PEGylated thioxanthone photoinitiator and photosensitive resin composition
11174239 · 2021-11-16
Assignee
- Jenkem Technology Co., Ltd. (Beijing) (Beijing, CN)
- JENKEM TECHNOLOGY CO., LTD. (TIANJIN) (Tianjin, CN)
Inventors
Cpc classification
International classification
C08F2/46
CHEMISTRY; METALLURGY
G03F7/00
PHYSICS
Abstract
The present invention discloses a PEGylated thioxanthone photoinitiator and a photosensitive resin composition, the PEGylated thioxanthone compound is eco-friendly and has low toxicity, high initiation efficiency and good thermal stability, meanwhile, as a kind of photoinitiator, the compound has a small amount of fragment residue after cured, and may improve the compatibility of the photoinitiator and photosensitive resin composition system. The photosensitive resin composition provided by the present invention has reasonable allocation of ingredients and content in the components thereof, capable of 3D-printing a hydrogel having a specific structure; the hydrogel has lower cytotoxicity and better biocompatibility, and may applied in bioengineering fields, e.g., 3D cell culture.
Claims
1. A PEGylated thioxanthone compound, comprising a structure shown in the formula VII, ##STR00013## X is a linking group and selected from any one or a combination of two or more of the group consisting of: the above —(CH.sub.2).sub.iO—, —(CH.sub.2).sub.iS—, —(CH.sub.2).sub.iNH—, —(CH.sub.2).sub.iCONH—, and —(CH.sub.2).sub.iNHCONH—, wherein i is an integer of 0 to 10; PEG is a polyethylene glycol residue and has the molecular weight of 2000 Da-10000 Da.
2. The compound according to claim 1, wherein i is an integer of 0 to 5.
3. The compound according to claim 1, wherein the PEG is a linear polyethylene glycol residue and has a structure shown in the general formula II: ##STR00014## wherein, p is an integer of 45 to 226; or, the PEG is a Y-shaped or U-shaped polyethylene glycol residue and has one of structures shown in general formulas III or IV: ##STR00015## wherein, n and i are independently selected from an integer of 23 to 113.
4. The compound according to claim 3, wherein the PEG is a linear polyethylene glycol residue and has a structure shown in the general formula II.
5. The compound according to claim 1, wherein the molecular weight of PEG ranges from 3000 Da to 5000 Da.
6. A photoinitiator, comprising the PEGylated thioxanthone compound according to claim 1.
7. A photosensitive resin composition, comprising a photosensitizer, wherein the photosensitizer comprises the photoinitiator according to claim 6; preferably, the composition further comprises an active component (such as 8-armed polyethylene glycol acrylate) and a diluent; more preferably, content of the active component in the composition ranges from 1% to 40%, preferably 10% to 30%; and/or, content of the diluent in the composition ranges from 40% to 90%, preferably 60% to 85%; and/or, content of the photoinitiator in the composition ranges from 0.1%, preferably 0.5% to 5%.
8. The photosensitive resin composition according to claim 7, wherein the active component is selected from: one or more of PEG acrylate, PEG epoxy ether, monodispersed polyethylene glycol acrylate, monodispersed polyethylene glycol epoxy ether, diol diacrylate and diol dialkylene oxide.
9. The photosensitive resin composition according to claim 8, wherein the PEG acrylate is PEG diacrylate or PEG acrylate with 3-8 arms; and/or, the PEG epoxy ether is PEG diepoxy ether or PEG epoxy ether with 3-8 arms; and/or, the monodispersed polyethylene glycol acrylate is monodispersed polyethylene glycol diacrylate; and/or, the monodispersed polyethylene glycol epoxy ether is monodispersed polyethylene glycol diepoxy ether; and/or, the diol is selected from: ethylene glycol, propylene glycol and butylene glycol.
