CN114129542A - Polymer composite microsphere and preparation method and application thereof - Google Patents
Polymer composite microsphere and preparation method and application thereof Download PDFInfo
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- CN114129542A CN114129542A CN202111226284.2A CN202111226284A CN114129542A CN 114129542 A CN114129542 A CN 114129542A CN 202111226284 A CN202111226284 A CN 202111226284A CN 114129542 A CN114129542 A CN 114129542A
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- polymer
- water
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- 239000004005 microsphere Substances 0.000 title claims abstract description 76
- 239000002131 composite material Substances 0.000 title claims abstract description 52
- 229920000642 polymer Polymers 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 109
- 229940079593 drug Drugs 0.000 claims abstract description 98
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 82
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 30
- 239000002245 particle Substances 0.000 claims abstract description 28
- 239000011159 matrix material Substances 0.000 claims abstract description 17
- 229920005615 natural polymer Polymers 0.000 claims abstract description 16
- 229920002521 macromolecule Polymers 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 13
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- 239000007864 aqueous solution Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 26
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- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 claims description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 6
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 claims description 6
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- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims description 4
- 206010068516 Encapsulation reaction Diseases 0.000 claims description 4
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims description 4
- 229960003260 chlorhexidine Drugs 0.000 claims description 4
- 229920006237 degradable polymer Polymers 0.000 claims description 4
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims description 4
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 4
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 3
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- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims description 3
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims description 3
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- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 3
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- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 2
- 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
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229920000070 poly-3-hydroxybutyrate Polymers 0.000 claims description 2
- 229920002961 polybutylene succinate Polymers 0.000 claims description 2
- 239000004631 polybutylene succinate Substances 0.000 claims description 2
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 2
- 229960003292 rifamycin Drugs 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 235000019166 vitamin D Nutrition 0.000 claims description 2
- 239000011710 vitamin D Substances 0.000 claims description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 2
- 229940046008 vitamin d Drugs 0.000 claims description 2
- HODBJNPCEPMORW-UHFFFAOYSA-N 2,4,5-trichloro-3-phenoxyphenol Chemical compound OC1=CC(Cl)=C(Cl)C(OC=2C=CC=CC=2)=C1Cl HODBJNPCEPMORW-UHFFFAOYSA-N 0.000 claims 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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- 229910021641 deionized water Inorganic materials 0.000 description 10
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- 229910052757 nitrogen Inorganic materials 0.000 description 5
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- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
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- 238000006731 degradation reaction Methods 0.000 description 3
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- 229920000728 polyester Polymers 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- REKYPYSUBKSCAT-UHFFFAOYSA-N 3-hydroxypentanoic acid Chemical compound CCC(O)CC(O)=O REKYPYSUBKSCAT-UHFFFAOYSA-N 0.000 description 2
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 2
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- 229920000609 methyl cellulose Polymers 0.000 description 2
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
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Images
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- A—HUMAN NECESSITIES
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- 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
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- 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
- A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a polymer composite microsphere and a preparation method and application thereof. A polymeric composite microsphere comprising: the preparation raw materials of the microsphere matrix comprise hydrophobic degradable macromolecules; the drug particles are dispersed in the microsphere matrix and comprise hydrophobic drug cores and water-soluble polymer layers coated on the surfaces of the hydrophobic drug cores; the coating is wrapped on the surface of the microsphere matrix, and the preparation raw materials of the coating comprise natural polymers. The macromolecular composite microsphere can effectively improve the loading capacity, release amount and controlled release effect of the macromolecular composite microsphere on hydrophobic drugs by regulating and controlling the components.
Description
Technical Field
The invention belongs to the technical field of high-molecular drugs, and particularly relates to a high-molecular composite microsphere as well as a preparation method and application thereof.
Background
The biodegradable microspheres are micro spherical materials prepared by utilizing bioabsorbable materials, are influenced by the properties of raw materials and processing technology, have particle sizes mainly distributed between dozens of nanometers and hundreds of micrometers, and are neat in shape and uniform in dispersion. With the development of the drug preparation technology, biodegradable microspheres have become a representative of 3 rd generation drug preparations, can be used as carriers for loading drugs, and slowly release the drugs through active degradation; the Chinese medicinal composition also has the remarkable advantages of short medicament taking period, long medicament action time, high safety, good curative effect and the like, and attracts more and more researchers.
