CN114940746A - Star-shaped lactide-glycolide copolymer and application thereof as drug sustained-release carrier - Google Patents
Star-shaped lactide-glycolide copolymer and application thereof as drug sustained-release carrier Download PDFInfo
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- CN114940746A CN114940746A CN202210687989.2A CN202210687989A CN114940746A CN 114940746 A CN114940746 A CN 114940746A CN 202210687989 A CN202210687989 A CN 202210687989A CN 114940746 A CN114940746 A CN 114940746A
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- lactide
- star
- glycolide
- drug
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- 239000003814 drug Substances 0.000 title claims abstract description 77
- 229940079593 drug Drugs 0.000 title claims abstract description 70
- 229920001577 copolymer Polymers 0.000 title claims abstract description 47
- 238000013268 sustained release Methods 0.000 title claims abstract description 21
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 21
- 239000000178 monomer Substances 0.000 claims abstract description 33
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 25
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 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 18
- 239000003405 delayed action preparation Substances 0.000 claims abstract description 13
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical group 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 11
- 229960004338 leuprorelin Drugs 0.000 claims abstract description 11
- 229920005862 polyol Polymers 0.000 claims abstract description 8
- 150000003077 polyols Chemical class 0.000 claims abstract description 8
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- 238000011068 loading method Methods 0.000 claims abstract description 7
- 238000010254 subcutaneous injection Methods 0.000 claims abstract description 6
- 239000007929 subcutaneous injection Substances 0.000 claims abstract description 6
- 108010037003 Buserelin Proteins 0.000 claims abstract description 5
- 108010050144 Triptorelin Pamoate Proteins 0.000 claims abstract description 5
- 229960002719 buserelin Drugs 0.000 claims abstract description 5
- 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 claims abstract description 5
- 229960002193 histrelin Drugs 0.000 claims abstract description 5
- 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 claims abstract description 5
- 108700020746 histrelin Proteins 0.000 claims abstract description 5
- 239000003999 initiator Substances 0.000 claims abstract description 5
- 229960004824 triptorelin Drugs 0.000 claims abstract description 5
- 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 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 3
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- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 42
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- 239000007788 liquid Substances 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 7
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 5
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- 238000005303 weighing Methods 0.000 claims description 5
- 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 4
- 102000006771 Gonadotropins Human genes 0.000 claims description 4
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- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 2
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- 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 claims description 2
- 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 claims description 2
- -1 alkane diol Chemical class 0.000 claims description 2
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- 125000003944 tolyl group Chemical group 0.000 claims description 2
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 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
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- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 2
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- 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
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
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Images
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, belonging to the technical field of drug sustained-release preparations. The preparation method comprises the following steps: lactide and glycolide are used as monomers, alkanediol or saturated polyol is used as an initiator, stannous octoate is used as a catalyst, and the lactide-glycolide copolymer is obtained by melt polymerization, wherein the weight average molecular weight of the copolymer is 2W-5W, the lactide accounts for 50% -87%, and the glycolide accounts for 13% -50%. The application of the star lactide-glycolide copolymer as a drug sustained release carrier in the preparation of sustained release drug preparations. The invention also discloses a subcutaneous injection long-acting sustained release preparation, which comprises a medicament, a star-shaped lactide-glycolide copolymer and a solvent, wherein the medicament is selected from leuprorelin acetate, triptorelin, histrelin and buserelin; the drug loading is 5-15%. When the star lactide-glycolide copolymer is used as a drug sustained release carrier, the burst release of the drug can be better controlled, and a better sustained release effect is 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 polymer materials have appeared, and among them, the polymer having a special chemical structure and a special molecular configuration has received much 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. Poly (lactide-co-glycolide) (PLGA) is an excellent biodegradable polymer and has been approved by the FDA as a pharmaceutical adjuvant. The PLGA can be used as a carrier of drug controlled release, and has long-acting slow release, targeting property and degradability compared with other injection preparations. PLGA sustained release formulations are now being used in the fields of polypeptides, proteins, small molecules, and up to a dozen long acting sustained release formulations are on the market worldwide. Sustained-release preparations for injection are favored in the field of domestic drug development, but are of particular importance for evaluation of pharmacological action mechanisms, pharmacokinetic characteristics and safety because of belonging to a new field. The duration of the drug effect of the long-acting sustained-release preparation is closely related to the performance, the structure, the physicochemical property and the like of auxiliary materials for preparing the sustained-release preparation.
