CN113786396B - Thymol-loaded cyclodextrin complex and preparation method thereof - Google Patents
Thymol-loaded cyclodextrin complex and preparation method thereof Download PDFInfo
- Publication number
- CN113786396B CN113786396B CN202110963108.0A CN202110963108A CN113786396B CN 113786396 B CN113786396 B CN 113786396B CN 202110963108 A CN202110963108 A CN 202110963108A CN 113786396 B CN113786396 B CN 113786396B
- Authority
- CN
- China
- Prior art keywords
- thymol
- cyclodextrin
- complex
- mother solution
- potassium
- 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.)
- Active
Links
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 title claims abstract description 192
- 239000005844 Thymol Substances 0.000 title claims abstract description 96
- 229960000790 thymol Drugs 0.000 title claims abstract description 96
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 56
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000010668 complexation reaction Methods 0.000 title description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000013078 crystal Substances 0.000 claims abstract description 31
- 239000010413 mother solution Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000005406 washing Methods 0.000 claims abstract description 14
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims abstract description 13
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims abstract description 13
- 239000012452 mother liquor Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 10
- 239000011591 potassium Substances 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- 239000001116 FEMA 4028 Substances 0.000 claims description 5
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 5
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 5
- 229960004853 betadex Drugs 0.000 claims description 5
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 3
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 3
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 2
- 238000011068 loading method Methods 0.000 abstract description 15
- 230000014759 maintenance of location Effects 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000002288 cocrystallisation Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000013119 CD-MOF Substances 0.000 description 14
- 239000012153 distilled water Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 235000013305 food Nutrition 0.000 description 5
- 230000000717 retained effect Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000013329 compounding Methods 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- -1 phenolic monoterpene Chemical class 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229940109262 curcumin Drugs 0.000 description 2
- 235000012754 curcumin Nutrition 0.000 description 2
- 239000004148 curcumin Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 238000009920 food preservation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 240000007232 Illicium verum Species 0.000 description 1
- 235000008227 Illicium verum Nutrition 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 108010073771 Soybean Proteins Proteins 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010041 electrostatic spinning Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930003658 monoterpene Natural products 0.000 description 1
- 235000002577 monoterpenes Nutrition 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000019710 soybean protein Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000013146 β-CD-MOF Substances 0.000 description 1
Classifications
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
- A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
- A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
- A23L3/3463—Organic compounds; Microorganisms; Enzymes
- A23L3/3481—Organic compounds containing oxygen
- A23L3/349—Organic compounds containing oxygen with singly-bound oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
- A61K8/347—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/738—Cyclodextrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Birds (AREA)
- Communicable Diseases (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Microbiology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicinal Preparation (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention discloses a cyclodextrin complex loaded with thymol and a preparation method thereof, comprising the following steps: (1) Fully dissolving cyclodextrin, a potassium-containing compound and thymol in water to obtain mother liquor; (2) In a closed container, standing the mother solution in a volatile alcohol atmosphere for reaction until complex crystals are separated out from the mother solution; (3) And separating the crystals from the mother solution, washing to remove free thymol, centrifuging, and drying to obtain the cyclodextrin complex carrying thymol. The complex is prepared by adopting a one-step co-crystallization method, so that the loading capacity and stability of thymol are obviously improved, and compared with the traditional gamma-cyclodextrin, the loading capacity is improved from 124mg/g to more than 250mg/g, and the thymol retention rate is improved from 30% to more than 60% under the condition of 50 days at room temperature; and the complex prepared by the method has good biological safety due to the adoption of food-grade raw materials and a green and simple synthesis process.
Description
Technical Field
The invention relates to a preparation method of thymol complex with high-efficiency load and sustained release, belonging to the field of food and chemical industry.
Background
Thymol is a natural phenolic monoterpene, mainly found in thymus plants, with a strong odor. Because of the excellent antibacterial, antiviral, anti-inflammatory and sedative functions, thymol is often used as an expectorant, an anti-inflammatory agent, an antiviral agent, an antibacterial agent and a preservative for a long time in traditional medicine, and has good therapeutic effects on diseases such as upper respiratory tract infection, bronchitis, parasitic infection, dermatitis and the like.
