CN112656844A - Medicine for preventing and treating osteoporosis - Google Patents
Medicine for preventing and treating osteoporosis Download PDFInfo
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- CN112656844A CN112656844A CN202011475594.3A CN202011475594A CN112656844A CN 112656844 A CN112656844 A CN 112656844A CN 202011475594 A CN202011475594 A CN 202011475594A CN 112656844 A CN112656844 A CN 112656844A
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Abstract
The invention discloses a medicine for preventing and treating osteoporosis, and belongs to the technical field of natural medicines. According to the application, the kava-kava lactone can inhibit osteoclast proliferation in vitro, increase the bone density of osteoporosis rats in vivo and improve the bone tissue morphology, and the discovery that the kava-kava lactone can effectively prevent and treat the occurrence and development of osteoporosis in vivo and in vitro proves a new application of the kava-kava lactone, and provides a foundation for natural drug treatment of osteoporosis.
Description
Technical Field
The invention belongs to the technical field of natural medicines, and particularly relates to a medicine for preventing and treating osteoporosis.
Background
Osteoporosis is a metabolic bone disease characterized by decreased bone mass and destruction of bone microarchitecture, resulting in decreased bone strength, increased fragility, and susceptibility to fracture. With the aging population, osteoporosis has become one of the elderly diseases of worldwide concern. It has been found that about half of white postmenopausal women experience osteoporosis. China is the most old people in the world, and the incidence rate of the disease gradually rises, so that the physiological and psychological health of patients is influenced, and the life quality is greatly reduced. Osteoporosis belongs to degenerative diseases, and no specific medicine exists at present. The existing anti-osteoporosis drugs on the market can be roughly divided into three main categories: bone resorption inhibitors, bone mineralizers and bone formation promoters. Because the chemical drugs for treating osteoporosis are usually combined and have large toxic and side effects, finding the extract which has small side effects and can prevent and treat osteoporosis diseases from natural plants becomes a research hotspot.
Piper methysticum Forst f, commonly known as Kava or K awa, is a perennial Piperaceae (Piperaceae) Piper shrub plant wild in the islands of the Nanpacific ocean, such as Vanuatu, Fiji, Thangka, and Solomon. The root, stem and fresh leaf of kava pepper has good medicinal value, has the functions of sedation and hypnosis, antibiosis and disinsection, antispasmodic, local anesthesia and the like, can treat convulsion, asthma, anxiety and depression, has obvious curative effect on promoting sleep and improving sleep quality, and has small toxic and side effect. Piper methysticum is one of the best-selling Chinese herbal medicines in the world. The main component of Piper methysticum is alpha-Pyrone (alpha-Pyrone) compound called Kavalactone. Due to the different harvesting age and cultivar, kavalactones are present in kava root in varying amounts, 3-20%, and 25-70% of the total extract, the 6 most important lactones being kavain, dihydrokavain, kavain, yangonin, methysticin, dihydromethysticin, and desmethoxykavain. At present, researches on kava and lactone components thereof mostly concentrate on aspects of sedation hypnosis, depression treatment and the like, and no research report and patent application on the application of the kava and the lactone components thereof in preventing and treating osteoporosis are found.
Therefore, how to provide a novel medicament for preventing and treating osteoporosis is a problem to be solved urgently in the field.
Disclosure of Invention
The invention discloses a medicine for preventing and treating osteoporosis.
