CN114903873A - Polygalate microcapsule and preparation method and application thereof - Google Patents
Polygalate microcapsule and preparation method and application thereof Download PDFInfo
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- CN114903873A CN114903873A CN202210549675.6A CN202210549675A CN114903873A CN 114903873 A CN114903873 A CN 114903873A CN 202210549675 A CN202210549675 A CN 202210549675A CN 114903873 A CN114903873 A CN 114903873A
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- peganum
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- 239000003094 microcapsule Substances 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 241000159204 Peganum Species 0.000 claims abstract description 17
- 235000005126 Peganum harmala Nutrition 0.000 claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 17
- 239000012071 phase Substances 0.000 claims description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical group OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 claims description 25
- 229960002258 fulvestrant Drugs 0.000 claims description 24
- 239000000839 emulsion Substances 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 238000010926 purge Methods 0.000 claims description 18
- 239000011541 reaction mixture Substances 0.000 claims description 18
- 239000004864 galbanum Substances 0.000 claims description 16
- -1 galbanum ester Chemical class 0.000 claims description 16
- 230000006320 pegylation Effects 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 15
- 239000008367 deionised water Substances 0.000 claims description 14
- 229910021641 deionized water Inorganic materials 0.000 claims description 14
- 239000000178 monomer Substances 0.000 claims description 14
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 13
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 13
- 241000116713 Ferula gummosa Species 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 11
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 11
- YOCIJWAHRAJQFT-UHFFFAOYSA-N 2-bromo-2-methylpropanoyl bromide Chemical compound CC(C)(Br)C(Br)=O YOCIJWAHRAJQFT-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000003999 initiator Substances 0.000 claims description 8
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims description 8
- 229930182490 saponin Natural products 0.000 claims description 8
- 150000007949 saponins Chemical class 0.000 claims description 8
- VGUWFGWZSVLROP-UHFFFAOYSA-N 1-pyridin-2-yl-n,n-bis(pyridin-2-ylmethyl)methanamine Chemical compound C=1C=CC=NC=1CN(CC=1N=CC=CC=1)CC1=CC=CC=N1 VGUWFGWZSVLROP-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 230000001502 supplementing effect Effects 0.000 claims description 5
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 15
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- 239000003431 cross linking reagent Substances 0.000 abstract description 6
- 238000010526 radical polymerization reaction Methods 0.000 abstract description 6
- 230000007547 defect Effects 0.000 abstract description 5
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- 238000010560 atom transfer radical polymerization reaction Methods 0.000 description 5
- 229920002125 Sokalan® Polymers 0.000 description 4
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000004584 polyacrylic acid Substances 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- 235000005827 Arthrocnemum glaucum Nutrition 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000201895 Salicornia Species 0.000 description 3
- 235000003042 Salicornia europaea Nutrition 0.000 description 3
- 239000012752 auxiliary agent Substances 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002088 nanocapsule Substances 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 229920000877 Melamine resin Polymers 0.000 description 2
- 239000004640 Melamine resin Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Substances CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 229920001600 hydrophobic polymer Polymers 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- ICNCZFQYZKPYMS-UHFFFAOYSA-N 2-methylpropanoyl bromide Chemical compound CC(C)C(Br)=O ICNCZFQYZKPYMS-UHFFFAOYSA-N 0.000 description 1
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920001744 Polyaldehyde Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 239000012975 dibutyltin dilaurate Substances 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 1
- 229960000249 pregnenolone Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F118/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an acyloxy radical of a saturated carboxylic acid, of carbonic acid or of a haloformic acid
- C08F118/02—Esters of monocarboxylic acids
- C08F118/12—Esters of monocarboxylic acids with unsaturated alcohols containing three or more carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2438/00—Living radical polymerisation
- C08F2438/01—Atom Transfer Radical Polymerization [ATRP] or reverse ATRP
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
Abstract
The invention provides a peganum polygeritan microcapsule and a preparation method and application thereof, belonging to the technical field of preparation of entrapment materials; in the invention, the peganum polygeritan polymer polymerized by the interfacial atom transfer free radical is used as a microcapsule wall material, and the spherical hollow microcapsule with good physical property and controllability is obtained by the interfacial atom transfer free radical polymerization under the condition of not adding a cross-linking agent, so that the defects of complex process, heavy pollution and difficulty in realizing industrial production in the prior art are solved, the problem of high toxicity of cross-linking agents such as formaldehyde and the like is avoided, and the peganum polygeritan polymer can be well used for long-acting entrapment and protection of medicaments.