10. The photosensitive resin composition according to claim 7, wherein the diluent comprises an inactive diluent and/or an active diluent; preferably, the inactive diluent is solvent, and selected from: water, buffer solution, ethanol, isopropanol, DMSO, DMF, dioxane and THF; and/or, the active diluent is selected from: one or more of ethyl acrylate, butyl acrylate, isobutyl acrylate, epoxy propyl acrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, epoxypropyl methacrylate, allyl methacrylate, monomethoxyl PEG acrylate, monomethoxyl PEG epoxy ether, monomethoxyl monodispersed polyethylene glycol acrylate and monomethoxyl monodispersed polyethylene glycol epoxy ether.
11. The photosensitive resin composition according to claim 8, wherein the molecular weight of PEG ranges from 500 Da to 80000 Da; and/or, polymerization degree of the ethylene glycol in the monodispersed polyethylene glycol is 2-50.
12. The photosensitive resin composition according to claim 7, wherein the photosensitive resin composition further comprises an auxiliary additive; the auxiliary additive is selected from: one or more of co-initiator, antifoaming agent, flatting agent, polymerization inhibitor, antioxidant, antisettling agent, pigment, fluorescent agent, filler, wetting dispersant, flexibilizer and cross-linking agent; content of the auxiliary additive in the composition ranges from 0% to 10%; preferably, the auxiliary additive comprises a co-initiator; the co-initiator is selected from: one or more of triethanolamine, N,N-dimethyl benzylamine, N,N-dimethylaniline and triethylamine; content of the co-initiator in the photosensitive resin composition ranges from 0% to 5%; and/or, the auxiliary additive comprises a polymerization inhibitor; the polymerization inhibitor is selected from: one or more of phenolic polymerization inhibitors, quinone polymerization inhibitors, aromatic nitro-compound polymerization inhibitors and inorganic compound polymerization inhibitors; content of the polymerization inhibitor in the photosensitive resin composition ranges from 0% to 1%.
13. The photosensitive resin composition according to claim 7, wherein the composition further comprises an auxiliary functional component; preferably, content of the auxiliary functional component in the composition ranges from 0% to 20%, preferably, 0.1% to 20.0%, more preferably, 0.1% to 10.0%.
14. The photosensitive resin composition according to claim 13, wherein the auxiliary functional component comprises any one or a combination of two or more of the group consisting of: gelatin and acrylic acid-derived gelatin, hyaluronic acid and acrylic acid-derived hyaluronic acid, chitosan and modified chitosan, cellulose and carboxymethyl cellulose, alginate and modified alginate, collagen, agarose and cell nutrient solution, and/or, a block polymer of multi-armed or linear polyethylene glycol polyester whose terminal group is modified by acrylate.
15. The photosensitive resin composition according to claim 14, wherein in the block polymer of multi-armed or linear polyethylene glycol polyester, the polyester chain portion is selected from any one or a combination of two or more of the group consisting of: polylactide, polyglycollide, glycolide, lactide copolymer and polycaprolactone; and/or, molecular weight of the polyester chain portion ranges from 800 Da to 80000 Da; and/or, molecular weight of the PEG chain portion ranges from 800 Da to 80000 Da; and/or, in the block polymer of the multi-armed polyethylene glycol polyester, the number of arms ranges from 3 to 8.
16. The photosensitive resin composition according to claim 13, wherein the auxiliary functional component is acrylic acid-derived hyaluronic acid, acrylic acid-derived gelatin or a block polymer of multi-armed polyethylene glycol polycaprolactone whose terminal group is modified by acrylate.
17. A hydrogel obtained by 3D-printing the photosensitive resin composition according to claim 7.
Description
BRIEF DESCRIPTION OF DRAWINGS
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DETAILED DESCRIPTION OF THE EMBODIMENTS
(6) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in which the present invention involves, e.g.:
(7) “alkyl” refers to linear or branched hydrocarbon-chain free radical without unsaturated bond, C.sub.1-6 alkyl refers to a linear or branched alkyl containing 1-6 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, n-amyl, n-hexyl, etc.; if alkyl is substituted by aryl, it is an “aralkyl” free radical accordingly, C.sub.7-14 aralkyl refers to an aralkyl containing 7-14 carbon atoms, e.g., benzyl, benzhydryl or phenethyl, etc.; if alkyl is substituted by heterocyclyl, it is a “heterocyclyl alkyl” accordingly.
