CN106589337B - Degradable biological film, preparation method and nitre azole sustained release preparation - Google Patents
Degradable biological film, preparation method and nitre azole sustained release preparation Download PDFInfo
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- CN106589337B CN106589337B CN201611138412.7A CN201611138412A CN106589337B CN 106589337 B CN106589337 B CN 106589337B CN 201611138412 A CN201611138412 A CN 201611138412A CN 106589337 B CN106589337 B CN 106589337B
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- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims description 52
- 238000002360 preparation method Methods 0.000 title claims description 27
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 title claims description 26
- 239000003405 delayed action preparation Substances 0.000 title claims description 25
- 229920001577 copolymer Polymers 0.000 claims abstract description 55
- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000178 monomer Substances 0.000 claims abstract description 16
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229920000151 polyglycol Polymers 0.000 claims abstract description 12
- 239000010695 polyglycol Substances 0.000 claims abstract description 12
- 239000003999 initiator Substances 0.000 claims abstract description 10
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229920001610 polycaprolactone Polymers 0.000 claims abstract description 9
- 239000004632 polycaprolactone Substances 0.000 claims abstract description 9
- -1 polyethylene Polymers 0.000 claims abstract description 7
- 239000004698 Polyethylene Substances 0.000 claims abstract description 4
- 229920000573 polyethylene Polymers 0.000 claims abstract description 4
- 229920005604 random copolymer Polymers 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 229960000282 metronidazole Drugs 0.000 claims description 21
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 18
- 239000003921 oil Substances 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 229920001427 mPEG Polymers 0.000 claims description 11
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 claims description 10
- 229960002313 ornidazole Drugs 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 238000006116 polymerization reaction Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000009826 distribution Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 238000004062 sedimentation Methods 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 5
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical group O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims description 4
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 claims description 3
- 239000002362 mulch Substances 0.000 claims description 3
- 239000002985 plastic film Substances 0.000 claims description 3
- 229920006255 plastic film Polymers 0.000 claims description 3
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims description 3
- 229960005053 tinidazole Drugs 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 abstract description 6
- 238000007142 ring opening reaction Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000012528 membrane Substances 0.000 description 31
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 230000000844 anti-bacterial effect Effects 0.000 description 13
- 229920000642 polymer Polymers 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 241000605986 Fusobacterium nucleatum Species 0.000 description 8
- 241000194019 Streptococcus mutans Species 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
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- 238000002835 absorbance 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
- 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
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 4
- 238000009423 ventilation Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 229960004106 citric acid Drugs 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
- 238000000338 in vitro Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 208000028169 periodontal disease Diseases 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000010183 spectrum analysis Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 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
- 239000008187 granular material Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000003239 periodontal effect Effects 0.000 description 2
- 229920001420 poly(caprolactone-co-lactic acid) Polymers 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
- 238000012545 processing Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012876 topography Methods 0.000 description 2
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 230000010148 water-pollination Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000010266 Aggressive Periodontitis Diseases 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
- 239000005977 Ethylene Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 239000006169 McIlvaine's buffer solution Substances 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 1
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 206010060932 Postoperative adhesion Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 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
- 210000004556 brain Anatomy 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000001013 cariogenic effect Effects 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 229940022769 d- lactic acid Drugs 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 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
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 210000000887 face Anatomy 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
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 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
- 244000005700 microbiome Species 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
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 201000006727 periodontosis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 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
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229920001897 terpolymer Polymers 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical compound FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Manufacturing & Machinery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Materials Engineering (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of degradable biological film, it be using poly glycol monomethyl ether as initiator, with levorotatory lactide (L-LA) and 6-caprolactone (ε-CL) is polyethylene glycol-polylactide obtained by monomer ring-opening polymerisation-polycaprolactone random copolymer, it is characterized in that, the number-average molecular weight of the copolymer is 8.0 × 104~9.0 × 104In the range of, there is structural formula shown in following (1):Wherein, the ratio of L-LA and ε-CL unit is 3 to 1.
Description
Technical field
The present invention relates to a kind of degradable biological film, preparation method and nitre azole sustained release preparations.
Background technique
Plaque is the initiation factor of periodontosis, and the microorganism of infection is based on gram-negative anaerobic bacteria.Effectively suppression
System and elimination anaerobic bacteria become the key of periodontal disease treatment.Clinically, sustained-release antibacterial drug is using relatively reasonable administration way
Diameter, finds effective periodontal local sustained release antibacterials and slow-released carrier is the emphasis of current periodontal disease therapeutic clinical research.