Description
Technical Field
The invention belongs to the technical field of preparation of entrapment materials, and particularly relates to a peganum polygeritan microcapsule as well as a preparation method and application thereof.
Background
With the development of the pharmaceutical industry, the embedding technology gradually receives attention from people, and researches on embedding micro-nano capsules (hereinafter referred to as microcapsules) are increasing day by day. The microcapsule embeds the active ingredient in the capsule, thereby improving the stability of the core material of the embedded active ingredient and reducing the deterioration loss caused by the influence of external factors such as oxygen, light, enzyme and the like. In addition, the microcapsule can also regulate and control the release mode of the core material, so that the core material can be slowly and controllably released to achieve the aims of targeting and accurate action.
In recent years, microcapsules are mainly prepared by using wall materials such as starch, gelatin, sodium alginate, polyacrylic acid and the like as microcapsule wall materials. However, the preparation process of the collagen/starch microspheres prepared by the emulsification/crosslinking method is complex, and the use of a large amount of emulsifier and oil phase organic solvent brings troublesome post-treatment process to the microspheres; the sodium alginate micro-nano capsule prepared by adopting sodium alginate has the problems of easy moisture absorption, uneven pore structure distribution, abnormal deterioration and the like; the melamine resin micro-nano capsule prepared by adopting melamine resin as a wall material has lower strength and low entrapment rate. Compared with other methods, the polyacrylic acid microcapsule prepared by adopting polyacrylic acid as the wall material has the advantages of controllable microcapsule structure, no formaldehyde residue, slow release and the like, but is difficult to be well applied due to the defects of bad taste, poor stability and the like of polyacrylic acid. In addition, in the existing preparation process of the polymer material microcapsule, formaldehyde or other polyaldehyde compounds are added as a cross-linking agent and cured to be used as a microcapsule wall material, but the microcapsule has the defect of high toxicity and is difficult to be used for long-acting entrapment of drugs.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a peganum polygeritan microcapsule and a preparation method and application thereof. In the invention, the peganum polyglaucor ester polymer polymerized by the interfacial active free radical is used as a microcapsule wall material, and the spherical hollow microcapsule with good physical property and controllability is obtained by interfacial atom transfer free radical polymerization under the condition of not adding a cross-linking agent, so that the defects of complex process, heavy pollution and difficulty in realizing industrial production in the prior art are solved, the problem of high toxicity of cross-linking agents such as formaldehyde and the like is avoided, and the peganum polyglaucor ester polymer can be well used for long-acting entrapment and protection of medicaments.
The invention firstly provides a poly-galbanum ester microcapsule, wherein a poly-galbanum ester macromolecule is used as a microcapsule wall material, the microcapsule is of a spherical hollow structure, the thickness of the wall material of the microcapsule is 10-30 nm, the diameter of the microcapsule is 5-15 mu m, and the rupture strength reaches 2.5-5 mu N.
The invention also provides a preparation method of the peganum polygeritan microcapsule, which comprises the following steps:
(1) pretreatment of the water phase and the oil phase:
water phase: adding saponin into deionized water to form water phase, and removing oxygen by nitrogen purging;
oil phase: mixing a galbanum ester monomer, an initiator 2-bromoisobutyryl bromide, a catalyst tri (2-pyridylmethyl) amine and an active molecule into caprylic capric triglyceride to form an oil phase, and removing oxygen by nitrogen purging for later use;
(2) preparation of the poly galbanum ester microcapsule:
mixing the obtained water phase and oil phase, stirring at a high speed to form a concentrated emulsion, removing oxygen by nitrogen purging, adding a cuprous bromide aqueous solution, mixing, supplementing deionized water, and recovering the emulsion to obtain a reaction mixture;
and (3) carrying out low-temperature reaction on the reaction mixture in a stirring environment, then heating the reaction mixture to 40-65 ℃ for constant-temperature reaction for 5-15 h, and obtaining the pegylation ester microcapsule after the reaction is finished.
