CN114767638A - Preparation method of ibuprofen-loaded polylactic acid degradable microspheres - Google Patents
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Abstract
The invention discloses a preparation method of ibuprofen-loaded polylactic acid degradable microspheres, which comprises the following steps: s1: adding polylactic acid or modified polylactic acid into dichloromethane, magnetically stirring until the polylactic acid or the modified polylactic acid is completely dissolved, adding ibuprofen, and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use; s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle head to be 0.8mm and the receiving distance to be 15 cm; s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3 hours to obtain the degradable drug-loaded microsphere. The invention adopts the electrostatic spraying method to prepare the ibuprofen-loaded polylactic acid degradable microspheres for the first time, has simple operation steps and controllable preparation conditions, can prepare the three-dimensional spherical structure with good formability, mellow and full surface and good dispersibility and densely distributed micropores on the surface without operating under the conditions of high temperature and high pressure, and has good loading performance and slow release performance on the ibuprofen.
Description
Technical Field
The invention belongs to the field of sustained-release drug preparation, and particularly relates to a preparation method of ibuprofen-loaded polylactic acid degradable microspheres.
Background
Ibuprofen (Ibuprofen, IBU) also known as Ibuprofen is a non-steroidal antipyretic analgesic and anti-inflammatory drug widely used for postoperative pain, rheumatic pain, toothache, arthritis and the like, but Ibuprofen has poor water solubility and short biological half life, frequent administration is required for maintaining treatment concentration, gastrointestinal side effects are easily caused, and certain damage is generated to the kidney. The ibuprofen is prepared into a sustained release preparation, so that the medicine taking frequency can be reduced, the medicine taking compliance of patients is improved, the bioavailability of the medicine is improved, and the adverse reaction of the medicine can be relieved.
Common polymer drug carriers comprise polymer micelles, microgels, dendritic polymers, polymer microspheres and the like, wherein the polymer microspheres consist of compact polymer matrixes, can effectively load (embed, adsorb or chemically couple) various drugs, and are widely applied to the field of drug sustained and controlled release at present. Chitosan, polylactic-co-polyglycolic acid (PLGA), polylactic acid (PLA) and Polybutylcyanoacrylate (PBCA) are the most commonly used carrier matrices for the construction of polymer drug-loaded microspheres in biomedical applications. PLA, polylactide, is a synthetic polymer material with good biodegradability, biocompatibility and bioabsorbability. PLA mostly takes corn and other grains as raw materials, can be decomposed by bacteria, mold and other microorganisms in nature, and can be finally degraded into O without environmental pollution2And H2And O. PLA is used as a natural biological base material which can be finally degraded and is in the nature, and is widely applied to the fields of disposable tableware, disposable transfusion tools, drug release packaging agents, tissue repair materials, artificial skin and the like in the process of paying attention to environmental protection and popularization of novel bio-based environment-friendly materials.
Although the application of degradable polymeric microspheres in the field of controlled drug release has been advanced to some extent, the number of microsphere formulations actually used in clinical applications is not large. The polymer microsphere controlled release system still has many defects, such as crystallization and burst release of hydrophobic micromolecule drugs, volatile activity and denaturation of macromolecular bioactive substances and other key problems, and is still not well solved so far. The preparation method of the polymer microsphere mainly comprises a coacervation phase separation method, a solvent evaporation method, a spray drying method and the like, but the methods generally have the defects of more experimental steps, harsh preparation conditions, insufficiently compact microsphere structure, easy burst release and the like.
