者差。国外研制HCMV病毒活疫苗，能诱导产生抗体，但排除疫苗的致癌潜能，有待解决。
中药人参是名贵药材，人参皂苷作为人参的主要有效成分，被广泛研究和使用，其中以人参提取物及其衍生物最为引人瞩目，其作为人参的主要有效成分，安全性良好，已经被制成抗肿瘤口服制剂应用于临床，作为注射剂被深入研究。
本发明人通过大量的现代科学研究，采用先进的分离纯化技术从人参药材中提取其治疗人巨细胞病毒感染的有效成分人参提取物及其衍生物，并对人参提取物及其衍生物及其相应的药物制剂进行了治疗人巨细胞病毒感染的药效学、药理学研究，结果表明人参提取物及其衍生物单体药理作用清楚，治疗人巨细胞病毒感染功效强，毒副作用低，安全性高，可以为治疗人巨细胞病毒感染提供一种高效低毒的药物。
发明内容
本发明的首要目的是针对上述治疗人巨细胞病毒感染病症存在的技术问题，提供人参提取物、人参皂苷或人参皂苷衍生物在制备治疗人巨细胞病毒感染病症的药物或保健品中的新用途，人参提取物、人参皂苷、人参皂苷衍生物具有治疗人巨细胞病毒感染的性能和功效。
为实现上述目的，本发明一方面提供一种人参提取物、人参皂苷或人参皂苷衍生物在制备用于治疗人巨细胞病毒感染病症的药物或保健品中的应用。
其中，人巨细胞病毒感染所引起的相关疾病包括患者在治疗心脑血管疾病、肿瘤，烧伤，艾滋病，器官移植或处于围产期等过程中感染人类巨细胞病毒所导致的疾病。
在筛选具有治疗人巨细胞病毒感染作用的天然活性成分的过程中，发明人发现人参的化学成分中 人参提取物、人参皂苷、人参皂苷衍生物具有强烈的治疗人巨细胞病毒感染的作用。
其中，所述药物由人参提取物、人参皂苷或人参皂苷衍生物和药学上可接受的载体组成。
特别是，所述的人参提取物选择人参醇提取物、人参水提取物；所述人参皂苷为人参总皂苷、人参二醇类皂苷、20(R)-人参皂苷rg3；所述人参皂苷衍生物为20(R)-人参皂苷rg3衍生物。
尤其是，所述人参皂苷rg3衍生物为20(R)-人参皂苷Rg3八正丁酸酯，其分子式为：C86H144O21；结构式如式(Ⅰ)：
Figure PCTCN2016079844-appb-000001
其中，所述人参醇提取物按照如下步骤制备而成：
1)将药材人参与提取溶剂混合均匀后，进行浸泡处理；
2)对浸泡后的人参与提取溶剂混合物进行加热提取，过滤并收集提取液；
3)将收集的提取液浓缩处理，制成浸膏后进行干燥处理，即得。
特别是，步骤1)所述浸泡处理时间为30-60min，优选为30min。
尤其是，人参药材与提取溶剂的重量份配比为1:8-12，优选为1:10。
特别是，所述提取溶剂为体积百分比浓度≥50％的乙醇溶液，优选为50-75％的乙醇溶液。
其中，步骤2)中所述加热提取次数为2-3次，优选为3次。
特别是，每次加热提取过程中，所述人参药材与提取溶剂的重量份配比为1:8-12，优选为1:8；每次加热提取的温度为60-80℃，优选为70℃；加热提取时间为0.5-2h，优选为1h。
其中，步骤3)中所述浓缩处理过程中浓缩温度65-85℃，优选为80℃；浓缩后的浸膏的相对密度为1.05-1.15，优选为1.1；所述干燥处理过程中温度为70-90℃，优选为85℃。
特别是，所述人参醇提取物中人参总皂苷含量为2-5％(检测方法按照国家标准：GB/T19506-2009附录B的方法进行检测)。
其中，所述人参水提取物按照如下步骤制备而成：
1)将药材人参与水混合均匀后，进行浸泡处理；
2)对浸泡后的人参与提取溶剂混合物进行煎煮提取，过滤并收集提取液；
3)将收集的提取液浓缩处理，制成浸膏后进行干燥处理，即得。
特别是，步骤1)所述浸泡处理时间为30-60min，优选为30min。
尤其是，人参药材与水的重量份配比为1:8-12，优选为1:10。
其中，步骤2)中所述煎煮提取次数为2-3次，优选为3次。
特别是，每次煎煮提取过程中，所述人参药材与水的重量份配比为1:8-12，优选为1:8；每次煎煮提取的温度为90-100℃，优选为90-95℃；加热提取时间为0.5-2h，优选为1h。
其中，步骤3)中所述浓缩处理过程中浓缩温度70-95℃，优选为80℃；浓缩后的浸膏的相对密度为1.05-1.15，优选为1.1；所述干燥处理过程中温度为70-95℃，优选为85℃。
特别是，所述人参水提取物中人参总皂苷含量为2-5％(检测方法按照国家标准：GB/T19506-2009附录B的方法进行)。
其中，所述人参总皂苷按照如下步骤制备而成：
1)将药材人参与提取溶剂混合均匀后，进行浸泡处理；
2)对浸泡后的人参与提取溶剂混合物进行加热提取，过滤并收集提取液；
3)将收集的人参提取液采用大孔树脂柱进行分离处理，收集、合并洗脱液，得到人参树脂柱洗脱液；
4)对人参树脂柱洗脱液进行浓缩、干燥处理，即得。
特别是，步骤1)所述浸泡处理时间为30-60min，优选为30min。
尤其是，人参药材与提取溶剂的重量份配比为1:8-12，优选为1:10。
特别是，所述提取溶剂为体积百分比浓度≥50％的乙醇溶液，优选为50-75％的乙醇溶液。
其中，步骤2)中所述加热提取次数为2-3次，优选为3次。
特别是，每次加热提取过程中，所述人参药材与提取溶剂的重量份配比为1:8-12，优选为1:8；每次加热提取的温度为60-80℃，优选为70℃；加热提取时间为0.5-2h，优选为1h。
特别是，还包括将步骤2)收集是人参提取液进行浓缩处理，制成人参浓缩液后再进行所述的大孔树脂柱分离处理。
尤其是，浓缩处理后获得的人参浓缩液每毫升含有生药人参1-3.5g，即相当于1-3.5g生药/ml，优选为2.5g生药/ml。
其中，步骤3)中所述大孔树脂柱层析处理包括以下顺序进行的步骤：3A)将人参提取液注入大孔树脂柱，接着采用水为洗脱剂进行洗脱；3B)采用体积百分比浓度为30％-50％的乙醇溶液为洗脱剂进行洗脱并收集乙醇洗脱液，获得人参树脂洗脱液。
特别是，大孔树脂柱层析过程中，人参提取液中人参的重量与大孔树脂体积之比为1：0.8-2.5，优选为1：1。
尤其是，大孔树脂柱分离处理过程中，大孔树脂柱的柱直径与树脂的柱高之比为1：5-10，优选为1： 5-7，进一步优选为1：5.5-5.9。
其中，步骤3)中所述的大孔吸附树脂选择X-5、AB-8、NK-2、NKA-2、NK-9、D3520、D101、WLD中的一种，优选为D101。
特别是，步骤3A)中水的用量与大孔树脂柱的柱体积之比为2-4：1，优选为4：1；步骤3B)中体积百分比浓度为30％-50％的乙醇溶液的用量与大孔树脂柱的柱体积之比为2-8：1，优选为4-8：1，进一步优选为8：1。
尤其是，步骤3B)中洗脱剂乙醇溶液的体积百分比浓度为50％。
其中，步骤4)中浓缩处理过程中浓缩温度65-90℃，优选为80℃；所述干燥处理过程中温度为75-95℃，优选为85℃。
特别是，所述人参总皂苷含量为20-50％(检测方法按照国家标准：GB/T19506-2009附录B的方法进行)。
其中，所述人参二醇类皂苷按照如下步骤制备而成：
1)将药材人参与提取溶剂混合均匀后，进行浸泡处理；
