CN116999412A - Sustained-release microsphere preparation containing betamethasone medicine and preparation method thereof - Google Patents
Sustained-release microsphere preparation containing betamethasone medicine and preparation method thereof Download PDFInfo
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- CN116999412A CN116999412A CN202310972502.XA CN202310972502A CN116999412A CN 116999412 A CN116999412 A CN 116999412A CN 202310972502 A CN202310972502 A CN 202310972502A CN 116999412 A CN116999412 A CN 116999412A
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- 239000004005 microsphere Substances 0.000 title claims abstract description 185
- 239000003814 drug Substances 0.000 title claims abstract description 112
- 229960002537 betamethasone Drugs 0.000 title claims abstract description 94
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 title claims abstract description 94
- 238000013268 sustained release Methods 0.000 title claims abstract description 61
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- 229920001577 copolymer Polymers 0.000 claims abstract description 28
- 239000000463 material Substances 0.000 claims abstract description 11
- 239000011148 porous material Substances 0.000 claims abstract description 7
- 239000002245 particle Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000012530 fluid Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 239000007764 o/w emulsion Substances 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- 125000005456 glyceride group Chemical group 0.000 claims description 8
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000006185 dispersion Substances 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical group OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 229960004648 betamethasone acetate Drugs 0.000 claims description 2
- AKUJBENLRBOFTD-QZIXMDIESA-N betamethasone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]1(C)C[C@@H]2O AKUJBENLRBOFTD-QZIXMDIESA-N 0.000 claims description 2
- 229960001102 betamethasone dipropionate Drugs 0.000 claims description 2
- CIWBQSYVNNPZIQ-XYWKZLDCSA-N betamethasone dipropionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CIWBQSYVNNPZIQ-XYWKZLDCSA-N 0.000 claims description 2
- 229960005354 betamethasone sodium phosphate Drugs 0.000 claims description 2
- PLCQGRYPOISRTQ-LWCNAHDDSA-L betamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-LWCNAHDDSA-L 0.000 claims description 2
- 229960004311 betamethasone valerate Drugs 0.000 claims description 2
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 229920001992 poloxamer 407 Polymers 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 39
- 238000002347 injection Methods 0.000 abstract description 17
- 239000007924 injection Substances 0.000 abstract description 17
- 230000009471 action Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 230000005847 immunogenicity Effects 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 abstract 1
- 239000007864 aqueous solution Substances 0.000 description 14
- 230000001276 controlling effect Effects 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 238000011068 loading method Methods 0.000 description 12
- 238000010008 shearing Methods 0.000 description 12
- 238000005303 weighing Methods 0.000 description 12
- 238000005538 encapsulation Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000001878 scanning electron micrograph Methods 0.000 description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 238000001514 detection method Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 230000037303 wrinkles Effects 0.000 description 3
- 241001260012 Bursa Species 0.000 description 2
- 206010006811 Bursitis Diseases 0.000 description 2
- 206010050296 Intervertebral disc protrusion Diseases 0.000 description 2
- 206010034464 Periarthritis Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 208000000491 Tendinopathy Diseases 0.000 description 2
- 208000004760 Tenosynovitis Diseases 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005297 material degradation process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 210000002435 tendon Anatomy 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 208000023835 Tendon disease Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 230000036544 posture Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 208000013515 tendinosis Diseases 0.000 description 1
Classifications
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- 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
- A61K9/5089—Processes
-
- 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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a sustained-release microsphere preparation containing betamethasone medicine, which takes polylactic acid-glycolic acid copolymer as a base material and betamethasone medicine as an effective medicine component, and the sustained-release microsphere of the betamethasone medicine with a hole structure and uniform particle size is obtained by a microfluidic technology. The betamethasone-polylactic acid-glycolic acid copolymer microsphere prepared by the invention has folds on the surface, is easy to adhere on the cell surface, has pore channels inside the prepared microsphere, is beneficial to slow release of the drug compared with the material, can prolong the action time of the drug, avoid frequent injection, reduce the compliance of the drug and reduce the side effect of the drug; the polylactic acid-glycolic acid copolymer is adopted as the base material of the microsphere, so that the microsphere has good biocompatibility and lower immunogenicity, can be completely degraded in vivo, and is nontoxic and harmless to organisms; the micro-fluidic preparation technology is adopted, the prepared microsphere has uniform and controllable size, small batch-to-batch difference, good repeatability and stable drug release.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a sustained-release microsphere preparation containing betamethasone medicine and a preparation method thereof.
