CN110330623A - Polyaminoester microball and preparation method thereof with pH responsiveness - Google Patents
Polyaminoester microball and preparation method thereof with pH responsiveness Download PDFInfo
- Publication number
- CN110330623A CN110330623A CN201910464630.7A CN201910464630A CN110330623A CN 110330623 A CN110330623 A CN 110330623A CN 201910464630 A CN201910464630 A CN 201910464630A CN 110330623 A CN110330623 A CN 110330623A
- Authority
- CN
- China
- Prior art keywords
- responsiveness
- polyaminoester microball
- added
- reaction
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000011806 microball Substances 0.000 title claims abstract description 28
- 230000004043 responsiveness Effects 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000004970 Chain extender Substances 0.000 claims abstract description 19
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 17
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims abstract description 16
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 229920001610 polycaprolactone Polymers 0.000 claims abstract description 14
- 239000004632 polycaprolactone Substances 0.000 claims abstract description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 150000002009 diols Chemical class 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 11
- 125000005442 diisocyanate group Chemical group 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 30
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000005058 Isophorone diisocyanate Substances 0.000 claims description 10
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 10
- NIMLQBUJDJZYEJ-UHFFFAOYSA-N isophorone diisocyanate Chemical group CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1 NIMLQBUJDJZYEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000839 emulsion Substances 0.000 claims description 9
- 239000006210 lotion Substances 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 235000019260 propionic acid Nutrition 0.000 claims description 7
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 5
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 4
- CRVGTESFCCXCTH-UHFFFAOYSA-N methyl diethanolamine Chemical compound OCCN(C)CCO CRVGTESFCCXCTH-UHFFFAOYSA-N 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- IXAWXWACDBWEJF-UHFFFAOYSA-L C(CCCCCCC)[Sn+2]CCCCCCCC.C(CCCCCCCCCCC)(=O)[O-].C(CCCCCCCCCCC)(=O)[O-].[Sn+4] Chemical compound C(CCCCCCC)[Sn+2]CCCCCCCC.C(CCCCCCCCCCC)(=O)[O-].C(CCCCCCCCCCC)(=O)[O-].[Sn+4] IXAWXWACDBWEJF-UHFFFAOYSA-L 0.000 claims description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class 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 2
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- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 125000005473 octanoic acid group Chemical group 0.000 claims 1
- 125000000341 threoninyl group Chemical class [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 17
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 5
- CIVVRPHZRYVSCF-UHNVWZDZSA-N (2s,3r)-2-(dimethylamino)-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@H](N(C)C)C(O)=O CIVVRPHZRYVSCF-UHNVWZDZSA-N 0.000 description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 4
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- 238000003786 synthesis reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
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- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000003587 threonine derivatives Chemical class 0.000 description 3
- DGADNPLBVRLJGD-UHFFFAOYSA-N 2,3-dihydroxy-2-methylpropanoic acid Chemical compound OCC(O)(C)C(O)=O DGADNPLBVRLJGD-UHFFFAOYSA-N 0.000 description 2
- UPMLOUAZCHDJJD-UHFFFAOYSA-N 4,4'-Diphenylmethane Diisocyanate Chemical compound C1=CC(N=C=O)=CC=C1CC1=CC=C(N=C=O)C=C1 UPMLOUAZCHDJJD-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
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- 238000004090 dissolution Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
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- 125000005474 octanoate group Chemical group 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical group [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- RWNLRKYARZOSQI-UHFFFAOYSA-N C(CCCCCCC)[Sn]CCCCCCCC.C(C=CC1=CC=CC=C1)(=O)O Chemical compound C(CCCCCCC)[Sn]CCCCCCCC.C(C=CC1=CC=CC=C1)(=O)O RWNLRKYARZOSQI-UHFFFAOYSA-N 0.000 description 1
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- DTPCFIHYWYONMD-UHFFFAOYSA-N decaethylene glycol Polymers OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO DTPCFIHYWYONMD-UHFFFAOYSA-N 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- AYOHIQLKSOJJQH-UHFFFAOYSA-N dibutyltin Chemical compound CCCC[Sn]CCCC AYOHIQLKSOJJQH-UHFFFAOYSA-N 0.000 description 1