It is a kind of with potent anaerobe resistant effect using metronidazole, Tinidazole, Ornidazole as the nitre azole drug of representative
Antimicrobial has obtained the favor of clinician and patient with the expansion of application field, also has during treating periodontal disease
Good clinical efficacy.
Yang Linghui et al.[1]Using sodium carboxymethylcellulose, polyvinyl alcohol as slow-released carrier, using made of solution evaporation method
Metronidazole Compound slow-release medicine-membrane, the medicament slow release time was at 5 days or so.Zheng Zengwei[2]To using soluble hydroxypropyl cellulose as matrix
Metromidaxole membrane studied, which plays a role the time at 7 days or so.
Polycaprolactone (PCL), polylactide (PLLA) are common biodegradable polyesters, have good mechanicalness
It can, can blended, biocompatibility and degradability.Poly glycol monomethyl ether (mPEG) is used as good hydrophilic polymer,
Good biocompatibility, nontoxic, immunogenicity is low, can be excreted by kidney.
Xu Liangliang etc.[3]It is total that amphipathic caprolactone-ethylene glycol-lactide (PCELA) three block has been synthesized using the precipitation method
Polymers, but in the document, what is be prepared is the nano-micelle of copolymer, rather than biofilm, and without reference to will be total to
Polymers is used for sustained release preparation, the more research without reference to release in vitro, film forming etc..
Chen Hongli[4]Polycaprolactone/polyoxyethylene/polylactide terpolymer has been synthesized Deng using PEG 6000, has been copolymerized
The ratio of the different monomers of object 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 has studied the biological degradability of copolymer, without reference to release property in the film forming of copolymer, oral cavity etc.
Research.
Zheng Zhang[5](gather in oneself etc. triblock copolymer (polycaprolactone-lactide)-polyethylene glycol-has been synthesized
Ester-lactide), i.e. PCLA-PEG-PCLA, the document has studied bio-safety performance, degradation property and the prevention of the polymer
The barrier action of post-operation adhesion, without reference to the film forming of copolymer, load pharmacological property and slow release.
Existing technical literature
[1] Yang Linghui, Wang Shuxia, Wang Quanliang wait preparation and quality control [J] China of Metronidazole Compound slow-release medicine-membrane
Modern Application pharmacy, 1999,16 (2): 32-33.
[2] observation of curative effect [J] Chinese journals of practical medicine of Zheng Zengwei metromidaxole membrane treatment periodontitis, 2010,26
(12):2211-2213.
[3] Xu Liangliang, Chen Qiang, Li Li wait the amphipathic copolymer nano micella of polycaprolactone/polyethyleneglycol/polylactide
Preparation and representation [J] material Leader, 2006,20 (11): 131-133.
[4] Chen Hongli, Bei Jianzhong, Wang Shenguo Biodegradable high molecular-polycaprolactone/polyoxyethylene/polylactide ternary
Research [J] macromolecule journal of copolymer conduct hydrolysis, 2000, (5): 626-631.
[5]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.
Summary of the invention
Technical problems to be solved by the inivention
It is a kind of with some strength and degradable life hydrophilic, for being sustained nitre azole drug the present invention is directed to develop
Object film and nitre azole sustained release preparation.
For solving the scheme of above-mentioned technical problem
Inventors have found that with poly glycol monomethyl ether (mPEG) for initiator, levorotatory lactide (L-LA) and caprolactone (ε-
It CL is) mPEG-P (LLA-co-CL) (poly glycol monomethyl ether-polylactide-polycaprolactone) nothing of monomer ring-opening polymerisation preparation
Copolymer is advised, 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, it can obtain that there is certain hydrophily and good mechanical strength while have both good load medicine
The degradable biological film of performance and medicine-releasing performance.
Specifically, the present invention includes the following contents.
It is using poly glycol monomethyl ether as initiator, with levorotatory lactide and ε-in oneself 1. a kind of degradable biological film
Ester is polyethylene glycol-polylactide-polycaprolactone random copolymer obtained by monomer ring-opening polymerisation, which is characterized in that described total
The number-average molecular weight of polymers is 8.0 × 104~9.0 × 104In the range of, there is structural formula shown in following (1):
Wherein, the ratio of L-LA and ε-CL unit is 3 to 1.