PLGA formulations have been approved with 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. Compared with a microsphere preparation, the gel serving as a long-acting in-situ precipitation preparation has the characteristics of large drug loading rate, easiness in preparation and more lasting drug effect.
The in-situ precipitation preparation has certain requirements on the lipid solubility, the water solubility and the subcutaneous degradation speed of the PLGA as the auxiliary material, and the drug release of the subcutaneous injection long-acting in-situ precipitation preparation has a linear relation with the degradation of the PLGA, so the research on the degradation of the PLGA is particularly important. The degradation rate of PLGA in vivo is determined by the ratio of lactide to glycolide, as described in US patent nos. 4938763 and 532419, which describe pharmaceutical compositions made from polymers made from lactic acid or lactic acid hydroxycarboxylic acid copolymers, and the degradation time of the precipitated solids is determined by the ratio of lactide to glycolide in the polymer. At present, most of conventional PLGA is carboxyl-terminated and ester-terminated, namely the following two simple structure models: HO (hydroxyl-terminated) -PLGA-COOH (carboxyl-terminated); HO (hydroxyl terminated) -PLGA-COOCxHy (ester terminated). The structure A and the structure B respectively have high water solubility and high fat solubility, under the same molecular weight, the structure A is degraded rapidly under the skin, and the degradation rate of the structure B in a human body is too slow. Although the degradation rate of the PLGA after the A and B are synthesized can be adjusted by the proportion of the A and the B in the PLGA, the polymer has a linear structure (shown as the following formula), so that the medicine cannot be effectively included, the medicine carrying amount is small, the composition is injected into a body, after a solvent flows away, the burst release of a solid is large, the medicine is wasted, and adverse reactions are generated to the human body.
Disclosure of Invention
In view of the prior art, the invention provides a star-shaped lactide-glycolide copolymer (having a two-arm or multi-arm structure), wherein the polymer forms a net-shaped space structure in the form of AB2, AB3, AB4, AB5 or AB6, and is terminated by alkanediol or saturated polyol (having terminal hydroxyl groups but substantially no terminal carboxyl groups and ester groups), and when the polymer with the structure is used as a drug sustained-release carrier, the burst release of the drug can be better controlled.
The invention is realized by the following technical scheme:
a star lactide glycolide copolymer (star PLGA for short) is prepared by the following method: lactide and glycolide are used as monomers, alkanediol or saturated polyol is used as an initiator, stannous octoate is used as a catalyst, and the copolymer is subjected to melt polymerization to obtain the lactide-glycolide copolymer, wherein the weight-average molecular weight is 2W-5W, the weight ratio of the lactide in the copolymer is 50% -87%, and the weight ratio of the glycolide is 13% -50%. The reaction formula is shown below.
Taking hexanediol as an example (x is 50-100, y is 280-560):
taking pentaerythritol as an example (x is 85-170; y is 476-952):
further, the alkanediol is selected from 1, 3-propanediol, hexanediol; the saturated polyol is selected from glycerol (glycerin), pentaerythritol, sorbitol, and mannitol.
Further, the weight ratio of the lactide to the glycolide is 1-9: 1.
Further, the using amount of the alkane diol or the saturated polyol is 1-6% of the total mass of the monomers.
Further, the dosage of the catalyst stannous octoate is 0.2% of the total mass of the monomers.
Further, the specific operation steps are as follows: taking lactide, glycolide and an initiator, mixing, adding a proper amount of solvent for dissolving, carrying out reduced pressure distillation to remove the solvent, adding stannous octoate, reacting for 6-8 hours at 130-210 ℃ in a nitrogen atmosphere to obtain viscous liquid, and recrystallizing by using an organic solvent to obtain the star-shaped PLGA.
Further, the solvent is selected from toluene and dichloromethane.
Further, the organic solvent used for recrystallization is selected from chloroform, diethyl ether, dichloromethane and ethanol.
The star lactide-glycolide copolymer is used as a drug sustained release carrier.
The star lactide-glycolide copolymer is applied to the preparation of sustained-release pharmaceutical preparations.
Further, the sustained-release pharmaceutical preparation is a subcutaneous long-acting sustained-release preparation (gel).
Furthermore, the drug in the sustained-release pharmaceutical preparation is gonadotropin drug, which is selected from leuprorelin acetate, triptorelin, histrelin, buserelin and the like.
A long-acting sustained-release preparation (gel) for subcutaneous injection comprises a drug, a star-shaped lactide-glycolide copolymer and a solvent, wherein the drug is a gonadotropin drug selected from leuprorelin acetate, triptorelin, histrelin, buserelin and the like; the drug loading (namely the weight ratio of the drug to the carrier star-shaped lactide-glycolide copolymer) is 5 to 15 percent.
