CN109966505B - Nano-pore natural sustained and controlled release carrier material and preparation method thereof - Google Patents

Nano-pore natural sustained and controlled release carrier material and preparation method thereof Download PDF

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CN109966505B
CN109966505B CN201910256346.0A CN201910256346A CN109966505B CN 109966505 B CN109966505 B CN 109966505B CN 201910256346 A CN201910256346 A CN 201910256346A CN 109966505 B CN109966505 B CN 109966505B
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calcium carbonate
powder
drug
sustained
release
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CN109966505A (en
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尹应武
李金萍
杨少梅
廖翠莺
吐松
叶李艺
倪锋
赵玉芬
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Beijing Th Unis Insight Co ltd
Xiamen University
Ningbo University
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Xiamen University
Ningbo University
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    • A—HUMAN NECESSITIES
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    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
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    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
    • A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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Abstract

The invention relates to a natural sustained and controlled release carrier material with a nanometer pore canal and a preparation method thereof, which takes shrimp and crab shells and other natural products with nanometer pore canals as carriers to produce a series of functional chemical substance sustained and controlled release carriers with natural nanometer pore canals directly or by a co-production process and a production and use method thereof. Researches find that the micro-pore channel with the average pore diameter of about 10 nanometers can effectively store and slowly release various functional substances, and provides abundant new carrier product series and flexible combination for meeting the performance requirements of various sustained and controlled release products. The process has the advantages that the biomass raw materials are wide in source and low in price, the prepared carrier can meet the cost performance requirements of simplicity, high efficiency, greenness and safety, the process promotes the application of medicines, pesticides and plant growth regulators for slow release, controlled release and long-acting fertilizers, and can avoid decomposition or loss by enzymes or microorganisms by means of the protection of nanopores which cannot be accessed by the microorganisms, so that a new high-efficiency, long-acting, safe and low-cost animal and plant pesticide fertilizer system is developed.

Description

Nano-pore natural sustained and controlled release carrier material and preparation method thereof
Technical Field
The invention belongs to the field of development, production and application of a drug sustained-release material, and particularly relates to the field of preparation and application of green safe carriers filled with drugs, fertilizers and other functional chemical substances. The invention discloses a carrier with natural nanometer pore canals and a simple preparation method, wherein the carrier takes natural biomasses such as shrimp and crab shells and the like as raw materials.
Background
The sustained and controlled release carrier is a material which can control the functional components to be automatically released at a certain speed within a preset time so as to maintain the effective concentration of the functional components, and can be widely used for animals, plants and microorganisms. The most important thing is to control the speed, time and position of drug release, while the drug slow-release carrier can change the mode and distribution of drug entering animal and plant, to control the release speed and concentration of drug, to improve drug absorption. The slow-release drug carrier has outstanding advantages in the aspects of reducing administration times, reducing administration dosage, reducing toxic and side effects, improving curative effect and the like, and is an important direction for drug development.
The research of the existing drug sustained-release carrier is very active all the time, and a basic system is formed: drug carriers have been developed to include three types, namely inorganic carriers, natural polymer carriers and synthetic polymer carriers, and drug coating and controlled release technologies include two types, namely carrier types such as microspheres, gels, nanoparticles, films and tablets, and load types such as solution adsorption, embedding (spray drying, emulsion solvent volatilization, self-emulsion solvent diffusion and phase separation) and filling. However, the problems of poor sustained and controlled release effect, toxicity and safety problems or high production cost and the like always plague the development of the industry, the cost performance is high, and the safe and efficient sustained and controlled release carrier is still the biggest bottleneck of the development of sustained and controlled release medicines.
For example, patent CN107536806A describes a cumulative release profile of methotrexate loaded on chitosan-calcium carbonate carrier, which uses a calcium carbonate complex formed by the reaction of chitosan-embedded calcium chloride and sodium bicarbonate as a carrier to adsorb anti-tumor methotrexate, and because the pore and pores of the calcium carbonate synthesized by the synthesis are different in size, it is difficult to obtain uniform nanopores, so the sustained release effect is not ideal, about 50% of the calcium carbonate is released in about 100 minutes, and the calcium carbonate is not released in about 200 minutes under neutral conditions, and the sustained release effect is improved under acidic conditions (see fig. 15). The calcium carbonate- (polyornithine/fucosan) carrier described in patent CN107375217A can slowly release the drug, but the preparation of the carrier is complicated and the industrial application is difficult. Therefore, the existing drug carrier adopting chitosan as a film forming agent and a compound of artificially synthesized porous nano calcium carbonate has the problems of small drug adsorption amount and unsatisfactory sustained release effect.
The pesticide is the guarantee of the yield increase and the stable yield of crops, and the three functions of pest control, weeding and plant growth promotion are the pesticide. The existing pesticides adopt dosage forms such as Microemulsion (ME), emulsion in water (EW), suspending agent (SC), missible oil (EC), Wettable Powder (WP) and the like, are only limited to the dispersion and convenient use of the pesticides, and can not well solve the problems of difficult adsorption on the surface of leaf wax of plants and easy rain washing. The pesticide has large using amount in the using process, short effective period, damage to an ecological system, serious residue and environmental pollution, quick enhancement of the drug resistance of plant diseases and insect pests and other series of negative problems, and needs an effective solution. The state department puts forward the requirement of 'double reduction' of pesticide and fertilizer, obviously reduces the using amount of pesticide, avoids pesticide loss, environmental pollution and damage to a microbial system as far as possible, develops high-efficiency long-acting low-toxicity pesticide, develops a pesticide carrier with high cost performance and safe use, is the direction of pesticide development, and currently, a pesticide slow-release agent (BR) is just in the initial stage of research and development, and a formed slow-release pesticide finished product does not exist, so the development prospect is huge.
The plant growth regulator can obviously promote the growth and development of plants, realize the yield increase and stable yield, improve the quality of crops and enhance the stress resistance of crops, can be artificially synthesized or extracted from biomass, and chitin, chitosan and carboxymethyl chitosan which are originally in shrimp and crab shells and carriers are plant growth promoters with high development and application values. In conclusion, the existing sustained-release technology has the series problems of high cost, unstable product performance, small drug loading capacity, poor using effect, safe use, poor biocompatibility and the like, and has great significance in developing green, safe, stable and universal high-cost-performance drug carriers by using biomass as a raw material.
