CN106474163B - Application of antrodia camphorata fruiting body extraction composition - Google Patents
Application of antrodia camphorata fruiting body extraction composition Download PDFInfo
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- CN106474163B CN106474163B CN201610737664.5A CN201610737664A CN106474163B CN 106474163 B CN106474163 B CN 106474163B CN 201610737664 A CN201610737664 A CN 201610737664A CN 106474163 B CN106474163 B CN 106474163B
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- fruiting body
- antrodia camphorata
- camphorata fruiting
- extract
- red blood
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Classifications
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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
- A61K36/06—Fungi, e.g. yeasts
- A61K36/07—Basidiomycota, e.g. Cryptococcus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/37—Extraction at elevated pressure or temperature, e.g. pressurized solvent extraction [PSE], supercritical carbon dioxide extraction or subcritical water extraction
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Mycology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention provides an application of an antrodia cinnamomea fruiting body extraction composition for manufacturing a medicine for treating erythrocyte and/or thrombocytopenia, wherein the antrodia cinnamomea fruiting body extraction composition comprises a carbon dioxide supercritical fluid extract of antrodia cinnamomea fruiting body, and preferably can be used for manufacturing a medicine for treating erythrocyte and/or thrombocytopenia and leucopenia or a medicine for losing weight.
Description
Technical Field
The invention relates to the use of Antrodia camphorata fruiting body extract; in particular for the treatment of red blood cell and/or platelet depletion.
Background
In cancer treatment, the use of chemotherapeutic drugs plays a very important role, however, chemotherapeutic drugs can kill cancer cells and also poison many normal cells, causing many side effects. Generally, cancer cells are cells with fast growth and division speed, the poisoning mechanism of chemotherapy drugs is usually related to the inhibition of cell division, and the growth and division speed of many normal tissue cells in vivo is also fast, so that the chemotherapy drugs can also affect the physiological functions of these cells, and the cells usually affected by the chemotherapy drugs are: hematopoietic cells of bone marrow, epidermal mucosal cells of digestive tract, cells of reproductive system, and hair follicle cells.
Among the cells susceptible to the chemotherapeutic drugs, the hematopoietic cells of bone marrow are important cells, which are main hematopoietic tissues and have the characteristic of rapid growth and division, and according to different degrees of sensitivity of the hematopoietic cells of bone marrow to the chemotherapeutic drugs, the side effects of bone marrow suppression with different degrees are almost generated during the chemotherapeutic drugs, and the symptoms of the side effects are that the numbers of white blood cells, red blood cells and platelets are reduced; wherein the reduction in white blood cell count predisposes the patient to infection; anemia may occur when the number of red blood cells is reduced, and symptoms such as weakness and fatigue may occur; a decrease in platelet count decreases the coagulation function of the patient.
At present, different treatment mechanisms are adopted clinically according to the bone marrow suppression state, for example, a granular-macrophage-stimulating factor (G-CSF) is used for leucopenia; iron preparation can be administered for erythrocyte reduction, and transfusion or administration of erythropoiesis hormone (EPO) is required if necessary; platelet lowering requires platelet transfusion for treatment. However, in the aforementioned treatments, such as safety and supply of blood preparations, the production of erythropoiesis hormone is expensive, and the use of macrophage-stimulating factor granules causes many side effects including bone soreness, muscular soreness, headache, fatigue, nausea, vomiting, fever, insomnia, etc.; on biochemical tests, it can be found that alkaline phosphatase is increased, liver function index is increased, and uric acid is increased; furthermore, it has effects on the musculoskeletal system, skin, respiratory system, cardiovascular system, renal function, and the like.
Therefore, there is still a need for the development of a drug which can cope with the side effects of bone marrow suppression in the chemotherapy of cancer.
Antrodia cinnamomea (Antrodia cinmamoma) is a specific fungus in Taiwan, belongs to the perennial fungi of Basidiomycotina, Hymenomycetes, Aphyllophorales, Polyporaceae and Antrodia in the taxonomy of fungi, and only grows on the inner wall of a hollow core material of a specific Cinnamomum kanehirai in Taiwan, and the fruiting body of the Antrodia cinnamomea grows from one year to many years, is bright red, orange red or light cinnamon and has the fragrance of the Cinnamomum kanehirai.
The antrodia camphorata is regarded as a good medicine for relieving hangover by original residents in taiwan in early stage, has the effect of relieving hangover, contains Triterpenoids (Triterpenoids), polysaccharides (Poly-saccharides) and beta-glucan (beta-glucan) and the like, and has the functions of resisting hepatitis B virus, resisting cancer, regulating immunity, resisting inflammation, resisting oxidation, resisting vascular proliferation, reducing blood pressure, reducing blood fat, protecting nerves, resisting bacteria, whitening skin and the like after being widely researched.
Antrodia camphorata is a fungus, the growth of which can be divided into different stages of hypha, mycelium, sporocarp and sporophyte, and the cultivation cost, the composition and the content of the components are different. The mycelium and the mycelium can be cultured by liquid fermentation or solid culture, wherein the liquid fermentation has low cost and short culture time, the solid fermentation can obtain the mycelium similar to the shape of the fruiting body, but the triterpene components contained in the mycelium and the mycelium are extremely low and have far lower curative effect than the fruiting body; the fruiting bodies can be collected only in the field, the price is high, the ecological cost is high, basswood cultivation is developed, the Antrodia camphorata host basswood is used as a culture medium to cultivate the fruiting bodies, and the method is the most similar to the Antrodia camphorata collected in the field and has the best curative effect.
Because the variety of physiological active ingredients contained in the fruiting body of antrodia camphorata is wide, the development of curative effect to expand the application of antrodia camphorata is still the aim of the industry.
Disclosure of Invention
The invention provides an application of an antrodia camphorata fruiting body extraction composition for preparing a medicine for treating low red blood cells and/or platelets, wherein the antrodia camphorata fruiting body extraction composition comprises a carbon dioxide supercritical fluid extract of an antrodia camphorata fruiting body.
the use is preferably for the manufacture of a medicament for the treatment of red blood cell and/or platelet depletion and leukopenia or for the manufacture of a medicament for the treatment of red blood cell and/or platelet depletion and weight loss.