2. the degradable biological film as described in above-mentioned (1), which is characterized in that the initiator poly glycol monomethyl ether is
mPEG 4000。
3. the degradable biological film as described in above-mentioned (1), which is characterized in that the molecular weight distribution of the copolymer is
1.5。
4. the degradable biological film as described in above-mentioned (1), which is characterized in that the number-average molecular weight of the copolymer is
8.1×104。
5. a kind of preparation method of degradable biological film, which is characterized in that the described method includes:
Pre-process 6-caprolactone, L- lactide, poly glycol monomethyl ether；
Under the protection of inert gas, 6-caprolactone, L- lactide and poly glycol monomethyl ether are added to reaction and held
In device, it is placed in oil bath and vacuumizes；
Under the protection of inert gas, stannous iso caprylate solution is added dropwise into reaction system；
Reaction vessel is placed in the oil bath that temperature is 120~150 DEG C and carries out one day night of polymerization；
It is cooled to room temperature, methylene chloride dissolution is added, dropwise reaction reaction mixture is sunk into the petroleum ether stirred
Drop；
It is dried in vacuo sedimentation products.
6. the preparation method as described in above-mentioned (4), which is characterized in that the oil bath temperature is 140 DEG C.
7. a kind of nitre azole sustained release preparation, which is characterized in that the degradable life as described in any one of above-mentioned (1) to (4)
Object film is formed with nitre azole drug.
8. the nitre azole sustained release preparation as described in above-mentioned (7), which is characterized in that drugloading rate 5wt%-10wt%.
9. the nitre azole sustained release preparation as described in above-mentioned (7), which is characterized in that the nitre azoles be metronidazole, Tinidazole or
Ornidazole.
10. a kind of preparation method of nitre azole sustained release preparation, which is characterized in that weigh any one of above-mentioned (1) to (4) institute
The degradable biological film and nitre azole drug stated, are dissolved in chloroform, stand after mixing well, and plastic film mulch is in poly- after bubble eliminates
On tetrafluoroethene plate, drying at room temperature rear demoulding.
Invention effect
By the invention it is possible to which providing a kind of have certain hydrophily while having both good film forming and good delaying
Release the degradable pharmaceutical biofilm of effect and the nitre azole antibiotic preparation with good slow release effect.
Detailed description of the invention
Fig. 1 is mPEG-P (LLA-co-CL)1H NMR spectra
Fig. 2 is scanning electron microscope (SEM) figure on co-polymer membrane surface under different multiples
(72 times, 500 times, 4000 times)
The blank film of A-C:mPEG-P (LLA-co-CL) copolymer 1
D-F: the 5wt% medicine carrying membrane of copolymer 1
Fig. 3 is the SEM figure on the 5wt% medicine carrying membrane surface of copolymer 1
A: positive B: reverse side
Fig. 4 is the SEM figure on three kinds of medicine carrying membrane surfaces of copolymer 1
A:5wt% medicine carrying membrane B:8wt% medicine carrying membrane C:10wt% medicine carrying membrane
Fig. 5 is the film surface SEM figure of the copolymer 1 after impregnating for 24 hours in buffer
A:5wt% medicine carrying membrane B:8wt% medicine carrying membrane C:10wt% medicine carrying membrane
Fig. 6 is that different proportion metronidazole pharmaceutical film made from copolymer 1 is sustained result (n=3) in vitro
Fig. 7 is the Bactericidal test result of metronidazole sustained-release preparation made from copolymer 1
Wherein A indicates Fusobacterium nucleatum (S.mutans), and B indicates streptococcus mutans (F.nucleatum)
Fig. 8 is the Bactericidal test result of ornidazole sustained-release preparation made from copolymer 3
Wherein a indicates Fusobacterium nucleatum (S.mutans), and b indicates streptococcus mutans (F.nucleatum).
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 and unlimited
Due to following embodiments, those skilled in the art can carry out within the scope of the technical concept of the present invention various changes and replace
It changes.
