CN116803382A - Triamcinolone acetonide sustained release microsphere, preparation method and triamcinolone acetonide sustained release preparation - Google Patents
Triamcinolone acetonide sustained release microsphere, preparation method and triamcinolone acetonide sustained release preparation Download PDFInfo
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- CN116803382A CN116803382A CN202311050982.0A CN202311050982A CN116803382A CN 116803382 A CN116803382 A CN 116803382A CN 202311050982 A CN202311050982 A CN 202311050982A CN 116803382 A CN116803382 A CN 116803382A
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- triamcinolone acetonide
- microsphere
- sustained release
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- 239000004005 microsphere Substances 0.000 title claims abstract description 119
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 title claims abstract description 110
- 229960002117 triamcinolone acetonide Drugs 0.000 title claims abstract description 109
- 238000013268 sustained release Methods 0.000 title claims abstract description 57
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 89
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 75
- 229940079593 drug Drugs 0.000 claims abstract description 64
- 239000012074 organic phase Substances 0.000 claims abstract description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000002994 raw material Substances 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000002245 particle Substances 0.000 claims abstract description 25
- 239000012071 phase Substances 0.000 claims abstract description 25
- 239000000839 emulsion Substances 0.000 claims abstract description 23
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims abstract description 22
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 229920001577 copolymer Polymers 0.000 claims abstract description 13
- 238000004945 emulsification Methods 0.000 claims abstract 2
- 229920000642 polymer Polymers 0.000 claims description 15
- 239000008346 aqueous phase Substances 0.000 claims description 14
- 239000012456 homogeneous solution Substances 0.000 claims description 14
- 239000008213 purified water Substances 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 13
- 238000000265 homogenisation Methods 0.000 claims description 12
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 10
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 7
- 238000007711 solidification Methods 0.000 claims description 7
- 230000008023 solidification Effects 0.000 claims description 7
- 238000005063 solubilization Methods 0.000 claims description 7
- 230000007928 solubilization Effects 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229940074404 sodium succinate Drugs 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- 238000009210 therapy by ultrasound Methods 0.000 claims description 3
- 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 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 230000015271 coagulation Effects 0.000 claims description 2
- 238000005345 coagulation Methods 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 230000002917 arthritic effect Effects 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical group [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims 2
- 238000005538 encapsulation Methods 0.000 abstract description 21
- 238000011068 loading method Methods 0.000 abstract description 19
- 238000009826 distribution Methods 0.000 abstract description 17
- 230000001954 sterilising effect Effects 0.000 abstract description 17
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 16
- 238000001914 filtration Methods 0.000 abstract description 15
- 239000003509 long acting drug Substances 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 26
- 238000004519 manufacturing process Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 11
- 238000005227 gel permeation chromatography Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 238000000635 electron micrograph Methods 0.000 description 8
- VOBDXTSTTMAKHK-VHDCPBDGSA-N 3870-07-3 Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O VOBDXTSTTMAKHK-VHDCPBDGSA-N 0.000 description 7
- 239000012752 auxiliary agent Substances 0.000 description 6
- 239000003517 fume Substances 0.000 description 5
- 238000003760 magnetic stirring Methods 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 238000001647 drug administration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000011056 performance test Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 239000013557 residual solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RZHBMYQXKIDANM-UHFFFAOYSA-N dioctyl butanedioate;sodium Chemical compound [Na].CCCCCCCCOC(=O)CCC(=O)OCCCCCCCC RZHBMYQXKIDANM-UHFFFAOYSA-N 0.000 description 2
- -1 dioctyl sodium succinate Chemical compound 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- YHAIUSTWZPMYGG-UHFFFAOYSA-L disodium;2,2-dioctyl-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCCCCCC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CCCCCCCC YHAIUSTWZPMYGG-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid group Chemical group C(CCC(=O)O)(=O)O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention belongs to the technical field of drug sustained-release preparations, and in particular relates to triamcinolone acetonide sustained-release microspheres, a preparation method and a triamcinolone acetonide sustained-release preparation. The preparation method of the triamcinolone acetonide sustained-release microsphere comprises the steps of adding an organic phase containing solvent dichloromethane, triamcinolone acetonide raw material medicine, polylactic acid-glycollic acid copolymer and dioctyl sodium sulfosuccinate into a water phase for emulsification to form emulsion, and solidifying dispersed emulsion drops in the emulsion to form the triamcinolone acetonide sustained-release microsphere. In the method, the organic phase and the water phase are respectively homogeneous solutions, so that the organic phase and the water phase can be subjected to filtration sterilization operation after the preparation of the organic phase and the water phase is finished, and the slow release microsphere product can meet the sterile requirement. Besides, the triamcinolone acetonide sustained-release microsphere prepared by the method has the advantages of high encapsulation efficiency, large drug loading capacity, less solvent residue, uniform particle size distribution, and stable and long-acting drug release.
Description
Technical Field
The invention belongs to the technical field of drug sustained-release preparations, and in particular relates to triamcinolone acetonide sustained-release microspheres, a preparation method and a triamcinolone acetonide sustained-release preparation.
