CN117883389A - Multiphase composite microsphere and preparation method and application thereof - Google Patents
Multiphase composite microsphere and preparation method and application thereof Download PDFInfo
- Publication number
- CN117883389A CN117883389A CN202311652318.3A CN202311652318A CN117883389A CN 117883389 A CN117883389 A CN 117883389A CN 202311652318 A CN202311652318 A CN 202311652318A CN 117883389 A CN117883389 A CN 117883389A
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- CN
- China
- Prior art keywords
- microsphere
- polylactic acid
- graphene oxide
- composite
- multiphase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002131 composite material Substances 0.000 title claims abstract description 129
- 239000004005 microsphere Substances 0.000 title claims abstract description 124
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 91
- 239000004626 polylactic acid Substances 0.000 claims abstract description 91
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 49
- 229910021389 graphene Inorganic materials 0.000 claims abstract description 49
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims abstract description 28
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims abstract description 26
- 239000000843 powder Substances 0.000 claims description 49
- 239000000243 solution Substances 0.000 claims description 46
- 239000012071 phase Substances 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 21
- 239000011574 phosphorus Substances 0.000 claims description 21
- 229910052698 phosphorus Inorganic materials 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 17
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- 239000011575 calcium Substances 0.000 claims description 17
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 229940052299 calcium chloride dihydrate Drugs 0.000 claims description 7
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 claims description 6
- 238000000227 grinding Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
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- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 claims description 2
- JNVXRQOSRUDXDY-UHFFFAOYSA-N 1,1-diiodoethane Chemical compound CC(I)I JNVXRQOSRUDXDY-UHFFFAOYSA-N 0.000 claims description 2
- ZHJGWYRLJUCMRT-UHFFFAOYSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-UHFFFAOYSA-N 0.000 claims description 2
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 23
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- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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- 229960004329 metformin hydrochloride Drugs 0.000 description 8
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- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 2
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Classifications
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- 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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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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Abstract
The application relates to the technical field of drug-loaded microspheres, and provides a multiphase composite microsphere, a preparation method and application thereof, wherein the multiphase composite microsphere comprises the following components in parts by weight: 90-100 parts of nano hydroxyapatite; 0.1 to 0.5 part of graphene oxide; 50-600 parts of polylactic acid. According to the multiphase composite microsphere, the preparation method and the application thereof, the synergistic effect among three phases of nano hydroxyapatite, graphene oxide and polylactic acid can endow the microsphere with more excellent performance, and finally the polylactic acid can be degraded by lysozyme in a living body to generate natural metabolites, so that the multiphase composite microsphere is nontoxic and can be completely absorbed by the living body, the drug carrying capacity of the multiphase composite microsphere and the drug release speed controlling capacity are effectively improved, and the drug burst problem is effectively solved.
Description
Technical Field
The application belongs to the technical field of drug-loaded microspheres, and particularly relates to a multiphase composite microsphere, and a preparation method and application thereof.
Background
The microsphere is a novel drug carrier with great development and application potential. The composite material is produced by coupling and hybridization of natural polymers and inorganic materials (mainly inorganic minerals), and has various synergistic excellent physical and chemical properties. Can realize the controlled release of the medicine and has better application prospect in the field of medicine slow release.
Various microspheres exist in the prior art, and the hydroxyapatite/polylactic acid composite microspheres prepared by adopting a spray drying method have poor drug carrying performance although the microspheres have good biocompatibility; the naringenin-loaded polylactic acid microsphere prepared by the water-in-oil emulsion technology has improved drug carrying capacity, but has poorer mechanical property and slow release capacity. For drug-loaded microspheres, microsphere burst release is a major problem in microsphere formulations, and because of the burst release of drugs, the blood concentration level in the body is suddenly increased in a short time to generate toxic and side effects.
In summary, the existing microspheres have the problems of poor sustained release capability and even sudden drug release.
Disclosure of Invention
The application aims to provide a multiphase composite microsphere, a preparation method and application thereof, and aims to solve the problems of poor microsphere slow release capability and drug burst release.
In order to achieve the purposes of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the present application provides a multiphase composite microsphere comprising the following components in parts by weight:
90-100 parts of nano hydroxyapatite;
0.1 to 0.5 part of graphene oxide;
50-600 parts of polylactic acid.
The multiphase composite microsphere provided by the first aspect of the application, wherein the nano hydroxyapatite is similar to inorganic components of human bones, has good biocompatibility and bioactivity, and can participate in vivo metabolism; the graphene oxide has amphiphilicity, high surface area and better adsorption capacity, so that hydrophilic or hydrophobic drugs can be loaded in high efficiency; in addition, the layered structure of the graphene oxide can also enhance the mechanical property of the material, and has good compatibility and dispersibility in biological environment; polylactic acid is formed by polymerization reaction of lactic acid monomer, has the characteristic of allowing use in human body, in addition, the intermediate product of polylactic acid degradation is lactic acid, and finally, the polylactic acid is degraded into carbon dioxide and water harmless to human body and natural environment; polylactic acid has become an important polymer material for biomedical applications due to its properties such as biocompatibility, biodegradability, mechanical strength, and processability. The multiphase composite microsphere is prepared by compounding nano hydroxyapatite, graphene oxide and polylactic acid, so that the multiphase composite microsphere has the plasticity, workability and biocompatibility of an organic material, the rigidity and other properties of an inorganic substance, can realize the controlled release of a drug, has a good application prospect in the field of drug release, effectively improves the drug carrying performance and the release capability, and solves the problem of abrupt release of the microsphere.