In order to achieve the purpose, the invention adopts the following technical scheme:
a medicine for preventing and treating osteoporosis comprises: lactone of kava;
preferably, the kava lactone comprises at least: at least one of dihydromethysticin, dihydrokawain, kawain B, kawain A, kawain C, methysticin, kawain, desmethoxykawain and kawain, wherein the sum of the mass of the components is more than 50% of the total mass of kavalactones;
preferably, the kava lactone comprises at least: kavain, dihydrokavain, methysticin, dihydromethysticin and demethoxykavain, and the sum of the 6 components is more than 50% of the total mass of kava-kava lactone;
preferably, the detection method of the kavalactones is a high performance liquid chromatography;
the application of the medicine for treating osteoporosis in preparing bone resorption inhibitors;
the application of the medicine for treating osteoporosis in preparing a bone formation promoter;
a preparation method of kava-kava lactone comprises the following steps:
s1 extraction: drying Piper methysticum Forst, pulverizing, adding 10 times of 80% ethanol, reflux extracting for 3 hr, extracting for 3 times, heat filtering, and drying the filtrate to obtain Piper methysticum Forst extract;
s2 purification: according to the weight ratio of the macroporous resin to the raw medicinal materials of 1: 1, adding the kava-kava extract obtained in the step S1 into macroporous adsorption resin for elution, eluting with 10 times of column volume of water until the kava-kava extract is nearly colorless, sequentially eluting with 20% ethanol, 30% ethanol, 50% ethanol and 70% ethanol, collecting the 30-70% ethanol elution part, concentrating under reduced pressure, and drying to obtain kava-kava lactone;
preferably, the Piper methysticum Piper is root and rhizome of Piper methysticum Forst f of Piperaceae, Piper, and the Piper methysticum Forst f, and the Piper methysticum lactone component is α -Pyrone (α -Pyrone) compound of Piper methysticum Piper, including dihydromethysticin, dihydrokawain, Piper methysticin B (flavokavain B), Piper methysticin A (flavokavain A), Piper methysticin C (flavokavain C), Piper methysticin, Piper:
in conclusion, the invention discloses a medicament for preventing and treating osteoporosis. In the research process of the kava, a sufficient amount of kava-kava lactone extract is prepared from the kava, and the determination of the in vitro osteoclast proliferation rate and the determination of the in vivo bone density and bone tissue morphology of the rat with osteoporosis proves that the kava-kava lactone extract has a new application of preventing and treating osteoporosis, and provides a basis for the prevention and treatment of natural medicines for osteoporosis.
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FIG. 1 shows that kava-kava lactone inhibits osteoclast proliferation in vitro; the ordinate is the proliferative activity of osteoclasts; the abscissa, from left to right, is: blank control, 1mg/mL piperonolide, 0.1mg/mL piperonolide, 0.01mg/mL piperonolide, 0.001mg/mL piperonolide, and 0.0001 mg/mL piperonolide;
FIG. 2 shows that kava-kava lactone inhibits osteoclast TRAP enzyme action in vitro; the ordinate is the TRA P enzyme activity of osteoclasts; the abscissa, from left to right, is: blank control, 1mg/mL piperonolide, 0.1mg/mL piperonolide, 0.01mg/mL piperonolide, 0.001mg/mL piperonolide, and 0.0001 mg/mL piperonolide;
FIG. 3 shows that kava-kava lactone acts to increase bone density in osteoporotic rats; the ordinate is the bone density value, and the abscissa, from left to right, is: a sham operation group, a model group, a positive drug group (estradiol valerate 1mg/kg/d) and a kavalactone group (60 mg/kg/d).
FIG. 4 shows the effect of kava-kava lactone in improving the bone morphology of osteoporosis rats; the operation group, the model group, the positive drug group (estradiol valerate 1mg/kg/d) and the kavalactone group (60mg/k g/d) are arranged from the top left to the bottom right in sequence.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Reagents and instruments and materials RAW264.7 cell line (Biotech, Inc., Johan boat, Shanghai); kavalactone (YL-20180519) was purchased from KANGLU Biotech limited; M-CSF and RANKL antibodies were purchased from Perro Tech, USA; DMEM medium and FBS fetal bovine serum were purchased from Hyclone corporation; cyan/streptomycin double antibody, MTT, was purchased from Gibco, usa; dimethyl sulfoxide (DMSO, tianjin mao chemical reagent factory); corning96 well plate microplate reader (seimer feishell science ltd); analytical balance (A L104, METTLER TOLEDO, Metler-Tollido instruments Shanghai Co., Ltd.); desktop high speed refrigerated centrifuges (model 1-15K, shanghai' an kiosk instrument factory); ultra-low temperature refrigerators (Forma-86C ULT Freezer, B io-Rad Co.); CO2 cell culture incubator (Saimer Feishell science Co., Ltd.).
