CN110559273A - Preparation method of cellulose-based protein hollow double-shell microcapsule and drug carrier - Google Patents

Preparation method of cellulose-based protein hollow double-shell microcapsule and drug carrier Download PDF

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Publication number
CN110559273A
CN110559273A CN201910843224.1A CN201910843224A CN110559273A CN 110559273 A CN110559273 A CN 110559273A CN 201910843224 A CN201910843224 A CN 201910843224A CN 110559273 A CN110559273 A CN 110559273A
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CN
China
Prior art keywords
cellulose
hollow double
based protein
shell microcapsule
preparing
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CN201910843224.1A
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Chinese (zh)
Inventor
单志华
刘鹏
戴睿
陈慧
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Sichuan University
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Sichuan University
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Priority to CN201910843224.1A priority Critical patent/CN110559273A/en
Publication of CN110559273A publication Critical patent/CN110559273A/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5052Proteins, e.g. albumin
    • A61K9/5057Gelatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5089Processes

Abstract

The invention belongs to the technical field of preparation of amphiphilic adsorption or slow release materials, and discloses a preparation method of a cellulose-based protein hollow double-shell microcapsule and a drug carrier; preparing a precursor solution with good compatibility from two components, and then performing countercurrent spray drying; controlling the temperature of a two-component precursor solution with the solid content of 20-30% at 45-55 ℃, pumping the two-component precursor solution into a sprayer feeding pressure pump, and granulating by adopting countercurrent spray drying, wherein the feeding rate is 250-300L/h, the inlet temperature is 150-200 ℃, and the air flow is 3500-5500 m3and h, preparing the hollow double-shell microcapsule with the diameter of 70-100 mu m, wherein the water content of the capsule is 8-10%. The inner layer is composed of cellulose, and the outer layer is composed of protein polypeptideAnd (4) forming. The invention can keep the structural integrity after being dispersed in different dispersants; the product has good fluidity and mechanical strength in a dry state; the specific surface area is large; the product is nontoxic and degradable.

Description

Preparation method of cellulose-based protein hollow double-shell microcapsule and drug carrier
Technical Field
The invention belongs to the technical field of preparation of amphiphilic adsorption or slow release materials, and particularly relates to a preparation method of a cellulose-based protein hollow double-shell microcapsule and a drug carrier.
Background
Currently, the current state of the art commonly used in the industry is such that: the cellulose derivative contains hydroxyl, carbonyl and carboxyl groups, can be bonded with active substances sensitive to pH and easy to oxidize, can embed active substances without mutual effect, has good biocompatibility, is non-toxic and harmless, can reduce the stimulation of medicaments on digestive organs such as intestines and stomach, and is a good medicament carrier material. The cellulose-based microcapsule can reduce the sensitivity of the drug to the environmental reaction, and realizes the slow release of the drug by the permeation of the solvent and the dissolution of the polymer. The nano particles are prepared into ultra-small-volume nano particles, can pass through tissue gaps (including the smallest capillary vessels of a human body) to reach a designated position, and realize accurate release of the medicament. The cellulose derivative prepared micelle can be self-assembled into a core-shell structure through hydrophilic and hydrophobic effects, wherein the hydrophobic core can be used as a container for various hydrophobic drug molecules, and the hydrophilic shell can play a role in protecting the drugs.
Unlike cellulose derivatives alone, the present invention employs protein and cellulose to form a two-component based complex. The function of the pure cellulose derivative particles as a carrier is obtained by surface adsorption. The double components of the invention are hollow double-shell microspheres. The inner cavity of the microsphere has lipophilicity, and the shell has hydrophilicity. The shell can be used as a stable component of polar aqueous solution or a polar substance carrier which is easy to be adsorbed by protein, and the inner cavity can be used as a carrier of lipophilic substance. The double-shell trace of the invention can be adsorbed on hydrophobic substances in aqueous solution and ensures that substances in the inner cavity can be stabilized in aqueous solution and polar environment by utilizing the hydrophilicity of the outer shell.
