CN114748427B - Mifepristone solid lipid nanoparticle and preparation method thereof - Google Patents
Mifepristone solid lipid nanoparticle and preparation method thereof Download PDFInfo
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Abstract
The invention provides mifepristone solid lipid nanoparticles and a preparation method thereof, wherein mifepristone is loaded on the nanoparticles, the nanomaterial consists of glyceryl monostearate and oleic acid (or soybean phospholipid), and the loaded mifepristone accounts for 10% of the total nanoparticles. The invention adopts a solvent diffusion method to prepare mifepristone SLN. The preparation method improves the traditional preparation method, fully considers the advantages of simple operation, rapid production process, easy realization and the like, and adopts a solvent diffusion method to prepare mifepristone solid lipid nanoparticles. The preparation method has reasonable design, simple and convenient operation, rapid production process and easy realization. Compared with the common SLN preparation method by high-pressure emulsion or microemulsion, the preparation method has the advantages of low cost, simple and convenient operation, rapid generation process, simple equipment and easy realization, and most importantly, the in-vitro release drug burst release amount is small and the drug encapsulation rate is relatively high.
Description
Technical Field
The invention belongs to the field of pharmacy, relates to targeting nanoparticles and preparation, and in particular relates to mifepristone solid lipid nanoparticles and a preparation method thereof.
Background
Mifepristone, developed by Roussel-ucraf, france, is a progestin receptor antagonist that was originally used to terminate early pregnancy. Currently, research on other indications of mifepristone is increasing, and the diseases are relatively wide, such as endometriosis, adenomyosis, endometrial cancer, ovarian cancer, breast cancer, cervical cancer, cushing's syndrome, depression and the like, and some researches are still in the in vitro experimental research stage. Despite the numerous therapeutic effects of mifepristone, the therapeutic effects are still far from ideal, particularly where the drug is difficult to accumulate at the tissue site of interest, and in order to address these issues, efforts have been made to develop drug delivery systems, such as nanodrug delivery systems, to deliver active molecules to desired targets in order to improve the efficacy, safety, physicochemical properties and pharmacokinetic/pharmacodynamic profile of the drug.
Solid lipid nanoparticles (solid lipid nanoparticles, SLN), introduced in the beginning of the 90 s of the last century, are considered as an alternative to polymer microparticles, nanosystems, a very promising drug delivery system that allows drugs with longer circulation times, more specific targeting and higher efficacy, and more importantly, in a biomimetic manner to reduce toxicity.
Disclosure of Invention
The invention aims to provide mifepristone solid lipid nanoparticles, which are loaded with mifepristone, wherein the nanomaterial of the mifepristone solid lipid nanoparticles consists of glyceryl monostearate and oleic acid (or soybean phospholipid), the ratio of the glyceryl monostearate to the oleic acid (or soybean phospholipid) is 3:2, and the loaded mifepristone accounts for 10% of the total nanoparticles.
The invention also aims to provide a preparation method of the mifepristone solid lipid nanoparticle, which is realized by the following steps:
the mifepristone SLN is prepared by a solvent diffusion method. Glycerin monostearate and oleic acid (or soybean phospholipid) were dissolved in ethanol to prepare 100mg/mL of mother liquor, and heated in a water bath at 70 ℃. Then 600. Mu.L of glyceryl stearate and 400. Mu.L of oleic acid (or soybean lecithin) solution are mixed, 100. Mu.L of fepristone (100 mg/mL) ethanol solution is added into the lipid solution and is complemented to 5mL by ethanol, then the mixture is rapidly injected into 50mL of poloxamer 188 containing solution (0.1% w/v) at the water bath 70 ℃ and the stirring speed of 400r/min, stirring is continued for 48h, and then the superfluous free medicine is removed by using an ultrafiltration centrifugation method (ultrafiltration tube 12000r/min,15 min) to obtain the mifepristone solid lipid nanoparticles.
The preparation method improves the traditional preparation method, fully considers the advantages of simple operation, rapid production process, easy realization and the like, and adopts a solvent diffusion method to prepare mifepristone solid lipid nanoparticles. The preparation method has reasonable design, simple and convenient operation, rapid production process and easy realization. Compared with the common SLN preparation method by high-pressure emulsion or microemulsion, the preparation method has the advantages of low cost, simple and convenient operation, rapid generation process, simple equipment and easy realization, and most importantly, the in-vitro release drug burst release amount is small and the drug encapsulation rate is relatively high.