In 2018, the global yield of the shrimps and crabs exceeds 300 million tons, the shrimp and crab shells are as high as more than million tons, and the shrimps and crab shells are valuable resources such as chitin, protein, calcium carbonate and the like because the shrimps and crab shells are rich in valuable components. Chitin (Chitin) is an amino polysaccharide natural polymer with the yield second to that of cellulose, and has wide application in many fields such as crop cultivation, medicines, foods, bioengineering, daily chemical industry, textile printing and dyeing, papermaking, tobacco, water treatment and the like. Chitosan is a deacetylated derivative of chitin, is the only one stably existing basic polysaccharide in the nature, and contains a large number of active groups-OH and-NH in the molecule2The chitosan has various excellent performances of good water absorption, moisture retention, film forming property, metal chelation, plant growth promoting activity, biocompatibility, degradability and the like, so that the chitosan is known as a key substance influencing the scientific and technological progress of human society in the twenty-first century.
The shrimp and crab shell is a natural composite material with a regular structure formed by three components of chitin, protein and calcium carbonate, and a capillary network structure which takes the protein and the chitin as main structural components and meets the requirement of body fluid circulation exists, so that the shrimp and crab shell is an ideal material of a sustained and controlled release carrier.
The content of calcium carbonate in the shrimp and crab shells is 40-50%, the content of protein is 20-30%, and the content of chitin is 20-30%. Most of the shrimp and crab shells are discarded due to difficult recovery, only the shrimp and crab shells which are byproducts of a processing factory are crushed into powder to be used as feed or fertilizer, and only a very small amount of raw materials are used as raw materials for extracting chitin and producing chitosan. However, in the existing general process for extracting chitin from shrimp and crab shells, excessive hydrochloric acid is used for removing calcium carbonate, so that acidic organic wastewater with a large amount of high-concentration calcium chloride is generated, and alkaline organic wastewater can be generated in the process of producing a crude chitin product by removing protein from materials which are not dissolved in acid through thermokalite hydrolysis by using a sodium hydroxide solution. The waste water amount of the chitin crude product is up to 300 tons/ton, the shrimp and crab shell consumption amount is about 10 tons/ton, and the acid and alkali consumption amount is also very large. Therefore, the traditional chitin extraction process has the problems of high material consumption and energy consumption, serious wastewater pollution, high production cost, poor enterprise benefit, environmental limitation on production and difficulty in large-scale production. Therefore, the annual output of chitin and chitosan derivatives thereof is less than twenty million tons, and the development of the industry is greatly limited.
Disclosure of Invention
The development of safe, efficient and good-cost-performance bio-based sustained and controlled release drug carriers is an important direction for solving the industrial problems of high production cost, unstable performance, large dosage, high release speed of active ingredients, short drug effect duration, low bioavailability, high toxicity, poor safety, large environmental pollution, poor sustained and controlled release effect and the like of the existing drugs and sustained release carriers. The shrimp and crab shell raw materials can be originally used as food or feed, and have the advantages of safety, no toxicity, abundance and low price. Chitosan has also been a long felt coating material for sustained and controlled release carriers. The protein and the chitin in the shrimp and crab shells and the calcium carbonate form a shell body structure of the shrimp and crab together, a capillary microtubule network system for ensuring the smoothness of body fluid is also constructed, and the protein and the chitin have the potential of being used as a sustained and controlled release carrier, for example, the pore path can be further expanded by combining with innovative processes of removing the protein or/and extracting the chitosan and synthesizing the carboxymethyl chitosan by a one-pot method, a series of natural carrier materials with nanometer pore paths (see attached figure 1) are developed, and a novel sustained and controlled release carrier library which is green, safe, low in cost and developed in use is created.
The subject group creates the following new process method in the patent 'a new process for cleanly producing chitosan and carboxymethyl chitosan from crustacean raw materials CN 104788584A': the shrimp and crab shell powder is subjected to alkaline hydrolysis reaction at the boiling temperature of a mixed system of isopropanol, sodium hydroxide and water, so that protein can be rapidly hydrolyzed and acetyl can be removed simultaneously under the condition of less alkali, and a compound with more than 90% of protein and chitosan acetyl removed, namely a calcium carbonate-chitosan compound bio-based material with a nano pore channel, can be conveniently obtained. If chloroacetic acid is added without separation, a calcium carbonate-carboxymethyl chitosan mixture with nano-pores can be obtained through a one-pot reaction, and two products can be separated by dissolving with water. Therefore, according to the solubility difference of the raw materials, intermediates, products or byproducts in acid or alkali or alcohol or water or mixed solvents thereof, the chitosan calcium carbonate solid compound can be obtained by separation, and the products with calcium carbonate as the main component can be co-produced after the chitosan or the carboxymethyl chitosan is dissolved out, the carboxymethyl chitosan/calcium carbonate solid mixture, the chitosan solution or the chitosan product, the carboxymethyl chitosan solution or powder and other series products, and the liquid fertilizer raw materials with amino acid-small peptide and potassium acetate as the main components.
In-depth research, the novel process not only avoids the series of problems of shell structure damage, chitin degradation, large acid consumption, difficult treatment of acid-containing organic wastewater and the like caused by acid decalcification, but also can co-produce a series of porous natural bio-based materials with an average pore size of 10 nanometers, can thoroughly solve the industrial problems of high production cost, large pollution, serious hydrolytic degradation, poor quality and low yield of chitosan and derivatives thereof, promotes the development of a chitosan industrial chain, and can open up a green and safe novel slow-release carrier material library.