Further, the solvent is selected from NMP (N-methylpyrrolidone).
The preparation method of the subcutaneous injection long-acting sustained-release preparation comprises the following steps: mixing the star lactide-glycolide copolymer and the solvent, standing to remove bubbles, adding the medicine, and mixing.
Further, the dosage proportion relationship of the star lactide-glycolide copolymer and the solvent is as follows: 1g of star lactide-glycolide copolymer and 8-12 ml of solvent.
Furthermore, the subcutaneous injection long-acting sustained-release preparation also contains a diluent (used for diluting gel so as to ensure that the medicine is mixed more uniformly), wherein the diluent is selected from 0.9% sodium chloride solution, 0.5% sodium carboxymethylcellulose solution and 0.1% tween 80 solution.
The star lactide glycolide copolymer disclosed by the invention forms a net-shaped space structure in the form of AB2, AB3, AB4, AB5 or AB6, and when the star lactide glycolide copolymer is used as a drug slow-release carrier, the burst release of a drug can be better controlled, is smaller than carboxyl-terminated PLGA, and has smaller influence on inflammatory reaction of a human body; target drug concentrations are achieved more rapidly than ester-terminated PLGA (failure to achieve plasma drug concentrations may lead to reduced efficacy). Compared with microsphere drug loading, the sustained-release tablet has the advantages of large drug loading, simple preparation process and more lasting sustained-release effect. According to the invention, researches show that the degradation of PLGA has a direct relationship with the molecular weight of PLGA, the steric hindrance between molecular chains is reduced along with the increase of the molecular weight of the star-shaped PLGA, the stability of a copolymer molecular layer is enhanced, the encapsulation rate of the drug is increased, the degradation rate of the drug is obviously slowed down, and further a better sustained release effect is achieved.
The various terms and phrases used herein have the ordinary meaning as is well known to those skilled in the art.
Drawings
FIG. 1: example 1 is a schematic comparison of the in vitro release profiles of comparative example 1.
FIG. 2: example 2 is a schematic comparison of the in vitro release profile of comparative example 1.
FIG. 3: example 3 is a schematic comparison of the in vitro release profiles of comparative example 2.
FIG. 4: examples 1, 2, 3 comparative in vitro release profiles.
FIG. 5 is a schematic view of: the curve of the blood concentration in human body is compared with a schematic diagram.
Detailed Description
The present invention will be further described with reference to the following examples. However, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
Unless otherwise specified, the instruments, reagents, materials and the like used in the following examples are conventional instruments, reagents, materials and the like known in the art and are commercially available. Unless otherwise specified, the experimental methods, detection methods, and the like described in the following examples are conventional experimental methods, detection methods, and the like in the prior art.
EXAMPLE 1 preparation of lactide-glycolide copolymer (three arms)
60g of lactide monomer, 40g of glycolide monomer and 2.6g of glycerol are weighed, the mixture is poured into a three-mouth flask, 200ml of toluene is added for stirring, the solvent is removed by reduced pressure distillation at 80 ℃, 0.2% equivalent weight of stannous octoate is weighed, the mixture is added into the three-mouth flask, nitrogen is replaced for 3 times, a viscous liquid is obtained after reaction for 7 hours at 170 ℃, the viscous liquid is dissolved by chloroform, precipitated by diethyl ether for three times, and vacuum drying is carried out to obtain white semitransparent solid, namely the 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 51.58%, and the GA is 48.42%.
Preparing a drug-loaded gel: placing 1.0g of PLGA prepared above and 10ml of NMP in a beaker, stirring and dissolving at 500rpm at room temperature for 60min, then standing at room temperature for 1 h, removing air bubbles, adding 100mg of leuprorelin acetate, flatly placing, and mutually pushing for 200 times from side to uniformly mix to obtain the product.