Background
The human body generates concentrated stress locally in a movement system due to long-term, repeated and continuous postures or occupational actions, and when the compensatory capability is exceeded, slight damage is formed, and the accumulated and migrated bone joints, tendons, ligaments, fascia and bursa are caused to be chronically damaged, and the chronic injury clinically represents lesions such as lumbar disc herniation, tenosynovitis, scapulohumeral periarthritis, bursitis and tendinitis, and the like, and causes pain or continuous pain of relevant parts, even loses partial functions and reduces the life quality. Clinically, the diseases such as tenosynovitis, scapulohumeral periarthritis, bursitis, lumbar disc herniation, tendinosis and the like can be treated by injecting a known betamethasone injection into the parts such as bursa, tendon, tenosynovia, joint cavity, nerve plexus, epidural space and the like, so that the pain parts can be rapidly diminishing inflammation and easing pain. However, the existing betamethasone injection medicine has short effective action time and needs frequent injection medicine, so that the compliance of the medicine is poor, the auxiliary use of the medicine is more obvious, and the betamethasone injection medicine is extremely unfriendly to human bodies. The existing sustained release microsphere preparation can effectively prolong the acting time of the medicine. The main methods of the sustained-release microsphere preparation include a homogenizing emulsification method and a physical grinding method, and the prepared microsphere has wide particle size distribution, poor repeatability and large batch-to-batch difference, so that the drug release is unstable.
Disclosure of Invention
The invention aims to provide a sustained-release microsphere preparation containing betamethasone medicine, which has a microsphere hole structure and a fold structure.
The invention also aims to provide a specific preparation method of the sustained-release microsphere preparation containing the betamethasone medicine.
The invention is realized by the following technical scheme: a sustained-release microsphere preparation containing betamethasone medicine is prepared from polylactic acid-glycolic acid copolymer as base material, betamethasone medicine as effective component, and micro-fluidic technique to obtain sustained-release microsphere with pore structure and uniform particle diameter.
The technical scheme has the working principle that the micro-fluidic technology platform is used for adjusting the type content of the solvent in the disperse phase and the solvent volatilization process such as temperature to enable the solvent in the disperse liquid drops to be diffused and dissolved out in different forms and rates, so that the control preparation of the microsphere hole structure and the fold structure is realized, and the purpose of controlling the release of the medicine is achieved. The method for preparing the microsphere by the micro-fluidic technology is to produce liquid drops through micro-channels, flow immiscible continuous phases and disperse phases in the respective channels respectively by utilizing the driving force of volume or pressure, meet the two phases at the intersection of the channels, and utilize continuous relative disperse phases to perform extrusion or shearing action so as to promote unstable and broken interfaces and generate dispersed liquid drops with uniform size.
In order to better realize the invention, the betamethasone medicine is at least one of betamethasone, betamethasone acetate, betamethasone sodium phosphate, betamethasone valerate, betamethasone dipropionate and betamethasone propionate.
In order to better realize the invention, further, the inclusion amount of the effective drug components in the sustained-release microsphere of the betamethasone medicine is 1-50%.
In order to better realize the invention, the particle size of the sustained-release microsphere for preparing the betamethasone medicine is 10um to 1000um.
In order to better realize the invention, further, in the polylactic acid-glycolic acid copolymer, the molar ratio of lactic acid units to glycolic acid units is 95: 5-50: 50, the molecular weight is 5000Da to 120000Da, and the molecular weight distribution coefficient is 1 to 10.