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- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
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- DVKJHBMWWAPEIU-UHFFFAOYSA-N toluene 2,4-diisocyanate Chemical compound CC1=CC=C(N=C=O)C=C1N=C=O DVKJHBMWWAPEIU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/08—Processes
- C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
- C08G18/12—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step using two or more compounds having active hydrogen in the first polymerisation step
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/4009—Two or more macromolecular compounds not provided for in one single group of groups C08G18/42 - C08G18/64
- C08G18/4018—Mixtures of compounds of group C08G18/42 with compounds of group C08G18/48
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/4009—Two or more macromolecular compounds not provided for in one single group of groups C08G18/42 - C08G18/64
- C08G18/4081—Mixtures of compounds of group C08G18/64 with other macromolecular compounds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
- C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
- C08G18/4269—Lactones
- C08G18/4277—Caprolactone and/or substituted caprolactone
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/48—Polyethers
- C08G18/4825—Polyethers containing two hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/64—Macromolecular compounds not provided for by groups C08G18/42 - C08G18/63
- C08G18/6484—Polysaccharides and derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
- C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
- C08G18/6666—Compounds of group C08G18/48 or C08G18/52
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
- C08G18/72—Polyisocyanates or polyisothiocyanates
- C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
- C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
- C08G18/751—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring
- C08G18/752—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group
- C08G18/753—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group containing one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group having a primary carbon atom next to the isocyanate or isothiocyanate group
- C08G18/755—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group containing one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group having a primary carbon atom next to the isocyanate or isothiocyanate group and at least one isocyanate or isothiocyanate group linked to a secondary carbon atom of the cycloaliphatic ring, e.g. isophorone diisocyanate
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- Polyurethanes Or Polyureas (AREA)
Abstract
The present invention relates to a kind of polyaminoester microballs with pH responsiveness, it is made of the raw material of following mass fraction, 20~30% oligomer dihydric alcohol, 45~55% diisocyanate, 3~5% sodium carboxymethylcellulose, 3~5% acid nuclear unit, 5~15% chain extender, 10~15% neutralizer and 0.01~0.05% catalyst, wherein, oligomer dihydric alcohol is the mixture of polyethylene glycol and polycaprolactone diols that molar ratio is 1:1~2:1.The synthetic method of invention is simple, and obtained product has good pH responsiveness in alkaline environment, and relatively stable in acidic environment, can be used as the pH response type polyaminoester microball pharmaceutical carrier of targeted delivery of drugs.
Description
Technical field
The present invention relates to functional high molecule material technical field more particularly to a kind of polyurethane with pH responsiveness are micro-
Ball and preparation method thereof.
Background technique
The continuous improvement of medical level be unable to do without the fast development of medical material, leads to pharmaceutical preparation from the 1970s
Miniature coating technology has been crossed applied to since microcapsules field, the microcapsules prepared using bioabsorbable polymer material in biological medicine and
The fields such as genetic engineering are rapidly developed and are widely applied.Microcapsules are a kind of miniature appearances of the closing with nucleocapsid structure
The releasing mechanism with capsule: device wherein by drug cladding, discharges drug by diffusion or the degradation of carrier.For making
The material for making microcapsules is divided into natural polymer and synthesis macromolecule two major classes: natural polymer mainly includes collagen, bright
Glue, alginate, chitosan etc.;Synthesizing macromolecule mainly includes polyethylene glycol oxide, polyacrylic acid, polyvinyl alcohol, poly- N- isopropyl
Base acrylamide etc..
