WO2019050522A1 - Extraits de magnolia, procédé de préparation de ceux-ci et utilisation associée - Google Patents

Extraits de magnolia, procédé de préparation de ceux-ci et utilisation associée Download PDF

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Publication number
WO2019050522A1
WO2019050522A1 PCT/US2017/050476 US2017050476W WO2019050522A1 WO 2019050522 A1 WO2019050522 A1 WO 2019050522A1 US 2017050476 W US2017050476 W US 2017050476W WO 2019050522 A1 WO2019050522 A1 WO 2019050522A1
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WIPO (PCT)
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subject
xin
administering
extract
need
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PCT/US2017/050476
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English (en)
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Shou Fang Wu
Yuh Shan Chung
Chao Tsen Lu
Yu Ting Wang
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Development Center For Biotechnology
Dcb-Usa Llc
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Priority to PCT/US2017/050476 priority Critical patent/WO2019050522A1/fr
Publication of WO2019050522A1 publication Critical patent/WO2019050522A1/fr

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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)
    • A61K36/57—Magnoliaceae (Magnolia family)
    • A61K36/575—Magnolia
    • 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

Definitions

  • the present invention relates to the preparation of an herbal extract of Magnolia, the extract prepared therefrom, and the use of the extract in the prevention or treatment of periodontitis.
  • Magnolia is a large genus of about 210 flowering plant species in the subfamily Magnolioideae of the family Magnoliaceae.
  • traditional Chinese herbal medicine the bark and flower buds of Magnolia are called “hou po” and the flower buds of Magnolia are called “xin yi.”
  • Magnolia has long been used in the fields of horticulture and traditional Chinese medicine (TCM).
  • TCM traditional Chinese medicine
  • Magnolia is reported to be effective for the treatment of rhinitis, pneumonia, bronchitis, etc. Its flowers, leaves and bark can be prepared into fragrant oils; and its branches and leaves can be distilled into essential oils.
  • Magnolia can be used for the treatment of runny nose, snuffles, allergic rhinitis, eye diseases, nasal affections, body fever and chills, headache, fever in children, respiratory tract infection in children, etc.
  • Magnolia extracts have been found to have an effect on aggregation/release of platelet and constriction of blood vessel, and thus Magnolia extracts may be a good candidate for treating cardiovascular diseases.
  • Some references also demonstrated in animal models that Magnolia has potential in the treatment of asthma and control of the transmission of neural signals sensitive to ovalbumin.
  • WO 2017/061781 Al discloses a pharmaceutical composition containing ⁇ Magnolia flower extract, a fraction thereof, or Magnolin or Fargesin as an active ingredient.
  • WO 2017/061781 Al describes that the Magnolia flower extract and the fraction thereof can be used to promote the growth of dental roots and periodontal tissues, and thus can be used to prevent and treat periodontitis.
  • Periodontitis is not only a main cause of tooth loss in adults older than 35, but also a factor that influences human health, such as affecting blood sugar control and increasing the incidence of heart disease, myocardial infarction, stroke, premature delivery in pregnant women, aspiration pneumonia, etc. Periodontitis is also one of the six complications of diabetes mellitus.
  • One aspect of the invention is to provide a method for the preparation of a xin yi active extract.
  • Another aspect of the invention is to provide a xin yi extract obtainable from the method of the invention.
  • Another aspect of the invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the xin yi extract of the invention and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is to provide a method for preventing or treating destruction and/or degeneration of alveolar bone of a subject in need thereof, comprising administering to the subject the extract or pharmaceutical composition of the invention.
  • Another aspect of the invention is to provide a method for preventing or treating periodontitis a subject in need thereof, comprising administering to the subject the extract or pharmaceutical composition of the invention.
  • Still another aspect of the invention is to provide the use of the extract or the pharmaceutical composition of the invention in the manufacture of a medicament for preventing or treating destruction and/or degeneration of alveolar bone.
  • a further aspect of the invention is to provide the use of the extract or the composition of the invention in the manufacture of a medicament for preventing or treating periodontitis.
  • Figure 1 is an experimental design of ligature-induced periodontitis model.