Preparing kava-kava lactone:
s1 preparation of kava extract: 1kg of kava, drying and crushing the kava, adding 8 times of 80% ethanol, and carrying out reflux extraction for 3 hours for 3 times; hot filtering, mixing filtrates, concentrating under reduced pressure to obtain fluid extract without alcohol smell to obtain Piper methysticum Forst extract;
s2 preparation of kava-kava lactone: adding the kava extract obtained in the step S1 to a pretreated macroporous adsorption resin, wherein the weight ratio of the macroporous adsorption resin to the raw medicinal materials is 1: 1; eluting with 10 times of water until it is colorless, sequentially eluting with 20% ethanol, 30% ethanol, 50% ethanol, and 70% ethanol, collecting 30-70% ethanol eluate, concentrating, and drying under reduced pressure to obtain kava-kava lactone.
The sum of the content of dihydromethysticin, dihydrokavain, kavain B, kavain A, kavain C, methysticin, kavain, desmethoxykavain and kavain in kava-lactone was 56.2% as determined by HPLC.
Example 1: in vitro cell assay
Preparing kava-kava lactone: taking a proper amount of the kava-kava lactone obtained above, precisely weighing 123.90 mg, placing in a centrifuge tube, adding 1.239ml DMSO, completely dissolving to obtain a stock solution with an initial concentration of 100mg/ml, and diluting with DMEM to obtain kava-kava lactone test drugs with concentrations of 1mg/ml, 0.1mg/ml, 0.01mg/ml and 0.001mg/ml for later use;
preparation of MTT solution: taking MTT powder, precisely weighing about 50mg, placing the MTT powder in a 10mL centrifuge tube, adding 10mL of PBS buffer solution, shaking to dissolve the MTT powder to the maximum extent, filtering and sterilizing the MTT powder by a 0.22-micron microporous filter membrane, and storing the MTT powder at the temperature of-4 ℃ for later use.
Preparation of TRAP Activity measurement reaction solution: 0.4g of p-nitrophenyl disodium phosphate is dissolved by deionized water, 2.0g of potassium sodium tartrate is added, water is added to dissolve the mixture to 150ml, HCL is used for adjusting the pH value to 3.5, and water is added to fix the volume to 200 ml for later use.
The establishment of an osteoclast model: placing RAW264.7 cells into a culture flask, culturing under the condition of DMEM culture medium, 10% FBS and 1% double antibody, and changing the solution every 2-3 days; to be RAW264.7 cell bornAfter long stabilization, the cell concentration was adjusted to 2X 103And/ml, inoculated into a 96-well plate, cultured for 6 days in a DMEM medium supplemented with M-CSF (30ng/ml), RANKL (25ng/ml), and changed 1 time every 3 days, after 6 days, osteoclasts differentiated and matured.
Determination of osteoclast proliferation rate: and (3) replacing the culture medium with reagent culture media with the kava-kava lactone concentration of 1mg/ml, 0.1mg/ml, 0.01mg/ml and 0.001mg/ml, repeating each test for 3 times, culturing for 48 hours, adding 20 mu L of MTT solution into each hole 4 hours before detection, putting the MTT solution into an incubator for continuous incubation for 4 hours, taking out the culture plate, discarding the supernatant, adding 150 mu LD MSO into each hole, shaking for 5-10 minutes to completely dissolve the formed formazan particles, and detecting the OD value at 570nm by using an enzyme labeling instrument.
