CN116948071A - Poly fatty acid granule emulsifier for preparing W/O/W emulsion and application thereof - Google Patents
Poly fatty acid granule emulsifier for preparing W/O/W emulsion and application thereof Download PDFInfo
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- CN116948071A CN116948071A CN202310840309.0A CN202310840309A CN116948071A CN 116948071 A CN116948071 A CN 116948071A CN 202310840309 A CN202310840309 A CN 202310840309A CN 116948071 A CN116948071 A CN 116948071A
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- Prior art keywords
- linoleic acid
- emulsion
- conjugated linoleic
- emulsifier
- oil
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- 239000003995 emulsifying agent Substances 0.000 title claims abstract description 59
- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 9
- 239000000194 fatty acid Substances 0.000 title claims abstract description 9
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 9
- 150000004665 fatty acids Chemical class 0.000 title claims abstract description 9
- 239000008307 w/o/w-emulsion Substances 0.000 title abstract description 5
- 239000008187 granular material Substances 0.000 title abstract description 4
- 239000000839 emulsion Substances 0.000 claims abstract description 215
- JBYXPOFIGCOSSB-GOJKSUSPSA-N 9-cis,11-trans-octadecadienoic acid Chemical compound CCCCCC\C=C\C=C/CCCCCCCC(O)=O JBYXPOFIGCOSSB-GOJKSUSPSA-N 0.000 claims abstract description 152
- 229940108924 conjugated linoleic acid Drugs 0.000 claims abstract description 152
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 claims abstract description 152
- 239000002245 particle Substances 0.000 claims abstract description 118
- 239000003921 oil Substances 0.000 claims abstract description 54
- 238000004132 cross linking Methods 0.000 claims abstract description 37
- 229920000642 polymer Polymers 0.000 claims abstract description 35
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 235000019198 oils Nutrition 0.000 claims description 50
- 239000012071 phase Substances 0.000 claims description 45
- 239000002285 corn oil Substances 0.000 claims description 33
- 235000005687 corn oil Nutrition 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000000725 suspension Substances 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 229910052708 sodium Inorganic materials 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 13
- WYPBVHPKMJYUEO-NBTZWHCOSA-M sodium;(9z,12z)-octadeca-9,12-dienoate Chemical compound [Na+].CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O WYPBVHPKMJYUEO-NBTZWHCOSA-M 0.000 claims description 13
- 230000000087 stabilizing effect Effects 0.000 claims description 10
- 239000000178 monomer Substances 0.000 claims description 8
- 238000006116 polymerization reaction Methods 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 230000005587 bubbling Effects 0.000 claims description 7
- 239000011521 glass Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 230000001678 irradiating effect Effects 0.000 claims description 6
- 229920002545 silicone oil Polymers 0.000 claims description 6
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- 238000007789 sealing Methods 0.000 claims description 4
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 claims description 3
- 239000010495 camellia oil Substances 0.000 claims description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000944 linseed oil Substances 0.000 claims description 3
- 235000021388 linseed oil Nutrition 0.000 claims description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000003813 safflower oil Substances 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- 235000020238 sunflower seed Nutrition 0.000 claims description 3
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 3
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 3
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 3
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims description 2
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims description 2
- 229960004488 linolenic acid Drugs 0.000 claims description 2
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000000977 initiatory effect Effects 0.000 claims 1
- 230000004043 responsiveness Effects 0.000 abstract description 8
- 230000000638 stimulation Effects 0.000 abstract description 2
- 238000010556 emulsion polymerization method Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 17
- 239000002105 nanoparticle Substances 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- UVCJGUGAGLDPAA-UHFFFAOYSA-N ensulizole Chemical compound N1C2=CC(S(=O)(=O)O)=CC=C2N=C1C1=CC=CC=C1 UVCJGUGAGLDPAA-UHFFFAOYSA-N 0.000 description 8
- 229960000655 ensulizole Drugs 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 6
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 5
- 239000013283 Janus particle Substances 0.000 description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- MRQIXHXHHPWVIL-ISLYRVAYSA-N Sudan I Chemical compound OC1=CC=C2C=CC=CC2=C1\N=N\C1=CC=CC=C1 MRQIXHXHHPWVIL-ISLYRVAYSA-N 0.000 description 5
- 235000017471 coenzyme Q10 Nutrition 0.000 description 5
- VQHHOXOLUXRQFQ-UHFFFAOYSA-L dipotassium;4,5,6,7-tetrachloro-2',4',5',7'-tetraiodo-3-oxospiro[2-benzofuran-1,9'-xanthene]-3',6'-diolate Chemical compound [K+].[K+].O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(I)=C([O-])C(I)=C1OC1=C(I)C([O-])=C(I)C=C21 VQHHOXOLUXRQFQ-UHFFFAOYSA-L 0.000 description 5
- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 description 5
- 238000004945 emulsification Methods 0.000 description 5
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229940080264 sodium dodecylbenzenesulfonate Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000001804 emulsifying effect Effects 0.000 description 4
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229910021642 ultra pure water Inorganic materials 0.000 description 4
- 239000012498 ultrapure water Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000000265 homogenisation Methods 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- DCAYPVUWAIABOU-UHFFFAOYSA-N hexadecane Chemical compound CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 description 2
- 239000008384 inner phase Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000008385 outer phase Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- UUGXJSBPSRROMU-UHFFFAOYSA-N 2,3-dimethoxy-5-methyl-2-<(all-E)-3',7',11',15',19',23',27',31',35'-nonamethylhexatriaconta-2',6',10',14',18',22',26',30',34',nonaenyl>cyclohexa-2,5-dien-1,4-dion Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O UUGXJSBPSRROMU-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-M 9-cis,12-cis-Octadecadienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O OYHQOLUKZRVURQ-HZJYTTRNSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229910021389 graphene Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229940049918 linoleate Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- IZGYIFFQBZWOLJ-CKAACLRMSA-N phaseic acid Chemical compound C1C(=O)C[C@@]2(C)OC[C@]1(C)[C@@]2(O)C=CC(/C)=C\C(O)=O IZGYIFFQBZWOLJ-CKAACLRMSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/62—Monocarboxylic acids having ten or more carbon atoms; Derivatives thereof
- C08F120/64—Acids; Metal salts or ammonium salts thereof
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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
- C08F2/46—Polymerisation initiated by wave energy or particle radiation
- C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Colloid Chemistry (AREA)
Abstract
The application discloses a poly fatty acid granule emulsifier for preparing W/O/W emulsion and application thereof, belonging to the technical field of emulsifier preparation. The application uses partially neutralized conjugated linoleic acid as oil phase and emulsifier, and prepares high polymer conjugated linoleic acid particles with the crosslinking degree of 80-85% and the average particle diameter of 15nm by a two-step emulsion polymerization method. The high conjugated linoleic acid particles are taken as a single emulsifier, and stable W/O/W Pickering multiple emulsion with pH stimulation responsiveness can be prepared singly and once when the minimum addition is 0.021 wt%; moreover, the oil phase used can be various low-polarity oils and can be used for embedding and slowly releasing hydrophilic drugs and hydrophobic drugs simultaneously.