The thymol has strong volatilization capability and low water solubility, and severely restricts the industrialized application thereof. Packaging in a suitable wall material to slow down the degradation and loss of thymol has become one of the main research contents. At present, mainly polysaccharides, cyclodextrin, lipid, glycerol, protein and the like are adopted as an encapsulation wall material, and are complexed with thymol through means of spray drying, freeze drying, electrostatic spinning, coprecipitation and the like. However, the complex constructed by taking polysaccharide, cyclodextrin and protein as wall materials has generally low thymol loading, such as thymol-chitosan oligosaccharide complex prepared by Chinese patent CN111771968A, wherein the thymol loading is 52.3mg/g at most; the content of thymol in the fiber membrane synthesized by taking thymol, beta-cyclodextrin and cellulose acetate as raw materials is 48.6mg/g (Materials Science & Engineering C,2020,115,111155); the thymol content of the polymer particles obtained by complexing the isolated soybean protein with thymol was 103.6mg/g (Food Chemistry,2021,334,127594)
Cyclodextrin-metal organic frameworks (CD-MOFs) are a class of porous crystalline materials with high specific surface area, adjustable pore size formed by self-assembly of cyclodextrin and alkali metal salts in solution, with a periodic network structure. Experiments prove that the CD-MOF prepared from food-grade cyclodextrin and food-grade alkali metal salt has nontoxic property and high safety. In view of the special application in the fields of foods, medicines and the like, the raw materials for constructing the complex system are required to have good biological safety and adopt a green synthesis means, so that the CD-MOF is used as an excellent and green safe carrier for encapsulating bioactive substances such as glycyrrhizic acid, folic acid, curcumin, polyphenol of star anise leaves and the like. The complex of the extract and thymol can effectively overcome the defect of thymol application.
The combination of CD-MOF and the guest substance is usually realized by adopting a mixed heating method or an impregnation adsorption method, such as Chinese patent CN111513356A, beta-CD-MOF is taken as a packaging wall material, and the high-efficiency load L-menthol is realized by adopting a direct mixed heating method. For another example, a guest substance (curcumin) is dissolved in methanol in advance, and γ -CD-MOF crystals are added and stirred for several hours to achieve the adsorption (Food Chemistry,2021,347,128978). The two methods are all to complex and adsorb on the basis of the prepared CD-MOF crystal, and have long preparation period and complicated working procedures.
At present, polysaccharide or cyclodextrin is used as a carrier, the thymol content is generally low, and the complex of gamma-cyclodextrin and thymol is used as an example, wherein the thymol loading amount is only 124mg/g.
Disclosure of Invention
In order to solve the defects and shortcomings of the prior art, the invention aims to provide a preparation method of a thymol-cyclodextrin complex which has high efficient load of thymol, high biological safety, green and simple process and is beneficial to improving the dispersion capacity and stability of thymol.
The invention aims at realizing the following technical scheme:
a method for preparing a thymol-loaded cyclodextrin complex, comprising the steps of:
(1) Fully dissolving cyclodextrin, a potassium-containing compound and thymol in water to obtain mother liquor;
(2) In a closed container, standing the mother solution in a volatile alcohol atmosphere for reaction until complex crystals are separated out from the mother solution;
(3) And separating the crystals from the mother solution, washing to remove free thymol, centrifuging, and drying to obtain the cyclodextrin complex carrying thymol.
Preferably, the cyclodextrin in the step (1) is one or more than two of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin.
Preferably, the potassium-containing compound of step (1) is KOH, CH 3 One or more of COOK and KCl.
Preferably, the concentration of cyclodextrin in the mother liquor in the step (1) is 0.01-0.25 mol/L, the concentration of the potassium-containing compound is 0.08-2 mol/L, and the concentration of thymol is 0.1-1.25 mol/L.
Preferably, the molar ratio of the cyclodextrin, the potassium-containing compound and the thymol in the step (1) is 1 (6-12) (1-10); more preferably 1 (8-10) to 4-8.
Preferably, the reaction conditions of step (2) are: the temperature is 25-50 ℃, and the reaction time is 5-20 days.
Preferably, in the step (2), the volatile alcohol is methanol or ethanol, and the volume of the alcohol is 2-5 times of that of the mother solution.
Preferably, the removal of the free thymol in the step (3) is realized by washing with ethanol for 3 to 5 times, and after each washing, the mixed solution is centrifuged for 3 to 5 minutes under the condition of 3000r/min to 4500 r/min; the drying is vacuum drying, the temperature is 30-50 ℃, and the treatment time is 4-6 h.