Further, in the step (1), the mass ratio of the saponin in the water phase to the deionized water is 0.5-1 g: 14-15.5 g.
Further, in the step (1), the oil phase contains the galbanum ester monomer, 2-bromine isobutyryl bromide, tri (2-pyridylmethyl) amine, active molecule and caprylic capric triglyceride in the following ratio: 0.01-0.02 mol: 0.1 mmol: 0.4 mmol: 0.3 mmol: 0.4 mol.
Further, the active molecule is fulvestrant.
Further, in the step (2), the dosage ratio of the water phase to the oil phase is 25 g: 15-20 g.
Further, in the step (2), the using amount ratio of the concentrated emulsion, cuprous bromide and the emulsion is 30-35 g: 0.02-0.05 g: 50 g.
Further, in the step (2), 0.2mmol of cuprous bromide was contained per 1g of the cuprous bromide aqueous solution.
Further, in the step (2), the conditions of the low-temperature reaction in advance in the stirring environment are as follows: keeping the temperature at 25 ℃ for 0.5-2 hours under the stirring environment of 200 revolutions per minute.
The invention also provides application of the polyglaucor ester microcapsule in serving as an active molecule embedding material, wherein the active molecule is fulvestrant.
Compared with the prior art, the invention has the beneficial effects that:
the invention uses atom transfer radical polymerization to form microcapsule, adds emulsifier in water phase, adds galbanum ester monomer, initiator and cocatalyst in oil phase, stirs to form emulsion, adds catalyst in emulsion, adopts atom transfer radical polymerization method to prepare long-chain of galbanum ester molecule, and polymerizes the galbanum ester microcapsule on oil-water interface of emulsion drop under heating action. The principle of the living radical polymerization method is as follows: the glasswort ester has a carbon-carbon double bond group, 2-bromoisobutyryl bromide is used as an initiator, cuprous bromide in a polymerization auxiliary agent is used as a catalyst, a transition metal catalyst mode is used, tri (2-pyridylmethyl) amine is used as a main catalyst, glasswort ester monomers are initiated to polymerize by the initiator at an emulsion droplet interface, an atom transfer radical polymerization auxiliary agent is used for assisting, the free radical double-radical termination reaction is effectively inhibited, dormant active participation reaction is formed, and the method for preparing the glasswort ester by radical polymerization can be efficiently carried out by integrally forming an active polymerization system. The pegylation prepared by the method has controllable molecular weight and terminal groups, uniform molecular weight distribution and high controllability of wall material thickness and size structure of the microcapsule.
The invention takes the galbanum ester as a monomer to prepare the micro-capsule of the galbanum ester, which is the first successful synthesis of the polymer of the galbanum ester, the interface of the emulsion is polymerized with the hydrophobic polymer of the polymer, the hydrophobic polymer has high hydrophobicity and a network structure with gaps, can effectively micro-encapsulate and embed the medicine, reduce the contact of the medicine and the external substances, prevent the deterioration and the loss of the effective components of the medicine, simultaneously slow down the loss of the medicine and improve the storage time of the medicine. The polymer monomer raw material has high biocompatibility and low toxicity.
The invention uses the poly-glauconate as the wall material of the microcapsule, is environment-friendly, has no high-toxicity cross-linking agent such as formaldehyde and the like, has no addition of high-toxicity organic metal auxiliary agents (dibutyltin dilaurate and the like) adopted in the traditional method, and effectively avoids the problem of residual formaldehyde and other toxic compounds in the microcapsule. The method belongs to oil-water interface initiated living radical polymerization, has simple operation process, uses the raw materials which are all commercial products, can be used without complicated purification process, and has low price, easy obtainment, simple production process and highly controllable production process. According to the invention, grafting is carried out by adopting an atom transfer radical polymerization reaction mechanism, the theory is mature, and the prepared microcapsule has the advantages of uniform thickness, high entrapment rate (over 29%), high entrapment efficiency (over 99%), high breaking strength, good stability and the like. The peganum polygeritan microcapsules prepared by the invention have great promotion effect on the industrialization of the embedded microcapsules and the high molecular chemistry industry.
Drawings
FIG. 1 is an optical microscope photograph of the peganum pregnenolone microcapsules of example 1 of the present invention.