2)对浸泡后的人参与提取溶剂混合物进行加热提取，过滤并收集提取液；
3)将收集的人参提取液采用大孔树脂柱进行第一次大孔树脂层析分离处理，收集、合并洗脱液，得到人参树脂柱第一洗脱液；
4)将人参树脂柱第一洗脱液采用大孔树脂柱进行第二次大孔树脂层析分离处理，收集、合并洗脱液，得到人参树脂柱第二洗脱液；
5)对人参树脂第二洗脱液进行浓缩、干燥处理，即得。
特别是，步骤1)所述浸泡处理时间为30-60min，优选为30min。
尤其是，人参药材与提取溶剂的重量份配比为1:8-12，优选为1:10。
特别是，所述提取溶剂为体积百分比浓度≥50％的乙醇溶液，优选为50-75％的乙醇溶液。
其中，步骤2)中所述加热提取次数为2-3次，优选为3次。
特别是，每次加热提取过程中，所述人参药材与提取溶剂的重量份配比为1:8-12，优选为1:8；每次加热提取的温度为60-80℃，优选为70℃；加热提取时间为0.5-2h，优选为1h。
特别是，还包括步骤2A)，即将步骤2)收集的人参提取液进行浓缩处理，制成人参浓缩液后再进行所述的第一次大孔树脂柱层析分离处理。
尤其是，浓缩处理后获得的人参浓缩液每毫升含有生药人参1-3.5g，即相当于1-3.5g生药/ml，优选为2.5g生药/ml。
其中，步骤3)中所述第一次大孔树脂柱层析处理包括以下顺序进行的步骤：3A)将人参提取液注入大孔树脂柱，接着采用水为洗脱剂进行洗脱；3B)采用体积百分比浓度为30％-50％的乙醇溶液为洗脱剂进 行洗脱并收集乙醇洗脱液，获得人参-大孔树脂第一洗脱液。
特别是，大孔树脂柱层析过程中，人参提取液中人参的重量与大孔树脂体积之比为1：0.8-2.5，优选为1：1。
尤其是，大孔树脂柱分离处理过程中，大孔树脂柱的柱直径与树脂的柱高之比为1：5-10，优选为1：5-7，进一步优选为1：5.5-5.9。
其中，步骤3)中所述的大孔吸附树脂选择X-5、AB-8、NK-2、NKA-2、NK-9、D3520、D101、WLD中的一种，优选为D101。
特别是，步骤3A)中水的用量与大孔树脂柱的柱体积之比为2-4：1，优选为4：1；3B)中体积百分比浓度为30-50％的乙醇溶液的用量与大孔树脂柱的柱体积之比为2-8：1，优选为4-8：1，进一步优选为8：1。
尤其是，步骤3B)中洗脱剂乙醇溶液的体积百分比浓度为50％。
特别是，还包括将步骤3)收集的人参树脂第一洗脱液进行浓缩处理，制成人参树脂第一浓缩液后再进行所述的第二次大孔树脂柱层析分离处理。
尤其是，浓缩处理后获得的人参浓缩液每毫升含有生药人参3.5-6g，即相当于3.5-6g生药/ml，优选为5.0g生药/ml。
特别是，步骤4)中所述第二次大孔树脂柱层析处理包括以下顺序进行的步骤：4A)将人参树脂柱第一洗脱液注入大孔树脂柱，接着采用体积百分比浓度为50～60％的乙醇溶液为洗脱剂进行洗脱；4B)采用体积百分比浓度为70～80％的乙醇溶液为洗脱剂进行洗脱并收集乙醇洗脱液，获得人参树脂第二洗脱液。
特别是，步骤4)第二次大孔树脂柱层析过程中，人参树脂柱第一洗脱液中人参的重量与大孔树脂体积之比为1：0.8-2.5，优选为1：1。
尤其是，大孔树脂柱分离处理过程中，大孔树脂柱的柱直径与树脂的柱高之比为1：5-10，优选为1：5-7，进一步优选为1：5.5-5.9。
其中，步骤4)中所述的大孔吸附树脂选择HPD-200、D203、XAD-4、HPD-100中的一种，优选为HPD-100。
特别是，步骤4A)中体积百分比浓度为50～60％的乙醇溶液的用量与大孔树脂柱的柱体积之比为2-4：1，优选为4：1；步骤4B)中质量百分比浓度为70～80％的乙醇溶液的用量与大孔树脂柱的柱体积之比为2-8：1，优选为4-8：1，进一步优选为8：1。
其中，步骤5)中所述浓缩处理过程中浓缩温度65-95℃，优选为80℃；所述干燥处理过程中温度为70-95℃，优选为85℃。
特别是，所述人参二醇类皂苷含量为30-70％检测方法按照国家标准：GB/T19506-2009附录B的方法进行)。
其中，所述的20(R)-人参皂苷Rg3含量为1％～98％；优选为30～80％，进一步优选为60％。
特别是，所述的20(R)-人参皂苷Rg3含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％。
其中，所述的20(R)-人参皂苷Rg3衍生物含量为1％～98％；优选为30～80％，进一步优选为60％。
特别是，所述的20(R)-人参皂苷Rg3衍生物含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％。
其中，所述人参醇提取物中人参总皂苷含量为2-5％；所述人参水提取物中人参总皂苷含量为2-5％；所述人参总皂苷中人参总皂苷含量为20-50％；所述人参二醇类皂苷中人参二醇皂苷含量为30-70％。
特别是，药学上可接受的载体通常被保健专家认可用于这一目的且作为药剂的非活性成分。有关药学上可接受的载体的汇编可以在《药物赋形剂手册》(Handbook of Pharmaceutical excipients，第2版，由A.Wade和P.J.Weller编辑；American Pharmaceutical Association出版，Washington and The Pharmaceutical Press，London，1994)等工具书中找到。
尤其是，所述的载体包括赋形剂，如淀粉、水等；润滑剂，如硬脂酸镁等；崩解剂，如微晶纤维素等；填充剂，如乳糖等；粘结剂，如预胶化淀粉、糊精等；甜味剂；抗氧化剂；防腐剂、矫味剂、香料等；
其中，所述药物以片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂、溶液剂、乳剂、注射剂、喷雾剂、气雾剂、凝胶型、霜剂、酊剂、巴布剂、橡胶贴膏剂或贴膏剂形式存在。
本发明另一方面提供一种含有人参提取物、人参皂苷或人参皂苷衍生物的治疗人巨细胞病毒感染疾病的药物或保健品。
其中，所述的人参提取物选择人参醇提取物、人参水提取物；所述人参皂苷为人参总皂苷、人参二醇类皂苷、20(R)-人参皂苷rg3；所述人参皂苷衍生物为20(R)-人参皂苷rg3衍生物。
特别是，所述人参皂苷rg3衍生物为20(R)-人参皂苷Rg3八正丁酸酯。
其中，所述的20(R)-人参皂苷Rg3含量为1％～98％；优选为30～80％，进一步优选为60％。
特别是，所述的20(R)-人参皂苷Rg3含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％。
其中，所述的20(R)-人参皂苷Rg3衍生物含量为1％～98％；优选为30～80％，进一步优选为60％。
特别是，所述的20(R)-人参皂苷Rg3衍生物含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％。