“alkoxy” refers to a substituent group formed by that H in hydroxyl thereof is substituted by alkyl, C.sub.1-6 alkoxy refers to an alkoxy containing 1-6 carbon atoms, e.g., methoxyl, ethyoxyl, propoxy, butoxy, etc.
“aryl” refers to a monocyclic or polycyclic free radical, including a polycyclic free radical with mono-aryl group and/or fused aryl group, e.g., the one containing 1-3 simple or fused ring(s) and 6-18 carbocyclic atoms, e.g., phenyl, xenyl, naphthyl, anthryl, phenanthryl, indenyl, pyrenyl, etc.
“heterocyclyl” includes a heteroaromatic group and heteroalicyclic group containing 1-3 monocyclic or fused rings as well as 3 to about 18 carbocyclic atoms. Proper heteroaryl in the compound of the present invention contains 1, 2 or 3 kinds of heteroatom, and the heteroatom is selected from atom N, O or S, preferably N.
(8) In the present invention, as for the definition of the linking group X, the “combination” refers to a group formed by bonding two or more of the linking groups via a chemical bond, for example, combination of —(CH.sub.2).sub.i— and —(CH.sub.2).sub.iCONH— may be —(CH.sub.2).sub.iCONH(CH.sub.2).sub.I, specifically, combination of —CH.sub.2— and —CH.sub.2CH.sub.2CONH— may be —CH.sub.2CH.sub.2CONHCH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2CONH—. The “combination” serves to define the chemical structure of the linking group instead of preparation steps and combining sequence of the linking group, etc.
(9) The polyethylene glycol in the present invention is preferably characterized by molecular weight, and secondly by the number of repeating units.
(10) The technical solution of the present invention will be described clearly and completely hereafter with reference to embodiments of the present invention, apparently, embodiments described herein are only a part of embodiments of the present invention, and are not all of embodiments thereof. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without any creative efforts are within the protection scope of the present invention.
Embodiment 1: mPEG-TX Synthesis
(11) mPEG-TX synthetic route is shown in
(12) Thiosalicylic acid (6 g, 38.9 mmol) were added to concentrated sulfuric acid (45 mL) and stirred for 5 min for mixing evenly (ice-water bath). 2,3-dimethylphenol (14.25 g, 116 mmol) were added to the mixed solution during stirring in batches within 30 min, the mixed solution was stirred for 2 h at 10° C., and heated up to the temperature of high-temperature reaction, then stirred for 3 h, and at the end of reaction, the reaction liquid was placed at room temperature over night. In stirring condition, reaction liquid was put into 10 times (volume) of boiling water for boiling for 5 min, and filtered after cooling, the filtrate was recrystallized by water and dioxane (20:80, V/V). Finally, about 7.8 g intermediate TX-OH was obtained. NMR: 7.5-8.4 5H, H on benzene ring; 2.51, 3H, methyl H; 2.25, 3H, methyl H.
(13) mPEG (14 g, 4 mmol, molecular weight: 3500 Da) and methylbenzene were co-boiled for water removal and cooling, then added TX-OH (2.56 g, 10 mmol) and ph3P (2620 mg, 10 mmol), DIAD (diisopropyl azodiformate) (1.4 mL, 8 mmol) were added dropwise for reaction at room temperature over night, and the solution was filtered and concentrated to obtain isopropanol/ether precipitate, where the solution turned red slowly with the addition of DIAD and the reaction was monitored by HPLC, finally, ether was fully washed to remove DIAD and dried to obtain 12.5 g product. HPLC(>95%), NMR: 7.4-8.5 5H, H on benzene ring; 3.4-0.38:320H, H on mPEG; 3.3, 3H, CH3O; 2.55, 3H, methyl H; 2.23, 3H, methyl H.
