CN112920147A - Sesquiterpenoids, preparation method thereof and application thereof in preparing antitumor drugs - Google Patents
Sesquiterpenoids, preparation method thereof and application thereof in preparing antitumor drugs Download PDFInfo
- Publication number
- CN112920147A CN112920147A CN202110125383.5A CN202110125383A CN112920147A CN 112920147 A CN112920147 A CN 112920147A CN 202110125383 A CN202110125383 A CN 202110125383A CN 112920147 A CN112920147 A CN 112920147A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- platinum
- sesquiterpene
- drugs
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a sesquiterpene compound, which comprises one of the following compounds:
it has high efficiency and low toxicity, has effects of enhancing sensitivity of platinum chemotherapy drugs and reversing drug resistance of tumor cells, and can be used for preparing antitumor drugs and/or tumor drug resistance reversal agent drugs. The invention also provides a drug combination and a drug preparation, wherein the active ingredients of the drug combination and the drug preparation comprise sesquiterpene compounds and platinum compounds, and the combination of the sesquiterpene compounds and the platinum compounds can generate a synergistic effect.
Description
Technical Field
The invention relates to the field of medicines, in particular to a sesquiterpene compound and a preparation method and application thereof.
Background
Cancer has now become one of the leading diseases threatening human health, and data shows a trend towards an annual increase in both cancer incidence and mortality, especially in developing countries, including china, where the population of the patient is growing faster. Platinum chemotherapeutic drugs (cisplatin, carboplatin and oxaliplatin) are commonly used antitumor drugs in clinic at present, and the main target of the effect is DNA. Platinum drugs enter cells, combine with DNA in tumor cells to form Pt-DNA adducts, resulting in DNA structural changes, DNA replication, transcriptional failure, and ultimately tumor cell death. However, with the widespread use of chemotherapeutic drugs, more and more patients develop resistance, resulting in failure of clinical chemotherapy. The platinum drug resistance mechanism mainly comprises: enhanced DNA repair, increased drug detoxification, reduced drug uptake accumulation, increased tolerance of the body to platinum-DNA complexes, and the like, involving a variety of genes, proteins, and signal transduction pathways. The generation of drug resistance seriously restricts the clinical use and development of platinum drugs, so that the finding of compounds with the effect of reversing the drug resistance of the platinum drugs has extremely important significance.
Sesquiterpene compounds are characteristic components of plants of inula of Compositae, and mainly comprise eudesmane type, germacrane type and guaiane type. Research shows that the sesquiterpenoids have various biological activities of anti-inflammation, antibiosis, anti-tumor and the like, and are important sources of natural medicine biological active ingredients. The elecampane inula root is a plant of inula and is rich in sesquiterpene compounds. Therefore, the development of sesquiterpene compounds with pharmaceutical application is significant.
Disclosure of Invention
The present invention aims to solve, at least to some extent, one of the technical problems of the prior art, whereby, in a first aspect of the invention, the invention provides a sesquiterpene compound comprising the following compounds:
in a second aspect of the invention, the invention provides a use of the sesquiterpene compound in preparation of an antitumor drug.
In a third aspect of the invention, the invention provides an application of the sesquiterpene compound in preparation of a tumor drug resistance reversal agent drug.
In a fourth aspect of the present invention, the present invention provides a pharmaceutical combination comprising as active ingredients:
the above sesquiterpene compound and
a platinum compound;
the active ingredients are formulated together or separately for compatible, simultaneous or separate use.
In the technical scheme of the invention, the molar ratio of the sesquiterpene compound to the platinum compound is 200: 1-1: 100.
Preferably, the pharmaceutical combination is in the form of a single dose unit, and the pharmaceutical combination is a pharmaceutical composition comprising the sesquiterpene compound and the platinum compound as active ingredients.
In the technical scheme of the invention, the platinum compounds comprise cisplatin, carboplatin and oxaliplatin.
In a fifth aspect of the invention, the invention provides a pharmaceutical formulation prepared from the active ingredients of the above pharmaceutical combination and a pharmaceutically acceptable diluent, carrier, excipient, adjuvant or vehicle.
In the technical scheme of the invention, the dosage form of the pharmaceutical preparation is selected from one of granules, tablets, pills, capsules and injections.
In a sixth aspect of the invention, the invention provides the use of the above-mentioned pharmaceutical combination and/or the above-mentioned pharmaceutical preparation in the preparation of an anti-tumor medicament.