The invention also provides a pharmaceutical composition for treating red blood cell and/or platelet depletion, which comprises a therapeutically effective amount of the antrodia camphorata fruiting body extraction composition, wherein the antrodia camphorata fruiting body extraction composition comprises a carbon dioxide supercritical fluid extract of antrodia camphorata fruiting body.
The pharmaceutical composition is preferably used for treating low red blood cells and/or platelets and low white blood cells or for treating low red blood cells and/or platelets and weight loss.
On the other hand, the aforementioned antrodia cinnamomea fruiting body extraction composition further comprises a sesame extract.
Drawings
FIG. 1 shows the effect of THP-1 cells on the secretion of granular-macrophage-stimulating factor (macrophage-stimulating factor) after 24 hours of treatment with different concentrations of Antrodia camphorata fruiting body extract composition (SR 4).
FIG. 2 shows the effect of THP-1 cells on the secretion of stimulating factors of granular macrophage cell line after 24 hours of treatment with different concentrations of the Antrodia camphorata fruiting body extract composition (SR4 s).
Detailed Description
The invention provides an application of an antrodia camphorata fruiting body extraction composition for preparing a medicine for treating low red blood cells and/or platelets, wherein the antrodia camphorata fruiting body extraction composition comprises a carbon dioxide supercritical fluid extract of an antrodia camphorata fruiting body. A pharmaceutical composition comprising an Antrodia camphorata fruiting body extract composition for treating red blood cell and/or platelet depletion in an individual, the pharmaceutical composition comprising an effective amount of the Antrodia camphorata fruiting body extract composition and optionally a pharmaceutically acceptable carrier or excipient.
The present invention may be understood more readily by reference to the following detailed description of the various aspects, examples, and chemical diagrams and tables accompanying the related description. Before the present uses and extracts are disclosed and described, it is to be understood that this invention is not limited to particular methods of preparation, carriers or formulations, or to particular modes of formulating the compounds of the invention into products or compositions for topical, oral or parenteral administration, unless otherwise specifically indicated by the claims, as such may vary, as will be readily apparent to those skilled in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to limit the scope of the present invention.
The following terms as used in the present invention should be construed to have the following meanings unless otherwise indicated.
Ranges are generally expressed herein as "about" one particular value, and/or to "about" another particular value. When such a range is expressed, an aspect is a range that includes one particular value and/or to another particular value. Similarly, when values are expressed as approximations, by use of the word "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
"optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally including an agent" means that the agent may or may not be present.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular.
The term "individual" as used herein means any animal, preferably a mammal, and more preferably a human. Examples of subjects include humans, non-human primates, rodents, guinea pigs, rabbits, sheep, pigs, goats, cows, horses, dogs, and cats.
The term "effective amount" of a compound as provided herein refers to an amount of the compound sufficient to provide a desired modulation of a desired function, such as gene expression, protein function, or induction of a particular type of response. As noted below, the exact amount required will vary from individual to individual depending on the disease state, physical condition, age, sex, species and weight of the individual, the nature and formulation of the composition, and the like. The dosing regimen may be adjusted to induce the optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be reduced proportionally to the urgency of the treatment situation. Therefore, it is difficult to specify an exact "effective amount". However, an appropriate effective amount can be determined by one skilled in the art using routine experimentation.
The term "treating" as used herein means reversing, alleviating or ameliorating the disorder or condition to which such term applies, or one or more symptoms of the disorder or condition, or inhibiting the progression thereof.
The term "carrier" or "excipient" as used herein refers to any substance that is not a therapeutic agent by itself, but rather is used as a carrier and/or diluent and/or adjuvant or vehicle for delivery of the therapeutic agent to an individual, or is added to a formulation to improve handling or storage properties of the formulation or to allow or facilitate formation of dosage units of the composition into dosage units (such as capsules or tablets) suitable for oral administration. Suitable carriers or excipients are well known to those skilled in the art of making pharmaceutical formulations or foods. Carriers or excipients may include, by way of example and not limitation, buffers, diluents, disintegrants, binders, adhesives, humectants, polymers, lubricants, glidants, substances added to mask or counteract an unpleasant taste or odor, flavoring agents, dyes, fragrances, and substances added to improve the appearance of the composition. Acceptable carriers or excipients include citrate buffers, phosphate buffers, acetate buffers, bicarbonate buffers, stearic acid, magnesium stearate, magnesium oxide, the sodium and calcium salts of phosphoric and sulfuric acid, magnesium carbonate, talc, gelatin, acacia, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, gelatin, cellulosic materials (such as cellulose esters and alkyl esters of alkanoic acids), low melting waxes, cocoa butter, amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g., serum albumin), Ethylene Diamine Tetraacetic Acid (EDTA), dimethyl sulfoxide (DMSO), sodium chloride or other salts, liposomes, mannitol, sorbitol, glycerin or powders, polymers (such as polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene glycol), and other pharmaceutically acceptable materials. The carrier should not destroy the pharmacological activity of the therapeutic agent and should be non-toxic when administered at a dose sufficient to deliver a therapeutic amount of the agent.
Preferably, the antrodia camphorata fruiting body extraction composition is contained in one composition. The composition according to the invention is preferably a food composition or a pharmaceutical composition.
The Antrodia Camphorata fruiting body extract composition can be added into common food composition (edible food or beverage or its precursor) in food preparation process. Almost all food compositions can be added with the antrodia camphorata fruiting body extraction composition according to the present invention. The food composition to which the antrodia camphorata fruiting body extraction composition according to the present invention can be added includes, but is not limited to, candies, baked goods, ice cream, dairy products, desserts and savory snacks, meat substitute products, snack foods, soups, pasta, noodles, canned foods, frozen foods, dried foods, refrigerated foods, fats and oils, baby foods, soft foods, or bread sauce, or a mixture thereof.
