CN114940746B - Star-shaped lactide-glycolide copolymer and application thereof as drug slow-release carrier - Google Patents
Star-shaped lactide-glycolide copolymer and application thereof as drug slow-release carrier Download PDFInfo
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- CN114940746B CN114940746B CN202210687989.2A CN202210687989A CN114940746B CN 114940746 B CN114940746 B CN 114940746B CN 202210687989 A CN202210687989 A CN 202210687989A CN 114940746 B CN114940746 B CN 114940746B
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- 239000003814 drug Substances 0.000 title claims abstract description 83
- 229940079593 drug Drugs 0.000 title claims abstract description 66
- 229920001577 copolymer Polymers 0.000 title claims abstract description 37
- 239000000178 monomer Substances 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 19
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims abstract description 15
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 15
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims abstract description 12
- 239000003405 delayed action preparation Substances 0.000 claims abstract description 10
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims abstract description 10
- 229960004338 leuprorelin Drugs 0.000 claims abstract description 10
- 238000013268 sustained release Methods 0.000 claims abstract description 10
- 239000012730 sustained-release form Substances 0.000 claims abstract description 10
- 238000010254 subcutaneous injection Methods 0.000 claims abstract description 9
- 239000007929 subcutaneous injection Substances 0.000 claims abstract description 9
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- 238000011068 loading method Methods 0.000 abstract description 6
- -1 alkane diol Chemical class 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 229920005862 polyol Polymers 0.000 abstract description 5
- 150000003077 polyols Chemical class 0.000 abstract description 5
- 229920006395 saturated elastomer Polymers 0.000 abstract description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 abstract description 4
- 108010037003 Buserelin Proteins 0.000 abstract description 3
- 108010050144 Triptorelin Pamoate Proteins 0.000 abstract description 3
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 abstract description 3
- 229960002719 buserelin Drugs 0.000 abstract description 3
- 239000003999 initiator Substances 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 abstract description 3
- 229960004824 triptorelin Drugs 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 229960001340 histamine Drugs 0.000 abstract description 2
- 238000006116 polymerization reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 230000000052 comparative effect Effects 0.000 description 19
- 229920000642 polymer Polymers 0.000 description 13
- 239000000499 gel Substances 0.000 description 12
- 239000000523 sample Substances 0.000 description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000004005 microsphere Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000004185 ester group Chemical group 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 102000006771 Gonadotropins Human genes 0.000 description 2
- 108010086677 Gonadotropins Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000002622 gonadotropin Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 108010000817 Leuprolide Proteins 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
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
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- 238000007865 diluting Methods 0.000 description 1
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- 239000002552 dosage form Substances 0.000 description 1
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- 238000005538 encapsulation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 1
- 229940051250 hexylene glycol Drugs 0.000 description 1
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 1
- 229960002193 histrelin Drugs 0.000 description 1
- 108700020746 histrelin Proteins 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- LLWFBEQLNVSCKV-UHFFFAOYSA-N hydrogen carbonate;hydron;2-hydroxypropanoate Chemical compound OC(O)=O.CC(O)C(O)=O LLWFBEQLNVSCKV-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000002052 molecular layer Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 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
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- C08G63/78—Preparation processes
Abstract
The invention discloses a star-shaped lactide-glycolide copolymer, and belongs to the technical field of drug sustained-release preparations. The preparation method comprises the following steps: lactide and glycolide are used as monomers, alkane diol or saturated polyol is used as an initiator, stannous octoate is used as a catalyst, and melt polymerization is carried out to obtain the lactide-glycolide copolymer, wherein the weight average molecular weight of the lactide-glycolide copolymer is 2W-5W, the lactide accounts for 50% -87%, and the glycolide accounts for 13% -50%. The star-shaped lactide-glycolide copolymer is applied to the preparation of a sustained-release pharmaceutical preparation as a drug sustained-release carrier. The invention also discloses a subcutaneous injection long-acting slow release preparation which comprises a drug, star-shaped lactide-glycolide copolymer and a solvent, wherein the drug is selected from leuprorelin acetate, triptorelin, histamine relin and buserelin; the drug loading rate is 5% -15%. When the star-shaped lactide-glycolide copolymer is used as a drug slow-release carrier, the burst release of the drug can be better controlled, and a better slow-release effect can be achieved.
