CN114469888A - Drug-loaded yeast microcapsule pharmaceutical preparation and preparation method thereof - Google Patents
Drug-loaded yeast microcapsule pharmaceutical preparation and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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Abstract
The invention belongs to the field of pharmaceutical preparations, and discloses a preparation method and application of an adriamycin oral drug delivery system. The invention wraps the nano zinc oxide carrying the adriamycin in the microzyme cell wall particles to ensure that the medicine can not leak in the gastrointestinal tract. The invention prepares the nano zinc oxide drug carrier by an alkali precipitation method, and loads the broad-spectrum anti-tumor drug adriamycin by electrostatic action. The nanometer zinc oxide has good biodegradability and high drug-loading rate, can reduce the toxic and side effects of the carrier on organisms, and the microzyme cell wall particles can specifically target M cells in gastrointestinal tract Peltier-type knots, so that the loaded drug enters lymphatic circulation. In vitro pharmacodynamic test researches show that the yeast microcapsule can obviously improve the antitumor effect of the adriamycin and has good application prospect in the aspect of improving the treatment effect of the adriamycin.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a drug-loaded yeast microcapsule pharmaceutical preparation and a preparation method and application thereof.
Background
Doxorubicin (DOX) is used as a broad-spectrum antitumor drug, has extremely strong antitumor effect, has good inhibitory action to multiple tumors, at present, the administration mode of DOX is usually injection administration, but DOX solubility is low, the curative effect is poor, lack the targeting ability, the oxic side effect is strong, and long-term application DOX is apt to appear drug resistance, reduce the curative effect of medication, has limited DOX in clinical application, therefore, construct a new oral targeting antitumor drug delivery system, reduce DOX in the distribution of the normal tissue, reduce the adverse reaction of the medicament, reduce the toxicity of DOX, it is necessary to improve the curative effect of DOX effectively, meanwhile, oral administration is the most convenient and the most safe clinical administration route too. Nanometer zinc oxide is used as a low-cost nanometer material, is certified by the food and drug administration as one of five metal oxides which can be safely applied to food and drug, and becomes a better choice of a drug carrier due to the advantages of good biodegradability, high drug loading capacity and the like, but the nanometer zinc oxide can be dissolved under an acidic condition and is difficult to pass through the environment of gastric acid, so that the nanometer zinc oxide with a biological shell is a better choice. The yeast microcapsule is derived from yeast cells, is cheap and easy to obtain, has safety, is suitable for being used as a drug delivery system of a medicament, and simultaneously, the main component beta-1, 3-d-glucan of the yeast microcapsule can be specifically targeted to M cells of intestinal tracts, and then is taken up by macrophages to enter lymphatic circulation, so that the accumulation of the medicament at a tumor part is realized, and the bioavailability of the medicament in a body is improved.
Disclosure of Invention
The invention aims to provide an oral antitumor drug delivery system, namely a drug-loaded yeast microcapsule preparation, which can reduce the side effect of chemotherapeutic drugs and enhance the treatment effect. The drug delivery system prepared by the invention has good stability and convenient use, and provides a new idea for the oral administration mode of DOX.
The technical scheme adopted by the invention is as follows: a drug-loaded yeast microcapsule drug preparation comprises drug-loaded nano-zinc oxide and a yeast microcapsule, wherein the drug-loaded nano-zinc oxide is deposited inside the yeast microcapsule through electrostatic interaction.
Preferably, the drug-loaded yeast microcapsule pharmaceutical preparation is obtained by edible yeast.
Preferably, in the drug-loaded yeast microcapsule pharmaceutical preparation, the zinc oxide is modified by 3-mercaptopropionic acid in the synthesis process.
Preferably, in the drug-loaded yeast microcapsule pharmaceutical preparation, the drug loaded in the drug-loaded nano zinc oxide is adriamycin.
The preparation method of the drug-loaded yeast microcapsule pharmaceutical preparation comprises the following steps:
1) edible yeast is used for removing the content and remaining the shell for use;
2) dissolving zinc chloride in a solution of water and alcohol, and adding 3-mercaptopropionic acid into the solution; adding sodium hydroxide until the pH value is 11, and continuing the reaction for 24 hours;
3) mixing and stirring the zinc oxide carrying the medicine and the adriamycin for 24 hours;
4) modifying the cell wall of the saccharomycete by using polyethyleneimine;
5) mixing and stirring the modified yeast cell wall and the drug-loaded nano zinc oxide solution.