Description
Technical Field
The application relates to an emulsifier, in particular to a poly fatty acid granule emulsifier for preparing W/O/W emulsion and application thereof.
Background
Multiple emulsions are multiple emulsions formed by dispersing one emulsion in another continuous phase. Common multiple emulsions are largely divided into two categories: water-in-oil-in-water (W/O/W), oil-in-water-in-oil (O/W/O). W/O/W emulsions are one type of emulsion system that is currently common. The "three-phase two-film" structure within the W/O/W gives it a number of advantages over conventional emulsions, such as the ability to synergistically entrap polar and non-polar active substances.
At present, two emulsifying agents, including two small molecular hydrophobic and hydrophilic emulsifying agents or a small molecular emulsifying agent and a particle emulsifying agent, are generally used for preparing the multiple emulsion, and the emulsion preparation process is complex; furthermore, the emulsion oil has certain selectivity or suitability for the emulsifier. The emulsion obtained by using the particles as an emulsifier is called Pickering emulsion and is a near-thermomechanical stable system. Compared with emulsion adopting a small molecular emulsifier, the Pickering emulsion has better biocompatibility. Most Pickering emulsifiers, when used alone, stabilize conventional emulsions rather than multiple emulsions. However, it is also possible to obtain multiple emulsions by one-step emulsification with only a single Janus particle emulsifier, but the problems of complicated process, increased energy consumption, etc. are advanced to the stage of preparing Janus particle emulsifier, and Janus particles are difficult to mass-produce.
The oil phase properties of the emulsion determine the oil/water interfacial tension, the thiokett et al uses graphene oxide sheets to stabilize the Pickering emulsion, and uses a nonpolar solvent (hexadecane) and an aromatic solvent (benzene, toluene, styrene) as the oil phase to prepare an O/W emulsion; however, when a weak polar solvent (ethyl acetate, chloroform, methyl acrylate) was used as the oil phase, no emulsion was formed. The properties of the oil phase can also influence the properties of particles, zhang et al use superfine pearl powder as an emulsifier to study the influence of four oil phases, namely alkane, ester, vegetable oil and alcohol ether, on Pickering emulsion, use alkane and ester as the oil phases to prepare O/W emulsion, use vegetable oil to prepare W/O emulsion, and use alcohol ether as the oil phase to fail to form emulsion due to too low interfacial tension.
Therefore, there is a need to develop an emulsifier which can be used alone to emulsify multiple emulsion Pickering emulsions which are simple to prepare and have a wide application range, and which will be beneficial for co-embedding hydrophilic/hydrophobic drugs.
Disclosure of Invention
[ technical problem ]
The application aims to solve the technical problems that two kinds of emulsifying agents, namely hydrophobic and hydrophilic, are generally needed for preparing multiple emulsion, the oil phase varieties suitable for the particle emulsifying agent are narrow, and the environment-friendly multiple emulsion which is responded by environmental stimulus is difficult to prepare by using the particle emulsifying agent of a single variety for co-embedding the hydrophilic/hydrophobic medicine. The Pickering emulsifier and emulsion preparation technology of multiple emulsions with nanometer level, wide oil phase application range and environmental stimulus response can be prepared by using a single variety of particle emulsifier, and the Pickering emulsifier can be used for embedding and slowly releasing hydrophilic drugs and hydrophobic drugs.
Technical scheme
The application discloses a particle emulsifier for stabilizing W/O/W multiple emulsion, which is high polymer fatty acid particles, wherein the high polymer is unsaturated fatty acid with a crosslinking degree of 80-85%, and the fatty acid can be conjugated linoleic acid or sodium salt thereof, or conjugated linolenic acid or sodium salt thereof; preferably, the high-polymer conjugated linoleic acid-sodium high-polymer conjugated linoleic acid particles (i.e., particles obtained by partially neutralizing high-polymer conjugated linoleic acid) coexist with high-polymer conjugated linoleic acid and sodium high-polymer conjugated linoleic acid, and the high-polymer conjugated linoleic acid particles are referred to as high-polymer conjugated linoleic acid-sodium high-polymer conjugated linoleic acid particles in the application for convenience of expression. The particle emulsifier is widely applicable to various weak polar oils (such as corn oil, sunflower seed oil, soybean oil, linseed oil, safflower seed oil, tea seed oil, linoleic acid, caprylic/capric triglyceride (GTCC), dimethyl silicone oil and phenyl silicone oil), and the W/O/W type Pickering emulsion prepared by applying the particle emulsifier can be used for co-embedding hydrophilic/hydrophobic drugs.