Description
Technical Field
The invention relates to a star-shaped lactide-glycolide copolymer and application thereof as a drug sustained-release carrier, belonging to the technical field of drug sustained-release preparations.
Background
In recent years, with the continuous development of medical polymer materials, various types of polymer materials are appeared, and polymer polymers with special chemical structures and special molecular configurations are attracting more attention due to the advantages of intelligence, environmental responsiveness and the like. The high molecular polymer can be further used for preparing medicinal carriers with special functions, such as temperature sensitive hydrogel, pH sensitive polymer micelle and the like. Lactide-co-glycolide (PLGA) is an excellent biodegradable polymer and has been approved by the FDA as a pharmaceutical excipient. PLGA can be used as carrier for drug controlled release, and has long-acting slow release property, targeting property and degradability compared with other injection formulations. PLGA sustained release formulations have been used in the field of polypeptides, proteins, small molecules gradually today, and up to ten long-acting sustained release formulations have been marketed worldwide. The sustained release preparation for injection is favored in the field of research and development of domestic medicaments, but belongs to a new field, and is particularly important for evaluating pharmacological action mechanism, pharmacokinetic characteristics and safety. The maintenance time of the drug effect of the long-acting sustained-release preparation is closely related to the performance, structure, physicochemical property and the like of the auxiliary materials for preparing the sustained-release preparation.
PLGA formulations have been approved for use in microspheres, solid implants, and long-acting in situ precipitation formulations. Among them, microsphere formulations and long-acting in situ precipitation formulations have been widely used because they are easy to administer relative to other dosage forms. The gel serving as a long-acting in-situ precipitation preparation has the characteristics of large drug loading capacity, easy preparation and longer drug effect compared with a microsphere preparation.
The in-situ precipitation preparation has certain requirements on the fat solubility, water solubility and subcutaneous degradation speed of the auxiliary material PLGA, and the drug release of the subcutaneous injection long-acting in-situ precipitation preparation has a linear relation with the degradation of PLGA, so that the research on the degradation of PLGA is particularly important. The rate of degradation of PLGA in vivo is determined by the ratio of lactide to glycolide, as described in U.S. Pat. Nos. 4,937,63 and 5, 532419, which describe pharmaceutical combinations made of polymers made of copolymers of lactic acid or lactic acid hydroxycarboxylic acid, the degradation time of the precipitated solids being determined by the ratio of lactide to glycolide in the polymer. At present, most of conventional PLGA is carboxyl end-capped and ester end-capped, namely, the following two simple structural models: HO (terminal hydroxy) -PLGA-COOH (terminal carboxyl); HO (terminal hydroxy) -PLGA-COOCxHy (ester end capping). Structures A and B have high water solubility and high fat solubility respectively, and under the same molecular weight, structure A is degraded quickly under the skin, and structure B is degraded at too slow a human body. Although the degradation rate of PLGA after the synthesis of A and B can be regulated by the proportion of A and B in PLGA, the polymer has a linear structure (shown in the following formula), can not effectively contain medicines, has small medicine loading capacity, and has large burst release of solid matters after the solvent is removed after the composition is injected into a body, so that medicines are wasted and adverse reactions are generated on a human body.
Disclosure of Invention
In view of the above prior art, the present invention provides a star-shaped lactide-glycolide copolymer (having a two-arm or multi-arm structure), wherein the polymer forms a network space structure in the form of AB2, AB3, AB4, AB5 or AB6, and the polymer with the structure is capped with an alkylene glycol or saturated polyol (having a terminal hydroxyl group but substantially no terminal carboxyl group and ester group), and when the polymer with the structure is applied as a drug sustained release carrier, burst release of a drug can be better controlled.
The invention is realized by the following technical scheme:
A star-shaped lactide-glycolide copolymer (star-shaped PLGA for short) is prepared by the following method: lactide and glycolide are used as monomers, alkylene glycol or saturated polyol is used as an initiator, stannous octoate is used as a catalyst, and melt polymerization is carried out to obtain the lactide-glycolide copolymer, wherein the weight average molecular weight is 2-5W, the weight ratio of lactide in the copolymer is 50% -87%, and the weight ratio of glycolide is 13% -50%. The reaction formula is shown below.