Embodiment
One, the preparation of mPEG-P (LLA-co-CL) polymer
1 material and equipment
1.1 experimental material
| 6-caprolactone | Purity 99.9% | Aldrich |
| Levorotatory lactide | Purity 98% | Changchun Inst. of Applied Chemistry, Chinese Academy of Sciences |
| Stannous iso caprylate | Purity 99.9% | Aldrich |
| Calcium hydride | It analyzes pure | Shanghai Ling Feng chemical reagent Co., Ltd |
| Anhydrous ether | > 99.7% | Shanghai Ling Feng chemical reagent Co., Ltd |
| mPEG 4000 | Chemistry is pure | Shanghai Ling Feng chemical reagent Co., Ltd |
| Toluene | It analyzes pure | Shanghai Ling Feng chemical reagent Co., Ltd |
1.2 capital equipment
| Instrument title | Model | Manufacturer |
| Vacuum oven | XMTD-8222 | Jing Hong Co., Ltd |
| Oil pump | ZXZ-4 type | Shanghai De Ying vacuum Lighting Co., Ltd |
| Nmr analysis instrument | Bruker | Switzerland Bruker |
| Gel permeation chromatograph | Waters1515 | U.S. Waters |
2 experimental methods
The pre-treatment of 2.1 experimental raws
(1) 6-caprolactone: 6-caprolactone is poured into round-bottomed flask, weighs fraction of calcium hydride (CaH2) pour into wherein,
It is stirred to react 72 hours, removes micro-moisture, vacuum distillation obtains dry 6-caprolactone, and hermetically drying saves.
(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- lactide: the levorotatory lactide to weigh with scale pours into appropriate volume in the reaction ball bottle of 250ml
Dry toluene stirs at 105-110 DEG C, lactide monomer dissolved in toluene completely after, rapid dumps in beaker,
It is sealed with preservative film, is placed in refrigerator and recrystallizes, be precipitated to crystal, filtered using vacuum pump completely.Such recrystallization repeats two
It is secondary.The L- lactide of processing twice is contained in round-bottomed flask, suitable dry toluene is added, is stirred at reflux at 130 DEG C, to
Toluene flows back two hours from oil water separator.Solution is poured into beaker, is sealed with preservative film, is placed in refrigerator and recrystallizes,
It has just been precipitated to crystal, has been filtered using vacuum pump.Such to be repeated twice, last time, which filters, to be completed to use anhydrous ether
Product is evacuated three hours by elution with water pump, and the D-lactic acid monomer purified is stored in dry container after being sealed against
It is interior to be used in case of subsequent polymerization experiment.
(4) mPEG4000: mPEG4000 is contained in round-bottomed flask, and suitable dry toluene is added, and is stirred at 130 DEG C
Reflux, vacuum distillation removes toluene after toluene is from two hours of flowing back in 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 cannot be by generation
It thanks, and degradation speed can be slack-off, therefore it is preferable to use mPEG4000.
The preparation of 2.2mPEG-P (LLA-co-CL) copolymer
It, will be through two kinds of monomers of aforementioned pretreated 6-caprolactone and L- lactide and initiator under the protection of argon gas
MPEG is quickly adding into reaction eggplant-shape bottle roasted in advance, is placed in 45 DEG C or so of oil bath and is vacuumized.Under the protection of argon gas,
Catalyst stannous iso caprylate toluene solution is added dropwise into reaction system, ventilation.It is 120~150 DEG C that polymerization bottle, which is placed on temperature,
It is polymerize in the oil bath pan of dimethicone.After reaction, it is cooled to room temperature to system, it is molten that suitable methylene chloride is added
Solution is settled dropwise in the petroleum ether of dropwise reaction reaction mixture to stirring.Polymerizate after sedimentation is put at normal temperature
Vacuum oven in constant weight.
In the present invention, reaction temperature is preferably controlled in 120~150 DEG C, if be lower than 120 DEG C, 6-caprolactone monomer it is anti-
Answer activity lower, the ratio of 6-caprolactone is often below design proportion in the copolymer of preparation, and polymer also tends to assume that block
Characteristic.Temperature is more than 150 DEG C, i.e., under higher reaction temperature, the catalytic activity of stannous iso caprylate is substantially reduced, and is unfavorable for anti-
The progress answered.It is ideal reaction temperature at 140 DEG C.
Preparation example 1
It, will be through aforementioned pretreated 2.2278g 6-caprolactone and 4.2222g L- lactide two under the protection of argon gas
Kind monomer and initiator 0.3g mPEG 4000 are quickly adding into together in preparatory roasted reaction eggplant-shape bottle three times, are 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) are into reaction system, and ventilation is three times.It is 140 DEG C that polymerization bottle, which is placed on temperature,
It is polymerize for 24 hours in the oil bath pan of dimethicone.After reaction, it is cooled to room temperature to system, suitable dichloromethane is added
Alkane dissolution is settled dropwise in the petroleum ether of dropwise reaction reaction mixture to stirring.Polymerizate after sedimentation is placed on often
To constant weight in vacuum oven under temperature, mPEG-P (LLA-co-CL) copolymer 1 is obtained.