Stimuli responsive type microcapsules because it can simulate the response process of living systems, therefore have received widespread attention.This
Kind microcapsules can respond the minor change of environment, and it includes structure, polarity, phase structure and change that physical and chemical performance, which occurs,
Learn substantially changeing for composition etc..Different, stimuli responsive type microcapsules differential temperature, pH, light, electricity and complex response according to stimulation
Microcapsules.Since the pH of digestion is there are notable difference, pH responsiveness high molecule microcapsule is widely used
Prospect.Such as insulin can be decomposed into peptide by proteolytic enzyme under one's belt, and can by pH response polymer carrier
Insulin and other protein medicaments are effectively protected from the digestion of enzyme in stomach, it is neutral for then releasing medicine pH
In small intestine.It for pH response type microcapsules, can be also used in the treatment of cancer, because during the pH in normal tissue and blood is
Property, and in some tumours, pH 0.5-1.0, well below normal value.Therefore have biodegradable, pH responsiveness micro-
Capsule can be realized: (1) medicament slow release, reduce poisonous side effect of medicine, extend drug bioactivity;(2) degradation absorbs, and will not make
Human body generates immunity;(3) drug is discharged under specific pH environment;(4) in the functions such as human organ or tissue Targeting delivery.
Polyurethane can be used as the biomaterial of implantation human body as a kind of synthesis macromolecule, have excellent biological property
And mechanical property, extensive research is obtained in terms of drug release.Such as Liu Yuhong is with 2,4 toluene diisocyanate, diphenyl
Methane diisocyanate and lignin are raw material, are prepared for polyurethane microcapsule, and have studied by aids drug of nifedipine
Influence the factor of drug release;Lin Song with polyethylene glycol, polycaprolactone, isophorone diisocyanate etc. for raw material, with dihydroxy
Methylpropanoic acid is chain extender, has synthesized polyurethane microcapsule, has studied its degradability.Mohajnlnad etc. is with diphenyl methane
Diisocyanate and multi-functional polyurethane polyol are raw material, and PVP is dispersing agent, and ethylenediamine is chain extender, feed change
With the ratio of chain extender, a series of polyaminoester microball of different-grain diameters has been synthesized.There is presently no one kind to have in alkaline environment
Good pH responsiveness, and the metastable polyaminoester microball in acidic environment.
Summary of the invention
The purpose of the present invention is to provide a kind of polyaminoester microballs with pH responsiveness, and having has in alkaline environment
Good pH responsiveness, and the metastable feature in acidic environment.
Another object of the present invention is to provide a kind of preparation methods of polyaminoester microball with pH responsiveness.
To achieve the above object, the present invention provides a kind of polyaminoester microball with pH responsiveness, by following mass fraction
Raw material be made, 20~30% oligomer dihydric alcohol, 45~55% diisocyanate, 3~5% carboxymethyl cellulose
Sodium, 3~5% acid nuclear unit, 5~15% chain extender, 10~15% neutralizer and 0.01~0.05% catalysis
Agent, wherein the oligomer dihydric alcohol is the mixture of polyethylene glycol and polycaprolactone diols that molar ratio is 1:1~2:1.
Preferably, the molecular weight of the polyethylene glycol is 200~800, and the molecular weight of the polycaprolactone diols is
1500~2500.
Preferably, the diisocyanate is isophorone diisocyanate.
Preferably, the degree of substitution of the sodium carboxymethylcellulose is 0.7~1.2.
Preferably, the chain extender is the mixture that molar ratio is 1:4~1:1 dihydromethyl propionic acid and 1,4-butanediol.
Preferably, the acid nuclear unit is the alkylated threonine of N-.
Preferably, the neutralizer is at least one in triethanolamine, triethylamine, N methyldiethanol amine and ethylenediamine
Kind.
Preferably, the catalyst is stannous octoate or tin dilaurate dioctyl tin.
To achieve the above object, the present invention also provides a kind of preparation method of polyaminoester microball with pH responsiveness, packets
Include following steps:
Diisocyanate and ethyl acetate are added in reaction kettle by prepolymerization, are opened stirring, are then added oligomeric
Object dihydric alcohol, sodium carboxymethylcellulose and acid nuclear unit, are eventually adding catalyst, and control temperature of reaction system is 80 DEG C~
100 DEG C, react 2~3h;
Temperature of reaction system is reduced to 50~70 DEG C, chain extender is added, reacts 2~3h by chain extending reaction;
Temperature of reaction system is reduced to 40~45 DEG C, neutralizer is added, reacts 0.5~1h by neutralization reaction;
Temperature of reaction system is reduced to 25~30 DEG C, deionized water is added, stirs 2~3h by emulsion reaction.