FIG. 2 is a scanning electron microscope image of the peganum pregelatinium microcapsules of example 1 of the present invention.
Detailed Description
The present invention will be further described with reference to the following drawings and specific examples, which are briefly described below with the example of fulvestrant, but the scope of the present invention is not limited thereto.
Example 1:
(1) pretreatment of the water phase and the oil phase:
water phase: 0.75g of saponin was added to 24.25g of deionized water to form an aqueous phase, and oxygen was removed by nitrogen purge for use.
Oil phase: 3.02g of a grignard monomer, 0.023g of initiator 2-bromoisobutyryl bromide, 0.116g of catalyst tris (2-pyridylmethyl) amine and 0.2g of fulvestrant were mixed into 15g of caprylic capric triglyceride to form an oil phase such that the ratio of the amounts of the grignard monomer, 2-bromoisobutyryl bromide, tris (2-pyridylmethyl) amine, fulvestrant and caprylic capric triglyceride used was: 0.016 mol: 0.1 mmol: 0.4 mmol: 0.3 mmol: 0.4mol, then oxygen is removed by nitrogen purge, ready for use.
(2) Preparation of the poly galbanum ester microcapsule:
mixing all the water phase and the oil phase obtained in the step (1), stirring at a high speed to form an emulsion, removing oxygen by nitrogen purging, adding 1g of cuprous bromide aqueous solution (the cuprous bromide content is 0.029g), mixing, supplementing 5.641g of deionized water to make the total weight be 50g, and re-stirring to obtain an emulsion to obtain a reaction mixture;
and (3) keeping the reaction mixture at 25 ℃ for 1 hour under stirring at the speed of 200 rpm, then heating the reaction mixture to 55 ℃ for constant-temperature reaction for 10 hours, and obtaining the pegylation ester microcapsule after the reaction is finished. The size of the polyglacyl microcapsules is detected by a light scattering technology, the size of the polyglacyl microcapsules is 5-15 mu m, and the average size of the polyglacyl microcapsules is 7 mu m.
FIG. 1 is a microscopic view of a microcapsule of poly-galbanum ester, which shows that the microcapsule has a spherical structure, a regular structure, a transparent center and a hollow structure, and the outer wall material contains fulvestrant.
Fig. 2 is a scanning electron microscope image of the pegylation microcapsule, and it can be seen from the image that the pegylation microcapsule maintains its physical integrity under stress, is a complete spherical structure, has no rupture under the vacuum condition of the scanning electron microscope, and has strong mechanical properties.
In this embodiment, the polymer microcapsule is prepared by extracting the oil phase core material with methanol, then blending the oil phase core material with deuterated dimethyl sulfoxide, and characterizing by proton nuclear magnetic resonance, where the result is: peak position 0.86(q, 6H, CH) 3 )，1.40(q，2H，(CH 3 ) 2 CHCH 2 )，1.67(m，1H，CH(CH 3 ) 2 )，3.48(t，2H，CH 2 CH 2 O)，4.11(s，2H，OCH 2 CO)，4.60(d，2H，COOCH 2 ) 5.22(d, 1H, J-11.5 Hz), 5.31(d, 1H, J-17.5 Hz), 5.92(m, 1H, RHC). This indicates the presence of poly galbanum ester.
Example 2:
(1) pretreatment of the water phase and the oil phase:
water phase: 0.75g of saponin was added to 24.25g of deionized water to form an aqueous phase, and oxygen was removed by nitrogen purge for use.
Oil phase: 3.02g of a grignard monomer, 0.023g of initiator 2-bromoisobutyryl bromide, 0.116g of catalyst tris (2-pyridylmethyl) amine and 0.2g of fulvestrant were mixed into 15g of caprylic capric triglyceride to form an oil phase such that the ratio of the amounts of the grignard monomer, 2-bromoisobutyryl bromide, tris (2-pyridylmethyl) amine, fulvestrant and caprylic capric triglyceride used was: 0.016 mol: 0.1 mmol: 0.4 mmol: 0.3 mmol: 0.4mol, then oxygen is removed by nitrogen purge, ready for use.