The biodegradable microspheres can be mainly used for preparing wound dressings, stent materials and drug carriers. The preparation method has the advantages of adjustable particle size and free application form, so that the preparation method can be used for preparing wound dressings and can be filled in irregular tissue defects, and the micro-nano structure and the porous structure of the preparation method are favorable for adhesion and proliferation of cells, so that tissue reconstruction is accelerated. Because of the controllable degradability, when the modified polyvinyl alcohol is used as a drug carrier, the modified polyvinyl alcohol can improve the solubility of the drug and carry out local sustained release of the drug, thereby prolonging the half-life period of the drug.
The main materials for preparing the biodegradable microspheres can be classified into inorganic materials, natural high molecular materials and synthetic polymer materials. The degradable polyester is a biodegradable synthetic polymer material which is most researched and widely applied at present, and specific materials comprise polylactic acid, polyglycolic acid, poly epsilon-caprolactone, poly beta-hydroxybutyric acid, poly beta-hydroxyvaleric acid and copolymers thereof. The degradable polyester is basically a hydrophobic material, which has made a remarkable progress in the field of controlled release of hydrophilic drugs, but the main component of human body fluid is water, so if the degradable polyester is used as a carrier of a hydrophobic drug, the release resistance of the hydrophobic drug is increased, and the expected curative effect of the hydrophobic drug cannot be achieved.
In order to improve the problems in the related art, two ideas are provided, one is that a hydrophobic macromolecule is still adopted as a carrier material of a hydrophobic drug, but a drug-loaded microsphere with a porous communicated structure is prepared on the drug-loaded material to improve the release amount of the hydrophobic drug, and the batch stability of the degradable microsphere prepared by the method is poor; secondly, water-soluble polymers such as chitosan, sodium alginate, hyaluronic acid, gelatin and the like are used as carrier materials of the hydrophobic drugs, but the degradation behaviors of the water-soluble polymers are uncontrollable, so that phenomena such as over-high burst release and the like which are not beneficial to controlled release of the drugs are easily caused.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides the polymer composite microsphere, and the loading amount, the release amount (the release percentage of the hydrophobic drug when the release balance is achieved) and the controlled release effect of the polymer composite microsphere on the hydrophobic drug can be effectively improved through the regulation and control of the components.
The invention also provides a preparation method of the polymer composite microsphere.
The invention also provides application of the polymer composite microspheres in preparation of medicines for treating tissue injury, gastrointestinal diseases and cardiovascular and cerebrovascular diseases.
According to an aspect of the present invention, there is provided a polymer composite microsphere, comprising:
the preparation raw materials of the microsphere matrix comprise hydrophobic degradable macromolecules;
the drug particles are dispersed in the microsphere matrix and comprise hydrophobic drug cores and water-soluble polymer layers coated on the surfaces of the hydrophobic drug cores;
the coating is wrapped on the surface of the microsphere matrix, and the preparation raw materials of the coating comprise natural polymers.
According to a preferred embodiment of the present invention, at least the following advantages are provided:
(1) the drug particles of the invention utilize water-soluble macromolecule layers to coat hydrophobic drugs, and the drug particles are dispersed in a hydrophobic microsphere matrix, and the surface of the hydrophobic microsphere matrix is also coated with a hydrophilic film layer formed by hydrophilic natural macromolecules; in conclusion, the invention can achieve the purpose of controlling the release of the hydrophobic drug by blending the hydrophobic substance and the hydrophilic substance; in addition, the addition of hydrophilic raw materials (including the film layer and the water-soluble polymer layer) can improve the contact area between the hydrophobic drug and the liquid sustained-release medium (mainly water), thereby effectively improving the release amount of the hydrophobic drug.
(2) The raw materials for preparing the film layer comprise natural polymers, so that the surface of the obtained polymer composite microsphere has good biocompatibility and bioactivity, and the biocompatibility of the film layer used as a plant intervention substance is favorably improved.
(3) The water-soluble polymer layer can be combined with the hydrophobic drug in non-covalent bond forms such as electrostatic force, hydrogen bond, hydrophilic and hydrophobic acting force and the like, so that the affinity of the water-soluble polymer layer to the hydrophobic drug is improved, and the degradation performance of the microsphere matrix is not influenced.