The invention uses cyclodextrin crystals prepared by re-crystallizing after the cyclodextrin and the potassium-containing compound (potassium salt) are dissolved together as the packaging wall material, thus realizing the encapsulation and stabilization of thymol. The cyclodextrin and potassium ions coexisting in the mother liquor coordinate spontaneously, and the metal ions bridge so that cyclodextrin molecules are mutually connected and stacked to form a loose and porous cyclodextrin metal organic framework (CD-MOF). The CD-MOF has good thermal stability, high specific surface area and adjustable pores, and can form stable inclusion compound with guest molecules. The invention takes cyclodextrin crystal (CD-MOF) as the packaging wall material to load thymol, has the characteristics of high loading efficiency, high stability, green and non-toxicity and the like, and provides more choices for the application fields of thymol in food preservation, oral care, medical antibacterial preparation development and the like.
Compared with the prior art, the invention has the advantages that:
(1) The complex is prepared by adopting a one-step co-crystallization method, so that the loading capacity and stability of thymol are obviously improved, and compared with the traditional gamma-cyclodextrin, the loading capacity is improved from 124mg/g to more than 250mg/g, and the thymol retention rate is improved from 30% to more than 60% under the condition of 50 days at room temperature; after 50 days of storage in a low-temperature environment (4 ℃), the retention rate of thymol is more than 72 percent.
(2) The cyclodextrin complex carrying thymol is prepared by adopting a one-step co-crystallization method, and the thymol is synchronously complexed in the process of forming the CD-MOF crystal, so that the preparation process can be simplified, the preparation period is shortened, the energy consumption is reduced, the preparation cost is reduced, the environment is protected, the food grade raw material is selected in the preparation process, the complex can be endowed with good biological safety, and the cyclodextrin complex can be applied to the fields of food preservation, oral care, medical antibacterial preparation development and the like.
Drawings
FIG. 1 is a standard plot of peak area versus thymol concentration.
FIG. 2 is a topography of a thymol-loaded cyclodextrin complex; a: gamma-CD-THY (comparative example 1); b-CD-MOF-THY (comparative example 2); c: gamma-CD-MOF-THY (example 1); d: beta-CD-MOF-THY (example 2); e: α -CD-MOF-THY (example 3); f: gamma-CD-MOF-THY (example 4); g: gamma-CD-MOF-THY (example 5).
Detailed Description
For a better understanding of the present invention, the present invention will be further described with reference to the following examples, but the scope of the present invention is not limited to the scope expressed by the examples.
In the examples, the method for determining thymol in the complex is as follows: accurately weighing 5mg of complex in a 5mL centrifuge tube, adding 1mL of distilled water, covering a centrifuge tube cap, magnetically stirring at a speed of 1000r/min for 0.5h, adding 2mL of ethyl acetate for extraction, collecting supernatant, passing through a 0.22 μm organic filter membrane, transferring into a gas phase bottle, and measuring the thymol content by adopting a gas chromatography method. The peak area of thymol was calculated as thymol content based on the thymol standard curve.
Comparative example 1
The complex of gamma-cyclodextrin and thymol is used as a comparison: taking 2g of gamma-cyclodextrin and 1g of thymol in a mortar, manually grinding for 3min, uniformly mixing, transferring into a closed reaction kettle, and compounding for 4h at 75 ℃. After the compounding is finished, the sample is washed by ethanol for 3 to 5 times, centrifuged for 3min at 4000r/min, and dried in vacuum at 40 ℃ for 6h to obtain white powdery complex.
According to tests, the thymol loading amount in the complex is 124mg/g, the thymol retention rate is about 30% after the complex is stored for 50 days in an open environment at normal temperature, and the thymol retention rate is about 58% after the complex is stored for 50 days in a low-temperature environment (4 ℃).