Preparation example 2
It, will be through aforementioned pretreated 2.2304g 6-caprolactone and 4.2298g L- lactide two under the protection of argon gas
Kind monomer and initiator 0.3g mPEG 4000 are quickly adding into together in preparatory roasted reaction eggplant-shape bottle three times, are 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) are into reaction system, and ventilation is three times.It is 120 DEG C that polymerization bottle, which is placed on temperature,
One day night of polymerization is carried out in the oil bath pan of dimethicone.After reaction, it is cooled to room temperature to system, is added suitable two
Chloromethanes dissolution is settled dropwise in the petroleum ether of dropwise reaction reaction mixture to stirring.Polymerizate after sedimentation is put
To constant weight in vacuum oven at normal temperature, mPEG-P (LLA-co-CL) copolymer 2 is obtained.
Preparation example 3
It, will be through aforementioned pretreated 2.2232g 6-caprolactone and 4.2152g L- lactide two under the protection of argon gas
Kind monomer and initiator 0.3g mPEG 4000 are quickly adding into together in preparatory roasted reaction eggplant-shape bottle three times, are 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) are into reaction system, and ventilation is three times.It is 150 DEG C that polymerization bottle, which is placed on temperature,
One day night of polymerization is carried out in the oil bath pan of dimethicone.After reaction, it is cooled to room temperature to system, is added suitable two
Chloromethanes dissolution is settled dropwise in the petroleum ether of dropwise reaction reaction mixture to stirring.Polymerizate after sedimentation is put
To constant weight in vacuum oven at normal temperature, mPEG-P (LLA-co-CL) copolymer 3 is obtained.
The characterization of 2.3 polymer
2.3.1 spectral analysis of the nuclear magnetic resonance (NMR)
1H NMR is used to characterize the monomer ratio and sequential structure of mPEG-P (LLA-co-CL) copolymer of preparation
Distribution.Concrete operations are as follows: weighing mPEG-P (LLA-co-CL) copolymer of about 5mg, be dissolved in CDCl3In, using Germany
Bruker AV 400MHz spectral analysis of the nuclear magnetic resonance instrument tests mPEG-P (LLA-co-CL's)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 as to
To determine the structure of mPEG-P (LLA-co-CL) copolymer.
Hereinafter, the structure elucidation process of copolymer is described in detail by taking mPEG-P (LLA-co-CL) copolymer 1 as an example.Fig. 7 is
MPEG-P (LLA-co-CL) copolymer 11H NMR spectra, the chemistry of all protons go out peak position and are labeled in it one by one
In.From1H NMR spectra can be seen that in mPEG-P (LLA-co-CL) copolymer 1, the proton appearance in L-LA unit be g and
H, the appearance of each proton is labeled as b, c, d, e, f in 6-caprolactone structural unit, and the peak position that goes out of mPEG is 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), the proton (b) on α methylene and the proton (f) on ε methylene on sub (d), β and δ 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 be CL and LA influence each other it is lower caused by all kinds of inclined peaks.
By above-mentioned spectral analysis of the nuclear magnetic resonance it is found that 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 repetitive unit is 3:1.
With with above-mentioned 2.3.1 same method, to the copolymer 2 as made from preparation example 2 and as made from preparation example 3 altogether
Polymers 3 is characterized, as the result is shown: copolymer 2,3 also has 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 using the U.S.
The gel chromatography analyzer of the model water1515 of Waters, using THF as eluting solvent, the flow velocity of 1mL/min into
Row measurement.
By measuring above, the number-average molecular weight and molecular weight distribution of mPEG-P (LLA-co-CL) copolymer such as 1 institute of table
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 repetitive unit is preferably 3:1 in mPEG-P (LLA-co-CL) copolymer,
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 nitre azole oral cavity sustained release preparation as made from the co-polymer membrane can be provided simultaneously with long-acting sustained release performance and good mechanical property
Energy (film forming), and both performances are particularly important for oral cavity sustained release preparation.
