CN113616623A - Microcapsule oral medicine based on yeast delivery carrier and preparation method and application thereof - Google Patents

Microcapsule oral medicine based on yeast delivery carrier and preparation method and application thereof Download PDF

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CN113616623A
CN113616623A CN202111062351.1A CN202111062351A CN113616623A CN 113616623 A CN113616623 A CN 113616623A CN 202111062351 A CN202111062351 A CN 202111062351A CN 113616623 A CN113616623 A CN 113616623A
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yeast
carrier
drug
microcapsule
oral
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杨青
杨君
侯佳男
刘田
屈明博
刘霖
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Dalian University of Technology
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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
    • A61K9/48—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
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/70—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
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/16—Yeasts; Culture media therefor
    • C12N1/18—Baker's yeast; Brewer's yeast

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Abstract

The invention discloses a yeast delivery carrier-based microcapsule oral drug, and a preparation method and application thereof, and belongs to the technical field of preparation of oral drug delivery carriers. The microcapsule oral medicament is a microcapsule oral medicament which takes yeast as a carrier to load isoquinoline alkaloid medicaments and releases the medicaments in intestinal tracts. The invention takes wild saccharomyces cerevisiae as a drug carrier, has low price and wide source, simultaneously yeast cells are widely applied to the food field, and the invention can be more prominent in the oral drug field and has obvious safety.