Simulating in vivo release through a dissolution test, wherein the specific operation of the dissolution test is as follows: according to high performance liquid chromatography (general rule 0512), octadecylsilane chemically bonded silica is used as a stationary phase, acetonitrile and water (60:40) are used as a mobile phase, an ultraviolet detector is used, the wavelength is 240nm, the column temperature is 35 ℃, and the flow rate is 1.0 ml/min. Taking a proper amount of reference substance, adding acetonitrile to prepare a 0.2mg/ml stock solution, taking the stock solution, adding a medium to dilute to prepare a 40 mu g/ml reference solution. And respectively taking 20 mu l of the control solution and 20 mu l of the test solution, injecting into a high performance liquid chromatograph, and recording the chromatogram. And calculating the cumulative release amount of each time point according to an 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; weighing 0.2% equivalent weight of stannous octoate, adding the stannous octoate into a three-neck flask, replacing with nitrogen for 3 times, reacting at 170 ℃ for 7 hours to obtain viscous liquid, dissolving the viscous liquid with dichloromethane, precipitating with ethanol for three times, and drying in vacuum to obtain white semitransparent solid, namely the lactide-glycolide copolymer (carboxyl-terminated), wherein the weight average molecular weight is 21077, the number average molecular weight is 13281, the monomer proportion is LA% ═ 73.56%, and GA% ═ 26.44%.
Preparing a drug-loaded sample: placing 1.0g of the prepared lactide-glycolide copolymer (carboxyl terminated) and 10ml of NMP in a beaker, stirring and dissolving at 500rpm at room temperature for 60min, standing at room temperature for 1 h, removing bubbles, adding 100mg of leuprorelin acetate, keeping flat, and pushing left and right for 200 times to mix uniformly to obtain the final product.
The drug-loaded gel prepared in example 1 is compared with the drug-loaded sample prepared in comparative example 1, and the result is shown in fig. 1, it can be seen that the cumulative release rate of the drug in comparative example 1 reaches more than 80% after the drug is released for 72h, and the cumulative release rate of the drug in example 1 reaches 80% after the drug is released for 120h, which indicates that the sample in example 1 can release drug molecules more slowly. The sample weight average molecular weight of example 1 was 15081, and the sample weight average molecular weight of comparative example 1 was 21077, and the difference between the two molecular weights was large, which may cause the increase of the controlled release effect due to the difference in the molecular weights of PLGA or the difference in the capping agent.
EXAMPLE 2 preparation of lactide glycolide copolymer (four arms)
22.5g of lactide monomer, 2.5g of glycolide monomer and 1.5g of pentaerythritol are weighed, poured into a three-mouth flask, 200ml of dichloromethane is added for stirring, the solvent is removed by reduced pressure distillation at normal temperature, 0.2% equivalent weight of stannous octoate is weighed, added into the three-mouth flask, replaced by nitrogen for 3 times, reacted at 180 ℃ for 7 hours to obtain viscous liquid, dissolved by dichloromethane and precipitated by ethanol for three times, and dried in vacuum to obtain white semitransparent solid, namely the four-arm star-shaped PLGA, wherein the yield is 86.17%, the weight average molecular weight is 20642, the number average molecular weight is 11598, the monomer proportion is 86.55%, and the GA% is 13.45%.
Preparing a drug-loaded gel: placing 1.0g of PLGA prepared above and 10ml of NMP in a beaker, stirring and dissolving at 500rpm at room temperature for 60min, then standing at room temperature for 1 h, removing air bubbles, adding 100mg of leuprorelin acetate, flatly placing, and mutually pushing for 200 times from side to uniformly mix to obtain the product.
The drug-loaded gel prepared in example 2 is compared with the drug-loaded sample prepared in comparative example 1, and the result is shown in fig. 2, the drug release time in example 2 is greatly prolonged compared with that in comparative example 1, and the difference between the two molecular weights is less than 1000, which indicates that the alcohol group-terminated PLGA sample prepared in example 2 can release drug molecules more slowly in a long term under the molecular weight level.
EXAMPLE 3 preparation of lactide glycolide copolymer (six arms)
60g of lactide monomer, 18g of glycolide monomer and 0.16g of mannitol are weighed, poured into a three-neck flask, added with 80ml of toluene and stirred, decompressed and distilled at 80 ℃ to remove the solvent, weighed 0.2% of equivalent weight of stannous octoate, added into the three-neck flask, replaced by nitrogen for 3 times, reacted at 190 ℃ for 7 hours to obtain viscous liquid, dissolved by chloroform, precipitated by ethanol for three times, and dried in vacuum 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 55.34%, and the GA% is 44.66%.
Preparing a drug-loaded gel: placing 1.0g of PLGA prepared above and 10ml of NMP in a beaker, stirring and dissolving at 500rpm at room temperature for 60min, then standing at room temperature for 1 h, removing air bubbles, adding 100mg of leuprorelin acetate, flatly placing, and mutually pushing for 200 times from side to uniformly mix to obtain the product.
