CN106822066A - Minocycline sustained release preparation - Google Patents
Minocycline sustained release preparation Download PDFInfo
- Publication number
- CN106822066A CN106822066A CN201710207548.7A CN201710207548A CN106822066A CN 106822066 A CN106822066 A CN 106822066A CN 201710207548 A CN201710207548 A CN 201710207548A CN 106822066 A CN106822066 A CN 106822066A
- Authority
- CN
- China
- Prior art keywords
- minocycline
- sustained release
- release preparation
- copolymer
- preparation
- 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.)
- Granted
Links
- 229960004023 minocycline Drugs 0.000 title claims abstract description 40
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 35
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 title claims abstract 19
- 239000000178 monomer Substances 0.000 claims abstract description 18
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003999 initiator Substances 0.000 claims abstract description 12
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical group O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229920001610 polycaprolactone Polymers 0.000 claims abstract description 11
- 239000004632 polycaprolactone Substances 0.000 claims abstract description 11
- 229920005604 random copolymer Polymers 0.000 claims abstract description 10
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920000151 polyglycol Polymers 0.000 claims abstract description 8
- 239000010695 polyglycol Substances 0.000 claims abstract description 8
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 73
- 229920001577 copolymer Polymers 0.000 claims description 42
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical group Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 claims description 29
- 229960002421 minocycline hydrochloride Drugs 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 229920001427 mPEG Polymers 0.000 claims description 11
- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002362 mulch Substances 0.000 claims description 3
- 229920006255 plastic film Polymers 0.000 claims description 3
- 239000002985 plastic film Substances 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 229920000747 poly(lactic acid) Polymers 0.000 abstract description 6
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 2
- 239000002202 Polyethylene glycol Substances 0.000 abstract 1
- 239000012528 membrane Substances 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 21
- 229920000642 polymer Polymers 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 230000000844 anti-bacterial effect Effects 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 16
- 241000894006 Bacteria Species 0.000 description 13
- 238000002386 leaching Methods 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 231100000135 cytotoxicity Toxicity 0.000 description 11
- 230000003013 cytotoxicity Effects 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 241000605986 Fusobacterium nucleatum Species 0.000 description 10
- 241000194019 Streptococcus mutans Species 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 238000013268 sustained release Methods 0.000 description 7
- 239000012730 sustained-release form Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000006116 polymerization reaction Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 201000001245 periodontitis Diseases 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 229940008099 dimethicone Drugs 0.000 description 4
- 239000004205 dimethyl polysiloxane Substances 0.000 description 4
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- QAZGSZIABORBEG-UHFFFAOYSA-N octanoic acid;toluene Chemical compound CC1=CC=CC=C1.CCCCCCCC(O)=O QAZGSZIABORBEG-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000004062 sedimentation Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000001013 cariogenic effect Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000007334 copolymerization reaction Methods 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000003239 periodontal effect Effects 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000010183 spectrum analysis Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 239000006169 McIlvaine's buffer solution Substances 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 239000006059 cover glass Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012531 culture fluid Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 238000002389 environmental scanning electron microscopy Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229920001420 poly(caprolactone-co-lactic acid) Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012876 topography Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 230000010148 water-pollination Effects 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000004237 Crocus Nutrition 0.000 description 1
- 241000596148 Crocus Species 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 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 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 206010060932 Postoperative adhesion Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229920000229 biodegradable polyester Polymers 0.000 description 1
- 239000004622 biodegradable polyester Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229940022769 d- lactic acid Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- -1 dichloromethane Alkane Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000021186 dishes Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 229940073514 dynacin Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004195 gingiva Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 210000002379 periodontal ligament Anatomy 0.000 description 1
- 210000004261 periodontium Anatomy 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229920001897 terpolymer Polymers 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000004357 third molar Anatomy 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of minocycline sustained release preparation, it is characterized in that, formed by degradable biological film and minocycline, the degradable biological film be with poly glycol monomethyl ether as initiator, with levorotatory lactide and ε caprolactones obtained by monomer ring-opening polymerisation polyethylene glycol polylactide polycaprolactone random copolymer, the number-average molecular weight of the random copolymer is 8.0 × 104~9.0 × 104In the range of, with the structural formula shown in following (1)：Wherein, the ratio of levorotatory lactide unit and ε caprolactone units is 3 to 1.
Description
Technical field
The present invention relates to a kind of minocycline sustained release preparation.
Background technology
Periodontitis is department of stomatology common disease, is the main cause that the mankind lose tooth.Machinery is mainly for slight periodontitis to control
Treat.As the progress of the state of an illness, periodontal tissue destruction are increasingly serious, oral pocket is deepened, and simple mechanical treatment is extremely difficult to be satisfied with effect
Really, its pathogenic bacteria being present in gingiva tissue or in tissue of tooth is difficult to remove completely.In recent years, antibiotic is applied to periodontal
Scorching treatment increasingly attracts attention, and the treatment of local sustained release medicine turns into a kind of new treatment method.
Minocycline hydrochloride is clinically conventional periodontitis local sustained release medicine, is efficient, quick-acting, long-acting semi-synthetic
Tetracycline novel formulation, drug-fast bacteria is few, has a broad antifungal spectrum, antibacterial activity strong, easily infiltration, is four with unique drug release profile
One kind that antibacterial activity is most strong and blood medicine effective time is most long in ring element family antibiotic.To the pathogenic bacteria height of all kinds of periodontitis
Sensitivity, and Collage Activitv can be suppressed, promotion organization healing, with wide application and development space.Wang Yinfu[1]By research
Confirm, Minocycline ointment is met after water is hardened and forms the envelope with mesh sample, be conducive to delaying preferably in oral pocket
On The Drug Release, and high local concentrations stabilization can be kept up to 7 days, while the breakdown speed of alveolar bone can also significantly slowed down, to reach
Long-acting treatment purpose.
Polycaprolactone (PCL), polylactide (PLLA) are common biodegradable polyesters, possess good mechanicalness
Energy, blending property, biocompatibility and degradability.Poly glycol monomethyl ether (mPEG) as good hydrophilic polymer, its
Good biocompatibility, nontoxic, immunogenicity is low, can be excreted by kidney.
Xu Liangliang etc.[2]Amphipathic caprolactone-ethylene glycol-lactide (PCELA) three block is synthesized using the precipitation method common
In polymers, but the document, what is prepared is the nano-micelle of copolymer, rather than biofilm, and without reference to by altogether
Polymers is used for sustained release preparation, more without reference to the research of release in vitro, film forming etc..