In a second aspect, the present application provides a method for preparing a multiphase composite microsphere, comprising the steps of:
providing the composite powder and the polylactic acid;
dissolving the polylactic acid in a first solvent to obtain an organic phase, and dissolving an emulsifier in water to obtain a water phase;
adding the organic phase and the composite powder into the water phase, and uniformly mixing to obtain a mixed phase;
and volatilizing the mixed phase to volatilize the first solvent thoroughly, and then performing first post-treatment to obtain the multiphase composite microsphere.
According to the preparation method of the multiphase composite microsphere provided by the second aspect of the application, by preparing the nano hydroxyapatite-graphene oxide-polylactic acid phase carrier material, the advantages of each phase (such as large specific surface area, high surface activity and hydrogen bonding effect of the nano hydroxyapatite, excellent mechanical property and high-efficiency drug loading capacity of the graphene oxide, and capability of enhancing toughness of the microsphere by the polylactic acid) are combined, and the synergistic effect among the three phases (the graphene oxide contains hydrophilic groups and has stronger interface effect when combined with the polylactic acid) can be improved, so that the stability of the drug-loaded microsphere can be improved, meanwhile, the antibacterial effect can be realized, the more excellent performance can be endowed to the composite carrier, the burst release of the microsphere can be reduced, and the release speed of the drug can be controlled better.
In a third aspect, the present application provides a pharmaceutical sustained release formulation comprising the multiphase composite microsphere provided in the first aspect or the multiphase composite microsphere prepared by the preparation method provided in the second aspect and an active pharmaceutical agent coated by the multiphase composite microsphere.
In some embodiments, the active drug comprises at least one of curcumin, theophylline, metformin hydrochloride, ibuprofen.
The drug sustained-release preparation provided by the third aspect of the application has good drug release control capability, and solves the problem of drug burst release.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following description will briefly introduce the drawings that are needed in the embodiments or the description of the prior art, it is obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic flow chart of a method for preparing multiphase composite microspheres according to an embodiment of the present application;
FIG. 2 is an XRD pattern of the multiphase composite microspheres obtained in examples 1 to 4 of the present application;
FIG. 3 is a FTIR chart of multiphase composite microspheres obtained in examples 1 to 4 of the present application;
fig. 4 is a roman characterization diagram of graphene oxide and composite powder provided in an embodiment of the present application;
FIG. 5 is an SEM image of multiphase composite microspheres obtained in example 1 of the present application;
FIG. 6 is an enlarged view of FIG. 5;
FIG. 7 is an SEM image of multiphase composite microspheres obtained according to example 2 of the present application;
FIG. 8 is an enlarged view of FIG. 7;
FIG. 9 is an SEM image of multiphase composite microspheres obtained according to example 3 of the present application;
fig. 10 is an enlarged view of fig. 9;
FIG. 11 is an SEM image of multiphase composite microsphere obtained in example 4 of the present application;
fig. 12 is an enlarged view of fig. 11;
FIG. 13 is a microscopic image of L929 cells of the heterogeneous composite microspheres obtained in example 1 of the present application under liquid culture with a drug extraction concentration of 100% for different models;
fig. 14 is a standard curve of ibuprofen in absolute ethanol;
FIG. 15 is a graph of drug loading encapsulation rate of ibuprofen at different concentrations under multiphase composite microspheres;
fig. 16 is an in vitro release profile of various drug-loaded multiphase composite microspheres in a ph=1.5 solution.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved by the present application more clear, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the present application.
In this application, the term "and/or" describes an association relationship of an association object, which means that there may be three relationships, for example, a and/or B may mean: a alone, a and B together, and B alone. Wherein A, B may be singular or plural. The character "/" generally indicates that the context-dependent object is an "or" relationship.
In the present application, "at least one" means one or more, and "a plurality" means two or more. "at least one of" or the like means any combination of these items, including any combination of single item(s) or plural items(s). For example, "at least one (individual) of a, b, or c," or "at least one (individual) of a, b, and c," may each represent: a, b, c, a-b (i.e., a and b), a-c, b-c, or a-b-c, wherein a, b, c may be single or multiple, respectively.
It should be understood that, in various embodiments of the present application, the sequence number of each process does not mean that the sequence of execution is sequential, and some or all of the steps may be executed in parallel or sequentially, where the execution sequence of each process should be determined by its functions and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.
The terminology used in the embodiments of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weights of the relevant components mentioned in the embodiments of the present application may refer not only to specific contents of the components, but also to the proportional relationship between the weights of the components, and thus, any ratio of the contents of the relevant components according to the embodiments of the present application may be enlarged or reduced within the scope disclosed in the embodiments of the present application. Specifically, the mass described in the specification of the examples of the present application may be a mass unit known in the chemical industry such as μ g, mg, g, kg.
The terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated for distinguishing between objects such as substances from each other. For example, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX, without departing from the scope of embodiments of the present application. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature.
The term "HA" is an english abbreviation for hydroxyapatite, and it should be noted that the term "HAP" is also regarded as an english abbreviation for hydroxyapatite in some cases; the term "nHA" is an english abbreviation for nano-hydroxyapatite; the term "GO" is an english abbreviation for graphene oxide; the term "PLA" is an english abbreviation for polylactic acid; the term "nHA/GO" represents a composite powder; the term "nHA/GO/PLA" stands for multiphase composite microspheres.
In a first aspect, the present application provides a multiphase composite microsphere comprising the following components in parts by weight:
90-100 parts of nano hydroxyapatite;
0.1 to 0.5 part of graphene oxide;
50-600 parts of polylactic acid.