The double-shell microsphere of the invention has higher technical requirements and needs to solve two problems:
1) the proper precursor structure ensures the combination of the two components, and the two components are not separated and are respectively assembled into shell layers in the drying process.
2) The good spray drying ensures the leaving speed of water molecules on the surfaces of the two components, so that the two components form spheres under the action of surface tension.
disclosure of Invention
aiming at the problems in the prior art, the invention provides a preparation method of a cellulose-based protein hollow double-shell microcapsule and a drug carrier.
The invention is realized in such a way, the preparation method of the cellulose-based protein hollow double-shell microcapsule is characterized in that the preparation method of the cellulose-based protein hollow double-shell microcapsule prepares a precursor solution with better compatibility from two components, and then adopts countercurrent spray drying; controlling the temperature of a two-component precursor solution with the solid content of 20-30% at 45-55 ℃, pumping the two-component precursor solution into a sprayer feeding pressure pump, and granulating by adopting countercurrent spray drying, wherein the feeding rate is 250-300L/h, the inlet temperature is 150-200 ℃, and the air flow is 3500-5500 m3And h, preparing the hollow double-shell microcapsule with the diameter of 70-100 mu m, wherein the water content of the capsule is 8-10%.
Further, the preparation method of the two-component precursor solution comprises the following steps: stirring and heating 100 parts of carboxymethyl cellulose, 5-10 parts of sodium chloride and 300 parts of water to 80-90 ℃, dropwise adding 30-50 parts of 20% gelatin solution, keeping the temperature at 80-90 ℃, stirring for 30-40 min, uniformly mixing to obtain a transparent solution, cooling to 45-50 ℃, adding hydrochloric acid to adjust the pH of the mixed solution to 5.5-6.5, placing the mixed solution in an electrolytic cell, and adjusting the current density to 4-6 mA/cm2and keeping the temperature at 45-50 ℃, stirring and electrolyzing until the mixed solution is yellowish emulsion to obtain a two-component precursor solution with the solid content of 20-30%, and cooling for later use.
Furthermore, the electrolytic cell is diaphragm-free and takes graphite as a positive electrode and a negative electrode.
Further, the acid solution is 20% hydrochloric acid or 10% sulfuric acid.
further, the relative molecular mass of the gelatin is 6-8 ten thousand.
Further, the ratio of 20% protein solution to carboxymethyl cellulose is, based on the solid content of the two components: 1/5-1/2: 1.
The invention also aims to provide the cellulose-based protein hollow double-shell microcapsule prepared by the preparation method, wherein the inner layer of the cellulose-based protein hollow double-shell microcapsule is composed of oleophilic or weak hydrophilic cellulose, and the outer layer is composed of hydrophilic protein polypeptide; the diameter of the capsule is 70-100 μm.
Another object of the present invention is to provide a drug carrier prepared from the cellulose-based protein hollow double-shell microcapsules.
The invention also aims to provide a capsule for slowly releasing vitamins, medicines and pesticides, which is prepared from the cellulose-based protein hollow double-shell microcapsule.
In summary, the advantages and positive effects of the invention are:
1) The product can be combined with gelatin amino to generate Schiff base crosslinking reaction to form complex mixture precursor solution. During the drying and dehydration process, the two components are specially separated and arranged to form the double-shell microcapsule.
2) The double-layer hollow outer layer enables the capsule to be suspended in water and electrolyte solution or adsorbed on a polar carrier due to good hydrophilic action. Carboxymethyl cellulose can be oxidized to form a yellowish viscous liquid when electrified.
3) The hydrophilic and hydrophobic double-shell microsphere structure has a hydrophobic inner core which can be used as a container for various hydrophobic drug molecules, and a hydrophilic outer shell which can play a role in protecting the drugs. The inner cavity of the cellulose derivative in the double-shell microsphere is used as a lipophilic substance carrier. Adsorb and embed some active substances which are vulnerable to environmental effects (oxidation, photothermal and polar substance effects). As an oral medicine, the composition can resist amylase and gastric acid and is rapidly degraded and damaged, so that the medicine enters deep intestinal tract to act and reaches a designated part, and the accurate release of the medicine is realized; it can also prevent the rapid release of some surface drug carriers (such as cellulose-based microcapsules) or direct irritation to digestive organs.