Determination of TRAP activity: taking the differentiated and matured osteoclast, replacing the culture medium with a test drug culture medium with kava lactone concentration of 1mg/ml, 0.1mg/ml, 0.01mg/ml and 0.001mg/ml, repeating each test for 3 times, culturing for 48h, removing supernatant, washing with PBS, breaking cells with 20ul cell lysate (RIPA) at room temperature for 15min, adding 100ul TRAP activity determination reaction solution, reacting at 37 ℃ for 30min, rapidly adding 100ul NaOH of 1mol/L to terminate the reaction, determining the OD value at the position of 40nm wavelength, and calculating the activity of TR AP.
Data processing: in the determination of osteoclast proliferation and TRAP enzyme activity, each concentration of all drugs is provided with 6 multiple wells, all experimental data are statistically analyzed by SPSS 23.0 software, the measurement data are expressed by (x +/-s), and the comparison between groups is carried out by pairwise comparison by adopting One-way ANOVA and LSD-t methods; p <0.05 was considered statistically significant and the results are shown in figures 1 and 2.
Example 2: in vivo animal testing
(1) Experimental animals: SD female rats of 3 months of age, with a weight of 280 + -20 g, from the laboratory animal center of Ningxia medical university;
(2) positive control drug: estradiol valerate tablets (bujiale), DELPHARM lilles s.a.s. bayer pharmaceutical health ltd, guangzhou division;
(3) medicine preparation: kava lactone prepared by the above method;
(4) the experimental method comprises the following steps: SD female rats were 40 and randomly divided into 4 groups of 10 rats each, i.e.: a sham operation group, a model group, a positive medicine group (estradiol valerate 1mg/kg/d) and a kavalactone group (60mg/k g/d); rats were anesthetized with an intraperitoneal injection of 0.5mL/kg of chloral hydrate at a concentration of 8% and then had bilateral incisions on the back, and 4 groups except the sham group, in which only the back was incised but the ovaries were not extirpated, were extirpated under aseptic conditions as osteoporosis model rats. Dissolving the medicine in normal saline according to the administration dosage, feeding the medicine (10mL/kg), continuously feeding the medicine for 3 months, and feeding the pseudo-operation group and the model group with the same volume of normal saline;
(5) determination of bone Density
After the rats died, the left femurs were quickly removed, the total bone density (t-BMD) of the left femurs was measured using a dual energy X-ray bone densitometer, and single-factor analysis of variance was performed using the sps software for statistical analysis. Significant differences between total bone density of rats in each group and total bone density of the control group were expressed as p <0.05 and p < 0.01. The results of the total bone density measurements for each group of rats are shown in FIG. 3. As can be seen from fig. 3, each administration group significantly increased total bone density (/ p <0.05,/p <0.01) compared to the model control group.
(6) Bone tissue morphometry
Taking the left femur of the rat with the bone density being measured, removing muscles and soft tissues, vertically cutting the proximal tuberosity of the femur along the femur at a position of about 1cm by using a cutting machine, scanning in a micro-CT, and reconstructing a three-dimensional image of each sample by using Mic view three-dimensional reconstruction processing software; carrying out data analysis processing by ABA special skeleton analysis software; a sham operation group, a model group, a positive drug group (estradiol valerate 1mg/kg/d) and a kavalactone group (60 mg/kg/d); the results of bone histomorphometry in rats of each group are shown in FIG. 4. The results in fig. 4 show that the selected areas of the trabecular bone of the rats in the sham operation group are denser, the number of the trabecular bone is greater, the selected areas of the trabecular bone of the model group are looser, hollow zones appear, the number of the trabecular bone is obviously reduced, and the gaps are obviously increased; compared with a model group rat (OVX), the bone tissue morphology of rats of a positive control group and a kavalactone group (60mg/kg/d) is obviously improved greatly, the filling volume of a selected area of trabecular bone is obviously increased, the number of the trabecular bone is obviously increased, and the connection is tight.