Preferably, in the above method for preparing a drug-loaded yeast microcapsule pharmaceutical preparation, in step 1), the edible yeast is subjected to acid-base content removal.
Preferably, in the above preparation method of a drug-loaded yeast microcapsule pharmaceutical preparation, in step 2), in the solution of water and alcohol, the volume ratio of water to alcohol is 1: 1.
preferably, in the above method for preparing a drug-loaded yeast microcapsule pharmaceutical preparation, in step 2), the concentration of the sodium hydroxide solution is 2M.
Preferably, in the above method for preparing a drug-loaded yeast microcapsule pharmaceutical formulation, in step 5), the mixing and stirring conditions are kept in the dark.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention deposits the drug-loaded nano zinc oxide in the yeast microcapsule through electrostatic adsorption, loads the broad-spectrum anti-tumor drug DOX, is used for oral administration, and is proposed for the first time.
2. Currently, intravenous injection is the common mode of administration of DOX. Compared with other administration modes, the oral administration mode has good patient compliance and safety, is the administration mode which is widely applied at present, but has poor DOX oral administration absorption, low bioavailability and strong gastrointestinal tract corrosion effect, and the medicine-carrying yeast microcapsule prepared by the invention can improve the problems.
3. The yeast microcapsule is derived from common baker's yeast, the main component of the yeast microcapsule is beta-1-3-d-glucan, and the yeast microcapsule can be phagocytized by macrophages through intestinal M cells after being orally taken and enters lymphatic circulation, so that the yeast microcapsule is accumulated at a tumor part based on the inflammation trend action of the macrophages, and the bioavailability of the medicine is improved; meanwhile, the yeast microcapsules cover the yeast microcapsules, so that the leakage of the medicine in the gastrointestinal tract is reduced, the administration dosage and toxic and side effects are reduced, the medicine can play a better treatment role in vivo, and a new possibility is provided for the oral research of DOX.
In a word, the novel oral administration preparation prepared by depositing the drug-loaded nano zinc oxide in the yeast microcapsules can improve the anti-tumor effect of the drug and is beneficial to the better therapeutic effect of the drug in vivo.
Drawings
In FIG. 1, A is the transmission electron microscope image of yeast, B is the transmission electron microscope image of blank yeast microcapsule; c is the particle size diagram of yeast, D is the particle size diagram of blank yeast microcapsule; e is the potential diagram of the yeast, and F is the potential diagram of the blank yeast microcapsule.
In FIG. 2, A is the potential diagram of the drug-loaded yeast microcapsules, and B is the transmission electron microscope diagram of the drug-loaded yeast microcapsules.
Fig. 3 is a graph of the release effect of the drug-loaded yeast microcapsules in artificial simulated gastric fluid and artificial simulated intestinal fluid.
FIG. 4 is a graph showing the release effect of the drug-loaded yeast microcapsules in a simulated tumor environment.
Detailed Description
The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1 preparation of Yeast Microcysts carrying drugs
Preparing medicine-carrying nano zinc oxide: 0.129g of ZnCl was weighed2Dissolved in 60mL ethanol: to the water (1: 1) solution, 0.2mL of 3-mercaptopropionic acid (MPA) was added, after which the pH was rapidly adjusted to about 11 with a 2M NaOH solution, after which stirring was carried out at room temperature for 24 hours to obtain the product, which was dried under vacuum.
Preparation of blank yeast microcapsules: 15g baker's yeast, dispersed in 250mL NaOH (1M) solution, stirred at 80 ℃ for 1 hour, centrifuged at 3000rpm for 10min, the obtained precipitate was washed with deionized water, dispersed in 250mL deionized water, adjusted to pH 4-5 with HCL, stirred at 60 ℃ for 1 hour, centrifuged at 3000rpm for 10min, the obtained precipitate was washed with deionized water, the supernatant was removed, washed twice with isopropanol and acetone, and the precipitate was vacuum dried for 24 hours.
The particle size, Zeta potential and appearance of the yeast and blank yeast microcapsules are measured by a particle size analyzer and a transmission electron microscope.
As shown in FIG. 1A, 1C, and 1E, the yeast has particle diameter of 4641nm, potential of-17.4 mV, and is round-like and opaque under transmission electron microscope. As can be seen from FIGS. 1B, 1D and 1F, the treated yeast microcapsules have particle size of 4020nm, potential of-4.98 mV, and a porous and hollow structure under a transmission electron microscope. The contents of the yeast are mostly removed compared to before treatment.