The possible mechanism that the high-polymer conjugated linoleic acid particles can independently stabilize the W/O/W multiple emulsion is that the high-polymer conjugated linoleic acid particles can be on-line Janus-like due to the high-density carboxyl on the surfaces of the particles, so that the high-polymer conjugated linoleic acid particles can have double emulsifying properties, namely the common Pickering emulsifying property and the Janus-like Pickering emulsifying property. On-line Janus formation means that when a particle with all carboxyl groups on its surface is used, under certain conditions, the original uniform distribution of H on its surface carboxyl array is achieved due to the presence of the oil/water phase at the two partial surface fractions of each fatty acid particle at the oil/water interface + And Na (Na) + It is possible to be environmentally induced to redistribute on both partial oil/water surfaces, i.e. in situ Janus functionalization (near water surface Na + Chemical approach to oil surface H + Chemical) so that the homogeneous SCU particles exhibit properties that mimic Janus particles at the oil/water interface. At the same time, the carboxyl array on the particle surface has stimulus responsiveness, and the emulsion stabilized by the carboxyl array has the possibility of showing pH/Ca 2+ And the like. Therefore, the step-by-step emulsification process of two kinds of emulsifying agents, namely hydrophobic and hydrophilic, is not needed, and the complex Janus particle emulsifying agent is not needed to be prepared, so that the complex preparation process of the multiple emulsion is simplified, and the greenness, the sustainability and the practicability of the multiple emulsion are enhanced.
The application discloses a method for preparing high-polymer conjugated linoleic acid particles, which takes conjugated linoleic acid as an oil phase, takes conjugated sodium linoleate as an emulsifier to emulsify conjugated linoleic acid (inner phase) -water (outer phase), takes the conjugated sodium linoleate as the emulsifier to be adsorbed on a conjugated linoleic acid-water interface and participates in the following self-crosslinking reaction. Namely, the conjugated linoleic acid suspension with a certain pH is simply mechanically homogenized to prepare O/W emulsion with a high internal phase and a certain particle size range, and then the high-polymer conjugated linoleic acid particles with a certain polymerization degree are obtained through self-crosslinking.
In one embodiment of the application, the method comprises the steps of:
(1) 28 g of conjugated linoleic acid was reacted with 33-50mL of sodium bicarbonate (0.1 mol.L) -1 ) The neutralization is carried out,
(2) Homogenizing for 5min at 12000rpm to obtain emulsion, repeatedly homogenizing until the average particle size of the emulsion reaches 50nm or below, wherein conjugated linoleic acid in the emulsion is used as an oil phase, and partially neutralized conjugated linoleic acid, namely conjugated sodium linoleate, is used as an emulsifier to emulsify conjugated linoleic acid (inner phase) -water (outer phase), and the conjugated sodium linoleate is used as the emulsifier to be adsorbed on the interface of the conjugated linoleic acid-water and participates in the self-crosslinking reaction in the step (3); conjugated linoleic acid in the corresponding high concentration emulsion or polymer prepared under the condition and a total mass concentration of about 56% to 84% of sodium conjugated linoleate (when calculated as monomer);
(3) Adding the emulsion into a glass polymerization reactor, and using N under the condition of avoiding light 2 Bubbling for 5min to eliminate oxygen from the solution, adding water solution of photo initiator APS (APS added amount is 1wt% of conjugated linoleic acid), sealing the reactor, irradiating the solution with ultraviolet point light source at 365nm wavelength for self-crosslinking, adding APS (APS added amount is 1wt% of conjugated linoleic acid) after irradiation for 1-2 hr, and reacting at 75-80 deg.c for 3 hr and 5 hr to obtain suspension of high conjugated linoleic acid-sodium high conjugated linoleic acid particle with crosslinking degree of 80% and 85%. The diameter of the obtained high conjugated linoleic acid-high conjugated linoleic acid sodium particles is about 15 nm.
In one embodiment of the application, the method comprises the steps of:
(1) 28 g of conjugated linoleic acid was combined with 33mL of sodium bicarbonate solution (0.1 mol.L -1 ) The concentration of the conjugated sodium linoleate in the neutralized product is about 170g/L, and the concentration of the conjugated sodium linoleate is about 678g/L;
(2) Homogenizing at 12000rpm for 5min to obtain emulsion, repeatedly homogenizing until the average particle diameter of the emulsion is below 50 nm; the total mass concentration of conjugated linoleic acid and sodium conjugated linoleic acid (calculated as monomer) in the corresponding high concentration emulsion or polymer prepared under this condition is about 84 wt.%;
(3) The emulsion is added into a glass polymerization reactor and used in the darkN 2 Bubbling for 5min to eliminate oxygen from the solution, adding water solution of photo initiator APS (APS added amount is 1wt% of conjugated linoleic acid), sealing the reactor, irradiating the solution with ultraviolet point light source at 365nm wavelength for self-crosslinking, adding APS (APS added amount is 1wt% of conjugated linoleic acid) after irradiation for 1 hr, and reacting at 75 deg.C for 3 hr to obtain suspension of high conjugated linoleic acid particle with crosslinking degree of 80%.
In another embodiment of the present application, the method comprises the steps of:
(1) 28 g of conjugated linoleic acid was reacted with 50mL of sodium hydrogencarbonate (0.1 mol. L) -1 ) The concentration of the conjugated sodium linoleate in the neutralized product is about 51g/L, and the concentration of the conjugated sodium linoleate is about 509g/L;
(2) Homogenizing at 12000rpm for 5min to obtain emulsion, repeatedly homogenizing until the average particle diameter of the emulsion reaches 50nm or less; the total mass concentration of conjugated linoleic acid and sodium conjugated linoleic acid (calculated as monomer) in the corresponding high concentration emulsion or polymer prepared under this condition was about 56wt%;
(3) The emulsion was introduced into a glass polymerization reactor and protected from light by N 2 Bubbling for 5min to eliminate oxygen from the solution, adding water solution of photo initiator APS (APS added amount is 1wt% of conjugated linoleic acid), sealing the reactor, irradiating the solution with ultraviolet point light source at 365nm wavelength for self-crosslinking, adding APS (APS added amount is 1wt% of conjugated linoleic acid) after irradiation for 2 hr, and reacting at 75 deg.C for 5 hr to obtain suspension of high conjugated linoleic acid particle with crosslinking degree of 85%.