Taking hexanediol as an example (x value range: 50-100; y value range: 280-560):
taking pentaerythritol as an example (x value range: 85-170; y value range: 476-952):
further, the alkylene glycol is selected from 1, 3-propylene glycol and hexylene glycol; the saturated polyol is selected from glycerol (glycerin), pentaerythritol, sorbitol, mannitol.
Further, the weight ratio of the lactide to the glycolide is 1-9:1.
Further, the dosage of the alkane diol or the saturated polyol is 1 to 6 percent of the total mass of the monomer.
Further, the catalyst stannous octoate is used in an amount of 0.2% of the total mass of the monomers.
Further, the specific operation steps are as follows: mixing lactide, glycolide and an initiator, adding a proper amount of solvent for dissolution, distilling under reduced pressure to remove the solvent, adding stannous octoate, reacting for 6-8 hours in a nitrogen atmosphere at 130-210 ℃ to obtain viscous liquid, and recrystallizing by an organic solvent to obtain the star-shaped PLGA.
Further, the solvent is selected from toluene, methylene chloride.
Further, the organic solvent used for the recrystallization is selected from chloroform, diethyl ether, dichloromethane, ethanol.
The star-shaped lactide-glycolide copolymer is used as a drug sustained-release carrier.
The application of the star-shaped lactide-glycolide copolymer in preparing sustained-release pharmaceutical preparations.
Further, the sustained release pharmaceutical preparation is a subcutaneous injection long-acting sustained release preparation (gel).
Further, the medicine in the slow-release medicine preparation is gonadotropin medicine, which is selected from leuprorelin acetate, triptorelin, histamine relin, buserelin and the like.
A subcutaneous injection long-acting slow release preparation (gel), which comprises a medicine, star-shaped lactide-glycolide copolymer and a solvent, wherein the medicine is gonadotropin medicine, and is selected from leuprorelin acetate, triptorelin, histrelin, buserelin and the like; the drug loading rate (namely the weight ratio of the drug to the carrier star-shaped lactide-glycolide copolymer) is 5-15%.
Further, the solvent is selected from NMP (N-methylpyrrolidone).
The preparation method of the subcutaneous injection long-acting slow release preparation comprises the following steps: mixing the star-shaped lactide-glycolide copolymer and the solvent, standing to remove bubbles, adding the medicine, and mixing uniformly to obtain the final product.
Further, the dosage ratio relationship of the star-shaped lactide-glycolide copolymer and the solvent is as follows: 1g of star-shaped lactide-glycolide copolymer and 8-12 ml of solvent.
Further, the subcutaneous injection long-acting slow release preparation also comprises a diluent (used for diluting gel and enabling the medicine to be mixed more uniformly), wherein the diluent is selected from 0.9% sodium chloride solution, 0.5% sodium carboxymethyl cellulose solution and 0.1% tween 80 solution.
The star-shaped lactide-glycolide copolymer forms a reticular space structure in the form of AB2, AB3, AB4, AB5 or AB6, can better control the burst release of the drug when being applied as a drug slow release carrier, has smaller burst release compared with carboxyl end-capped PLGA and has smaller influence on human inflammatory reaction; the target drug concentration is more rapidly achieved than the ester-terminated PLGA (a blood concentration that is not expected may result in a decrease in drug efficacy). Compared with microsphere drug loading, the microsphere drug loading is large, the preparation process is simple, and the slow release effect is more durable. According to the invention, the research shows that the degradation of PLGA has a direct relation with the molecular weight, the steric hindrance between molecular chains is reduced along with the improvement of the molecular weight of star-shaped PLGA, the stability of a copolymer molecular layer is enhanced, the encapsulation rate of a drug is improved, the degradation rate of the drug is obviously slowed down, and a better slow release effect is achieved.
The various terms and phrases used herein have the ordinary meaning known to those skilled in the art.
Drawings
Fig. 1: example 1 is a schematic comparison of in vitro release profiles with comparative example 1.
Fig. 2: example 2 is a schematic comparison of in vitro release profiles with comparative example 1.
Fig. 3: example 3 is a schematic comparison of in vitro release profiles with comparative example 2.
Fig. 4: comparative in vitro release curves for examples 1,2, 3.
Fig. 5: a comparison schematic diagram of the blood concentration curve in human body.