(4) In the prepared macromolecular composite microsphere, the release speed of the hydrophobic drug is 0.5-30%/day, and long-term effective drug delivery is realized.
In some embodiments of the present invention, the particle size of the polymer composite microsphere is between 1 μm and 200 μm.
In some embodiments of the present invention, the mass ratio of the hydrophobic drug to the water-soluble polymer layer is 1 (1-9).
In some embodiments of the invention, the hydrophobic drug is selected from at least one of resveratrol, vitamin D, N-acetyl-5-methoxytryptamine (melatonin), naringin, 3- [ [ (4-methyl-1-piperazinyl) imino ] methyl ] -rifamycin (rifampin), triclosan (triclosan), and chlorhexidine (chlorhexidine).
In some embodiments of the present invention, the raw material for preparing the water-soluble polymer layer includes at least one of carboxymethyl chitosan, hyaluronic acid, polyvinyl alcohol, albumin, polyethyleneimine, and sodium carboxymethyl cellulose.
The preparation raw materials of the water-soluble polymer layer selected by the invention are charged, so that the formed drug particles are also charged, and due to the action of charge repulsion, the uniform distribution of the drug particles in the microsphere matrix can be improved, and the burst release of the hydrophobic drug is avoided.
The water-soluble polymer selected by the invention has amphiphilicity, and can adjust the release speed of the hydrophobic drug and also adjust the distribution of the hydrophobic drug in the microsphere matrix.
In some embodiments of the present invention, the mass ratio of the water-soluble polymer layer to the microsphere matrix is 1: (2-15).
In some embodiments of the present invention, the hydrophobic degradable polymer is at least one selected from the group consisting of poly-3-hydroxyalkanoate, polylactic acid, polycaprolactone, poly-lactic-co-glycolic acid, poly-3-hydroxybutyrate-co-3-hydroxyvalerate, poly (3-hydroxybutyrate), polybutylene succinate and polytrimethylene carbonate.
In some embodiments of the present invention, the hydrophobic degradable macromolecule has an average molecular weight of between 3000 and 150000 daltons.
In some preferred embodiments of the present invention, the average molecular weight of the hydrophobic degradable macromolecule is between 5000 and 100000 daltons.
Controlling the mass ratio of the hydrophobic drug to the water-soluble polymer layer within 1 (1-9), and controlling the mass ratio of the water-soluble polymer layer to the microsphere matrix within 1: and (2) within 15), the high drug loading capacity of the polymer composite microspheres can be realized, the release amount of the hydrophobic drug can be improved, and the optimal controlled release effect on the hydrophobic drug can be achieved.
In some embodiments of the invention, the natural macromolecule comprises at least one of chitosan, dopamine, chitosan hydrochloride, type I collagen, and type II collagen.
The natural polymer has excellent hydrophilicity, and can balance the hydrophilic and hydrophobic properties of the obtained polymer composite microspheres. According to another aspect of the present invention, a method for preparing the polymer composite microsphere is provided, which comprises the following steps:
s1, wrapping the hydrophobic drug with a water-soluble polymer to obtain drug particles;
s2, dispersing the medicine particles in the organic solution of the hydrophobic degradable macromolecules;
s3, dispersing the mixture obtained in the step S2 into an aqueous solution of a surfactant to obtain a precipitate;
and S4, dispersing the precipitate obtained in the step S3 into the water solution of the natural polymer to obtain the precipitate.
The preparation method according to a preferred embodiment of the present invention has at least the following advantageous effects:
the preparation method provided by the invention has the advantages of simple process, low requirement on equipment, industrialized raw materials, easily-obtained sources, low cost and easiness in realizing industrialization.
In some embodiments of the present invention, in step S1, the hydrophobic drug is dispersed in the aqueous solution of the water-soluble polymer, and an encapsulation reaction is performed.
In some embodiments of the present invention, the water-soluble polymer in the aqueous solution of water-soluble polymer has a mass concentration of 0.06 to 0.2 g/mL.
In some embodiments of the present invention, in the encapsulation reaction, a volume ratio of the mass of the hydrophobic drug to the aqueous solution of the water-soluble polymer is 1 g: (10-100) ml.