Preferably, further include post-processing step: after the completion of emulsion reaction, lotion being evaporated under reduced pressure, system temperature control
System is dried in vacuo after removing ethyl acetate at 80~90 DEG C, obtains pulverulent solids product.
The beneficial effects of the present invention are:
The present invention uses oligomer dihydric alcohol, diisocyanate for main raw material(s), during the reaction by carboxymethyl fibre
Tie up plain sodium and acid nuclear unit be introduced into the molecular structure of polyurethane, synthesized a kind of pair of human body it is substantially nontoxic there is pH to ring
Answering property and degradable polyaminoester microball.The synthetic method of the invention is simple, and obtained product has good in alkaline environment
PH responsiveness, and it is relatively stable in acidic environment, it can be used as the pH response type polyaminoester microball pharmaceutical carrier of targeted delivery of drugs.
Specific embodiment
In order to which technical problems, technical solutions and advantages to be solved are more clearly understood, tie below
Embodiment is closed, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only used to solve
The present invention is released, is not intended to limit the present invention.
A kind of polyaminoester microball with pH responsiveness, is made of the raw material of following mass fraction, 20~30% it is oligomeric
Object dihydric alcohol, 45~55% diisocyanate, 3~5% sodium carboxymethylcellulose, 3~5% acid nuclear unit, 5~
15% chain extender, 10~15% neutralizer and 0.01~0.05% catalyst, wherein the oligomer dihydric alcohol is
Molar ratio is the polyethylene glycol of 1:1~2:1 and the mixture of polycaprolactone diols.
Sodium carboxymethylcellulose is introduced into polyurethane by the present invention, and sodium carboxymethylcellulose is a kind of water-soluble cellulose
Ether, daily use chemicals, petroleum, light industry, geology, video, medicine etc. industry in field extensive application, by stringent biology,
After toxicologic study and test, it is approved for food, has been a kind of very small sodium salt of toxicity.
The present invention carries out modification by copolymerization processing to polyurethane using electrically charged acid nuclear unit, and treated, and polyurethane is micro-
Ball has stronger stability, while more sensitive to alkaline environment because of the presence of acid nuclear unit in the environment of low pH, raw
Biodegradable is improved.
Polyethylene glycol and polycaprolactone diols both reactants of oligomer dihydric alcohol as polyurethane soft segment are selected,
The two collocation uses helpful to the drug release in later period.The molar ratio of polyethylene glycol and polycaprolactone diols is 1:1~2:
1, if the dosage of polycaprolactone is greater than the range, reacts and easily form spawn.
The molecular weight of the polyethylene glycol is 200~800, the molecular weight of the polycaprolactone diols is 1500~
2500, if the molecular weight of the two is less than the range, it can't be ball-type, molecular weight is greater than the range, then product easily becomes solidifying
Colloid substance.
The diisocyanate is isophorone diisocyanate, using the polyurethane of the compound synthesis there is degradation to produce
Object is non-toxic to humans, and tissue will not be inflamed, and surface is easily attached biological reagent, and it is excellent that abiotic specific action is small etc.
Point.
The degree of substitution of the sodium carboxymethylcellulose is 0.7~1.2, and within this range, transparency is preferable for degree of substitution.
The chain extender is the mixture that molar ratio is 1:4~1:1 dihydromethyl propionic acid and 1,4- butanediol.Use dihydroxy
Methylpropanoic acid can introduce carboxylic group, and carboxylate can be generated by neutralizer, polyurethane is made to achieve the effect that self-emulsifying.Increase
Add its content that the rigidity of polyurethane molecular chain can be improved, hard section ratio increases, and the microspherulite diameter of synthesis reduces, and emulsifying effectiveness becomes
It is good;1,4-butanediol is added, the polyaminoester emulsion appearance prepared can be made good, excellent storage stability, addition molar ratio is 1:4
The mixture of dihydromethyl propionic acid and 1,4-butanediol within the scope of~1:1 can make the microballoon of preparation have suitable water absorption rate,
Be conducive to the load medicine release in later period.