The application discloses a method for preparing W/O/W type Pickering emulsion by using the particle emulsifier for stabilizing W/O/W multiple emulsion, which takes high conjugated linoleic acid particles as a single emulsifier to prepare the W/O/W type Pickering emulsion in one step, wherein one of the mechanisms for preparing the W/O/W type Pickering emulsion by the high conjugated linoleic acid particles in one step is as follows: the particles can be Janus-changed on-line when preparing W/O/W Pickering emulsion due to the dense carboxyl array. The method comprises the following steps: simply mixing the high-polymer conjugated linoleic acid nano particles with the oil phase and the water phase, and then using the mixtureHomogenizing by a mass machine to directly obtain the W/O/W Pickering emulsion. The homogenization is carried out at 8k-14k r.min by using a homogenizer -1 Homogenizing for 2-8min. The volume fraction of the oil phase is 30-85%, and the addition amount of the high polymer conjugated linoleic acid particles is 0.021-0.21 wt% of the emulsion.
In one embodiment, the preferred oil phase volume fraction80 percent of high-polymer conjugated linoleic acid particles with the addition of 0.21 percent of the weight of the emulsion and the rotation speed of a homogenizer of 12k r.min -1 Homogenizing for 5min.
The application discloses a W/O/W type Pickering emulsion prepared by applying the particle emulsifier for stabilizing W/O/W multiple emulsion. The W/O/W type Pickering emulsion has good storage stability, and the concentration of the emulsion is 0-1.2 mol.L -1 The multi-emulsion structure can be maintained after 30 days of storage under the NaCl concentration (namely, the highest NaCl final concentration is 7.02 percent); increasing or decreasing the ambient temperature of storage in the range of 4-50 ℃ does not affect the structure of the multiple emulsion; in the pH range of 7.7 to 12.6, the multiple emulsion structure is maintained, and pH responsiveness is provided in the vicinity of pH 7.7.
The application discloses application of a W/O/W Pickering emulsion, which comprises application in the technical field of medicine preparation, including application in co-embedding of hydrophilic/hydrophobic medicines, slow release of hydrophilic medicines and hydrophobic medicines.
[ advantageous effects ]
The application takes high polymer conjugated linoleic acid particles with the crosslinking degree of 80-85% and the average particle diameter of 15nm as a single emulsifier, and can singly prepare the stable W/O/W type Pickering multiple emulsion with pH stimulation responsiveness at one time when the minimum addition amount is 0.021 wt%; moreover, the oil phase used can be various low-polarity oils and can be used for embedding and slowly releasing hydrophilic drugs and hydrophobic drugs simultaneously.
Drawings
Fig. 1 is a TEM image of a high conjugated linoleic acid particle.
FIG. 2 SEM of (A) emulsions of different weakly polar oils and (B) dyed corn oil emulsions stabilized with high conjugated linoleic acid particlesA photograph; (C) Confocal laser microscopy image of dyed corn oil emulsion. B (B) 1 -B 3 Corn oil was dyed yellow with sudan I and the high conjugated linoleic acid particle suspension was dyed red with rose bengal B, respectively, and corn oil and the high conjugated linoleic acid particle suspension were dyed together with sudan I and rose bengal B. C (C) 1 -C 3 Corn oil was dyed red with nile red, the suspension of high conjugated linoleic acid particles was dyed green with FITC, and the suspension of corn oil and high conjugated linoleic acid particles were dyed together with FITC, respectively.
FIG. 3 shows the anionic surfactants Sodium Dodecyl Sulfate (SDS), sodium Dodecyl Benzene Sulfonate (SDBS), conjugated Linoleic Acid (CLA), and CLA@Fe 3 O 4 Nanoparticles micrographs of liquid paraffin/corn oil emulsions prepared under identical conditions for the four emulsifiers.
FIG. 4 multiple emulsions were prepared with varying amounts of high conjugated linoleic acid particles. (A): emulsion appearance, (B): emulsion super depth microscopic image, (C): emulsion droplet diameter and (D): emulsion viscosity. Homogenize 5min at 12000rpm at 25 ℃.
Figure 5 multiple emulsions of corn oil with varying oil phase volume fractions stabilized with high conjugated linoleic acid particles. (A): emulsion appearance, (B): emulsion SEM image, (C): emulsion droplet diameter and (D): emulsion viscosity.
FIG. 6 multiple emulsions prepared with different homogenizer speeds. (A): appearance, (B): microscopic image and (C): homogenizer speed-droplet diameter.
FIG. 7 pH responsiveness of multiple emulsions. The (A) appearance, (B) microscopic image and (C) pH-droplet diameter relationship of the multiple emulsion.
FIG. 8 storage stability of salt-containing multiple emulsions stabilized with high conjugated linoleic acid particles.
Figure 9 temperature stability of multiple emulsions stabilized with high conjugated linoleic acid particles. (A): appearance, (B): microscopic image and (C): time-droplet diameter relationship.
FIG. 10 in vitro release profile of (A) CoQ10 and (B) PBSA in a multiple high conjugated linoleic acid particle stabilized microemulsion co-embedding system.
Detailed Description
Conjugated linoleic acid used in the following examples was supplied by Dalian North Bio Inc. Unless otherwise specified, the Pickering W/O/W type multiple emulsion in the following examples had an oil phase volume fraction of 75% and the oil phase oil was corn oil. The suspension of particles of high conjugated linoleic acid was prepared in the same manner as in example 1, except that the pH was 8.6.