Background
Triamcinolone acetonide sustained-release microspheres are approved by the United states FDA to be marketed by FLEXION THERAS company in 10 and 6 of 2017 at the earliest time, and are a medicament for treating knee osteoarthritis pain.
Triamcinolone acetonide is a corticosteroid with anti-inflammatory and immunomodulating effects, CAS number 76-25-5, formula C 24 H 31 FO 6 The structural formula is shown in figure 1. The triamcinolone acetonide solid is white crystalline powder, is dissolved in acetone, and has low solubility in other organic solvents such as dichloromethane, methanol and ethanol and water.
Considering the indissolvable property of triamcinolone acetonide, the process for preparing triamcinolone acetonide sustained-release microspheres disclosed in the original patent US8828440B2 is to suspend the bulk drug in a solid state in an organic phase, so that the organic phase cannot be subjected to sterilization and filtration operation. Filtering and sterilizing means that the liquid medicine is filtered by a filtering device to remove harmful impurities such as microorganisms and the like in the liquid medicine so as to ensure that the purity of the liquid medicine meets the standard. However, triamcinolone acetonide, a poorly soluble drug, is suspended in an organic phase in a solid state and is difficult to permeate through the filtration device, thus affecting the performance of the aseptic filtration operation. In addition, the triamcinolone acetonide raw material is unstable in nature, so that terminal sterilization modes such as high temperature and irradiation are not feasible.
In view of the fact that triamcinolone acetonide suspension is not suitable for adopting sterilization methods such as filtration sterilization, high-temperature sterilization, irradiation sterilization and the like, the sterilization of microsphere products can be guaranteed only by means of a sterile production process, and the technical difficulty and the production cost are remarkably improved. In particular, aseptic manufacturing processes require highly automated and isolated operations throughout the process, with very high demands on both hardware and software for the manufacturing enterprise. First, the sterility assurance of the production environment requires maintenance of a class a environment, which involves quality and operational management of efficient filters, RABSs, and isolators. Secondly, enterprises need to develop closed production processes, and open operation is reduced. The producer needs to have strong consciousness about GMP production, and the production is strictly carried out according to aseptic operation rules. In addition, aseptic raw materials are required to be used in aseptic production, the price of the aseptic raw materials is far higher than that of common non-aseptic raw materials, and the aseptic raw materials are not easy to obtain. Therefore, the aseptic production process is a great challenge for the hardware equipment and personnel quality of enterprises, and the production cost is greatly increased compared with that of the traditional process.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a triamcinolone acetonide sustained release microsphere, a preparation method and a triamcinolone acetonide sustained release preparation.
The first aim of the invention is to avoid using triamcinolone acetonide suspension as a raw material to prepare the sustained-release microspheres, and develop a method for preparing the sustained-release microspheres based on triamcinolone acetonide homogeneous solution, which creates conditions for adopting low-cost and simple and easy filtration sterilization operation, thereby greatly reducing the occupation ratio of the whole production process needing to implement a sterile production process.
The second purpose of the invention is to develop a triamcinolone acetonide sustained release microsphere and a preparation with high encapsulation efficiency, large drug loading capacity, less solvent residue, uniform particle size distribution, and stable and long-acting drug release.
The invention provides a preparation method of triamcinolone acetonide sustained-release microspheres, which comprises the steps of adding an organic phase containing solvent Dichloromethane (DCM), triamcinolone acetonide bulk drug, polylactic acid-glycolic acid copolymer (PLGA) and dioctyl sodium succinate into a water phase to emulsify and form emulsion, and solidifying dispersed emulsion drops in the emulsion to form the triamcinolone acetonide sustained-release microspheres; in the process of preparing an organic phase, the triamcinolone acetonide raw material medicine is dissolved in dichloromethane under the solubilization action of dioctyl sodium sulfosuccinate; and during solidification, the polylactic acid-glycollic acid copolymer is precipitated and coagulated to form microspheres along with the reduction of the dichloromethane content in emulsion drops, and the triamcinolone acetonide raw material is filled in the microspheres to prepare the triamcinolone acetonide slow-release microspheres.
As a further preferable scheme of the preparation method of the triamcinolone acetonide sustained-release microsphere, the weight ratio of dioctyl sodium sulfosuccinate to triamcinolone acetonide bulk drug in the organic phase is in the range of 1:2-2:1.
The preparation method of the triamcinolone acetonide sustained-release microsphere mainly comprises the following steps in the implementation process:
step one, preparing an organic phase: dissolving polylactic acid-glycollic acid copolymer in solvent dichloromethane, then adding dioctyl sodium sulfosuccinate for dissolution, then adding triamcinolone acetonide bulk drug, shaking and carrying out ultrasonic treatment until a homogeneous solution is obtained;
step two, preparing a water phase: adding a stabilizer into water to dissolve to obtain a homogeneous solution;
step three, preparing emulsion: slowly adding the organic phase prepared in the first step into the water phase prepared in the second step under the condition of homogenization, and continuing to homogenize to obtain emulsion;
step four, preparing microspheres: and (3) maintaining the emulsion prepared in the step (III) in a stirring state, solidifying the emulsion drops dispersed in the emulsion to form a microsphere crude product, and then washing and freeze-drying to obtain the triamcinolone acetonide sustained-release microsphere.