In some embodiments of the present invention, the hydrophobic drug is dispersed by stirring at 10000-30000 rpm.
In some embodiments of the present invention, the hydrophobic drug is dispersed for 5-15 min.
In some embodiments of the invention, the temperature of the coating reaction is 20 to 95 ℃.
In some embodiments of the present invention, the time of the coating reaction is 1 to 6 hours.
In some embodiments of the invention, the encapsulation reaction is carried out under stirring conditions.
In some embodiments of the present invention, the coating reaction is performed under stirring conditions at a rotation speed of 800rpm to 3000rpm, and a specific stirring rotation speed may also be 1000 rpm.
When the water-soluble polymer is carboxymethyl chitosan, the coating reaction is carried out under the action of a catalyst.
In some embodiments of the invention, the catalyst is sodium hydroxide.
The catalyst can promote the cross-linking reaction of carboxyl and amino in the carboxymethyl chitosan.
In some embodiments of the present invention, the coating step S1 further comprises washing and drying the obtained drug particles after the coating reaction.
In some embodiments of the present invention, in step S2, the dispersing method is stirring, and the stirring speed is 5000 to 18000 rpm.
In some embodiments of the present invention, in step S2, the dispersion time is 2min to 8 min.
In some embodiments of the present invention, in step S2, the mass volume concentration of the hydrophobic degradable macromolecule in the organic solution is (1-4) g: 10 ml.
In some embodiments of the present invention, in step S2, the mass-to-volume ratio of the drug particles to the organic solution of the hydrophobic degradable polymer is about (0.01-0.04) g/ml.
In some embodiments of the present invention, in step S2, the solvent of the organic solution of the hydrophobic degradable polymer is at least one of dichloromethane, chloroform, ethyl acetate and tetrahydrofuran.
In some embodiments of the present invention, in step S3, the dispersing method is stirring, and the stirring speed is 200 to 1500 rpm.
In some embodiments of the present invention, in step S3, the dispersion time is 15h to 30 h.
In some embodiments of the invention, in step S3, the volume ratio of the mixture to the aqueous solution of the surfactant is 1: (20-60).
In some embodiments of the invention, in step S3, the surfactant is selected from at least one of polyvinyl alcohol, gelatin, tween, methyl cellulose and span.
In some embodiments of the present invention, in step S3, the surfactant in the aqueous solution of the surfactant accounts for 0.5 to 2.5% by mass.
In some embodiments of the present invention, in step S4, the dispersing method is stirring, and the stirring speed is 300 to 800 rpm.
In some embodiments of the invention, in the step S4, the time period of the dispersion is 2-6 h.
In some embodiments of the present invention, in step S4, the mass-to-volume ratio of the precipitate to the aqueous solution of the natural macromolecule is 1 mg: (0.1-1) ml.
In some embodiments of the present invention, in step S4, the concentration of the natural polymer in the aqueous solution of the natural polymer is 1 g: (50-200) ml.
In some embodiments of the present invention, step S4 further comprises washing and drying the obtained precipitate after the obtaining of the precipitate.
In some embodiments of the invention, the method of drying is freeze-drying.
In some embodiments of the invention, the drying time is between 24h and 72 h.
According to another aspect of the invention, the application of the polymer composite microspheres in preparing medicines for treating tissue injury, gastrointestinal diseases and cardiovascular and cerebrovascular diseases is provided.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 is a diagram showing in vitro solute release performance of polymer composite microspheres obtained in examples 1 to 5 of the present invention and comparative examples 1 to 5.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
Example 1
The embodiment prepares the polymer composite microsphere by the following specific processes:
D1. mixing 100mg naringin with 4mL of 100mg/mL polyethyleneimine-containing aqueous solution, and stirring at 20000rpm for 8 min;
stirring at the rotation speed of 3000rpm for 2h at the temperature of 60 ℃ under the protection of nitrogen, and carrying out wrapping reaction;
after the reaction is finished, centrifugally cleaning the mixture for 5 times by using deionized water (the mass-volume ratio of the cleaning solid to the deionized water is 1:200g/ml) and freeze-drying the mixture for 48 hours to obtain medicine particles;
D2. dissolving 2g of polylactic acid-glycolic acid copolymer (molecular weight about 3 kilodalton) in 10mL of dichloromethane, adding 4000mg of the drug granules obtained in step D1 thereto, and stirring at 10000rpm for 5 min;
D3. pouring the mixture obtained in the step D2 into 300mL of aqueous solution containing 1% of polyvinyl alcohol 1799, continuously stirring at 300rpm for 24h, and centrifuging to obtain a precipitate;
D4. dispersing 1g of the precipitate obtained in step D3 into 100ml of an aqueous solution containing 1% chitosan (stirring at 600rpm for 3 h); the product is washed with water and centrifuged for 3 times (each time the centrifugation conditions are 3000rpm, 20min, 10 ℃), the precipitated product is collected, and the polymer composite microspheres are obtained after freeze drying for 48 h.