Description

Microcapsule oral medicine based on yeast delivery carrier and preparation method and application thereof
Technical Field
The invention belongs to the technical field of preparation of oral drug delivery carriers, and particularly relates to a yeast delivery carrier-based micro-capsule oral drug, and a preparation method and application thereof.
Background
The drug carrier is a system which can change the mode of entering the human body and the distribution of the drug in the human body, control the release speed of the drug and deliver the drug to a target organ. Controlled release systems for drugs have received attention because they improve the availability, safety and effectiveness of the drug, thereby reducing the frequency of drug administration. Oral administration is one of the most commonly used administration modes of pharmacotherapy, can ensure that the medicine is absorbed through gastrointestinal mucosa, has the advantages of simple administration mode, no direct damage to skin or mucosa, relatively low price and the like, and is particularly suitable for certain medicines which are not suitable for injection administration.
The oral drug carrier can be prepared into various dosage forms, and if the carried drug has certain bitter taste and is not beneficial to oral administration, the carried drug is usually prepared into micro-capsules, sugar-coated tablets and the like; if the medicine is affected by gastric acid too much, the medicine is usually prepared into enteric-coated tablets; if the medicine is wanted to play a role quickly, the medicine can also be prepared into forms of oral liquid, dispersing agent, soluble powder and the like; on the contrary, the medicine takes effect slowly, and can be made into sustained release tablets, sustained release microcapsules, etc.
Berberine, also known as berberine, is an isoquinoline alkaloid extracted from Coptidis rhizoma, and is the main component of Chinese medicinal Coptidis rhizoma for exerting its medicinal effect. Berberine hydrochloride is one of clinical application forms, can effectively inhibit the synthesis of microorganism DNA and protein, and is often used as a broad-spectrum antibacterial agent. More researchers find that berberine hydrochloride has certain functions in the aspects of anti-inflammation, antibiosis, tumor resistance, nerve protection, blood sugar reduction, blood fat reduction and the like, and is particularly used for treating tumor resistance and diabetes. However, berberine hydrochloride has poor water solubility and lipid solubility, and is usually only soluble in hot water. And because berberine hydrochloride injection has strong side effect and has death risk when serious, the berberine hydrochloride injection is forbidden in China at present. When the berberine hydrochloride is taken as an oral medicine, the gastric acid environment has certain destructiveness to the berberine hydrochloride, the absorption degree of an intestinal tract to the berberine hydrochloride is poor, so that the oral availability is low, and meanwhile, the berberine hydrochloride has certain bitter taste, so that the oral difficulty is increased, and therefore, the selection of a proper oral carrier has a far-reaching significance for the development and utilization of the berberine hydrochloride.
The yeast has wide sources and low price, is often used for packaging substances such as food, essence and the like, has certain guarantee on oral safety, has certain resistance to digestion of stomach and intestinal tract, and is gradually used for drug delivery at present, and Roshanak Salari and the like use yeast microcapsules to package berberine hydrochloride, but the yeast cells are treated by NaCl and the package of the berberine hydrochloride is realized through 72 hours of ultra-long drug loading time. Too long drug loading time has great influence on the hardness of yeast cell walls, resulting in the rapid release of berberine hydrochloride in a slightly acidic environment. However, berberine hydrochloride has a general inhibitory effect on escherichia coli in the environment, and has a good inhibitory effect on coliform bacteria in the intestinal tract, so that berberine hydrochloride can be rapidly released in a slightly acidic environment, and the medical application value of berberine hydrochloride cannot be well realized.
Disclosure of Invention
The technical problem to be solved by the invention is that saccharomyces cerevisiae which is widely available is used as a good oral drug carrier to prepare an oral drug delivery system with slow release performance, so that the controllable release and the fixed-point release of drugs in the field of oral drugs are realized, and the drugs are released in the gastric acid environment and the intestinal juice environment.
Therefore, the invention selects wild saccharomyces cerevisiae as an oral carrier form of berberine hydrochloride, determines a preparation method of a proper isoquinoline alkaloid-yeast microcapsule by characterizing the drug loading rate, the encapsulation rate, the form and the like, establishes a pH response system, slows down the release of the drug in gastric acid, enhances the controllable slow release of the drug in intestinal juice environment, improves the utilization rate of the drug and reduces the waste caused by the loss of the drug.
The first object of the present invention is to prepare suitable microencapsulated oral medicaments. The method utilizes the firm cell wall and proper micron-sized size of wild yeast to perform certain permeability treatment for drug loading.
The second purpose of the invention is to control the release of the drug in the intestinal tract and reduce the loss of the drug in gastric juice. By utilizing the characteristics of yeast cell walls, the microcapsule is kept to be stable in shape under the gastric acid condition, thereby protecting the medicine and reducing the loss. The specific operation steps are as follows: selecting proper drugs, proper drug loading time, determining the optimal material-drug ratio between the drugs and the carrier, and carrying out a drug release experiment after the drug loading is successful, wherein the drug release experiment is carried out under a water phase and a pH response system respectively.
A microcapsule oral medicament based on a yeast delivery carrier is prepared by loading isoquinoline alkaloid medicaments by taking yeast as a carrier to obtain the microcapsule oral medicament capable of releasing medicaments in intestinal tracts.
Further, in the above technical scheme, the ratio of the yeast carrier to the isoquinoline alkaloid aqueous solution is 0.5-2 g: 50-300 mg/mL.