Compared with the single carboxymethyl cellulose capsule, the double-shell capsule of the invention has the following characteristics:
1) The structure can be kept complete when the water-soluble polymer is dispersed in different dispersing agents;
2) The product has good fluidity and mechanical strength in a dry state;
3) The specific surface area is large;
4) The product is nontoxic, can be safely used and is degradable.
Drawings
Fig. 1 is a flow chart of a preparation method of a cellulose-based protein hollow double-shell microcapsule provided by the embodiment of the invention.
FIG. 2 is a schematic diagram showing the appearance of a capsule after spray drying with two components in various ratios according to an embodiment of the present invention;
In the figure: (a) a pure protein polypeptide; (b) after the treatment of pure cellulose; (c) too much cellulose; (d) cellulose is suitable; (d) too little cellulose.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The cellulose derivative provided by the invention can be used for preparing micelles, and the micelles can be self-assembled into a core-shell structure through hydrophilic and hydrophobic effects, wherein the hydrophobic core can be used as a container for various hydrophobic drug molecules, and the hydrophilic shell can play a role in protecting drugs.
The following detailed description of the principles of the invention is provided in connection with the accompanying drawings.
As shown in fig. 1, the preparation method of the cellulose-based protein hollow double-shell microcapsule provided by the embodiment of the invention comprises the following steps:
S101: preparing a two-component precursor solution: stirring and heating 100 parts of carboxymethyl cellulose, 5-10 parts of sodium chloride and 300 parts of water to 80-90 ℃, dropwise adding 30-50 parts of 20% gelatin solution, keeping the temperature at 80-90 ℃, stirring for 30-40 min, uniformly mixing to obtain a transparent solution, cooling to 45-50 ℃, adding hydrochloric acid to adjust the pH of the mixed solution to 5.5-6.5, putting the mixed solution into electrolysisIn the tank, the current density is adjusted to 4-6 mA/cm2Keeping the temperature at 45-50 ℃, slowly stirring and electrolyzing until the mixed solution is yellowish emulsion to obtain a two-component precursor solution with the solid content of 20-30%, and cooling for later use;
S102: preparation of cellulose-based protein hollow double-shell microcapsule: controlling the temperature of a two-component precursor solution with the solid content of 20-30% at 45-55 ℃, pumping the two-component precursor solution into a sprayer feeding pressure pump, and granulating by adopting a countercurrent spray drying technology, wherein the feeding rate is 250-300L/h, the inlet temperature is 150-200 ℃, and the air flow is 3500-5500 m3And h, preparing the hollow double-shell microcapsule with the diameter of 70-100 mu m, wherein the water content of the capsule is 8-10%.
In a preferred embodiment of the invention, the cell is diaphragm-free and graphite is the negative and positive electrode.
In a preferred embodiment of the invention, the acid solution is 20% hydrochloric acid or 10% sulfuric acid.
In the preferred embodiment of the invention, the gelatin has specific requirement relative molecular mass of 6-8 ten thousand, and can be a degradation product of animal skin collagen by adopting a plurality of methods. The preparation method of the precursor solution comprises the following steps: 1) the relative molecular mass of the carboxymethyl cellulose is more than 10000; 2) the gelatin requires a relative molecular mass of 6-8 ten thousand; 3) the electrolytic cell is diaphragm-free and takes graphite as a positive electrode and a negative electrode.
in a preferred embodiment of the present invention, the ratio of the 20% protein polypeptide liquid amount to the carboxymethyl cellulose is preferably: (1/5-1/2): 1.
The cellulose-based protein hollow double-shell microcapsule provided by the embodiment of the invention has the inner layer formed by oleophylic or weakly hydrophilic cellulose and the outer layer formed by protein polypeptide with a hydrophilic function.