Chen Hongli[3]Polycaprolactone/polyoxyethylene/polylactide terpolymer is synthesized Deng using PEG 6000, copolymerization
The ratio of the different monomers of thing is 14/14/72,25/25/50, and the document is also used for sustained release preparation without reference to by copolymer, and
And the document only have studied the biological degradability of copolymer, release property in film forming, oral cavity without reference to copolymer etc.
Research.
Zheng Zhang[4]Etc. synthesized triblock copolymer (polycaprolactone-lactide)-polyethylene glycol-(gather oneself in
Ester-lactide), i.e. PCLA-PEG-PCLA, the document have studied bio-safety performance, degradation property and the prevention of the polymer
The barrier action of post-operation adhesion, film forming, the load property of medicine and slow release without reference to copolymer.
Prior art literature
[1] Comparative Analysis of Pu Wang Yin Minocycline ointments and Tinidazole topical therapy periodontitis
[J] chinese medicine sciences, 2011,1 (24):87-88.
[2] Xu Liangliang, Chen Qiang, Li Li, wait the amphipathic copolymer nano micella of polycaprolactone/polyethyleneglycols/polylactide
Preparation with characterize [J] material Leaders, 2006,20 (11):131-133.
[3] Chen Hongli, Bei Jianzhong, Wang Shen state Biodegradable high moleculars-polycaprolactone/polyoxyethylene/polylactide ternary
Research [J] macromolecule journals of copolymer conduct hydrolysis, 2000, (5):626-631.
[4]Zheng Zhang,Jian Ni,Liang Chen,et al.Biodegradable and
thermoreversible PCLA-PEG-PCLA hydrogel as a barrier for prevention of post-
operative adhesion.
Biomaterials,2011,32(21):4725-4736.
The content of the invention
The invention technical problem to be solved
It is contemplated that a kind of minocycline sustained release preparation with good slow releasing function of exploitation.
Scheme for solving above-mentioned technical problem
Inventor has found, with poly glycol monomethyl ether (mPEG) as initiator, levorotatory lactide (L-LA) and caprolactone (ε-
CL) it is mPEG-P (LLA-co-CL) (poly glycol monomethyl ether-polylactide-polycaprolactone) nothing of monomer ring-opening polymerisation preparation
Rule copolymer, when the number-average molecular weight of the polymer is controlled 8.0 × 104~9.0 × 104In the range of, the weight of L-LA and ε-CL
When the ratio of multiple unit is 3 to 1, can obtain with certain hydrophily and good mechanical strength, while having good load medicine concurrently
The degradable biological film of performance and medicine-releasing performance, can be obtained by the degradable biological film and made with good sustained release
Minocycline sustained release preparation.
Specifically, the present invention includes herein below.
1. a kind of minocycline sustained release preparation, it is characterised in that formed by degradable biological film and minocycline, it is described
Degradable biological film be with poly glycol monomethyl ether as initiator, with levorotatory lactide and 6-caprolactone be monomer ring-opening polymerisation
Obtained by PEG-PDLLA-polycaprolactone random copolymer, the number-average molecular weight of the random copolymer 8.0 ×
104~9.0 × 104In the range of, and with the structural formula shown in following (1)：
Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
2. minocycline sustained release preparation as described above described in (1), the minocycline can pharmaceutically be connect with minocycline
The form of the salt received is provided.
3. minocycline sustained release preparation as described above described in (2), the shape of the pharmaceutically acceptable salt of the minocycline
Formula is minocycline hydrochloride.
4. minocycline sustained release preparation as described above any one of (1)-(3), it is characterised in that the initiator gathers
Glycol monoethyl ether is mPEG 4000.
5. minocycline sustained release preparation as described above any one of (1)-(3), it is characterised in that the copolymer
Molecular weight distribution is 1.5.
6. minocycline sustained release preparation as described above any one of (1)-(3), it is characterised in that the copolymer
Number-average molecular weight is 8.1 × 104。
7. minocycline sustained release preparation as described above any one of (1)-(3), it is characterised in that drugloading rate is
5wt%-10wt%.
8. a kind of preparation method of minocycline sustained release preparation, it is characterised in that weigh degradable biological film and minot
Ring element pharmaceutically acceptable salt, be dissolved in chloroform and methyl alcohol respectively, fully mix after stand, after bubble is eliminated plastic film mulch in
On polyfluortetraethylene plate, drying at room temperature rear demoulding, the degradable biological film be with poly glycol monomethyl ether as initiator, with
Levorotatory lactide and 6-caprolactone are PEG-PDLLA-polycaprolactone random copolymer obtained by monomer ring-opening polymerisation,
The number-average molecular weight of the random copolymer is 8.0 × 104~9.0 × 104In the range of, and with the structure shown in following (1)
Formula：
Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
9. the preparation method of minocycline sustained release preparation as described above described in (8), it is characterised in that the minocycline
Pharmaceutically acceptable salt is minocycline hydrochloride.
10. the preparation method of minocycline sustained release preparation as described above described in (8) or (9), it is characterised in that the copolymerization
The number-average molecular weight of thing is 8.1 × 104。
Invention effect
By the invention it is possible to provide a kind of minocycline sustained release preparation with good slow release effect, the minot
Ring element sustained release preparation has a biodegradable film, this kind of film have certain hydrophily and good mechanical strength, while
Have good drug carrying ability and medicine-releasing performance concurrently.
Brief description of the drawings
Fig. 1 is mPEG-P (LLA-co-CL)1H NMR spectras
Fig. 2 is the infrared spectrogram of minocycline hydrochloride, polymer and medicine carrying membrane
A represents minocycline hydrochloride, and b represents polymer, and c represents medicine carrying membrane
Fig. 3 is SEM (SEM) figure on medicine carrying membrane surface under different multiples
A:54 times, B:1000 times, C:2000 times, D:4000 times
Fig. 4 is ESEM (SEM) figure on the medicine carrying membrane surface after stretching under different multiples
A:54 times, B:1000 times, C:2000 times, D:4000 times
Fig. 5 is the Bactericidal test result of minocycline hydrochloride sustained-release preparation obtained in copolymer 1
A represents the antibacterial ring size to cariogenic bacteria streptococcus mutans (S.m), and B represents the antibacterial ring size to Fusobacterium nucleatum (F.n)
Fig. 6 is the laser co-focusing experimental result picture of medicine carrying membrane
A, B represent antibacterial action (A of the medicine carrying membrane to Fusobacterium nucleatum biomembrane:0wt%, B:10wt%), C, D are represented
Antibacterial action (C of the 0wt% medicine carrying membranes to streptococcus mutans:Flcating germ, D:Biomembrane), E, F represent 10wt% medicine carrying membranes to becoming
Streptococcic antibacterial action (the E of shape:Flcating germ, F:Biomembrane).