The pharmaceutical compositions of the present invention may be administered locally or systemically by any method known in the art of the present invention, including but not limited to, administration by intramuscular, intradermal, intravenous, subcutaneous, intraperitoneal, intranasal, oral, mucosal or external routes. The appropriate route of administration, method of formulation and time course of administration may be determined by one skilled in the art. In the present invention, the pharmaceutical composition may be formulated in various ways according to the respective administration routes, such as liquid solutions, suspensions, emulsions, syrups, lozenges, pills, capsules, sustained-release formulations, powders, granules, ampoules, injections, infusions, kits, ointments, lotions, liniments, creams or combinations thereof. If necessary, it may be sterilized or mixed with any pharmaceutically acceptable carrier or excipient, many of which are known to those skilled in the art.
The term "antrodia cinnamomea fruiting body extraction composition" as used herein refers to a composition comprising an antrodia cinnamomea fruiting body extract, specifically a carbon dioxide supercritical fluid extract comprising antrodia cinnamomea fruiting body.
The invention relates to Antrodia camphorata which is a special fungus in taiwan and belongs to the multinomial fungi of Basidiomycotina (Basidiomycotina), Hymenomycetes (Hymenomycetes), Aphyllophorales (Aphyllophorales), Polyporaceae (Polyporaceae) and Botrytis (Antrodia) in the taxonomic classification, and the scientific names of the Antrodia cinnamomea cindomoea, Garoderma complex, Antrodia camphora or Taiwanofunguscamphorus.
The 'antrodia camphorata fruiting body' refers to a multicellular sexual sporulation structure generated by antrodia camphorata, and structures such as sporogenous ascomycetes, basidiomycetes and the like are attached to the multicellular sexual sporulation structure, and the fruiting body is in a sexual stage in the life history of the antrodia camphorata, is bright red, orange red or light cinnamon and has camphor tree fragrance. The antrodia cinnamomea fruiting body according to the present invention may be collected from antrodia cinnamomea or cultured from basswood of antrodia cinnamomea, preferably cultured from basswood of antrodia cinnamomea.
The carbon dioxide supercritical fluid extract of the antrodia camphorata fruiting body according to the present invention is an extract obtained by extracting the antrodia camphorata fruiting body with a carbon dioxide supercritical fluid. Supercritical fluids are fluids that, when the critical temperature and pressure are exceeded, the properties of the gas and liquid tend to be similar, eventually achieving a homogeneous phase (homogenous). The supercritical fluid has compressibility similar to gas and liquidity similar to liquid, can be used for extraction, and commercial supercritical fluid extraction equipment can be used, for example, NATEX, SEPAREX, UHDE and Taiko all provide commercial supercritical fluid extraction equipment, the type specification of which is generally expressed by the capacity that an extraction tank can process, can be selected from 500g to 2000kg, and the appropriate supercritical fluid extraction equipment can be selected according to the requirement.
In one embodiment of the present invention, the carbon dioxide supercritical fluid extract of antrodia camphorata fruiting body is extracted at a pressure of about 150bar to about 1000 bar; preferably from about 200bar to about 800 bar; more preferably from about 350bar to about 600 bar.
In one embodiment of the present invention, the carbon dioxide supercritical fluid extract of Antrodia camphorata fruiting body is extracted at a temperature of about 25 ℃ to about 80 ℃; preferably from about 35 ℃ to about 70 ℃; more preferably from about 40 ℃ to about 65 ℃.
In one embodiment of the present invention, the carbon dioxide supercritical fluid extract of Antrodia camphorata fruiting body has a carbon dioxide flow rate of about 20kg/h to about 70 kg/h; preferably from about 30kg/h to about 60 kg/h; particularly preferably from about 35kg/h to about 55 kg/h.
In one embodiment of the present invention, the carbon dioxide supercritical fluid extract of antrodia camphorata fruiting body is extracted for about 40 minutes to about 120 minutes; preferably from about 50 minutes to about 100 minutes.
In one embodiment of the present invention, the carbon dioxide supercritical fluid extract of Antrodia camphorata fruiting body is extracted in the presence of a co-solvent, such as about 1% to about 10% 95% ethanol.
In one embodiment of the present invention, in the extraction of the carbon dioxide supercritical fluid extract of the antrodia camphorata fruiting body, the weight ratio of the antrodia camphorata fruiting body to the carbon dioxide supercritical fluid is about 10: 1 to about 1: 10; preferably about 5: 1 to about 1: 5; more preferably about 3: 1 to 1: 3.
In a preferred embodiment of the present invention, the Antrodia camphorata fruiting body is first pulverized into small pieces, and more preferably, the small pieces are pulverized into powder. The manner of chopping and/or mincing is well known to those skilled in the art.
Preferably, the supercritical fluid extraction process further comprises a concentration step. In a preferred embodiment, the carbon dioxide supercritical fluid extract of Antrodia camphorata fruiting body is concentrated by a Simulated Moving Bed (SMB) and carbon 18 solid adsorbent after carbon dioxide supercritical fluid extraction, and the components with the Henry constant of more than 2.8 are collected. The simulated moving bed according to the present invention is a simulated moving bed in which the active components of antrodia camphorata are separated and concentrated according to their polarity characteristics (henry constant H), and the embodiment thereof is described in taiwan patent No. I487531, "concentration step", which is incorporated herein by reference.
The red blood cell and/or platelet low according to the present invention refers to red blood cell and/or platelet low caused by any reason, such as congenital or acquired, or caused by other diseases and drugs. In a preferred embodiment of the present invention, the red blood cell and/or platelet lowering is drug induced red blood cell and/or platelet lowering; preferably, the drug is a drug that treats tumors and has myelosuppressive side effects, such as chemotherapeutic drugs for treating cancer. The term "chemotherapeutic agent" as used herein refers to an agent that inhibits cancer cell division. As used herein, "myelosuppression" refers to a side effect of the chemotherapy drugs that affects the normal physiological status of hematopoietic cells, including a decrease in the number of white blood cells, red blood cells, and/or platelets.