COMPARATIVE EXAMPLE 2 preparation of lactide-glycolide copolymer (ester-terminated)
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; weighing 0.2% equivalent weight of stannous octoate, adding the stannous octoate into a three-neck flask, replacing with nitrogen for 3 times, reacting for 7 hours at 190 ℃ to obtain viscous liquid, dissolving the viscous liquid with dichloromethane, precipitating the viscous liquid with ethanol for three times, and drying the viscous liquid in vacuum to obtain a white semitransparent solid with the weight-average molecular weight of 36837, the number-average molecular weight of 21419, the monomer ratio of LA% ═ 84.59%, and the GA% > -15.41%.
Preparing a drug-loaded sample: placing 1.0g of the prepared lactide-glycolide copolymer (ester-terminated) and 10ml of NMP in a beaker, stirring and dissolving at 500rpm at room temperature for 60min, standing at room temperature for 1 h, removing bubbles, adding 100mg of leuprorelin acetate, keeping flat, and pushing left and right for 200 times to mix uniformly to obtain the product.
The drug-loaded gel prepared in example 3 was examined for drug release comparison with the drug-loaded sample prepared in comparative example 2, and the results are shown in fig. 3. The release time of the drug in example 3 is greatly prolonged compared with that of comparative example 2, and the molecular weight difference between the two is less than 1000, which shows that in the molecular weight range of 3W-4W, the sample prepared in example 3 can still release drug molecules for a longer time compared with PLGA prepared by ester group end capping in comparative example 2.
Examples 1, 2, 3 in vitro release profiles are shown in fig. 4. As can be seen from the figure, the weight average molecular weight of the star-type PLGA polymer in example 1 is 15081, the weight average molecular weight of the star-type PLGA polymer in example 2 is 20642, the weight average molecular weight of the star-type PLGA polymer in example 3 is 37155, the difference of the cumulative drug release rates at different time points of the three examples is obvious, the higher the molecular weight of example 3 is, the cumulative drug release rate is the lowest, and the drug can be slowly released for a longer time, while the lowest the molecular weight of example 1 is, the highest the cumulative drug release rate is, and the worst slow release effect is achieved.
Experiment 4
One of the drug-loaded gel samples prepared in examples 1, 2 and 3 and comparative examples 1 and 2 was taken, 15ml of PBS buffer (pH7.4) was injected, sampling and detection were performed on days 0, 1, 2, 3, 7, 14, 18, 21, 25, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91 and 98, HPLC (280nm) external standard method measurement was performed, and the cumulative elution was calculated, and further the human blood concentration was calculated. The blood concentration profile in human body is shown in figure 5.
The results of the studies of the comparative examples and comparative examples show that there is a significant difference in leuprolide blood levels 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 it can be seen from the monitoring of the blood concentration in the subsequent experiments that the blood concentration in the examples is more gradual and always significantly higher than those of the comparative examples, which shows that the drug-loaded gel prepared by the present invention can release drug molecules more effectively and stably compared with the drug-loaded sample prepared by conventional PLGA.
The embodiment shows that the lactide-glycolide copolymer is prepared into an injection type drug-loading sustained-release preparation, the burst release is smaller than that of carboxyl terminated PLGA, the inflammatory reaction of an injection part caused by the burst release can be effectively controlled, and the drug can be safely released; compared with the ester-group terminated PLGA, the target drug concentration can be reached more quickly (the drug effect is reduced probably because the blood drug concentration is not reached as expected), and the treatment effect is realized quickly and efficiently.
The above examples are provided to enable those skilled in the art to fully disclose and describe how to make and use the claimed embodiments, and are not intended to limit the scope of the disclosure. Modifications apparent to those skilled in the art are intended to be within the scope of the appended claims.
Claims (10)
1. The preparation method of the star lactide glycolide copolymer is characterized by comprising the following steps: lactide and glycolide are used as monomers, alkanediol or saturated polyol is used as an initiator, stannous octoate is used as a catalyst, and the lactide-glycolide copolymer is obtained by melt polymerization, wherein the weight-average molecular weight of the copolymer is 2W-5W, the weight ratio of the lactide in the copolymer is 50% -87%, and the weight ratio of the glycolide is 13% -50%.
2. The method for preparing the star-shaped lactide-glycolide copolymer according to claim 1, characterized in that: the weight ratio of the lactide to the glycolide is 1-9: 1;
the alkanediol is selected from 1, 3-propanediol and hexanediol; the saturated polyol is selected from glycerol, pentaerythritol, sorbitol and mannitol;
the using amount of the alkane diol or the saturated polyol is 1 to 6 percent of the total mass of the monomers;
the dosage of the catalyst stannous octoate is 0.2 percent of the total mass of the monomers.