Further, in the above technical scheme, the isoquinoline alkaloid includes at least one of berberine hydrochloride, berberine, 9-lauroyl berberine, tetrahydroberberine, coptisine, palmatine, jateorhizine, tetrahydropalmatine, and gentamicin.
A preparation method of a microcapsule oral medicine based on a yeast delivery carrier comprises the following steps:
(1) preparing a yeast vector: activating and expanding yeast, washing with ethanol and ultrapure water, centrifuging after washing, collecting thallus, and freeze drying;
(2) preparing a microcapsule oral medicament: and (2) preparing an isoquinoline alkaloid water solution, adding the yeast carrier obtained in the step (1) into the isoquinoline alkaloid water solution, stirring under a heating state, centrifuging and collecting a solid to obtain the yeast extract.
Further, in the above technical scheme, the concentration of ethanol in step (1) is 10% -20% (v/v).
Further, in the above technical scheme, the yeast activated in step (1) is specifically: preferably, the yeast is inoculated into the culture medium according to different growth states of the yeast, the activation is carried out for 14-18 h, 10-15 mL of activated bacteria liquid is taken to be subjected to propagation culture into 1L of fresh culture medium, and propagation culture is carried out for 18-24 h according to the growth states of the yeast.
Further, in the above technical solution, the concentration of the isoquinoline alkaloid aqueous solution in the step (2) is 2.5-6.25 mg/mL.
Further, in the above technical scheme, the stirring time in the step (2) is 4-24 h.
Further, in the above technical scheme, the ratio of the yeast carrier to the isoquinoline alkaloid aqueous solution is 0.5-2 g: 50-300 mg/mL.
Application of microcapsule oral medicine based on yeast delivery vehicle in preparing intestinal tract release medicine is provided.
For the above technical solution, preferably, the maximum drug loading rate is different according to different drug loading times and the action relationship between different drugs and carriers. The drug loading time is controlled within 4-24h, the drug loading system is controlled within 20-100 mL, the addition amount of the carrier is controlled within 0.5-2 g in terms of the material-drug ratio, and the drug concentration is controlled within 50-300 mg/mL.
Compared with the prior oral drug carrier preparation technology, the invention has the following advantages:
1. the invention takes wild saccharomyces cerevisiae as a drug carrier, has low price and wide source, simultaneously yeast cells are widely applied to the food field, and the invention can be more prominent in the oral drug field and has obvious safety.
2. The invention takes wild saccharomyces cerevisiae as a drug carrier, can fully encapsulate drugs, improves the characteristic that drugs with bitter taste are not beneficial to oral administration, and reduces the uncomfortable feeling of the drugs during oral administration.
3. The invention takes wild saccharomyces cerevisiae as a drug carrier, and fully plays the roles of reducing drug release and increasing drug absorption in intestinal tracts in a gastric acid environment, ensures the drug amount and avoids excessive drug loss.
4. The invention takes wild saccharomyces cerevisiae as a drug carrier and takes yeast bacterial culture as a main method for preparing the carrier, and the used organic reagents have few types and low dosage, thereby greatly reducing the oral risk, having better biocompatibility and degradability and being beneficial to environmental protection.
Drawings
FIG. 1 is a schematic diagram of the optimal drug loading adsorption time of berberine hydrochloride-yeast microcapsules prepared in example 2;
FIG. 2 is an SEM photograph of berberine hydrochloride-yeast microcapsules prepared in example 2; a, no-load yeast; b, carrying out medicine loading for 4 hours; c, carrying out medicine loading for 8 h; d, carrying out medicine loading for 12 h; e, carrying the medicine for 16 h; f, carrying a medicine for 24 h;
FIG. 3 is a schematic diagram showing the determination of the optimal drug-drug ratio of berberine hydrochloride-yeast microcapsules prepared in example 2
FIG. 4 is an FTIR chart of berberine hydrochloride-yeast microcapsules prepared in example 2; a, total reflection; b, transmission;
FIG. 5 is a thermal stability analysis of berberine hydrochloride-yeast microcapsules prepared in example 2; a weight loss percentage; b, the weight loss rate;
FIG. 6 is the slow release performance measurement of berberine hydrochloride-yeast microcapsule prepared in example 2; releasing an aqueous phase; b, pH response release;
Detailed Description
The following non-limiting experiments will allow one of ordinary skill in the art to more fully understand the present invention, but do not limit the invention in any way. Unless otherwise specified, the experimental methods adopted by the invention are all conventional methods, and experimental equipment, materials, reagents and the like used in the experimental method can be purchased from chemical companies.
Example 1
Preparing yeast microcapsules. The yeast has wide sources and low price, is often used for packaging substances such as food, essence and the like, and has certain guarantee on the oral safety. Taking the bacterium-protecting medium liquid, activating for 16-18h at 30 ℃ and 200r/min in an YPD culture medium, transferring into a fresh YPD culture medium, performing centrifugal bacterium collection at 30 ℃ and 200r/min for 20-22h at 8000r/min for 10min, and storing the collected thalli in a refrigerator at-20 ℃. The yeast was washed 2 times with excess 10% -20% (v/v) ethanol solution and 1 time with excess ultrapure water, and the cells were centrifuged at 2100g for 5min between each wash and finally once again to remove excess water. And then placing the centrifuged precipitate in a freeze dryer for freeze drying, grinding the dried substance into white powder to obtain the yeast microcapsule, and collecting the yeast microcapsule for subsequent experiments.
Example 2
Preparing berberine hydrochloride-yeast microcapsule. Berberine, also known as berberine, is an isoquinoline alkaloid extracted from Coptis chinensis Franch, berberine hydrochloride is one of its clinical application forms, can effectively inhibit the synthesis of microbial DNA and protein, and is often used as broad-spectrum antibacterial agent. However, berberine hydrochloride has poor water solubility and lipid solubility, and is usually only soluble in hot water. When the berberine hydrochloride is taken as an oral medicine, the berberine hydrochloride is damaged to a certain extent by the gastric acid environment, and the berberine hydrochloride is poorly absorbed by intestinal tracts, so that the oral availability is low.