Comparative example 2
By reacting gamma-cyclodextrin, CH 3 COOK is dissolved in distilled water in a molar ratio of 1:8, and stirred for 3 hours to fully dissolve the COOK, so as to obtain a mother solution with cyclodextrin concentration of 0.05 mol/L; standing 20mL of mother liquor in an ethanol atmosphere at 25 ℃ for 10 days, wherein the ethanol dosage in a closed container is 50mL; separating CD-MOF crystals from the mother liquor, washing with ethanol for 3 times, centrifuging at 4000r/min for 3min, and vacuum drying at 40deg.C for 5 hr to obtain crystal particles. To obtain a thymol-loaded complex, the CD-MOF crystal and thymol are manually ground for 3min according to the mass ratio of 1:1, uniformly mixed, transferred into a closed reaction kettle and compounded for 6h at 75 ℃. After the compounding is finished, washing the crystal with ethanol for 3-5 times, centrifuging at a rotating speed of 4000r/min for 3min, and vacuum drying at 40 ℃ for 6h to obtain the thymol complex crystal.
According to tests, the thymol loading in the complex is 243mg/g, the thymol retention rate is about 54% after the complex is stored for 50 days in an open environment at normal temperature, and the thymol retention rate is about 66% after the complex is stored for 50 days in a low-temperature environment (4 ℃).
Example 1
Dissolving gamma-cyclodextrin, KOH and thymol in distilled water according to a molar ratio of 1:8:5, and stirring for 3 hours to fully dissolve the gamma-cyclodextrin, the KOH and the thymol, thereby obtaining a mother solution with the cyclodextrin concentration of 0.1 mol/L; standing 20mL of mother liquor in an ethanol atmosphere at 25 ℃ for 7 days, wherein the ethanol dosage in a closed container is 50mL; separating the crystal from the mother solution, washing with ethanol for 3 times, centrifuging at 4000r/min for 3min, and vacuum drying at 40deg.C for 5 hr to obtain crystal particles.
Through testing, the thymol loading in the crystal is 327mg/g, the thymol is stored for 50 days in an open environment at normal temperature, the thymol retention rate is about 65%, and the thymol can be retained by about 80% in a low-temperature environment (4 ℃).
Example 2
Dissolving beta-cyclodextrin, KOH and thymol in distilled water according to a molar ratio of 1:8:8, and stirring for 3 hours to fully dissolve the beta-cyclodextrin, the KOH and the thymol, so as to obtain a mother solution with the cyclodextrin concentration of 0.1 mol/L; standing 20mL of mother liquor in an ethanol atmosphere at 50 ℃ for 10 days, wherein the ethanol dosage in a closed container is 50mL; separating the crystal from the mother solution, washing with ethanol for 3 times, centrifuging at 4000r/min for 3min, and vacuum drying at 50deg.C for 4 hr to obtain crystal particles.
Through testing, the thymol loading in the crystal is 269.2mg/g, the thymol is stored for 50 days in an open environment at normal temperature, the thymol retention rate is about 68%, and the thymol can be retained by about 75% in a low-temperature environment (4 ℃).
Example 3
Alpha-cyclodextrin, CH 3 COOK and thymol are dissolved in distilled water in a molar ratio of 1:10:5, and stirred for 3 hours to fully dissolve the COOK and the thymol, so as to obtain a mother solution with cyclodextrin concentration of 0.1 mol/L; standing 30mL of mother liquor in an ethanol atmosphere at 25 ℃ for 20 days, wherein the ethanol consumption in a closed container is 75mL; separating the crystal from the mother solution, washing with ethanol for 3 times, centrifuging at 4000r/min for 3min, and vacuum drying at 30deg.C for 6 hr to obtain crystal particles.
Through testing, the thymol loading capacity in the crystal is 284.6mg/g, the thymol is stored for 50 days in an open environment at normal temperature, the thymol retention rate is about 63%, and more than 70% can be retained in a low-temperature environment (4 ℃).
Example 4
By reacting gamma-cyclodextrin, CH 3 COOK and thymol are dissolved in distilled water in a molar ratio of 1:10:5, and stirred for 3 hours to fully dissolve the COOK and the thymol, so as to obtain a mother solution with cyclodextrin concentration of 0.1 mol/L; standing 30mL of mother liquor in an ethanol atmosphere at 40 ℃ for 10 days, wherein the ethanol consumption in a closed container is 75mL; separating the crystal from the mother solution, washing with ethanol for 3 times, centrifuging at 4000r/min for 3min, and vacuum drying at 40deg.C for 6 hr to obtain crystal particles.
According to tests, the thymol loading in the crystal is 313.5mg/g, the thymol is stored for 50 days in an open environment at normal temperature, the thymol retention rate is about 78%, and the thymol can be retained by about 82% in a low-temperature environment (4 ℃).
