Degradable drug-loaded microspheres as well as preparation method and application thereof
Degradable drug-loaded microspheres prepared using microfluidic technology have achieved targeted drug release in the treatment of adenomyosis, solving the problems of short drug half-life and repeated injections in existing technologies, and improving treatment compliance and efficacy.
Patent Information
- Application Number
- CN202511277739.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-09
- Publication Date
- 2025-11-28
AI Technical Summary
Existing targeted injection drugs for the treatment of adenomyosis have short half-lives, require repeated injections, may cause local tissue fibrosis and side effects, affecting compliance and efficacy.
Degradable drug-loaded microspheres were prepared using microfluidic technology. The drug was then released in the myometrium via a microfluidic chip device. A uniform coating layer was formed using degradable polymers and surfactants to achieve stable drug release.
This achieves a long-term stable concentration of the drug at the adenomyosis lesion site, avoiding repeated injections, reducing side effects, improving compliance, and lowering the recurrence rate.
Smart Images
Figure CN121015589A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biodegradable drug-loaded microspheres, specifically to a biodegradable drug-loaded microsphere, its preparation method, and its application. Background Technology
[0002] Adenomyosis is a benign gynecological disease characterized by the invasion of endometrial glands and stroma into the myometrium, accompanied by proliferation of the surrounding myometrium. Treatment for adenomyosis primarily includes medication and surgery. Medication is used throughout the entire treatment process and requires long-term management to control disease progression and prevent recurrence.
[0003] Current drug treatments for adenomyosis mainly include combined oral contraceptives, oral progestins, LNG-IUS, GnRH agonists (GnRHa), GnRH antagonists, dinogest, danazol, and some experimental drugs such as aromatase inhibitors, antiplatelet drugs, and oxytocin antagonists. While drug treatment for adenomyosis has some effect, its side effects should not be ignored. These include gastrointestinal reactions such as nausea, vomiting, and diarrhea; endocrine disorders leading to irregular menstrual cycles, reduced menstrual flow, or amenorrhea; and long-term or high-dose use may damage liver cells and cause abnormal liver function.
[0004] Currently, common drug administration methods include oral administration and targeted injection. Targeted injection therapy for adenomyosis precisely targets the lesion, improving local efficacy and reducing systemic exposure, thus enhancing treatment effectiveness while reducing side effects. This is more advantageous than oral administration. However, commonly used targeted injection drugs have a short half-life, and the complex blood supply to the myometrium makes the drugs easily metabolized or eliminated rapidly. Long-term symptom control requires repeated injections, which not only increases patient suffering but may also reduce compliance and lead to local tissue fibrosis, affecting subsequent drug absorption and further reducing efficacy. Summary of the Invention
[0005] This invention provides an application of microfluidic technology-based biodegradable drug-loaded microspheres in targeted therapy for adenomyosis. The microspheres directly target the myometrium, stably release the drug, avoid repeated injections, reduce blood drug concentration, and thus reduce adverse reactions caused by hormone therapy.
[0006] On one hand, a biodegradable drug-loaded microsphere is characterized by comprising a dispersed phase and a continuous phase, wherein the continuous phase forms a uniform coating layer on the surface of the dispersed phase via a microfluidic chip device; the dispersed phase comprises a biodegradable polymer, an organic solvent, and a loaded drug; and the continuous phase comprises a surfactant and water.
[0007] Furthermore, the degradable polymers in the dispersed phase include any one or more blends of lactic acid, polyglycolic acid, polytrimethylene carbonate, polyβ-hydroxybutyrate, lactic acid-glycolic acid copolymer, and polycaprolactone.
[0008] Furthermore, the organic solvent in the dispersed phase includes any one or more of chloroform, dichloromethane, and ethyl acetate.
[0009] Furthermore, the drug loaded in the dispersed phase includes any one or more of mifepristone and GnRHa drugs.
[0010] Furthermore, in the dispersed phase, the mass of the drug loaded is 5%-40% of the mass of the degradable polymer, and the mass of the degradable polymer is 2%-30% of the mass of the organic solvent.
[0011] Furthermore, the surfactant in the continuous phase is any one or a mixture of several of the following: vitamin E polyethylene glycol succinate, sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene polymer, lecithin, sodium lauryl sulfate, and poloxamer 188.
[0012] Furthermore, in the continuous phase, the mass of the surfactant is 1%-10% of the water.
[0013] On the one hand, the preparation method of biodegradable drug-loaded microspheres includes the following steps:
[0014] The drug-loaded component and the biodegradable polymer are dissolved in an organic solvent to form a microfluidic dispersed phase; the surfactant is dissolved in water to form a microfluidic continuous phase; using a microfluidic chip, the outer phase is the continuous phase and the inner phase is the dispersed phase. The dispersed phase and the continuous phase are injected into a T-shaped microchannel through polytetrafluoroethylene tubing. The flow rate of the dispersed phase is 0.1-20 mL / h, and the flow rate of the continuous phase is 1-200 mL / h. After polymer droplets are generated, the polymer droplets are collected, solidified, washed, and dried to obtain biodegradable drug-loaded microspheres.