In the second step, the stabilizer added during the preparation of the aqueous phase can inhibit aggregation of the microspheres in the curing process to a certain extent, and the stabilizer can be selected from polyvinyl alcohol, poloxamer and carbomer, preferably polyvinyl alcohol.
In the process of preparing the triamcinolone acetonide sustained-release microsphere, the raw material ratio of the organic phase and the water phase can be implemented according to the following preferred scheme:
in step one, an organic phase is formulated containing the following components:
0.7-0.9 parts by weight of triamcinolone acetonide;
0.4-1.6 parts by weight of dioctyl sodium sulfosuccinate;
15-20 parts of dichloromethane;
1.7-2.3 parts by weight of polylactic acid-glycollic acid copolymer;
in step two, an aqueous phase is prepared which contains the following components:
1.2-1.8 parts by weight of a stabilizer;
350-450 parts of purified water.
In the process of preparing the triamcinolone acetonide sustained-release microsphere, the further preferable scheme of the raw material ratio of the organic phase and the water phase is as follows:
in step one, an organic phase is formulated consisting of:
triamcinolone acetonide 0.8 weight portions;
0.4-1.6 parts by weight of dioctyl sodium sulfosuccinate;
18 parts by weight of methylene chloride;
2 parts by weight of polylactic acid-glycollic acid copolymer;
in the second step, an aqueous phase is prepared which consists of the following components:
1.5 parts by weight of polyvinyl alcohol;
400 parts by weight of purified water.
The invention also provides a triamcinolone acetonide sustained-release microsphere which is provided with a microsphere body formed by the coagulation of polylactic acid-glycollic acid copolymer and a triamcinolone acetonide bulk drug embedded in the microsphere body, wherein the weight average molecular weight Mw of a polymer in the microsphere is controlled within the range of 8.5 kDa-12.5 kDa.
In order to control the weight average molecular weight Mw of the polymer in the triamcinolone acetonide sustained release microsphere to be in the range of 8.5 kDa to 12.5 kDa, an emulsion can be formed by mixing a water phase and an oil phase containing triamcinolone acetonide raw material medicine and the mixture is solidified to obtain the microsphere, and the weight average molecular weight Mw of the polymer in the microsphere is controlled to be in the range of 8.5 kDa to 12.5 kDa by adding dioctyl sodium sulfosuccinate into the oil phase and controlling the weight ratio of the dioctyl sodium sulfosuccinate to the triamcinolone acetonide raw material medicine to be 1:2 to 2:1.
As a further preferable scheme of the triamcinolone acetonide sustained-release microsphere, the drug loading rate is in the range of 24.5% -25.0%, and the solvent residue rate is less than or equal to 0.04%.
As a further preferable scheme of the triamcinolone acetonide sustained-release microsphere, the particle diameter D10 is in the range of 24.5-28.0 μm, and the particle diameter D90 is in the range of 70.0-72.5 μm.
Based on the triamcinolone acetonide sustained-release microsphere, the invention also provides a triamcinolone acetonide sustained-release microsphere preparation for treating arthritis pain, in particular to a triamcinolone acetonide sustained-release microsphere preparation which is prepared by adding a sterile diluent into a container filled with the triamcinolone acetonide sustained-release microsphere and uniformly mixing the mixed solution. Wherein the sterile diluent is an aqueous solution containing 0.9% by mass of sodium chloride, 0.5% by mass of sodium carboxymethyl cellulose and 0.1% by mass of tween 80. When in use, the triamcinolone acetonide sustained-release microsphere preparation is sucked by an injector and injected into the joint cavity of a patient, so that the long-acting pain relieving effect exceeding 12 weeks can be achieved.
Advantageous effects
According to the method for preparing the triamcinolone acetonide sustained-release microsphere, the organic phase and the aqueous phase are respectively homogeneous solutions, so that the aseptic production process extremely harsh to personnel, raw materials, equipment and environment is not needed to be carried out in the early-stage operations of raw material preparation, organic phase preparation, aqueous phase preparation and the like, but the organic phase and the aqueous phase are subjected to filtration sterilization operation respectively after the organic phase and the aqueous phase are prepared, and the sustained-release microsphere product is ensured to meet the aseptic requirement.
On the basis of simplifying the process, the triamcinolone acetonide sustained-release microsphere which has high encapsulation efficiency, large drug loading, less solvent residue, uniform particle size distribution, stable and long-acting drug release can be prepared, the encapsulation efficiency reaches 99%, the drug loading is approximately 25%, the solvent residue is not more than 0.04%, the particle size distribution curve is normally distributed, the Span is approximately equal to 1, and the drug release curve is stable and continuous within 0-170 h.