Two, the preparation of nitre azole preparation
1 experimental section
1.1 materials and equipment
1.1.1 experimental material
Metronidazole, light yellow crystalline powder, purity 99% (Mayan reagent Co., Ltd)；
Ornidazole, light yellow crystalline powder, purity 99% (Mayan reagent Co., Ltd)；
Chloroform, colourless transparent liquid, Sinopharm Chemical Reagent Co., Ltd.；
Brain heart infusion (BHI), U.S. company BD；
Agar powder (lot number: 110914), Shanghai Bai Ao Biotechnology Co., Ltd；
Citric acid, Shantou City's brilliance laboratory；
Disodium hydrogen phosphate dodecahydrate, Sinopharm Chemical Reagent Co., Ltd.；
PH precision test paper (6.4~8.0), Sinopharm Chemical Reagent Co., Ltd.；
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 balance (Shanghai Precision Scientific Apparatus Co., Ltd)；
Magnetic stirring apparatus (B11-3, Shanghai Si Le Instrument Ltd.)；
PH tester (Shanghai Precision Scientific Apparatus Co., Ltd)；
Vernier caliper (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 company, Britain)；
Spectrophotometer (UV-1601, Shimadzu company, Japan).
1.2 experimental method
1.2.1 the preparation of medicine carrying membrane
Precision weighs 1.5g mPEG-P (LLA-co-CL) and appropriate bulk pharmaceutical chemicals nitre azole drug is dissolved in chloroform, sufficiently mixed
It is stood after even, for plastic film mulch on polyfluortetraethylene plate, content of dispersion difference is made in 72 hours rear demouldings of drying at room temperature after bubble eliminates
For three kinds of medicine carrying membranes of 5wt%, 8wt% and 10wt% and the blank film of non-drug containing.It is big that diaphragm broken into 6mm diameter with punch
Small circular film, ultraviolet light irradiation 30min sterilizing, is sealed in spare in clean brown bottle.Every medicine film drug containing 0.5~
1.0mg。
1.2.2SEM the surface topography of film is characterized
Every group of film randomly selects the small strip for being cut into 3mm × 10mm size, in scanning electron microscope after metal spraying processing
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 measures
A film in every group of film is randomly selected, different 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 the thickness uniformity measures
A film in every group of film is randomly selected, the thickness of 5 different locations of film is measured with micrometer caliper,
Calculate average value.
1.2.3.3 surface pH measures
Each group film is cut into the diaphragm of same size 1cm × 1cm, every group Duplicate Samples 5, is placed in the culture accordingly numbered
It in ware, injects McIlvaine buffer (pH 6.6), after impregnating 2 hours, is measured with PH test paper.
1.2.4 the medicament slow release performance research of medicine carrying membrane
1.2.4.1McIlvaine the preparation of buffer
Precision weighs disodium hydrogen phosphate 35.814g, anhydrous citric acid 9.6065g, uses 500ml deionized water respectively
It is dissolved, matches to obtain 0.2mol/L Na2HPO4After 0.1mol/L citric acid solution, then 145.5ml 0.2mol/L is taken respectively
Na2HPO4The McIlvaine buffer solution that pH value is 6.6 is mixed to prepare with 54.5ml 0.1mol/L citric acid.
1.2.4.2 the determination of Detection wavelength
The metronidazole solution and Ornidazole solution for preparing 0.02mg/ml respectively, carry out in 200~400nm wave-length coverage
UV absorption length scanning, metronidazole, Ornidazole maximum absorption wavelength be 320nm.
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 coverage
Length scanning is found at 320nm wavelength without absorption, thus can be excluded medicine film auxiliary material and be detected at the wavelength to nitre azole drug
Interference.
1.2.4.4 the foundation of standard curve
Precision weighs metronidazole 10mg and is dissolved in 50ml measuring bottle respectively, after constant volume, take respectively 100ul, 250ul,
375ul, 500ul, 750ul, 1000ul, 1250ul and 1500ul constant volume in 10ml measuring bottle, obtain concentration be respectively 2.0ug/ml,
The metronidazole dilution of 5.0ug/ml, 7.5ug/ml, 10.0ug/ml, 15ug/ml, 20ug/ml, 25ug/ml and 30ug/ml,
Trap is surveyed at 320nm, is mapped with concentration C to trap A, and carry out linear regression.
And the standard curve of Ornidazole is established in the same way.