Analysis method
Determination and calculation of the degree of crosslinking of conjugated linoleic acid
The absorbance of the conjugated sodium linoleate aqueous solution at 234nm is measured by using an ultraviolet-visible spectrophotometer, and an ultraviolet absorption standard curve is drawn. According to the concentration of conjugated double bonds in the sample before and after self-crosslinking and in combination with an ultraviolet absorption standard curve of a conjugated linoleic acid sodium solution, the crosslinking degree of fatty acid in the high-polymer conjugated linoleic acid particles is calculated: (c) 0 -c)/c 0 Wherein c 0 The concentration of conjugated double bonds in a reaction system before self-crosslinking, namely the total concentration of conjugated linoleic acid and conjugated sodium linoleate before self-crosslinking, and the concentration of conjugated double bonds after self-crosslinking.
The sodium conjugated linoleic acid is dissolved in water, so when the concentration of conjugated double bonds is measured by establishing ultraviolet absorption standard curve, the standard solution takes the sodium conjugated linoleic acid aqueous solution as the standard solution; the standard curve can also be made of the ethanol aqueous solution of conjugated linoleic acid, but the sample needs to be prepared by the ethanol aqueous solution, and the result is the same.
Morphological structure characterization of Pickering multiple emulsions
The morphology of the droplets of the multiple emulsion was observed using a VHX-1000c 3d microscope and the average droplet size was counted by the "Nano Measurer" software.
Multiple emulsion types were judged using a droplet dispersion method and a staining method. The liquid drop dispersing method is to drop one drop of emulsion into ultrapure water, stir, and if the drop is diffused into water, the emulsion external phase is the water phase, if the drop is not diffused, the emulsion external phase is the oil phase. The emulsion type was judged by using rose bengal B to dye the high conjugated linoleic acid particle suspension red, sudan I to dye corn oil yellow, and making and observing the emulsion. FITC was further added to the high conjugated linoleic acid particle suspension, nile red to corn oil, and emulsion type was identified by confocal laser microscopy of emulsion structure and fluorescent position.
EXAMPLE 1 preparation of high conjugated linoleic acid particles
28 g of conjugated linoleic acid was reacted with 33mL of sodium hydrogencarbonate (0.1 mol. L) -1 ) And (3) neutralizing, wherein the concentration of the conjugated linoleic acid is about 170g/L and the concentration of the conjugated linoleic acid is about 678g/L. Homogenizing at 12000rpm for 5min, and repeating homogenizing until the average particle size of the emulsion reaches 50nm or less. The emulsion was introduced into a glass polymerization reactor and protected from light by N 2 Bubbling for 5min to remove oxygen from the solution, an aqueous solution of the photoinitiator APS (APS added in an amount of 1wt% of conjugated linoleic acid) was added rapidly, and the reactor was sealed. The solution was subjected to self-crosslinking by irradiation with an ultraviolet spot light source at 365nm wavelength, and after 1 hour of irradiation, APS was supplemented (APS addition amount was 1wt% of conjugated linoleic acid) and reacted at 75℃for 3 hours to obtain a suspension of high-polymer conjugated linoleic acid particles having a crosslinking degree of 80%, wherein the total mass concentration of conjugated linoleic acid and sodium conjugated linoleic acid (calculated as monomer) was about 84wt%.
28 g of conjugated linoleic acid was reacted with 50mL of sodium hydrogencarbonate (0.1 mol. L) -1 ) And (3) neutralizing, wherein the concentration of the conjugated linoleic acid is about 51g/L and the concentration of the conjugated linoleic acid is about 509g/L. Homogenizing at 12000rpm for 5min, and repeating homogenizing until the average particle size of the emulsion reaches 50nm or less. The emulsion was introduced into a glass polymerization reactor and protected from light by N 2 Bubbling for 5min to remove oxygen from the solution, an aqueous solution of the photoinitiator APS (APS added in an amount of 1wt% of conjugated linoleic acid) was added rapidly, and the reactor was sealed. The solution was irradiated with an ultraviolet spot light source at 365nm wavelength to perform self-crosslinking, and after 2 hours irradiation, APS was supplemented (APS addition amount was 1wt% of conjugated linoleic acid) and reacted at 75℃for 5 hours, whereby a suspension of high-polymer conjugated linoleic acid particles having a crosslinking degree of 85% was obtained, wherein the total mass concentration of conjugated linoleic acid and sodium conjugated linoleic acid (calculated as monomer) was about 56wt%.
High conjugated linoleic acid particles with a degree of crosslinking of 80% and 85% were observed by TEM. FIG. 1 shows that the high conjugated linoleic acid particles have a spherical structure, and the diameters of the particles are about 15 nm.
Example 2 preparation of W/O/W Pickering emulsions of various Low polarity oils Using high conjugated linoleic acid particles
Ten kinds of weak polar oil are used as oil phases to prepare Pickering emulsion, which are corn oil, sunflower seed oil, soybean oil, linseed oil, safflower seed oil, tea seed oil, linoleic acid, caprylic/capric triglyceride (GTCC), dimethyl silicone oil and phenyl silicone oil respectively. 1mL of the suspension of conjugated linoleic acid particles having a crosslinking degree of 80% as prepared in example 1 was mixed with 3mL of oil, and the mixture was stirred at a rotation speed of 9000 r.min -1 Homogenizing for 5min (25deg.C).
Fig. 2A is a microscopic image of each emulsion, showing that the high conjugated linoleic acid particles have good emulsifying effect on the ten weak polar solvents, and can be used as a single emulsifier to prepare multiple emulsion through simple one-step homogeneous emulsification.