In recent years, a new technology for preparing micro-scale particles (spheres or cavities) by using an electrostatic spraying method has attracted much attention. The electrostatic spraying technology is that fluid is atomized into tiny droplets by utilizing a high-voltage electrostatic field, and the tiny droplets are adsorbed on a target object in a directional motion under the combined action of electrostatic field force and external force. The whole preparation process is simple, the preparation time is short, the electrostatic effect effectively reduces the surface tension of the fogdrop, reduces the size of the fogdrop, accelerates the volatilization of the solvent, provides a larger surface area to volume ratio for the release of the medicament, and reduces the occurrence of burst release; meanwhile, fog drops formed by spraying have the same negative charge, are mutually exclusive in space motion, are not easy to agglomerate and have good dispersibility. In addition, the electrostatic spraying technology has controllable conditions, does not involve high-temperature operation, is less in contact with an organic solvent, can keep the activity of the medicine, has simple process, and can prepare the degradable polymer microspheres in one step. At present, the method is widely applied to the field of drug-loading controlled release, particularly to the encapsulation and release of low-water-solubility bioactive molecules, NGUYEN and the like adopt an electrostatic spray technology to prepare quercetin-loaded polylactic acid-glycolic acid copolymer (PLGA) microspheres with a long-acting release mode, no chemical action exists between quercetin and PLGA in the obtained microspheres, the quercetin shows a slow release mode in vitro for 30 days, and no burst release phenomenon exists. HSU et al prepared Doxorubicin-loaded PLGA microspheres (DOX-PLGAMS) by electrospray method, with MSs having mean diameter of 6.74 + -1.01 μm, and evaluated DOX release from MSs by in vitro elution found that DOX showed 12.3% burst release on day 1 and 85.8% drug release after 30 days. However, so far, the preparation of ibuprofen-loaded polylactic acid degradable sustained-release microspheres by an electrostatic spraying method has not been reported.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of ibuprofen-loaded polylactic acid degradable microspheres.
The technical scheme of the invention is summarized as follows:
a preparation method of ibuprofen-loaded polylactic acid degradable microspheres comprises the following steps:
s1: adding polylactic acid or modified polylactic acid into dichloromethane, magnetically stirring until the polylactic acid or the modified polylactic acid is completely dissolved, adding ibuprofen, and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use;
s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle head to be 0.8mm and the receiving distance to be 15 cm;
s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3h to obtain the ibuprofen-loaded polylactic acid degradable microspheres.
Preferably, the modified polylactic acid is one of chitosan-polylactic acid graft copolymer and gelatin-polylactic acid graft copolymer.
Preferably, the ratio of the polylactic acid or modified polylactic acid, dichloromethane and ibuprofen is 50 mg: 1mL of: (2-8) mg.
Preferably, the ibuprofen-loaded polylactic acid degradable microspheres prepared by the preparation method are in a three-dimensional spherical structure with densely-distributed surface micropores, and the particle size distribution of the ibuprofen-loaded polylactic acid degradable microspheres is 2.4-11.2 microns.
Preferably, the ratio of the polylactic acid or modified polylactic acid, dichloromethane and ibuprofen is 50 mg: 1mL of: 6 mg.
Preferably, the ibuprofen-loaded polylactic acid degradable microspheres prepared by the preparation method have good moldability, are round and full, have particle size distribution of 4.0-11.2 microns, have 83% of particle size of 5.6-8.8 microns, have 7.2 microns of average particle size, are densely distributed in micropores, and are easy for drug loading.
The invention has the beneficial effects that:
1. the invention adopts the electrostatic spraying method to prepare the ibuprofen-loaded polylactic acid degradable microspheres for the first time, has simple operation steps and controllable preparation conditions, does not need to operate under high temperature and high pressure, and can successfully prepare the three-dimensional spherical structure with good formability, smoothness, fullness and good dispersibility and densely distributed surface micropores, so that the ibuprofen-loaded polylactic acid degradable microspheres have good loading performance and slow release performance on ibuprofen.
2. The invention uses polylactic acid or modified polylactic acid as a framework carrier material to embed ibuprofen, and the ibuprofen is highly wrapped in a polylactic acid or modified polylactic acid matrix in a molecular or irregular state, so that the bioactivity of the ibuprofen is maintained, the polylactic acid is stably combined with the ibuprofen through intermolecular hydrogen bond action, or amino in a modified polylactic acid structure and carboxyl in the ibuprofen generate chemical crosslinking action through amidation reaction, and the ibuprofen is stably embedded through covalent bonds and intermolecular hydrogen bond action, so that the thermal stability of the ibuprofen medicament is improved to a certain extent, and the controlled release effect is achieved. Therefore, the polylactic acid or the modified polylactic acid is used as a skeleton carrier material, so that the structural stability of the degradable microspheres is further improved, and the drug release time is prolonged.