Example 2
The embodiment prepares the polymer composite microsphere by the following specific processes:
D1. mixing 100mg melatonin with 4.5mL of aqueous solution containing 200mg/mL carboxymethyl chitosan, and stirring at 12000rpm for 10 min;
pouring the mixture into 1mol/L sodium hydroxide solution at the temperature of 95 ℃ under the protection of nitrogen, and continuously stirring the mixture at 2500rpm for 4 hours;
after the reaction is finished, centrifugally cleaning the mixture for 7 times by using deionized water (the mass-volume ratio of the solid to the deionized water is 1:150g/ml), and freeze-drying the mixture for 48 hours to obtain medicine particles;
D2. dissolving 3.6g of poly-3-hydroxybutyrate-co-3-hydroxyvalerate (molecular weight about 15 kilodaltons) in 10mL of tetrahydrofuran, adding 800mg of the drug particles obtained in step D1, and stirring at 18000rpm for 2 min;
D3. pouring the mixture obtained in the step D2 into 400mL of aqueous solution containing 0.8% of polyvinyl alcohol 1788, continuously stirring at 1500rpm for 15h, and centrifuging to obtain a precipitate;
D4. dispersing 0.6g of the precipitate obtained in step D3 into 100ml of an aqueous solution containing 1.2% type I collagen (stirring at 300rpm for 6 h); the product is washed with water and centrifuged for 3 times (each time the centrifugation conditions are 3000rpm, 20min, 10 ℃), the precipitated product is collected, and the polymer composite microspheres are obtained after 24h of freeze drying.
Example 3
The embodiment prepares the polymer composite microsphere by the following specific processes:
D1. mixing 100mg of resveratrol with 10mL of polyethyleneimine aqueous solution containing 70mg/mL, and stirring at 18000rpm for 15 min;
stirring at 4000rpm for 1h at 60 ℃ under the protection of nitrogen to perform wrapping reaction;
after the reaction is finished, centrifugally cleaning the obtained solid substance by using deionized water (the mass volume ratio of the solid substance to the deionized water is 1:250g/ml) for 8 times, and then freeze-drying for 48 hours to obtain medicine particles;
D2. dissolving 1.4g of polylactic acid (molecular weight about 0.3 ten thousand daltons) in 10mL of methylene chloride, adding 600mg of the drug particles obtained in step D1 thereto, and stirring at 12000rpm for 8 min;
D3. pouring the mixture obtained in the step D2 into 200mL of aqueous solution containing 1.5% of methylcellulose, continuously stirring at 1000rpm for 18h, and centrifuging to obtain a precipitate;
D4. dispersing 0.5g of the precipitate obtained in step D3 into 100ml of an aqueous solution containing 0.5% chitosan (stirring at 400rpm for 4 h); the product is washed by water and centrifuged for 3 times (each time the centrifugation condition is 3000rpm, 20min, 10 ℃), the precipitated product is collected, and the molecular composite microspheres are obtained after freeze drying for 36 h.