In application, the nano hydroxyapatite has good biocompatibility and bioactivity as the nano hydroxyapatite is similar to inorganic components of human bones, and can participate in vivo metabolism; the graphene oxide has amphiphilicity, high surface area and better adsorption capacity, so that hydrophilic or hydrophobic drugs can be loaded in high efficiency; in addition, the layered structure of the graphene oxide can also enhance the mechanical property of the material, and has good compatibility and dispersibility in biological environment; polylactic acid is formed by polymerization reaction of lactic acid monomer, has the characteristic of allowing use in human body, in addition, the intermediate product of polylactic acid degradation is lactic acid, and finally, the polylactic acid is degraded into carbon dioxide and water harmless to human body and natural environment; due to its properties of biocompatibility, biodegradability, mechanical strength and processability. The multiphase composite microsphere is prepared by compounding nano hydroxyapatite, graphene oxide and polylactic acid, so that the multiphase composite microsphere has the plasticity, workability and biocompatibility of an organic material, the rigidity and other properties of an inorganic substance, can realize the controlled release of a drug, has a good application prospect in the field of drug release, effectively improves the drug carrying performance and the release capability, and solves the problem of abrupt release of the microsphere.
In some embodiments, the nano hydroxyapatite and the graphene oxide react to generate composite powder, the graphene oxide accounts for 0.1-0.5% of the specific gravity of the composite powder, and the mass ratio of the composite powder to the polylactic acid is 1:0.5-6.
Wherein the proportion of the graphene oxide to the composite powder is within the range of 0.1-0.5%, the graphene oxide and the nano hydroxyapatite can be ensured to react to obtain the composite powder, the mass ratio of the composite powder to the polylactic acid is limited within the range of 1:0.5-6, the composite powder and the polylactic acid can be ensured to be further compounded to obtain the multiphase composite microsphere,
in other embodiments, the specific gravity of graphene oxide to the composite powder may also be any ratio ranging from 0.1%, 0.2%, 0.3%, 0.4%, 0.5% and the like, wherein in a preferred embodiment, the mass ratio of graphene oxide to composite powder is 1:1000. The mass ratio of the composite powder to the polylactic acid is any ratio in the range of 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, etc., wherein in a preferred embodiment, the mass ratio of the composite powder to the polylactic acid is 1:2, 1:4, 1:6.
In some embodiments, the nano-hydroxyapatite has a particle size of 1nm to 100nm;
the molar mass of the polylactic acid is 5000 g/mol-10000 g/mol.
In application, the nano hydroxyapatite with the particle size within the range has better biological activity, can participate in human metabolism, and is beneficial to human absorption and utilization of the medicine loaded by the multiphase composite microsphere; the graphene oxide has stronger chemical reactivity and hydrophilicity, can have stronger interface effect when being combined with PLA, can improve the stability of the multiphase composite microsphere, and can play an antibacterial role. Polylactic acid with the molar mass in the range has the characteristics of good biocompatibility, biodegradability, mechanical strength, processing capacity and the like, and PLA has become an important polymer material for biomedical application.
In a second aspect, as shown in fig. 1, an embodiment of the present application provides a method for preparing a multiphase composite microsphere, including the following steps:
s1, providing the composite powder and polylactic acid;
s2, dissolving polylactic acid in a first solvent to obtain an organic phase, and dissolving an emulsifier in water to obtain a water phase;
s3, adding the organic phase and the composite powder into the water phase, and uniformly mixing to obtain a mixed phase;
s4, volatilizing the mixed phase to volatilize the first solvent thoroughly, and then performing first post-treatment to obtain the multiphase composite microsphere.
The polylactic acid is dissolved by adopting the first solvent, the polylactic acid can be uniformly dispersed by utilizing the principle of similar compatibility, then the organic phase containing the polylactic acid and the composite powder are added into the water phase for carrying out a mixing reaction, so that the polylactic acid and the composite powder are polymerized to generate the multiphase composite microsphere, and the first solvent is volatilized and removed to obtain the multiphase composite microsphere without the first solvent. Firstly, preparing the microsphere by using an emulsion solvent volatilization method, wherein the obtained microsphere has better performance, the experimental condition is simple and easy to apply, secondly, synthesizing nHA/GO by using a one-pot hydrothermal method, further synthesizing nHA/GO/PLA three-phase composite microsphere with different proportion components, and finally, polylactic acid can be degraded by lysozyme in a living body to generate natural metabolites, and the polylactic acid is nontoxic and can be completely absorbed by the living body.
In the application, the nano hydroxyapatite-graphene oxide-polylactic acid phase carrier material is prepared, so that the advantages of each phase (such as large specific surface area, high surface activity and hydrogen bonding of the nano hydroxyapatite, excellent mechanical property and high-efficiency drug loading capacity of the graphene oxide, and toughness of the microsphere can be enhanced by the polylactic acid) are combined, and the synergistic effect among the three phases (the graphene oxide contains hydrophilic groups and has stronger interfacial effect when combined with the polylactic acid) can be improved, the stability of the drug-loaded microsphere can be improved, meanwhile, the antibacterial effect can be realized, the superior performance of the composite carrier can be endowed, the burst release of the microsphere can be reduced, and the release speed of the drug can be controlled better.
In the step S1, the preparation of the composite powder comprises the following steps:
s11, providing a calcium source solution, a phosphorus source solution and graphene oxide;
s12, adding graphene oxide into a calcium source solution for dispersion to obtain a mixed solution;
s13, adding the phosphorus source solution into the mixed solution, and carrying out a composite reaction to obtain a reactant;
s14, carrying out second post-treatment on the reactant to obtain the composite powder.
In this embodiment, the nano hydroxyapatite is generated by reacting a calcium source solution with an phosphorus source solution, and because the amount of graphene oxide is small, if the graphene oxide is directly mixed with the nano hydroxyapatite, the graphene oxide is not uniformly distributed, so that the mechanical properties of the finally prepared multiphase composite microsphere are inconsistent, and the drug carrying capacity is affected.