Drawings
Fig. 1 is a schematic diagram of the preparation of mifepristone Solid Lipid Nanoparticles (SLNs) using solvent diffusion.
Fig. 2 is a transmission electron microscope image of mifepristone SLN.
Fig. 3 is an in vitro release profile of mifepristone SLN.
Fig. 4 is a confocal microscopy image of mifepristone SLN cell uptake.
FIG. 5 is a graph showing the effect of Transwell on cell migration of mifepristone SLN, wherein A is a control group; b is mifepristone SLN group.
Detailed Description
The invention is further described with reference to the drawings and examples.
Example 1: preparation of mifepristone solid lipid nanoparticles
Glycerin monostearate and oleic acid were dissolved in ethanol to prepare 100mg/mL of mother liquor, respectively, and heated in a water bath at 70 ℃. Then 600. Mu.L of glyceryl stearate and 400. Mu.L of oleic acid solution were mixed, 100. Mu.L of an ethanol solution of mifepristone (100 mg/mL) was added to the above lipid solution and made up to 5mL with ethanol, then the mixed organic phase was rapidly injected into a solution (0.1%, w/v) containing 50mL of poloxamer 188 at 70℃in a water bath and a stirring speed of 400r/min, stirring was continued for 48 hours as shown in FIG. 1, and then the excess free drug was removed using ultrafiltration centrifugation (ultrafiltration tube 12000r/min,15 min) to give mifepristone SLN.
FIG. 1 is a process of dissolving lipid and mifepristone in ethanol (organic phase) and then injecting into aqueous phase containing emulsifier (A); gradually diffusing the solvent into the aqueous phase (B); as the lipid concentration increases, the droplet breaks apart and the particle size slowly decreases (C); stable SLN (D) was formed.
The particle size, surface potential, drug encapsulation efficiency and drug loading were measured using a particle size and surface potential meter, respectively, for mifepristone SLN (table 1). The particle size and morphology were observed under a transmission electron microscope (see FIG. 2). SLN is spherical and has uniform particle size distribution.
TABLE 1 particle size, surface potential and drug encapsulation efficiency of mifepristone SLN
Example 2: preparation of mifepristone SLN nanoparticles
Glycerin monostearate and soybean phospholipid were dissolved in ethanol to prepare 100mg/mL of mother liquor, respectively, and heated in a water bath at 70 ℃. Then 600. Mu.L of glyceryl stearate and 400. Mu.L of soybean phospholipid solution were mixed, 100. Mu.L of ethanol solution of mifepristone (100 mg/mL) was added to the above lipid solution and made up to 5mL with ethanol, then the mixed organic phase was rapidly injected into a solution (0.1%, w/v) containing 50mL of poloxamer 188 at 70℃in water bath and a stirring speed of 400r/min, stirring was continued for 48 hours as shown in FIG. 1, and then the excess free drug was removed using ultrafiltration centrifugation (ultrafiltration tube 12000r/min,15 min) to give mifepristone SLN.
The particle size, surface potential, drug encapsulation efficiency and drug loading were measured using a particle size and surface potential meter, respectively, for mifepristone SLN (table 2).
TABLE 2 particle size, surface potential and drug encapsulation efficiency of mifepristone SLN
Example 3: mifepristone SLN drug delivery
1.0ml of mifepristone SLN liquid is taken and placed in a dialysis bag, ethanol and water (1:4) are taken as release mediums, the dialysis bag is placed in a 37 ℃ water bath for oscillation (100 r/min), and samples (0, 2h,4h,8h,24h,48h,72h,96h,120h and 168 h) are taken at different time points, and l.0ml of medium is taken out each time while l.0ml of medium is added, the concentration of the medicine is measured by an ultraviolet spectrophotometer, and the cumulative release rate is calculated. As shown in FIG. 3, mifepristone SLN can be slowly and stably released in an in-vitro environment, and the release time can be as long as 7 days.