Corn oil was chosen as representative for further characterization of the type of multiple emulsion produced. FIG. 2B is a microscopic image of a multiple emulsion with corn oil as the oil phase, wherein B 1 -B 3 The corn oil is dyed into yellow by sudan I, the high-polymer conjugated linoleic acid particle suspension is dyed into red by rose bengal B, and the corn oil and the high-polymer conjugated linoleic acid particle suspension are dyed together by sudan I and rose bengal B, so that the emulsion can be judged to be W/O/W type multiple emulsion according to the color position distribution. The contrast of the image color observed using the super depth of field three-dimensional microscope is not sufficiently apparent, so further using confocal laser microscopy, C in FIG. 2C 1 -C 3 The corn oil is dyed into red by the nile red, the high-polymer conjugated linoleic acid particle suspension is dyed into green by the FITC, the corn oil and the high-polymer conjugated linoleic acid particle suspension are dyed by the nile red and the FITC together, and the multiple emulsion can be clearly judged to be of a W/O/W type according to the positions of fluorescence of different colors. The emulsion type results judged by the three methods are identical, which shows that the multiple emulsion is of W/O/W type.
Comparative example 1 corn oil and liquid paraffin emulsions prepared with a small molecule emulsifier and other particulate emulsifiers
In general, both hydrophilic and hydrophobic emulsifiers are required for the preparation of multiple emulsions, whereas the high conjugated linoleic acid particles can be used as a single emulsifier to prepare multiple emulsions by simple one-time homogeneous emulsification. Part of the particulate emulsifier can also stabilize the multiple emulsion alone.
The emulsion is prepared by using emulsifying agents with different properties, namely anionic surfactants of Sodium Dodecyl Sulfate (SDS), sodium Dodecyl Benzene Sulfonate (SDBS), conjugated Linoleic Acid (CLA) and CLA@Fe 3 O 4 Nanoparticle four emulsifiers an emulsion was prepared under the same conditions. The same condition means that 1mL of the emulsifier suspension and 3mL of oil are mixed, and the mixed solution is stirred at a rotation speed of 9000 r.min -1 Homogenizing for 5min (25deg.C).
Hard particles CLA@Fe 3 O 4 The nano particles are conjugated linoleic acid and sodium salt thereof are wrapped in Fe 3 O 4 Nanoparticles outside the nanoparticles. The preparation method comprises the following steps: nano Fe 3 O 4 Dispersing in 100mL of ultrapure water, adjusting the pH of the system to pH10, transferring into a 250mL three-neck flask, and carrying out ultrasonic treatment for 20min. Dropwise adding conjugated linoleic acid water solution neutralized to pH10 into the nano Fe at 80 DEG C 3 O 4 In the aqueous dispersion (Fe 3 O 4 The mass ratio of the conjugated linoleic acid to the conjugated linoleic acid is 1:2.5), and nitrogen is introduced for deoxidization in the whole process. Cooling the system to room temperature after the dripping is finished for 2 hours, regulating the pH value to be about 5 by using 0.1M hydrochloric acid aqueous solution, placing the mixture at the bottom of a flask to adsorb particles by using a magnet, washing the particles for 3 times by using ultrapure water through a magnetic decantation method, collecting the particles, placing the particles in a 55 ℃ vacuum drying oven for drying to obtain Fe jointly modified by conjugated linoleic acid and conjugated sodium linoleate 3 O 4 And (3) nanoparticles.
For convenience of description, fe modified with conjugated linoleic acid 3 O 4 Nanoparticles, i.e. CLA@Fe 3 O 4 Particles for expressing Fe co-modified by conjugated linoleic acid and conjugated sodium linoleate 3 O 4 And (3) nanoparticles.
FIG. 3 is a microscopic image of emulsions made with different emulsifiers showing that both the surfactant SDBS and SDS stabilized corn oil-water systems form O/W emulsions.
Conjugated linoleic acid and sodium salt thereofCLA) and hard particles cla@fe 3 O 4 Nanoparticle stabilized corn oil-water systems can produce W/O/W multiple emulsions (fig. 3), but CLA stabilized corn oil multiple emulsions have poor stability, i.e., demulsification within a day.
EXAMPLE 3 Effect of high conjugated linoleic acid particle usage on particle size and viscosity of multiple emulsions prepared
The suspension of water, corn oil and high conjugated linoleic acid particles with a degree of crosslinking of 85% prepared in example 1 was homogenized at 9000rpm and 25℃for 5min to obtain a corn oil W/O/W type multiple emulsion.
The appearance, emulsion super depth microscopic image, emulsion droplet diameter and emulsion viscosity of the corn oil W/O/W type multiple emulsion prepared by using different amounts of the high conjugated linoleic acid particles (accounting for 0.021wt% to 0.21wt% of the total mass of the emulsion) are shown in figure 4.
When corn oil is used as the oil phase, the high-polymer conjugated linoleic acid particles can form stable emulsion (figure 4A) when the adding amount of the high-polymer conjugated linoleic acid particles is in the range of 0.021wt% to 0.21wt% of the total mass of the emulsion, and each emulsion shows multiple structures (figure 4B) according to microscopic images, so that the multiple emulsion can be stable under the condition of very low particle use amount (namely 0.021 wt%).
While the variation in droplet size is inversely related to the particle concentration, and the particle size distribution of the multiple emulsion becomes narrower when the particle concentration is high (fig. 4C). In addition, at the same shear rate, the greater the emulsifier concentration, the greater the multiple emulsion viscosity; at the same concentration, the multiple emulsion viscosity decreased with increasing shear rate, indicating that the multiple emulsion had shear thinning behavior (fig. 4D).
0.21wt% is recommended as the optimum amount of the high conjugated linoleic acid particles, and 0.021wt% as the minimum amount of the high conjugated linoleic acid particles.
Example 4 preparation of multiple emulsions with high internal phase volume fraction Using high conjugated linoleic acid particles
Corn oil multiple emulsions of different oil phase volume fractions were stabilised with high conjugated linoleic acid particles prepared in example 1 with a degree of cross-linking of 85% (added in an amount of 0.21% by weight of the emulsion). Fig. 5 is the appearance of multiple emulsions, emulsion SEM images, emulsion droplet diameter, and emulsion viscosity.