Example 4
The embodiment prepares the polymer composite microsphere by the following specific processes:
D1. mixing 100mg rifampicin with 5mL of 60mg/mL polyethyleneimine-containing aqueous solution, and stirring at 10000rpm for 12 min;
stirring at 3000rpm for 2h at room temperature (about 25 ℃) under the protection of nitrogen for wrapping reaction;
after the reaction is finished, centrifugally cleaning the obtained solid substance for 5 times by using deionized water (the mass-volume ratio of the solid substance to the deionized water is 1:200g/ml), and freeze-drying for 48 hours to obtain medicine particles;
D2. dissolving 3g of polylactic acid-glycolic acid copolymer (molecular weight about 5 kilodalton) in 10mL of tetrahydrofuran, adding 300mg of the drug granules obtained in step D1, and stirring at 5000rpm for 7 min;
D3. pouring the mixture obtained in the step D3 into 600mL of aqueous solution containing 1.2% of gelatin, continuously stirring at 450rpm for 30h, and centrifuging to obtain a precipitate;
D4. dispersing 0.8g of the precipitate obtained in step D3 into 100ml of an aqueous solution containing 2% dopamine (stirring at 300rpm for 2 h); and (3) washing the solid product with water and centrifuging for three times (the centrifugation conditions are 3000rpm, 20min and 10 ℃ for each time), collecting the precipitate, and freeze-drying for 72 hours to obtain the polymer composite microspheres.
Example 5
The embodiment prepares the polymer composite microsphere by the following specific processes:
D1. mixing chlorhexidine 100mg with carboxymethyl chitosan solution 1mL containing 100m/mL, and stirring at 30000rpm for 6 min;
pouring the mixture into 1mol/L sodium hydroxide solution at 90 ℃ under the protection of nitrogen, and stirring at 2000rpm for 6 h;
after the reaction is finished, centrifugally cleaning the mixture for 6 times by using deionized water (the mass-volume ratio of the solid to the deionized water is 1:150g/ml), and freeze-drying the mixture for 48 hours to obtain medicine particles;
D2. dissolving 1.5g polycaprolactone (molecular weight about 6 kilodalton) in 10mL chloroform, adding 100mg of the drug granules obtained in step D1, and stirring at 8000rpm for 8 min;
D3. pouring the mixture obtained in the step D2 into 500mL of aqueous solution containing 2.5% of gelatin, continuously stirring at 600rpm for 24h, and centrifuging to obtain a precipitate;
D4. dispersing 0.1g of the precipitate obtained in step D3 into 100ml of an aqueous solution containing 1.5% chitosan hydrochloride (stirring at 800rpm for 2 h); washing the obtained solid product with water, centrifuging for 3 times (each time centrifuging at 3000rpm, 20min, 10 deg.C), collecting precipitate, and freeze drying for 48h to obtain polymer composite microsphere.
Comparative example 1
The comparative example prepares a polymer composite microsphere, and the specific process is different from that of example 1:
(1) step D1 is not included;
(2) in step D2, 4000mg of the drug granules obtained in step D1 were replaced with 100mg of naringin.
Comparative example 2
The comparative example prepares a polymer composite microsphere, and the specific process is different from that of example 1:
"dispersing 1g of the precipitate obtained in step D3 into 100ml of an aqueous solution containing 10% chitosan" in step D4 was excluded; directly washing the product obtained in the step D3 with water and centrifuging and the like.
Comparative example 3
The comparative example prepares a polymer composite microsphere, and the specific process is different from that of example 1:
(1) step D1 is not included;
(2) in step D2, 4000mg of the drug granules obtained in step D1 were replaced with 100mg of naringin.
(3) "dispersing 1g of the precipitate obtained in step D3 into 100ml of an aqueous solution containing 1% chitosan" in step D4 was excluded; directly washing the product obtained in the step D3 with water and centrifuging and the like.
Comparative example 4
The comparative example prepares a polymer composite microsphere, and the specific process is different from that of example 1:
in step D2, the drug granules obtained in step D1 were changed from 4000mg to 8000 mg.
Comparative example 5
The comparative example prepares a polymer composite microsphere, and the specific process is different from that of example 1:
(1) in the step D2, changing the medicine particles obtained in the step D1 from 4000mg to 8000 mg;
(2) "dispersing 1g of the precipitate obtained in step D3 into 100ml of an aqueous solution containing 1% chitosan" in step D4 was excluded; directly washing the product obtained in the step D3 with water and centrifuging and the like.
Test examples
The test example tests the performance of the polymer composite microspheres prepared in the examples and comparative examples. The specific method and the result are as follows:
the polymer composite microspheres prepared in examples 1 to 5 and comparative examples 1 to 5 were evaluated for solute release in vitro, and the results are shown in fig. 1.