The preparation method of the sustained-release microsphere preparation containing the betamethasone medicine comprises the following steps:
(1) Dissolving betamethasone medicine and polylactic acid-glycolic acid copolymer in an organic solvent to completely dissolve the betamethasone medicine and the polylactic acid-glycolic acid copolymer to form a transparent solution, preparing a dispersion phase, and temporarily storing the dispersion phase at the temperature of 4-10 ℃ for later use;
(2) Dissolving surfactant in water to obtain continuous phase, and temporarily storing at 4-10 deg.c;
(3) Injecting the disperse phase and the continuous phase into a microfluidic device through a pump respectively, controlling the fluid flow rate of the disperse phase, the fluid flow rate of the continuous phase and the temperature in the microfluidic device to obtain an oil-in-water emulsion, and temporarily storing the oil-in-water emulsion in a receiver containing a water phase to obtain semi-solidified microspheres;
(4) Placing the semi-cured microspheres in the receiver in a volatilizer, and continuously stirring at the temperature of 3-60 ℃ until the solvent is volatilized to obtain fully-cured microspheres;
(5) Washing the obtained fully-cured microspheres with pure water, sieving, collecting and drying to obtain the final product.
The microsphere prepared by the preparation method has a hole structure for releasing the medicine, and realizes the stable slow release of the medicine. Compared with the conventional sustained-release microsphere preparation for releasing the drug through material degradation, the microsphere with the structure releases the drug through the hole structure in the microsphere, has the advantage of releasing the drug stably, and solves the traditional problems that the drug effect cannot be achieved in the early stage of drug administration due to delayed release of the drug, and the drug is released suddenly through material degradation, so that the drug is excessive and has strong side effect. On a microfluidic technology platform, the pore structure and the size of the drug-carrying microsphere are effectively controlled by adjusting the types and the proportions of organic dissolution in a disperse phase, so that the controllable and stable release of the drug is realized, and the difficult problem of difficult release of the drug of the microsphere preparation is solved.
In order to better realize the method of the invention, further, the mass fraction of the betamethasone live medicine in the disperse phase is 0.1-15%, and the mass fraction of the polylactic acid-glycolic acid copolymer in the oil phase is 1-25%; the mass fraction of the surfactant in the continuous phase is 0.1-5%.
In order to better implement the method of the present invention, further, the mass fraction of the surfactant in the continuous phase is 0.5 to 2%.
In order to better implement the method of the present invention, further, the organic solvent for dissolving the betamethasone medicine and the polylactic acid-glycolic acid copolymer in the step (1) is one or a mixture of more of dichloromethane, caprylic capric glyceride, dimethyl sulfoxide, methanol, ethyl acetate, chloroform, diethyl ether, benzyl alcohol, N-dimethylformamide and N, N-dimethylacetamide.
In order to better realize the method of the invention, the surfactant in the step (2) is one or a mixture of any more of Pluronic F-127, sodium dodecyl sulfate and polyvinyl alcohol (polyvinyl alcohol).
In order to better implement the method of the present invention, further, in the step (3), the flow rate ratio between the dispersed phase and the continuous phase is 1:2-1:200, and the temperature in the microfluidic device is 4-35 ℃.
To better carry out the process of the invention, further, the flow ratio between the dispersed phase and the continuous phase is from 1:4 to 1:50.
In order to better implement the method of the present invention, further, in the step (4), the solvent volatilizes at a temperature of 4 to 55 ℃.
Compared with the prior art, the invention has the following advantages:
(1) The betamethasone-polylactic acid-glycolic acid copolymer microsphere prepared by the invention has the pore structure with the fold structure on the surface, so that the specific surface area of the microsphere is greatly increased, the medicine in the microsphere can be released slowly, the diffusion and volatilization temperature of the solvent can be regulated and controlled by regulating the component and the dosage of the oil phase, the controllable preparation of the fold degree on the surface of the microsphere and the size of the internal pore structure is realized, the control of the medicine release speed is realized, the control of different indications or diseases is facilitated, in addition, the microsphere can realize the slow release of the medicine, the action time of the medicine can be prolonged, the frequent injection of the medicine is avoided, the compliance of the medicine is reduced, and the side effect of the medicine is reduced;
(2) The polylactic acid-glycolic acid copolymer is adopted as the base material of the microsphere, has good biocompatibility and lower immunogenicity, can be completely degraded in vivo, and is nontoxic and harmless to organisms;
(3) The invention adopts the microfluidic preparation technology, the prepared microsphere has uniform and controllable size, small batch-to-batch difference, better repeatability and controllable and stable drug release.