Drawings
FIG. 1 shows the structural formula of triamcinolone acetonide.
FIG. 2 shows the amounts of raw materials used for the samples of preparation example 1 and comparative examples a1 to d 1.
Fig. 3 shows the results of performance tests of the samples of example 1 and comparative examples a1 to d 1.
FIG. 4 shows an electron micrograph of a sample of comparative example a 1.
FIG. 5 shows the particle size distribution of the sample of comparative example a 1.
Fig. 6 shows drug release curves for samples of example 1 and comparative examples a1 to d 1.
FIG. 7 shows an electron micrograph of a sample of comparative example b 1.
FIG. 8 shows the particle size distribution of the sample of comparative example b 1.
FIG. 9 shows an electron micrograph of a sample of comparative example c 1.
FIG. 10 shows the particle size distribution of the sample of comparative example c 1.
FIG. 11 shows an electron micrograph of a sample of comparative example d 1.
FIG. 12 shows the particle size distribution of the sample of comparative example d 1.
FIG. 13 is an electron micrograph of the sample of example 1.
FIG. 14 shows the particle size distribution of the sample of example 1.
FIG. 15 shows the molecular weights of the polymers in the samples of example 1 and comparative examples a1 to d 1.
FIG. 16 shows GPC gel chromatograms of the samples of example 1.
FIG. 17 shows GPC gel chromatograms of samples of comparative example a 1.
FIG. 18 shows GPC gel chromatograms of samples of comparative example b 1.
FIG. 19 shows GPC gel chromatograms of comparative example c1 samples.
FIG. 20 shows GPC gel chromatograms of the samples of comparative example d 1.
FIG. 21 shows the amounts of raw materials used to prepare the samples of comparative examples b1 to b 6.
FIG. 22 shows the results of performance tests of the samples of comparative examples b1 to b 6.
FIG. 23 shows the amounts of raw materials used to prepare the samples of comparative examples c1 to c 4.
Fig. 24 shows the results of performance tests of the samples of comparative examples c1 to c 4.
FIG. 25 shows the amounts of raw materials used to prepare d8 samples of comparative examples d1 to d 8.
Fig. 26 shows the performance test results of the d8 samples of comparative examples d1 to d 8.
FIG. 27 shows the amounts of raw materials used for the samples of preparation examples 1 to 9.
Fig. 28 shows the results of performance testing of the samples of examples 1 to 9.
FIG. 29 shows the molecular weights of the polymers in the samples of examples 1 and to 9.
Fig. 30 shows drug release profiles for samples of examples 1 and through 9.
Detailed Description
The triamcinolone acetonide sustained release microspheres of the present invention were prepared as follows. According to the prescription amount shown in fig. 2, a single solvent or a mixed solvent is prepared, PLGA is dissolved in the solvent, then dioctyl sodium sulfosuccinate or sodium dodecyl sulfate is not added or is selectively added for dissolution, finally triamcinolone acetonide or triamcinolone acetonide acetate is added, and the organic phase is obtained by shaking and ultrasonic treatment for 10 min. Adding polyvinyl alcohol into purified water according to the prescription amount to completely dissolve, thus obtaining water phase. Under homogenization conditions, the organic phase was slowly added to the aqueous phase and homogenization continued for 5min. Afterwards, the liquid medicine is put into a fume hood and is solidified for 3 hours by using magnetic stirring. And after solidification, washing with purified water, and freeze-drying the washed microspheres in a freeze dryer to obtain the slow-release microsphere sample.
As a result, as shown in FIG. 3, the preparation method of comparative example a1 is similar to that of the original developer, and other methods are not adopted to promote dissolution of the crude drug in the preparation of the organic phase, which is in suspension, and the triamcinolone acetonide crude drug is suspended in the liquid medicine as solid particles, so that the organic phase cannot be subjected to the sterilization and filtration operation. Nevertheless, sustained-release microspheres with a drug loading (23.64%) and an encapsulation rate (82.32%) which are still available can be prepared by the method of comparative example a1, and most of the bulk drug dispersed in the form of microparticles in suspension can be finally encapsulated in PLGA microspheres. However, as can be seen from fig. 4 and 5, the sustained-release microsphere prepared in comparative example a1 has irregular spherical shape, poor size uniformity, uneven particle size distribution, and obvious difference in transparency between different microspheres, which indicates that the drug loading of different microspheres is significantly different. Irregular shape and size and uneven drug loading rate can have adverse effects on the stable release of the drug. As shown in fig. 6, the release profile of the sample of comparative example a1 also verifies that the triamcinolone acetonide has a rapid early release and a slow late release, and thus is disadvantageous in maintaining a stable and effective concentration of the drug in the human body.