Embodiment 2: mPEG-CO-TX Synthesis
(14) mPEG-CO-TX synthetic route is shown in
(15) mPEG (14 g, 4 mmol, molecular weight: 3500 Da) were added to succinic anhydride (0.5 g, 5 mmol, 100), slightly heated (about 37° C.), dissolved by stirring, then added TEA (0.83 mL, 6 mmol) for reacting over night, it was detected by HPLC and washed for once. The solution was concentrated to obtain isopropanol precipitate, and ether was washed to obtain 13 g intermidate mPEG-SA. HPLC>97%, NMR: 4.1, 2H, CH2OCO; 3.4-3.8, 310H, H on PEG; 3.3, 3H, CH3O; 2.3-2.5, 2-group H, 2 for each group, OCOCH2CH2COOH.
(16) DCC (165 mg, 0.8 mmol), DMAP (12 mg, 0.1 mmol), QTX-1(203 mg, 0.8 mmol), HOBt (108 mg, 0.8 mmol) and DCM (30 mL) were added to mPEG-SA (2.35 g, 0.67 mmol) for stirring over night at room temperature, and by HPLC monitoring, the reaction was almost complete. The solution was concentrated to obtain precipitate, and the precipitate was filtered to obtained 2.3 g product. HPLC(>95%), NMR: 7.4-8.5 5H, H on benzene ring; 4.3, 2H, CH2OCO; 3.4-3.8, 310H, H on PEG; 3.3, 3H, CH30; 2.8-3.0, 2-group H, 2 for each group, OCOCH2CH2COOH; 2.55, 3H, methyl H; 2.23, 3H, methyl H.
Embodiment 3: Contrast of the Two Photoinitiators mPEG-TX and mPEG-CO-TX
(17) Preparation of Solution A and B:
(18) Solution A: 8arm-PEG-Aclt (500 mg), mPEG-TX (17 mg, prepared by Embodiment 1) were added to water (1.5 mL), and then triethanolamine (40 μL) were added.
(19) Solution B: 8arm-PEG-Aclt (500 mg), mPEG-CO-TX (17 mg, prepared by Embodiment 2) were added to water (1.5 mL), and then triethanolamine (40 μL) were added.
(20) Standing for 12 h, solution A and B were put into a constant-temperature illumination box (22° C., 2750 Lux) after defoaming, and then taken out after being illuminated for 60 min, as shown in
Embodiment 4: Formula 1 and 3D Printing Thereof
(21) TABLE-US-00001 TABLE 1 Component and content of the formula 1 Component Content 8arm-PEG.sub.10k-Aclt 25% Photoinitiator (mPEG.sub.3500-TX) 1% Triethanolamine 0.9% Water 73.09%.sup. Hydroquinone 0.01% Total quantity 100%
(22) 100 g solution was prepared according to the formula of table 1. 100 g solution was put into a resin tank of a BESK 3D printer (1510) for 3D printing by Q3DP software. The obtained product was solid yellow hydrogel.
Embodiment 5: Formula 2 and 3D Printing Thereof
(23) TABLE-US-00002 TABLE 2 Component and content of the formula 2 Component Content 8arm-PEG.sub.10k-Aclt 20% Photoinitiator (mPEG.sub.3500-TX) 1% Water 78.09%.sup. Triethanolamine 0.9% Hydroquinone 0.01% Total quantity 100%
(24) 100 g solution was prepared according to the formula of table 2. 100 g solution was put into a resin tank of a BESK 3D printer (1510) for 3D printing by Q3DP software. The obtained product was solid yellow hydrogel.