Environment: the temperature is 37 ℃, the stirring speed is 60rpm, and the temperature control device is a constant temperature shaking table;
liquid slow-release medium: PBS (pH 7.4 phosphate buffer);
the proportion is as follows: 50mg of polymer composite microspheres: 20 mLPBS;
determination of the Release Rate of hydrophobic drugs: periodically collecting PBS test solution, supplementing PBS with equal amount, and measuring solute (hydrophobic drug) content of the collected test solution by High Performance Liquid Chromatography (HPLC);
substituting the absorbance of the solute at a certain time point into the standard curve to obtain the actual amount of the hydrophobic drug at the time point; and dividing the actual amount by the total amount of the hydrophobic drug loaded in the polymer composite microspheres to obtain the cumulative release amount of the hydrophobic drug at the time point.
As can be seen from FIG. 1, compared with comparative examples 1 to 5, examples 1 to 5 all have normal hydrophobic drug release behavior, and the release curve of example 1 is the most stable, which proves that the polymer composite microspheres pre-coated with the hydrophobic drug by the water-soluble polymer prepared by the method of the present invention have an obvious regulation effect on the release effect of the hydrophobic drug, and the release rate of the hydrophobic drug can be 0.5% to 30% per day;
compared with example 1, in comparative example 1, naringin is directly dispersed in the polylactic acid-glycolic acid copolymer solution, the hydrophobic drug is not coated by the water-soluble polymer, and the release of the hydrophobic drug in the polymer composite microsphere without the water-soluble polymer layer is very slow.
Comparative example 2, which did not use a natural polymer for the encapsulation treatment, resulted in the release of the hydrophobic drug also being slower, compared to example 1.
In comparison with example 1, comparative example 3, which neither coated the hydrophobic drug with the water-soluble polymer nor surface-coated with the natural polymer, released the hydrophobic drug the slowest.
Compared with the example 1, the comparative example 4, step D2, in which too many drug particles are added, greatly increases the specific surface area of the polymer composite microsphere where the hydrophobic drug contacts the sustained-release medium (PBS), and causes a severe burst release phenomenon.
Compared with example 1, the drug particles added in step D2 of comparative example 5 are too many, and although natural polymer is not used to wrap the microspheres, the specific surface area of the polymer composite microspheres where the hydrophobic drug can contact with the sustained release medium is greatly increased, and the burst release phenomenon also occurs.
The release amounts of the hydrophobic drugs in fig. 1 are shown in table 1.
TABLE 1 in vitro release Properties of hydrophobic drugs in Polymer composite microspheres obtained in examples and comparative examples
The results of the examples and comparative examples show that only the components of the present invention cooperate with each other to enhance the release amount of the hydrophobic drug and simultaneously control the release of the hydrophobic drug.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A polymer composite microsphere, comprising:
the preparation raw materials of the microsphere matrix comprise hydrophobic degradable macromolecules;
the drug particles are dispersed in the microsphere matrix and comprise hydrophobic drug cores and water-soluble polymer layers coated on the surfaces of the hydrophobic drug cores;
the coating is wrapped on the surface of the microsphere matrix, and the preparation raw materials of the coating comprise natural polymers.
2. The polymer composite microsphere according to claim 1, wherein the particle size of the polymer composite microsphere is between 1 μm and 200 μm.
3. The polymer composite microsphere according to claim 1, wherein the mass ratio of the hydrophobic drug to the water-soluble polymer layer is 1 (1-9); preferably, the hydrophobic drug is selected from at least one of resveratrol, vitamin D, N-acetyl-5-methoxytryptamine, naringin, 3- [ [ (4-methyl-1-piperazinyl) imino ] methyl ] -rifamycin (rifampin), dichlorophenoxy chlorophenol, and chlorhexidine; preferably, the raw material for preparing the water-soluble polymer layer comprises at least one of carboxymethyl chitosan, hyaluronic acid, polyvinyl alcohol, albumin, polyethyleneimine and sodium carboxymethyl cellulose.
4. The polymer composite microsphere according to claim 1, wherein the mass ratio of the water-soluble polymer layer to the microsphere matrix is 1: (2-15); preferably, the hydrophobic degradable macromolecule is selected from at least one of poly-3-hydroxyalkanoate, polylactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, poly-3-hydroxybutyrate-co-3-hydroxyvalerate, poly (3-hydroxybutyrate), polybutylene succinate and polytrimethylene carbonate; preferably, the average molecular weight of the hydrophobic degradable macromolecule is between 3000 and 150000 daltons.