The preparation method of the comparative example b1 adopts a scheme that the crude drug is prepared into soluble salt, triamcinolone acetonide acetate can be dissolved in methylene dichloride to form an organic phase homogeneous solution, so that the organic phase can be subjected to sterilization and filtration operation. However, after the soluble salt of triamcinolone acetonide is used, the drug loading rate (21.65%) and the encapsulation rate (70.76%) of the prepared slow-release microsphere are obviously reduced compared with those of the suspension drug. The drug loading of the slow-release microspheres is reduced, so that the concentration of the drugs in the microspheres is reduced, the treatment effect is affected, the administration period is shortened, and the convenience of the patients in administration is reduced; the decrease of the encapsulation efficiency can lead to the easier release of the drug from the microsphere, and cause excessive release of the drug in the initial stage of drug administration, thereby increasing the risk of side effects, and also lead to the shortening of the drug administration period and the damage of the convenience of drug administration. From the electron micrographs and particle size distribution diagrams shown in fig. 7 and 8, it is apparent that the microspheres prepared by the process using triamcinolone acetonide acetate soluble salt have very distinct size differences and are mostly irregularly spherical and have adhesion. As can be seen from the release curve shown in fig. 6, the sample of comparative example b1 has rapid early release of triamcinolone acetonide acetate, and has remarkable burst release phenomenon and poor slow release effect.
The preparation method of comparative example c1 adopts a scheme of dissolving triamcinolone acetonide in a mixed solvent composed of acetone and methylene dichloride, and observes that the triamcinolone acetonide as a raw material is completely dissolved in the mixed solvent to form an organic phase homogeneous solution, so that the organic phase can be subjected to a sterilization and filtration operation. Although the mixed solvent formed by introducing acetone can solve the problem of dissolution of the bulk drug, according to the detection result of fig. 3, compared with the suspension scheme, the microsphere prepared by the method has very remarkable reduction of drug loading (20.15%) and encapsulation rate (65.24%), thereby affecting the curative effect, increasing the risk of side effects and shortening the administration period. And the compound solvent is adopted, so that the solvent is more difficult to remove in the preparation process, the solvent residue is obviously increased, and the risk of side effects of the medicine is increased. It can also be seen from the electron micrograph shown in fig. 9 that the adhesion between microspheres is severe and the surface is rough due to excessive residual solvent. In addition, as can be seen from the particle size distribution chart shown in FIG. 10, the microspheres prepared by the process have uneven particle size distribution and smaller overall size. As can also be seen from the release profile shown in fig. 6, the drug substance of the comparative example c1 sample was extremely severely released during the release.
The preparation method of the comparative example d1 adopts a scheme of adding an auxiliary agent for promoting the dissolution of the medicine, and the used auxiliary agent is sodium dodecyl sulfate. After adding sodium dodecyl sulfate as a surfactant to the organic phase, it was observed that triamcinolone acetonide, a raw material, was completely dissolved in methylene chloride to form a homogeneous solution of the organic phase, and thus the organic phase was subjected to a sterilization filtration operation. However, the test results in fig. 3 show that the microspheres solubilized with sodium dodecyl sulfate also have a somewhat reduced drug loading (21.35%) and encapsulation (79.64%) compared to the suspension regimen, which has a negative impact on patient dosing. However, as can be seen from the electron micrographs and the particle size distribution diagrams shown in FIGS. 11 and 12, the slow-release microspheres prepared in comparative example d1 are irregularly spherical, have a certain adhesion with each other, and have very uneven sizes. The microspheres have larger shape and size difference, and are easy to cause unstable release of the drug. As shown in fig. 6, the release curve of the sample d1 of the comparative example also shows that the pre-drug release is rapid, the obvious burst release phenomenon exists, and the drug release period is short, so that the stable and effective concentration of the drug in the human body is not easy to maintain, and the administration of the drug to patients is inconvenient.
The preparation method of example 1 also adopts a scheme of adding an auxiliary agent for promoting the dissolution of the medicine, wherein the used auxiliary agent is dioctyl sodium sulfosuccinate, and the raw material medicine triamcinolone acetonide is completely dissolved in methylene dichloride to form an organic phase homogeneous solution, so that the organic phase can be subjected to a sterilization and filtration operation. Surprisingly, dioctyl sodium sulfosuccinate as a surfactant, in addition to promoting complete dissolution of triamcinolone acetonide, causes significant changes in the encapsulation and release behavior of the drug. Before the prior art, triamcinolone acetonide is completely dissolved in an organic phase by various methods such as forming soluble salt, using a mixed solvent, adding an auxiliary agent sodium dodecyl sulfate and the like, but the drug loading and the encapsulation efficiency are reduced to different degrees, the curative effect of the drug is affected, the side effect of the drug is increased, and the administration period is shortened. Compared with the suspension scheme, as shown in fig. 3, the slow release microsphere prepared under the solubilization of dioctyl sodium succinate has the advantages that the drug loading rate (24.95%) and the encapsulation rate (98.85%) are not reduced, and the encapsulation rate, particularly the encapsulation rate, is remarkably improved to be close to complete encapsulation. From the electron microscope pictures and the particle size distribution diagrams shown in fig. 13 and 14, the microspheres prepared by the process have uniform color, smooth and round surface, normal particle size distribution, no obvious adhesion between the microspheres and uniform dispersion. The most critical is that the sudden drug release phenomenon which is commonly existed after the triamcinolone acetonide is solubilized is obviously improved in the sample of the embodiment 1, the drug release is stable and slow according to the release curve of the sample of the embodiment 1 in fig. 6, no obvious sudden drug release phenomenon exists in the early stage, and the release period of the drug is obviously prolonged, so that the stable effective concentration of the drug in the human body is maintained, and the drug administration of patients is more convenient.