[0015] Furthermore, the flow channel size of the microfluidic chip is 10-500μm, the number of washing cycles can be 2-5, the solvent removal is carried out in an open container at a temperature of 25-60℃, and the drying time is 6-12h.
[0016] On the other hand, there is the application of biodegradable drug-loaded microspheres in the preparation of drugs for targeted treatment of adenomyosis.
[0017] The beneficial effects of this invention are:
[0018] The biodegradable drug-loaded microspheres prepared in this invention are based on microfluidic technology. They are fabricated using a T-shaped microfluidic chip with a simple structure, easy to process and manipulate, and capable of rapid mixing of the internal and external phases. By precisely adjusting the ratio of the internal and external phases, uniform droplet formation and consistent microsphere size are ensured, thereby improving the quality of the microspheres. These biodegradable drug-loaded microspheres are used in the preparation of therapeutic drugs for adenomyosis. Targeted injection of these microspheres at the adenomyosis lesion site achieves a long-term stable drug concentration at the target lesion, avoiding repeated injections and significantly reducing the inconvenience and hassle of repeated drug administration in clinical treatment. This effectively alleviates patient symptoms and reduces the recurrence rate of adenomyosis, demonstrating high clinical value. Attached Figure Description
[0019] Figure 1 Schematic diagram of microspheres for microfluidic control;
[0020] Figure 2 This is an optical micrograph of the drug-loaded microsphere S2 from Example 2. Detailed Implementation
[0021] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.
[0022] The microfluidic chip was purchased from Juwei Fuzhong Technology Co., Ltd., model number Regular Serial 002-01, a 100-micron wide T-channel chip. A schematic diagram of the microfluidic microsphere is shown below. Figure 1 As shown.
[0023] Example 1
[0024] 0.2 g of dinogest and 1.0 g of PCL were fully dissolved in 10 mL of dichloromethane to form a microfluidic dispersion.
[0025] 1.0 g of VE-TPGS was fully dissolved in 50 mL of water to form a continuous phase for microfluidics.
[0026] The above solutions were injected into a 20 μm channel microfluidic chip via polytetrafluoroethylene tubing. The dispersed phase flow rate was 1 mL / h, and the continuous phase flow rate was 15 mL / h. The resulting polymer droplets were placed in a 100 mL beaker and evaporated in a fume hood at 40 °C for 6 h with magnetic stirring at 400 rpm. Subsequently, the microspheres were washed three times with anhydrous ethanol and vacuum dried for 8 h to obtain biodegradable drug-loaded microsphere sample S1.
[0027] Example 2
[0028] 0.2 g of dinogest and 1.0 g of PCL were fully dissolved in 10 mL of dichloromethane to form a microfluidic dispersion.
[0029] 1.0 g of VE-TPGS was fully dissolved in 50 mL of water to form a continuous phase for microfluidics.
[0030] The above solutions were injected into a 20 μm channel microfluidic chip via polytetrafluoroethylene tubing. The dispersed phase flow rate was 10 mL / h, and the continuous phase flow rate was 15 mL / h. The resulting polymer droplets were placed in a 100 mL beaker and evaporated in a fume hood at 40 °C for 6 h with magnetic stirring at 400 rpm. The microspheres were then washed three times with anhydrous ethanol and vacuum dried for 8 h to obtain biodegradable drug-loaded microsphere sample S2. Optical micrographs are shown below. Figure 2 As can be seen, the microspheres have a uniform particle size.
[0031] Example 3
[0032] 0.2 g of dinogest and 1.0 g of PCL were fully dissolved in 10 mL of dichloromethane to form a microfluidic dispersion.
[0033] 1.0 g of VE-TPGS was fully dissolved in 50 mL of water to form a continuous phase for microfluidics.
[0034] The above solutions were injected into a 20 μm channel microfluidic chip via polytetrafluoroethylene tubing. The dispersed phase flow rate was 1 mL / h, and the continuous phase flow rate was 150 mL / h. The resulting polymer droplets were placed in a 100 mL beaker and evaporated in a fume hood at 40 °C for 6 h with magnetic stirring at 400 rpm. Subsequently, the microspheres were washed three times with anhydrous ethanol and vacuum dried for 8 h to obtain biodegradable drug-loaded microsphere sample S3.
[0035] test
[0036] Microsphere average particle size test:
[0037] Standardized analysis was performed using a laser particle size analyzer. For samples S1, S2, and S3 in the above embodiments, the microsphere size was measured using a laser particle size analyzer.