  • Figure 2A shows the results of tomography in Control group), Ligature group and Ligature + ML-E (10 %) group in ligature-induced periodontitis model.
  • Figure 2B shows the measured results of the distance between cemento-enamel junction CEJ and alveolar bone crest (ABC).
  • Figure 3A shows the CEJ and the ABC in the sliced specimens of the Control group.
  • Figure 3B shows the results of the sliced specimens of Control group, Ligature group and Ligature + ML-E (10 %) group in ligature-induced periodontitis model.
  • Figure 3C shows the measured results of the distance between CEJ and ABC of the sliced specimens.
  • Figures 4A to 4C show the effects of the xin yi extract ML-E determined by LPS- injection animal model.
  • Figures 5A to 5C show the effects of the xin yi active extract mixture of ML-AF determined by LPS-injection animal model.
  • Figure 6 shows the HPLC fingerprint of the xin yi extract (ML-AF) obtained from the macroporous resin chromatography.
  • ranges are expressed herein as from “about” one particular value and/or to "about” another particular value. When such a range is expressed, an embodiment includes the range from the one particular value and/or to the other 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 embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to and independently of the other endpoint. As used herein the term "about” refers to ⁇ 30%, preferably ⁇ 20%, more preferably ⁇ 10%, and even more preferable ⁇ 5%.
  • magnolia refers to any species of the Magnolia genus.
  • xin yi refers to the flower buds ofMagnolia, and preferably, the flower buds before blooming.
  • extract refers to all possible extracts that are obtained during the sample preparation process and comprise an active (lead) compound(s).
  • the extract may be in the form of a liquid, extractum spissum, solid or powder.
  • active extract refers to all possible extracts that show the desired bioactivity.
  • active extracts of the invention include, but are not limited to, crude extracts, column chromatographic fractions, High Performance Liquid Chromatography (HPLC)-purified fractions, etc.
  • organic solvent refers to a carbon-based liquid capable of dissolving another substance.
  • non-polar solvent refers to any organic solvents with a polarity index of not greater than about 2.0.
  • non-polar solvents include, but are not limited to, hexane, petroleum ether, carbon tetrachloride, and a mixture thereof.
  • polar solvent refers to any organic solvents with a polarity index of greater than about 2.0, and generally easily miscible with water.
  • moderately polar solvent include, but are not limited to, methanol, ethanol, acetonitrile, and a mixture thereof.
  • macroporous adsorbent resin refers to any polymer/copolymer adsorbent resin that can be an adsorbent to eliminate hydrophobic compounds, antibiotics, biomolecules, etc.
  • the term "elution solution” as used herein refers to the solution that is used to elute the extract from the column chromatography, ion exchange resin, etc.
  • the term “preventing” or “prophylaxis” refers to delaying the onset of symptoms of a susceptible subject, reducing the occurrence of a disorder or condition, or inhibiting the occurrence of the disorder or condition, or arresting the development of the disorder or condition.
  • peripheralodontitis refers to a set of inflammatory diseases affecting the periodontium, i.e., the tissues that surround and support the teeth.
  • inflammatory disease refers to lesions caused by a defensive reaction or an inflammatory reaction of a living body against the harmful influence of various circumstances (e.g. physical, chemical and biological circumstances).
  • the classical signs of inflammatory disease are pain, heat, redness, swelling, and loss of function.
  • treating refers to alleviating, relieving, reversing and/or improving a disorder or condition or one or more symptoms thereof, or stopping the symptoms of the disease or condition in a susceptible subject.
  • the term "subject” refers to animals, especially mammals. In one preferred embodiment, the term “subject” denotes "humans.”
  • the term "therapeutically effective amount” refers to the amount of an active ingredient used alone or in combination with other treatments/medicaments for preventing or treating periodontitis that shows therapeutic efficacy.
  • the term "pharmaceutically acceptable carrier” refers to solvents, diluents, binders, adhesives, adjuvants, excipients, acceptors, stabilizer, analogues, flavoring agents, sweetening agents, emulsifying agents or preservative agents, which are well known to persons of ordinary skill in the art, for manufacturing pharmaceutical or dietary compositions.
  • pharmaceutically acceptable carriers include, but are not limited to, water, saline, buffers, and inert, nontoxic solids.