3. The ibuprofen-loaded polylactic acid degradable microspheres prepared by the invention have uniform particle size, controllable size, uniformity and roundness, the particle size is 2.4-11.2 mu m, the slow release effect of the ibuprofen medicament can be effectively achieved while the bioactivity of the ibuprofen medicament is maintained, the burst release phenomenon is not found, the bioavailability of the ibuprofen is obviously improved, and the ibuprofen-loaded polylactic acid degradable microspheres are suitable for large-scale batch production.
Drawings
Fig. 1 is an SEM image of ibuprofen-loaded polylactic acid degradable microspheres prepared in example 1;
fig. 2 is an SEM image of ibuprofen-loaded polylactic acid degradable microspheres prepared in example 2;
fig. 3 is an SEM image of ibuprofen-loaded polylactic acid degradable microspheres prepared in example 3;
fig. 4 is an SEM image of ibuprofen-loaded polylactic acid degradable microspheres prepared in example 4;
fig. 5 is a particle size distribution diagram of the ibuprofen-loaded polylactic acid degradable microspheres prepared in example 1;
fig. 6 is a particle size distribution diagram of the ibuprofen-loaded polylactic acid degradable microspheres prepared in example 2;
fig. 7 is a particle size distribution diagram of the ibuprofen-loaded polylactic acid degradable microspheres prepared in example 3;
fig. 8 is a particle size distribution diagram of the ibuprofen-loaded polylactic acid degradable microspheres prepared in example 4;
FIG. 9 is XRD patterns of ibuprofen-loaded polylactic acid degradable microspheres prepared in examples 1-4, polylactic acid microspheres in comparative example 1 and ibuprofen in comparative example 2;
FIG. 10 is a DSC analysis chart of the ibuprofen-loaded polylactic acid degradable microspheres prepared in examples 1 to 4, the polylactic acid microspheres in comparative example 1 and the ibuprofen in comparative example 2;
FIG. 11 is FTIR analysis graphs of ibuprofen-loaded polylactic acid degradable microspheres prepared in examples 1-4, polylactic acid microspheres in comparative example 1 and ibuprofen in comparative example 2;
FIG. 12 is a TG analysis chart of the ibuprofen-loaded polylactic acid degradable microspheres prepared in examples 1-4, the polylactic acid microspheres in comparative example 1 and the ibuprofen in comparative example 2;
FIG. 13 is a slow release curve diagram of ibuprofen-loaded polylactic acid degradable microspheres prepared in examples 1-4 and ibuprofen in comparative example 2;
fig. 14 is a flow chart of a preparation method of ibuprofen-loaded polylactic acid degradable microspheres.
In fig. 9 to 11, curve 1 represents the polylactic acid microsphere of comparative example 1, curves 2 to 5 represent the ibuprofen-loaded polylactic acid degradable microspheres in examples 1 to 4, respectively, and curve 6 represents the ibuprofen of comparative example 2.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.
Example 1
A preparation method of ibuprofen-loaded polylactic acid degradable microspheres comprises the following steps:
s1: adding 500mg of polylactic acid into 10mL of dichloromethane, magnetically stirring until the polylactic acid is completely dissolved, adding 20mg of ibuprofen (namely accurately weighing the ibuprofen according to 4 percent of the dosage), and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use;
s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle to be 0.8mm and the receiving distance from the needle to an aluminum foil to be 15 cm;
s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3h to obtain the ibuprofen-loaded polylactic acid degradable microspheres.