[0038] The optical micrograph of sample S2 is shown below. Figure 2 As shown, the microspheres have uniform particle size, good dispersibility, and no aggregation.
[0039] Testing of drug loading capacity of microspheres:
[0040] First, a quantitative working curve for the drug was established. A small amount of the drug was dissolved in dichloromethane, and the UV-Vis absorption spectrum of the drug was measured in a quartz cuvette, using the maximum peak value as the detection wavelength. Subsequently, dichloromethane standard solutions with drug concentrations of 0, 0.001, 0.01, and 0.1 mg / mL were prepared, and the corresponding UV absorbance values at different drug concentrations were measured to create a working curve relating concentration and absorbance. A certain mass m1 of dried microspheres was accurately weighed, dissolved in dichloromethane, and its UV absorbance value was measured. The drug content m2 was calculated using the working curve, and the drug loading was calculated as m2 / m1 × 100%. For samples S1, S2, and S3 in the above examples, 1 mg of dinogest was accurately weighed, dissolved in 1 mL of dichloromethane to prepare a 1 mg / mL solution, and the UV-Vis absorption spectrum of the drug was measured in a quartz cuvette, with the maximum absorption wavelength being 300 nm. The above solution was diluted with dichloromethane to prepare standard solutions with drug concentrations of 0, 0.001, 0.01, and 0.1 mg / mL, respectively. The absorbance was measured at the maximum absorption wavelength of 300 nm to create a working curve showing the relationship between concentration and absorbance. The content of dinogest in each sample was calculated using the working curve, and the corresponding drug loading was also calculated. The test results are shown in Table 1. S1 showed the best drug loading, indicating that the dispersed phase flow rate and continuous phase flow rate were optimal for preparing S1.
[0041] Table 1. Particle size and drug loading of microspheres in the examples.
[0042] sample S1 S2 S3 Particle size (μm) 12.5±2.7 17.6±3.6 8.3±1.9 Drug loading (%) 15.1±1.8 13.5±2.1 14.5±1.2
[0043] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered illustrative and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the scope of the invention. No reference numerals in the claims should be construed as limiting the scope of the claims.
[0044] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims
1. A degradable drug-loaded microsphere, characterized in that, The microspheres are prepared by microfluidic chip device, and the continuous phase forms a uniform coating layer on the surface of the dispersed phase.
2. The degradable drug-loaded microspheres according to claim 1, characterized in that, The degradable polymer in the dispersed phase includes any one or a blend of several of lactic acid, polyglycolic acid, polytrimethylene carbonate, poly-β-hydroxybutyric acid, lactic acid-glycolic acid copolymer and polycaprolactone.
3. The degradable drug-loaded microspheres according to claim 1, characterized in that, The organic solvent in the dispersed phase includes any one or several of chloroform, dichloromethane and ethyl acetate.
4. The degradable drug-loaded microspheres according to claim 1, characterized in that, The drug in the dispersed phase includes any one or several of mifepristone and GnRHa drugs.
5. The degradable drug-loaded microspheres according to claim 1, characterized in that, In the dispersed phase, the mass of the drug is 5%-40% of the mass of the degradable polymer, and the mass of the degradable polymer is 2%-30% of the mass of the organic solvent.
6. The degradable drug-loaded microspheres according to claim 1, characterized in that, The surfactant in the continuous phase is a mixture of any one or several of vitamin E polyethylene glycol succinate, sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene polymer, lecithin, sodium dodecyl sulfate and poloxamer 188.
7. The degradable drug-loaded microspheres according to claim 1, characterized in that, In the continuous phase, the mass of the surfactant is 1%-10% of the mass of the water.
8. A method of preparing the degradable drug-loaded microspheres according to any one of claims 1-8, characterized in that, The method comprises the following steps: The drug and the degradable polymer are dissolved in the organic solvent to form the dispersed phase of the microfluidic chip, and the surfactant is dissolved in water to form the continuous phase of the microfluidic chip; the outer phase is the continuous phase, the inner phase is the dispersed phase, the dispersed phase and the continuous phase are injected into the T-shaped microchannel through the polytetrafluoroethylene pipeline, the flow rate of the dispersed phase is 0.1-20 mL / h, the flow rate of the continuous phase is 1-200 mL / h, the polymer droplets are collected after the polymer droplets are generated, solidified, washed and dried to obtain the degradable drug-loaded microspheres.
9. The method for preparing biodegradable drug-loaded microspheres according to claim 8, characterized in that, The flow channel size of the microchannel chip is 10-500 μm, the number of washing can be 2-5 times, the desolvation is carried out in an open container, the temperature is 25-60°C, and the drying time is 6-12 h.
10. The use of the degradable drug-loaded microspheres according to any one of claims 1-7 in the preparation of a medicament for targeted treatment of uterine adenomyosis.