Specific embodiment
Hereinafter, the specific embodiment that present invention will be described in detail with reference to the accompanying.In addition, embodiments of the present invention are not limited
Due to following implementation methods, those skilled in the art can carry out various changes and replace in range of the technology design of the invention
Change.
Embodiment
First, the preparation of mPEG-P (LLA-co-CL) polymer
1 material and equipment
1.1 experiment materials
1.2 capital equipments
| Instrument title | Model | Manufacturer |
| Vacuum drying chamber | XMTD-8222 | Jing Hong Co., Ltds |
| Oil pump | ZXZ-4 types | Shanghai De Ying vacuum Lighting Co., Ltd |
| Nmr analysis instrument | Bruker | Switzerland Bruker |
| Gel permeation chromatograph | Waters1515 | U.S. Waters |
2 experimental techniques
The pre-treatment of 2.1 experimental raws
(1) 6-caprolactone：In pouring 6-caprolactone into round-bottomed flask, fraction of calcium hydride (CaH is weighed2) pour into wherein,
Stirring reaction 72 hours, removes micro-moisture, and vacuum distillation obtains dry 6-caprolactone, and hermetically drying is preserved.
(2) toluene：A certain amount of sodium silk is added in toluene to be dried, is flowed back at 250 DEG C 7-8 hour, distillation
Obtain dry toluene, kept dry.
(3) L- lactides：The levorotatory lactide that weighs with scale is placed in the reaction pin of 250ml, pours into appropriate volume
Dry toluene, stirs at 105-110 DEG C, lactide monomer dissolve in toluene it is complete after, rapid dumps in beaker,
Sealed with preservative film, be placed in refrigerator and recrystallize, treat that crystal is separated out completely, use vavuum pump suction filtration.Such recrystallization repeats two
It is secondary.To process during L- lactides twice contain round-bottomed flask, add appropriate dry toluene, be stirred at reflux at 130 DEG C, treat
Toluene flows back two hours from oil water separator.Solution is poured into beaker, is sealed with preservative film, be placed in refrigerator and recrystallize,
Treat that crystal is just separated out, use vavuum pump suction filtration.Such to be repeated twice, last time suction filtration completes to use absolute ether
, be evacuated product three hours with water pump by drip washing, and the D-lactic acid monomer for being purified is stored in dry container after being sealed against
It is interior in case follow-up polymerization experiment is used.
(4)mPEG 4000：During mPEG4000 contained into round-bottomed flask, appropriate dry toluene is added, stirred at 130 DEG C
Backflow is mixed, vacuum distillation removes toluene after toluene flows back two hours from oil water separator, obtains dry mPEG
4000。
In the present invention, the molecular weight of mPEG is too greatly, big in polymer terminal group role, in vivo can not be by generation
Thank, and degradation speed can be slack-off, therefore preferably use mPEG4000.
The preparation of 2.2mPEG-P (LLA-co-CL) copolymer
Under the protection of argon gas, will be through two kinds of monomers of foregoing pretreated 6-caprolactone and L- lactides and initiator
MPEG is quickly adding into reaction eggplant-shape bottle roasted in advance, and the oil bath for being placed in 45 DEG C or so is vacuumized.Under the protection of argon gas,
It is added dropwise in catalyst stannous iso caprylate toluene solution to reaction system, ventilation.It is 120~150 DEG C that polymerization bottle is placed on into temperature
It is polymerized in the oil bath pan of dimethicone.After reaction terminates, the system for the treatment of is cooled to room temperature, adds appropriate dichloromethane molten
Solution, dropwise in dropwise reaction reaction mixture to the petroleum ether for stirring, is settled.Polymerizate after sedimentation is put at normal temperatures
Vacuum drying chamber in constant weight.
In the present invention, reaction temperature is preferably controlled in 120~150 DEG C, if be less than 120 DEG C, 6-caprolactone monomer it is anti-
Should be active relatively low, the ratio of 6-caprolactone is often below design proportion in the copolymer of preparation, and polymer also tends to that block is presented
Characteristic.More than 150 DEG C, i.e., under reaction temperature higher, the catalysis activity of stannous iso caprylate is substantially reduced temperature, is unfavorable for anti-
The carrying out answered.It is ideal reaction temperature at 140 DEG C.
Preparation example 1
Under the protection of argon gas, will be through foregoing pretreated 2.2278g 6-caprolactones and 4.2222g L- lactides two
Plant monomer and initiator 0.3g mPEG 4000 are quickly adding into the reaction eggplant-shape bottle of roasted three times in advance together, be placed in 45
DEG C oil bath vacuumize 4h.Under the protection of argon gas, the stannous iso caprylate toluene solution of 1g/mol is added dropwise by micro syringe
32.25 μ l (0.5/1000th of monomer gross mass) take a breath three times in reaction system.It is 140 DEG C that polymerization bottle is placed on into temperature
Polymerization 24h is carried out in the oil bath pan of dimethicone.After reaction terminates, the system for the treatment of is cooled to room temperature, adds appropriate dichloromethane
Alkane dissolves, and dropwise in dropwise reaction reaction mixture to the petroleum ether for stirring, is settled.Polymerizate after sedimentation is placed on often
To constant weight in vacuum drying chamber under temperature, mPEG-P (LLA-co-CL) copolymer 1 is obtained.
Preparation example 2
Under the protection of argon gas, will be through foregoing pretreated 2.2304g 6-caprolactones and 4.2298g L- lactides two
Plant monomer and initiator 0.3g mPEG 4000 are quickly adding into the reaction eggplant-shape bottle of roasted three times in advance together, be placed in 45
DEG C oil bath vacuumize 4h.Under the protection of argon gas, the stannous iso caprylate toluene solution of 1g/mol is added dropwise by micro syringe
32.22 μ l (0.5/1000th of monomer gross mass) take a breath three times in reaction system.It is 120 DEG C that polymerization bottle is placed on into temperature
The one day night that is polymerized is carried out in the oil bath pan of dimethicone.After reaction terminates, the system for the treatment of is cooled to room temperature, adds appropriate two
Chloromethanes dissolves, and dropwise in dropwise reaction reaction mixture to the petroleum ether for stirring, is settled.Polymerizate after sedimentation is put
To constant weight in vacuum drying chamber at normal temperatures, mPEG-P (LLA-co-CL) copolymer 2 is obtained.