By means of the patents, the invention develops the shrimp and crab shell powder raw material which is obtained by taking shrimp and crab shells as the raw material through simple processing or further alkali or acid treatment, the deproteinized chitosan-calcium carbonate composite material, the byproduct biological calcium carbonate material for separating carboxymethyl chitosan, and the composite biological base material of protein and chitin in which calcium carbonate is separated by acid, and the detection is carried out through a scanning electron microscope, the aperture, the pore volume, the specific surface area, the water absorption capacity, different substances, a dissolving and desorbing system, the loading capacity and a release curve, so that the two materials except the composite biological base material of the protein and the chitin have a pore structure with the average aperture within 10 nanometers, and the specific surface area is increased by more than 10 times compared with the raw material. The four bio-based materials with natural nanopores not only have the unique advantages of rich raw materials, low production cost, no toxicity, edible property, safety, environmental protection and complete biodegradation, but also have the characteristics of selective adsorption in solution and large-scale storage of various functional chemical substances including various medicaments, and can be developed as an ideal controlled release carrier material.
Further intensive research also finds that the adsorption quantity difference of different carrier materials is obvious and is closely related to the surface tension of feed liquid, the system with the smaller surface tension is easier to load, and the loading quantity can be obviously improved by adsorption under the condition of reduced pressure. The material which is not easy to load can be embedded, the compound has obvious long-time sustained and controlled release function, and can meet the sustained and controlled release requirements of functional products such as medicines, pesticides and the like. SSP refers to Shrimp Shell meal (Shrimp Shell Powder); CSP refers to Crab Shell Powder (Crab Shell Powder); Ct-Pro refers to chitin-protein composite bio-based material; CS-CaCO3The chitosan-calcium carbonate composite bio-based material; CaCO3Refers to porous calcium carbonate, S-refers to a product from shrimp shell powder, and C-refers to a product from crab shell powder. See the chart for relevant performance.
Based on the patent method, the invention discovers a natural carrier material library which has large specific surface, pore volume and multiplied water absorption capacity and has a nano-pore structure and takes shrimp and crab shell powder as a raw material. The discovery that different carriers have different adaptability and loading capacity, the surface tension of the system, the properties of the carriers and the loading matters have great influence on the loading capacity, and the release curves of different drug carrier compounds have obvious difference, lays a research foundation for the development and combination optimization of sustained and controlled release systems with different requirements, and shows various possibilities. The carrier material with natural nanometer pore canal can reach the loading capacity of 10-44% by heating and discharging air and water from the nanometer carrier, reducing pressure and adsorbing, absorbing with saturated solution or supersaturated solution, absorbing with aqueous solution, organic solution and mixed solution, improving surface tension by mixed solvent, and coating again to increase the filling quantity and prolong the release period. The sustained and controlled release effects of various load drugs are measured according to a general analysis method, and the results prove that the load drugs have good sustained and controlled release characteristics: has no burst release, can be uniformly and continuously released for a long time, has little drug residue, can be degraded and absorbed by the carrier, is safe to use, and can greatly reduce the drug consumption.
The two parts of the Chinese pharmacopoeia 2005 edition introduce that the half-life period of ibuprofen is 1.8-2 h, the ibuprofen needs to be administrated 3-4 times every day, and the defects of low bioavailability, large administration dosage and the like exist. The common preparations and specifications at present are: (1) ibuprofen tablet: 100 mg; 200 mg; 400mg (2) ibuprofen extended release capsule: 300mg (3) ibuprofen sustained release tablet: 200mg (4) ibuprofen effervescent tablets: 100mg (5) ibuprofen liniment: 5mL 250 mg. The release amount of the sustained and controlled release produced at present is 10 to 35 percent, 25 to 55 percent, 50 to 80 percent and more than 75 percent of the marked amount in pharmacopoeia in 1 hour, 2 hours, 4 hours and 7 hours.
Ibuprofen sodium/porous calcium carbonate (IBU-Na/CaCO)3) Compound and ibuprofen/chitosan-calcium carbonate compound (IBU/CS-CaCO)3) The sustained and controlled release drug of the ibuprofen can be controlled to release 70 percent of the drug in about 7 hours, and the sustained and controlled release effect of the drug is better. The potassium chloride/chitin-protein-envelope compound (KCl/Ct-Pro) can control the release of the potassium chloride to be only 85 percent within 10 hours. The mass of each tablet or capsule is usually 100-200 mg, and the single tablet drug amount of the drugs for hypertension and the like is usually about 5mg, namely about 5% of the loading amount can meet the requirement. Thus, various vectors have potential for development.
The performance study of mesoporous activated carbon avermectin drug delivery system in the 12 th stage of 2012 of "journal of agro-pharmaceutical science" by grandson et al describes: the mesoporous activated carbon avermectin drug-loaded activated carbon carrier with the average particle size of 814nm has the drug loading rate of 18.07 percent to avermectin, the drug release time is over 672 hours, and good slow release effect is shown. Plum-bead column and the likeThe preparation and performance research of the novel avermectin nano controlled release agent in the 7 th phase of 2005 of the journal of the agro-pharmacology describes: hollow porous SiO2The drug loading rate of the nano particles to the abamectin can reach 62.5 percent, and the controlled release time of the abamectin nano controlled release agent (Av-PHSN) in a continuously stirred dissolution medium can reach 33 hours. Liuqi et al in "ecological environment science report" 2009 18 volume "surface modification of nano-silica and its adsorption and sustained release properties to avermectin" show that: modified SiO2The drug loading rate of the avermectin is 7.02-35.96%. The release speed of the avermectin-silicon dioxide nanoparticles is slowly increased along with the prolonging of time to about 14 hours, and the dissolution is basically balanced. But only about 50 percent of abamectin is dissolved out, and the release speed of the abamectin-silicon dioxide nano-particle is basically kept unchanged and can last for about 80 hours. Li Jiacheng et al in "preparation and performance research of avermectin granule using polymer/diatomite as sustained and controlled release material" at volume 24, phase 4 of "Nature science edition of university of Hainan university" show that: the abamectin granules taking the polymer/diatomite as the controlled-release material cumulatively release 50 percent of abamectin in 60 hours, reach the balance in 80 percent in 100 hours and basically reach the balance in 150 hours, and show good slow-release effect. As can be seen, the inorganic porous materials are activated carbon and SiO2The polymer/diatomite has a good sustained and controlled release effect when being used as a drug carrier, but has the serious problems of potential environmental safety hazards such as excessive residual drug (the residual drug is close to one half to one third), difficult degradation and the like, and needs to be used with caution.