  • administering refers to the methods that may be used to enable delivery of the composition or medicament of the present invention to the desired site of biological action. These methods include, but are not limited to, oral, intraduodenal, nasal, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or intradermal), topical and rectal administration.
  • Magnolia species include, but are not limited to, Magnolia biondii, Magnolia denudate, Magnolia sprengeri, Magnolia liliflor, Magnolia grandiflora, Magnolia guatemalensis, Magnolia iltisiana, Magnolia paciflca, Magnolia panamensis, Magnolia poasana, Magnolia zzieana, Magnolia sharpii, Magnolia sororum, Magnolia tamaulipana, Magnolia virginiana, Magnolia yoroconte, Magnolia albosericea, Magnolia championii, Magnolia coco, Magnolia delavayi, Magnolia fistulosa, Magnolia henryi, Magnolia nana, Magnolia odoratissima, Magnolia pterocarpa, Magnolia gigantifolia, Magnolia hodgsonii, Magnolia lasia, Magnolia liliifera, Magnolia mariusjacobsia, Magnolia persuaveolens, Magnolia sarawakensis, Magnolia villosa, Magnolia allenii, Magnolia amazonica, Magnolia arcabu
  • the Magnolia species may include
  • Magnolia biondii Magnolia denudate, Magnolia sprengeri, Magnolia liliflora and any of the combinations thereof.
  • the invention provides a method for extracting, isolating and purifying active extracts from the xin yi of Magnolia.
  • one aspect of this invention is to provide a method for the preparation of a xin yi extract, which comprises the steps of:
  • any conventional method for separation can be used, such as filtration, centrifugation, or the combination thereof.
  • the suspension can be filtrated through one or more filters, and the the filter can be a Grade 1 filter paper having pore size of 11 ⁇ , a Grade 2 filter paper having pore size of 8 ⁇ , a Grade 3 filter paper having pore size of 6 ⁇ , a Grade 4 filter paper having pore size of 20-25 ⁇ , a Grade 4 filter paper having pore size of 6 ⁇ , and/or a Grade 602 h filter paper having pore size of 2 ⁇ .
  • step (c) prior to step (c), the solid portion of step (b) is optionally subjected to repeat steps (a) and (b) for at least one more time.
  • the crude extract obtained from step (c) may be concentrated to a concentrated extract in the form of a liquid, extractum spissum, solid or powder by using any conventional concentration methods for solutions, such as vacuum concentration and rotary evaporation.
  • the macroporous adsorbent resin used can be Diaion ® HP- 10, Diaion ® HP-20, Diaion ® HP-30, Diaion ® HP-40, Diaion ® HP-50, Amberlite ® XAD-4, Amberlite ® XAD-6, Amberlite ® XAD-7, Amberlite ® XAD-16, Amberlite ® XAD- 1180, or Amberlite ® XAD-160.
  • the elution solutions used in the column chromatography may be two or more of those known in the art such as 9: 1 to 1 : 1 of ft-hexane/ethyl acetate, 95% alcohol.
  • the elution solutions used in the column chromatography may be two or more of those known in the art such as 60-95% of alcohol, 1 : 1 of alcohol/ethyl acetate.
  • the column is sequentially eluted with 3x- column volume of 60% ethanol, 5x-column volume of 70% alcohol and 4x-column volume of 95% alcohol /ethyl acetate (1 : 1); 3x-column volume of 60% ethanol, 4x-column volume of 80% alcohol and 4x-column volume of 95% alcohol /ethyl acetate (1 : 1); or 3x-column volume of 60% alcohol, 4x-column volume of 95% alcohol and 4x-column volume of 95% alcohol /ethyl acetate (1 : 1).
  • the present invention also provides xin yi extracts obtainable from the processes described herein.
  • the invention provides a composition comprising a therapeutically effective amount of a xin yi extract obtainable from the preparation method of the present invention and a pharmaceutically acceptable carrier.
  • the composition optionally comprises a conventional drug or agent useful in the prevention or treatment of periodontitis.
  • a conventional drug or agent useful in the prevention or treatment of periodontitis.
  • the normal dosages of these conventional drugs or agents are well known in the art.
  • These conventional drugs or agents include, but are not limited to, antibiotics (e.g.
  • Oral compositions generally include an inert diluent or an edible carrier. Oral compositions can be liquid, or can be enclosed in gelatin capsules or compressed into tablets. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of an oral composition.
  • Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and/or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.
  • composition can be administered to a patient orally or parenterally in the conventional forms of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups.
  • Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic carriers, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder),
  • the composition of the present invention can be in the form of a semi-solid or solid such as a toothpaste, a gel dentifrice, a dental powder, a denture cleansing tablet, a chewing gum, or a solid lozenge or the like.