Example 2
A preparation method of ibuprofen-loaded polylactic acid degradable microspheres comprises the following steps:
s1: adding 500mg of polylactic acid into 10mL of dichloromethane, magnetically stirring until the polylactic acid is completely dissolved, adding 40mg of ibuprofen (namely accurately weighing the ibuprofen according to 8 percent of the dosage), and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use;
s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle to be 0.8mm and the receiving distance from the needle to an aluminum foil to be 15 cm;
s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3h to obtain the ibuprofen-loaded polylactic acid degradable microspheres.
Example 3
A preparation method of ibuprofen-loaded polylactic acid degradable microspheres comprises the following steps:
s1: adding 500mg of polylactic acid into 10mL of dichloromethane, magnetically stirring until the polylactic acid is completely dissolved, adding 60mg of ibuprofen (namely accurately weighing the ibuprofen according to 12 percent of the dosage), and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use;
s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle to be 0.8mm and the receiving distance from the needle to an aluminum foil to be 15 cm;
s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3h to obtain the ibuprofen-loaded polylactic acid degradable microspheres.
Example 4
A preparation method of ibuprofen-loaded polylactic acid degradable microspheres comprises the following steps:
s1: adding 500mg of polylactic acid into 10mL of dichloromethane, magnetically stirring until the polylactic acid is completely dissolved, adding 80mg of ibuprofen (namely accurately weighing the ibuprofen according to 16 percent of the dosage), and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use;
s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle to be 0.8mm and the receiving distance from the needle to an aluminum foil to be 15 cm;
s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3h to obtain the ibuprofen-loaded polylactic acid degradable microspheres.
Example 5
A preparation method of ibuprofen-loaded polylactic acid degradable microspheres comprises the following steps:
s1: adding 500mg of chitosan-polylactic acid graft copolymer into 10mL of dichloromethane, magnetically stirring until the chitosan-polylactic acid graft copolymer is completely dissolved, adding 20mg of ibuprofen (namely accurately weighing the ibuprofen according to 4% of the dosage), and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use;
s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle to be 0.8mm and the receiving distance from the needle to an aluminum foil to be 15 cm;
s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3h to obtain the ibuprofen-loaded polylactic acid degradable microspheres.
Example 6
A preparation method of ibuprofen-loaded polylactic acid degradable microspheres comprises the following steps:
s1: adding 500mg of gelatin-polylactic acid graft copolymer into 10mL of dichloromethane, magnetically stirring until the gelatin-polylactic acid graft copolymer is completely dissolved, adding 80mg of ibuprofen (namely accurately weighing the ibuprofen according to 16% of the dosage), and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use;
s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle to be 0.8mm and the receiving distance from the needle to an aluminum foil to be 15 cm;
s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3h to obtain the ibuprofen-loaded polylactic acid degradable microspheres.
Comparative example 1: the preparation method of the pure polylactic acid microspheres prepared by the electrostatic spraying method is the same as that of the embodiment 1, and the difference is that: ibuprofen is not added in the preparation process.
Comparative example 2: ibuprofen is pure product.
Firstly, the ibuprofen-loaded polylactic acid degradable microspheres prepared in examples 1 to 4 and comparative examples 1 to 2 are subjected to structure representation and performance test
1. SEM characterization test: the accelerating voltage was 20kV, and the surface morphology of the IBU/PLA microspheres (ibuprofen-loaded polylactic acid degradable microspheres) prepared in examples 1-4 was observed.
FIGS. 1-4 and 5-8 are SEM images and particle size distribution plots of IBU/PLA microspheres prepared in examples 1-4: as can be seen from SEM images in figures 1-4, under the preparation condition, IBU/PLA microspheres with different dosage are in a three-dimensional spherical structure with pores on the surface, are uniform and round and have good dispersibility. A particle size frequency distribution histogram 5-8 drawn by randomly selecting 50 microspheres by using Nano Measurer 1.2 is known, and the particle size pairs of the microspheres do not have a certain change relation due to the increase of IBU content, which indicates that the increase of the drug concentration has no obvious influence on the particle size of the microspheres in a concentration range capable of forming dispersed particles. The particle sizes of the microspheres with different dosages in examples 1-4 are distributed in a range from 2.4 μm to 11.2 μm, and in comparison, the microspheres with 12% of IBU in example 3 have good formability and are round and full, the particle size is 5.6 μm to 8.8 μm, the percentage of the particles is 83%, the average particle size is 7.2 μm, and micropores are densely distributed and are easy to load the medicine.