Preparation example 3
Under the protection of argon gas, will be through foregoing pretreated 2.2232g 6-caprolactones and 4.2152g L- lactides two
Plant monomer and initiator 0.3g mPEG 4000 are quickly adding into the reaction eggplant-shape bottle of roasted three times in advance together, be placed in 45
DEG C oil bath vacuumize 4h.Under the protection of argon gas, the stannous iso caprylate toluene solution of 1g/mol is added dropwise by micro syringe
32.28 μ l (0.5/1000th of monomer gross mass) take a breath three times in reaction system.It is 150 DEG C that polymerization bottle is placed on into temperature
The one day night that is polymerized is carried out in the oil bath pan of dimethicone.After reaction terminates, the system for the treatment of is cooled to room temperature, adds appropriate two
Chloromethanes dissolves, and dropwise in dropwise reaction reaction mixture to the petroleum ether for stirring, is settled.Polymerizate after sedimentation is put
To constant weight in vacuum drying chamber at normal temperatures, mPEG-P (LLA-co-CL) copolymer 3 is obtained.
The sign of 2.3 polymer
2.3.1 spectral analysis of the nuclear magnetic resonance (NMR)
1H NMR are used for the monomer ratio and sequential structure of mPEG-P (LLA-co-CL) copolymer for characterizing preparation
Distribution.Concrete operations are as follows：MPEG-P (LLA-co-CL) copolymer of about 5mg is weighed, CDCl is dissolved in3In, using Germany
Bruker AV 400MHz spectral analysis of the nuclear magnetic resonance instrument test mPEG-P (LLA-co-CL)1H NMR.In nucleus magnetic hydrogen spectrum figure
In obtain in mPEG-P (LLA-co-CL) copolymer proton hydrogen on molecule go out peak position and relative integral peak area so that can
To determine the structure of mPEG-P (LLA-co-CL) copolymer.
Hereinafter, by taking mPEG-P (LLA-co-CL) copolymer 1 as an example in detail, the structure elucidation process of copolymer is described in detail.Fig. 1 is
MPEG-P (LLA-co-CL) copolymer 11H NMR spectras, the chemistry of all protons goes out peak position and is labeled in it one by one
In.From1H NMR spectras can be seen that in mPEG-P (LLA-co-CL) copolymer 1, the proton appearance in L-LA units be g and
H, the appearance of each proton is labeled as b, c, d, e, f in 6-caprolactone construction unit, and mPEG's goes out peak position for a.
The appearance of two kinds of monomers is specific as follows：Chemical shift appearance of all protons on nucleus magnetic hydrogen spectrum in caprolactone units
Position is respectively 1.35ppm, 1.65ppm, 2.31-2.39ppm and 4.06-4.14ppm, corresponds respectively to the matter on γ methylene
Proton (e and c) on sub (d), β and δ methylene, the proton (b) on α methylene and the proton (f) on ε methylene.It is left-handed
Chemistry of all Hydrogen Protons on nuclear magnetic spectrogram goes out peak position respectively in 1.49-1.55ppm and 5.05- in lactide repeat unit
Between 5.18ppm, corresponding thereto be Hydrogen Proton (h) on methyl and the Hydrogen Proton (g) on methine.b、c、d、e、f、g、
H lower produced all kinds of inclined peaks for CL and LA influences each other.
From above-mentioned spectral analysis of the nuclear magnetic resonance, structure such as following formula (1) institute of mPEG-P (LLA-co-CL) copolymer 1
Show：
Wherein, the ratio of L-LA and ε-CL repeat units is 3：1.
With with above-mentioned 2.3.1 same method, to the copolymer 2 as obtained in preparation example 2 and as obtained in preparation example 3 altogether
Polymers 3 is characterized, and is as a result shown：Copolymer 2,3 also has the structure shown in formula (1).
2.3.2 gel permeation chromatograph (GPC)
The number-average molecular weight (Mn) and its molecular weight distribution (PDI) of mPEG-P (LLA-co-CL) copolymer are to use the U.S.
The gel chromatography analyzer of the model water1515 of Waters, using THF as eluting solvent, the flow velocity of 1mL/min enters
Row is determined.
Determined more than, number-average molecular weight and the molecular weight distribution such as institute of table 1 of mPEG-P (LLA-co-CL) copolymer
Show.
Table 1：
| Copolymer 1 | Copolymer 2 | Copolymer 3 | |
| Number-average molecular weight (Mn) | 80678 | 81004 | 81596 |
| Molecular weight distribution (PDI) | 1.5 | 1.5 | 1.5 |
Here, the ratio of lactide and caprolactone repeat unit is preferably 3 in mPEG-P (LLA-co-CL) copolymer:1,
And the number-average molecular weight of copolymer is preferably in the range of 80,000~90,000, inventor it was unexpectedly observed that when the conditions are satisfied,
The minocycline hydrochloride oral cavity sustained release preparation as obtained in the co-polymer membrane can be provided simultaneously with long-acting sustained release performance with it is good
Mechanical property (film forming), and both performances are particularly important for oral cavity sustained release preparation.
2nd, the preparation of Dynacin
1 experimental section
1.1 materials and equipment
1.1.1 experiment material
Minocycline hydrochloride, yellow crystalline powder, odorless, bitter, purity 99% (Mayan reagent Co., Ltd)；
Methyl alcohol, colourless transparent liquid, the upper smooth Science and Technology Ltd. of Haitai；
Chloroform, colourless transparent liquid, Chemical Reagent Co., Ltd., Sinopharm Group；
Brain heart infusion (BHI), U.S. company BD；
Agar powder (lot number：110914), Shanghai Bai Ao bio tech ltd；
Citric acid, Shantou City's brilliance laboratory；
Disodium hydrogen phosphate dodecahydrate, Chemical Reagent Co., Ltd., Sinopharm Group；
PH precision test papers (6.4~8.0), Chemical Reagent Co., Ltd., Sinopharm Group；
International standard bacterial strain streptococcus mutans (UA159), Fusobacterium nucleatum (AT25586), Shanghai City dentistry emphasis
Laboratory Microbiological Lab provides.