其中，所述人参醇提取物中人参总皂苷含量为2-5％；所述人参水提取物中人参总皂苷含量为2-5％；所述人参总皂苷中人参总皂苷含量为20-50％；所述人参二醇类皂苷中人参二醇皂苷含量为30-70％。
特别是，所述人参提取物、人参皂苷或人参皂苷衍生物的重量与所述药物或保健品的总重量之比为0.01-10：100，优选为0.1～10：100，进一步优选为1～10：100。
特别是，所述药物或保健品中还包括山豆根提取物、苍耳子提取物、半枝莲提取物、苦参提取物、蒲公英提取物、金银花提取物、生姜提取物、葡萄子提取物、石榴子提取物、维生素C及其衍生物或维生素E及其衍生物中的一种或多种。
所述药物可以采用本领域公知的方法制成各种剂型，如片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂、溶液剂、注射剂、喷雾剂、气雾剂、凝胶型、霜剂、酊剂、巴布剂、橡胶贴膏剂或贴膏剂等。
本发明还提供了一种治疗人巨细胞病毒感染病症的方法，包括向受试者给予治疗有效量的人参提取物、人参皂苷或人参皂苷衍生物，其治疗有效量为0.6～12mg/kg·d，优选为1～6mg/kg·d，进一步优选为1.5～3mg/kg·d。
除非另外说明，本文所用的术语“治疗有效量”为需要产生有效作用的药物的用量；“治疗有效量”是可以调整和变化的，最终由医务人员确定，其所考虑的因素包括给药途径和制剂的性质、接受者的体重、年龄等一般情况以及所治疗疾病的性质和严重程度。
与现有技术相比，本发明具有如下的明显优点：
1、本发明对人参提取物、人参皂苷或人参皂苷衍生物发掘了新的药用价值，将其用于治疗人巨细胞病毒感染的相关疾病，所述相关疾病包括心脑血管疾病、器官移植，围产期，肿瘤，烧伤，艾滋病等疾病治疗过程中患者的人类巨细胞病毒感染，尤其是处于器官移植、骨髓移植而接受免疫抑制剂治疗及恶性肿瘤患者接受放疗和化疗后，处于免疫缺陷或免疫抑制状态下的人巨细胞病毒感染。并可制备成用于治疗人巨细胞病毒感染的药物或保健食品，从而为人参药材的应用开拓了一个新的领域。
2、本发明的系列试验研究证明人参提取物、人参皂苷或人参皂苷衍生物具有显著的预防、治疗人巨细胞病毒感染的功效。
3、本发明的人参提取物、人参皂苷或人参皂苷衍生物药理作用强，用于治疗人巨细胞病毒感染的功效显著，见效快、毒副作用小、安全性好，能够长期服用，具有良好的药用前景。
4、本发明的产品原料来源丰富、价廉、临床使用安全，制备工艺简单，可制成各种剂型，且服量小，使用方便，因此易于推广。
5、本发明既可采用人参提取物、人参皂苷或人参皂苷衍生物活性成分制备治疗人巨细胞病毒感染的药物，又可采用人参提取物、人参皂苷或人参皂苷衍生物与其它活性成分(例如与山豆根提取物、苍耳子提取物、半枝莲提取物、苦参提取物、蒲公英提取物、金银花提取物、生姜提取物、葡萄子提取物、石榴子提取物、维生素C及其衍生物或维生素E及其衍生物中的一种或多种)共同组方，制备治疗人巨细胞病毒感染的复方药物。
具体实施例方式
下面通过具体实施方式来进一步描述本发明及其有益效果，这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的配方思路、用途范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
实施例1 人参醇提取物的制备方法
1、第一次提取处理
向中药多功能提取罐内中加入粉碎后的人参(300g)、体积百分比浓度为70％的乙醇溶液(3000g)，混合均匀，浸泡30min后，开启多功能提取罐电源，加热，对人参药材进行第一次加热提取处理，在温度保持70℃下恒温提取1小时后过滤，得到第一次提取液和第一药渣；其中，人参与提取溶剂(乙醇溶液)的重量配比为1:10。
本发明中人参与提取溶剂的重量配比除了为1:10之外，其他配比如1：8-12均适用于本发明；浸泡时间除了30min之外，其他浸泡时间≥30min均适用于本发明，优先为30-60min；提取溶剂除了体积百分比浓度为70％的乙醇溶液之外，其他体积百分比浓度≥50％的乙醇溶液均适用于本发明，优选浓度为50-75％的乙醇溶液、无水乙醇；提取温度60-80℃、加热提取时间0.5-2h均适用于本发明。
2、第二次提取处理
向第一药渣中加入体积百分比浓度为70％的乙醇溶液，加热，对人参药材进行第二次加热提取处理，在温度保持70℃下恒温提取1小时后过滤，得到第二次提取液和第二滤渣；其中，人参与提取溶剂的重量配比为1:10。
3、第三次提取处理
向第二药渣中加入体积百分比浓度为70％的乙醇溶液，加热，对人参药材进行第三次加热提取处理，在温度保持70℃下恒温提取1小时后过滤，得到第三次提取液；其中，人参与提取溶剂的重量配比为1:10。
本发明实施例中人参醇提取物进行第二、第三次提取过程中使用的提取溶剂除了体积百分比浓度为70％的乙醇溶液之外，其他体积百分比浓度≥50％的乙醇溶液均适用于本发明，优选浓度为50-75％的乙醇溶液、无水乙醇；提取温度60-80℃均适用于本发明；加热提取时间0.5-2h均适用于本发明。
本发明实施例中人参醇提取物制备过程中加热提取次数为3次，提取次数为2-3次均适用于本发明。
4、浓缩、干燥处理
将3次过滤得到的第一、二、三次提取液合并后置于旋转蒸发器中在温度80℃下进行蒸发浓缩处理，得到相对密度为1.1的浸膏，然后置于烘箱中于85℃下干燥至恒重，即得人参醇提取物。
人参醇提取物为浅棕黄色粉末，有特殊气味，溶于乙醇。采用国家标准(GB/T19506-2009附录B方法，地理标志产品吉林长白山人参)方法测量人参醇提取物中人参总皂苷的含量，含有人参总皂苷3％。
本发明的人参醇提取物浓缩处理过程中，浓缩温度65-85℃、浓缩后的浸膏的相对密度为1.05-1.15均适用于本发明；干燥过程中温度70-90℃均适用于本发明。采用本发明方法制备的人参醇提取物中人 参总皂苷含量为2-5％。
实施例2 人参水提取物的制备方法
1、浸泡处理
将粉碎后的人参(300g)、提取溶剂自来水(3000g)置于中药多功能提取罐内，混合均匀，并进行浸泡处理，其中浸泡时间为30min；人参与提取溶剂水的重量配比为1:10。
本发明人参水提取物的制备过程中，浸泡时间≥30min均适用于本发明，优先为30-60min；人参与提取溶剂水的重量配比除了为1:10之外，其他配比如1：8-12均适用于本发明。
2、第一次提取处理
浸泡30min后，开启多功能提取罐电源，加热，对人参药材进行第一次煎煮提取处理，在温度保持95℃下恒温提取1小时后过滤，得到第一次提取液和第一药渣；
3、第二次提取处理
向第一药渣中加入自来水，加热，对人参药材进行第二次煎煮提取处理，在温度保持90℃下恒温提取1小时后过滤，得到第二次提取液和第二滤渣；其中，人参与提取溶剂的重量配比为1:10。
4、第三次提取处理
向第二药渣中加入自来水，加热，对人参药材进行第三次煎煮提取处理，在温度保持90℃下恒温提取1小时后过滤，得到第三次提取液；其中，人参与提取溶剂的重量配比为1:10。