2. XRD characterization: Cu-Kalpha rays, the range of a scanning diffraction angle is 5-80 degrees, the scanning speed is 10 degrees/min, the voltage is 40kV, the current is 50mA, and the IBU/PLA microspheres prepared in examples 1-4 and the crystal forms of comparative examples 1-2 are analyzed.
FIG. 9 is XRD patterns of IBU/PLA microspheres prepared in examples 1-4, pure PLA microspheres of comparative example 1, and IBU of comparative example 2, wherein curve 1 represents the comparative example 1(PLA microspheres), curves 2-5 represent the IBU/PLA microspheres in examples 1-4, respectively, and curve 6 represents the comparative example 2 (IBU): as can be seen from the figure, IBU has obvious crystal diffraction peaks at 6.12 degrees, 12.28 degrees, 16.85 degrees, 17.71 degrees, 19.15 degrees, 20.14 degrees and 22.44 degrees, and the pure PLA microspheres prepared by the electrostatic spraying method of the comparative example 1 are of an amorphous structure. The XRD patterns of the IBU/PLA microspheres with different dosages prepared by the electrostatic spraying methods in examples 1-4 are not obviously attributed to characteristic diffraction peaks of IBU, and only a wide and weak absorption peak appears near 16 degrees 2 theta just like pure PLA microspheres, which indicates that the crystal lattices of IBU are damaged in the electrostatic spraying process, IBU is highly dispersed in PLA matrixes in a molecular or random state, and the IBU/PLA microspheres have amorphous structures similar to PLA because of relatively short receiving distance in the electrostatic spraying process, high solvent volatilization speed and insufficient time for crystallization of IBU chains, and the interaction between PLA and IBU inhibits the crystallization process.
3. DSC characterization: the temperature rise rate was 10 ℃/min, and the melting and crystallization behaviors of the IBU/PLA microspheres prepared in examples 1-4 and comparative examples 1-2 were analyzed.
FIG. 10 is a DSC analysis chart of IBU/PLA microspheres prepared in examples 1 to 4, pure PLA microspheres of comparative example 1, and IBU of comparative example 2, wherein curve 1 represents the IBU/PLA microspheres of comparative example 1(PLA microspheres), curves 2 to 5 represent the IBU/PLA microspheres in examples 1 to 4, respectively, and curve 6 represents the IBU of comparative example 2 (IBU): as can be seen, the IBU has a sharp and narrow melting endothermic peak at 75.74 ℃ and a melting enthalpy Δ Hm of 128.90J/g, indicating that the IBU has a crystal structure. Comparative example 1 the pure PLA microspheres prepared by electrostatic spray process showed a broad and weak melting endotherm at 164.94 c with a melting enthalpy Δ Hm of 53.38J/g. When a sample is prepared by adopting an electrostatic spraying method, the Tm of IBU/PLA microspheres is gradually reduced from 164.94 ℃ to 156.09 ℃ along with the increase of the content of IBU, the melting range is gradually increased, and the melting enthalpy is reduced to be 42.98J/g-55.38J/g compared with that of 128.90J/g of pure IBU, so that the crystal lattice of the IBU is damaged, although IBU molecules easily enter a PLA amorphous structure to induce PLA to generate crystals, the heterogeneously formed crystal structure is not perfect, the Tm is reduced, and the melting range is widened. On the other hand, the IBU/PLA microspheres in the different dosages of the examples 1-4 have no melting peak attributed to IBU, but show the same melting tendency as PLA, which also shows that IBU is completely loaded in PLA and is consistent with the research result of XRD.
4. FTIR characterization: preparing a sample by a KBr tabletting method, wherein the test wavelength range is 4000-500 cm-1The characteristic functional groups of the IBU/PLA microspheres prepared in examples 1 to 4 and comparative examples 1 to 2 were analyzed.
FIG. 11 is an FTIR analysis chart of IBU/PLA microspheres prepared in examples 1-4, pure PLA microspheres of comparative example 1, and IBU of comparative example 2, wherein Curve 1 represents the comparative example 1(PLA microspheres), curves 2-5 represent the IBU/PLA microspheres of examples 1-4, respectively, and curve 6 represents the comparative example 2 (IBU): as can be seen from the figure, 1764cm is in the PLA structure-1The strong absorption peak corresponds to the C ═ O stretching vibration, 1630cm-1Stretching vibration of 3660-3290 cm corresponding to C ═ O in terminal carboxyl-1Is the free-OH stretching vibration peak. In the IBU construction, 1720cm-1The strong absorption peak at position (1508 cm) corresponds to the stretching vibration of C ═ O at the carboxyl group-1And 1458cm-1Is the characteristic skeleton vibration of a benzene ring, 936cm-1866cm for out-of-plane deformation vibration of-OH group in carboxyl group-1And 776cm-1Out-of-plane deformation vibration corresponding to para-substitution of C-H in the benzene ring. For the IBU/PLA microspheres prepared in the electrostatic spraying of the embodiments 1-4, the characteristic functional group absorption peak of PLA still exists, the position is unchanged, and an out-of-plane deformation vibration peak of para-position substituted C-H in a benzene ring appears, which indicates that IBU is successfully loaded in PLA.
5. TG characterization: the flow rate of nitrogen atmosphere is 50mL/min, the heating rate is 10K/min, the temperature rise range is room temperature to 700 ℃, and Al is added2O3And (3) analyzing the thermal weight loss conditions of the IBU/PLA microspheres prepared in examples 1-4 and comparative examples 1-2.
FIG. 12 is a TG analysis chart of IBU/PLA microspheres prepared in examples 1-4, pure PLA microspheres of comparative example 1, and IBU of comparative example 2: as can be seen from the figure, both the PLA microspheres prepared by IBU and the electrostatic spraying method have an obvious weight loss stage, the weight loss starts at about 100 ℃ and 280 ℃ respectively, the weight loss is complete at about 220 ℃ and 380 ℃, and the weight loss is rapid. The IBU/PLA microspheres prepared by the electrostatic spraying method of examples 1-4 at different dosages show two mass loss trends, the first trend is 120-280 ℃ due to the thermal decomposition of IBU, and the second trend is 280-390 ℃, which can be attributed to the thermal decomposition of PLA. With the increase of the dosage, the two trends of weight loss with heat are more obvious, the thermal decomposition rate of the IBU is also gradually improved, but both the thermal decomposition rate and the thermal decomposition rate are smaller than those of pure IBU, and the thermal stability of the IBU/PLA microspheres is improved to a certain extent compared with that of the IBU.
Second, in vitro slow release performance test
1. Determination of the IBU Standard Curve
Accurately weighing 50mg of IBU standard substance, dissolving in PBS buffer solution, diluting to 50mL to obtain 1mg/mL mother solution, precisely measuring the appropriate volume of the mother solution, and diluting to a certain multiple with the buffer solution to obtain IBU standard solutions with concentrations of 0.75, 0.5, 0.25, 0.1 and 0.05 mg/mL. And (3) taking the PBS buffer solution as a reference substance, and respectively testing the absorbance of each standard solution at 265nm under the conditions of a scanning wavelength of 200-400 nm, a scanning speed of 600nm/min and a slit width of 2 nm.
And (3) test results: the measurement result of the IBU standard curve is subjected to linear analysis, the linear relation between the ultraviolet absorbance of IBU at 265nm and the mass concentration of the IBU is good in the concentration range of 0.05-0.75mg/mL, and the linear regression equation is as follows: a is 2.2364c +0.0395(R2 is 0.9996).