Researches find that the abamectin slow-release and controlled-release system and the abamectin/chitosan-calcium carbonate compound (AVM/CS-CaCO) are prepared from shrimp and crab shell powder and various carriers obtained by processing through adsorption method3) About 50% of abamectin is released in 200 hours in an accumulated way, about 80% of abamectin is released in 260 hours, balance is basically achieved, and a better slow release effect is shown; avermectin/porous calcium carbonate complex (AVM/CaCO)3) At 150h, 50% of abamectin is released in an accumulated way, and 80% of abamectin is released in 300h, so that an excellent slow release effect is shown; the abamectin/chitin-protein compound (AVM/Ct-Pro) releases 50% of abamectin in 150hThe release can be basically complete in 240 hours, namely, more than 10 days.
The release time of the control agent of glyphosate isopropylamine salt/shrimp shell powder (NPPMG/SSP) in a continuously stirred dissolution medium is 100 hours, and the glyphosate isopropylamine salt/shrimp shell powder basically reaches balance within 120 hours; glyphosate isopropylamine salt/chitosan-calcium carbonate complex (NPPMG/CS-CaCO)3) 50% of glyphosate isopropyl salt is released in 96 hours in a cumulative way, 88% of glyphosate isopropyl salt is released in 300 hours in a cumulative way, balance is basically achieved, and the ideal sustained and controlled release requirement of the pesticide is met; the glyphosate isopropylamine salt/chitin-protein complex (NPPMG/Ct-Pro) basically reaches a balanced state when the release of the glyphosate isopropylamine salt is about 72 hours, and also has a certain slow release effect; glyphosate isopropylamine salt/porous calcium carbonate composite (NPPMG/CaCO)3) 90 percent of glyphosate isopropylamine salt is released within 300 hours, thus meeting the requirement of ideal sustained and controlled release pesticide. Glyphosate/chitosan-calcium carbonate complex (PMG/CS-CaCO)3) 90 percent of glyphosate isopropylamine salt is released within 370 hours, and the requirement of ideal sustained and controlled release pesticide is also met. Similarly, the Imidacloprid/chitin-protein complex (Imidacloprid/Ct-Pro) only releases 75% of Imidacloprid within 400 hours, and the sustained and controlled release effect is more obvious. The sustained-release pesticide requires that the dosage of the high-efficiency pesticide per mu is mostly below 50g, and the sustained-release load type pesticide can greatly save the dosage of the original pesticide, reduce or relieve pollution and prolong the pesticide effect, so the actual dosage is not greatly increased.
As a carrier of the slow and controlled release fertilizer, the fertilizer can also produce high-efficiency and long-acting fertilizer with little increase of cost and dosage. Therefore, the shrimp and crab shell waste powder is used as a raw material, and the natural nanometer pore canal of the shrimp and crab shell waste powder is used as a functional chemical substance sustained and controlled release carrier, so that the requirements of simplicity, high efficiency, greenness, safety and cost performance can be well met, and other orange stem powder has no sustained and controlled release effect and has poor bamboo fiber effect.
In conclusion, the achievement of the invention can promote the slow release of medicines, pesticides, plant growth regulators, the controlled release of various medicines and the application of high-efficiency fertilizers, has the protection of nanopores which can not be entered by microorganisms, can better avoid the medicines from being decomposed or lost by enzymes or microorganisms, ensures the long-acting property of the medicines, ensures the natural degradable property of the carrier and can ensure the medication safety. Therefore, the invention promotes the development and establishment of long-acting safe and cheap animal and plant medical fertilizers and other functional sustained and controlled release new systems.
Specifically, the invention provides a method for developing a natural drug carrier by taking shrimp and crab shells as raw materials and building a nanometer pore channel, wherein a solid product or a mixture of the solid product in any one of the following steps (1) to (4) is selected as a drug carrier according to different systems and specific requirements, a drug, a fertilizer or a plant growth promoter series product which can meet the biological regulation and control requirements and has a sustained and controlled release function is produced by a solution adsorption loading method, and the specific obtaining method of the carrier is as follows:
(1) cleaning raw materials of shrimp and crab shell, boiling to remove soluble substances, drying, pulverizing into powder of more than 200 meshes, and sieving for later use to directly serve as one of sustained and controlled release carrier materials;
(2) adding the product prepared in the step (1) as a raw material into an isopropanol-potassium hydroxide-water system, heating and carrying out alkaline hydrolysis at a reflux temperature for about 3 hours to remove acetyl groups of chitin to form chitosan, degrading proteins into amino acids and small peptides, dissolving the amino acids and the small peptides in a mixed solvent, filtering solid powder from a reaction mixture, washing the solid powder to be neutral, drying to obtain a chitosan-calcium carbonate composite bio-based material serving as one of sustained and controlled release carrier materials, and taking filtrate as amino acid and potassium fertilizer raw materials;
(3) directly adding chloroacetic acid into the mixture obtained by the reaction in the step (2) without separation, then heating to perform carboxymethylation reaction of chitosan, filtering the reaction mixture, taking the obtained filtrate as raw materials of amino acid and potash fertilizer, washing and filtering the obtained solid mixture by isopropanol, adding water to dissolve carboxymethyl chitosan, washing the filtered byproduct calcium carbonate solid to be neutral, obtaining porous calcium carbonate with a nano-pore structure, filtering and drying the porous calcium carbonate to be used as one of nano sustained and controlled release carrier materials, and precipitating a carboxymethyl chitosan solid product by adding alcohol into an aqueous solution;
(4) directly treating and dissolving shrimp and crab shell raw materials or powder raw materials in the step (1) by using an acid solution to remove calcium carbonate, filtering, washing to be neutral, drying, grinding by using a grinder and sieving to obtain the chitin-protein composite biological base material serving as one of the biological base slow-release carrier materials.
Preferably, the method is characterized in that the stirring reaction temperature of the shrimp and crab shell raw material powder in an isopropanol-potassium hydroxide-water system is 50-90 ℃, the reaction time is 1-20 hours, or the stirring is carried out for about 3 hours at the boiling temperature; in the step (3), the temperature of carboxymethylation reaction is 50-70 ℃, and the reaction time is 0.5-10 hours.