In the technical scheme of the invention, the tumor is selected from one or more of ovarian cancer, uterine cancer, lung cancer, breast cancer, gastric cancer, liver cancer, colorectal cancer, skin cancer, kidney cancer and esophagus cancer.
In a seventh aspect of the present invention, the present invention provides the above sesquiterpene compound isolated from the root of elecampane inula root.
The inventor separates a series of sesquiterpene compounds from the root of elecampane Inula L, finds that some sesquiterpene compounds have the effects of enhancing the sensitivity of platinum chemotherapeutic drugs and reversing the drug resistance of tumor cells, and has the advantages of high efficiency and low toxicity when being used as a tumor drug resistance reversing agent.
The invention has the beneficial effects that:
1. the invention provides a sesquiterpene compound which is efficient and low in toxicity, has the effects of enhancing the sensitivity of platinum chemotherapeutic drugs and reversing the drug resistance of tumor cells, and can be used for preparing antitumor drugs and/or tumor drug resistance reversing agent drugs.
2. The invention provides a drug combination, the active ingredients of the drug combination comprise a sesquiterpene compound and a platinum compound, the sesquiterpene compound and the platinum compound can be used for preparing anti-tumor drugs and/or tumor drug resistance reversal agent drugs, and the sesquiterpene compound and the platinum compound can produce synergistic effect.
3. The invention provides a pharmaceutical preparation, the active ingredients of which comprise sesquiterpene compounds and platinum compounds, and the pharmaceutical preparation can be used for preparing antitumor drugs and/or tumor drug resistance reversal agent drugs.
Drawings
FIG. 1 is a graph of the results of the effect of different treatment groups on SKOV-3 nuclei;
wherein, the first row of pictures are sequentially blank group, cisplatin (30 mu M) processing group and cisplatin (45 mu M) processing group result graphs from left to right; the second row of pictures shows the results of the compound (10. mu.M) treatment group of formula 1, the compound (10. mu.M) + cisplatin (30. mu.M) treatment group of formula 1, and the compound (10. mu.M) + cisplatin (45. mu.M) treatment group of formula 1, in that order from left to right; the third panel shows the results of the compound (10. mu.M) treatment group of formula 2, the compound (10. mu.M) + cisplatin (30. mu.M) treatment group of formula 2, and the compound (10. mu.M) + cisplatin (45. mu.M) treatment group of formula 2, in this order from left to right.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The following examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer, by using conventional methods known in the art without specific descriptions, and by using consumables and reagents which were commercially available without specific descriptions. Unless otherwise defined, technical and scientific terms used herein have the same meaning as is familiar to those skilled in the art. In addition, any methods or materials similar or equivalent to those described herein can also be used in the present invention.
Example 1
This example provides a sesquiterpene compound comprising the following compounds:
the preparation method of the compound shown in the formula 1-5 is as follows:
pulverizing radix Inulae, extracting with methanol for 3 times, recovering methanol, and extracting the obtained extract with petroleum ether, dichloromethane and ethyl acetate to obtain solvent extract. The dichloromethane extracted fractions were separated by silica gel chromatography, TLC detection, and the same fractions were combined to give 8 fractions, fraction 5 was separated by gel chromatography to give 2 fractions, fraction 1 was separated by silica gel chromatography (petroleum ether: ethyl acetate: 3: 1) to give the compound of formula 2, fraction 6 was separated by gel chromatography to give 2 fractions, and fraction 2 was separated by reverse phase chromatography (60% to 100% methanol) to give the compound of formula 5. The petroleum ether extraction fractions were separated by silica gel separation and TLC detection, and the same fractions were combined to give 5 fractions in total, fraction 2 was separated by gel chromatography to give 2 fractions, fraction 1 was separated by silica gel column chromatography (petroleum ether: ethyl acetate: 8: 1) to give the compound represented by formula 1, and fraction 2 was separated by silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1) to give the compound represented by formula 3 and the compound represented by formula 4. The compound of formula 1 is novel and its NMR data are shown in Table 1.
Table 1.1H(400MHz)NMR[δ,mult(J in Hz)]and 13C NMR(100MHz)Spectroscopic Data for Compound 1 in CDCl3.