本发明实施例中人参水提取物进行第一、二、三次提取过程中人参药材与提取溶剂水的重量配比除了为1:10之外，其他配比如1：8-12均适用于本发明；提取温度90-100℃均适用于本发明，优选为90-95℃；加热提取时间0.5-2h均适用于本发明，优选为1h。
本发明实施例中人参水提取物制备过程中加热提取次数为3次，提取次数为2-3次均适用于本发明。
5、浓缩、干燥处理
将3次过滤得到的第一、二、三次提取液合并后置于旋转蒸发器中在温度80℃下进行蒸发浓缩处理，得到相对密度为1.1的浸膏，然后置于烘箱中于85℃下干燥至恒重，即得人参水提取物。
人参水提取物为浅棕黄色粉末，有特殊气味，水溶性良好。采用GB/T19506-2009附录B方法测量人参水提取物中人参总皂苷的含量，含有人参总皂苷2％。
本发明的人参醇提取物的浓缩处理过程中，浓缩温度70-95℃、浓缩后的浸膏的相对密度为1.05-1.15适用于本发明；干燥温度70-95℃均适用于本发明。采用本发明方法制备的人参水提取物中人参总皂苷含量为2-5％。
实施例3 人参总皂苷的制备方法
1、第一次提取处理
与实施例1相同。
2、第二次提取处理
与实施例1相同。
3、第三次提取处理
与实施例1相同。
4、浓缩处理
将3次过滤得到的第一、二、三次提取液合并后置于旋转蒸发器中在温度80℃下进行浓缩处理，得到人参浓缩液(120ml)，相当于2.5g生药/ml的人参溶液。
本发明浓缩处理过程中人参浓缩液浓度除了每毫升浓缩液相当于2.5g生药之外，其他每毫升浓缩液相当于1-3.5g生药(即1-3.5g生药/ml)也适用于本发明。
5、大孔树脂柱层析
将人参浓缩液上样于大孔树脂柱上，进行大孔树脂柱分离处理，其中，大孔吸附树脂选择D101型大孔吸附树脂，树脂柱内树脂的体积(300ml)与人参重量(干重)之比为1：1(即如果人参干重1公斤，大孔树脂的体积是1L；如果药材干重1g，则大孔树脂的体积为1ml)，待浓缩后的上清液完全流入树脂柱后，先用4倍柱体积的水洗涤，弃去洗脱液；接着用8倍柱体积的体积百分比浓度为50％的乙醇溶液洗脱，收集洗脱液，得人参-大孔树脂洗脱液；
本发明人参浓缩液进行大孔树脂柱层析过程中人参提取液中人参的重量与大孔树脂体积之比为1：0.8-2.5均适用于本发明；大孔吸附树脂除了D101之外，其他X-5、AB-8、NK-2、NKA-2、NK-9、D3520、D101、WLD均适用于本发明；水洗脱过程中，水的用量与大孔树脂柱的柱体积之比为2-4：1适用于本发明；洗脱剂为乙醇溶液时，乙醇溶液的体积百分比浓度除了50％之外，其他30％-50％均适用；乙醇溶液的用量与大孔树脂柱的柱体积之比为2-4：1适用于本发明。
6、浓缩、干燥处理
将人参-大孔树脂洗脱液置于旋转蒸发器中在温度80℃下进行减压浓缩处理，回收溶剂，浓缩残留物置于干燥箱内于85℃下进行干燥处理，得人参总皂苷2.6g。
人参总皂苷为浅棕黄色粉末，有特殊气味。采用GB/T19506-2009附录B方法测量制得的人参总皂苷的含量，含有人参总皂苷32％。
本发明的人参-大孔树脂洗脱液的浓缩处理过程中，浓缩温度65-90℃均适用于本发明；干燥温度75-95℃均适用于本发明。采用本发明方法制备的人参总皂苷含量为20-50％。
实施例4 人参二醇类皂苷的制备方法
1、第一次提取处理
与实施例3相同。
2、第二次提取处理
与实施例3相同。
3、第三次提取处理
与实施例3相同。
4、浓缩处理
与实施例3相同。
5、第一次大孔树脂柱层析
与实施例3相同，获得人参-大孔树脂第一洗脱液。
6、第二次大孔树脂柱层析
将人参-大孔树脂第一洗脱液置于旋转蒸发器中在温度80℃下进行浓缩处理，得到人参-大孔树脂第一浓缩液(60ml)，相当于5.0g生药/ml的人参溶液；
将人参-大孔树脂第一浓缩液上样于大孔树脂柱上，进行大孔树脂柱分离处理，其中，大孔吸附树脂选择HPD-100型大孔吸附树脂，树脂柱内树脂的体积(300ml)与人参重量(干重)之比为1：1(即如果人参干重1公斤，大孔树脂的体积是1L；如果药材干重1g，则大孔树脂的体积为1ml)，待浓缩后的上清液完全流入树脂柱后，先用4倍柱体积的体积百分比浓度为60％的乙醇溶液洗涤，弃去洗脱液；接着用8倍柱体积的体积百分比浓度为80％的乙醇溶液洗脱，收集洗脱液，得人参-大孔树脂第二洗脱液。
本发明浓缩处理过程中人参浓缩液浓度除了每毫升浓缩液相当于5.0g生药之外，其他每毫升浓缩液相当于3.5-6g生药(即3.5-6g生药/ml)也适用于本发明。
本发明人参-大孔树脂第一浓缩液进行大孔树脂柱层析过程中人参-大孔树脂第一浓缩液中人参的重量与大孔树脂体积之比为1：0.8-2.5均适用于本发明；大孔吸附树脂除了HPD-100之外，其他HPD-200、D203、XAD-4均适用于本发明；60％的乙醇溶液洗脱过程中，60％的乙醇溶液的用量与大孔树脂柱的柱体积之比为2-4：1适用于本发明；80％的乙醇溶液洗脱过程中，80％的乙醇溶液的用量与大孔树脂柱的柱体积之比为2-4：1适用于本发明。
7、浓缩、干燥处理
将人参-大孔树脂第二洗脱液置于旋转蒸发器中在温度80℃下进行减压浓缩处理，回收溶剂，浓缩残留物置于干燥箱内于85℃下进行干燥处理，得人参二醇类总皂苷0.7g。
人参二醇类皂苷为浅黄色粉末，有特殊气味。水溶性良好。采用2010年版中国药典一部附录Ⅵ高效液相色谱法测得制得的人参二醇类皂苷的含量，含有人参二醇类皂苷59％。
本发明的人参-大孔树脂洗脱液的浓缩处理过程中，浓缩温度65-95℃均适用于本发明；干燥温度70-95℃均适用于本发明。采用本发明方法制备的人参二醇类皂苷中人参二醇皂苷含量为30-70％。
实施例5 人参醇提取物片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000002
2、将人参醇提取物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例6 人参醇提取物片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000003
2、将人参醇提取物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例7 人参醇提取物片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000004
2、将人参醇提取物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例8 人参醇提取物胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000005
2、将人参醇提取物、山豆根提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例9 人参醇提取物颗粒剂
1、按照如下重量配比备料
Figure PCTCN2016079844-appb-000006