In order to further investigate the cause of the remarkable difference in drug release behavior of the samples of example 1, the present invention further examined the molecular weight of the polymer in the above samples by GPC gel chromatography, and the results are summarized in fig. 15, and the GPC gel chromatograms of the respective samples are shown in fig. 16 to 20, respectively. The result shows that the microsphere is prepared by a scheme of forming soluble salt, using a mixed solvent, adding auxiliary agent sodium dodecyl sulfate and the like to enable triamcinolone acetonide to be completely dissolved, the molecular weight of a polymer forming a main body of the microsphere is smaller, the polymer is concentrated to 30 kDa-45 kDa according to weight average molecular weight measurement, and the weight average molecular weight of the microsphere prepared after the sodium dioctyl succinate sulfonate is added for solubilization is close to 100kDa and is obviously higher than that of other schemes. Due to the increase of the molecular weight of the polymer, the structural stability of the microsphere is improved, and the combination of the drug and the microsphere body is enhanced, so that the release of the drug is delayed. The analysis may be that the sulfonated succinic acid groups in the dioctyl sodium sulfosuccinate are embedded into the high molecular polymer, so that the binding force between polylactic acid and glycolic acid in PLGA is increased, and the degradation speed of the polymer is slowed down.
Aiming at the problem that the raw material medicine is not easy to form an organic homogeneous solution in the preparation process of the triamcinolone acetonide sustained-release microsphere so as to influence the sterilization and filtration operation, the invention also researches a plurality of methods for preparing the raw material medicine into soluble salt, using a mixed solvent and adding a solubilizer and a cosolvent.
With respect to the preparation of soluble salts, the present invention investigated the process of preparing microspheres using triamcinolone acetonide acetate as starting material. PLGA was dissolved in DCM, then dissolved without or optionally with sodium dioctyl sulfosuccinate or sodium dodecyl sulfate, and finally triamcinolone acetonide acetate was added, shaken and sonicated for 10min, according to the recipe shown in FIG. 21. Adding polyvinyl alcohol into purified water according to the prescription amount, heating and stirring to completely dissolve, and obtaining a water phase. Under homogenization conditions, the organic phase was slowly added to the aqueous phase and homogenization continued for 5min. Afterwards, the liquid medicine is put into a fume hood and is solidified for 3 hours by using magnetic stirring. And after solidification, washing with purified water, and freeze-drying the washed microspheres in a freeze dryer to obtain the slow-release microsphere sample.
The results show that although triamcinolone acetonide acetate is easier to dissolve and the formed organic phase is homogeneous solution, the problem that the encapsulation rate of the prepared microspheres is not qualified is found no matter how the prescription and the technological parameters are adjusted. As shown in fig. 22, it can be seen from the encapsulation efficiency data that a large amount of raw materials are released on the microsphere surface, which results in significantly faster drug release rate and serious burst. The analysis may be that after the soluble salt is prepared, the binding force between the drug substance and the polymer forming the microsphere is weakened, and effective drug loading cannot be realized.
Regarding the use of mixed solvents, it is known that triamcinolone acetonide is only soluble in acetone and is poorly soluble in other solvents, and the present invention studied the use of acetone instead of methylene chloride and the use of a mixed solvent of acetone and methylene chloride to dissolve triamcinolone acetonide raw material to prepare microspheres. PLGA was dissolved in DCM, and triamcinolone acetonide was added thereto, shaken and sonicated for 10min to give an organic phase, which was weighed according to the recipe shown in FIG. 23. Adding polyvinyl alcohol into purified water according to the prescription amount, and stirring by shaking and heating to completely dissolve to obtain water phase. Under homogenization conditions, the organic phase was slowly added to the aqueous phase and homogenization continued for 5min. Afterwards, the liquid medicine is put into a fume hood and is solidified for 3 hours by using magnetic stirring. And after solidification, washing with purified water, and freeze-drying the washed microspheres in a freeze dryer to obtain the slow-release microsphere sample.
The results show that when the addition amount of acetone is low, the raw materials still cannot be completely dissolved in the organic phase, and although the problem of dissolution of the raw materials can be solved by increasing the amount of acetone, the encapsulation efficiency and the drug loading rate are reduced, and the solvent residue is obviously increased. As shown in fig. 24, the encapsulation efficiency and the drug loading rate were both significantly reduced with the increase in the acetone ratio, and the average particle diameter of the microspheres was also smaller, using acetone or a mixed solvent of acetone and dichloromethane. And due to the introduction of acetone, the acetone is difficult to completely remove in the preparation process, and new residual solvent is added.