1.1.2 capital equipment
JA2003N electronic balances (Shanghai Precision Scientific Apparatus Co., Ltd)；
Magnetic stirring apparatus (B11-3, Shanghai Si Le Instrument Ltd.)；
PH testers (Shanghai Precision Scientific Apparatus Co., Ltd)；
Slide measure (precision 0.02mm, Shanghai Measuring and Cutting Tools Plant)；
Constant incubator (SANYO, SANYO GS mechanical ＆ electrical corporation, Japan)；Anaerobic culture box (Whitley DG250, Don
Whitley scientific companies, Britain)；
Spectrophotometer (UV-1601, Shimadzu company, Japan).
1.2 experimental techniques
1.2.1 the preparation of medicine carrying membrane
Precision weighs 1.5g mPEG-P (LLA-co-CL) and appropriate bulk drug minocycline hydrochloride, and 15mL chlorine is dissolved in respectively
In imitative and 1mL methyl alcohol, then minocycline hydrochloride solution is slowly added dropwise in polymer solution, is stood after fully mixing, treated
Bubble eliminates rear plastic film mulch on polyfluortetraethylene plate, 72 hours rear demouldings of drying at room temperature, prepared content of dispersion be respectively 5wt%,
Three kinds of medicine carrying membranes of 8wt% and 10wt% and the not blank film of pastille.Diaphragm is broken into the circle of 6mm diameters with card punch
Diaphragm, ultra violet lamp 30min sterilizings, is sealed in standby in clean brown bottle.Every 0.5~1.0mg of medicine film drug containing.
1.2.2SEM the surface topography of film is characterized
Every group of film randomly selects a small strip for being cut into 3mm × 10mm sizes, in ESEM after metal spraying treatment
On the surface topography of every cluster film is analyzed.
1.2.3 the physicochemical property test of medicine carrying membrane
1.2.3.1 quality uniformity is determined
A film in every group of film is randomly selected, diverse location cuts out the diaphragm of 1cm × 1cm at the 5 of film, uses respectively
Electronic balance weighing, calculates average value.
1.2.3.2 thickness evenness is determined
A film in every group of film is randomly selected, the thickness to 5 diverse locations of film is measured with micrometer caliper,
Calculate average value.
1.2.3.3 surface pH is determined
Each group film is cut into the diaphragm of formed objects 1cm × 1cm, every group of Duplicate Samples 5 are placed in the culture of corresponding numbering
In ware, McIlvaine buffer solutions (pH 6.6) is injected, after soaking 2 hours, be measured with PH test paper.
1.2.3.4 Measuring Mechanical Properties
According to GB/T 1040.3-2006《The measure third portion of plastic tensile performance:The experimental condition of film and thin slice》,
Film is cut into by 4mm wide, the dumbbell shape sample of gauge length 25mm, every group of Duplicate Samples 5 using Standard Module.After sample is cut into,
Normal temperature and pressure is deposited 12 hours, the stress that release is caused during cutting.Rate of extension 200mm/min, test temperature (25 ± 2)
DEG C, average.
1.2.4 the medicament slow release performance research of medicine carrying membrane
1.2.4.1McIlvaine the preparation of buffer solution
Precision weighs disodium hydrogen phosphate 35.814g, anhydrous citric acid 9.6065g, and 500ml deionized waters are used respectively
Dissolved, with 0.2mol/L Na2HPO4After 0.1mol/L citric acid solutions, then 145.5ml 0.2mol/L are taken respectively
Na2HPO4The McIlvaine cushioning liquid that pH value is 6.6 is mixed to prepare with 54.5ml 0.1mol/L citric acids.
1.2.4.2 the determination of Detection wavelength
The minocycline hydrochloride solution of 0.02mg/ml is prepared, UV absorption ripple is carried out in 200~400nm wave-length coverages
Long scan, a length of 345nm of maximum absorption wave of minocycline hydrochloride.
1.2.4.3 interference experiment
10mg/ml mPEG-P (LLA-co-CL) solution is prepared, UV absorption is carried out in 200~400nm wave-length coverages
Length scanning, finds at 345nm wavelength without absorption, thus can exclude medicine film auxiliary material at the wavelength to minocycline hydrochloride medicine
The interference of analyte detection.
1.2.4.4 the foundation of standard curve
Precision weighs minocycline hydrochloride 10mg and is dissolved in 50ml measuring bottles, after constant volume, take respectively 100ul, 250ul,
375ul, 500ul, 750ul, 1000ul, 1250ul and 1500ul constant volume in 10ml measuring bottles, obtain concentration respectively 2.0ug/ml,
The minocycline hydrochloride of 5.0ug/ml, 7.5ug/ml, 10.0ug/ml, 15ug/ml, 20ug/ml, 25ug/ml and 30ug/ml is dilute
Liquid is released, trap is surveyed at 345nm, trap A mapped with concentration C, and carry out linear regression.
1.2.4.5 medicament slow release experiment
Precision weighs medicine carrying membrane piece (medicine content is respectively 0.5mg, 0.8mg, 1.0mg) and is put into 200ml conical flasks, adds
The Mcllvaine buffer solutions of 50ml, insert in 37 DEG C of full incubators and stand.In particular point in time 0.5h, 1h, 2h, 4h, 8h, 12h,
24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h, 288h, 312h and 336h liquid-transfering gun from
5ml McIlvaine buffer solutions accurately are measured in conical flask, while adding the fresh McIlvaine bufferings that 5ml temperature is 37 DEG C
Liquid, keeps cumulative volume constant, and the absorbance of medicine is measured with ultraviolet specrophotometer, calculates cumulative release amount percentage.Every group
3 parallel laboratory tests are carried out, experimental result is averaged.
1.2.5 the in-vitro antibacterial performance study of medicine carrying membrane
1.2.5.1 the preparation of bacterium solution
Test and select Periodontal Pathogens Fusobacterium nucleatum (F.nucleatum), cariogenic bacteria streptococcus mutans (S.mutans),
With aseptic inoculation ring picking BHI agar plate surface monoclonal bacterium colonies in 3ml BHI fluid nutrient mediums, S.mutans is in general
Logical incubator, F.nucleatum is in 37 DEG C of culture 24h of anaerobic culture box.Dyeing microscopic examination is pure culture, and spectrophotometer is by bacterium
Liquid concentration is adjusted to 1 × 106CFU/ml is standby.