Figure PCTCN2016079844-appb-000007
2、将人参醇提取物、生姜提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例10 人参醇提取物口服液
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000008
2、取人参醇提取物用少量乙醇溶解后、加入半枝莲提取物、苦参提取物、葡萄糖糖浆,最后补加去离子水至100ml，即得。
实施例11 人参水提取物片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000009
2、将人参水提取物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例12 人参水提取物片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000010
2、将人参水提取物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例13 人参水提取物片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000011
2、将人参水提取物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例14 人参水提取物胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000012
2、将人参水提取物、山豆根提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例15 人参水提取物颗粒剂
1、按照如下重量配比准备原料
Figure PCTCN2016079844-appb-000013
2、将人参水提取物、生姜提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例16 人参水提取物口服液
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000014
2、取人参水提取物用少量乙醇溶解后、加入半枝莲提取物、苦参提取物、葡萄糖糖浆,最后补加去离子水至100ml，即得。
实施例17 人参总皂苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000015
2、将人参总皂苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例18 人参总皂苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000016
2、将人参总皂苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例19 人参总皂苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000017
2、将人参总皂苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例20 人参总皂苷胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000018
2、将人参总皂苷、山豆根提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例21 人参总皂苷颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000019
2、将人参总皂苷、生姜提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例22 人参总皂苷口服液
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000020
Figure PCTCN2016079844-appb-000021
2、取人参总皂苷用少量乙醇溶解后、加入半枝莲提取物、苦参提取物、葡萄糖糖浆,最后补加去离子水至100ml，即得。
实施例23 人参二醇类皂苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000022
2、将人参二醇类皂苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例24 人参二醇类皂苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000023
2、将人参二醇类皂苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例25 人参二醇类皂苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000024
2、将人参二醇类皂苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例26 人参二醇类皂苷胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000025
2、将人参二醇类皂苷、山豆根提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例27 人参二醇类皂苷颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000026
2、将人参二醇类皂苷、生姜提取物、维生素C和蔗糖粉混合均匀制颗粒装袋，制成10000袋。
实施例28 人参二醇类皂苷口服液
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000027
2、取人参二醇类皂苷用少量乙醇溶解后、加入半枝莲提取物、苦参提取物、葡萄糖糖浆,最后补加去离子水至100ml，即得。
实施例29 人参皂苷rg3片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000028
2、将人参皂苷rg3和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例30 人参皂苷rg3片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000029
2、将人参皂苷rg3和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例31 人参皂苷rg3片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000030