With respect to the addition of a co-solvent or solubilizing agent, the present invention contemplates another 4 surfactants including sodium dodecyl sulfate, poloxamer, tyloxapol, and tween 80. The amount of PLGA was weighed according to the recipe shown in FIG. 25, dissolved in DCM, then surfactant was added, finally triamcinolone acetonide was added, and the mixture was shaken and sonicated for 10min to give an organic phase. Adding polyvinyl alcohol into purified water according to the prescription amount, heating and stirring to completely dissolve, and obtaining a water phase. Under homogenization conditions, the organic phase was slowly added to the aqueous phase and homogenization continued for 5min. Afterwards, the liquid medicine is put into a fume hood and is solidified for 3 hours by using magnetic stirring. And after solidification, washing with purified water, and freeze-drying the washed microspheres in a freeze dryer to obtain the slow-release microsphere sample.
As shown in FIG. 26, the addition of sodium dodecyl sulfate also greatly improved the solubility of triamcinolone acetonide, resulting in a homogeneous solution of the organic phase, while the other 3 surfactants did not significantly improve the solubility of the starting materials, failing to form a homogeneous solution of the organic phase. On the other hand, although the machine phase forms a homogeneous solution under the action of the sodium dodecyl sulfate, the detection result shows that the drug loading and the encapsulation efficiency of the microsphere prepared by solubilization with the sodium dodecyl sulfate are obviously reduced, and the practical application requirements cannot be met.
Therefore, aiming at the problem of low triamcinolone acetonide solubility, the solution of triamcinolone acetonide can be mostly solved by adopting the multiple schemes of preparing soluble salt, using mixed solvent, adding solubilizer or cosolvent and the like, but the prepared sustained-release microsphere cannot achieve ideal drug release effect anyway by adjusting the scheme, and is difficult to meet the practical use requirement.
To further verify the feasibility of the solubilization scheme with sodium dioctyl succinate, the present invention attempted multiple schemes of different ratios as shown in FIG. 27. PLGA is dissolved in DCM according to the prescribed amount, then dioctyl sodium sulfosuccinate is added for dissolution, finally triamcinolone acetonide is added, and the mixture is shaken and sonicated for 10min to obtain an organic phase. Adding polyvinyl alcohol into purified water according to the prescription amount, heating and stirring to completely dissolve, and obtaining a water phase. Under homogenization conditions, the organic phase was slowly added to the aqueous phase and homogenization continued for 5min. Afterwards, the liquid medicine is put into a fume hood and is solidified for 3 hours by using magnetic stirring. And after solidification, washing with purified water, and freeze-drying the washed microspheres in a freeze dryer to obtain the slow-release microsphere sample.
As shown in fig. 28, 29 and 30, the detection indexes of examples 1, 2, 3, 6 and 7 were all ideal, which means that the ideal effect can be obtained by keeping the ratio of dioctyl sodium sulfosuccinate to the drug substance within the range of 1:2 to 2:1. Too low a proportion of dioctyl sodium sulfosuccinate affects the solubilization and thus the quality of the microspheres, while too high a proportion slows down the drug release rate of the microspheres and does not maintain an effective drug concentration in the patient.
In the above cases, the drug loading and encapsulation efficiency test is carried out by adopting an HPLC method; the particle size and the particle size distribution are detected by a laser particle size analyzer; detecting residual solvent by gas chromatography; the molecular weight of the polymer in the sustained release microsphere was measured by GPC gel chromatography.
The above embodiments are illustrative for the purpose of illustrating the technical concept and features of the present invention so that those skilled in the art can understand the content of the present invention and implement it accordingly, and thus do not limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (12)
1. A preparation method of triamcinolone acetonide sustained release microspheres is characterized by comprising the following steps: adding an organic phase containing solvent dichloromethane, triamcinolone acetonide raw material medicine, polylactic acid-glycollic acid copolymer and dioctyl sodium sulfosuccinate into a water phase for emulsification to form emulsion, and solidifying dispersed emulsion drops in the emulsion to form triamcinolone acetonide slow release microspheres; in the process of preparing an organic phase, the triamcinolone acetonide raw material medicine is dissolved in dichloromethane under the solubilization action of dioctyl sodium sulfosuccinate; and during solidification, the polylactic acid-glycollic acid copolymer is precipitated and coagulated along with the reduction of the dichloromethane content in emulsion drops to form microspheres, and the triamcinolone acetonide raw material is filled in the microspheres to prepare the triamcinolone acetonide sustained release microspheres.
2. The method for preparing triamcinolone acetonide sustained release microspheres according to claim 1, characterized in that: in the organic phase, the weight ratio of dioctyl sodium sulfosuccinate to triamcinolone acetonide bulk drug is in the range of 1:2-2:1.