Detailed Description
The invention is further illustrated below with reference to examples. However, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.
The instruments, reagents, materials, etc. used in the examples described below are conventional instruments, reagents, materials, etc. known in the art, and are commercially available. The experimental methods, detection methods, and the like in the examples described below are conventional experimental methods, detection methods, and the like that are known in the prior art unless otherwise specified.
Example 1 preparation of a lactide-glycolide copolymer (three-arm)
Weighing 60g of lactide monomer, 40g of glycolide monomer and 2.6g of glycerol, pouring into a three-neck flask, adding 200ml of toluene, stirring, distilling under reduced pressure at 80 ℃ to remove the solvent, weighing 0.2% equivalent of stannous octoate, adding into the three-neck flask, replacing with nitrogen for 3 times, reacting at 170 ℃ for 7 hours to obtain viscous liquid, dissolving with chloroform, precipitating with diethyl ether for three times, and vacuum drying to obtain white semitransparent solid, namely three-arm star-shaped PLGA, wherein the yield is 66.84%, the weight average molecular weight is 15081, the number average molecular weight is 8739, the monomer proportion is LA% = 51.58%, and the GA% = 48.42%.
Preparing medicine carrying gel: placing 1.0g of PLGA and 10ml of NMP prepared in the above way in a beaker, stirring and dissolving at 500rpm at room temperature for 60min, then standing at room temperature for 1h, removing bubbles, adding 100mg of leuprorelin acetate as a drug, horizontally placing, and pushing for 200 times to uniformly mix, thus obtaining the medicine.
In vivo release was simulated by a dissolution test, specific operation of the dissolution test: according to high performance liquid chromatography (general rule 0512), octadecylsilane chemically bonded silica is used as stationary phase, acetonitrile and water (60:40) are used as mobile phase, and an ultraviolet detector with wavelength of 240nm and column temperature of 35 ℃ and flow rate of 1.0ml/min is used. Taking a proper amount of reference substance, adding acetonitrile to prepare a stock solution of 0.2mg/ml, taking the stock solution, and adding a medium to dilute the stock solution to prepare a reference solution of 40 mug/ml. Taking 20 μl of control solution and 20 μl of sample solution, respectively, injecting into high performance liquid chromatograph, and recording chromatogram. The cumulative release at each time point was calculated by the external standard method.
Comparative example 1 preparation of lactide-glycolide copolymer (carboxyl end-capped)
Weighing 20g of lactide monomer, 5g of glycolide monomer and 0.15g of glycolic acid, adding into a three-neck flask, adding 150ml of dichloromethane, stirring, and distilling under reduced pressure at normal temperature to remove the solvent; 0.2% equivalent stannous octoate is weighed, added into a three-neck flask, replaced by nitrogen for 3 times, reacted for 7 hours at 170 ℃ to obtain viscous liquid, dissolved by methylene dichloride, precipitated by ethanol for three times, and dried in vacuum to obtain white semitransparent solid, namely the lactide-glycolide copolymer (carboxyl end-capped), wherein the weight average molecular weight is 21077, the number average molecular weight is 13281, the monomer proportion is LA% = 73.56%, and the GA% =26.44%.
Preparing a drug-loaded sample: placing 1.0g of the prepared lactide-glycolide copolymer (carboxyl end-capped) and 10ml of NMP into a beaker, stirring and dissolving at 500rpm at room temperature for 60min, then standing at room temperature for 1h, removing bubbles, adding 100mg of leuprorelin acetate as a drug, horizontally placing, and pushing about 200 times to uniformly mix, thereby obtaining the preparation.
Experiment 1
The drug-loaded gel prepared in example 1 was compared with the drug-loaded sample prepared in comparative example 1 to examine the drug release, and the results are shown in fig. 1, and it can be seen that the cumulative drug release rate in comparative example 1 reaches 80% or more when the drug is released for 72 hours, but the cumulative drug release rate in example 1 reaches 80% when the drug is released for 120 hours, which means that the sample in example 1 can release drug molecules for a longer period of time. The sample weight average molecular weight in example 1 was 15081, the sample weight average molecular weight in comparative example 1 was 21077, and the molecular weight difference between the two was large, and the reason for the improvement of the controlled release effect was probably the difference in molecular weight of PLGA or the difference in capping agent.