Weighing 100mg berberine hydrochloride, dissolving with hot deionized water, adding 1g yeast microcapsule, placing on a heatable magnetic stirrer, heating and stirring, setting stirring adsorption time to 4-24h, setting a sampling point every 4h, centrifuging and collecting at 8000r/min for 5min, and measuring drug loading and encapsulation efficiency, wherein the result is shown in figure 1, and under the optimal condition is 16 h. Dissolving berberine hydrochloride with different amounts with hot deionized water, preparing into water solution with drug concentration of 2.5-6.25mg/mL, adding yeast microcapsule 1g into different solutions, placing on heatable magnetic stirrer, heating and stirring, stirring and adsorbing for the same time, centrifuging at 8000r for 5min, collecting, and determining drug loading and encapsulation efficiency of berberine hydrochloride, with the result shown in figure 3 that when 1g of yeast microcapsule is selected and added, the optimal drug concentration is 2.5 mg/mL.
And performing physical and chemical property characterization on the prepared berberine hydrochloride-yeast microcapsules, and performing SEM (scanning Electron microscope), particle size and Zeta potential analysis, FTIR (Fourier transform Infrared) and thermogravimetric analysis respectively. The results are as follows: FIG. 2 is an SEM photograph of berberine hydrochloride-yeast microcapsules prepared in example 1; a yeast cells (no drug loaded); b, carrying out medicine loading for 4 hours; c, carrying out medicine loading for 8 h; d, carrying out medicine loading for 12 h; e, carrying the medicine for 16 h; f, carrying a medicine for 24 h; analysis shows that the yeast microcapsules without drug loading are in a relatively mellow state, but still have a concave part, the drugs enter the yeast microcapsules along with the prolonging of the drug loading time, the shapes of the yeast microcapsules are still intact, and fig. 2-E and fig. 2-F show that the yeast microcapsules are obviously broken after the drug loading time exceeds 16h, the carrier structure is disintegrated and is in a flaky structure, the yeast microcapsules are not in a complete carrier shape any more, and the method provides a good explanation for the reduction of the later-period encapsulation efficiency and the drug loading rate. Table 1 shows the results of particle size and Zeta potential analysis of yeast microcapsules and berberine hydrochloride-yeast microcapsules, the concentration of the yeast control group is 0.125mg/mL, and the concentration of other experimental groups is 0.25 mg/mL. The results show that the particle size is gradually increased along with the drug loading time, the PDI is gradually increased, the dispersity is reduced, and the PDI is obviously reduced due to the disintegration of the yeast microcapsules at 24h according to the results of an SEM image. The Zeta potential can show that the charge of the yeast microcapsule is changed from negative charge to positive charge, which indicates that a certain electrostatic adsorption exists between the drug and the carrier.
TABLE 1 particle size and Zeta potential analysis
Figure BDA0003257137800000041
FIG. 4 is an FTIR chart of berberine hydrochloride-yeast microcapsules prepared in example 1; a, total reflection; b, transmission; as can be seen from the analysis, the infrared total reflection pattern (FIG. 4-A) is as 4000-400 cm-1In the interior, the infrared spectra of the yeast microcapsules before and after loading the drug are almost consistent and have no obvious change, so that the berberine hydrochloride is confirmed not to stay on the surface of the yeast microcapsules. From FIG. 4-B, at 1300-1200 cm-1In the method, compared with the result before carrying the medicine, the characteristic absorption peak of C-O in berberine hydrochloride appears in the yeast micro-capsule after carrying the medicine; at 940-735 cm-1The C-C characteristic absorption peak of the benzene ring in the berberine hydrochloride appears in the yeast microcapsule, which indicates that the berberine hydrochloride is successfully loaded into the yeast microcapsule and exists in a drug form. FIG. 5 is a thermal stability analysis of berberine hydrochloride-yeast microcapsules prepared in example 1; a weight loss percentage; b, the weight loss rate; analysis shows that berberine hydrochloride has obvious weight loss at 100 deg.c and is compared with the original medicine at raised temperatureBy 290 ℃, the sample weight loss in the carrier is less and the weight loss rate is slower, and the addition of the carrier in a certain temperature range can better maintain the thermal stability of the drug and shift the heat loss time of the drug backwards.
And (3) measuring the slow release performance of the berberine hydrochloride-yeast microcapsule. FIG. 6 is the slow release performance measurement of berberine hydrochloride-yeast microcapsule prepared in example 1; releasing an aqueous phase; b, pH response release; the berberine hydrochloride technical product and the yeast micro-capsule carrying the medicine are released at 37 ℃ to verify the slow release performance of the carrier. Deionized water was used as the release system and samples were taken at different time points to determine the concentration of drug released. The total release is 400mL, and the volume in the dialysis bag is 5 mL. The molecules show that compared with the original medicine group, the experimental group shows better slow release performance, 80% of the original medicine is released within two days, the release of the experimental group exceeds 60% and tends to be balanced about 30 hours, and the good combination effect between the medicine and the carrier is shown. Taking a certain amount of berberine hydrochloride-yeast microcapsules carrying the drugs, carrying out pH responsive release at 37 ℃, setting the pH value to be 1.2 (simulated gastric juice environment) and 7.4 (simulated blood environment), and sampling at different time points to measure the concentration of the released drugs. The total release is 400mL, and the volume in the dialysis bag is 5 mL. Analysis shows that the release rate of the drug in the simulated intestinal fluid environment (pH 7.4) is obviously higher than that in the simulated gastric fluid environment (pH 1.2), the release in the simulated gastric fluid in the first 4h is only (13.20 +/-4.23)%, a relatively good release process is observed in the simulated intestinal fluid, the release rate of the drug in 48h reaches (92.82 +/-2.29)%, and the fixed-point controllable release of the berberine hydrochloride is realized.