Preparing a drug-loaded yeast microcapsule: firstly, incubating 10mg of yeast microcapsules and 5mg of Polyethyleneimine (PEI) in 1mL of carbonate buffer solution, thoroughly washing with deionized water, then dispersing the PEI-modified yeast microcapsules in a drug-loaded nano zinc oxide solution for stirring and mixing for 4 hours, centrifuging at 3000rpm for 10min, and obtaining a precipitate, and drying in vacuum.
The particle size, Zeta potential and appearance of the yeast microcapsule are measured by a particle size analyzer and a transmission electron microscope.
For example, fig. 2A is the potential of the drug-loaded yeast microcapsule, which shows that the potential of the drug-loaded yeast microcapsule is +5.03mV, and fig. 2B is the transmission electron microscope image of the drug-loaded yeast microcapsule, which shows that the drug-loaded nanoparticles appear in the yeast microcapsule.
Example 2 gastrointestinal tract stability experiment and simulated tumor environmental release experiment of drug-loaded yeast microcapsules
Gastrointestinal stability experiments: preparing 50mL of artificial gastric juice (containing pepsin) and 50mL of artificial intestinal juice (containing trypsin), preheating a constant-temperature water bath oscillator to 37 ℃, taking a proper amount of single carrier drug and yeast microcapsule drug to respectively shake in the artificial gastrointestinal juice, sampling 2mL of the single carrier drug and the yeast microcapsule drug, feeding the same amount of the artificial gastric juice (artificial intestinal juice) for 10min,30min,1h,1.5h,2h,3h,4h,5,6h,7h and 8h, filtering the sample by using a 0.25 mu m filter head, injecting the sample, calculating the amount of DOX retained in the single carrier and the drug-loaded yeast microcapsule, and showing that the retention curve is shown in figure 3, as can be seen, the retention amount of the DOX in the drug-loaded yeast microcapsule is all over 80 percent after the single carrier is incubated for 11 hours in the artificial simulated gastrointestinal juice, and the retention amount of the drug is lower than that of the yeast microcapsule drug is retained in the drug-loaded yeast microcapsule after the single carrier is incubated for 11 hours under the same condition, which shows that the cell wall prevents the drug from leaking in the stomach and the stomach to a certain degree, has good protection effect on the medicine.
Tumor environment release simulation experiment: preparing 50mL of PBS solution with the pH value of 6.5, simulating a tumor environment, preheating a constant-temperature water bath oscillator to 37 ℃, taking a proper amount of individual carrier drug-loaded yeast microcapsules and appropriate amount of individual carrier drug-loaded yeast microcapsules to vibrate in a simulated tumor body fluid respectively, sampling 2mL of the individual carrier drug-loaded yeast microcapsules and supplementing equivalent simulated tumor body fluid in 15min,30min,1h,2h,4h,7h,10h,24h,32h,48h,72h,96h,120h,144h,168h and 192h, filtering the samples by using a 0.25 mu m filter head, injecting samples, calculating the DOX amount released by the individual carrier and the individual carrier drug-loaded yeast microcapsules, wherein a release curve is shown in figure 4, and as can be seen, after incubating for 8 days (192 hours) in the simulated tumor environment, compared with the individual carrier, the drug in the drug-loaded yeast microcapsules is released obviously slowly, which indicates that a drug release effect is achieved to a certain extent.
EXAMPLE 3 pharmacodynamic experiment of Yeast Microcapsules carrying drugs
Method for determining the growth inhibitory activity (IC50) of HepG-2 cells: HepG-2 cells in the logarithmic growth phase were trypsinized and individually suspended in DMEM medium containing penicillin (25U/mL) and streptomycin (25. mu.g/mL). The cells were seeded on a 96-well plate and cultured in an incubator for 24 hours (37 ℃ C., 5% CO content)2Air, relative humidity 100%), adding a culture solution containing a series of test samples (equivalent to an equivalent amount of adriamycin) at a concentration of 2 wells in each concentration, incubating for 48 hours, adding 20 μ L of 5mg/mL MTT to each well, incubating for 4 hours under the same conditions, adding DMSO to dissolve, shaking on a shaker for 5min to accelerate dissolution of purple crystals, and measuring the optical density of each well using a microplate reader at 490 nm. Calculating the cell inhibition rate:
the cell inhibition rate was 100% (1-OD490 administration group/OD 490 negative control group).