  • the extract, crude extract and composition of the present invention can be used to prevent or treat destruction and/or degeneration of alveolar bone in a subject in need thereof. Therefore, the present invention provides a method for preventing or treating destruction and/or degeneration of alveolar bone in a subject in need thereof, which comprises administering to the subject the extract, crude extract and composition of the present invention.
  • the crude extract refers to the crude extract obtainable from step (d) of the method described above; and the extract refers to the xin yi extract obtainable from step (g) of the method described above.
  • the extract, crude extract and composition of the present invention can also be used to prevent or treat periodontitis in a subject in need thereof. Therefore, the present invention further provides a method for preventing or treating periodontitis in a subject in need thereof, which comprises administering to the subject the extract, crude extract and composition of the present invention.
  • a method for inhibiting oral bacteria in a subject in need thereof which comprises administering the extract, crude extract or composition to the oral cavity of the subject.
  • the oral bacteria include, but are not limited to,
  • Actinobacillus actinomycetemcomitans Porphyromonas gingivalis, Prevotella intermedia group species, Peptostreptococcus micros, Streptococcus constellatus , Streptococcus intermedius-anginosus, Campylobacter (Wolinella) rectus, Fusobacterium nucleatum, Tannerella (Bacteroides) forsythia, Enteric gram negative rods, Enterococcus faecalis and Candida species (yeast).
  • a method for preventing or treating oral inflammatory diseases in a subject in need thereof comprises administering to the oral cavity of the subject the extract, crude extract or composition to the subject.
  • the extract, crude extract and composition can be optionally administered in combination with a conventional drug or agent, which is useful in the prevention or treatment of inflammatory diseases.
  • a conventional drug or agent which is useful in the prevention or treatment of inflammatory diseases.
  • the normal dosages of these conventional drugs or agents are well known in the art.
  • These conventional drugs or agents include, but are not limited to, steroids or non-steroidal anti-inflammatory drug (NSAID).
  • NSAID include, but are not limited to, salicylates (e.g. aspirin, diflunisal, salicylic acid, salsalate), propionic acid derivatives (e.g.
  • ibuprofen dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen
  • acetic acid derivatives e.g. indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone
  • enolic acid derivatives e.g. piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone
  • anthranilic acid derivatives e.g. mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid
  • selective cox-2 inhibitors and sulfonanilides e.g. nimesulide
  • the invention further provides a method for inhibiting osteoclast differentiation in a subject in need thereof, which comprises administering the extract, crude extract or composition to a subject.
  • a conventional drug or agent used in the inhibition of osteoclast differentiation is co-administered.
  • the normal dosages of these conventional drugs or agents are well known in the art.
  • These conventional drugs or agents include but are not limited to antiresoptive agent (e.g.
  • RTKL nuclear factor kappa-B ligand
  • SERMs selective estrogen receptor modulator
  • clomifene ormeloxifene
  • raloxifene tamoxifen
  • toremifene lasofoxifene and ospemifene
  • anabolic agent e.g. teriparatide
  • strontium ranelate e.g. teriparatide
  • the invention further provides a method for inhibiting inflammation in a subj ect in need thereof, which comprises administering the extract, crude extract or composition to a subject.
  • Step 1 Establishment of Ligature-Induced Periodontitis Model
  • Periodontitis is a prevalent oral inflammatory disease that leads to alveolar bone loss and may exert an adverse impact on systemic health.
  • Ligature-induced periodontitis model has been used frequently in relatively large animals, including non-human primates, to assess the host response and its effects on the tooth-supporting tissues (gingiva and bone) under well-controlled conditions (see Toshiharu Abe and Georage Hajishengallis; J Immunol Methods. 2013 August 30; 394(0): 49-54).
  • CEJ cemento- enamelj unction
  • xin yi extract (ML-E) can decrease the destruction/degeneration of alveolar bone in ligature-induced periodontitis animal model.
  • the animals were randomized into 3 groups, i.e., Control group; Ligature group; and Ligature + ML-E (10 %) group
  • the tomography results reveal that the animals of ligature group showed severe bone matrix absorption, but the treatment of ML-E could significantly prevent destruction/degeneration of alveolar bone at the interdental site in the animals of group by the treatment with ML-E (10%).
  • Figs. 3Ato 3C The results of the sliced specimens from the animals are shown in Figs. 3Ato 3C.