1.2.4.5 medicament slow release is tested
Precision weighs medicine carrying membrane piece (medicine content is respectively 0.5mg, 0.8mg, 1.0mg) and is put into 50ml conical flask, is added
The McIlvaine buffer of 20ml is placed in 37 DEG C of full incubators and stands.In particular point in time 0.5h, 1h, 2h, 4h, 8h, 12h,
For 24 hours, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h, 264h are accurately measured from conical flask with liquid-transfering gun
500ul McIlvaine buffer, while the fresh McIlvaine buffer that 500ul temperature is 37 DEG C is added, keep total volume
It is constant, with the absorbance of ultraviolet specrophotometer measurement drug, calculate cumulative release amount percentage.Every group of carry out 3 times parallel realities
It tests, 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
Periodontal Pathogens Fusobacterium nucleatum (F.nucleatum) is selected in experiment, cariogenic bacteria streptococcus mutans (S.mutans),
With aseptic inoculation ring picking BHI agar plate surface monoclonal bacterium colony in 3mlBHI fluid nutrient medium, S.mutans is in general
Logical incubator, F.nucleatum are cultivated for 24 hours in 37 DEG C of anaerobic culture box.Dyeing microscopic examination is pure culture, and spectrophotometer is by bacterium
Liquid concentration is adjusted to 1 × 107CFU/ml is spare.
1.2.5.2 Bactericidal test
In superclean bench, the BHI Solid agar culture disinfected is poured into sterile petri dish, cooling obtains
After culture medium flat plate, with liquid-transfering gun draw 50ul bacterium solution be added dropwise on culture medium flat plate, sterile L stick push away it is even, be made containing bacterium cultivate
Base plate.It is put into the circular film disinfected is equidistant in plate containing bacterium culture medium, after being placed with, with the light press mold of aseptic nipper
Piece contacts it suitably with agar surface.It is control with mPEG-P (LLA-co-CL) blank film, makees 3 culture dishes in parallel.Respectively
It is inverted in 37 DEG C of anaerobic culture boxes, observes result afterwards for 24 hours.With vernier caliper measurement antibacterial circle diameter.Experiment 3 times is repeated, is taken
Average value.
2 results
2.1 appearance
Co-polymer membrane obtained by preparation example 1~3 is off-white color sheet type film, bright and clean complete, consistency of thickness, and color is equal
It is even, without obvious bubble.
2.2 film surface micro-analysis
As shown in Fig. 2, A-C is the blank film of copolymer 1 made from preparation example 1, surface texture is relatively smooth, and D-F is total
The medicine carrying membrane of polymers 1, surface texture is more coarse, the high-visible MNZ crystalline particle of film surface, and partial size is in micron, sub-micron
Size range.
As shown in figure 3, the one side that the medicine film of copolymer 1 faces upward does not occur drug granule, and one side downwards then has
The drug granule of more aggregation.
As shown in figure 4, the 5wt% film surface MNZ of copolymer 1 is in granular form aggregation, film surface is finer and close；8wt% and
10wt% film surface MNZ assembles in lumps, and film surface is more loose.
Quality, thickness and the surface p H analysis of 2.3 films
The quality and the thickness uniformity of medicine film are the direct factors for influencing film drug dose.The results show that of the invention is total to
The quality and thickness of polymers medicine film are all more uniform, and can be obtained according to specific needs by solution film casting method.Medicine carrying membrane table
Face pH value range is between 6.7~7, and close with the pH value 6.6 of level in gingival sulcus fluid, partial neutral, the results are shown in Table 2.
Table 2: the physical and chemical performance of different films
The sustained release performance of 2.4 medicine carrying membranes is evaluated
2.4.1 for metronidazole standard curve using metronidazole present C as abscissa, the absorbance A at 320nm is that ordinate must return
Return equation: A=0.0517C-0.0121 (r=0.97665), at 320nm, the concentration C of metronidazole is in 2.0~30.0ug/ml
There is good linear relationship with absorbance A in range.
2.4.2 the absorbance that external sustained release tests that each time point measures measures drug release amount by regression equation, calculates accumulation and releases
Dose percentage maps to the time with cumulative release amount percentage.Fig. 5 is the copolymer 1 after impregnating for 24 hours in buffer
Three kinds of medicine carrying membrane surface SEM figures.Fig. 5 is shown, after film impregnates 24 hours in buffer, hole spline structure occurs in film surface,
Middle 5wt% film surface is minimum, and 8wt% and 10wt% are more.Fig. 6 is the different proportion metronidazole drug as made from copolymer 1
Result is sustained outside membrane body.Fig. 6 shows that pharmaceutical release time shortens, 10wt% metronidazole medicine with the increase of metronidazole content
Film slow-release time is one week, and then up to 10 days, and with the increase of medicament contg, drug accumulation discharges 5wt% metronidazole membranet
Rate also obviously increases.