The application of the principles of the present invention will now be described in further detail with reference to specific embodiments.
example 1
The preparation method of the cellulose-based protein hollow double-shell microcapsule provided by the embodiment of the invention comprises the following steps:
100 parts of carboxymethyl cellulose, 5 parts of sodium chloride and 300 parts of waterstirring and heating to 80 deg.C, adding 20% gelatin solution 100 parts dropwise, maintaining the temperature at 80 deg.C, stirring for 300min, mixing to obtain transparent solution, cooling to 45 deg.C, adding hydrochloric acid to adjust pH to 5.5, placing the mixed solution in an electrolytic bath, and adjusting current density to 4mA/cm2Slowly stirring and electrolyzing at 45 ℃ until the mixed solution is yellowish emulsion to obtain a two-component precursor solution with the solid content of 25%, and cooling for later use;
Controlling the temperature of the two-component precursor solution with the content of 25 percent at 50 ℃, pumping the two-component precursor solution into a sprayer feeding pressure pump, and granulating by adopting a countercurrent spray drying technology, wherein the feeding rate is 250L/h, the inlet temperature is 150 ℃, and the air flow is 4000m3and h, preparing the hollow double-shell microcapsule with the diameter of 70-100 mu m, wherein the water content of the capsule is 8-10%.
Example 2
The preparation method of the cellulose-based protein hollow double-shell microcapsule provided by the embodiment of the invention comprises the following steps:
Stirring and heating 100 parts of carboxymethyl cellulose, 10 parts of sodium chloride and 300 parts of water to 80 ℃, slowly adding 150 parts of normal-temperature 25% gelatin solution, keeping the temperature at 80 ℃, stirring for 30min, uniformly mixing to obtain transparent solution, cooling to 45 ℃, adding hydrochloric acid to adjust the pH of the mixed solution to 5.5, placing the mixed solution in an electrolytic cell, and adjusting the current density to 5mA/cm2Slowly stirring and electrolyzing at 45 ℃ until the mixed solution is yellowish emulsion to obtain a two-component precursor solution with the solid content of 30%, and cooling for later use;
Controlling the temperature of 30% bicomponent precursor solution at 50 deg.C, pumping into sprayer feeding pressure pump, granulating by countercurrent spray drying technology at feeding rate of 270L/h, inlet temperature of 170 deg.C, and air flow rate of 3000m3And h, preparing the hollow double-shell microcapsule with the diameter of 70-100 mu m, wherein the water content of the capsule is 8-10%.
Example 3
the preparation method of the cellulose-based protein hollow double-shell microcapsule provided by the embodiment of the invention comprises the following steps:
will 100 part of carboxymethyl cellulose, 10 parts of sodium chloride and 300 parts of water are stirred and heated to 80 ℃, 200 parts of normal-temperature 30% gelatin solution is slowly added, the temperature is kept at 80 ℃, the mixture is stirred for 30min and is uniformly mixed into transparent solution, the temperature is reduced to 45 ℃, hydrochloric acid is added to adjust the pH of the mixed solution to be 5.5, the mixed solution is placed in an electrolytic cell, the current density is adjusted to be 6mA/cm2Slowly stirring and electrolyzing at 45 ℃ until the mixed solution is yellowish emulsion to obtain a two-component precursor solution with the solid content of 20%, and cooling for later use;
Controlling the temperature of 20% bicomponent precursor solution at 50 deg.C, pumping into sprayer feeding pressure pump, granulating by countercurrent spray drying technology at feeding rate of 300L/h, inlet temperature of 200 deg.C and air flow rate of 5000m3And h, preparing the hollow double-shell microcapsule with the diameter of 70-100 mu m, wherein the water content of the capsule is 8-10%. The samples prepared in example 1 were examined as follows.
spray drying can give different particle structures ranging from solid, bowl-like to hollow sphere, but the hollow effect is poor when the proportions are not appropriate. See fig. 2.