Example 2
The compound shown in the formulas 1-5 has synergistic and sensitization effect on ovarian cancer cells (SKOV-3): in this example, SKOV-3 cells in logarithmic phase were treated with each of the five compounds represented by formulas 1 to 5 in combination with cisplatin for 24 hours, the medium was replaced, 20ul MTT solution (5mg/ml) was added to each well, the culture was continued for 4 hours, the supernatant was removed, 100 μ L DMS0 was added to each well, OD was measured at 570nm with a microplate reader, the inhibition ratio was calculated, and the Combined Index (CI) of the compounds represented by formulas 1 to 5 and cisplatin was calculated by quantitative analysis using CompuSyn software, and the results are shown in table 2. CI <1 is additive and CI <1 is synergistic; CI >1 is antagonistic action, and as can be seen from table 2, the compounds shown in formulas 1-5 and cisplatin are combined to have synergistic action.
TABLE 2 Combined Index (CI) of the compounds of formulae 1 to 5 with cisplatin
Example 3
The compound of formula 1 and the compound of formula 2 are combined with cisplatin to promote SKOV-3 apoptosis: the specific process is as follows: the influence of the compound shown in the formula 1 and the compound shown in the formula 2 on SKOV-3 cell nucleus after being combined with cisplatin is observed under a fluorescence microscope by adopting a Hoechst 33258 staining method, and after the medicine acts for 24 hours, the cell nucleus is treated and photographed. The results are shown in FIG. 1, wherein the first row of pictures are the results of the blank group, the cisplatin (30 μ M) treatment group and the cisplatin (45 μ M) treatment group from left to right; the second row of pictures shows the results of the group treated with the compound of formula 1 (10. mu.M), the group treated with the compound of formula 1 (10. mu.M) + cisplatin (30. mu.M), and the group treated with the compound of formula 1 (10. mu.M) + cisplatin (45. mu.M), in that order from left to right; the third panel shows the results of the compound (10. mu.M) treatment group of formula 2, the compound (10. mu.M) + cisplatin (30. mu.M) treatment group of formula 2, and the compound (10. mu.M) + cisplatin (45. mu.M) treatment group of formula 2, in this order from left to right. From the results, it was found that the morphology of nuclei was not significantly changed in the group treated with the compound represented by formula 1 (10. mu. M), the compound represented by formula 2 (10. mu. M), cisplatin (30. mu.M) or cisplatin (45. mu.M) alone. In contrast, the cells treated by the compound shown in the formula 1 + cisplatin and the compound shown in the formula 2 + cisplatin combined treatment group have more obvious cell fragmentation, chromosome condensation and apoptotic body generation. Therefore, the combination of the compound shown in the formula 1 and the compound shown in the formula 2 and cisplatin promotes SKOV-3 apoptosis.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A sesquiterpene compound comprising the following compounds:
2. the use of sesquiterpenes of claim 1 in the preparation of antineoplastic drugs.
3. The use of sesquiterpenes of claim 1 in the preparation of drugs for reversing drug resistance of tumors.
4. A pharmaceutical combination comprising as active ingredients:
the sesquiterpene compound of claim 1 and
a platinum compound;
the active ingredients are formulated together or separately for compatible, simultaneous or separate use.
5. The pharmaceutical combination according to claim 4, wherein the mole ratio of the sesquiterpene compound to the platinum compound is 200: 1-1: 100.
6. The pharmaceutical combination according to claim 4 or 5, wherein the platinum-based compounds comprise cisplatin, carboplatin and oxaliplatin.
7. A pharmaceutical preparation, prepared from the active ingredients of the pharmaceutical combination according to claim 4 together with a pharmaceutically acceptable diluent, carrier, excipient, adjuvant or vehicle.
8. The pharmaceutical preparation according to claim 7, wherein the dosage form of the pharmaceutical preparation is selected from one of granules, tablets, pills, capsules and injections.
9. Use of a pharmaceutical combination according to claim 4 and/or a pharmaceutical preparation according to claim 7 for the preparation of an antitumor medicament.