1.2.5.2 Bactericidal test
In superclean bench, the BHI Solid agar cultures that will be disinfected are poured into sterile petri dish, and cooling is obtained
After culture medium flat plate, draw 50ul bacterium solutions with liquid-transfering gun and drop on culture medium flat plate, aseptic L rods push away even, are obtained containing bacterium culture
Base flat board.The circular film that to disinfect is equidistant to be put into flat board containing bacterium culture medium, after being placed with, with the light press mold of aseptic nipper
Piece makes it suitably be contacted with agar surface.It is control with mPEG-P (LLA-co-CL) blank films, it is parallel to make 3 culture dishes.Respectively
It is inverted in 37 DEG C of anaerobic culture boxes, result is observed after 24h.Use vernier caliper measurement antibacterial circle diameter.Experiment 3 times is repeated, is taken
Average value.
1.2.6 the vitro cytotoxicity research of medicine carrying membrane
1.2.6.1 leaching liquor is prepared and is grouped
Will 0wt%~10wt%MH/mPEG-P (LLA-co-CL) medicine film ultraviolet lighting 2h sterilize after by surface of test piece product and
The ratio between nutrient solution is 6cm2/ ml (ISO10993-12), medicine film is put into the sterile centrifugation tube of the cell culture fluids of DMEM containing 10ml
In, it is placed in 37 DEG C of constant-temperature tables and places 24 ± 2h.Cell leaching liquor is filtered with the filter of a diameter of 0.22um after culture, then dilute
Release the material leaching liquor for being made into 50%, 100% respectively.Setup Experiments positive control and negative control, adding dimethyl sulfoxide group is
Positive controls, addition cell culture fluid group is negative control group.
1.2.6.2 cytotoxicity test (MTT)
Using the method for Cell culture invitro, according to ISO10993-5, experiment is using sensitivity MTT method high
(mtt assay) carries out vitro cytotoxicity detection.Experiment selects periodontal ligament fibroblasts in vitro, cell to take from three volunteers, age
Between 20-25 Sui, the periodontium of the third molar of extraction, subculture is to the 3rd in DMEM cell culture fluids
In generation, it is 4 × 10 to be configured to concentration3/ ml cell suspensions, are then inoculated in 96 orifice plates, per hole 200ul, every group of 6 holes.37 DEG C of perseverances
After temperature culture 24h, nutrient solution is abandoned in suction, and 50%, 100% two kind of concentration material leaching liquor is separately added into 96 orifice plates, per hole
200ul.24h is cultivated in 37 DEG C of cell constant temperature casees, 20ul (5mg/mL) MTT solution lucifuge cultures 4h is added per hole.Suction is abandoned respectively
Boreliquid, 200ul dimethyl sulfoxide (DMSO)s are added per hole, 10min are shaken at room temperature, in measuring each hole on enzyme linked immunological instrument in 490nm
The absorbance (OD) at place, experiment is in triplicate.Calculate the relative activity (RGR) of cell in each group.
1.2.7 the laser co-focusing experiment of medicine carrying membrane
By 2.4 × 2.4cm2Cover glass is inserted in 6 orifice plates, and about 2ml 10 is separately added into per hole5The streptococcus mutans of CFU/ml
With Fusobacterium nucleatum bacterium solution, biomembrane is formed after Anaerobic culturel 24h, with normal saline flushing 2 times after, contained with different pharmaceutical respectively
The medicine carrying membrane leaching liquor of amount carries out treatment 30min, and blank film leaching liquor treatment group is as a control group.Meanwhile, it is floating in former 6 orifice plate
Bacterium is processed with the medicine film leaching liquor of equivalent volumes for trip.After 30min, biological membrane sample physiological saline gently rinses 5 times, together
When flcating germ collect and mix, lucifuge is separately added into LIVE/ BacLightTMBacterial Viability Kit are thin
, be placed in cover glass under laser confocal microscope after 15min observe by bacterium survival kit fluorescence dye liquor.488nm/561nm light
After source excitation, viable bacteria is combined with SYTO9 sends green fluorescence, and dead bacterium nucleus DNA is combined with PI sends red fluorescence.Experimental group
Respectively contain three samples.
2 results
2.1 outward appearances
Co-polymer membrane obtained by preparation example 1~3 is yellow sheet type film, and bright and clean complete, consistency of thickness, color and luster is equal
It is even, without obvious bubble.
2.2 film surface microanalysis
Fig. 2 is the infrared spectrogram of minocycline hydrochloride, polymer and medicine carrying membrane, and wherein curve a is minocycline hydrochloride,
Curve b is mPEG-P (LLA-co-CL) polymer, and curve c is medicine carrying membrane, and infrared spectrogram shows, nothing between main ingredient and polymer
Interact, therefore it may be speculated that medicine and polymer are compatible, film forming can be prepared.
Fig. 3 is SEM (SEM) figure that 10wt% carries medicine co-polymer membrane surface under different multiples, wherein A, B,
C, D are respectively 54 times, 1000 times, 2000 times, the medicine carrying membrane surface microscopic figure under 4000 times of mirrors, it is seen then that drug crystallization particle from
Assembling is embedded in thin polymer film in order in disc-shaped.
The quality of 2.3 films, thickness and surface p H analysis
The quality and thickness evenness of medicine film are the direct factors for influenceing film drug dose.Result shows, of the invention common
The quality and thickness of polymers medicine film are all more uniform, and can be obtained by solution film casting method according to specific needs.Medicine carrying membrane table
Between 6.7~7, the pH value 6.6 with level in gingival sulcus fluid is approached face pH value range, partial neutral, as a result as shown in table 2.
Table 2：The physical and chemical performance of different films
The Evaluating Mechanical Properties of 2.4 medicine carrying membranes
The mechanical property of medicine carrying membrane is done and has tested (table 3), wherein, the elongation at break of medicine carrying membrane is very high, peak load
Smaller, tensile strength is smaller, i.e., the toughness of material is very well, more soft, as the load medicine film in oral pocket, can be very good
Laminating affected part.Meanwhile, Electronic Speculum (Fig. 4) is shot to the medicine carrying membrane after stretching as can be seen that white particle part is hydrochloric acid rice really
Promise ring crude granule, during black portions are extension test, particle out after the hole that leaves on polymer, wherein A, B, C, D point
Not Wei 54 times, 1000 times, 2000 times, stretch under 4000 times of mirrors after medicine carrying membrane surface microscopic figure.