The composition and the proportion of surface elements of the sample are analyzed by X-ray photoelectron spectroscopy (XPS), and the relative atomic concentration (expressed by X/C based on the C atomic concentration) of the surface elements of each sample is found. Protein polypeptide/cellulose can be obtained at 3/7, 5/5, 4/6, and the N/C atomic concentration ratio on the surface of the hollow double-shelled capsule is 0.193, 0.211, 0.223, respectively.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (9)

1. The preparation method of the cellulose-based protein hollow double-shell microcapsule is characterized in that a precursor solution with good compatibility is prepared from two components, and then countercurrent spray drying is adopted; controlling the temperature of the two-component precursor solution with the solid content of 20-30% at 45-55 DEG CPumping into a sprayer feeding pressure pump, and granulating by adopting countercurrent spray drying, wherein the feeding rate is 250-300L/h, the inlet temperature is 150-200 ℃, and the air flow is 3500-5500 m3And h, preparing the hollow double-shell microcapsule with the diameter of 70-100 mu m, wherein the water content of the capsule is 8-10%.
2. The method of preparing a cellulose-based protein hollow double-shell microcapsule according to claim 1, wherein the method of preparing the two-component precursor solution comprises: stirring and heating 100 parts of carboxymethyl cellulose, 5-10 parts of sodium chloride and 300 parts of water to 80-90 ℃, dropwise adding 30-50 parts of 20% gelatin solution, keeping the temperature at 80-90 ℃, stirring for 30-40 min, uniformly mixing to obtain a transparent solution, cooling to 45-50 ℃, adding hydrochloric acid to adjust the pH of the mixed solution to 5.5-6.5, placing the mixed solution in an electrolytic cell, and adjusting the current density to 4-6 mA/cm2And keeping the temperature at 45-50 ℃, stirring and electrolyzing until the mixed solution is yellowish emulsion to obtain a two-component precursor solution with the solid content of 20-30%, and cooling for later use.
3. The method for preparing a cellulose-based protein hollow double-shell microcapsule according to claim 2, wherein the electrolytic bath is diaphragm-free and uses graphite as a positive and negative electrode.
4. The method for preparing a cellulose-based protein hollow double-shell microcapsule according to claim 2, wherein the acid solution is 20% hydrochloric acid or 10% sulfuric acid.
5. The method for preparing a cellulose-based protein hollow double-shell microcapsule according to claim 2, wherein the protein is derived from gelatin and has a relative molecular mass of 6 to 8 ten thousand.
6. the method for preparing a cellulose-based protein hollow double-shell microcapsule according to claim 2, wherein the degree of substitution of the carboxymethyl cellulose is not more than 0.8.
7. the method for preparing a cellulose-based protein hollow double-shell microcapsule according to claim 2, wherein in the two-component precursor solution with the solid content of 20-30%, the weight ratio of the protein to the carboxymethyl cellulose is as follows: 1/5-1/2: 1.
8. A cellulose-based protein hollow double-shell microcapsule prepared by the method for preparing the cellulose-based protein hollow double-shell microcapsule according to claim 1, wherein the inner layer of the cellulose-based protein hollow double-shell microcapsule is composed of oleophilic or weakly hydrophilic cellulose, and the outer layer is composed of a hydrophilic protein polypeptide; the diameter of the capsule is 70-100 μm.
9. A carrier for sustained release of a drug mainly from the cellulose-based protein hollow double-shell microcapsules of claim 7.
CN201910843224.1A 2019-09-06 2019-09-06 Preparation method of cellulose-based protein hollow double-shell microcapsule and drug carrier Pending CN110559273A (en)

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Publication number Priority date Publication date Assignee Title
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JPH07275688A (en) * 1994-04-14 1995-10-24 Kyowa Yakuhin Kogyo Kk Sustained release microcapsule and its production
CN105534952A (en) * 2016-01-08 2016-05-04 福建师范大学 Preparation method of composite porous microspheres of core-shell structure
CN107240677A (en) * 2016-03-28 2017-10-10 国家纳米科学中心 A kind of micro-nano structure carbon silicon complex microsphere and its production and use
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Application publication date: 20191213