Example 5
Dissolving gamma-cyclodextrin, KCl and thymol in distilled water according to a molar ratio of 1:8:4, and stirring for 3 hours to fully dissolve the gamma-cyclodextrin and the KCl to obtain a mother solution with cyclodextrin concentration of 0.15 mol/L; standing 25mL of mother liquor in an ethanol atmosphere at 25 ℃ for 15 days, wherein the ethanol dosage in a closed container is 75mL; separating the crystals from the mother liquor, washing with ethanol for 4 times, centrifuging at 4000r/min for 3min, and vacuum drying at 45deg.C for 5.5 hr to obtain crystal particles.
Through testing, the thymol loading in the crystal is 255.3mg/g, the thymol is stored for 50 days in an open environment at normal temperature, the thymol retention rate is about 60%, and the thymol can be retained by more than 72% in a low-temperature environment (4 ℃).
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (3)
1. A method for preparing a thymol-loaded cyclodextrin complex, comprising the steps of:
(1) Fully dissolving cyclodextrin, a potassium-containing compound and thymol in water to obtain mother liquor; the potassium-containing compound is KOH, CH 3 One or two of COOK;
(2) In a closed container, standing the mother solution in a volatile alcohol atmosphere for reaction until complex crystals are separated out from the mother solution;
(3) Separating the crystals from the mother solution, washing to remove free thymol, centrifuging, and drying to obtain cyclodextrin complex carrying thymol;
the cyclodextrin in the step (1) is one or more than two of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin;
the concentration of cyclodextrin in the mother solution in the step (1) is 0.05-0.1 mol/L, the concentration of potassium-containing compound is 0.4-0.8 mol/L, and the concentration of thymol is 0.25-1 mol/L;
the molar ratio of the cyclodextrin to the potassium-containing compound to the thymol in the step (1) is 1 (8-10), namely (4-8);
the reaction conditions in the step (2) are as follows: the temperature is 25-50 ℃, and the reaction time is 5-20 days;
the volatile alcohols in the step (2) are methanol or ethanol, and the volume of the alcohols is 2-5 times of that of the mother solution.
2. The preparation method of claim 1, wherein the removal of the free thymol in the step (3) is achieved by washing with ethanol for 3-5 times, and after each washing, centrifuging the mixed solution for 3-5 min under the condition of 3000 r/min-4500 r/min; the drying is vacuum drying, the temperature is 30-50 ℃, and the treatment time is 4-6 hours.
3. A thymol-loaded cyclodextrin complex obtainable by the process according to claim 1 or 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110963108.0A CN113786396B (en) | 2021-08-20 | 2021-08-20 | Thymol-loaded cyclodextrin complex and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110963108.0A CN113786396B (en) | 2021-08-20 | 2021-08-20 | Thymol-loaded cyclodextrin complex and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113786396A CN113786396A (en) | 2021-12-14 |
| CN113786396B true CN113786396B (en) | 2023-12-05 |
Family
ID=79181990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110963108.0A Active CN113786396B (en) | 2021-08-20 | 2021-08-20 | Thymol-loaded cyclodextrin complex and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113786396B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054782A (en) * | 2019-04-22 | 2019-07-26 | 华南理工大学 | A kind of Beta-cyclodextrin-based metal-organic framework material and preparation method thereof |
| CN110180008A (en) * | 2019-05-10 | 2019-08-30 | 浙江大学 | It is a kind of with release Xiang Gong can cyclodextrin metal organic frame inclusion compound and preparation method thereof |
| CN110663763A (en) * | 2019-09-04 | 2020-01-10 | 华南理工大学 | Cyclodextrin carrier with efficient ethylene loading and sustained-release functions and preparation method thereof |
| CN111513356A (en) * | 2020-04-10 | 2020-08-11 | 华南理工大学 | Preparation method of menthol microcapsule with efficient loading and sustained release effects |
| CN111607018A (en) * | 2020-06-05 | 2020-09-01 | 江南大学 | Preparation method of thymol embedded object intelligent antibacterial preservative film |
| CN111659327A (en) * | 2020-05-11 | 2020-09-15 | 华南理工大学 | Thymol microcapsule based on starch wall material and preparation method thereof |
-
2021