10. Use according to claim 2, claim 3 and claim 8, wherein the tumour is selected from one or more of ovarian, uterine, lung, breast, gastric, liver, colorectal, skin, renal and oesophageal cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110125383.5A CN112920147B (en) | 2021-01-29 | 2021-01-29 | Sesquiterpenoids, preparation method thereof and application thereof in preparing antitumor drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110125383.5A CN112920147B (en) | 2021-01-29 | 2021-01-29 | Sesquiterpenoids, preparation method thereof and application thereof in preparing antitumor drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112920147A true CN112920147A (en) | 2021-06-08 |
| CN112920147B CN112920147B (en) | 2022-07-05 |
Family
ID=76168433
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110125383.5A Active CN112920147B (en) | 2021-01-29 | 2021-01-29 | Sesquiterpenoids, preparation method thereof and application thereof in preparing antitumor drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112920147B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287627A (en) * | 2015-10-23 | 2016-02-03 | 武汉大学 | Unsaturated lactone ingredient and chemotherapy drug composition and application thereof |
| CN111018877A (en) * | 2019-10-28 | 2020-04-17 | 武汉大学 | Sesquiterpene derivative in elecampane inula root, preparation method and application thereof |
-
2021
- 2021-01-29 CN CN202110125383.5A patent/CN112920147B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287627A (en) * | 2015-10-23 | 2016-02-03 | 武汉大学 | Unsaturated lactone ingredient and chemotherapy drug composition and application thereof |
| CN111018877A (en) * | 2019-10-28 | 2020-04-17 | 武汉大学 | Sesquiterpene derivative in elecampane inula root, preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| JAE SIK YU ET AL.: "A new rearranged eudesmane sesquiterpene and bioactive sesquiterpenes from the twigs of Lindera glauca (Sieb. et Zucc.) Blume", 《ARCH. PHARM. RES.》 * |
| YAN-YAN MA ET AL.: "Structural Investigation and Biological Activity of Sesquiterpene Lactones from the Traditional Chinese Herb Inula racemosa", 《JOURNAL OF NATURAL PRODUCTS》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112920147B (en) | 2022-07-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111704594B (en) | Artemisia polyanthrene lactone A-S and Artemisia polyanthrin A-G as well as pharmaceutical composition and application thereof | |
| Teng et al. | HYR-2 plays an anti-lung cancer role by regulating PD-L1 and Akkermansia muciniphila | |
| CN114524825A (en) | Artemisia sphaerocephala lactone A-T, pharmaceutical composition thereof, and preparation method and application thereof | |
| CN102731276A (en) | Diterpene compound possessing antitumor activity, preparation method thereof and application thereof | |
| CN112920147B (en) | Sesquiterpenoids, preparation method thereof and application thereof in preparing antitumor drugs | |
| CN101366827A (en) | Manchurian walnut bark extract and preparation method thereof | |
| CN102908340B (en) | Isolicoflavonol-containing antitumor drug and application thereof | |
| CN106580937B (en) | The preparation method of euphorbia ebiacteolata Hayata element A and its preparing the application in breast cancer medicines | |
| CN105712963A (en) | Coumarin dimer and preparation method and application thereof | |
| Lien et al. | Innovative purification method of ovatodiolide from Anisomeles indica to induce apoptosis in human gastric cancer cells | |
| CN102070573B (en) | Mono-tetrahydrofuran type sugar apple lactone compound with anti-tumor activity and application thereof | |
| CN106749124B (en) | Neighbour's double tetrahydrofuran type Annonaceousacetogenicompounds compounds with anti-tumor activity and the preparation method and application thereof | |
| CN103263409B (en) | Application of bixanthone compound FLBG-1108 or its pharmaceutical salts in preparation of anti-cancer drugs | |
| CN103833823A (en) | Diterpene dimer compounds and pharmaceutical compositions and preparation method and application thereof | |
| CN106588614B (en) | A kind of preparation method and applications of diphenylmethyl alkanes compound | |
| CN102440985A (en) | Application of bixanthone compound FLBG-1108 or its medicinal salt in preparing anticancer medicaments | |
| Parvizzadeh et al. | A metabonomic study of the effect of methanol extract of ginger on Raji cells using 1HNMR spectroscopy | |
| CN102675252B (en) | There is Cesong alkyl type diterpine compound and the application thereof of anti-tumor activity | |
| CN102000059B (en) | Medicinal application of querecetin dipolymer flavonoids to preparation of glycosidase enzyme inhibitors | |
| CN105541858A (en) | Xanthone compositions, and preparation method, compositions and application thereof | |
| CN104804005A (en) | Compound with anti-tumor effect as well as preparation method and application thereof | |
| CN109705183A (en) | Smelly seven secondary metabolites and its pharmaceutical composition and preparation method and its application | |
| Bada et al. | Phytochemical Analysis and Antiproliferative Activity of Ulex gallii Planch.(Fabaceae), a Medicinal Plant from Galicia (Spain) | |
| CN102153529B (en) | Single-tetrahydrofuran-type annonaceous acetogenin compounds with antitumor activity and application thereof | |
| CN109575089B (en) | Acylated glucose compounds, pharmaceutical composition, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |