CN114042044B - Trace polylactic acid/rifampicin drug-loaded microsphere and preparation method thereof - Google Patents
Trace polylactic acid/rifampicin drug-loaded microsphere and preparation method thereof Download PDFInfo
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- CN114042044B CN114042044B CN202111427744.8A CN202111427744A CN114042044B CN 114042044 B CN114042044 B CN 114042044B CN 202111427744 A CN202111427744 A CN 202111427744A CN 114042044 B CN114042044 B CN 114042044B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Abstract
The invention discloses a preparation method of a traceable polylactic acid/rifampicin drug-loaded microsphere, which comprises the steps of dissolving polylactic acid in dichloromethane, then adding span-80 and rifampicin, and performing ultrasonic emulsification to obtain emulsion; pouring the emulsion into PVA water solution for shearing and dispersing to obtain oil-in-water emulsion; the oil-in-water emulsion is stirred and is added with ioversol contrast agent solution, then sodium tripolyphosphate is added, and the microsphere is solidified and molded to obtain the polylactic acid two-layer composite drug carrier; placing the microspheres in a dichloromethane solution in which polylactic acid is dissolved to obtain three-layer composite drug-loaded microspheres, adding the microspheres into an ioversol contrast agent solution, and dripping TPP to obtain a solution; the resulting solution was centrifuged and the bottom microspheres were removed. The preparation process of the drug-loaded microsphere is simple and quick, the product has the tracing function, higher drug loading rate and encapsulation rate, longer slow release time, and polylactic acid with better biodegradability is used in the preparation process, so that the drug-loaded microsphere has a wide application prospect.
Description
Technical Field
The invention relates to a degradable drug carrier material, in particular to a traceable composite drug-carrying microsphere, and belongs to the technical field of biomedical technology.
Background
Bone joint tuberculosis is often secondary to pulmonary tuberculosis, is the most common extrapulmonary secondary tuberculosis, and bone joint tuberculosis treatment is comprehensive performance treatment, including antitubercular drug treatment, nutritional support, focus clearance and the like. Currently, antitubercular drug treatment regimens are rifampicin, isoniazid, pyrazinamide triple or tetrad regimen supplemented with streptomycin for 2 months of intensive treatment. However, due to the toxic and side effects of antitubercular drugs in the digestive tract, many patients are still difficult to tolerate and the compliance of the patients is poor. And because hardened bones exist around the focus of the bone joint tuberculosis, systemic medicines are difficult to reach the focus part, and are more difficult to permeate into dead bones in the focus. Therefore, in the anti-tuberculosis treatment of the bone joint tuberculosis, the method can more accurately locate the focus part, reduce the medication frequency and maintain the effective drug concentration for a long time at the focus part.
Polylactic acid (PLA for short) is a biodegradable functional polymer organic compound, has the characteristics of no toxicity, degradability, good biocompatibility and the like, is approved by the United states Food and Drug Administration (FDA) to be used for human bodies, and has huge application prospect in the field of pharmacy. At present, the polypeptide has very good development prospect in the aspects of bone defect repair, protein, anti-tumor, polypeptide, vaccine and other drug carriers. The nanocapsules, microspheres, gel and other injection prepared by the carrier material can play roles in protecting the drug, increasing the solubility of the drug and improving the bioavailability of the drug, achieve the purposes of long-time slow release and controlled release, and have wide development prospect.
Rifampicin (RFP) is a rifamycin antibiotic, inhibits RNA synthesis at the transcriptional level of mycobacterium tuberculosis, and has good effect of curing tuberculosis diseases. And the preparation is cheap and easy to obtain, is nontoxic and tasteless, has synergistic effect with other antitubercular drugs, and has no cross drug resistance. Has good therapeutic effect on bone joint tuberculosis.
In recent years, there are also some methods for treating tuberculosis of bone joint, such as treatment with antituberculosis drugs, but the methods cannot be accurately applied to the focus, and the patients are easy to generate tolerance and short drug release time, multiple drug administration is required, and the requirements of bone repair cannot be met. Therefore, the traceable ioversol contrast agent is added into the drug-carrying microsphere, and the microsphere surface is coated by adopting a layer-by-layer coating technology, so that the disease focus can be accurately treated, and the drug-carrying microsphere is an ideal drug release system.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: provides a method for preparing a traceable polylactic acid/rifampicin drug-loaded microsphere.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a method for preparing a traceable polylactic acid/rifampicin drug-loaded microsphere, comprising the following steps:
step 1): dissolving polylactic acid in dichloromethane until the polylactic acid is clear and transparent, then adding span-80 and rifampicin, and performing ultrasonic emulsification to obtain emulsion;
step 2): pouring the obtained emulsion into PVA water solution, and shearing and dispersing in a high-speed shearing emulsifying machine at the rotating speed of 3000-8000r/min to obtain oil-in-water emulsion;
step 3): magnetically stirring the obtained oil-in-water emulsion at room temperature, simultaneously dropwise adding ioversol contrast agent solution, then dropwise adding sodium tripolyphosphate, continuously stirring, completely volatilizing an organic solvent, and solidifying and forming microspheres to obtain a polylactic acid two-layer composite drug carrier; placing the microspheres in a dichloromethane solution in which polylactic acid is dissolved, carrying out ultrasonic oscillation at 25 ℃ and then carrying out centrifugal separation and cleaning to obtain three-layer composite drug-loaded microspheres, adding the three-layer composite drug-loaded microspheres into an ioversol contrast agent solution, and dropwise adding TPP after magnetic stirring to obtain a solution;
step 4): and centrifuging the obtained solution, taking out the microspheres at the bottom, washing with distilled water, and freeze-drying to obtain the polylactic acid/rifampicin drug-loaded microspheres.
Preferably, the molecular weight of the polylactic acid in the step 1) is between 3 and 64kDa, and poly-L-lactic acid, poly-D-lactic acid or a mixture of the two is adopted. Polylactic acid is excellent in biodegradability and is readily available.
Preferably, the weight ratio of polylactic acid to dichloromethane to span-80 to rifampicin in the step 1) is 10:40-80:1:1-5. The more the amount of rifampicin is administered, the more the rifampicin particles are distributed on the surface of the microspheres and the drug loading is increased.
Preferably, the mass concentration of the PVA aqueous solution emulsion in the step 2) is 1%; the weight ratio of the emulsion to the PVA aqueous solution is 1:2 to 10.
Preferably, the mass concentration of the ioversol contrast agent solution in the step 3) is 1%; the weight ratio of the emulsion to ioversol contrast agent solution to TPP is 400: 5-15: 1. ioversol contrast agent is a substance that can precisely locate a focal site.
Preferably, the ratio of the polylactic acid two-layer composite drug-carrying agent to the polylactic acid in the step 3) is 1:10 to 500; the weight ratio of the three-layer composite drug-carrying microsphere to the ioversol contrast agent solution is 2:1 to 3, and the weight ratio of the dripping TPP is 5:1 to 3.
Preferably, the number of times of washing with distilled water in the step 4) is 3 to 5.
The invention also provides the traceable polylactic acid/rifampicin drug-loaded microsphere prepared by the preparation method of the traceable polylactic acid/rifampicin drug-loaded microsphere.
Compared with the prior art, the invention has the advantages that:
1) The drug-loaded microsphere prepared by the invention has simple and quick process and better drug-loading capacity and encapsulation efficiency;
2) The drug-loaded microsphere prepared by the invention has tracer property and can be more accurately applied to focus positions.
Drawings
FIG. 1 is a topographical feature of the drug-loaded microspheres prepared in example 1;
FIG. 2 is a topographical feature of the drug-loaded microspheres prepared in example 2;
FIG. 3 is a topographical feature of the drug-loaded microspheres prepared in example 3;
FIG. 4 is a topographical feature of the drug-loaded microspheres prepared in comparative example 1;
fig. 5 is a graph showing the drug release profile of the drug-loaded microspheres of the present invention.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below.
The 1% PVA used in the present invention was prepared by the following method:
10.0g PVA is weighed and dissolved in 1000mL distilled water, and after stirring at room temperature to dissolve completely, the PVA solution with the concentration of 1% is obtained for standby.
Other reagents of the invention are all commercially available through the tatam platform.
The particle size is measured by a laser particle size analyzer, and the measurement temperature is room temperature.
The microsphere morphology was determined using Scanning Electron Microscopy (SEM).
The drug loading rate and the encapsulation rate are measured by an ultraviolet spectrophotometer.
Example 1
About 5g of PLA was dissolved in about 40mL of methylene chloride until clear and transparent. Adding 0.25g span-80 and 10mg rifampicin to carry out ultrasonic emulsification for 30min to obtain emulsion; pouring the obtained emulsion into 400mL of PVA (polyvinyl alcohol) water solution with the concentration of 1%, and shearing and dispersing the solution in a high-speed shearing emulsifying machine for 3min at the rotating speed of 5000r/min to obtain oil-in-water (O/W) emulsion; magnetically stirring the obtained (O/W) emulsion at room temperature, simultaneously dropwise adding 5g of ioversol contrast agent solution with the concentration of 1%, dropwise adding 1g of sodium Tripolyphosphate (TPP) after 0.5h, continuously stirring for 3h, completely volatilizing an organic solvent, and solidifying and forming the microspheres to obtain PLA two-layer composite drug-carrying microspheres; placing the three-layer composite drug-loaded microsphere in 40mL of dichloromethane solution dissolved with 5g of PLA, carrying out ultrasonic oscillation at 25 ℃ for 30min, carrying out centrifugal separation and cleaning to obtain the three-layer composite drug-loaded microsphere, adding the three-layer composite drug-loaded microsphere into 5g of ioversol contrast agent solution with the mass concentration of 1%, magnetically stirring for 0.5h, and then dropwise adding 1g of TPP to obtain a solution; centrifuging the obtained solution at a rotating speed of 8000r/min for 10min, washing with distilled water for 3 times, and freeze-drying for 24h to obtain PLA composite drug-carrying microsphere powder product. The average particle size, drug loading rate and encapsulation efficiency of the obtained product are shown in table 1.
Example 2
About 5g of PLA was dissolved in about 40mL of methylene chloride until clear and transparent. Adding 0.25g span-80 and 10mg rifampicin to carry out ultrasonic emulsification for 30min to obtain emulsion; pouring the obtained emulsion into 400mL of PVA (polyvinyl alcohol) water solution with volume concentration of 1%, and shearing and dispersing in a high-speed shearing emulsifying machine for 3min at the rotating speed of 5000r/min to obtain oil-in-water (O/W) emulsion; magnetically stirring the obtained (O/W) emulsion at room temperature, simultaneously dropwise adding 5g of ioversol contrast agent solution with the mass concentration of 1%, dropwise adding 1g of sodium Tripolyphosphate (TPP) after 0.5h, continuously stirring for 3h, completely volatilizing an organic solvent, and solidifying and forming microspheres to obtain the PLA two-layer composite drug carrier; placing the three-layer composite drug-loaded microsphere in 40mL of dichloromethane solution dissolved with 5g of PLA, carrying out ultrasonic oscillation at 25 ℃ for 30min, carrying out centrifugal separation and cleaning to obtain the three-layer composite drug-loaded microsphere, adding the three-layer composite drug-loaded microsphere into 10g of ioversol contrast agent solution with the mass concentration of 1%, magnetically stirring for 0.5h, and then dropwise adding 1g of TPP to obtain the solution; centrifuging the obtained solution at a rotating speed of 8000r/min for 10min, washing with distilled water for 3 times, and freeze-drying for 24h to obtain PLA composite drug-carrying microsphere powder product. The average particle size, drug loading rate and encapsulation efficiency of the obtained product are shown in table 1.
Example 3
About 5g of PLA was dissolved in about 40mL of methylene chloride until clear and transparent. Adding 0.25g span-80 and 10mg rifampicin to carry out ultrasonic emulsification for 30min to obtain emulsion; pouring the obtained emulsion into 400mL of PVA (polyvinyl alcohol) water solution with the concentration of 1%, and shearing and dispersing the solution in a high-speed shearing emulsifying machine for 3min at the rotating speed of 5000r/min to obtain oil-in-water (O/W) emulsion; magnetically stirring the obtained (O/W) emulsion at room temperature, simultaneously dropwise adding 5g of ioversol contrast agent solution with the mass concentration of 1%, dropwise adding 1g of sodium Tripolyphosphate (TPP) after 0.5h, continuously stirring for 3h, completely volatilizing an organic solvent, and solidifying and forming microspheres to obtain the PLA two-layer composite drug carrier; placing the three-layer composite drug-loaded microsphere in 40mL of dichloromethane solution dissolved with 5g of PLA, carrying out ultrasonic oscillation at 25 ℃ for 30min, carrying out centrifugal separation and cleaning to obtain the three-layer composite drug-loaded microsphere, adding the three-layer composite drug-loaded microsphere into 15g of 1% ioversol contrast agent solution, magnetically stirring for 0.5h, and then dropwise adding 1g of TPP to obtain a solution; centrifuging the obtained solution at a rotating speed of 8000r/min for 10min, washing with distilled water for 3 times, and freeze-drying for 24h to obtain PLA composite drug-carrying microsphere powder product. The average particle size, drug loading rate and encapsulation efficiency of the obtained product are shown in table 1.
Comparative example 1
About 5g of PLA was dissolved in about 40mL of methylene chloride until clear and transparent. Adding 0.25g span-80 and 10mg rifampicin to carry out ultrasonic emulsification for 30min to obtain emulsion; pouring the obtained emulsion into 400mL of PVA (polyvinyl alcohol) water solution with the concentration of 1%, and shearing and dispersing the solution in a high-speed shearing emulsifying machine for 3min at the rotating speed of 5000r/min to obtain oil-in-water (O/W) emulsion; magnetically stirring the obtained (O/W) emulsion at room temperature, centrifuging the obtained solution at a rotating speed of 8000r/min for 10min, washing with distilled water for 3 times, and freeze-drying for 24h to obtain PLA composite drug-carrying microsphere powder product. The average particle size, drug loading rate and encapsulation efficiency of the obtained product are shown in table 1.
Comparative example 1 is the result of drug-loaded microspheres without ioversol contrast agent, whereby the effect of the properties of particle size, drug loading rate, encapsulation rate, etc. of drug-loaded microspheres with different ioversol contrast agents are compared.
Table 1 performance parameters of drug-loaded microspheres
| Average particle diameter (μm) | Drug loading rate (%) | Encapsulation efficiency (%) | |
| Example 1 | 8.880 | 18.01 | 37.06 |
| Example 2 | 10.58 | 18.97 | 37.94 |
| Example 3 | 29.79 | 19.96 | 39.45 |
| Comparative example 1 | 5.354 | 17.38 | 35.95 |
As can be seen from table 1, when the drug-loaded polylactic acid microsphere is prepared, the particle size of the microsphere increases with the increase of the ioversol contrast agent content, and the drug loading rate and encapsulation rate also increase.
Meanwhile, the applicant has found that in table 1, the particle size of microspheres without ioversol contrast agent and with ioversol contrast agent is smaller in comparative example 1 than in examples 1, 2 and 3.
As can be seen from FIGS. 1-3, examples 1, 2, 3 were spherical, had a surface with a dimple and a fine pore, and as ioversol contrast agent increased, the more pores were distributed over the surface of the microspheres, and more drug could be loaded.
As can be seen from FIG. 4, comparative example 1 is a microsphere without ioversol contrast agent, and has a spherical shape, smooth surface and no pinholes.
As can be seen from fig. 5, the slower drug release in examples 1, 2 and 3 compared with comparative example 1, which is sufficient to demonstrate that the drug release can be increased by adding ioversol contrast agent, and the more the drug release is as the substance is increased, because it has a traceable effect, so that we can more accurately locate the focus, release the drug, and alleviate the disease. Whereas the tracing effect of ioversol contrast agent is more pronounced compared to comparative example 1.
Claims (4)
1. The preparation method of the traceable polylactic acid/rifampicin drug-loaded microsphere is characterized by comprising the following steps of:
step 1): dissolving polylactic acid in dichloromethane until the polylactic acid is clear and transparent, then adding span-80 and rifampicin, and performing ultrasonic emulsification to obtain emulsion; polylactic acid, methylene dichloride, span-80 and rifampicin with the weight ratio of 10:40-80:1:1-5;
step 2): pouring the obtained emulsion into PVA water solution, and shearing and dispersing in a high-speed shearing emulsifying machine at the rotating speed of 3000-8000r/min to obtain oil-in-water emulsion; the mass concentration of the PVA aqueous solution emulsion is 1%; the weight ratio of the emulsion to the PVA aqueous solution is 1:2 to 10;
step 3): magnetically stirring the obtained oil-in-water emulsion at room temperature, simultaneously dropwise adding ioversol contrast agent solution, then dropwise adding sodium tripolyphosphate, continuously stirring, completely volatilizing an organic solvent, and solidifying and forming microspheres to obtain a polylactic acid two-layer composite drug carrier; placing the microspheres in a dichloromethane solution in which polylactic acid is dissolved, carrying out ultrasonic oscillation at 25 ℃ and then carrying out centrifugal separation and cleaning to obtain three-layer composite drug-loaded microspheres, adding the three-layer composite drug-loaded microspheres into an ioversol contrast agent solution, and dropwise adding TPP after magnetic stirring to obtain a solution; the mass concentration of the ioversol contrast agent solution is 1%; the weight ratio of the emulsion to ioversol contrast agent solution to TPP is 400: 5-15: 1, a step of; the ratio of the polylactic acid to the two-layer composite drug-carrying polylactic acid is 1:10 to 500; the weight ratio of the three-layer composite drug-carrying microsphere to the ioversol contrast agent solution is 2:1 to 3, and the weight ratio of the dripping TPP is 5:1 to 3;
step 4): and centrifuging the obtained solution, taking out the microspheres at the bottom, washing with distilled water, and freeze-drying to obtain the polylactic acid/rifampicin drug-loaded microspheres.
2. The method for preparing the traceable polylactic acid/rifampicin drug-loaded microsphere according to claim 1, wherein the molecular weight of the polylactic acid in the step 1) is 3-64 KDa, and poly-l-lactic acid, poly-d-lactic acid or a mixture of the two is adopted; the mass concentration of the ioversol contrast agent solution is 1%; the weight ratio of the emulsion to ioversol contrast agent solution to TPP is 400: 5-15: 1.
3. the method for preparing the traceable polylactic acid/rifampicin drug-loaded microsphere according to claim 1, wherein the number of times of washing with distilled water in the step 4) is 3 to 5.
4. A traceable polylactic acid/rifampicin drug-loaded microsphere prepared according to the method of preparing the traceable polylactic acid/rifampicin drug-loaded microsphere of any one of claims 1-3.
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