- 2021-08-20 CN CN202110963108.0A patent/CN113786396B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054782A (en) * | 2019-04-22 | 2019-07-26 | 华南理工大学 | A kind of Beta-cyclodextrin-based metal-organic framework material and preparation method thereof |
| CN110180008A (en) * | 2019-05-10 | 2019-08-30 | 浙江大学 | It is a kind of with release Xiang Gong can cyclodextrin metal organic frame inclusion compound and preparation method thereof |
| CN110663763A (en) * | 2019-09-04 | 2020-01-10 | 华南理工大学 | Cyclodextrin carrier with efficient ethylene loading and sustained-release functions and preparation method thereof |
| CN111513356A (en) * | 2020-04-10 | 2020-08-11 | 华南理工大学 | Preparation method of menthol microcapsule with efficient loading and sustained release effects |
| CN111659327A (en) * | 2020-05-11 | 2020-09-15 | 华南理工大学 | Thymol microcapsule based on starch wall material and preparation method thereof |
| CN111607018A (en) * | 2020-06-05 | 2020-09-01 | 江南大学 | Preparation method of thymol embedded object intelligent antibacterial preservative film |
Non-Patent Citations (2)
| Title |
|---|
| "Encapsulation of menthol into cyclodextrin metal-organic frameworks:Preparation, structure characterization and evaluation of complexingcapacity";Ziman Hu et al;《Food Chemistry》;第338卷;127839 * |
| 羟丙基-β-环糊精对百里香挥发油包合作用的研究;马君义;王宝生;黄玉龙;王曼婷;张继;;食品工业科技(01);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113786396A (en) | 2021-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11091414B2 (en) | Complexes of 1-methylcyclopropene with metal coordination polymer networks | |
| CN114656645B (en) | Preparation method of cyclodextrin metal organic framework stably existing in water phase | |
| CN107628959B (en) | Choline eutectic solvent, preparation method and application in extraction of globeflower flavone C-glycoside | |
| KR101541938B1 (en) | Novel milk thistle extract, method for the production, and use | |
| CN100389754C (en) | Microcapsule preparing process utilizing waste beer yeast cell as wall material | |
| US20220282046A1 (en) | Cyclodextrin-based metal organic framework material and preparation method therefor | |
| CN105435853A (en) | Illite mesoporous composite material, supported catalyst and preparation method and application thereof and preparation method of cyclohexanone glyceryl ketal | |
| CN104940294A (en) | Preparation method for punicosides, and method for preparing punicosides microcapsule containing punicosides, prepared according to preparation method, and microcapsule | |
| CN103641717B (en) | A kind of method from extraction and isolation chlorogenic acid flowering period floral disc of sunflower into | |
| CN111513356B (en) | Preparation method of menthol microcapsule with efficient loading and sustained release effects | |
| CN112604005A (en) | Preparation method of citral hydroxypropyl-beta-cyclodextrin inclusion compound | |
| CN113786396B (en) | Thymol-loaded cyclodextrin complex and preparation method thereof | |
| CN105435854A (en) | Chlorite mesoporous composite, supported catalyst and preparation method and application thereof and preparation method of cyclohexanone glyceryl ketal | |
| CN102793272A (en) | Applications of tea polyphenol/beta-cyclodextrin inclusion compound taken as cigarette filter additive in reduction of cigarette smoke phenolic compound | |
| CN109603761B (en) | Preparation method and application of ZnO @ CTAB composite material | |
| JP2006169253A (en) | Process for preparing alpha lipoic acid/cyclodextrin complex and product prepared | |
| CN103755670B (en) | A kind of Andrographolide compound and pharmaceutical composition thereof | |
| CN105435850A (en) | Illite mesoporous composite material, supported catalyst and preparation method and application thereof and preparation method of cyclohexanone glyceryl ketal | |
| Yonezawa et al. | Stability of inclusion complexes of cyclodextrins with guaiazulene | |
| CN114404612B (en) | Zanthoxylum oil cyclodextrin inclusion compound and preparation method thereof | |
| CN113318137B (en) | Preparation method of water-soluble acanthopanax powder capsule | |
| CN114432460A (en) | Fisetin inclusion compound and preparation method thereof | |
| CN112370451A (en) | Maropritan citrate clathrate compound, injection and preparation method | |
| CN103536927A (en) | Edaravone composition freeze-dried powder injection | |
| CN118344507A (en) | Preparation method of cyclodextrin metal-organic framework polymer material |
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 |