In conclusion, the results show that the kava-kava lactone has certain inhibition effect on the growth of osteoclasts in vitro in the concentration range of 0.001mg/ml-1mg/ml, and can obviously inhibit the activity of osteoclast TRAP enzyme. Piperaceae kava lactone can remarkably inhibit the proliferation of osteoclast and the activity of related enzyme, thereby inhibiting bone resorption, and further inhibiting the formation and development of osteoporosis. Meanwhile, the kava-kava lactone in vivo has certain improvement on the bone density of the osteoporosis rat at the dosage of 60mg/kg/d, and can obviously improve the bone tissue morphology of the osteoporosis rat, thereby promoting the formation of bones and preventing the formation of osteoporosis. The results of the in vitro osteoclast and in vivo osteoporosis rat tests show that kava lactone is effective in preventing and treating osteoporosis.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to the above-described embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (7)
1. A medicine for preventing and treating osteoporosis is characterized by comprising kava-kava lactone.
2. The agent for preventing and treating osteoporosis of claim 1, wherein kavalactones comprise at least: one of dihydromethysticin, dihydrokawain, kawain B, kawain A, kawain C, methysticin, kawain, desmethoxykawain and kawain, and the sum of the mass of the components is more than 50% of the total mass of kavalactone.
3. The drug of claim 1, wherein the kava-kava lactone comprises at least: kavain, dihydrokavain, methysticin, dihydromethysticin and desmethoxykavain, and the sum of the 6 components is more than 50% of the total mass of kava-kava lactone.
4. The drug for preventing and treating osteoporosis as claimed in claim 2 or 3, wherein the kavalactone detection method is high performance liquid chromatography.
5. Use of the medicament for preventing and treating osteoporosis of claims 1 to 3 for the preparation of a bone resorption inhibitor.
6. Use of the agent for the prevention and treatment of osteoporosis of claims 1 to 3 in the preparation of an agent for promoting bone formation.
7. A process for the preparation of kava lactone according to any one of claims 1 to 3, comprising the steps of:
s1 extraction: drying Piper methysticum Forst, pulverizing, adding 10 times of 80% ethanol, reflux extracting for 3 hr, extracting for 3 times, heat filtering, and drying the filtrate to obtain Piper methysticum Forst extract;
s2 purification: according to the weight ratio of the macroporous resin to the raw medicinal materials of 1: 1, adding the kava-kava extract obtained in the step S1 into macroporous adsorption resin for elution, eluting with 10 times of column volume of water until the kava-kava extract is nearly colorless, sequentially eluting with 20% ethanol, 30% ethanol, 50% ethanol and 70% ethanol, collecting the 30-70% ethanol elution part, concentrating and drying to obtain kava-kava lactone.
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| CN102626447A (en) * | 2012-04-19 | 2012-08-08 | 南京泽朗医药科技有限公司 | Preparation method of kava lactone |
| CN104230867A (en) * | 2014-09-04 | 2014-12-24 | 南京标科生物科技有限公司 | Method for extracting kawain from piper methysticum |
| JP2018123111A (en) * | 2017-02-03 | 2018-08-09 | 一般財団法人日本食品分析センター | Bone metabolism improver |
| CN108685904A (en) * | 2018-05-09 | 2018-10-23 | 广西医科大学 | Application of the kawain in terms of preparing treatment medicine for treating osteoporosis |
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2020
- 2020-12-14 CN CN202011475594.3A patent/CN112656844A/en active Pending
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| CN1870955A (en) * | 2001-05-11 | 2006-11-29 | 卡瓦制药公司 | Kavalactone compositions and methods of use |
| WO2003031597A2 (en) * | 2001-10-12 | 2003-04-17 | Kava Pharmaceuticals, Inc. | Methods of inhibiting osteoclast activity |
| US20030229137A1 (en) * | 2001-10-12 | 2003-12-11 | Shoujun Chen | Methods of inhibiting osteoclast activity |
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| CN104230867A (en) * | 2014-09-04 | 2014-12-24 | 南京标科生物科技有限公司 | Method for extracting kawain from piper methysticum |
| JP2018123111A (en) * | 2017-02-03 | 2018-08-09 | 一般財団法人日本食品分析センター | Bone metabolism improver |
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