In particular embodiments of the invention, the tumor comprises, but is not limited to, malignant lymphoma, Wilm's tumor, head and neck squamous cell carcinoma, bone cancer, hypercalcemia of metastatic bone lesions, or testicular cancer.
In particular embodiments of the invention, the drug includes, but is not limited to Chlorambucil (Chlorambucil), Cytarabine (Cytarabine), Dactinomycin (Dactinomycin), Bleomycin (Bleomycin), plicamycin (Pilcamycin), Etoposide (Etoposide), nitrosourea (nitrosourea) or cyclophosphamide (cyclophosphamid); cyclophosphamide is preferred.
In a preferred embodiment of the present invention, the antrodia camphorata fruiting body extraction composition further comprises sesame extract. The sesame is called as flax, flax and oil flax, is a plant of the genus flax of the family of the benaceae, is known as Sesamum indicum, and preferably refers to seeds of sesame plants. The term "sesame extract" as used herein refers to a mixture obtained by extracting active ingredients of sesame seeds by methods including, but not limited to, solvent extraction, supercritical fluid extraction, thermal extraction, and solid phase extraction, preferably supercritical fluid extraction, and more preferably supercritical fluid extraction with carbon dioxide. In a preferred embodiment of the present invention, the sesame extract is sesamin (sesamin), and the term "sesamin" as used herein refers to a component of sesame lignan (lignans), which is a fat-soluble antioxidant group in sesame.
According to the present invention, sesame and antrodia camphorata can be respectively extracted and combined to form the antrodia camphorata fruiting body extraction composition, for example, the sesame extract and the carbon dioxide supercritical fluid extract of the antrodia camphorata fruiting body are respectively prepared, and a carrier/excipient is optionally added to prepare the antrodia camphorata fruiting body extraction composition. In a preferred embodiment of the present invention, the sesame extract and the carbon dioxide supercritical fluid extract of the fruiting body of antrodia camphorata are mixed in a weight ratio of about 1: 3 to about 3: 1; more preferably about 1: 2 to about 2: 1. on the other hand, the sesame and the antrodia camphorata fruiting body according to the invention can be combined and extracted by using carbon dioxide supercritical fluid, and then a carrier/excipient is added according to the requirement to prepare the antrodia camphorata fruiting body extraction composition. In a preferred embodiment of the present invention, the sesame and the fruiting body of antrodia camphorata are mixed in a weight ratio of about 1: 3 to about 3: 1; more preferably about 1: 2 to about 2: 1.
Preferably, the Antrodia camphorata fruiting body extraction composition according to the present invention can treat red blood cell and/or platelet and leucocyte hypofunction, to treat side effects of bone marrow suppression in all aspects, and improve the problem of lowering the number of hemoglobin and platelets while increasing the number of neutrophils, monocytes and lymphocytes in peripheral blood, and to avoid side effects caused by the use of granular macrophage cell line stimulating factor, which is known to be used when granular macrophage cell line stimulating factor is used.
In particular embodiments of the invention, the treatment of red blood cell and/or platelet low and leukopenia includes, but is not limited to, promoting an increase in total white blood cells, promoting an increase in granular white blood cell count, promoting an increase in neutrophilic cell count, promoting an increase in lymphocyte count, promoting an increase in monocyte count, and increasing the secretion of granular-macrophage cell line stimulating factor (macrophage-stimulating factor).
On the other hand, the antrodia camphorata fruiting body extraction composition according to the present invention can treat red blood cell and/or platelet low and body weight loss. Since the cancer patients almost have weight loss together, the composition of the Antrodia camphorata fruiting body according to the present invention can treat bone marrow suppression and weight loss together, thereby more widely assisting the treatment of cancer chemical drugs.
In the BALB/c mouse animal experiment model, efficacy test is carried out on Cyclophosphamide (CTX) induced bone marrow suppression side effect by the antrodia camphorata fruiting body extracting composition, the experimental mouse is respectively given 300mg/kg of chemotherapeutic drug CTX in an IP intraperitoneal injection mode according to the body weight on the 0 th day, and the antrodia camphorata fruiting body extracting composition is respectively given test substances in an oral (PO) mode from the 1 st day to the 4 th day. The results show that the toxicity of the chemotherapeutic drug of CTX can reduce the number of red blood cells of each group of mice to a low point on the 4 th day, while the oral Antrodia camphorata fruiting body extract composition can increase the number of red blood cells by 1.19 times and continuously increase the number of red blood cells by 1.23 times on the 7 th day; on the other hand, the administration of CTX resulted in a significant decrease in the platelet count in mice on day7, which was about 50% lower than that on day 0, and the platelet count was protected by the antrodia camphorata fruiting body extract composition administered in different concentrations.
For leukopenia, when a single dose of CTX (300mg/kg) was administered to the mice, the number of leukocytes in the mice significantly dropped to the lowest point on day4 and began to rise on day 7. When analyzed for these two observation points (Day4, Day7), the numbers of leukocytes in each group of mice tube-fed with the Antrodia camphorata fruiting body extract composition also decreased to the lowest point on Day4 (leukocyte reduction rate ranged from about 86.7 to 91.5%), and the number of leukocytes in each group of mice started to increase on Day7 after administration of CTX on Day 0. The white blood cells in the CTX group are increased by about 3 times on the 7 th day, and the number of the white blood cells is remarkably increased under the treatment of the antrodia camphorata fruiting body extraction composition.
Further analyzing the influence of the change of the secondary population granular leukocyte, neutrophilic globulin, monocyte and lymphocyte of the composition extracted from the Antrodia camphorata fruiting body. The results show that a single dose of CTX (300mg/kg) administered on day 0 causes the mice to bottom out the number of granular leukocytes and neutrophilic spheres on day4, the number of granular leukocytes and neutrophilic spheres can begin to rise on day7, and the test substance antrodia camphorata fruiting body extract composition has 2 times of capacity for remarkably promoting the rise of granular leukocytes; on the other hand, the Antrodia camphorata fruiting body extraction composition can increase the number of the neutral balls by 2.93 times on the 7 th day; in addition, the administration of the chemotherapeutic agent CTX also resulted in a significant decrease in the number of lymphocytes and monocytes on day4, and it was found that the administration of the Antrodia camphorata fruiting body extract composition on day7 increased the number of lymphocytes by 2.49 times; the Antrodia camphorata fruiting body extract composition has the potential of promoting the increase of mononuclear balls at the 7 th day when the number of mononuclear balls is expressed.