The mechanical property of the minocycline hydrochloride pharmaceutical film of table 3.
| Medicament contg | Peak load (N) | Tensile strength (MPa) | Elongation at break (%) | Elastic modelling quantity (N/mm) |
| 5wt% | 4.98 | 7.00 | 906.33 | 1.10 |
| 8wt% | 4.22 | 7.27 | 972.93 | 1.01 |
| 10wt% | 4.10 | 7.12 | 977.66 | 1.05 |
The sustained release performance evaluation of 2.5 medicine carrying membranes
2.5.1 minocycline hydrochloride standard curve
With minocycline hydrochloride concentration C as abscissa, absorbance A at 345nm obtains regression equation for ordinate：A=
0.0274C+0.0014(r2=0.9999), at 345nm, the concentration C of minocycline hydrochloride is in 2.0~24.0ug/ml scopes
It is interior to have good linear relationship with absorbance A.
2.5.2 external sustained release experiment
The absorbance that each time point measures determines drug release amount by regression equation, calculates cumulative release amount percentage, to accumulate
Drug release amount percentage is mapped to the time.Table 4 is that different proportion minocycline hydrochloride pharmaceutical film is external as obtained in copolymer 1
Sustained release result.Table 4 shows that pharmaceutical release time shortens, 10wt% hydrochloric acid minots with the increase of minocycline hydrochloride content
Ring element medicine film slow-release time is two weeks, and with the increase of medicament contg, drug accumulation release rate also substantially increases.
Minocycline hydrochloride pharmaceutical film release in vitro result (n=3, pH 6.6) of table 4.
The anti-microbial property evaluation of 2.6 medicine carrying membranes
2.6.1 antibacterial ring size experiment
Anti-microbial property to the minocycline hydrochloride sustained-release preparation as obtained in copolymer 1 is evaluated.
The antibacterial tests of minocycline hydrochloride sustained-release preparation show that each culture medium flat plate bacterial growth is good, medicine carrying membrane pair
S.m and F.n have antibacterial ring size to produce.Antibacterial effect gradually strengthens with the increase of medicament contg, and suppression of the medicine film to F.n
Effect is better than the inhibitory action to S.m.Result is shown in Fig. 5, wherein, A is the antibacterial ring size to cariogenic bacteria streptococcus mutans (S.m), and B is
To the antibacterial ring size of Fusobacterium nucleatum (F.n).
2.6.2 laser co-focusing experiment
At blank film leaching liquor group (Fig. 6 A, C, D), streptococcus mutans, the flcating germ of Fusobacterium nucleatum and biomembrane swash
In light copolymerization Jiao's picture, green fluorescence has been almost full with whole visual field, and the medicine carrying membrane leaching liquor in different pharmaceutical content is processed
In group (Fig. 6 B, E, F), green and red fluorescence respectively account for certain proportion and have part to overlap into crocus, that is, the overlap of the dead bacterium that lives,
With the increase of medicament contg, biomembrane and flcating germ contrast control group, and dead bacterium is in the majority, illustrates minocycline hydrochloride medicine film pair
The biomembrane and flcating germ of streptococcus mutans and Fusobacterium nucleatum have very strong inhibitory action.
The vitro Cytotoxicity Evaluation of 2.7 medicine carrying membranes
Cytotoxicity to material carries out grade assessment (Pyatyi).0 grade of cytotoxicity:RGR >=100%, cytotoxicity 1
Level:75%≤RGR≤99%, 2 grades of cytotoxicity:50%≤RGR≤74%, 3 grades of cytotoxicity:5%≤RGR≤49%, carefully
4 grades of cellular toxicity:1%≤RGR≤24%, 5 grades of cytotoxicity:RGR=0.Evaluation of result:If experimental result is 0 or 1 grade, represent
Belong to passing material；Experimental result is 2 grades, to carry out overall merit with reference to cell concrete form；Experimental result is 3-5 grades, then
Material is unqualified.The results are shown in Table 5,6.
The OD values of MH/mPEG-P (LLA-co-CL) each group medicine film leaching liquor when table 5.100% and 50% concentration
Table 6.MH/mPEG-P (LLA-co-CL) each group cells are with respect to appreciation rate and toxicity level
By table 5,6 is visible, except 10wt%MH/mPEG-P (LLA-co-CL) cell leaching liquor cell phase of 100% concentration
To appreciation rate 87.45%, cytotoxicity grade is 1 grade, and other 50% and 100% cell leaching liquor cells are equal with respect to appreciation rate
More than 100%, cytotoxicity grade is 0 grade.
Claims (10)
1. a kind of minocycline sustained release preparation, it is characterised in that formed by degradable biological film and minocycline, it is described to drop
Solution biofilm is obtained as monomer ring-opening polymerisation with poly glycol monomethyl ether as initiator, with levorotatory lactide and 6-caprolactone
PEG-PDLLA-polycaprolactone random copolymer, the number-average molecular weight of the random copolymer is 8.0 × 104~
9.0×104In the range of, and with the structural formula shown in following (1)：
Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
2. minocycline sustained release preparation as claimed in claim 1, the minocycline is with the pharmaceutically acceptable of minocycline
Salt form provide.
3. minocycline sustained release preparation as claimed in claim 2, the form of the pharmaceutically acceptable salt of the minocycline
It is minocycline hydrochloride.
4. the minocycline sustained release preparation as any one of claim 1-3, it is characterised in that the poly- second two of initiator
Alcohol monomethyl ether is mPEG 4000.
5. the minocycline sustained release preparation as any one of claim 1-3, it is characterised in that the molecule of the copolymer
Amount is distributed as 1.5.
6. the minocycline sustained release preparation as any one of claim 1-3, it is characterised in that the number of the copolymer is equal
Molecular weight is 8.1 × 104。
7. the minocycline sustained release preparation as any one of claim 1-3, it is characterised in that drugloading rate is 5wt%-
10wt%.