Embodiment 6: Formula 3 and 3D Printing Thereof
(25) TABLE-US-00003 TABLE 3 Component and content of the formula 3 Component Content 8arm-PEG.sub.10k-Aclt 15% Photoinitiator (mPEG.sub.3500-TX) 1% Water 83.09%.sup. Triethanolamine 0.9% Hydroquinone 0.01% Total quantity 100%
(26) 100 g solution was prepared according to the formula of table 3. 100 g solution was put into a resin tank of a BESK 3D printer (1510) for 3D printing by Q3DP software. The obtained product was solid yellow hydrogel.
Embodiment 7: Formula 4 and 3D Printing Thereof
(27) TABLE-US-00004 TABLE 4 Component and content of the formula 4 Component Content 8arm-PEG.sub.10k-Aclt 30% Photoinitiator (mPEG.sub.3500-TX) 1% Water 68.09%.sup. Triethanolamine 0.9% Hydroquinone 0.01% Total quantity 100%
(28) 100 g solution was prepared according to the formula of table 4. 100 g solution was put into a resin tank of a BESK 3D printer (1510) for 3D printing by Q3DP software. The obtained product was solid yellow hydrogel.
Embodiment 8: Formula 5 and 3D Printing Thereof
(29) TABLE-US-00005 Component Content 8arm-PEG.sub.10k-Aclt 25% Photoinitiator (mPEG.sub.3500-TX) 1.7% Water 72.79% Triethanolamine 0.5% Hydroquinone 0.01% Total Quantity 100%
(30) 100 g solution was prepared according to the formula of table 5. 100 g solution was put into a resin tank of a BESK 3D printer (1510) for 3D printing by Q3DP software. The obtained product was solid yellow hydrogel.
Embodiment 9: Formula 6 and 3D Printing Thereof
(31) TABLE-US-00006 TABLE 6 Component and content of the formula 6 Component Content 8arm-PEG.sub.10k-Aclt 25% Photoinitiator (mPEG.sub.3500-TX) 3.4% Water 0.9% Triethanolamine 70.69% Hydroquinone 0.01% Total quantity 100%
(32) 100 g solution was prepared according to the formula of table 6. 100 g solution was put into a resin tank of a BESK 3D printer (1510) for 3D printing by Q3DP software. The obtained product was solid yellow hydrogel.
Embodiment 10: Formula 7 and 3D Printing Thereof
(33) TABLE-US-00007 TABLE 7 Component and content of the formula 7 Component Content 8arm-PEG.sub.10k-Aclt 25% Photoinitiator (mPEG.sub.3500-TX) 7.1% Triethanolamine 1.9% Water 65.99% Hydroquinone 0.01% Total quantity 100%
(34) 100 g solution was prepared according to the formula of table 7. 100 g solution was put into a resin tank of a BESK 3D printer (1510) for 3D printing by Q3DP software. The obtained product was solid yellow hydrogel.
Embodiment 11: Formula 8 and 3D Printing Thereof
(35) TABLE-US-00008 TABLE 8 Component and content of the formula 8 Component Content 8arm-PEG.sub.10k-Aclt 25% Photoinitiator (mPEG.sub.3500-TX) 1.7% Triethanolamine 0.2% Water 73.09% Hydroquinone 0.01% Total quantity 100%
(36) 100 g solution was prepared according to the formula of table 8. 100 g solution was put into a resin tank of a BESK 3D printer (1510) for 3D printing by Q3DP software. The obtained product was solid yellow hydrogel.
Embodiment 12: Formula 9 and 3D Printing Thereof
(37) TABLE-US-00009 TABLE 9 Component and content of the formula 9 Component Content 8arm-PEG.sub.10k-Aclt 20% Photoinitiator (mPEG.sub.3500-TX) 1.7% Triethanolamine 0.2% Water 78.09% Hydroquinone 0.01% Total quantity 100%
(38) 100 g solution was prepared according to the formula of table 9. 100 g solution was put into a resin tank of a Form2 3D printer from FormLab company for 3D printing. The obtained product was solid yellow hydrogel.