3. The preparation method of triamcinolone acetonide sustained release microsphere according to claim 1 or 2, characterized in that: the method comprises the following steps:
step one, preparing an organic phase: dissolving polylactic acid-glycollic acid copolymer in solvent dichloromethane, then adding dioctyl sodium sulfosuccinate for dissolution, then adding triamcinolone acetonide bulk drug, shaking and carrying out ultrasonic treatment until a homogeneous solution is obtained;
step two, preparing a water phase: adding a stabilizer into water to dissolve to obtain a homogeneous solution;
step three, preparing emulsion: slowly adding the organic phase prepared in the first step into the water phase prepared in the second step under the condition of homogenization, and continuing to homogenize to obtain emulsion;
step four, preparing microspheres: and (3) maintaining the emulsion prepared in the step (III) in a stirring state, solidifying the emulsion drops dispersed in the emulsion to form a microsphere crude product, and then washing and freeze-drying to obtain the triamcinolone acetonide sustained-release microsphere.
4. The method for preparing triamcinolone acetonide sustained release microspheres according to claim 3, wherein: in the second step, the stabilizer added in the preparation of the water phase is polyvinyl alcohol.
5. The method for preparing triamcinolone acetonide sustained release microspheres according to claim 3, wherein:
in step one, an organic phase is formulated containing the following components:
0.7-0.9 parts by weight of triamcinolone acetonide;
0.4-1.6 parts by weight of dioctyl sodium sulfosuccinate;
15-20 parts of dichloromethane;
1.7-2.3 parts by weight of polylactic acid-glycollic acid copolymer;
in step two, an aqueous phase is prepared which contains the following components:
1.2-1.8 parts by weight of a stabilizer;
350-450 parts of purified water.
6. The method for preparing triamcinolone acetonide sustained release microspheres according to claim 3, wherein:
in step one, an organic phase is formulated consisting of:
triamcinolone acetonide 0.8 weight portions;
0.4-1.6 parts by weight of dioctyl sodium sulfosuccinate;
18 parts by weight of methylene chloride;
2 parts by weight of polylactic acid-glycollic acid copolymer;
in the second step, an aqueous phase is prepared which consists of the following components:
1.5 parts by weight of polyvinyl alcohol;
400 parts by weight of purified water.
7. A triamcinolone acetonide sustained release microsphere, characterized in that: the microsphere comprises a microsphere body formed by coagulation of polylactic acid-glycollic acid copolymer and triamcinolone acetonide bulk drug embedded in the microsphere body, wherein the weight average molecular weight Mw of the polymer in the microsphere is controlled within the range of 8.5 kDa-12.5 kDa.
8. The triamcinolone acetonide sustained release microsphere according to claim 7, wherein: the triamcinolone acetonide sustained release microsphere is obtained by mixing a water phase and an oil phase containing triamcinolone acetonide raw material medicine to form emulsion and solidifying, and the weight average molecular weight Mw of a polymer in the microsphere is controlled within the range of 8.5 kDa-12.5 kDa by adding dioctyl sodium succinate sulfonate into the oil phase and controlling the weight ratio of the dioctyl sodium succinate sulfonate to the triamcinolone acetonide raw material medicine to be 1:2-2:1.
9. The triamcinolone acetonide sustained release microsphere according to claim 7, wherein: the medicine carrying amount of the triamcinolone acetonide sustained-release microsphere is in the range of 24.5% -25.0%, and the solvent residue rate is less than or equal to 0.04%.
10. The triamcinolone acetonide sustained release microsphere according to claim 7, wherein: the particle size D10 of the triamcinolone acetonide sustained-release microsphere is in the range of 24.5-28.0 mu m, and the particle size D90 is in the range of 70.0-72.5 mu m.
11. A sustained release triamcinolone acetonide formulation for use in the treatment of arthritic pain, characterized in that: the triamcinolone acetonide sustained release preparation contains the triamcinolone acetonide sustained release microsphere as claimed in any one of claims 7 to 10.
12. A sustained release formulation of triamcinolone acetonide for use in the treatment of arthritic pain of claim 11, wherein: the triamcinolone acetonide sustained release preparation is a suspension prepared by uniformly mixing a sterile diluent and triamcinolone acetonide sustained release microspheres, wherein the sterile diluent is an aqueous solution containing 0.9 mass percent of sodium chloride, 0.5 mass percent of sodium carboxymethyl cellulose and 0.1 mass percent of tween 80.
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| CN110237052A (en) * | 2019-07-11 | 2019-09-17 | 苏州大学 | A kind of triamcinolone acetonide acetate sustained-release micro-spheres and preparation method thereof |
| CN112972753A (en) * | 2019-12-02 | 2021-06-18 | 太阳雨林（厦门）生物医药有限公司 | Sustained-release embolism microsphere for treating bronchiectasis hemoptysis caused by chronic inflammation |
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| CN110237052A (en) * | 2019-07-11 | 2019-09-17 | 苏州大学 | A kind of triamcinolone acetonide acetate sustained-release micro-spheres and preparation method thereof |
| CN112972753A (en) * | 2019-12-02 | 2021-06-18 | 太阳雨林（厦门）生物医药有限公司 | Sustained-release embolism microsphere for treating bronchiectasis hemoptysis caused by chronic inflammation |
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