Claims (10)

1. The microcapsule oral medicament based on the yeast delivery carrier is characterized in that the microcapsule oral medicament is a microcapsule oral medicament which takes yeast as a carrier and loads isoquinoline alkaloid medicaments to obtain the medicament released in intestinal tracts.
2. The microcapsule oral drug according to claim 1, wherein the ratio of the yeast carrier to the aqueous isoquinoline alkaloid solution is 0.5 to 2 g: 50-300 mg/mL.
3. The microencapsulated oral drug of claim 1, wherein the isoquinoline alkaloid comprises at least one of berberine hydrochloride, berberine, 9-lauroyl berberine, tetrahydroberberine, coptisine, palmatine, jateorhizine, tetrahydropalmatine, gentamicin.
4. A preparation method of a microcapsule oral medicine based on a yeast delivery carrier is characterized by comprising the following steps:
(1) preparing a yeast vector: activating and expanding yeast, washing with ethanol and ultrapure water, centrifuging after washing, collecting thallus, and freeze drying;
(2) preparing a microcapsule oral medicament: and (2) preparing an isoquinoline alkaloid water solution, adding the yeast carrier obtained in the step (1) into the isoquinoline alkaloid water solution, stirring under a heating state, centrifuging and collecting a solid to obtain the yeast extract.
5. The method according to claim 4, wherein the concentration of ethanol in step (1) is 10% to 20% (v/v).
6. The method according to claim 4, wherein the activated yeast in step (1) is selected from the group consisting of: inoculating the yeast into a culture medium, activating for 14-18 h, taking 10-15 mL of activated bacterial liquid, carrying out propagation culture on the activated bacterial liquid into 1L of fresh culture medium, and carrying out propagation culture for 18-24 h according to the growth state of the yeast.
7. The preparation method according to claim 4, wherein the concentration of the isoquinoline alkaloid aqueous solution in the step (2) is 2.5 to 6.25 mg/mL.
8. The method according to claim 4, wherein the stirring time in the step (2) is 4 to 24 hours.
9. The method according to claim 4, wherein the ratio of the yeast carrier to the aqueous alkali isoquinoline alkaloid solution is 0.5 to 2 g: 50-300 mg/mL.
10. Application of microcapsule oral medicine based on yeast delivery vehicle in preparing intestinal tract release medicine is provided.
CN202111062351.1A 2021-09-10 2021-09-10 Microcapsule oral medicine based on yeast delivery carrier and preparation method and application thereof Pending CN113616623A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114470228A (en) * 2021-12-08 2022-05-13 深圳先进技术研究院 Coagulation-carrying yeast immune micro-nano biological robot and preparation and application thereof

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US20060127489A1 (en) * 2002-10-24 2006-06-15 Michael Crothers Targeted delivery
CN101147855A (en) * 2007-07-01 2008-03-26 石国荣 Method for using yeast cell to prepare safety non-toxic good property microcapsule wall material

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Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114470228A (en) * 2021-12-08 2022-05-13 深圳先进技术研究院 Coagulation-carrying yeast immune micro-nano biological robot and preparation and application thereof

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