3. The method for preparing the radial lactide-glycolide copolymer according to claim 1 or 2, characterized in that: taking lactide, glycolide and an initiator, mixing, adding a solvent for dissolving, distilling under reduced pressure to remove the solvent, adding stannous octoate, reacting for 6-8 hours at 130-210 ℃ in a nitrogen atmosphere to obtain viscous liquid, and recrystallizing by using an organic solvent to obtain the star-shaped PLGA.
4. The method for preparing the star-shaped lactide-glycolide copolymer according to claim 3, characterized in that: the solvent is selected from toluene and dichloromethane;
the organic solvent is selected from chloroform, diethyl ether, dichloromethane and ethanol.
5. The method for preparing the star-shaped lactide-glycolide copolymer according to claim 3, characterized in that: 60g of lactide monomer, 40g of glycolide monomer and 2.6g of glycerol are poured into a three-mouth flask, 200ml of toluene is added for stirring, the solvent is removed by reduced pressure distillation at 80 ℃, 0.2% equivalent weight of stannous octoate is weighed and added into the three-mouth flask, nitrogen is substituted for 3 times, reaction is carried out for 7 hours at 170 ℃ to obtain viscous liquid, the viscous liquid is dissolved by chloroform, precipitated by diethyl ether for three times, and vacuum drying is carried out to obtain white semitransparent solid, namely the three-arm star-shaped PLGA, wherein 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%;
or: taking 22.5g of lactide monomer, 2.5g of glycolide monomer and 1.5g of pentaerythritol, pouring the lactide monomer, the glycolide monomer and the pentaerythritol into a three-neck flask, adding 200ml of dichloromethane, stirring, distilling under reduced pressure at normal temperature to remove the solvent, weighing stannous octoate with 0.2% equivalent weight, adding the stannous octoate into the three-neck flask, replacing with nitrogen for 3 times, reacting at 180 ℃ for 7 hours to obtain viscous liquid, dissolving the viscous liquid by dichloromethane and precipitating by ethanol for three times, and drying in vacuum to obtain white semitransparent solid, namely four-arm star PLGA, wherein the weight-average molecular weight of the four-arm PLGA is 20642, the number-average molecular weight of the four-arm PLGA is 11598, the monomer ratio of LA% ═ 86.55% and GA% ═ 13.45%;
or: 60g of lactide monomer, 18g of glycolide monomer and 0.16g of mannitol are poured into a three-mouth flask, 80ml of toluene is added for stirring, the solvent is removed by distillation under reduced pressure at 80 ℃, 0.2% equivalent weight of stannous octoate is weighed, the mixture is added into the three-mouth flask, nitrogen is substituted for 3 times, reaction is carried out for 7 hours at 190 ℃ to obtain viscous liquid, the viscous liquid is dissolved by chloroform and precipitated by ethanol for three times, and vacuum drying is carried out to obtain white semitransparent solid, namely six-arm star-shaped PLGA, wherein the weight-average molecular weight of the star-shaped PLGA is 37155, the number-average molecular weight of the star-shaped PLGA is 21989, the monomer proportion of LA% ═ 55.34%, and the GA% ═ 44.66%.
6. The star lactide-glycolide copolymer prepared by the preparation method of any one of claims 1 to 5.
7. The use of the star lactide-glycolide copolymer according to claim 6 as a drug sustained release carrier or in the preparation of sustained release pharmaceutical formulations.
8. Use according to claim 7, characterized in that: the sustained-release pharmaceutical preparation is a subcutaneous long-acting sustained-release preparation; the drug in the sustained-release pharmaceutical preparation is gonadotropin drug, and is selected from leuprorelin acetate, triptorelin, histrelin and buserelin.
9. A subcutaneous injection long-acting sustained release preparation is characterized in that: comprises a drug, the star-shaped lactide-glycolide copolymer of claim 6 and a solvent, wherein the drug is a gonadotropin drug selected from the group consisting of leuprorelin acetate, triptorelin, histrelin, buserelin; the drug loading is 5-15%.
10. The subcutaneous long-acting sustained release formulation according to claim 9, wherein: the solvent is selected from N-methyl pyrrolidone;
the dosage proportion relationship of the star lactide-glycolide copolymer and the solvent is as follows: 1g of star lactide-glycolide copolymer and 8-12 ml of solvent.
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