High internal phase emulsions refer to emulsions having a higher dispersed phase volume fractionCan store active substances with high efficiency. FIG. 5 shows that when->When the emulsion is used, stable Pickering W/O/W type multiple emulsion can be formed. And according to the appearance of the emulsion, when->No aqueous phase separated out, indicating that the Pickering emulsion was a high internal phase emulsion. The emulsion index (CI) may reflect emulsion stability, and its calculation formula is: ci=h s /H e X 100%, where H s For the height of the semitransparent clear liquid layer (serum layer) precipitated at the bottom of the emulsion, H e Is the total height of the emulsion. It is generally believed that emulsions are more stable at lower CI values, with acceptable ranges of 5% to 35%. Stabilization of different +.>Is a multiple emulsion of corn oil, when-> At this time, ci=0 (fig. 5C), reflecting that the emulsion stability is better at this time.
Recommended useAs the optimal oil phase volume fraction, the influence of critical conditions can be avoided.
EXAMPLE 5 preparation of multiple emulsions with high conjugated linoleic acid particles at different homogenizer speeds
The high conjugated linoleic acid particles prepared in example 1 with a degree of crosslinking of 85% were selectedThe addition amount is 0.21wt%,Corn oil is used as oil phase material, and high polymer conjugated linoleic acid particles are used for preparing multiple emulsion under different rotating speeds of a homogenizer.
FIG. 6 shows the rotational speed of the homogenizer (3 k-13k r min) -1 ) The appearance, microscopic image and homogenizer speed-droplet diameter relationship of the multiple emulsions prepared below. FIG. 6 shows that when the rotational speed of the homogenizer is 8k-14k r min -1 Stable Pickering emulsion can be formed within the range of k r.min -1 Failure to form milk; the rotation speed of the homogenizer is inversely related to the particle size of the liquid drops (figures 3-4B-C), i.e. the increase of the rotation speed of the homogenizer and the decrease of the particle size of the liquid drops are carried out, and the rotation speed of the homogenizer is increased to 12k r min -1 The average particle size of the liquid drops is basically unchanged after that, which shows that for a liquid paraffin emulsion system with stable SCU, 12k r.min -1 Sufficient energy input to achieve the system required, further increases in the homogenization rate result in more energy consumption, so that 12k r min is recommended -1 As a preferred homogenization condition.
In summary, when preparing a multiple emulsion using the high conjugated linoleic acid particles, the preferable conditions are selected such that the addition amount of the high conjugated linoleic acid particles is 0.21wt%,Homogenizer rotation speed 12k r min -1 Homogenizing for 5min.
The result was similar when multiple emulsions were prepared with high conjugated linoleic acid particles having a degree of crosslinking of 80%; the preferable condition is that the addition amount of the high conjugated linoleic acid particles is 0.21wt%,The rotation speed of the homogenizer is 8k r min -1 Homogenizing for 8min.
Example 6 pH responsiveness of high conjugated linoleic acid particle stabilized Pickering multiple emulsion with Cross-Linked 85% prepared in example 1
Fig. 7 is a graph of pH responsiveness of multiple emulsions. The (A) appearance, (B) microscopic image and (C) pH-droplet diameter relationship of the multiple emulsion.
Into a sample bottle, a suspension of particles of high conjugated linoleic acid (pH 8.6,30 mmol.L) -1 ) And a corn oil, wherein the corn oil,80% at 9k r min -1 The mixture was homogenized for 5min (25 ℃ C.). The emulsion pH was then adjusted to 7.5, 7.7, 8.0, 9.6, 10.6, 11.6, 12.6 using HCl and NaOH solutions, respectively, and the emulsion was observed for changes in pH at the different continuous phases.
FIG. 7 shows that the emulsion remains stable at pH7.7 to 12.6; and at a pH of <7.7, the emulsion breaks. Therefore, the multiple emulsion has pH responsiveness around pH 7.7.
EXAMPLE 7 stability of Pickering multiple emulsion stabilized with high conjugated linoleic acid particles prepared in example 1 having a degree of crosslinking of 85%
Into a sample bottle, a suspension of particles of high conjugated linoleic acid (pH 8.6,30 mmol.L) -1 ) And a corn oil, wherein the corn oil,80%,9k r min -1 Homogenizing the mixture for 5min to obtain Pickering multiple emulsion (25deg.C). The 30-day storage stability (fig. 8) and the temperature stability (fig. 9) of the resulting Pickering multiple emulsion were observed, respectively.
FIG. 8 is a graph showing the storage stability of a salt-added multiple emulsion stabilized with high conjugated linoleic acid particles. Adding salt often accelerates demulsification, and the emulsion containing NaCl with different concentrations is respectively kept stand for 1, 7, 15 and 30 days at 25 ℃. By observation of appearance and microstructure, it was found that different concentrations (0-1.2 mol.L -1 That is, the multiple emulsion with the final concentration of 7.02% NaCl can maintain the multiple structure within 30 days, and the multiple emulsion with the stable high-polymer conjugated linoleic acid has good storage stability.
FIG. 9 is a graph of the temperature stability of multiple emulsions (A) appearance, (B) microscopic image, and (C) time-droplet diameter relationship. The obtained Pickering multiple emulsion is respectively kept stand for 24 hours at the temperature of 4, 25, 37 and 50 ℃ and the temperature stability is observed. The temperature at which the multiple emulsion was initially prepared was 25 ℃, the appearance of the emulsion did not change significantly after standing in the range of 4-50 ℃, no demulsification or phase separation occurred, and the multiple emulsion remained stable (fig. 9A). Microscopic images of the emulsions were observed (fig. 9B), and it was found that the multiple emulsion maintained a multiple structure at each temperature, indicating that increasing or decreasing the ambient temperature of storage in the range of 4-50 ℃ did not affect the multiple structure of the SCU-stable multiple emulsion. The Pickering multiple emulsion has good temperature stability within the range of 4-50 ℃.