Preferably, in the method, the mass ratio of the isopropanol to the raw material is 1-5: 1, the mass ratio of the water to the raw material is 0.1-0.5: 1, and the mass ratio of the potassium hydroxide to the raw material is 7-8: 15, and in the step (3), the mass ratio of the chloroacetic acid to the raw material is 1: 5-7, and the chloroacetic acid can be continuously added or added in 3-7 times.
Preferably, in the above method, the isopropyl alcohol solvent recovered from the protein hydrolysate obtained by the filtration and separation is recycled, and the protein hydrolysate obtained by concentration is used as the liquid potash fertilizer raw material.
Preferably, in the method, the acid solution in the step (4) is hydrochloric acid, citric acid or glutamic acid, the reaction temperature is 30-60 ℃, the reaction time is 1-10 hours, preferably, the raw material is 100-200 mesh, and the reaction is ended when the pH is not changed and is less than 4.
Preferably, in the above method, the carrier materials obtained in the steps (1) to (4) have a nanopore structure, and the specific surface area is 2 to 100m2·g-1Preferably, the specific surface area of the carrier obtained in the steps (2), (3) and (4) is 40-50 m2·g-1Can be used as a carrier with higher loading capacity.
Preferably, in the above method, the solution adsorption-supporting method comprises the steps of: obtaining a powder sample carrier material according to the steps (1) - (4), drying to remove water so as to reduce air and water residues in a pore channel, immersing the powder sample carrier material in an excessive saturated or supersaturated aqueous solution or organic solution or mixed solution of a substance to be adsorbed for full adsorption, heating to a slightly boiling state if necessary, stirring for 0.5-24 hours at room temperature or in a reflux state, filtering, washing with deionized water or a corresponding solvent, drying under reduced pressure to constant weight to obtain sustained and controlled release product particles, wherein the specific conditions can be determined by heating or reduced pressure adsorption or optimization of selection of a proper solvent according to the characteristics of a medicament.
The invention also provides the application of the carrier material prepared by the method as a product after adsorbing one or more components of medicines, pesticides, fertilizers, disinfectants, preservatives, essences, spices, feeds and food additives, and is characterized in that the one or more components are adsorbed by the sustained-release carrier material obtained in the steps (1) to (4) of any one of claims 1 to 6.
Preferably, in the application, the composition is selected from medicines, health-care products and nutritional ingredients, preferably, the composition is selected from one or more of Chinese and western medicines, nutritional ingredients, vitamins, pesticides, plant growth promoters, amino acids, disinfectants, preservatives and flavors and fragrances, and preferably, the composition is glyphosate isopropylamine salt, ibuprofen sodium, imidacloprid, abamectin and potassium chloride.
The invention also provides a carrier material prepared by using the shrimp and crab shells as raw materials and developing a natural drug carrier by means of or constructing a nano-pore channel, wherein the carrier material is prepared in the steps (1) to (4) in the method of any one of claims 1 to 6, and the specific surface area of the carrier material is 2-100 m2·g-1Preferably, the specific surface area of the carrier obtained in the steps (2), (3) and (4) is 40-50 m2·g-1The carrier and various functional products produced.
Preferably, in the above method, the carrier may be other biomass material having nanopores, such as bamboo fiber having nanopores.
Specifically, the natural porous carrier chitin-protein composite biological base material, chitosan-calcium carbonate composite biological base material and porous calcium carbonate are obtained by taking shrimp and crab shells as raw materials by adopting the following general methods:
preparation of general method chitin-protein composite biological base material
Washing and drying shrimp and crab shells, then placing the shrimp and crab shells in a 5-12% citric acid solution, keeping the pH value below 4 at 30-80 ℃, electrically stirring for 1-10 hours, filtering, washing to be neutral, grinding by a grinder after drying treatment, sieving by a 200-mesh sieve to obtain the chitin-protein composite bio-based material without calcium carbonate, and drying for later use.
Preparation of general method secondary chitosan-calcium carbonate composite bio-based material
After being washed and dried, the shrimp shells are ground in a grinder, sieved by a 200-mesh sieve and dried for later use. Putting the dried shrimp and crab powder, solid KOH, isopropanol and water into a reactor according to the mass ratio of 3: 1.4: 6.3: 0.7, refluxing (boiling) for about 3 hours at normal pressure (65 ℃), cooling, filtering, washing with deionized water, drying, and finally drying to obtain the chitosan-calcium carbonate composite bio-based material. The analysis conditions of the samples are shown in tables 1-5 through digestion, distillation, absorption and titration by a Kjeldahl method.
General method calcium tricarbonate carrier and preparation of carboxymethyl chitosan
And adding chloroacetic acid into the mixture after the second reaction according to the general method for further carboxymethylation, wherein the chloroacetic acid is added for 3-7 times, the reaction temperature of the carboxymethylation is 50-70 ℃, and the reaction time is 0.5-10 hours. Washing the reacted solid to be neutral by isopropanol, adding water to dissolve, filtering, washing and drying to obtain porous calcium carbonate, and adding alcohol into the aqueous solution to precipitate a carboxymethyl chitosan solid product.
TABLE 1 analysis of protein content in raw materials and vectors
Figure BDA0002012611750000081
Therefore, under the condition of keeping the calcium carbonate skeleton structure, the removal rate of the protein in the shrimp and crab shells is up to more than 95%.
TABLE 2 elemental content analysis of raw materials and carriers
Figure BDA0002012611750000082
Figure BDA0002012611750000091
The C, H, N content of the shrimp and crab shells is obviously reduced after alkali treatment, which indicates that most of protein is removed.
TABLE 3 analysis of Water absorption of raw Material and Carrier
Figure BDA0002012611750000092
The water absorption of the carrier for removing the protein is doubled, and the pore-forming and pore-enlarging effects are proved to be obvious.
TABLE 4 Deacetyl degree of a sample by Infrared Spectroscopy
Figure BDA0002012611750000093
More than 90% of the chitin in the carrier has become chitosan.