Example 4: cellular uptake of mifepristone SLN
Cell culture: ectopic endometrial tissue obtained from endometriosis patients is sheared by surgical scissors, 0.1% type I collagenase is added for digestion for 1 hour at 37 ℃, residual tissue fragments are removed by a nylon cell sieve of 100 mu m, epithelial cells and interstitial cells are separated by a nylon cell sieve of 40 mu m, and the interstitial cells can pass through the cell sieve and enter the lower filtrate to obtain primary ectopic endometrial interstitial cells. Endometrial tissue obtained from a non-endometriotic patient was treated in the same manner as described above to obtain primary endometrial stromal cells. Patients who were included in the study all had a normal menstrual cycle and had no hormonal medication used for 3 months prior to surgery. Primary endometrial stromal cells were cultured in DMEM/F12 medium with 12% fetal bovine serum. Cellular uptake: after cell attachment, 4 control wells (nuclear staining with DAPI) were tested in 24-well cell plate wells with 2 μl (1 mg/mL) of FITC-labeled mifepristone SLN solution. After three washes with PBS at different time points (0, 1,2,4,8,24 h), the plates were observed by fluorescence microscopy. As a result, it was found (see FIG. 4) that mifepristone SLN can be introduced into cells within several hours, and is suitable for endocytosis of endometrial cells.
Example 5: mifepristone SLN inhibition of allogeneic cell migration
The effect of mifepristone SLN on cell migration was studied using a Transwell method. Cells were added with drug and mifepristone SLN for 36h, then digested with pancreatin and dispersed in serum-free medium, seeded in Transwell (Corning, 3422) upper chamber (5×104 cells, 200 mL), lower chamber added with 0.5mL of 10% serum-containing medium, and upper chamber cell dispersion continued to be added with the same drug concentration as in the previous treatment. After 12h incubation, the upper chamber was removed, fixed with crystal violet staining solution and stained, photographed by a laser confocal microscope, 5 fields were randomly selected for each sample, the number of stained cells was counted and averaged as the number of cells migrated for that sample. As a result, it was found (see FIG. 5) that the addition of mifepristone SLN significantly reduced the number of cells in the lower chamber, indicating that cell proliferation and migration can be inhibited.
The application examples show that the mifepristone SLN prepared by the invention has uniform particle size distribution, spherical particles with average size of 260-280nm, satisfactory drug loading and encapsulation rate, stable release, and can be taken up by endometriosis cells and inhibit the migration of the endometriosis cells.
Claims (2)
1. The preparation method of mifepristone solid lipid nanoparticles is characterized in that mifepristone is loaded on the nanoparticles, the nanomaterial of the mifepristone is composed of glyceryl monostearate and oleic acid or soybean phospholipid, wherein the proportion of the glyceryl monostearate to the oleic acid or the soybean phospholipid is 3:2, and the loaded mifepristone accounts for 10% of the total nanoparticles, and the preparation method is realized by the following steps:
respectively dissolving glyceryl monostearate and oleic acid or soybean phospholipid in ethanol to prepare 100mg/mL serving as mother solution, heating in a water bath at 70 ℃, mixing the glyceryl stearate and the oleic acid or soybean phospholipid solution, adding 100mg/mL of an ethanol solution of mifepristone into the lipid solution, supplementing the ethanol solution to 5mL, then mixing at 70 ℃ in the water bath at a stirring speed of 400r/min, rapidly injecting into a solution containing 50mL poloxamer 188, continuously stirring 48h, and removing excessive free medicine by using an ultrafiltration centrifugation method to obtain the mifepristone solid lipid nanoparticle.
2. The method according to claim 1, wherein the ultrafiltration centrifugation is performed using an ultrafiltration tube 12000r/min for 15 min.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102151250A (en) * | 2010-02-11 | 2011-08-17 | 王汀 | Novel preparation method of solid lipid nanoparticles |
| CN104771383A (en) * | 2015-03-25 | 2015-07-15 | 浙江大学 | Saquinavir phospholipid compound solid lipid nanoparticle and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102151250A (en) * | 2010-02-11 | 2011-08-17 | 王汀 | Novel preparation method of solid lipid nanoparticles |
| CN104771383A (en) * | 2015-03-25 | 2015-07-15 | 浙江大学 | Saquinavir phospholipid compound solid lipid nanoparticle and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Liposomes Co-Encapsulating Cisplatin/Mifepristone Improve the Effect on Cervical Cancer: In Vitro and In Vivo Assessment;Fabricio Ledezma-Gallegos 等;《Pharmaceutics》;第12卷(第9期);897 * |
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