Drawings
Other features, objects and advantages of the present invention will become more apparent upon reading of the detailed description of non-limiting embodiments, given with reference to the accompanying drawings in which:
FIG. 1 is an SEM image of the surface morphology of a slow release microsphere prepared in example 1 of the present invention;
FIG. 2 is an SEM image of the surface morphology of the slow release microspheres prepared in example 2 of the present invention;
FIG. 3 is an SEM image of the surface morphology of the slow release microspheres prepared in example 3 of the present invention;
FIG. 4 is an SEM image of the surface morphology of the slow release microspheres prepared in example 4 of the present invention;
FIG. 5 is an SEM image of the surface morphology of the slow release microspheres prepared in example 5 of the present invention;
FIG. 6 is an SEM image of the surface morphology of the slow release microspheres prepared in example 6 of the present invention;
FIG. 7 is an SEM image of the surface morphology of the slow release microspheres prepared in example 7 of the present invention;
FIG. 8 is an SEM image of the surface morphology of the slow release microspheres prepared in example 8 of the present invention;
FIG. 9 is an SEM image of the surface morphology of the slow release microspheres prepared in example 9 of the present invention;
FIG. 10 is an SEM image of the surface morphology of the slow release microspheres prepared in example 10 of the present invention;
FIG. 11 is an SEM image of the surface morphology of the slow release microspheres prepared in example 11 of the present invention;
FIG. 12 is a graph showing the cumulative release profile of the drug outside the microsphere containing betamethasone drug according to the present invention.
Detailed Description
In order to make the objects, process conditions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the following examples, but the embodiments of the present invention are not limited thereto, and various substitutions and modifications according to the general knowledge and conventional means of the art without departing from the technical spirit of the present invention, should be included in the scope of the present invention, and the specific examples described herein are only for explaining the present invention and are not limited thereto.
Example 1:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 61000, carboxyl end-capped), adding 11.8g of dichloromethane to dissolve, obtaining a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (4 ℃ for 1h,15 ℃ for 1h,25 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of the betamethasone medicine is observed by Scanning Electron Microscope (SEM) detection, as shown in figure 1, has no folds, but has no holes, and is formed by gradually shrinking the microsphere due to the fact that methylene dichloride in a disperse phase slowly diffuses into an aqueous solution at low temperature, so that the microsphere with a smooth surface is formed.
Example 2:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 61000, carboxyl end-capped), adding 10.62g of dichloromethane and 1.18g of methanol, mixing and dissolving to obtain a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (4 ℃ for 1h,15 ℃ for 1h,25 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of the betamethasone medicine is slightly wrinkled but no hole is generated as shown in figure 2 by detection and observation of a Scanning Electron Microscope (SEM), because the methanol has good water solubility, the added small amount of methanol diffuses into the water solution at low temperature more quickly, and the dichloromethane diffuses slowly, and the diffusion speed difference forms the surface wrinkled microsphere.
Example 3:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 61000, carboxyl end-capped), adding 10.62g of dichloromethane and 1.18g of methanol, mixing and dissolving to obtain a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (25 ℃ for 1h,35 ℃ for 1h,45 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of betamethasone medicine is detected and observed by a Scanning Electron Microscope (SEM), and as shown in figure 3, the surface of the microsphere is provided with folds and a certain number of holes. This is due to the good water solubility of methanol, which diffuses rapidly into the aqueous solution. And the boiling point of dichloromethane (39.8 ℃) is low, after the temperature is increased, the dichloromethane is gasified and leaks along the diffusion path of the methanol, and holes are formed in the microspheres.