TABLE 5 determination of specific surface area, pore volume and pore diameter of shrimp and crab shell samples
Figure BDA0002012611750000094
Figure BDA0002012611750000101
The results show that: the specific surface area of a sample obtained by the alcohol-alkali-water process is increased by about 20 times, the sample has an average pore channel of about 10 nanometers, the pore volume is greatly increased, and the method has basic conditions for serving as a drug carrier.
In contrast, the samples obtained by acid treatment, whether the specific surface area or the pore volume, were significantly reduced, indicating that the complex biobased material of protein and chitin, which lacks calcium carbonate support, is more easily associated due to elimination of steric constraints. But the porous structure can be restored in an aqueous system and can also be used as a drug carrier. The straw powder can not load the medicine, but the bamboo fiber with the nanometer pore canal can load a small amount of the medicine, which proves that the medicine can be loaded only by the carrier with the structure of the nanometer pore canal.
The scanning electron micrograph in FIG. 2 shows that the pores of the base-treated support are evident, and the acid-treated support is essentially free of pores.
Loading of drugs by general four-solution adsorption method
And (2) obtaining a powder sample according to the general method 1-3, drying at 160 ℃ for 2 hours to remove water as far as possible, cooling to below 100 ℃, immersing the powder sample in an excessive saturated or supersaturated aqueous solution or organic solution or mixed solution of a substance to be adsorbed under the condition of reducing air and water residues in a pore passage, slowly heating to a micro-boiling state, magnetically stirring for 1-24 hours under a reflux state, filtering, washing with deionized water or absolute ethyl alcohol for three times, drying under reduced pressure to constant weight, and analyzing the drug loading for later use.
General method five-slow controlled release performance determination
Accurately weighing the prepared drug-loaded powder in a dialysis bag, adding 2mL of water, clamping two ends of the drug-loaded powder, placing the drug-loaded powder in a beaker, adding 500mL of water or PBS solution or absolute ethyl alcohol, releasing the drug-loaded powder at 37 ℃, sampling at regular time, centrifuging to obtain supernatant, and characterizing by an ultraviolet spectrophotometer or high performance liquid chromatography. The test shows that the drug loading rate is 10-44%, the cumulative release rate of the drug is 80%, and the drug loading rate is certain, so that the slow release effect is good.
In a control experiment, medicine-carrying powder is weighed, Ethyl Cellulose (EC)/hydroxypropyl methyl cellulose (HPMC) with different concentrations are used for coating the medicine-carrying powder to prepare ethyl acetate solution with 3% EC, HPMC with the mass concentration of 5g/L is used as an inner coating swelling layer, EC is used as an outer layer controlled-release coating material, and the medicine release degree is controlled by controlling the weight increment of the swelling layer and the coating layer.
Quantitative evaluation of drug loading and sustained and controlled release effects was performed.
In this embodiment, load and release conditions of representative drugs such as potassium chloride, ibuprofen, and sodium ibuprofen, and representative pesticides such as avermectin, imidacloprid, glyphosate isopropylamine salt, and cypermethrin are evaluated, and it is proved that the load of the carrier can have a good sustained and controlled release effect in a range of 10% to 44%.
The invention fully shows the following beneficial effects:
the method takes the shrimp and crab shells which are rich, cheap, safe and green as raw materials, can realize full-price and high-added-value utilization through a clean production process, prepares chitosan-calcium carbonate composite biological base materials, porous calcium carbonate, chitin-protein composite biological base materials and the like with natural nanometer pore canals, larger specific surface area and pore volume and larger drug-loading capacity, is a carrier material with huge potential, and opens up a new way for improving the long-acting property of substances with various functions, reducing the dosage and toxic and side effects and developing safe and efficient animal and plant and microbial fertilizer systems.
Drawings
FIG. 1 a: shrimp shell meal (SSP), b: chitin-protein composite bio-based material (S-Ct/Pro), c: chitosan-calcium carbonate composite bio-based material (S-CS/CaCO)3) D: porous calcium carbonate (S-CaCO)3) TEM image of
FIG. 2 a: shrimp shell meal (SSP), b: chitin-protein composite bio-based material (S-Ct/Pro), c: chitosan-calcium carbonate composite bio-based material (S-CS/CaCO)3) D: porous calcium carbonate (S-CaCO)3) SEM image of
FIG. 3 a: crab Shell Powder (CSP), b: chitin-protein composite bio-based material (C-Ct/Pro), C: chitosan-calcium carbonate composite material (C-CS/CaCO)3) D: porous calcium carbonate (C-CaCO)3) SEM image of
FIG. 4N of shrimp shell meal2Adsorption-desorption isotherms and corresponding pore size profiles
FIG. 5N of chitin-protein composite bio-based material2Adsorption-desorption isotherms and corresponding pore size profiles
FIG. 6N of chitosan-calcium carbonate composite biobased material2Adsorption-desorption isotherms and corresponding pore size profiles
FIG. 7 porous calcium carbonate (S-CaCO)3) N of (A)2Adsorption-desorption, etcTemperature profile and corresponding aperture profile
FIG. 8 a: shrimp shell powder, b: chitin-protein composite bio-based material, c: chitosan-calcium carbonate composite bio-based material, d: FT-IR spectrum of porous calcium carbonate
FIG. 9 is the cumulative release curve of the shrimp shell powder, the chitosan-calcium carbonate composite bio-based material, the porous calcium carbonate and the chitin-protein bio-based material to the glyphosate isopropylamine salt
FIG. 10 is the cumulative release curve of shrimp shell powder, chitosan-calcium carbonate composite bio-based material and chitin-protein composite bio-based material to potassium chloride drug
FIG. 11 cumulative release curve of chitin-protein composite bio-based material for imidacloprid
FIG. 12 cumulative release profile of chitosan-calcium carbonate composite biobased materials to ibuprofen
FIG. 13 cumulative release curve of chitosan-calcium carbonate composite bio-based material on glyphosate
FIG. 14 porous calcium carbonate (S-CaCO)3) Cumulative release profile for sodium ibuprofen
FIG. 15 patent discloses cumulative release profiles of chitosan-embedded synthetic calcium carbonate complexed methotrexate
FIG. 16 preparation and in vitro release curve of ibuprofen sustained release tablet reported in literature
FIG. 17 reference report on hollow porous SiO2Release profile of nanoparticles to Avermectin
FIG. 18 is the cumulative release curve of the chitosan-calcium carbonate composite bio-based material, the porous calcium carbonate and the chitin-protein bio-based material to the avermectin
FIG. 19 flow chart of several carrier preparation processes using shrimp and crab shells as raw materials
In the diagram, SSP refers to Shrimp Shell meal (Shrimp Shell Powder); CSP refers to Crab Shell Powder (Crab Shell Powder); Ct-Pro refers to chitin-protein composite bio-based material; CS-CaCO3The chitosan-calcium carbonate composite bio-based material; CaCO3Refers to porous calcium carbonate, S-refers to a product from shrimp shell powder, and C-refers to a product from crab shell powder.