(2) Preparation of the polyglauconate microcapsules:
mixing the water phase and the oil phase obtained in the step (1), stirring at a high speed to form an emulsion, removing oxygen by nitrogen purging, adding 1g of cuprous bromide aqueous solution (the cuprous bromide content is 0.029g), mixing, supplementing 5.641g of deionized water to make the total weight be 50g, and re-stirring to obtain an emulsion to obtain a reaction mixture;
the reaction mixture was kept at 25 ℃ for 1 hour with stirring at 200 rpm, then the curing temperature of the reaction mixture was varied in 5 ℃ increments from 30 ℃ to 75 ℃ and the reaction was thermostated for 10 hours, after which different pegylation microcapsules were obtained.
The amount of fulvestrant loaded in the biomaterial microcapsules prepared by curing for 10 hours at different temperatures was also examined in this example, as follows: 0.1g of the microcapsule solution was mixed into 10mL of n-hexane solution to extract the unsupported fulvestrant, and then the fulvestrant and internal standard concentration were detected by a High Performance Liquid Chromatography (HPLC) system having an Inertsil YMC-ODS-AQ 3F C18 column coupled to a Sciex API III + triple quadrupole mass spectrometer. Next, the packing efficiency and packing rate of the fulvestrant population are calculated.
The calculation formula is as follows:
fulvestrant loading (% by weight) is (amount of drug dosed-weight of unencapsulated drug)/total amount of microcapsule system x 100%;
the entrapment efficiency (wt%) of fulvestrant is (drug dose-unencapsulated drug weight)/drug dose × 100%.
And (4) obtaining the entrapment rate and entrapment efficiency of the polyglaucor microcapsules prepared at different curing temperatures to the fulvestrant group through calculation.
And (3) carrying out nanoindentation test on the poly-galbanum ester microcapsules with different curing temperatures by adopting a nanoindenter equipped with a diamond glass type pressure head, and judging the mechanical strength of the microcapsules by detecting the rupture strength of the microcapsules.
Specific results are shown in table 1.
TABLE 1 encapsulation efficiency and entrapment efficiency of Polygalate microcapsules prepared at different curing temperatures to fulvestrant
| Curing temperature (. degree.C.) | Fulvestrant population entrapment rate | Fulvestrant population entrapment efficiency | Breaking strength (μ N) |
| 30 | 21.5％ | 62.1％ | 0.21 |
| 35 | 22.8％ | 83.2％ | 0.93 |
| 40 | 29.8％ | 99.7％ | 3.55 |
| 45 | 29.8％ | 99.8％ | 3.63 |
| 50 | 29.8％ | 99.8％ | 3.67 |
| 55 | 29.8％ | 99.8％ | 3.71 |
| 60 | 29.8％ | 99.8％ | 3.80 |
| 65 | 29.8％ | 99.7％ | 3.81 |
| 70 | 23.2％ | 66.2％ | 0.23 |
| 75 | 21.5％ | 63.2％ | 0.22 |
As can be seen from the table 1, the drug entrapment rate of fulvestrant in the capsule with the dosage of biomacromolecules of 40-65 ℃ is very high and can reach 30%, the drug entrapment efficiency can reach more than 97%, the rupture strength of the microcapsule reaches 2.5-5 mu N, and the microcapsule shows very high mechanical strength. When the curing temperature is lower than 40 ℃, the essential oil entrapment efficiency is only about 80%, and meanwhile, the mechanical strength of the microcapsule is poor, which shows that the rupture strength is less than 1 mu N; when the curing temperature is higher than 65 ℃, the microcapsules are combined with each other, the viscosity of the sample is too high, so the essential oil loading efficiency is reduced to below 70%, and the rupture strength is reduced to below 0.5 mu N, which shows that the mechanical strength of the microcapsules is greatly reduced. Therefore, the optimal curing temperature of the preparation method of the peganum polygeritan microcapsules is kept between 40 and 65 ℃.
Example 3:
(1) pretreatment of the water phase and the oil phase:
water phase: 0.75g of saponin was added to 24.25g of deionized water to form an aqueous phase, and oxygen was removed by nitrogen purge for use.