Example 4:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 61000, carboxyl end-capped), adding 9.44g of dichloromethane and 2.36g of methanol, mixing and dissolving to obtain a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (25 ℃ for 1h,35 ℃ for 1h,45 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of betamethasone medicine is observed by Scanning Electron Microscope (SEM) detection, as shown in figure 4, the surface of the microsphere is provided with a large number of holes, because methanol has good water solubility, can be rapidly diffused into aqueous solution, has low boiling point (39.8 ℃) of dichloromethane, is gasified at a higher temperature, leaks along the diffusion path of the methanol, and forms holes in the microsphere. As more methanol is added to the oil phase, the pores formed in the microspheres are also increased.
Example 5:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 61000, carboxyl end-capped), adding 11.45g of dichloromethane and 0.35g of caprylic/capric glyceride, mixing and dissolving to obtain a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (25 ℃ for 1h,35 ℃ for 1h,45 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of the betamethasone medicine is observed by Scanning Electron Microscope (SEM) detection, as shown in figure 5, the surface of the sustained release microsphere is provided with a large number of holes, and the holes are formed because the caprylic capric glyceride is uniformly distributed in the microsphere, and the caprylic capric glyceride is removed by washing to form a large number of hole structures.
Example 6:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 61000, carboxyl end-capped), adding 10.86g of dichloromethane and 0.94g of caprylic/capric glyceride, mixing and dissolving to obtain a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (25 ℃ for 1h,35 ℃ for 1h,45 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of the betamethasone medicine is observed by Scanning Electron Microscope (SEM) detection, as shown in figure 6, the surface of the sustained release microsphere is provided with a large number of holes, and the holes are formed due to the fact that larger and more hole structures are formed with the increase of the content of the caprylic capric glyceride.
Example 7:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=75:25, molecular weight 74000, ester group end-capped), adding 11.8g of dichloromethane to dissolve, obtaining a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (4 ℃ for 1h,15 ℃ for 1h,25 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of betamethasone medicine was observed by Scanning Electron Microscope (SEM) examination, as shown in fig. 7, and was free of wrinkles, but also free of voids, and had a morphology similar to that of example 1. Therefore, the LA to GA ratio and the molecular weight of the PLGA material have little influence on the surface morphology of the drug-loaded microsphere.
Example 8:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=85:15, molecular weight 72000, carboxyl end-capped), adding 11.8g of dichloromethane to dissolve, obtaining a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (4 ℃ for 1h,15 ℃ for 1h,25 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of betamethasone medicine was observed by Scanning Electron Microscope (SEM) examination, and as shown in fig. 8, it had no wrinkles but also no holes, and its morphology was similar to that of example 1. Therefore, the LA to GA ratio and the molecular weight of the PLGA material have little influence on the surface morphology of the drug-loaded microsphere.
Example 9:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 11200, carboxyl end-capped), adding 11.8g of dichloromethane to dissolve, obtaining a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (4 ℃ for 1h,15 ℃ for 1h,25 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of betamethasone medicine was observed by Scanning Electron Microscope (SEM) examination, as shown in fig. 9, and was free of wrinkles, but also free of holes, and similar in morphology to example 1. Therefore, the molecular weight change of the PLGA material has little influence on the surface morphology of the drug-loaded microsphere.
Example 10:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 11200, carboxyl end-capped), adding 10.62g of dichloromethane and 1.18g of methanol, mixing and dissolving to obtain a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (25 ℃ for 1h,35 ℃ for 1h,45 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of betamethasone medicine is detected and observed by a Scanning Electron Microscope (SEM), as shown in figure 10, the surface of the microsphere is provided with folds and a certain number of holes, and the morphology of the microsphere is similar to that of the embodiment 3. Therefore, the molecular weight change of the PLGA material has little influence on the surface morphology of the drug-loaded microsphere.