In some embodiments, the ratio of the molar amount of calcium in the calcium source solution to the molar amount of phosphorus in the phosphorus source solution is 1.67:1. At this ratio, it is ensured that nano hydroxyapatite can be generated, so that composite powder can be generated.
In some embodiments, in step S11, the calcium source in the calcium source solution comprises at least one of anhydrous calcium chloride, calcium chloride dihydrate, calcium nitrate tetrahydrate, calcium chloride trihydrate, calcium chloride tetrahydrate, preferably the calcium source solution is an aqueous calcium chloride dihydrate solution. The phosphorus source in the phosphorus source solution comprises at least one of sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate. Preferably, the phosphorus source solution is a disodium hydrogen gonorrhoeae aqueous solution.
In some embodiments, in step S12, that is, in the step of adding the phosphorus source solution to the mixed solution to perform the complex reaction to obtain the reactant, the method further includes:
when the phosphorus source solution is added into the mixed solution, the pH regulator is added into the mixed solution to control the pH value to be 10-11.
The mixed solution is alkaline, so that the calcium source and the phosphorus source can react conveniently to obtain nano hydroxyapatite, and then the nano hydroxyapatite is compounded with graphene oxide to obtain composite powder. In an embodiment, the pH adjustor is sodium hydroxide, potassium hydroxide, or the like.
In some embodiments, the conditions of the complexing reaction include: the reaction temperature is 150-200 ℃ and the reaction time is 18-30 h. In other embodiments, the reaction temperature is any temperature in the range of 150℃to 200℃such as 150℃160℃170℃180℃190℃200 ℃. The reaction time is any time ranging from 18h to 30h, such as 18h, 20h, 22h, 24h, 26h, 28h and 30h.
In step S14, the second post-treatment includes vacuum filtration of the reactants, washing to neutral pH, filtering, drying, and grinding. Therefore, clean composite powder can be obtained, and impurities such as solvents and the like are removed, so that the subsequent further composite with polylactic acid can be conveniently carried out to obtain the multiphase composite microsphere.
In one embodiment, the composite powder is prepared by the following steps:
calcium chloride dihydrate and disodium hydrogen phosphate are used as raw materials, and the molar ratio of calcium to phosphorus is 1.67:1 preparing 0.3mol/L aqueous solution respectively;
adding graphene oxide into a calcium chloride dihydrate aqueous solution, and performing ultrasonic dispersion for 20 minutes to obtain a mixed solution, wherein the content of the graphene oxide is 0.1mg/ml;
dropwise adding a disodium hydrogen phosphate aqueous solution into the mixed solution at a speed of 2.0mol/min by using a constant-flow titration pump, controlling the pH to be about 10.5 by using a 0.5mol/L NaOH solution, magnetically stirring at a temperature of 40 ℃ at a stirring speed of 300r/min, after the addition is finished, putting the mixed solution into a high-pressure reaction kettle, and reacting at 180 ℃ for 24 hours to obtain a reactant;
and cooling the obtained reactant to room temperature, performing vacuum suction filtration, washing with deionized water until the pH value is neutral, washing with absolute ethyl alcohol for three times, and drying the filtrate in a 60 ℃ oven for 12 hours, wherein the dried sample is ground to obtain the composite powder.
In some embodiments, in step S2, the first solvent comprises at least one of dichloromethane, chloroform, dibromoethane, diiodoethane, dichloroethane. Preferably, the first solvent is methylene chloride. The compatibility of the dichloromethane and the polylactic acid is better, and the polylactic acid can be better dissolved and dispersed in the dichloromethane, so that the subsequent fusion with the water phase and the composite powder is realized. The emulsifier comprises at least one of Tween 60, tween 80 and gelatin.
In some embodiments, in step S3, adding the organic phase and the composite powder into the aqueous phase, and mixing to obtain a mixed phase includes: the organic phase is slowly added into the aqueous phase dropwise while stirring the aqueous phase, and then the composite powder is added, and the mixture is uniformly stirred after the addition is finished to obtain a uniformly dispersed mixed phase.
In some embodiments, the multi-phase composite microsphere loaded with the corresponding active drugs can be obtained by adding the active drugs such as ibuprofen, curcumin and the like in the step S3.
In one embodiment, 1.0g of polylactic acid is weighed and added to 20ml of dichloromethane to form an organic phase; weighing 2.0g of Tween 80, adding into 40ml of pure water, and stirring at 30deg.C for hydrolysis to obtain water phase; slowly dropwise adding the organic phase into the aqueous phase while stirring the aqueous phase, adding 0.25g of composite powder, adding ibuprofen dissolved in 10ml of NaOH, stirring ultrasonically for 5min, stirring at room temperature for 6h, thoroughly volatilizing the dichloromethane, and obtaining the multiphase composite drug-carrying microsphere through standing, precipitation, washing, filtering, drying and grinding.
In some embodiments, in step S4, the volatilizing treatment includes ultrasonic treatment for 5min to 10min with an ultrasonic instrument, and then stirring at normal temperature for 5h to 6h to volatilize the first solvent thoroughly, thereby obtaining a solution containing the multiphase composite microspheres.
In some embodiments, the first post-treatment comprises sequentially subjecting to settling, washing, filtering, drying, grinding.
In a third aspect, embodiments of the present application provide a sustained-release pharmaceutical formulation comprising an active pharmaceutical agent and the multiphase composite microsphere of the first aspect or the multiphase composite microsphere prepared by the preparation method of the second aspect, wherein the active pharmaceutical agent is coated with the multiphase composite microsphere.
The drug sustained-release preparation provided by the second aspect of the application has good drug release control capability, and solves the problem of drug burst release.