2、将人参皂苷rg3和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例32 人参皂苷rg3胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000031
2、将人参皂苷rg3、山豆根提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例33 人参皂苷rg3颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000032
2、将人参皂苷rg3、生姜提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例34 人参皂苷rg3口服液
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000033
Figure PCTCN2016079844-appb-000034
2、取人参皂苷rg3用少量乙醇溶解后、加入半枝莲提取物、苦参提取物、葡萄糖糖浆,最后补加去离子水至100ml，即得。
实施例35 人参皂苷rg3衍生物(20(R)-人参皂苷Rg3八正丁酸酯)片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000035
2、将人参皂苷rg3衍生物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例36 人参皂苷rg3衍生物(20(R)-人参皂苷Rg3八正丁酸酯)片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000036
2、将人参皂苷rg3衍生物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例37 人参皂苷rg3衍生物(20(R)-人参皂苷Rg3八正丁酸酯)片剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000037
2、将人参皂苷rg3衍生物和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例38 人参皂苷rg3衍生物(20(R)-人参皂苷Rg3八正丁酸酯)胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000038
Figure PCTCN2016079844-appb-000039
2、将人参皂苷rg3衍生物、山豆根提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例39 人参皂苷rg3衍生物(20(R)-人参皂苷Rg3八正丁酸酯)颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000040
2、将人参皂苷rg3衍生物、生姜提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例40 人参皂苷rg3衍生物(20(R)-人参皂苷Rg3八正丁酸酯)口服液
1、按照如下配比准备原料
Figure PCTCN2016079844-appb-000041
2、取人参皂苷rg3衍生物用少量乙醇溶解后、加入半枝莲提取物、苦参提取物、葡萄糖糖浆,最后补加去离子水至100ml，即得。
试验例1 人参提取物、人参皂苷及其衍生物对HCMV感染模型小鼠免疫功能的影响
1、实验材料
1.1 动物、病毒及细胞
昆明种小鼠，雌雄各半，体重18～22g，由浙江中医药大学动物中心提供，许可证号SCXK(沪)2008-00l6。
病毒和细胞：HCMVADl69标准株、人胚肺成纤维细胞(HEL)，由山东省医学科学院病毒室提供。
巨细胞病毒单克隆抗体(HCMVMcAb)引自中国预防医学科学院病毒所诊断室，为早期抗原单克隆抗体。ELISA(enzyme-linked immunosorbent assay，酶联免疫吸附测定法)工作滴度为1×10-5。
1.2 药品
人参醇提取物：浅棕黄色粉末，含有人参总皂苷3％，大连富生天然药物开发有限公司生产，批号：20120601；
人参水提取物：浅棕黄色粉末，含有人参总皂苷2％，大连富生天然药物开发有限公司生产，批号： 20120602；
人参总皂苷：浅棕黄色粉末，含有人参总皂苷32％，大连富生天然药物开发有限公司生产，批号：20120502；
人参二醇类皂苷：浅黄色粉末，含有人参二醇类皂苷59％，大连富生天然药物开发有限公司生产，批号：20120403；
20(R)-人参皂苷Rg3(含量＞98％)，大连富生天然药物开发有限公司生产，批号：20120303；以中国药品生物制品检定所提供的人参皂苷Rg3标准品对照并进行HPLC标定，含量为98.2％；
人参皂苷rg3衍生物(20(R)-人参皂苷Rg3八正丁酸酯)；大连富生天然药物开发有限公司研制，经高效液相色谱两种检测器紫外检测器和蒸发光散射检测器面积归一化法测定，其纯度分别为99.6％。
阳性对照药：更昔洛韦(规格：250mg/支，丽珠集团湖北科益药业有限公司，批号020506)，临床人日用量45.5mg/kg体重。
1.3病毒标准株HCMVADl69的引进和增殖毒种于1999年10月引自中国预防医学科学院病毒所毒种室，将毒种以1640培养液溶解，接种于备用单层的HEL细胞上，37℃下16h后细胞出现病变，细胞胀大，胞浆内折光颗粒增多，部分细胞变圆，个别细胞脱落。随着培养时间的延长，病变范围扩大，至96h，病变可达到90％以上。将细胞病变出现达+++～++++的HEL培养上清弃掉，以PBS轻轻洗3次，加双蒸水，-20℃冻融3次，用力吹打，4℃10000r/min离心20min，收集上清，既得。
2、实验方法
2.1分组及给药
昆明种小鼠210只，雌雄各半，实验条件下预养1周，按性别和体质量随机分为21组：正常对照组；模型组；阳性药对照组；人参醇提取物高、中、低剂量组；人参水提取物高、中、低剂量组；人参总皂苷高、中、低剂量组；人参二醇类皂苷高、中、低剂量组；人参皂苷rg3高、中、低剂量组；人参皂苷rg3衍生物高、中、低剂量组。
阳性对照组给予更昔洛韦(45.5mg/kg/d)，人参醇提取物三个组分别给予人参醇提取物0.012mg/kg/d，0.06mg/kg/d，0.3mg/kg/d；人参水提取物三个组分别给予人参水提取物0.012mg/kg/d，0.06mg/kg/d，0.3mg/kg/d；人参总皂苷三个组分别给予人参总皂苷0.012mg/kg/d，0.06mg/kg/d，0.3mg/kg/d；人参二醇皂苷三个组分别给予人参二醇类皂苷0.012mg/kg/d，0.06mg/kg/d，0.3mg/kg/d；人参皂苷rg3三个组分别给予人参皂苷rg30.012mg/kg/d，0.06mg/kg/d，0.3mg/kg/d；人参皂苷rg3衍生物三个组分别给予人参皂苷rg3衍生物0.012mg/kg/d，0.06mg/kg/d，0.3mg/kg/d；均采用小鼠尾静脉注射HCMVl0-3，0.1ml/只，正常对照组注射0.9％生理盐水，0.1ml/只，于染毒第2天根据确定的剂量开始灌胃给药，用药21天。