Embodiment 13: Formula 10 and 3D Printing Thereof
(39) TABLE-US-00010 TABLE 10 Component and content of the formula 10 Component Content 8arm-PEG.sub.10k-Aclt 25% Gel-Aclt .sup. 1% Photoinitiator (mPEG.sub.3500-TX) 1.7% Triethanolamine 0.2% Water 72.1% Total quantity 100%
(40) Note: Gel-Aclt is acrylic acid-derived gelatin.
(41) 100 g solution was prepared according to the formula of table 10. 100 g solution was put into a resin tank of a Form2 3D printer from FormLab company for 3D printing. The obtained product was solid yellow hydrogel.
Embodiment 14: Formula 11 and 3D Printing Thereof
(42) TABLE-US-00011 TABLE 11 Component and content of the formula 11 Component Content 8arm-PEG.sub.10k-Aclt 25% HA-Aclt .sup. 2% Photoinitiator (mPEG.sub.3500-TX) 1.7% Triethanolamine 0.2% Water 71.09% Hydroquinone 0.01% Total quantity 100%
(43) Note: HA-Aclt is acrylic acid-derived hyaluronic acid.
(44) 100 g solution was prepared according to the formula of table 11. 100 g solution was put into a resin tank of a Form2 3D printer from FormLab company for 3D printing. The obtained product was solid yellow hydrogel.
Embodiment 15: Formula 12 and 3D Printing Thereof
(45) TABLE-US-00012 TABLE 12 Component and content of the formula 12 Component Content 8arm-PEG.sub.10k-Aclt 25% Photoinitiator (mPEG.sub.3500-TX) 1.7% Triethanolamine 0.2% Water 73.1% Total quantity 100%
(46) 150 g solution was prepared according to the formula of table 12, as shown in figure A of
(47) Solution of the above formula has moderate viscosity and fluidity, rapid forming speed of gel as well as mild conditions, moreover, it is easy to print and mold, and free from blocking the nozzle. The gel obtained by 3D printing has good molding property, small volume shrinkage, good strength, moderate hardness and good biocompatibility, meanwhile, the gel may maintain its shape and structure, free from collapse and swelling.
Embodiment 16: Formula 13 and 3D Printing Thereof
(48) TABLE-US-00013 TABLE 13 Component and content of the formula 13 Component Content 8arm-PEG.sub.10k-Aclt 25% 8arm-PEG.sub.10k-PCL.sub.3k-Aclt 1.3% Photoinitiator (mPEG.sub.3500-TX) 1.7% Triethanolamine 0.2% Water 71.8% Total quantity 100%
(49) Note: in the table, 8arm-PEG10k-PCL3k-Aclt is a block polymer of 8-armed PEG polyester modified by acrylate, of which, the polyester chain portion is polycaprolactone, and molecular weight of the PEG chain portion is 10 KDa, molecular weight of the polyester chain portion is 3 KDa.
(50) 150 g solution was prepared according to the formula of table 13, as shown in figure A of
(51) Solution of the above formula has moderate viscosity and fluidity, rapid forming speed of gel as well as mild conditions, moreover, it is easy to print and mold, and free from blocking the nozzle. The gel obtained by 3D printing has good molding property, small volume shrinkage, good strength, moderate hardness and good biocompatibility, meanwhile, the gel may maintain its shape and structure, free from collapse and swelling.
(52) In the formula of Embodiments 4-16 of the present invention, the content refers to mass percent, all photoinitiators used (mPEG3500-TX) are all products prepared by Embodiment 1, and the 8arm-PEG10k-Aclt used is provided by JenKem, has the molecular weight of 10 KDa and the following structure:
(53) ##STR00012##
(54) What is described above are merely preferred embodiments of the present invention, and are not to limit the present invention; any modification and equivalent replacement, etc. within the spirit and principle of the present invention shall be covered in the protection scope of the present invention.