In some embodiments, the active agent includes, but is not limited to, curcumin, theophylline, metformin hydrochloride, ibuprofen.
The following description is made with reference to specific embodiments.
Example 1
The embodiment of the invention provides a multiphase composite microsphere and a preparation method thereof.
The purifying process of single-wall carbon nanotube includes the following steps:
s1, providing 0.25g of composite powder and 1.0g of polylactic acid;
the preparation method of the composite powder comprises the following steps:
calcium chloride dihydrate and disodium hydrogen phosphate are used as raw materials, and the molar ratio of calcium to phosphorus is 1.67:1 preparing 0.3mol/L aqueous solution respectively; specifically weighing 2.20515g of calcium chloride dihydrate, dissolving to prepare 0.3mol/l of calcium chloride solution, weighing 2.1294g of disodium hydrogen phosphate, and dissolving to prepare 0.3mol/l of disodium hydrogen phosphate aqueous solution;
adding graphene oxide into a calcium chloride aqueous solution, and performing ultrasonic dispersion for 20 minutes to obtain a mixed solution, wherein the content of the graphene oxide is 0.1mg/ml;
dropwise adding a disodium hydrogen phosphate aqueous solution into the mixed solution at a speed of 2.0mol/min by using a constant-flow titration pump, controlling the pH to be about 10.5 by using a 0.5mol/L NaOH solution, magnetically stirring at a temperature of 40 ℃ at a stirring speed of 300r/min, after the addition is finished, putting the mixed solution into a high-pressure reaction kettle, and reacting at 180 ℃ for 24 hours to obtain a reactant;
and cooling the obtained reactant to room temperature, performing vacuum suction filtration, washing with deionized water until the pH value is neutral, washing with absolute ethyl alcohol for three times, and drying the filtrate in a 60 ℃ oven for 12 hours, wherein the dried sample is ground to obtain the composite powder.
S2, dissolving 1.0g of polylactic acid in 20ml of dichloromethane to obtain an organic phase, dissolving 2.0g of Tween 80 in 40ml of water, stirring and hydrolyzing at 30 ℃ to obtain a water phase, performing ultrasonic treatment for 5min by using an ultrasonic instrument, and stirring for 5h at normal temperature to completely volatilize the organic solution. Standing for precipitation, washing, filtering, drying and grinding to obtain nano hydroxyapatite/graphene oxide/polylactic acid composite microspheres;
s3, slowly dropwise adding the organic phase into the water phase while stirring the water phase, adding 0.25g of the composite powder prepared before, and uniformly stirring after the addition to obtain a mixed phase;
s4, carrying out ultrasonic treatment on the mixed phase for 5min, stirring for 5h at normal temperature, thoroughly volatilizing the first solvent, standing for precipitation, washing, filtering, drying and grinding to obtain the multi-phase composite microsphere.
Examples 2 to 4
Substantially the same as in example 1, the difference from example 1 is that the mass ratio of the composite powder to the polylactic acid is different, as shown in Table 1:
table 1 Table of the amounts of composite powder and polylactic acid used in each example
| nHA/GO | PLA | nHA/GO：PLA | |
| Example 1 | 0.25g | 1.0g | 1:4 |
| Example 2 | 0.167g | 1.0g | 1:6 |
| Example 3 | 0.5g | 1.0g | 1:2 |
| Example 4 | 2.0g | 1.0g | 2:1 |
Performance testing
The multiphase composite microspheres obtained in examples 1 to 4, and drug-sustained-release formulations obtained by drug-loading using the multiphase composite microspheres obtained in examples 1 to 4 were subjected to performance test.
1. X-ray diffraction (XRD)
And (3) utilizing a high-stability X-ray source to emit a beam of monochromatic X-rays to the surface of a crystal to be measured, then utilizing an X-ray diffractometer manufactured by using a diffraction working principle to detect the X-rays diffracted by crystal faces of a product body meeting Bragg diffraction, thereby obtaining the microstructure of the multiphase composite microsphere obtained in the examples 1-4, and finally carrying out product body analysis. An XRD pattern as shown in fig. 2 was obtained.
2. Fourier transform infrared spectroscopy (FTIR)
In this application, the model of He Lishe infrared-converted optical instrument used is IR Affinity-1. The background sample was potassium bromide (KBr), KBr and samples were finely ground to a powder and the volume ratio was 100:1 are uniformly mixed together in proportion, and are dried and then made into transparent slices for standby by a tabletting machine. The sample was set to a spectral resolution of 400-4000cm for the test -1 The corresponding wavelength is 25 μm-2.5 μm. The flakes were placed in a spectrometer for infrared scanning testing. Obtaining asAn infrared spectrum shown in fig. 3.
3. Raman spectrum (Raman)
The Lawsonia spectrum is a scattering spectrum of research molecules on excitation light, and in the application, an inVia Raman spectrometer manufactured by Renisshaw corporation in France is adopted, the excitation light wavelength is 532nm, and the detection range is 100-2500cm -1 . The composite powder and graphene oxide provided in the examples were tested by a raman spectrometer to obtain a raman spectrum as shown in fig. 4, wherein a in fig. 4 represents graphene oxide and b represents composite powder.
4. Scanning Electron Microscope (SEM)
The macrostructure of the sample was examined in the present application using an S-3400N (D) scanner electron microscope manufactured by Hitachi Corp. And (5) attaching the sample to a conductive adhesive tape, and spraying metal. The appearance of the sample particles can be seen from the SEM image. As shown in fig. 5 to 12.
5. Ultraviolet visible spectrophotometer (UV-VIS)
The ultraviolet-visible spectrophotometer used in the present application is of the type UV2550 of shimadzu, and the concentration of the sample is calculated by measuring absorbance from the absorption wavelength of the sample.