Application example 1: example 1 preparation of Pickering multiple emulsion with a degree of crosslinking of 80% stabilized with high conjugated linoleic acid particles simultaneously carried and released hydrophilic and hydrophobic actives
The multiple emulsion was used to co-encapsulate and release the hydrophobic active coenzyme Q10 (CoQ 10) and the hydrophilic active phenylbenzimidazole sulfonic acid (PBSA) (fig. 10). The oil phase solvent is n-hexane, and the water phase solvent is ultrapure water. CoQ10 (final concentration in oil phase 24 mg.multidot.mL) -1 ) And PBSA (final concentration in aqueous phase 10 mg.mL) -1 ) Added to the oil and water phases, respectively, and a Pickering multiple emulsion was prepared. Upon release, coQ10 diffuses from the emulsion into the oil phase and PBSA diffuses from the emulsion into the aqueous phase.
Fig. 10A shows a release profile of CoQ10, where CoQ10 is released continuously and slowly over 10 hours, with a good slow release effect. In fig. 10B, the release profile of PBSA shows a burst at 0-2h, because multiple emulsions were prepared by one-step emulsification, part of PBSA was present in the outer aqueous phase, and burst occurred due to rapid release at the initial stage of release; sustained and slow release is carried out within 2-10 hours, and the sustained release preparation has better sustained release effect. According to the release profiles of CoQ10 and PBSA, there is a difference in release rates at different pH: pH 11.5>pH 8.6>pH 7.5, thus enabling the release rate of multiple emulsions to be effectively controlled by pH.
While the application has been described with reference to the preferred embodiments, it is not limited thereto, and various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the application as defined in the appended claims.
Claims (10)
1. The particle emulsifier for stabilizing the W/O/W multiple emulsion is characterized by being high polymer fatty acid particles with the cross-linking degree of unsaturated fatty acid of 80-85%, wherein the unsaturated fatty acid is conjugated linoleic acid or sodium salt thereof, or conjugated linolenic acid or sodium salt thereof.
2. A process for preparing the particulate emulsifier for stabilizing W/O/W multiple emulsions of claim 1, comprising the steps of:
(1) The conjugated linoleic acid is partially neutralized and the conjugated linoleic acid,
(2) Homogenizing the mixture to obtain emulsion,
(3) And initiating self-crosslinking reaction of conjugated linoleic acid and conjugated sodium linoleate by utilizing a photoinitiator in an inert atmosphere to obtain the particle emulsifier.
3. The method according to claim 2, wherein the total mass concentration of conjugated linoleic acid and sodium conjugated linoleic acid calculated as monomers in the emulsion of step (2) is 56% to 84%.
4. The method according to claim 2, wherein step (3) is a self-crosslinking reaction under ultraviolet light irradiation.
5. The method according to claim 2, comprising the steps of:
(1) 28 g of conjugated linoleic acid was mixed with 33mL of 0.1 mol.L -1 Neutralizing with sodium bicarbonate solution to obtain a neutralized product with a concentration of conjugated linoleic acid of about 170g/L and a concentration of conjugated linoleic acid of about 678g/L;
(2) Homogenizing at 12000rpm for 5min to obtain emulsion, repeatedly homogenizing until the average particle diameter of the emulsion is below 50 nm; the total mass concentration of conjugated linoleic acid and sodium conjugated linoleic acid in the emulsion is about 84wt% calculated by monomer;
(3) The emulsion was introduced into a glass polymerization reactor and protected from light by N 2 Bubbling for 5min to remove oxygen in the solution, and rapidly adding lightSealing the reactor, irradiating the solution with ultraviolet point light source at 365nm wavelength for self-crosslinking, adding APS after irradiation for 1 hr, and reacting at 75deg.C for 3 hr to obtain suspension of high conjugated linoleic acid particles with crosslinking degree of 80%;
or alternatively, the first and second heat exchangers may be,
(1) 28 g of conjugated linoleic acid was mixed with 50mL of 0.1 mol.L -1 Neutralizing with sodium bicarbonate to obtain a neutralization product with a concentration of conjugated linoleic acid of about 51g/L and a concentration of conjugated linoleic acid of about 509g/L;
(2) Homogenizing at 12000rpm for 5min to obtain emulsion, repeatedly homogenizing until the average particle diameter of the emulsion reaches 50nm or less; the total mass concentration of conjugated linoleic acid and sodium conjugated linoleic acid in the emulsion is about 56wt%, calculated as monomer;
(3) The emulsion was introduced into a glass polymerization reactor and protected from light by N 2 Bubbling for 5min to eliminate oxygen from the solution, adding water solution of photoinitiator APS, sealing the reactor, irradiating the solution with ultraviolet light source at 365nm wavelength for self-crosslinking, irradiating for 2 hr, replenishing APS, and reacting at 75 deg.c for 5 hr to obtain suspension of high conjugated linoleic acid particle with crosslinking degree of 85%.
6. A granular emulsifier for stabilizing W/O/W multiple emulsions prepared by the method of any one of claims 2-5.
7. Use of a particulate emulsifier for stabilizing a W/O/W multiple emulsion according to claim 1 or 6 for the preparation of a W/O/W multiple emulsion.
8. A method for producing W/O/W multiple emulsion using the particulate emulsifier for stabilizing W/O/W multiple emulsion of claim 1 or 6, characterized in that the particulate emulsifier for stabilizing W/O/W multiple emulsion of claim 1 or 6 is mixed with an oil phase and an aqueous phase and homogenized.
9. The method of claim 8, wherein the oil phase comprises a less polar oil comprising: corn oil, sunflower seed oil, soybean oil, linseed oil, safflower seed oil, tea seed oil, linoleic acid, caprylic/capric triglyceride (GTCC), dimethyl silicone oil and phenyl silicone oil.
10. Use of a particulate emulsifier for stabilizing W/O/W multiple emulsions according to claim 1 or 6 for co-entrapping hydrophilic/hydrophobic drugs.
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