For weight loss, mice in each group administered with a single dose of CTX (300mg/kg) began to lose weight (about 10% decrease) on the third day compared to the blank group, while mice fed with the antrodia camphorata fruiting body extract composition observed weight regain, so that the antrodia camphorata fruiting body extract composition of the present invention can treat weight loss.
For increasing the secretion of macrophage granulosa stimulating factor, LPS induced monocyte production of GM-CSF was used as a positive control group. By using the test platform, the influence of the Antrodia camphorata fruiting body extract composition on the production of the cell hormone GM-CSF is discussed, the measured absorbance value of O.D.450nm is converted into percentage by ELISA, the production of GM-CSF secreted by the THP-1 cell strain is taken as 100%, the production of the cell hormone GM-CSF can be averagely increased by 1.6 times by the stimulation of the THP-1 cell on the LPS, and when the THP-1 cell treats the test sample Antrodia camphorata fruiting body extract composition with different concentrations, the production of GM-CSF is relatively increased along with the increase of the concentration of the Antrodia camphorata fruiting body extract composition. From these results, it was found that the concentration of the test substance, i.e., the extract composition from the fruiting body of Antrodia camphorata, was related to the amount of GM-CSF produced by the dose-dependent reaction (dose-dependent), and that the extract composition from the fruiting body of Antrodia camphorata, i.e., at a high concentration of 100. mu.g/ml, induced about 1.3-fold increase in the amount of GM-CSF produced.
The following non-limiting examples will assist those skilled in the art in practicing the present invention. These examples should not be construed as unduly limiting this invention. Modifications and variations of the embodiments discussed herein may be made by those skilled in the art without departing from the spirit or scope of the invention, and yet still fall within the scope of the invention.
Examples
Antrodia camphorata fruiting body extraction composition
Carbon dioxide supercritical extract of Antrodia camphorata fruiting body (SR4)
Taking 105 g of antrodia cinnamomea fruiting body, crushing the antrodia cinnamomea fruiting body into particles with the particle size of about 5 mm square, placing the particles into an extraction tank of supercritical fluid extraction equipment, setting the internal pressure of the extraction tank to be 350bar, the internal temperature to be 50 ℃, using 95% ethanol as an auxiliary solvent, and feeding at the rate of 3 ml per minute, wherein the weight ratio of the antrodia cinnamomea fruiting body to carbon dioxide supercritical fluid is 20: 80 to 40: 60, the supercritical carbon dioxide fluid is 35 to 55kg/h), because the antrodia camphorata extract is pasty and still contains 95 percent of ethanol, an oven with the temperature set to be 30 to 35 ℃ is used for removing the ethanol in the pasty antrodia camphorata extract so as to carry out the subsequent concentration step.
The concentration step is to take a simulated moving bed as a continuous feeding type purification platform to carry out group separation on the components with different Henry constants in the Antrodia camphorata extract; the Stationary Phase (SP) of the simulated moving bed in this example is a carbon 18 column, the Mobile Phase (MP) in this example is a mixture of water and methanol, the water contains 0.05% acetic acid, the Mobile phase is used to dissolve the antrodia camphorata extract, and the weight ratio of the water to the methanol is preferably 20: 80 to 40: 60, the more preferred weight ratio of water to methanol is 22: 78, the selection factor (Selective factor) of the mobile phase is more than 1.3, and the components A and B with different polarity characteristics can be separated more effectively.
The simulated moving bed of the present embodiment comprises at least three separation zones, which are α, β and γ zones in sequence, wherein the rear end of the α zone is provided with a first discharge port O α (called Extract outlet), the rear end of the γ zone is provided with a second discharge port O γ (called rafinate outlet), and the Feed port I (called Feed inlet) is disposed between the β and γ zones.
The three separation areas alpha, beta and gamma are respectively composed of two tubular columns c, the tubular columns c of the three separation areas are mutually communicated, the tubular columns c are filled with the fixed phase, particularly, pores are formed among particles of the fixed phase for the mobile phase to pass through, the mobile phase sequentially flows through the tubular columns c of the alpha, beta and gamma areas in the same direction, the fixed phase changes the relative position of the feed inlet I in the three separation areas after a feed inlet switching time Tsw by a feed inlet switching device, and the fixed phase is enabled to move in a simulated mode towards the other direction relative to the mobile phase.
According to the trigonometric theory of simulated moving beds, the components to be separated include: a component a having a henry constant of 2.8 or more and a component B having a henry constant of 2.8 or less in each of three separation regions α, β and γ, a net mass flux FA of the component a and a net mass flux FB of the component B satisfying the conditions of table 1, the component a moving toward the region α and the component B moving toward the region γ, and flow rate ratios n of the three separation regions α, β and γ (the flow rate ratios of the separation regions α, β and γ are, respectively, na, n β and n γ) in relation to the polarity of the component to be separated (i.e., the henry constant of the component a is HA and the henry constant of the component B is HB), the flow rate ratios n α, n β and n γ satisfying the conditions of table 1, wherein the henry constant H of each component is calculated according to formula i, T0 is a residence time of a substance not adsorbed by a stationary phase flowing through a column (T0 is 1.71), and Tr is a residence time of the component to be separated, ε is the porosity of the column used in this example (0.412).