The acidity nuclear unit is the alkylated threonine of N-.The alkylated threonine of N- is prepared by the following method: being claimed
It takes a certain amount of threonine to be placed in three-necked flask, paraformaldehyde and formic acid is added, three's molar ratio is controlled in 1:2:5~1:
Between 3.5:5, it is filled with N in the reactor2, and open vacuum pump and vacuumize, it is warming up to 100-120 DEG C of condensing reflux 5h later,
The vacuum distillation of obtained yellow liquid is removed into excessive reactant, remaining product will be evaporated under reduced pressure later in the condition of heating
Lower to be dissolved with dehydrated alcohol, ethanol solution to the pH value that dissolution sodium hydroxide is slowly added dropwise after dissolution completely is 6.1-6.3,
There is white precipitate generation in solution at this time, stand and filter out white precipitate, filtrate is taken to be handled to obtain target with Rotary Evaporators
Product N, N- dimethyl threonine.
The neutralizer is at least one of triethanolamine, triethylamine, N methyldiethanol amine and ethylenediamine.
The catalyst is stannous octoate or tin dilaurate dioctyl tin.
A kind of preparation method of the polyaminoester microball with pH responsiveness, comprising the following steps:
Diisocyanate and ethyl acetate are added in reaction kettle by prepolymerization, are opened stirring, are then added oligomeric
Object dihydric alcohol, sodium carboxymethylcellulose and acid nuclear unit, are eventually adding catalyst, and control temperature of reaction system is 80 DEG C~
100 DEG C, react 2~3h;Wherein, the additional amount of ethyl acetate, is not specially limited, as long as reactive material can normally lotion gather
Conjunction.
Temperature of reaction system is reduced to 50~70 DEG C, chain extender is added, reacts 2~3h by chain extending reaction;
Temperature of reaction system is reduced to 40~45 DEG C, neutralizer is added, reacts 0.5~1h by neutralization reaction;
Temperature of reaction system is reduced to 25~30 DEG C, deionized water is added, stirs 2~3h by emulsion reaction.Wherein, it goes
Ion water consumption is 2~4 times of each reaction raw materials gross mass.
After neutralization reaction, emulsion can be formed under strong stirring by adding deionized water progress lotion reaction,
The emulsion emulsifiers effect of preparation is better, and target product is easier to form uniform spherical structure.
Further include post-processing step: after the completion of emulsion reaction, lotion being evaporated under reduced pressure, system temperature control 80~
It 90 DEG C, is dried in vacuo after removing ethyl acetate, obtains white powdery solids product.
Embodiment 1
Raw material proportioning:
(1) three-necked flask is added in isophorone diisocyanate and ethyl acetate (with the quality such as overall reaction raw material)
In, stirring is opened, mixing speed 400rpm, being slowly added to oligomer dihydric alcohol, (molar ratio is the polyethylene glycol of 1:1 and gathers oneself
Lactone dihydric alcohol, molecular weight polyethylene glycol 200, polycaprolactone diols molecular weight be 1500), sodium carboxymethylcellulose (takes
Dai Du is 0.7) and N, N- dimethyl threonine are uniformly slowly added to brufen fine powder (oligomer binary after stirring 10min
Alcohol, isophorone diisocyanate, sodium carboxymethylcellulose, N, the 30% of N- dimethyl threonine and chain extender quality sum), stir
After mixing 3min, octoate catalyst stannous is added, opening condenser pipe recirculated water and controlling temperature of reaction system in flask is 90 DEG C, is stirred
It mixes rate and is increased to 400~500rpm, react 2h;
(2) temperature of reaction system is reduced to 60 DEG C, be added chain extender (molar ratio is the dihydromethyl propionic acid and 1 of 1:4,
The mixture of 4- butanediol), stirring rate is set as 300rpm, reacts 3h;
(3) temperature of reaction system being reduced to 40 DEG C, neutralizer triethanolamine is added dropwise, stirring rate is set as 200rpm,
Stir 0.5h;
(4) system temperature is reduced to 30 DEG C, be added deionized water (2 times of overall reaction material quality), stirring rate is set
Fixed 600~800rpm, is vigorously stirred 2.5h;
(5) obtained lotion is evaporated under reduced pressure, system temperature is controlled at 85 DEG C, carries out vacuum after removing ethyl acetate
Dry, drying temperature sets 100 DEG C, obtains white powdery solids.