6. Cytotoxicity assays
In the application, the MTT method is adopted to evaluate the cytotoxic activity, firstly, the sample is pretreated, firstly, 0.5g of the sample is soaked in absolute ethyl alcohol for 24 hours, then the filtration, the drying, the disinfection and the sterilization are carried out, and the whole process is completed in a sterile operation platform. Then immersing the sterilized sample in 20mL of complete medium, culturing in a constant temperature environment for 24h, filtering and recovering the leaching solution, dividing the concentration gradient based on the concentration of the leaching solution into 9 gradients of 5%, 15.0%, 20.0%, 30.0%, 60.0%, 80.0%, 100.0% of leaching solution and complete medium, taking the complete medium as a control group, taking the rest as an experimental group, culturing the treated mouse fiber allium (1929) in each 96-well plate with a volume of 100 μl, adding each dilution concentration of the leaching solution (5%, 15.0%, 20.0%, 30.0%, 60.0%, 80.0%, 100.0%) and the complete incubator (as a control) into the wells, culturing for 48h, adding each dilution concentration of the leaching solution (5%, 15.0%, 20.0%, 30.0%, 60.0%, 80.0%) into each wellMTT solution, CO at 37deg.C 2 Incubation was performed for 4h. Light absorption (STATFAX, USA) was then recorded by ELISA reader at a wavelength of 595mm the test was repeated 3 times for each dilution and the results recorded. As shown in fig. 13-16.
The meaning of the abscissa in the drawings is explained: the abscissa in fig. 2 is in degrees, the ordinate is in peak intensity, and the unit is a.u; the abscissa in FIG. 3 is the wave number in cm -1 The ordinate is light transmittance in units of; the abscissa in FIG. 4 is the wave number in cm -1 The ordinate is peak intensity in a.u; the left plot of FIG. 13 shows concentration in units of cells and relative proliferation rate in units of cells on the abscissa; the abscissa of FIG. 14 shows the concentration of ibuprofen in mg/ml and the ordinate shows absorbance; the abscissa in fig. 15 represents the concentration of ibuprofen in mg/ml, and the ordinate represents the encapsulation efficiency and drug loading in mg; the abscissa in fig. 16 is time in h, and the ordinate is cumulative release rate in%.
Analysis of results
As analyzed in conjunction with fig. 2, the diffraction peaks of the products of the composite powders and polylactic acid of examples 1 to 4, which were compounded at four different ratios, were almost identical, and the peak intensities of the individual peaks were different. As can be seen from comparing standard non-plates of nHA (PDF 09-0432), the characteristic diffraction peaks of nHA appear clearly and with higher intensity, at angles of 25.9 DEG, 31.7 DEG, 32.2 DEG, 32.9 DEG, 39.8 DEG, 46.7 DEG, 49.5 DEG, 52.26 DEG, respectively (002), (211), (112), (300), (310), (222), (213), (004) crystal planes of nHA, wherein the line-incidence peaks of (002), (211) crystal planes are the main diffraction peaks of nHA, and the peaks are obvious and have high intensity. Meanwhile, as polylactic acid increases, PLA diffraction peaks are stronger and GO is 0.1% by mass, and the characteristic peaks of graphene oxide are about 10 degrees, so that the characteristic peaks are not detected because of small addition amount. In conclusion, the quality of PLA has little influence on nHA crystallization, but has influence on PLA and is positive influence, and the nanometer light-based apatite/graphene oxide/polylactic acid is successfully compounded in the proportion of 1:4 and 1: the composite at 6 is better, namely the multiphase composite microspheres prepared in the example 1 and the example 2 have better performance.
From the analysis of FIG. 3, first observe nHA/GO/PLA blank multiphase composite microsphere at 1035cm -1 With PO (PO) 4 3- Stretching vibration peak of group 603/565cm -1 With PO (PO) 4 3- Bending vibration peaks of the group belong to characteristic peaks of nHA; at 1751cm -1 Has a C=O stretching vibration peak, 1186cm -1 Has C-O-C stretching vibration peak of 3500cm -1 These characteristic peaks belonging to PLA: at 1752cm- 1 /1620cm -1 Has C=O stretching vibration peak and 1168cm -1 C-O absorption peak of 3500cm -1 Is that the-OH absorption peak belongs to the GO characteristic peak.
The peaks of the functional groups of the respective substances are observed to be relatively close, and thus, the peaks become broader due to mutual interference. The infrared spectra of multiphase composite microspheres obtained by different proportions of nHA/GO and PLA are basically consistent, but the difference in peak intensity is only that the composition components of products compounded by different proportions are consistent, and the characteristic peaks of nHA/GO and PLA, such as 569cm, appear in the four proportions -1 PO at 4 3- Bending vibration peak of group, 1033cm -1 PO at 4 3- Stretching vibration peak of group 1454cm -1 CO at site 3 2- Is 1755cm, which belongs to the characteristic absorption peak of nHA -1 A telescopic vibration peak of C=O, 1186cm -1 Is a C-O-C stretching vibration peak, and belongs to the characteristic absorption peak of PLA. The ratio is 1 as a whole: the peak intensity at 4 is more pronounced, e.g. at 1755cm -1 C=o stretching vibration peak 1235cm -1 Anti-symmetrical vibration peak of C-O, 3415-3556cm -1 These characteristic peaks belonging to PLA; 1000-1350cm -1 PO of (2) 4 3- The group stretches out and draws back the vibration peak, this is characteristic peak of HA. So the mass ratio of nHA/GO to PLA is 1:4, the nHA/PLA composite microsphere obtained in the step 4 is more successful, namely the multiphase composite microsphere prepared in the example 1 has better performance.