Table 1: condition settings for the net mass flux F, flow rate ratio n and Henry constant H for each separation zone of the present example
| Region(s) | α | β | γ |
| Net mass flux F | FB>0；FA>0 | FB>0；FA<0 | FB>0；FA<0 |
| Flow rate ratio n | nα>HA>HB | HA>nβ>HB | HA>nγ>HB |
The simulated moving bed of the present example was pressurized by a liquid pump (HITACHI L-2130) to flow the mobile phase in the same direction in the column of each zone, the feed port switching time Tsw of the present example was set to simulate the condition that the stationary phase was directed in the opposite direction to the mobile phase, the antrodia camphorata extract was separated under the conditions shown in table 2, the component a having a henry constant of 2.8 or more was obtained at the first discharge port O α, and the component B having a henry constant of 2.8 or less, i.e., the carbon dioxide supercritical extract of antrodia camphorata fruiting body (SR4), was obtained at the second discharge port O γ.
The Antrodia camphorata fruiting body extraction composition (SR4s) comprises carbon dioxide supercritical extract of Antrodia camphorata fruiting body and sesame extract
Taking 250 g of sesame, placing the sesame in an extraction tank of supercritical fluid extraction equipment, setting the internal pressure of the extraction tank to be 350bar, the internal temperature to be 50 ℃, and an auxiliary solvent to be 95% ethanol, and feeding the sesame at a rate of 3 milliliters per minute, wherein the weight ratio of the sesame to the carbon dioxide supercritical fluid is 50: 91, because the sesame extract is pasty and still contains 95% ethanol, removing the ethanol in the pasty sesame extract by an oven with the temperature set at 30-35 ℃ to obtain the sesame extract.
Mixing the obtained sesame extract and the carbon dioxide supercritical extract (SR4) of the antrodia camphorata fruiting body according to the weight ratio of 7: 9 blending to obtain the antrodia camphorata fruiting body extraction composition (SR4 s).
Curative effect of composition extracted from antrodia camphorata sporocarp
test materials and methods
[ animal model ]
BALB/c mice (mouse) were administered with the chemotherapeutic drug Cyclophosphamide (CTX) to produce bone marrow suppression in animals induced by the chemotherapeutic drug, and whether the test substance improved the bone marrow suppression effect produced by the chemotherapeutic drug was observed.
[ test methods ]
The test animals are administered the test substance orally (PO) and analyzed for changes in the numbers of leukocytes and subfamily granulocytes, lymphocytes, erythrocytes and platelets.
[ test substance ]
The carbon dioxide supercritical extract (SR4) of the obtained Antrodia camphorata fruiting body and the composition (SR4s) of the Antrodia camphorata fruiting body are prepared.
[ design of experiment ]
Test drug and its preparation
Chemotherapeutic agents CTX (Sigma Chemical Co. CAS Number:6500-19-2(St Louis, MO, USA)), granular macrophage cell line stimulating factor (G-CSF, Filgrastim, Cat.08502A, Kirin Brewery Co. Ltd., Japan). CTX was added to physiological saline to prepare a final concentration of 45mg/mL as an intraperitoneal Injection (IP) formulation, and 300mg per kg body weight was administered to each mouse. The test substances SR4s and SR4 were dissolved in DMSO (Dimethyl sulfoxide from sigma), respectively, and the concentration of each test substance was 125mg/mL, and the concentration of each test substance was 12.5mg/mL, and the concentration of each test substance was 10mg/Kg per Kg of body weight, in an oral reagent diluted ten times with secondary water to a final concentration of 1.25 mg/mL.
Experimental animal feeding and grouping
The experimental animals for this experiment were BALB/c mice: the animals are male in 6-8 weeks old, all purchased from Lesco Biotechnology Ltd, bred at 25 + -2 deg.C with humidity ranging from 40-70%, and alternating light/dark for 12 hr, and the drinking water is not limited. Mice were given a one week acclimation period after purchase, weighed and randomly grouped to give no difference in mean body weight between groups, and animals were grouped into twelve groups of five animals each.
Experimental design of chemotherapeutic drug CTX and test substance
The experimental mice were administered 300mg/kg of chemotherapeutic drug CTX by IP intraperitoneal injection on day 0, respectively, to induce the experimental animals to generate bone marrow suppression model, and each of the experimental groups SR4s and SR4 was administered the test substance by oral administration (PO) starting on day 1 to day4, respectively. During the test, mice were weighed every three days and observed for changes in body weight, and blood was collected on days 0, 4 and 7 and observed for changes in blood items.
hematology analysis
The experimental animal is fixed by hands in a cheek blood sampling (Lancet) mode, a blood sampling needle is pricked into the back of the mandible of the face of the mouse, the effluent blood is collected by a centrifugal tube, and after enough blood volume is collected, sterile gauze is pressed against a bleeding opening for 10-30sec to stop bleeding. The collected peripheral trace blood of the mouse was shaken up, 20. mu.L of the blood was taken out, and five-fold dilution was performed with a cell diluent, and then quantitative detection of blood cells was performed with an XT-1800i blood analyzer (SYSMEX).
Results
SR4s and SR4 for treating CTX-induced erythrocyte and platelet count reduction
As shown in table 1 and table 2, the toxicity of chemotherapeutic agents in the administration of CTX resulted in a drop in the number of erythrocytes to the low point in each group of mice on day4, while oral administration of SR4s increased the number of erythrocytes by 1.19 times, SR4 increased the number of erythrocytes by 1.18 times, and continued increase in the number of erythrocytes on day7, oral administration of SR4s increased the number of erythrocytes by 1.17 times, and SR4 increased the number of erythrocytes by 1.23 times. Effect of administration of a single dose of CTX (300mg/kg) on the number of platelets in mice. As shown in table 2, administration of CTX resulted in a significant decrease in platelet number in mice on day7, compared to day 0, where CTX resulted in a decrease in platelet number of about 50% in each group fed with different concentrations of test substance SR4s, SR4, with the potential to protect platelet number, especially the best performance of test substance SR4 for its ability to protect platelet number.