The above score is mass fraction.
Embodiment 2
Raw material proportioning:
(1) three-necked flask is added in isophorone diisocyanate and ethyl acetate (with the quality such as overall reaction raw material)
In, stirring is opened, mixing speed 500rpm, being slowly added to oligomer dihydric alcohol, (molar ratio is the polyethylene glycol of 2:1 and gathers oneself
Lactone dihydric alcohol, molecular weight polyethylene glycol 800, polycaprolactone diols molecular weight be 2500), sodium carboxymethylcellulose (takes
Dai Du is 1.2) and N, N- dimethyl threonine are uniformly slowly added to brufen fine powder (oligomer binary after stirring 10min
Alcohol, isophorone diisocyanate, sodium carboxymethylcellulose, N, the 30% of N- dimethyl threonine and chain extender quality sum), stir
After mixing 3min, catalyst dibutyltin cinnamic acid dioctyl tin is added, open condenser pipe recirculated water and controls temperature of reaction system in flask
It is 80 DEG C, stirring rate is increased to 400~500rpm, reacts 3h;
(2) temperature of reaction system is reduced to 50 DEG C, be added chain extender (molar ratio is the dihydromethyl propionic acid and 1 of 1:1,
The mixture of 4- butanediol), stirring rate is set as 300rpm, reacts 2h;
(3) temperature of reaction system is reduced to 45 DEG C, neutralizer triethylamine is added dropwise, stirring rate is set as 200rpm, stirs
Mix 1h;
(4) system temperature is reduced to 25 DEG C, be added deionized water (3 times of overall reaction material quality), stirring rate is set
Fixed 600~800rpm, is vigorously stirred 2h;
(5) obtained lotion is evaporated under reduced pressure, system temperature is controlled at 80 DEG C, carries out vacuum after removing ethyl acetate
Dry, drying temperature sets 100 DEG C, obtains white powdery solids.
The above score is mass fraction.
Embodiment 3
Raw material proportioning:
(1) three-necked flask is added in isophorone diisocyanate and ethyl acetate (with the quality such as overall reaction raw material)
In, stirring is opened, mixing speed 600rpm is slowly added to the oligomer dihydric alcohol (polyethylene glycol and gather that molar ratio is 1.5:1
Caprolactone dihydric alcohol, molecular weight polyethylene glycol 500, polycaprolactone diols molecular weight be 2000), sodium carboxymethylcellulose
(degree of substitution 1) and N, N- dimethyl threonine are uniformly slowly added to brufen fine powder (oligomer binary after stirring 10min
Alcohol, isophorone diisocyanate, sodium carboxymethylcellulose, N, the 30% of N- dimethyl threonine and chain extender quality sum), stir
After mixing 3min, octoate catalyst stannous is added, opening condenser pipe recirculated water and controlling temperature of reaction system in flask is 100 DEG C,
Stirring rate is increased to 400~500rpm, reacts 2.5h;
(2) temperature of reaction system is reduced to 70 DEG C, be added chain extender (molar ratio is the dihydromethyl propionic acid and 1 of 1:2,
The mixture of 4- butanediol), stirring rate is set as 300rpm, reacts 2.5h;
(3) temperature of reaction system is reduced to 40 DEG C, neutralizer N methyldiethanol amine is added dropwise, stirring rate is set as
200rpm stirs 0.5h;
(4) system temperature is reduced to 30 DEG C, be added deionized water (4 times of overall reaction material quality), stirring rate is set
Fixed 600~800rpm, is vigorously stirred 3h;
(5) obtained lotion is evaporated under reduced pressure, system temperature is controlled at 90 DEG C, carries out vacuum after removing ethyl acetate
Dry, drying temperature sets 100 DEG C, obtains white powdery solids.