Example 2 preparation of lactide-glycolide copolymer (four-arm)
22.5G of lactide monomer, 2.5g of glycolide monomer and 1.5g of pentaerythritol are weighed, poured into a three-necked flask, 200ml of dichloromethane is added for stirring, the solvent is removed by reduced pressure distillation at normal temperature, 0.2% equivalent of stannous octoate is weighed, the solution is added into the three-necked flask, nitrogen is replaced for 3 times, the reaction is carried out for 7 hours at 180 ℃ to obtain viscous liquid, dichloromethane is used for dissolving and ethanol precipitating for three times, and vacuum drying is carried out to obtain white semitransparent solid, namely four-arm star-shaped PLGA, the yield is 86.17%, the weight average molecular weight is 20642, the number average molecular weight is 11598, the monomer proportion is LA% = 86.55%, and the GA% = 13.45%.
Preparing medicine carrying gel: placing 1.0g of PLGA and 10ml of NMP prepared in the above way in a beaker, stirring and dissolving at 500rpm at room temperature for 60min, then standing at room temperature for 1h, removing bubbles, adding 100mg of leuprorelin acetate as a drug, horizontally placing, and pushing for 200 times to uniformly mix, thus obtaining the medicine.
Experiment 2
The drug-loaded gel prepared in example 2 was compared with the drug-loaded sample prepared in comparative example 1 to examine drug release, and the results are shown in fig. 2, wherein the drug release in example 2 is greatly prolonged compared with the release time in comparative example 1, and the molecular weight difference between the two is less than 1000, which indicates that the alcohol-based end-capped PLGA sample prepared in example 2 can release drug molecules for a longer time.
Example 3 preparation of lactide-glycolide copolymer (six arms)
Weighing 60g of lactide monomer, 18g of glycolide monomer and 0.16g of mannitol, pouring into a three-neck flask, adding 80ml of toluene, stirring, distilling under reduced pressure at 80 ℃ to remove the solvent, weighing 0.2% equivalent of stannous octoate, adding into the three-neck flask, replacing with nitrogen for 3 times, reacting at 190 ℃ for 7 hours to obtain viscous liquid, dissolving with chloroform, precipitating with ethanol for three times, and vacuum drying to obtain white semitransparent solid, namely six-arm star-shaped PLGA, wherein the yield is 76.84%, the weight average molecular weight is 37155, the number average molecular weight is 21989, the monomer proportion is LA% = 55.34%, and the GA% = 44.66%.
Preparing medicine carrying gel: placing 1.0g of PLGA and 10ml of NMP prepared in the above way in a beaker, stirring and dissolving at 500rpm at room temperature for 60min, then standing at room temperature for 1h, removing bubbles, adding 100mg of leuprorelin acetate as a drug, horizontally placing, and pushing for 200 times to uniformly mix, thus obtaining the medicine.
Comparative example 2 preparation of lactide-glycolide copolymer (ester group end-capped)
Weighing 20g of lactide monomer, 5g of glycolide monomer and 0.28g of n-dodecanol, adding into a three-neck flask, adding 150ml of dichloromethane, stirring, and distilling under reduced pressure at normal temperature to remove the solvent; 0.2% equivalent stannous octoate is weighed, added into a three-neck flask, replaced by nitrogen for 3 times, reacted for 7 hours at 190 ℃ to obtain viscous liquid, dissolved by methylene dichloride and precipitated by ethanol for three times, and vacuum dried white semitransparent solid is provided with weight average molecular weight 36837, number average molecular weight 21419, monomer proportion of LA% = 84.59% and GA% = 15.41%.
Preparing a drug-loaded sample: placing 1.0g of the prepared lactide-glycolide copolymer (ester group end-capped) and 10ml of NMP into a beaker, stirring and dissolving at 500rpm at room temperature for 60min, then standing at room temperature for 1h, removing bubbles, adding 100mg of leuprorelin acetate as a medicament, horizontally placing, and pushing for 200 times to uniformly mix the materials.
Experiment 3
The drug-loaded gel prepared in example 3 was examined for drug release compared with the drug-loaded sample prepared in comparative example 2, and the results are shown in fig. 3. The substantial extension of drug release time in example 3 over comparative example 2, and the molecular weight difference between the two is less than 1000, demonstrates that the sample prepared in example 3 can still release drug molecules longer than the PLGA prepared by capping the ester group in comparative example 2 at a molecular weight of 3W to 4W.