Detailed Description
The technical scheme of the invention is further illustrated by combining specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
Example 1 preparation of chitin-protein composite biobased material from shrimp Shell
Washing shrimp shells, drying at 160 ℃, taking out the shrimp shells, adding the shrimp shells into a single-neck flask provided with an electric stirrer, preparing a citric acid solution with the concentration of 10%, wherein the mass ratio of the shrimp shells to the citric acid solution is 1: 10, heating to 50 ℃, carrying out heat preservation treatment for 4 hours for decalcification, selecting 50 ℃ warm water, filtering by using a mesh screen, recovering calcium citrate in filtrate, carrying out secondary decalcification on the obtained filtrate according to the same experimental conditions, finally filtering by using the mesh screen, washing the filtrate for multiple times by using a proper amount of distilled water to be neutral, drying, and crushing by using a crusher to 200 meshes to obtain the chitin-protein composite bio-based material. Drying again to constant weight for later use. The ash content is detected to be 0.26% by referring to a method in GB 5009.4-2016 (determination of ash content in national food safety standard).
Example 2 preparation of Chitosan-calcium carbonate composite biobased Material from shrimp Shell
Adding 150.0g of shrimp shell powder into a three-neck flask provided with an electric stirrer, mixing and dissolving 80.0g of potassium hydroxide solid and 40.0g of water, adding 400mL of isopropanol, uniformly stirring, pouring into the three-neck flask, reacting for 3.0h at a reflux temperature, fully hydrolyzing protein and removing acetyl, filtering, stirring the obtained solid with 200mL of isopropanol at normal temperature for 0.5h, filtering, washing with clear water for three times, and drying to constant weight to obtain the chitosan-calcium carbonate composite biological base material. The protein hydrolysate obtained by filtering contains amino acid, small peptide and potassium hydroxide, and can be used as liquid amino acid and potassium fertilizer raw materials after recycling the isopropanol solvent. The deacetylation degree is measured by acid-base titration or infrared spectroscopy, chitosan and calcium carbonate are dissolved by dilute hydrochloric acid, the chitosan is precipitated by ethanol, and calcium chloride is removed by repeated washing with 70% ethanol aqueous solution to obtain pure chitosan, wherein the deacetylation degree is 88%.
Example 3 preparation of crude calcium carbonate from shrimp Shell
Adding 150.0g of shrimp shell powder into a three-neck flask provided with an electric stirrer, mixing and dissolving 80.0g of potassium hydroxide solid and 40.0g of water, adding 400mL of isopropanol, stirring uniformly, pouring into the three-neck flask, reacting for 3.0h under the reflux temperature condition, fully hydrolyzing protein and removing acetyl, adding 25.0g of chloroacetic acid, adding for 5 times, reacting for 3.0h under the heat preservation condition of 60 ℃, performing carboxymethylation on chitosan, filtering and separating to obtain a carboxymethyl chitosan and calcium carbonate mixture, adding water into the mixture for dissolving, and filtering to obtain the by-product porous calcium carbonate. The filtrate can be added with 80 percent ethanol to precipitate carboxymethyl chitosan products.
Example 4 soluble Material dissolution of Carrier in Water
Accurately weighing about 1.0g of carrier (shrimp shell powder SSP, chitosan-calcium carbonate composite bio-based material CS-CaCO)3Porous calcium carbonate CaCO3Chitin-protein composite bio-based material Ct-Pro) is poured into a 50mL round-bottom flask, 10g of water is added into the round-bottom flask, the temperature is raised to slight boiling, the temperature is kept for 2h, and the filtration and the drying are carried out. SSP weight loss 2.91%, CS-CaCO34.89% weight loss, CaCO32.77 percent and Ct-Pro weight loss of 6.88 percent. The highly polar materials in each carrier will dissolve in water under these conditions.
EXAMPLE 5 preparation of Glyphosate isopropylamine salt/shrimp shell meal (NPPMG/SSP) complexes and Release Profile determination
1. Glyphosate isopropylamine salt load experiment
Accurately weighing 1.0g of shrimp shell powder sample SSP (carrier articles used in the following examples are all samples with performances described in tables 1 to 5), drying at 160 ℃ to constant weight, cooling to below 100 ℃, quickly pouring into a single-neck flask, adding 10.0g of 41% glyphosate isopropylamine salt solution (shaking a reaction flask while adding NPPMG solution), supplementing 5.0g of deionized water to enable the reaction system to have fluidity, stirring at room temperature for 0.5 hour, filtering, washing three times, and drying to constant weight. The drug loading (i.e., percent glyphosate isopropylamine salt) was measured to be 35.0%.
2. Glyphosate isopropylamine salt release test
Accurately weighing 1.0g of drug-loaded powder (the drug-loaded amount is 35.0%) in a dialysis bag, clamping two ends of the drug-loaded powder, placing the drug-loaded powder in a beaker, respectively adding 500mL of water, releasing at 30 ℃, sampling at regular time, centrifuging to obtain supernatant, filtering through a 0.45 mu m filter membrane, diluting, performing ultrasonic treatment for 20min, representing by using a high performance liquid chromatography, and measuring a sustained and controlled release curve, wherein the NPPMG/SSP in figure 9 is shown.