Example 11:
the embodiment provides a preparation method of a sustained-release microsphere preparation containing betamethasone medicine, which comprises the following steps:
1) Weighing 0.52g of betamethasone and 2.08g of polylactic acid-glycolic acid copolymer (LA: GA=50:50, molecular weight 11200, carboxyl end-capped), adding 11.45g of dichloromethane and 0.35g of caprylic/capric glyceride, mixing and dissolving to obtain a clear oil phase solution, and standing at 10 ℃ for later use;
2) Preparing 0.5wt% polyvinyl alcohol aqueous solution which is water phase and keeping at 10 ℃ for standby;
3) Injecting an oil phase (disperse phase) fluid and a water phase (continuous phase) fluid into a microfluidic device by using an injection pump respectively, adjusting the flow rate of the oil phase to be 100 mu L/h and the flow rate of the water phase to be 2000 mu L/h, shearing the disperse phase by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion, and collecting to obtain semi-solidified microspheres; placing the mixture in a receiver, and controlling the whole-course temperature to be 10 ℃;
4) After the receiver is fully received, transferring the semi-solidified microspheres into a volatilizer, and starting stirring; starting a temperature control program (25 ℃ for 1h,35 ℃ for 1h,45 ℃ for 2 h), and volatilizing the organic solvent;
5) Washing with pure water, filtering, collecting wet microsphere, and drying to obtain microsphere product, i.e. betamethasone long-acting slow-release microsphere.
The sustained release microsphere of the betamethasone medicine is observed by Scanning Electron Microscope (SEM) detection, as shown in figure 11, and the surface of the sustained release microsphere is provided with a large number of holes, which is similar to the appearance of the example 5. Therefore, the molecular weight change of the PLGA material has little influence on the surface morphology of the drug-loaded microsphere.
Example 12:
aiming at the six sustained release microsphere preparations containing betamethasone medicines, the embodiment carries out in-vitro release detection experiments of the medicines, and the specific process is as follows:
1) Preparing 0.01mol/L physiological isotonic phosphate buffer solution, pH7.4, wherein the physiological isotonic phosphate buffer solution contains 0.05% poloxamer and 0.05% sodium azide);
2) Precisely weighing the sustained release microspheres containing betamethasone medicines prepared in examples 1-11, placing the sustained release microspheres in a test tube, adding the sustained release microspheres into 30mL of physiological isotonic phosphate buffer solution, and placing the microspheres in a constant-temperature shaking table at 37 ℃ for culture;
3) Sampling respectively, filtering the samples, and measuring the content of active drugs in the sample liquid medium respectively by adopting an HPLC-UV method.
The experimental results are shown in fig. 12, wherein the theoretical drug loading of the sustained-release microsphere preparation containing betamethasone medicine is 0.52/(0.52+2.08) =20%.
The actual drug loading of the microspheres in the example 1 group is 19.62 percent, and the encapsulation efficiency is 98.1 percent;
the actual drug loading of the microspheres in the example 2 group is 19.21%, and the encapsulation efficiency is 96.1%;
the actual drug loading of the microspheres in the group 3 is 19.08%, and the encapsulation efficiency is 95.4%;
the actual drug loading of the microspheres in the example 4 group is 18.68%, and the encapsulation efficiency is 93.4%;
the actual drug loading of the microspheres in the example 5 group is 18.46%, and the encapsulation efficiency is 92.3%;
the actual drug loading of the microspheres in the group 6 is 17.34% and the encapsulation efficiency is 86.7%.
The actual drug loading of the microspheres in the example 7 group is 19.57%, and the encapsulation efficiency is 97.8%.
The actual drug loading of the microspheres in the example 8 group is 19.41 percent, and the encapsulation efficiency is 97.0 percent.
The actual drug loading of the microspheres in the example 9 group is 19.48%, and the encapsulation efficiency is 97.4%.
The actual drug loading of the microspheres in the example 10 group is 18.98%, and the encapsulation efficiency is 94.9%.
The actual drug loading of the microspheres in the example 11 group is 18.52 percent, and the encapsulation efficiency is 92.6 percent.
While embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that: many changes, modifications, substitutions and variations may be made to the embodiments without departing from the spirit and principles of the invention, the scope of which is defined by the claims and their equivalents.
Claims (13)
1. The sustained-release microsphere preparation containing the betamethasone medicine is characterized in that the sustained-release microsphere with a pore structure and uniform particle size is obtained by taking polylactic acid-glycolic acid copolymer as a base material and taking the betamethasone medicine as an effective medicine component through a microfluidic technology.