TABLE 1
The table 1 shows the inhibition effect of adriamycin, zinc oxide drug and the drug-loaded yeast microcapsule on HepG-2 liver cancer cells, and the drug-loaded yeast microcapsule disclosed by the invention shows excellent anti-tumor effect as an anti-tumor agent and can be used for preventing and treating diseases.
Claims (9)
1. A drug-loaded yeast microcapsule drug preparation is characterized by comprising drug-loaded nano zinc oxide and a yeast microcapsule, wherein the drug-loaded nano zinc oxide is deposited inside the yeast microcapsule through electrostatic interaction.
2. The drug-loaded yeast microcapsule pharmaceutical formulation according to claim 1, wherein the yeast microcapsules are obtained from edible yeast.
3. The drug-loaded yeast microcapsule pharmaceutical preparation according to claim 1, wherein the drug-loaded nano-zinc oxide is modified by 3-mercaptopropionic acid in the synthesis process.
4. The drug-loaded yeast microcapsule pharmaceutical preparation according to claim 1, wherein the drug loaded in the drug-loaded nano zinc oxide is doxorubicin.
5. The method for preparing the drug-loaded yeast microcapsule pharmaceutical preparation according to claim 1, which is characterized in that: the preparation method comprises the following steps:
1) edible yeast is used for removing the content and remaining the shell for use;
2) dissolving zinc chloride in a solution of water and alcohol, and adding 3-mercaptopropionic acid into the solution; adding sodium hydroxide until the pH value is 11, and continuing the reaction for 24 hours;
3) mixing and stirring the zinc oxide carrying the medicine and the adriamycin for 24 hours;
4) modifying the cell wall of the yeast by using polyethyleneimine;
5) mixing and stirring the modified yeast cell wall and the drug-loaded nano zinc oxide solution.
6. The method for preparing a drug-loaded yeast microcapsule pharmaceutical preparation according to claim 5, wherein the method comprises the following steps: in step 1), the edible yeast removes the content by acid and alkali.
7. The method for preparing a drug-loaded yeast microcapsule pharmaceutical preparation according to claim 5, wherein the method comprises the following steps: in the step 2), in the solution of water and alcohol, the volume ratio of water to alcohol is 1: 1.
8. the method for preparing a drug-loaded yeast microcapsule pharmaceutical preparation according to claim 5, wherein the method comprises the following steps: in step 2), the sodium hydroxide solution used had a concentration of 2M.
9. The method for preparing a drug-loaded yeast microcapsule pharmaceutical preparation according to claim 5, wherein the method comprises the following steps: in the step 5), the conditions required for mixing and stirring are light shielding.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060127489A1 (en) * | 2002-10-24 | 2006-06-15 | Michael Crothers | Targeted delivery |
| CN105168180A (en) * | 2015-09-30 | 2015-12-23 | 中国人民解放军第三军医大学 | Oral targeted carrier system based on yeast capsules and preparation method of oral targeted carrier system |
| CN112791068A (en) * | 2021-02-08 | 2021-05-14 | 郑州大学 | CO (carbon monoxide)2Preparation method and application of responsive micro-nano drug delivery system |
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- 2022-03-14 CN CN202210245820.1A patent/CN114469888A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060127489A1 (en) * | 2002-10-24 | 2006-06-15 | Michael Crothers | Targeted delivery |
| CN105168180A (en) * | 2015-09-30 | 2015-12-23 | 中国人民解放军第三军医大学 | Oral targeted carrier system based on yeast capsules and preparation method of oral targeted carrier system |
| CN112791068A (en) * | 2021-02-08 | 2021-05-14 | 郑州大学 | CO (carbon monoxide)2Preparation method and application of responsive micro-nano drug delivery system |
Non-Patent Citations (2)
| Title |
|---|
| S.-B. GHAFFARI ET AL.: ""Functionalization of ZnO nanoparticles by 3-mercaptopropionic acid for aqueous curcumin delivery:Synthesis, characterization, and anticancer assessment"", 《MATERIALS SCIENCE AND ENGINEERING C》 * |
| 车玲: ""含羧基小分子药物介导亲水聚合物自组装构建纳米给药系统研究"", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
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