2.2 体重、胸腺指数、脾指数的测定
实验过程观察动物时，于给药21天测定各组动物的体重，然后取胸腺、脾称重并计算其指数(胸腺 指数、脾脏指数是每10g体重胸腺、脾脏脏器的重量(mg))。
2.3 血清溶血素抗体的测定
末次给药后40min，摘取眼球取血，采血清，用生理盐水稀释100倍，取1mL稀释血清、0.5mL 5％鸡红细胞悬液和0.5mL 10％补体(豚鼠血清)混合均匀，在37℃恒温箱中保温30min，置0℃冰箱30min中止反应。离心，取上清液，于分光光度计540nm处比色，测光密度值(OD值)。
2.4 血清中IL-2水平的测定
每组随机选择6只小鼠采样，末次给药后40min，摘取眼球取血，用离心管收集血液。待血液凝固后进行高速离心，3000r/min离心5min，取血清。血清中IL-2的测定按照ELISA试剂盒说明书进行。
3、实验结果
3.1 感染HCMV小鼠存活率和体重测定
实验过程中记录死亡动物数，感染HCMV小鼠的存活率和体重检测结果见表1。
实验全程给药2ld，期间模型组小鼠在染毒2～4d，最早出现竖毛、偏瘫、全身共济失调和体重减轻等感染中毒症状，5～7d开始出现死亡，至21d时仅存活3只，说明造模成功。
人参醇提取物、人参水提取物、人参总皂苷、人参二醇类皂苷、20(R)-人参皂苷Rg3、20(R)-人参皂苷Rg3衍生物组小鼠中毒症状轻，死亡少，体重增长良好，说明这些药物对病毒有一定抑制作用，能不同程度增加小鼠的存活率。将各组存活动物数分别与模型组进行统计学比较，证实大剂量组差异显著，中、小剂量组也对感染HCMV的小鼠有一定保护作用。更昔洛韦动物存活数、体重增长和症状表现均与大剂量组相近。
表1 人参提取物及其衍生物对感染HCMV小鼠体重的影响比较(X±S)
Figure PCTCN2016079844-appb-000042
Figure PCTCN2016079844-appb-000043
3.2 对感染HCMV小鼠脾和胸腺指数的影响
胸腺和脾脏是重要的免疫器官,其脏器指数可在一定程度上反映机体免疫功能的强弱。胸腺的主要功能是产生T淋巴细胞和分泌胸腺素,主要参与细胞免疫；脾脏中有丰富的淋巴细胞和巨噬细胞。其重量与其功能以及其中免疫细胞数量有关,其高低取决于其中淋巴细胞增殖的程度。本实验的脾和胸腺指数结果见表2。
表2 人参提取物及其衍生物对感染HCMV小鼠脾和胸腺指数的影响比较(X±S)
Figure PCTCN2016079844-appb-000044
Figure PCTCN2016079844-appb-000045
实验表明，人参醇提取物、人参水提取物、人参总皂苷、人参二醇类皂苷、人参皂苷rg3、人参皂苷rg3衍生物对感染HCMV小鼠的免疫器官有明显增重作用，各实验组重量也均高于模型组，特别是人参皂苷rg3、人参皂苷rg3衍生物组的脾指数与胸腺指数分别与模型组相比有显著性差异。上述实验结果说明，人参提取物、人参皂苷及其衍生物能对HCMV感染模型小鼠的胸腺、脾脏起到细胞保护作用，有类似抗原的免疫作用，能恢复和促进脾淋巴细胞活性，具有正向的免疫调节作用。所以，人参提取物及其衍生物可用于治疗人类巨细胞病毒感染。
3.3 血清中IL-2水平的实验结果
IL-2即白细胞介素-2(interleukin-2，IL-2)，又名T细胞生长因子(T cell growth factor，TCRF)。主要由活化的CD4+Th1细胞产生的具有广泛生物活性的细胞因子。可促进Th0和CTL的增殖，故为调控免疫应答的重要因子。它是由多细胞来源(主要由活化T细胞产生)，又具有多向性作用的细胞因子(主要促进淋巴细胞生长、增殖、分化)；对机体的免疫应答和抗病毒感染等有重要作用，能刺激已被特异性抗原或致丝裂因数启动的T细胞增殖；能活化T细胞，促进细胞因子产生；刺激NK细胞增殖，增强NK杀伤活性及产生细胞因子，诱导LAK细胞产生；促进B细胞增殖和分泌抗体；激活巨噬细胞。小鼠血清中IL-2水平的实验结果见表3。
表3 感染HCMV小鼠血清中IL-2浓度测定结果(X±S)
Figure PCTCN2016079844-appb-000046
Figure PCTCN2016079844-appb-000047
表3的结果表明:模型组的IL-2水平最低，与正常对照组比较差异极显著(P<0.01)，说明造型成功。人参醇提取物、人参水提取物、人参总皂苷、人参二醇类皂苷、人参皂苷rg3、人参皂苷rg3衍生物均高于模型组，说明人参醇提取物、人参水提取物、人参总皂苷、人参二醇类皂苷、人参皂苷rg3、人参皂苷rg3衍生物对感染HCMV小鼠的IL-2水平有增高的作用；人参水提取物、人参总皂苷、人参二醇类皂苷、人参皂苷rg3、人参皂苷rg3衍生物组的IL-2水平与优于阳性药物对照组。说明人参水提取物、人参总皂苷、人参二醇类皂苷、人参皂苷rg3、人参皂苷rg3衍生物组对感染HCMV小鼠的治疗作用强于阳性药物。
3.4 血清中溶血素抗体的测定
小鼠血清中溶血素抗体的测定结果见表4。
表4 感染HCMV小鼠血清中溶血素抗体测定结果(X±S)
Figure PCTCN2016079844-appb-000048
Figure PCTCN2016079844-appb-000049
试验结果表明，人参醇提取物、人参水提取物、人参总皂苷、人参二醇类皂苷、人参皂苷rg3、人参皂苷rg3衍生物均对感染HCMV小鼠的血清溶血素抗体有提高的作用，其数值与模型组比较有显著性差异。特别是人参水提取物、人参总皂苷、人参二醇类皂苷、人参皂苷rg3、人参皂苷rg3衍生物组的血清溶血素抗体水平与优于阳性药物对照组。说明人参水提取物、人参总皂苷、人参二醇类皂苷、人参皂苷rg3、人参皂苷rg3衍生物组对感染HCMV小鼠的治疗作用强于阳性药物。

Claims (10)

  1. 人参提取物、人参皂苷、人参皂苷衍生物在制备用于治疗巨细胞病毒感染病症的药物或保健品中的应用。
  2. 根据权利要求1所述的应用，其特征是所述药物由人参提取物、人参皂苷或人参皂苷衍生物和药学上可接受的载体组成。
  3. 根据权利要求1或2所述的应用，其特征是所述药物以片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂、溶液剂、乳剂、注射剂、喷雾剂、气雾剂、凝胶型、霜剂、酊剂、巴布剂、橡胶贴膏剂或贴膏剂形式存在。
  4. 根据权利要求1或2所述的应用，其特征是所述的人参提取物选择人参醇提取物、人参水提取物；所述人参皂苷为人参总皂苷、人参二醇类皂苷、20(R)-人参皂苷rg3；所述人参皂苷衍生物为20(R)-人参皂苷rg3衍生物。