FIG. 4 shows the Raman spectra of GO and nHA/GO, where part a in FIG. 4 can observe graphene oxide with only two characteristic peaks at 1345cm -1 D peak and 1596cm -1 G peak and D peak of graphene oxide are D band disorderVibration peak, G peak is G band graphite vibration peak of graphene oxide, while 589cm in section b of FIG. 4 -1 And 960cm -1 Is a characteristic peak of HA, and corresponds to V3 (PO 4 3- ) Antisymmetric variable angle vibration peak, V1 (PO 4 3- ) Symmetrical vibration peaks. The intensity ratio of D and G bands (ID/IG) characterizes the degree of disorder of the graphite material. The intensity ratio of GO (ID/IG) =0.85, nha/GO (ID/IG) =0.94, and the composite sample had a higher ID/IG, indicating an increased defectivity of GO in the composite sample. This may be that when nano hydroxyapatite grows on the surface of GO, the lamellar structure of GO is damaged by the influence of stress, which eventually leads to an increase in the defect level of GO.
Fig. 5 to 12 show SEM images of the multiphase composite microspheres obtained in examples 1 to 4, respectively, and referring to fig. 5 and 6, when the mass ratio of nHA/GO to PLA is 1:4 (example 1), the microsphere surface is smooth, but there are many small holes, such a structure can increase the drug loading, and is beneficial to release the drug from the inside to the outside, which avoids the "burst release" phenomenon during the drug release to some extent: the most microspheres at this ratio are found to be most abundant, with the most spherical form.
When the mass ratio of nHA/GO to PLA is 1: at 6 (example 2), as shown in fig. 7 and 8, the number of microspheres was also large, but the size of the formed microspheres was not 1:4, uniformly, the microspheres are covered by a layer of substance to form solid spheres. It can be obtained that the formation of the microsphere is affected by too much or too little nano-based apatite/graphene oxide and polylactic acid, and the experiment shows that the mass ratio of nHA/GO to PLA is 1:4, is a preferred suitable ratio for forming nHA/GO/PLA composite microspheres.
When the mass ratio of nHA/GO to PLA is 1:2 (example 3), as shown in fig. 9 and 10, the surface of the microsphere compounded by nHA/GO and PLA is not covered by a layer of powder, which indicates that the attached nHA/GO is reduced, and the microsphere has marks for starting to form holes: the balling number is 2: and 1.
When the mass ratio of nHA/GO to PLA is 2:1 (example 4), as shown in fig. 11 and 12, solid microspheres with a small number of microspheres are formed, and most of the surfaces of the microspheres are coated with a thick layer of massive substances, compared with other ratio 2:1, the area of the outer surface that was coated was larger because this ratio of nHA/GO had the most mass, with some failing to make adequate contact with PLA: resulting in nHA/GO being attached only to the microsphere surface, which can hinder drug absorption by the microsphere.
In vitro cytotoxicity test is carried out on the carrier material according to the biological evaluation standard of iso10993.1-2018 medical equipment, and the cytotoxicity is detected by adopting a CCK-8 method, as shown in figure 13, microsphere extract solutions with different concentrations can be found to have no negative effect on cell proliferation, and the proliferation of cells is more obvious at a proper concentration, so that microsphere extract solutions can be obtained to have no negative effect on cell proliferation, which means that culture solution containing composite microsphere substances has no toxicity, and further means that microspheres have no toxicity on cell proliferation basically.
The right image in fig. 13 is a microscopic image of L929 cells at 100% of the nHA/GO/PLA-loaded ibuprofen extract after 48b culture, and it can be seen that when the extract reaches 100%, the growth state of the cells is not significantly different from that of the control group, the cell morphology is still better, and most of the cells are uniformly distributed and are transparent oval; only a few cells packed into spheres, the color was dull, and the number was reduced, indicating that few cells had died. The left graph in fig. 13 shows the relative proliferation rate of L929 cells cultured for 48h under the leaching solutions with different contents of nHA/GO/PLA-carried ibuprofen, the statistical quantity of the control group is taken as a reference standard, the experimental group takes the non-leaching solutions with different contents as a control condition, the control group is subjected to data processing, the average density of the cells under each concentration is sequentially 100%, 96.2%, 96.0%, 90.1%, 93.4%, 87.1%, 90.9%, 89.1% and 87.4%, and the relative proliferation rate of the L929 cells under the leaching solutions with the microspheres with different concentrations is above 80%, which is basically not negative to the cells, and is consistent with the cell microscopic graph. The nHA/GO/PLA carried ibuprofen composite microsphere is proved to have no toxicity by microscopic image and relative increment rate line graph analysis, and can be used as a drug carrier.
The standard curve of Ibuprofen (IBU) in absolute ethanol solution is shown in fig. 14, the absorbance of the known concentrated waste solution method is measured at 264mm wavelength by an ultraviolet spectrophotometer, and the standard curve is drawn,by linear fitting, the standard absorption curve is y=1.738 XX-0.0883, r 2 0.9991, which is linear in the range of 0.05 μg/ml to 0.6 μg/ml. From fig. 15, it is understood that the drug loading and the encapsulation efficiency increase with the increase of the drug concentration, and the encapsulation efficiency and the drug loading reach the highest when the ibuprofen concentration is 8mg/mL, and the encapsulation efficiency and the drug loading start to decrease when the ibuprofen concentration is higher than 8mg/mL, which is basically because the contact probability of the microsphere and the drug increases and the amount of microsphere adsorption increases when the original concentration of the drug increases. Until all adsorption sites of the microsphere are adsorbed, the drug loading is maximum. At this moment, the concentration of the medicine is increased, and only the excessive medicine cannot be counted down, so that the medicine is wasted. Therefore, the optimal drug loading rate of nHA/GO/PLA-loaded ibuprofen is 8mg/mL, the highest encapsulation efficiency is 70%, the drug loading rate is 4.0%, and the nHA/GO/PLA has better drug loading capacity in the overall view.