5. The polymeric composite microsphere according to claim 1, wherein said natural polymer comprises at least one of chitosan, dopamine, chitosan hydrochloride, type I collagen and type II collagen.
6. A method for preparing polymer composite microspheres according to any one of claims 1 to 5, comprising the following steps:
s1, wrapping the hydrophobic drug with a water-soluble polymer to obtain drug particles;
s2, dispersing the medicine particles in the organic solution of the hydrophobic degradable macromolecules;
s3, dispersing the mixture obtained in the step S2 into an aqueous solution of a surfactant to obtain a precipitate;
and S4, dispersing the precipitate obtained in the step S3 into the water solution of the natural polymer to obtain the precipitate.
7. The process according to claim 6, wherein in step S1, the hydrophobic drug is dispersed in an aqueous solution of the water-soluble polymer and an encapsulation reaction is carried out; preferably, the dispersing method of the hydrophobic drug is stirring, and the rotating speed of the stirring is 10000-30000 rpm; preferably, the dispersion time of the hydrophobic drug is 5-15 min.
8. The method according to claim 6, wherein in step S2, the dispersing method is stirring, and the stirring speed is 5000 to 18000 rpm; preferably, in step S2, the dispersing time is 2min to 8 min; preferably, in step S2, the mass-to-volume ratio of the drug particles to the organic solution of the hydrophobic degradable polymer is about (0.01-0.04) g/ml.
9. The method according to claim 6, wherein in step S3, the dispersing method is stirring at a speed of 200 to 1500 rpm; preferably, in step S3, the dispersing time is 15 to 30 hours; preferably, in step S4, the mass-to-volume ratio of the precipitate to the aqueous solution of the natural polymer is 1 mg: (0.1-1) ml; preferably, in step S4, the concentration of the natural polymer in the aqueous solution of the natural polymer is 1 g: (50-200) ml.
10. Use of the polymer composite microspheres according to any one of claims 1 to 5 in the preparation of medicaments for treating tissue injuries, gastrointestinal diseases and cardiovascular and cerebrovascular diseases.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286849A (en) * | 2022-08-04 | 2022-11-04 | 上海科邦医用乳胶器材有限公司 | Antibacterial and wear-resistant medical rubber gloves and preparation process thereof |
| CN115518195A (en) * | 2022-09-15 | 2022-12-27 | 广东省科学院生物与医学工程研究所 | Long-acting antibacterial composite microsphere and preparation method and application thereof |
| CN115581803A (en) * | 2022-09-14 | 2023-01-10 | 广东省科学院生物与医学工程研究所 | Polyester-based microsphere and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219119A (en) * | 2008-01-25 | 2008-07-16 | 吉林大学 | Method of preparing simvastatin sustained-release microsphere carried series |
| CN110302172A (en) * | 2019-07-18 | 2019-10-08 | 广东省医疗器械研究所 | A kind of polymer composite microsphere, preparation method and application |
-
2021
- 2021-10-21 CN CN202111226284.2A patent/CN114129542A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219119A (en) * | 2008-01-25 | 2008-07-16 | 吉林大学 | Method of preparing simvastatin sustained-release microsphere carried series |
| CN110302172A (en) * | 2019-07-18 | 2019-10-08 | 广东省医疗器械研究所 | A kind of polymer composite microsphere, preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| ALTINDAL D Ç, GÜMÜŞDERELIOĞLU M.: "Melatonin releasing PLGA micro/nanoparticles and their effect on osteosarcoma cells", 《JOURNAL OF MICROENCAPSULATION》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286849A (en) * | 2022-08-04 | 2022-11-04 | 上海科邦医用乳胶器材有限公司 | Antibacterial and wear-resistant medical rubber gloves and preparation process thereof |
| CN115581803A (en) * | 2022-09-14 | 2023-01-10 | 广东省科学院生物与医学工程研究所 | Polyester-based microsphere and preparation method and application thereof |
| CN115518195A (en) * | 2022-09-15 | 2022-12-27 | 广东省科学院生物与医学工程研究所 | Long-acting antibacterial composite microsphere and preparation method and application thereof |
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