The above score is mass fraction.
Microballoon obtained by Examples 1 to 3 is subjected to the measurement of pH responsiveness, specific assay method is as follows:
PH=3.5 is configured, the buffer solution of pH=7, pH=7.8 take the product of the Examples 1 to 3 of phase homogenous quantities, respectively
It is added in above-mentioned buffer, 37 DEG C of baking ovens is put into after sealing, timing sampling measures supernatant at 263nm after centrifuge separation
Absorbance, according to the difference of absorbance, conversion obtains the residual volume of brufen in polyaminoester microball.Experimental data such as 1 institute of table
Show:
The residual volume of brufen in 1 different time polyaminoester microball of table
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. a kind of polyaminoester microball with pH responsiveness, which is characterized in that it is made of the raw material of following mass fraction, 20~
30% oligomer dihydric alcohol, 45~55% diisocyanate, 3~5% sodium carboxymethylcellulose, 3~5% acid core
Unit, 5~15% chain extender, 10~15% neutralizer and 0.01~0.05% catalyst, wherein oligomer binary
Alcohol is the mixture of the polyethylene glycol that molar ratio is 1:1~2:1 and polycaprolactone diols.
2. the polyaminoester microball according to claim 1 with pH responsiveness, which is characterized in that described, the poly- second two
The molecular weight of alcohol is 200~800, and the molecular weight of the polycaprolactone diols is 1500~2500.
3. the polyaminoester microball according to claim 1 with pH responsiveness, which is characterized in that the diisocyanate is
Isophorone diisocyanate.
4. the polyaminoester microball according to claim 1 with pH responsiveness, which is characterized in that the carboxymethyl cellulose
The degree of substitution of sodium is 0.7~1.2.
5. the polyaminoester microball according to claim 1 with pH responsiveness, which is characterized in that the chain extender is mole
Than the mixture for 1:4~1:1 dihydromethyl propionic acid and 1,4- butanediol.
6. the polyaminoester microball according to claim 1 with pH responsiveness, which is characterized in that it is described acidity nuclear unit be
The alkylated threonine of N-.
7. the polyaminoester microball according to claim 1 with pH responsiveness, which is characterized in that the neutralizer is three second
At least one of hydramine, triethylamine, N methyldiethanol amine and ethylenediamine.
8. the polyaminoester microball according to claim 1 with pH responsiveness, which is characterized in that the catalyst is octanoic acid
Stannous or tin dilaurate dioctyl tin.
9. the preparation method of the polyaminoester microball according to any one of claims 1 to 8 with pH responsiveness, feature exist
In, comprising the following steps:
Diisocyanate and ethyl acetate are added in reaction kettle by prepolymerization, open stirring, and oligomer two is then added
First alcohol, sodium carboxymethylcellulose and acid nuclear unit are eventually adding catalyst, and control temperature of reaction system is 80~100 DEG C, instead
Answer 2~3h;
Temperature of reaction system is reduced to 50~70 DEG C, chain extender is added, reacts 2~3h by chain extending reaction;
Temperature of reaction system is reduced to 40~45 DEG C, neutralizer is added, reacts 0.5~1h by neutralization reaction;
Temperature of reaction system is reduced to 25~30 DEG C, deionized water is added, stirs 2~3h by emulsion reaction.
10. the preparation method of the polyaminoester microball according to claim 9 with pH responsiveness, which is characterized in that also wrap
It includes post-processing step: after the completion of emulsion reaction, lotion being evaporated under reduced pressure, system temperature is controlled at 80~90 DEG C, removes second
It is dried in vacuo after acetoacetic ester, obtains pulverulent solids product.
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