As shown in fig. 14 and 15, by calculating the drug loading and encapsulation efficiency of the microspheres, nHA/GO can be seen: PLA mass ratio is 1:4, and at nHA/GO: PLA ratio was 1: at 6, both drug loading and encapsulation efficiency were reduced at nHA/GO: PLA mass ratio is 1:4 and 1: the drug loading capacity and the encapsulation efficiency between 6 reach the peak value, which is probably due to the relative reduction of nHA/GO, the pore structure in the composite microsphere is reduced, and the drug loading performance of the microsphere is affected.
Fig. 16 is the results of in vitro cumulative release of nHA/GO/PLA-loaded Ibuprofen (IBU), theophylline (TH), curcumin (Cur), metformin hydrochloride (MF) at ph=1.5, with the release rate of theophylline and metformin hydrochloride being substantially in line with each other as seen from the release rate, the drug release rate being almost constant, except for the upward turning of the load MF at 70h, the drug release of theophylline and metformin hydrochloride being very low for up to 98h overall, the cumulative release rate of the load TH at 98h being 7.3%, the final cumulative release of MF at 1.6%. The ibuprofen is also in a diapause state in the first 5 hours, the accumulated released medicine is 1%, the speed of the ibuprofen is suddenly increased in the 7 th hour, and the ibuprofen is slowly released, but the IBU finally accumulated released is not high, and the IBU is 21.6%. The curcumin-carrying microsphere has slight burst release compared with the microspheres carrying other three medicines, the release rate is increased and then reduced in the whole process, and the release rate is cumulatively released for 98 hours by Cur28.6%.
As shown in fig. 16, the cumulative release rate of the different nHA/GO/PLA drug-loaded microspheres performed best compared to the drug-loaded microspheres by drug-loaded microspheres in a solution simulating artificial gastric juice (pH 1.5).
In conclusion, the multiphase composite microsphere prepared by the multiphase composite microsphere and the preparation method provided by the application has good drug carrying performance and capability of controlling the drug release speed, has no cytotoxicity, can be widely applied to a drug sustained release preparation, and can carry a drug to realize the sustained release purpose, thereby solving the problem of drug burst release.
The foregoing description of the preferred embodiments of the present application is not intended to be limiting, but is intended to cover any and all modifications, equivalents, and alternatives falling within the spirit and principles of the present application.
Claims (10)
1. The multiphase composite microsphere is characterized by comprising the following components in parts by weight:
90-100 parts of nano hydroxyapatite;
0.1 to 0.5 part of graphene oxide;
50-600 parts of polylactic acid.
2. The multiphase composite microsphere according to claim 1, wherein the nano hydroxyapatite and the graphene oxide react to generate composite powder, the graphene oxide accounts for 0.1% -0.5% of the specific gravity of the composite powder, and the mass ratio of the composite powder to the polylactic acid is 1:0.5-6.
3. The preparation method of the multiphase composite microsphere is characterized by comprising the following steps:
providing the composite powder according to any one of claims 1 to 3 and the polylactic acid;
dissolving the polylactic acid in a first solvent to obtain an organic phase, and dissolving an emulsifier in water to obtain a water phase;
adding the organic phase and the composite powder into the water phase, and uniformly mixing to obtain a mixed phase;
and volatilizing the mixed phase to volatilize the first solvent thoroughly, and then performing first post-treatment to obtain the multiphase composite microsphere.
4. A method of preparing the composite powder of claim 3, wherein the preparation of the composite powder comprises the steps of:
providing a calcium source solution, a phosphorus source solution and graphene oxide;
adding the graphene oxide into the calcium source solution for dispersion to obtain a mixed solution;
adding the phosphorus source solution into the mixed solution, and carrying out a composite reaction to obtain a reactant;
and carrying out second post-treatment on the reactant to obtain the composite powder.
5. The method of claim 4, wherein the ratio of the molar amount of calcium in the calcium source solution to the molar amount of phosphorus in the phosphorus source solution is 1:1.67.
6. The method according to claim 4, wherein the step of adding the phosphorus source solution to the mixed solution to perform a complex reaction to obtain a reactant further comprises:
when the phosphorus source solution is added into the mixed solution, a pH regulator is added into the mixed solution at the same time to control the pH value to be 10-11; and/or
The conditions of the complex reaction include: the reaction temperature is 150-200 ℃ and the reaction time is 18-30 h.
7. The method of manufacturing of claim 4, wherein the first post-treatment comprises:
through standing, precipitating, washing, filtering, drying and grinding; and/or
The second post-processing includes:
the reaction was vacuum filtered and washed to neutral pH, then filtered, dried and ground.
8. The method according to claim 4, wherein the calcium source in the calcium source solution comprises at least one of anhydrous calcium chloride, calcium nitrate tetrahydrate, calcium chloride dihydrate, calcium chloride trihydrate, and calcium chloride tetrahydrate;
the phosphorus source in the phosphorus source solution comprises at least one of sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate.
9. The production method according to any one of claims 3 to 8, wherein the first solvent comprises at least one of dichloromethane, chloroform, dibromoethane, diiodoethane, dichloroethane;
the emulsifier comprises at least one of Tween 60, tween 80 and gelatin.
10. A pharmaceutical sustained release formulation comprising an active agent and a multiphase composite microsphere according to claim 1 or 2 or a multiphase composite microsphere prepared by a method according to any one of claims 3 to 9, said active agent being coated with said multiphase composite microsphere.
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