Examples 1, 2, 3 in vitro release profile pairs are shown in figure 4. As can be seen from the graph, the star-shaped PLGA polymer in example 1 has a weight average molecular weight of 15081, the star-shaped PLGA polymer in example 2 has a weight average molecular weight of 20642, the star-shaped PLGA polymer in example 3 has a weight average molecular weight of 37155, the three examples have obvious differences in the cumulative release of the drug at different time points, the higher the molecular weight in example 3 is, the lowest the cumulative release of the drug can be used for a longer period of time, the lowest the molecular weight in example 1 is, the highest the cumulative release of the drug is, and the worst slow release effect is.
Experiment 4
One sample of the drug-loaded gel prepared in examples 1, 2 and 3 and comparative examples 1 and 2 was taken and poured into 15ml of PBS buffer (pH 7.4), and the samples were sampled and tested on days 0, 1, 2, 3, 7, 14, 18, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91 and 98, and the total elution was calculated by HPLC (280 nm) external standard method, thereby calculating the blood concentration in human body. The blood concentration curve in human body is shown in fig. 5.
Results of the study of pharmacokinetic comparison examples and comparative examples show that there is a significant difference in the plasma concentration of leuprorelin in examples 1,2, 3 compared to comparative examples 1,2 over a duration of 3 months. As can be seen from fig. 5, the blood concentration levels of examples 1,2 and 3 are significantly higher than those of comparative examples 1 and 2 from day 7, and the blood concentration in the examples is more gentle and always significantly higher than that of the comparative examples from the blood concentration monitoring in the subsequent experiments, which indicates that the drug-loaded gel prepared by the present invention can release drug molecules more effectively and stably than the drug-loaded samples prepared by conventional PLGA.
The embodiment shows that the lactide-glycolide copolymer is prepared into an injection type drug-carrying sustained and controlled release preparation, and compared with carboxyl end-capped PLGA, the burst release is smaller, so that the inflammatory reaction at the injection site caused by burst release can be controlled more effectively, and the drug is released safely; compared with the ester-terminated PLGA, the target drug concentration can be reached more rapidly (the drug effect can be reduced if the blood drug concentration is not expected), and the therapeutic effect can be realized rapidly and efficiently.
The foregoing examples are provided to fully disclose and describe how to make and use the claimed embodiments by those skilled in the art, and are not intended to limit the scope of the disclosure herein. Modifications that are obvious to a person skilled in the art will be within the scope of the appended claims.
Claims (3)
1. A subcutaneous injection long-acting sustained release preparation, which is characterized in that: the preparation method comprises the steps of preparing a drug, star-shaped lactide-glycolide copolymer and a solvent, wherein the drug is leuprorelin acetate; the weight ratio of the drug to the star-shaped lactide-glycolide copolymer is 1:10;
The star-shaped lactide-glycolide copolymer is prepared by the following method: pouring 60g of lactide monomer, 18g of glycolide monomer and 0.16g of mannitol into a three-neck flask, adding 80ml of toluene, stirring, distilling at 80 ℃ under reduced pressure to remove toluene, weighing stannous octoate, wherein the dosage of stannous octoate is 0.2% of the total mass of the monomers, adding the stannous octoate into the three-neck flask, replacing 3 times with nitrogen, reacting at 190 ℃ for 7 hours to obtain viscous liquid, dissolving with chloroform, precipitating with ethanol for three times, and vacuum drying to obtain white semitransparent solid, namely six-arm star-shaped PLGA, weight average molecular weight 37155, number average molecular weight 21989, and monomer ratio: the weight ratio of lactide was 55.34% and the weight ratio of glycolide was 44.66%.
2. The subcutaneous injection long-acting sustained release formulation according to claim 1, wherein: the solvent is selected from N-methylpyrrolidone.
3. The subcutaneous injection long-acting sustained release preparation according to claim 1, wherein the dosage proportioning relationship of the star-shaped lactide-glycolide copolymer and the solvent is as follows: 1g of star-shaped lactide-glycolide copolymer, 8-12 ml solvent.
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