2.4.3 the anti-microbial property evaluation of medicine carrying membrane
Ornidazole sustained-release preparation made from the metronidazole sustained-release preparation as made from copolymer 1 and copolymer 3 is resisted respectively
Bacterium performance is evaluated.
The antibacterial tests of metronidazole sustained-release preparation show that each culture medium flat plate bacterial growth is good, and three kinds of medicine carrying membranes are to S.m
There is antibacterial ring size generation with F.n.Antibacterial effect is gradually increased with the increase of medicament contg, and medicine film makees the inhibition of F.n
With the inhibiting effect being better than to S.m.It the results are shown in Table 3 and Fig. 7.
Table 3: the antibacterial circle diameter (x ± s n=3) of different medicine carrying membranes
In addition, as shown in figure 8, each culture medium flat plate bacterial growth is good in the antibacterial tests of ornidazole sustained-release preparation, three
Kind medicine carrying membrane also has antibacterial ring size generation to S.m and F.n, and antibacterial effect is gradually increased with the increase of medicament contg, and medicine
Film is better than the inhibiting effect to S.m to the inhibiting effect of F.n.
Claims (7)
1. a kind of nitre azole sustained release preparation, is formed, which is characterized in that described to drop by degradable biological film and nitre azole drug
Solving biofilm is to be obtained using poly glycol monomethyl ether as initiator, using levorotatory lactide and 6-caprolactone as monomer ring-opening polymerisation
Polyethylene glycol-polylactide-polycaprolactone random copolymer, the number-average molecular weight of the copolymer is 8.0 × 104~9.0
×104In the range of, there is structural formula shown in following (1):
Wherein, the molar ratio of levorotatory lactide unit and 6-caprolactone unit is 3 to 1.
2. nitre azole sustained release preparation as described in claim 1, which is characterized in that the initiator poly glycol monomethyl ether is
mPEG 4000。
3. nitre azole sustained release preparation as described in claim 1, which is characterized in that the molecular weight distribution of the copolymer is 1.5.
4. nitre azole sustained release preparation as described in claim 1, which is characterized in that the number-average molecular weight of the copolymer is 8.1
×104。
5. nitre azole sustained release preparation according to any one of claims 1 to 4, which is characterized in that drugloading rate 5wt%-
10wt%.
6. nitre azole sustained release preparation according to any one of claims 1 to 4, which is characterized in that the nitre azoles be metronidazole,
Tinidazole or Ornidazole.
7. a kind of preparation method of nitre azole sustained release preparation described in claim 1, which is characterized in that the described method includes:
Pre-process 6-caprolactone, L- lactide, poly glycol monomethyl ether；
Under the protection of inert gas, 6-caprolactone, L- lactide and poly glycol monomethyl ether are added in reaction vessel,
Oil bath is placed in vacuumize；
Under the protection of inert gas, stannous iso caprylate solution is added dropwise into reaction system；
Reaction vessel is placed in the oil bath that temperature is 120~150 DEG C and carries out one day night of polymerization；
It is cooled to room temperature, methylene chloride dissolution is added, dropwise reaction reaction mixture is settled into the petroleum ether stirred；
Sedimentation products are dried in vacuo, degradable biological film is obtained；
The degradable biological film and nitre azole drug are weighed, is dissolved in chloroform, is stood after mixing well, after bubble eliminates
Plastic film mulch is on polyfluortetraethylene plate, drying at room temperature rear demoulding.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201611138412.7A CN106589337B (en) | 2016-12-12 | 2016-12-12 | Degradable biological film, preparation method and nitre azole sustained release preparation |
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| CN201611138412.7A CN106589337B (en) | 2016-12-12 | 2016-12-12 | Degradable biological film, preparation method and nitre azole sustained release preparation |
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| 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 |
| CN104758256A (en) * | 2014-02-14 | 2015-07-08 | 苏州海特比奥生物技术有限公司 | Docetaxel nano polymer micelle freeze-drying preparation and preparation method thereof |
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| 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 |
| CN104758256A (en) * | 2014-02-14 | 2015-07-08 | 苏州海特比奥生物技术有限公司 | Docetaxel nano polymer micelle freeze-drying preparation and preparation method thereof |
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| 聚乙二醇-b-聚乳酸的合成及其电纺形成超细纤维研究;赵亚男等;《高分子学报》;20080520(第05期);405-409 * |
| 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;许亮亮等;《材料导报》;20061115(第11期);131-133 * |
| 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;刘瑞雪等;《北京化工大学学报(自然科学版)》;20070320;第34卷(第02期);142-144 * |
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