  • Fig. 3A shows the normal distance between CEJ and ABC.
  • Figs. 3B and 3C the animals of liateure group experienced severe bone matrix absorption but the destruction/degeneration of alveolar bone at the interdental site of the animals was significantly inhibitted by the treatment of ML-E.
  • Step 1 About 15 L of macroporous resin DIAION ® HP20 was soaked in 95% ethanol ("soaked solution”) overnight. The resin was washed with ddFhO twice to remove ethanol and then soaked in 60% ethanol ("alcohol solution"). The resin was filled into a reverse phase chromatography column and washed by 45 L of 60% ethanol. The resin was packed tightly to ensure that there were no bubble in the column.
  • Step 2 504 g of ML-E were dissolved in 750 mL of ethanol and then added to DIAION® HP20 resin. The contents (including the extract and the resin) were drained by a concentrator to obtain a dry powder.
  • Step 3 The sample was poured into a column and eluted with 3x-column volume of 60% ethanol, 4x-column volume of 80% ethanol and 4x-column volume of 95% ethanol/ethyl acetate (1 : 1), until the color of the eluates remained unchanged.
  • Step 4 All the eluted fractions were examined by HPLC and the active fractions were collected in an 80% alcohol solution.
  • Step 5 The obtained alcohol solution was concentrated to obtain a xin yi active extract (ML-AF) with a yield of 4.07%.
  • Example 5 Anti-Inflammatory Activity and Osteocleastgenesis inhibition of ML-E and a Xin Yi Active Extract (ML-AF)
  • RAW 264.7 cells were seeded in a 96-well plate (3 ⁇ 10 4 cells/ well) in a basal medium. After incubating for 24 h, cells were treated with a lipopolysaccaride (LPS) (100 ng/mL) and an indicated concentration of xin yi extract according to a modification of the method disclosed in Molecules., 2010, 15, 7815-7824. The nitrite concentrations of the supernatants were determined by using a Griess reagent kit after 24 h. Cell proliferation was evaluated by a cell growth inhibitory assay using MTS reagent.
  • LPS lipopolysaccaride
  • RAW 264.7 cell were seeded in a 96-well plate (10 3 cells/ well) in a basal medium. After incubating for 24 h, the medium was replaced with a differentiation medium containing 50 ng/mL RANKL and an indicated concentration of xin yi extract. After 4 days, the cellular enzymatic activity of tartrate-resistant acid phosphatase (TRAP), a marker enzyme of osteoclasts, was measured according to a modification of the method disclosed in Joumal of Biological Chemistry, 2004, 279, 13984-13992. Briefly, the medium was removed and the cells was gently washed twice with PBS.
  • TRIP tartrate-resistant acid phosphatase
  • the cells were fixed in 10% formalin for 10 min and washed in 95% ethanol, and then incubated in 0.1 mL of phosphatase substrate (3.7 mM p- nitrophenyl phosphate in 50 mM citrate buffer pH4.6) in the presence of 10 mM sodium tartrate at 25°C for 30 min. After incubation, the reaction mixtures were transferred to a new well plate containing an equal volume of 0.1 N NaOH and the absorbance of each well was measured at 405 nm using Bio-Rad Model 680 microplate reader.
  • phosphatase substrate 3.7 mM p- nitrophenyl phosphate in 50 mM citrate buffer pH4.6
  • Example 6 Effects of Xin Yi Extract (ML-E) and Xin Yi Active Extract Mixture of ML- AF Determined by LPS-injection Animal Model
  • ML-E and xin yi active extract mixture were respectively applied to the affected area of each rat on Day 1 to Day 8, and 5 mg/mL LPS were injected into the right jaw site (10 ⁇ / ⁇ ) of the rats on Day 2 to Day 4. The rats were sacrificed on Day 8 and the numbers of osteoclasts were counted by histochemical staining. [0085] The results are shown in Figures 4A to 4C and 5A to 5C. Data are mean ⁇ SD of 4-5 rats per group and statistically analyzed by Student's t-test. In summary, LPS significantly induced osteoclast differentiation and eroded alveolar bone surface in Group 2. However, administration of ML-E (10 %) as well as ML-AF (10 %) effectively reduced osteoclast differentiation and reduced the erosion of alveolar bone surface.
  • HPLC was used to analyze the components in the xin yi active extract mixture (ML-AF).
  • the parameters used for HPLC are listed in Table 3 below.

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Abstract

La présente invention concerne des extraits de xin yi (magnolia) et un procédé de préparation de ceux-ci. L'invention concerne également le traitement de la parodontite à l'aide des extraits de xin yi.
PCT/US2017/050476 2017-09-07 2017-09-07 Extraits de magnolia, procédé de préparation de ceux-ci et utilisation associée WO2019050522A1 (fr)

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CN117598204A (zh) * 2024-01-24 2024-02-27 西南林业大学 云南含笑组培快繁方法及应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117598204A (zh) * 2024-01-24 2024-02-27 西南林业大学 云南含笑组培快繁方法及应用
CN117598204B (zh) * 2024-01-24 2024-03-22 西南林业大学 云南含笑组培快繁方法及应用

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