Table 1: results of day4 blood analysis
Table 2: results of day7 blood analysis
SR4s, SR4 treatment of CTX-induced reduction in the number of leukocytes and their subfamilies of granulocytes, neutrophils, monocytes and lymphocytes
From the results of tables 1 and 2, it was found that when mice were administered a single dose of CTX (300mg/kg), the number of leukocytes in the mice significantly dropped to the lowest point on day4, and began to rise on day 7. When analyzed for these two observation points (Day4, Day7), the numbers of leukocytes in each group of mice fed with the test substances SR4s, SR4 also all decreased to a minimum on Day4 (leukocyte depletion rate ranged from about 86.7 to 91.5%). each group of mice began to increase in number of leukocytes on Day7 after administration of CTX on Day 0. From the results, it was found that the white blood cells in the CTX group were increased by about 3 times on day7, and the numbers of white blood cells were significantly increased by the treatment with the test substances SR4s and SR4 (the increase in the number of white blood cells was 7 and 5 times, respectively).
The test substances SR4s, SR4 were further analyzed for their effect on the change in subpopulations of granulocytes, neutrophils, monocytes and lymphocytes. As shown by the results in tables 1 and 2, administration of a single dose of CTX (300mg/kg) on day 0 caused the mice to bottom out in the number of granulocytes, neutrophils on day4, while on day7 the increase in the number of granulocytes was observed initially, whereas the test substance SR4s had a 2-fold significant capacity to promote the increase in granulocytes; on the other hand, SR4 increased the number of neutrophils by 2.93 times and SR4s increased the number of neutrophils by 1.99 times at day 7.
In addition, administration of the chemotherapeutic CTX also resulted in a significant reduction in the number of lymphocytes and monocytes on day4, and oral administration of SR4 increased the number of lymphocytes by 2.49-fold on day 7; in the case of the expression of the number of monocytes, test object SR4s has the potential to promote the ascent of the monocytes on day 7.
SR4s, SR4 for the treatment of CTX-induced weight loss
The effect of chemotherapeutic drug administration on body weight of the test animals revealed that the mice administered with a single dose of CTX (300mg/kg) began to lose weight (about 10% decrease) on the third day compared to the blank group, and thus the toxicity of chemotherapeutic drug administered with a single dose of CTX (300mg/kg) caused the weight of the mice of the test animals to decrease, while the weight of the mice fed with the test substance SR4 increased again, so that the Antrodia camphorata fruiting body extract composition of the present invention could treat the weight loss.
Effect of enhancing granular macrophage cell stimulating factor of Antrodia camphorata fruiting body extraction composition
Experimental materials and methods
[ test materials ]
Cell lines: THP-1 cell line [ ATCC-TIB-202 ].
Reagents required for cell culture and experimental correlation: RPMI-1640 medium, Fetal Calf Serum (FCS) and 2-mercaptoethanol (2-mercaptoethanol). Lipopolysaccharide (LPS, available from Sigma), Human GM-CSF ELISA kit (Biolegend), etc.
[ test methods ]
Culturing the THP-1 cell strain:
THP-1 cell is a suspended human monocytic acute leukemia cell line (human monoclonal leukemia cell line) cultured in RPMI medium containing 10% FCS and 2-mercaptoethanol at 37 deg.C in a 5% CO2 incubator. The medium solution was changed about every 2 to 3 days, and when the cells in the flask grew to about 8 days, subculture (subculture) was performed. In the experiment, the number of cells is calculated by a Vi-cell cytometer, and then the appropriate number of cells is taken for the experiment.
Preparation of Experimental materials
SR4 and SR4s were dissolved in DMSO at a concentration of 125mg/ml, stored at 4 ℃ until use, and diluted to the desired concentration at the time of use.
Preparation of LPS (10 mg/ml), LPS was dissolved in 1 XPBS, dispensed and stored at-20 ℃ until use. For the experiment, the solution is diluted to the required concentration.
Testing of the cytokine GM-CSF using THP-1 cells as a platform
THP-1 cells were cultured in 12-well plates at 4X 105/well, and then divided into a control group (0. mu.g/ml), an LPS group (1. mu.g/ml) and an experimental group (treated with each of the drugs at different concentrations, 0.01, 0.1, 1, 10, 100. mu.g/ml) after six hours of culture, each of which was repeated three times, and cultured in an incubator at 37 ℃ and 5% CO2 for 24 hours. The following day, the cells were removed from the incubator, centrifuged (1000rpm, 5 minutes, 4 ℃), and the cell supernatant was collected and assayed for the intracellular release of the cytokine GM-CSF using the GM-CSF ELISA kit.
Human GM-CSF ELISA assay
The cytokine GM-CSF assay was performed using the Human GM-CSF ELISA kit (Biolegend). The reaction reagent and the sample to be tested are placed in room temperature, the reaction reagent and the sample to be tested are placed in the room temperature, the reaction reagent and the sample to be tested are warmed for standby, the 96-well plate coated previously is washed by washing buffer solution, 200 mu l/well blocking is carried out, the reaction reagent and the sample to be tested are placed in the room temperature for 1 hour, then the reaction reagent and the sample to be tested are washed by the washing buffer solution, the standard solution is prepared into 500, 250, 125, 62.5, 31.2, 15.6 and 7.8pg/ml, the sample to be tested and the standard solution diluted in series are respectively added into the 96-well plate, the reaction reagent and the sample to be tested are placed in the room temperature for 2 hours for washing, the detection antibody is added, the reaction reagent A and the sample to be tested are placed in the room temperature for 1 hour for washing, then the substrate solution (coloring reagent A + B) with 100 mu l/well is added, the reaction is carried out for 30. The absorbance at O.D.450nm was measured by ELISA reader, and the concentration of the cytokine GM-CSF was calculated by interpolation using the measured O.D. value with the R-squared of its standard curve.
Results
LPS induced monocyte production of the cytokine GM-CSF was used as a positive control group. The results of examining the effect of the test samples SR4s and SR4 on the production amount of the cytokine GM-CSF using this test platform are shown in FIGS. 1 and 2.
The absorbance at O.D.450nm measured by ELISA was converted into percentage, taking the amount of GM-CSF secreted by the THP-1 cell line as 100%, the GM-CSF produced by the THP-1 cells stimulated by LPS was increased by about 1.6 times on average in the positive control group, and when the THP-1 cells were treated with the test sample SR4s at different concentrations, it was found that the GM-CSF produced was relatively increased with the increase in SR4s concentration. From this result, it was found that the concentration of the test substance SR4s exhibited a dose-response (dose-dependent) relationship with the amount of GM-CSF produced, and that SR4s at a high concentration of 100. mu.g/ml induced about a 1.3-fold increase in the amount of GM-CSF produced.