2. The sustained-release microsphere preparation containing betamethasone medicine according to claim 1, wherein the betamethasone medicine is at least one of betamethasone, betamethasone acetate, betamethasone sodium phosphate, betamethasone valerate, betamethasone dipropionate and betamethasone propionate.
3. The sustained-release microsphere preparation containing the betamethasone medicine according to claim 1 or 2, wherein the inclusion amount of the effective medicine component in the sustained-release microsphere of the betamethasone medicine is 1-50%.
4. The sustained-release microsphere preparation containing the betamethasone medicine according to claim 1 or 2, wherein the particle size of the sustained-release microsphere of the betamethasone medicine is 10 um-1000 um.
5. The sustained release microsphere formulation containing betamethasone according to claim 1 or 2, wherein the molar ratio of lactic acid unit to glycolic acid unit in the polylactic acid-glycolic acid copolymer is 95: 5-50: 50, the molecular weight is 5000Da to 120000Da, and the molecular weight distribution coefficient is 1 to 10.
6. The method for preparing a sustained-release microsphere preparation containing betamethasone medicine according to any one of claims 1 to 5, comprising the following steps:
(1) Dissolving betamethasone medicine and polylactic acid-glycolic acid copolymer in an organic solvent to completely dissolve the betamethasone medicine and the polylactic acid-glycolic acid copolymer to form a transparent solution, preparing a dispersion phase, and temporarily storing the dispersion phase at the temperature of 4-10 ℃ for later use;
(2) Dissolving surfactant in water to obtain continuous phase, and temporarily storing at 4-10 deg.c;
(3) Injecting the disperse phase and the continuous phase into a microfluidic device through a pump respectively, controlling the fluid flow rate of the disperse phase, the fluid flow rate of the continuous phase and the temperature in the microfluidic device to obtain an oil-in-water emulsion, and temporarily storing the oil-in-water emulsion in a receiver containing a water phase to obtain semi-solidified microspheres;
(4) Placing the semi-cured microspheres in the receiver in a volatilizer, and continuously stirring at the temperature of 3-60 ℃ until the solvent is volatilized to obtain fully-cured microspheres;
(5) Washing the obtained fully-cured microspheres with pure water, sieving, collecting and drying to obtain the final product.
7. The method for preparing a sustained-release microsphere preparation containing a betamethasone medicine according to claim 6, wherein the mass fraction of the betamethasone medicine in a dispersed phase is 0.1-15%, and the mass fraction of the polylactic acid-glycolic acid copolymer in an oil phase is 1-25%; the mass fraction of the surfactant in the continuous phase is 0.1-5%.
8. The method for preparing a sustained-release microsphere preparation containing betamethasone according to claim 7, wherein the mass fraction of the surfactant in the continuous phase is 0.5-2%.
9. The method for preparing a sustained-release microsphere preparation containing betamethasone according to any one of claims 6-8, wherein the organic solvent used for dissolving the betamethasone and the polylactic acid-glycolic acid copolymer in the step (1) is one or more of dichloromethane, caprylic capric glyceride, dimethyl sulfoxide, methanol, ethyl acetate, chloroform, diethyl ether, benzyl alcohol, N-dimethylformamide and N, N-dimethylacetamide.
10. The method for preparing a sustained-release microsphere preparation containing betamethasone according to any one of claims 6-8, wherein the surfactant in the step (2) is one or a mixture of more of Pluronic F-127, sodium dodecyl sulfate and polyvinyl alcohol (polyvinyl alcohol).
11. The method for preparing a sustained-release microsphere preparation containing betamethasone according to any one of claims 6 to 8, wherein in the step (3), the flow rate ratio between the dispersed phase and the continuous phase is 1:2 to 1:200, and the internal temperature of the microfluidic device is 4 to 35 ℃.
12. The method for preparing a sustained-release microsphere preparation containing betamethasone according to claim 11, wherein the flow rate ratio between the dispersed phase and the continuous phase is 1:4-1:50.
13. The method for preparing a sustained-release microsphere preparation containing betamethasone according to any one of claims 6 to 8, wherein in the step (4), the solvent volatilizes at a temperature of 4 to 55 ℃.
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