2. In vitro slow release curve drawing
Accurately weighing 30mg of IBU standard substance and 100mg of IBU/PLA microspheres with different dosage into a treated dialysis bag, adding 5mL of PBS buffer solution, sealing two ends, putting into a beaker containing 100mL of PBS buffer solution, sealing with a preservative film, and oscillating at constant temperature of 37.0 +/-0.5 ℃ at a rotating speed of 100 r/min. Samples were taken periodically at 4.0mL, while supplemented with 4.0mL of fresh medium. Absorbance at 265nm was measured for each sample according to "1.5.1" and cumulative percent release was calculated according to equation (1) to plot the IBU release profile from the microspheres.
FIG. 13 is a slow release profile of IBU/PLA microspheres prepared in examples 1-4 and IBU of comparative example 2: as can be seen from the figure, in examples 1-4, the IBU/PLA microspheres with different dosages released within 48 hours have a relatively high release speed, and then enter a slow release stage, and no burst release phenomenon occurs at the initial release stage. In the comparative example 2, more than 70% of IBU bulk drug is released within 8 hours; in the embodiment 1, the IBU/PLA microspheres with 4 percent of drug delivery amount release 19 percent within 48 hours, the cumulative drug release time is more than 192 hours, and the drug release amount is 35 percent, which indicates that the drug-loaded microspheres have obvious slow release effect; when the dosage is increased to 16%, 52% of the IBU/PLA microspheres release the medicine within 48h, and the final accumulative release amount of the medicine can reach 57%. From experimental results, the IBU/PLA microspheres prepared by the electrostatic spraying technology can realize the slow release effect on the loaded IBU, and the burst release phenomenon is not generated.
While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details without departing from the general concept defined by the claims and the scope of equivalents.
Claims (6)
1. A preparation method of ibuprofen-loaded polylactic acid degradable microspheres is characterized by comprising the following steps:
s1: adding polylactic acid or modified polylactic acid into dichloromethane, magnetically stirring until the polylactic acid or the modified polylactic acid is completely dissolved, adding ibuprofen, and stirring until the ibuprofen is completely dissolved to obtain a uniform solution for later use;
s2: carrying out high-voltage electrostatic spraying on the uniform solution obtained in the step S1, and controlling the flow rate to be 0.5mL/h, the voltage to be 17.5kV, the inner diameter of a spraying needle to be 0.8mm and the receiving distance to be 15 cm;
s3: and (3) drying the product obtained in the step S2 at 55 ℃ in vacuum for 3h to obtain the ibuprofen-loaded polylactic acid degradable microspheres.
2. The method for preparing the ibuprofen-loaded polylactic acid degradable microspheres according to claim 1, wherein the modified polylactic acid is one of chitosan-polylactic acid graft copolymer and gelatin-polylactic acid graft copolymer.
3. The method for preparing ibuprofen-loaded polylactic acid degradable microspheres according to claim 1, wherein the ratio of polylactic acid or modified polylactic acid, dichloromethane and ibuprofen is 50 mg: 1 mL: (2-8) mg.
4. The ibuprofen-loaded polylactic acid degradable microspheres prepared by the preparation method of any one of claims 1 to 3 are in a three-dimensional spherical structure with densely-distributed surface micropores, and the particle size distribution of the microspheres is 2.4 to 11.2 microns.
5. The method for preparing ibuprofen-loaded polylactic acid degradable microspheres according to claim 3, wherein the ratio of polylactic acid or modified polylactic acid, dichloromethane and ibuprofen is 50 mg: 1mL of: 6 mg.
6. The particle size distribution of the ibuprofen-loaded polylactic acid degradable microspheres prepared by the preparation method according to claim 5 is 4.0-11.2 μm, wherein the particle size is 5.6-8.8 μm and accounts for 83%, and the average particle size is 7.2 μm.
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