The above embodiments are merely illustrative of the principles and effects of the present invention, and do not limit the present invention. Modifications and variations of the above-described embodiments may be made by those skilled in the art without departing from the spirit of the invention. The scope of the invention is to be determined by the following claims.
Claims (9)
1. The application of the antrodia camphorata fruiting body extraction composition for manufacturing a medicine for treating low red blood cells and/or low blood platelets is characterized in that the antrodia camphorata fruiting body extraction composition comprises a carbon dioxide supercritical fluid extract of antrodia camphorata fruiting body, the carbon dioxide supercritical fluid extract of the antrodia camphorata fruiting body is extracted at the pressure of 150bar to 1000bar and the temperature of 25 ℃ to 80 ℃, the carbon dioxide supercritical fluid extract of the antrodia camphorata fruiting body is concentrated by a simulated moving bed and a carbon 18 solid adsorbent after being extracted by the carbon dioxide supercritical fluid, and components with the Henry constant of more than 2.8 are collected.
2. The use according to claim 1, wherein the red blood cell and/or platelet lowering is drug induced red blood cell and/or platelet lowering.
3. The use according to claim 2, wherein the medicament is a medicament for the treatment of tumors and has myelosuppressive side effects.
4. Use according to claim 3, wherein the tumour is selected from the group consisting of malignant lymphomas, Wilm's tumours, squamous cell carcinoma of the head and neck, bone cancer, hypercalcemia of metastatic bone disease and testicular cancer.
5. The use of claim 3, wherein the medicament is selected from the group consisting of chlorambucil, cytarabine, dactinomycin, bleomycin, plicamycin, etoposide, nitrosourea, and cyclophosphamide.
6. The use according to claim 1, wherein the antrodia camphorata fruiting body extraction composition further comprises sesame extract.
7. Use according to any one of claims 1 to 6, for the manufacture of a medicament for the treatment of red blood cell and/or platelet depletion and leukopenia.
8. The use according to claim 7, wherein the treatment of red blood cell and/or platelet low and leukopenia is selected from the group consisting of promoting an increase in the total number of white blood cells, promoting an increase in the number of granulosa leukocytes, promoting an increase in the number of neutrophiles, promoting an increase in the number of lymphocytes, promoting an increase in the number of monocytes and increasing the secretion of stimulating factors of the granulosa macrophage cell line.
9. Use according to any one of claims 1 to 6, for the manufacture of a medicament for the treatment of red blood cell and/or platelet low and weight loss.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TW104128214A TWI586359B (en) | 2015-08-27 | 2015-08-27 | Use of extract composition of fruiting body of antrodia cinnamomea |
| TW104128214 | 2015-08-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106474163A CN106474163A (en) | 2017-03-08 |
| CN106474163B true CN106474163B (en) | 2019-12-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610737664.5A Active CN106474163B (en) | 2015-08-27 | 2016-08-26 | Application of antrodia camphorata fruiting body extraction composition |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN106474163B (en) |
| PH (1) | PH12016000298A1 (en) |
| SG (1) | SG10201607009SA (en) |
| TW (1) | TWI586359B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102000047A (en) * | 2009-09-02 | 2011-04-06 | 国鼎生物科技股份有限公司 | Antrodia camphorata cyclonene compound for restraining growth of bone cancer cells |
| CN102764520A (en) * | 2011-05-04 | 2012-11-07 | 财团法人工业技术研究院 | High-pressure extraction equipment and extraction method thereof |
| CN103861099A (en) * | 2012-12-11 | 2014-06-18 | 财团法人工业技术研究院 | Vaccine adjuvant, vaccine composition and application of Antrodia camphorata fruiting body |
| CN104306410A (en) * | 2014-09-29 | 2015-01-28 | 深圳市仁泰生物科技有限公司 | Triterpene-enriched anti-tumor composition and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI238852B (en) * | 2003-09-09 | 2005-09-01 | Uni President Entpr Corp | A new extraction method and application of antrodia camphorata to reduce the damage from chemotherapy for cancer and enhance the erythropoiesis in bone marrow |
| TWI484967B (en) * | 2011-10-11 | 2015-05-21 | New Bellus Entpr Co Ltd | Pharmaceutical composition for assisting anti-cancer drugs |
| CN103251658B (en) * | 2012-02-21 | 2015-11-25 | 乔本生医股份有限公司 | Antrodia Camphorata extraction concentrate and manufacture method thereof |
-
2015
- 2015-08-27 TW TW104128214A patent/TWI586359B/en not_active IP Right Cessation
-
2016
- 2016-08-23 SG SG10201607009SA patent/SG10201607009SA/en unknown
- 2016-08-23 PH PH12016000298A patent/PH12016000298A1/en unknown
- 2016-08-26 CN CN201610737664.5A patent/CN106474163B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102000047A (en) * | 2009-09-02 | 2011-04-06 | 国鼎生物科技股份有限公司 | Antrodia camphorata cyclonene compound for restraining growth of bone cancer cells |
| CN102764520A (en) * | 2011-05-04 | 2012-11-07 | 财团法人工业技术研究院 | High-pressure extraction equipment and extraction method thereof |
| CN103861099A (en) * | 2012-12-11 | 2014-06-18 | 财团法人工业技术研究院 | Vaccine adjuvant, vaccine composition and application of Antrodia camphorata fruiting body |
| CN104306410A (en) * | 2014-09-29 | 2015-01-28 | 深圳市仁泰生物科技有限公司 | Triterpene-enriched anti-tumor composition and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| PH12016000298A1 (en) | 2018-03-05 |
| SG10201607009SA (en) | 2017-03-30 |
| TW201707717A (en) | 2017-03-01 |
| TWI586359B (en) | 2017-06-11 |
| CN106474163A (en) | 2017-03-08 |
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