8. a kind of preparation method of minocycline sustained release preparation, it is characterised in that weigh degradable biological film and minocycline
Pharmaceutically acceptable salt, be dissolved in chloroform and methyl alcohol respectively, fully mix after stand, plastic film mulch is in poly- four after bubble is eliminated
On PVF plate, drying at room temperature rear demoulding, the degradable biological film is with poly glycol monomethyl ether as initiator, with left-handed
Lactide and 6-caprolactone are PEG-PDLLA-polycaprolactone random copolymer obtained by monomer ring-opening polymerisation, described
The number-average molecular weight of random copolymer is 8.0 × 104~9.0 × 104In the range of, and with the structural formula shown in following (1)：
Wherein, the ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
9. the preparation method of minocycline sustained release preparation as claimed in claim 8, it is characterised in that the medicine of the minocycline
Acceptable salt is minocycline hydrochloride on.
10. the preparation method of minocycline sustained release preparation as claimed in claim 8 or 9, it is characterised in that the copolymer
Number-average molecular weight is 8.1 × 104。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710207548.7A CN106822066B (en) | 2017-03-31 | 2017-03-31 | Minocycline sustained release preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710207548.7A CN106822066B (en) | 2017-03-31 | 2017-03-31 | Minocycline sustained release preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106822066A true CN106822066A (en) | 2017-06-13 |
| CN106822066B CN106822066B (en) | 2019-10-01 |
Family
ID=59142854
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710207548.7A Expired - Fee Related CN106822066B (en) | 2017-03-31 | 2017-03-31 | Minocycline sustained release preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106822066B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756908A (en) * | 2010-01-25 | 2010-06-30 | 沈阳药科大学 | Hydroxyapatite micro-sphere with polyester coating and preparation method thereof |
| CN103254442A (en) * | 2013-04-28 | 2013-08-21 | 天津大学 | Disulfide bond linked polyester comb-type graft copolymer as well as preparation method and application thereof |
| CN104415029A (en) * | 2013-08-20 | 2015-03-18 | 苏州雷纳药物研发有限公司 | Andrographolide polymer micelle, preparation method and medicinal application thereof |
-
2017
- 2017-03-31 CN CN201710207548.7A patent/CN106822066B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756908A (en) * | 2010-01-25 | 2010-06-30 | 沈阳药科大学 | Hydroxyapatite micro-sphere with polyester coating and preparation method thereof |
| CN103254442A (en) * | 2013-04-28 | 2013-08-21 | 天津大学 | Disulfide bond linked polyester comb-type graft copolymer as well as preparation method and application thereof |
| CN104415029A (en) * | 2013-08-20 | 2015-03-18 | 苏州雷纳药物研发有限公司 | Andrographolide polymer micelle, preparation method and medicinal application thereof |
Non-Patent Citations (3)
| Title |
|---|
| 刘瑞雪等: ""聚己内酯-b-聚乙二醇大分子单体的酶催化合成及其原子转移自由基聚合"", 《北京化工大学学报》 * |
| 许亮亮等: ""聚己内酯/聚乙二醇/聚丙交酯两亲性共聚物纳米胶束的制备与表征"", 《材料导报》 * |
| 赵亚男等: ""聚乙二醇-b-聚乳酸的合成及其电纺形成超细纤维研究"", 《高分子学报》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106822066B (en) | 2019-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Guo et al. | Synthesis and characterization of anti-bacterial and anti-fungal citrate-based mussel-inspired bioadhesives | |
| Benamer et al. | Synthesis and characterisation of hydrogels based on poly (vinyl pyrrolidone) | |
| Haas et al. | Enzyme degradable polymersomes from hyaluronic acid-block-poly (ε-caprolactone) copolymers for the detection of enzymes of pathogenic bacteria | |
| Acosta-Torres et al. | Biocompatible metal-oxide nanoparticles: nanotechnology improvement of conventional prosthetic acrylic resins | |
| Wu et al. | Injectable biodegradable hydrogels and microgels based on methacrylated poly (ethylene glycol)-co-poly (glycerol sebacate) multi-block copolymers: synthesis, characterization, and cell encapsulation | |
| Zhu et al. | Photocrosslinkable biodegradable elastomers based on cinnamate-functionalized polyesters | |
| Wang et al. | The synthesis, characterization and biocompatibility of poly (ester urethane)/polyhedral oligomeric silesquioxane nanocomposites | |
| Luo et al. | Injectable self-healing anti-inflammatory europium oxide-based dressing with high angiogenesis for improving wound healing and skin regeneration | |
| Guo et al. | Bactericidal property and biocompatibility of gentamicin-loaded mesoporous carbonated hydroxyapatite microspheres | |
| Sukanya et al. | Degradation of Poly (ε-caprolactone) and bio-interactions with mouse bone marrow mesenchymal stem cells | |
| Chitra et al. | Indole-3-acetic acid/diol based pH-sensitive biological macromolecule for antibacterial, antifungal and antioxidant applications | |
| Hu et al. | Morphological and mechanical properties of tannic acid/PAAm semi-IPN hydrogels for cell adhesion | |
| CN106083791B (en) | A kind of coumarin derivative, its preparation method and by its obtained hydrogel | |
| Moeinzadeh et al. | Synthesis and gelation characteristics of photo-crosslinkable star poly (ethylene oxide-co-lactide-glycolide acrylate) macromonomers | |
| Filipović et al. | Biocompatible and degradable scaffolds based on 2-hydroxyethyl methacrylate, gelatin and poly (beta amino ester) crosslinkers | |
| WO2018136794A1 (en) | Fluorescent ph sensors and methods of preparing and using them | |
| CN101864069B (en) | Biodegradable hydrogel and synthesis method thereof | |
| Fan et al. | Preparation and characterization of a biodegradable hydrogel containing oligo (2, 2-dimethyltrimethylene carbonate) moieties with tunable properties | |
| CN106084140B (en) | A kind of polyamide containing guanidino group, its preparation method and by its obtained hydrogel | |
| Huang et al. | Physicochemical, antibacterial properties, and compatibility of ZnO-NP/chitosan/β-glycerophosphate composite hydrogels | |
| CN106822066B (en) | Minocycline sustained release preparation | |
| Wu et al. | Polyurethane tethering natural antibacterial substances for catheter applications | |
| Wang et al. | Preparation of a highly crosslinked biosafe dental nanocomposite resin with a tetrafunctional methacrylate quaternary ammonium salt monomer | |
| Kayaman-Apohan et al. | Poly (dl-lactic acid)/triblock PCL–PDMS–PCL copolymers: synthesis, characterization and demonstration of their cell growth effects in vitro | |
| Lai | Effect of chemical composition on corneal cellular response to photopolymerized materials comprising 2-hydroxyethyl methacrylate and acrylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20191001 |