Oil phase: 3.02g of a grignard monomer, 0.023g of initiator 2-bromoisobutyryl bromide, 0.116g of catalyst tris (2-pyridylmethyl) amine and 0.2g of fulvestrant were mixed into 15g of caprylic capric triglyceride to form an oil phase such that the ratio of the amounts of the grignard monomer, 2-bromoisobutyryl bromide, tris (2-pyridylmethyl) amine, fulvestrant and caprylic capric triglyceride used was: 0.016 mol: 0.1 mmol: 0.4 mmol: 0.3 mmol: 0.4mol, then oxygen is removed by nitrogen purge, ready for use.
(2) Preparation of the polyglauconate microcapsules:
mixing the water phase and the oil phase obtained in the step (1), stirring at a high speed to form an emulsion, removing oxygen by nitrogen purging, adding 1g of cuprous bromide aqueous solution (the cuprous bromide content is 0.029g), mixing, supplementing 5.641g of deionized water to make the total weight be 50g, and re-stirring to obtain an emulsion to obtain a reaction mixture;
keeping the reaction mixture at 25 ℃ for 1 hour under stirring at the speed of 200 rpm, and then reacting the reaction mixture at 55 ℃ for 5 hours, 7.5 hours, 10 hours, 12.5 hours and 15 hours respectively to obtain the pegylation ester microcapsule after the reaction is finished.
In this example, the effect of different reaction times on the molecular weight, molecular weight distribution and thickness of the pegylation microcapsules on the wall of the pegylation microcapsules was also examined. In this example, the molecular weight of the pegylation was characterized by Gel Permeation Chromatography (GPC), the thickness of the pegylation microcapsules was characterized by transmission electron microscopy, and the rupture strength of the microcapsules was characterized by nanoindentation test to determine the mechanical strength of the microcapsules. . Specific results are shown in table 2.
TABLE 2 Effect of different reaction times on Polygalate microcapsules
As can be seen from Table 2, the molecular weight of the poly-glaucoxate gradually increases with the polymerization time, the microcapsule wall gradually thickens with the polymerization time, and the rupture strength gradually increases, which shows that the poly-glaucoxate is synthesized by surface-initiated active radical synthesis work, and meanwhile, the molecular weight and the molecular weight distribution can be well controlled, and the mechanical strength is good.
Example 4:
(1) pretreatment of the water phase and the oil phase:
water phase: 0.75g of saponin was added to 24.25g of deionized water to form an aqueous phase, and oxygen was removed by nitrogen purge for use.
Oil phase: 3.02g of ethylene glycol dimethacrylate and 0.2g of fulvestrant were mixed into 15g of caprylic capric triglyceride to form an oil phase, and then oxygen was removed by nitrogen purge for use.
(2) Preparation of the polyglauconate microcapsules:
mixing the water phase and the oil phase obtained in the step (1) and stirring at a high speed to form an emulsion, removing oxygen by nitrogen purging, then adding 5g of an aqueous solution of ammonium persulfate and sodium metabisulfite (the contents of the ammonium persulfate and the metabisulfite are 0.046g and 0.092g respectively), adding 1.78g of deionized water after mixing to make the total weight 50g, and stirring again to obtain an emulsion to obtain a reaction mixture;
and (3) keeping the reaction mixture at 25 ℃ for 1 hour under stirring at the speed of 200 r/min, then heating the reaction mixture to 55 ℃ and reacting for 10 hours at constant temperature, and obtaining the poly-glaucosylate microcapsules after the reaction is finished.
The storage stability of the polyglacyl microcapsules prepared in example 1 and the polyglacyl microcapsules prepared in this example were also examined in this example, the procedure was examined as follows: the microcapsules prepared in examples 1 and 4 were dispersed at 1% in phosphoric acid buffer solution, then the samples were aged at 37 ℃ for a period of 80 days and the amount of leached fulvestrant was measured by direct injection by liquid chromatography. The results of the examination are shown in table 3:
TABLE 3 storage stability of Polygalate microcapsules prepared under different conditions
| Polygalate microcapsules | New preparation | Aging at 37 deg.C for 80 days |
| Example 1 | <10％ | 21％ |
| Example 4 | <10％ | 70％ |
As can be seen from the above table, the pegylation microcapsules prepared by the atom transfer radical polymerization method in example 1 after aging at 37 ℃ for 80 days retain most of the oil phase core and only less than 25% of the core material is leached, while the polyethylene glycol dimethacrylate microcapsules prepared by the conventional radical polymerization method in example 7 (70%) are leached, confirming that the pegylation microcapsules in example 1 have strong storage stability of the oil phase core material.