  5. 根据权利要求4所述的应用，其特征是所述20(R)-人参皂苷rg3、20(R)-人参皂苷rg3衍生物的含量≥1％。
  6. 一种治疗人类巨细胞病毒感染的药物或保健品，其特征是含有人参提取物、人参皂苷或人参皂苷衍生物。
  7. 根据权利要求6所述的药物或保健品，其特征是所述人参提取物、人参皂苷或人参皂苷衍生物的重量与所述药物或保健品的总重量之比为0.01-10：100。
  8. 根据权利要求6所述的药物或保健品，其特征是所述人参提取物选择人参醇提取物、人参水提取物；所述人参皂苷为人参总皂苷、人参二醇类皂苷、20(R)-人参皂苷rg3；所述人参皂苷衍生物为20(R)-人参皂苷rg3衍生物。
  9. 根据权利要求8所述的药物或保健品，其特征是所述20(R)-人参皂苷rg3、人参皂苷衍生物的含量≥1％。
  10. 根据权利要求6所述的药物或保健品，其特征是还包括山豆根提取物、苍耳子提取物、半枝莲提取物、苦参提取物、蒲公英提取物、金银花提取物、生姜提取物、葡萄子提取物、石榴子提取物、维生素C及其衍生物或维生素E及其衍生物中的一种或多种。
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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106668319A (zh) * 2016-12-09 2017-05-17 青岛海能海洋生物技术有限公司 一种降低艾滋病患者病毒载量及提升t淋巴细胞cd4免疫力的复合制剂及应用
CN113116763B (zh) * 2019-12-31 2023-10-27 广州市科能化妆品科研有限公司 胶原酶抑制剂，含该胶原酶抑制剂的修护霜及其制备方法
CN111557959A (zh) * 2020-06-09 2020-08-21 张建波 一种用于提高免疫力的药物制剂
CN114177220A (zh) * 2020-09-14 2022-03-15 富力 人参与连翘的组合物及其抗病毒等药用
JP2023539681A (ja) * 2020-09-04 2023-09-15 大▲連▼富生天然▲薬▼物▲開▼▲発▼有限公司 レンギョウ成分および任意選択のチョウセンニンジン成分ならびにその適用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050054A1 (en) * 1999-02-25 2000-08-31 Cv Technologies Inc. Treatment of autoimmune diseases with american ginseng extract
CN103536884A (zh) * 2013-10-19 2014-01-29 邱德山 一种广谱防疫抗病毒的中药组合物

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1182853C (zh) * 2000-01-01 2005-01-05 同济医科大学附属同济医院 一种抗人巨细胞病毒药物的应用
CN1269507C (zh) * 2003-03-19 2006-08-16 杨忠 解毒补津益气药
CN100496504C (zh) * 2006-08-30 2009-06-10 富力 20(R)-人参皂苷Rg3药用水溶性复合物及制备方法
KR101426888B1 (ko) * 2007-10-12 2014-08-05 주식회사 한국인삼공사 항-조류독감 바이러스 조성물
KR101081809B1 (ko) * 2008-04-23 2011-11-09 울산대학교 산학협력단 인삼을 처리하여 ＨＩＶ－１의 ５’ＬＴＲ／ｇａｇ유전자를 결손시키는 방법
CN102166238B (zh) * 2011-04-08 2012-06-20 桂林英美特生物技术有限公司 一种田七提取物及其应用
KR101355320B1 (ko) * 2012-01-06 2014-01-23 장재영 진세노사이드 Ｒｇ３을 유효성분으로 함유하는 Ｃ형 간염 예방 및 치료용 조성물
CN103845349A (zh) * 2012-11-30 2014-06-11 富力 20(R)-人参皂苷Rg3在制备白癜风药物中的应用
CN103845280B (zh) * 2012-11-30 2017-04-12 富力 一种20(R)‑人参皂苷Rg3外用制剂、制法与用途
CN103845348B (zh) * 2012-11-30 2016-07-13 富力 20(R)-人参皂苷Rg3在制备痛经药物中的应用
CN105616930A (zh) * 2014-10-27 2016-06-01 周子童 一种解毒补津益气药
CN104523790B (zh) * 2015-01-19 2016-03-30 四川联成迅康医药股份有限公司 一种熟三七及其制备方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050054A1 (en) * 1999-02-25 2000-08-31 Cv Technologies Inc. Treatment of autoimmune diseases with american ginseng extract
CN103536884A (zh) * 2013-10-19 2014-01-29 邱德山 一种广谱防疫抗病毒的中药组合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AN, NING ET AL.: "Effect of 20(R) ginsenoside Rg3 on protein expression of lung cancer cell line", CHINESE JOURNAL OF LUNG CANCER, vol. 11, no. 3, 30 June 2008 (2008-06-30), pages 311 - 320, XP055331675, ISSN: 1009-3419 *
See also references of EP3295950A4 *

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JP6457661B2 (ja) 2019-01-23
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CN106138139A (zh) 2016-11-23
CN106138139B (zh) 2020-07-28
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