The present invention is not limited to the above-described embodiments, and any obvious improvements, substitutions or modifications can be made by those skilled in the art without departing from the spirit of the present invention.
Claims (10)
1. A preparation method of a peganum polygermyl microcapsule is characterized by comprising the following steps:
(1) pretreatment of the water phase and the oil phase:
water phase: adding saponin into deionized water to form water phase, and removing oxygen by nitrogen purging;
oil phase: mixing a galbanum ester monomer, an initiator 2-bromoisobutyryl bromide, a catalyst tri (2-pyridylmethyl) amine and an active molecule into caprylic capric triglyceride to form an oil phase, and removing oxygen by nitrogen purging for later use;
(2) preparation of the polyglauconate microcapsules:
mixing the obtained water phase and oil phase, stirring at a high speed to form a concentrated emulsion, removing oxygen by nitrogen purging, adding a cuprous bromide aqueous solution, mixing, supplementing deionized water, and recovering the emulsion to obtain a reaction mixture;
and (3) carrying out low-temperature reaction on the reaction mixture in a stirring environment, then heating the reaction mixture to 40-65 ℃ for constant-temperature reaction for 5-15 h, and obtaining the pegylation ester microcapsule after the reaction is finished.
2. The preparation method of the pegaptanite microcapsule according to claim 1, wherein in the step (1), the mass ratio of the saponin to the deionized water in the aqueous phase is 0.5-1 g: 14-15.5 g.
3. The method for preparing the peganum polygermyl microcapsules according to claim 1, wherein in the step (1), the ratio of the amount of the peganum monomer, the 2-bromoisobutyryl bromide, the tris (2-pyridylmethyl) amine, the active molecule and the caprylic capric triglyceride in the oil phase is as follows: 0.01 to 0.02 mol: 0.1 mmol: 0.4 mmol: 0.3 mmol: 0.4 mol.
4. The method of claim 3, wherein said active molecule is fulvestrant.
5. The method for preparing the pegaptanite microcapsule according to claim 1, wherein the ratio of the amount of the water phase to the amount of the oil phase in step (2) is 25 g: 15-20 g.
6. The method for preparing the pegylation microcapsules according to claim 1, wherein in the step (2), the dosage ratio of the concentrated emulsion, the cuprous bromide and the emulsion is 30-35 g: 0.02-0.05 g: 50 g.
7. The method for preparing the pegylation microcapsules of claim 1, wherein the pre-low temperature reaction conditions in the stirring environment in step (2) are as follows: keeping the temperature at 25 ℃ for 0.5-2 hours under the stirring environment of 200 revolutions per minute.
8. The peganum polygamum ester microcapsule prepared by the preparation method according to any one of claims 1 to 7, wherein the microcapsule has a spherical hollow structure, the wall material of the microcapsule has a thickness of 10 to 30nm, the diameter of the microcapsule is 5 to 15 μm, and the rupture strength is 2.5 to 5 μ N.
9. Use of the peganum pregelatinium microcapsules according to claim 8 as active molecule embedding material.
10. The use according to claim 9, wherein the active molecule is fulvestrant.
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| CN108420739A (en) * | 2018-03-28 | 2018-08-21 | 东华大学 | Using polyethyleneglycol diacrylate as sun-proof microcapsules of wall material and preparation method thereof |
| CN111450079A (en) * | 2020-03-19 | 2020-07-28 | 上海交通大学 | Hollow drug-loaded nano capsule and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108420739A (en) * | 2018-03-28 | 2018-08-21 | 东华大学 | Using polyethyleneglycol diacrylate as sun-proof microcapsules of wall material and preparation method thereof |
| CN111450079A (en) * | 2020-03-19 | 2020-07-28 | 上海交通大学 | Hollow drug-loaded nano capsule and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
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| MEHMET GUMUSTAS ETAL.: "Optimization of a validated stability-indicatingRP-LC method for the determination of fulvestrant from polymeric based nanoparticlesystems, drugs and biological samples", 《BIOMEDICAL CHROMATOGRAPHY》, vol. 28, 27 May 2014 (2014-05-27), pages 1409 - 1417 * |
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