Example 6 Glyphosate isopropylamine salt/porous calcium carbonate (NPPMG/CaCO)3) Preparation of the complexes and determination of the Release Profile
1. Glyphosate isopropylamine salt load experiment
Accurately weighing 3.0g of porous calcium carbonate, drying at 160 ℃ to constant weight, cooling to below 100 ℃, quickly pouring into a single-neck flask, adding 30g of 41% glyphosate isopropylamine salt solution (shaking a reaction bottle while adding NPPMG solution), supplementing 5.0g of deionized water to make the reaction system have fluidity, stirring for 0.5 hour at room temperature, filtering, washing and drying to constant weight. The drug loading was found to be 43.0%.
2. Glyphosate isopropylamine salt release test
Accurately weighing 1.0g of drug-loaded powder (43.0% of drug-loaded amount), placing in a dialysis bag, clamping two ends, placing in a beaker, respectively adding 500mL of water, releasing at 30 ℃, sampling at regular time, centrifuging to obtain supernatant, filtering with a 0.45 μm filter membrane, diluting, performing ultrasound for 20min, and characterizing by high performance liquid chromatography. The sustained-release profile was determined and is shown in FIG. 9 as NPPMG/CaCO3。
Example 7 Glyphosate isopropylamine salt/Chitosan-calcium carbonate (NPPMG/CS-CaCO)3) Preparation of the complexes and determination of the Release Profile
Accurately weighing 1.0g of chitosan-calcium carbonate composite bio-based material, activating the material at 160 ℃ for 2h, cooling the material to below 100 ℃, quickly adding the material into a 100mL round-bottom flask, adding 10.0g of 41% glyphosate isopropylamine salt solution in batches at room temperature under a stirring state, supplementing 5.0g of water after the addition is finished, stirring the material at room temperature for 0.5h, filtering, washing, drying at 120 ℃, and measuring the drug loading capacity to be 40.90%.
Accurately weighing 1.0g of drug-loaded powder (40.90% drug-loaded), placing in a dialysis bag, clamping two ends, placing in a beaker, adding 500mL of water respectively, releasing at 30 deg.C, sampling at regular time, centrifuging to obtain supernatant, and filtering with a filter of 0.4Filtering with 5 μm filter membrane, diluting, ultrasonic treating for 20min, and characterizing by high performance liquid chromatography. The sustained-release profile was determined as NPPMG/CS-CaCO in FIG. 93。
EXAMPLE 8 preparation of Glyphosate isopropylamine salt/chitin-protein (NPPMG/Ct-Pro) complexes and Release Curve determination
Accurately weighing 1.0g of chitin-protein composite bio-based material, activating at 160 ℃ for 2h, cooling to below 100 ℃, quickly adding into a 100mL round-bottom flask, adding 10.0g of 41% glyphosate isopropylamine salt solution in batches at room temperature under a stirring state, supplementing 5.0g of water after the addition is finished, stirring at room temperature for 0.5h, filtering, washing, drying at 120 ℃, and measuring the drug-loading rate to be 41.99%.
Accurately weighing 1.0g of drug-loaded powder (with the drug loading of 41.99%) in a dialysis bag, clamping two ends of the drug-loaded powder, placing the drug-loaded powder in a beaker, respectively adding 500mL of water, releasing the drug-loaded powder at 30 ℃, sampling at regular time, centrifuging to obtain supernatant, filtering the supernatant through a 0.45 mu m filter membrane, diluting and ultrasonically treating the supernatant for 20min, and characterizing the supernatant by high performance liquid chromatography. The sustained-release curve was determined and is shown in FIG. 9 as NPPMG/Ct-Pro.
Example 9 preparation of Potassium chloride/chitin-protein (KCl/Ct-Pro) complexes and Release Curve determination
1. Potassium chloride load test
Preparing saturated potassium chloride solution in a single-neck flask at room temperature, accurately weighing 5g of chitin-protein composite bio-based material, drying at 160 ℃ for 2 hours, cooling to below 100 ℃, rapidly pouring, slowly heating to a slightly boiling state, stirring for one hour, cooling to room temperature, filtering, washing with certain mass water for three times, and drying to constant weight. The drug loading was measured to be 17.3%.
2. Drug-loaded powder coating treatment
Weighing 2g of medicine-carrying powder, spraying a proper amount of ethyl cellulose solution and hydroxypropyl methyl cellulose solution, drying and weighing.
Weighing medicine-carrying powder, coating the medicine-carrying powder with Ethyl Cellulose (EC)/hydroxypropyl methyl cellulose (HPMC) with different concentrations to prepare ethyl acetate solution with 3% EC, HPMC with mass concentration of 5g/L, HPMC as an inner coating swelling layer, EC as an outer controlled-release coating material, and controlling the release degree of the medicine by controlling the swelling layer and the coating layer.
3. Potassium chloride Release test
2.0g of drug-loaded powder is accurately weighed, coated, placed in a beaker, added with 500mL of water, released at 37 ℃, sampled at regular time and measured by conductivity. The sustained-release curve was determined and is shown in FIG. 10 as KCl/Ct-Pro-Coating.
EXAMPLE 10 preparation of Potassium chloride/shrimp Shell meal (KCl/SSP) complexes and Release Profile determination
1. Potassium chloride load test
Preparing saturated potassium chloride solution in a single-neck flask at room temperature, accurately weighing 5.0g of shrimp shell powder, drying at 160 ℃ for 2h, cooling to below 100 ℃, pouring rapidly, slowly heating to a slightly boiling state, stirring and refluxing for 2h, cooling to room temperature, filtering, washing with certain mass of water for three times, and drying to constant weight. The drug loading was found to be 3.9%.
2. Drug-loaded powder coating treatment
Weighing 2g of medicine-carrying powder, spraying a proper amount of ethyl cellulose solution and hydroxypropyl methyl cellulose solution, drying and weighing.
The specific experimental steps are as follows: weighing medicine-carrying powder, coating the medicine-carrying powder with Ethyl Cellulose (EC)/hydroxypropyl methyl cellulose (HPMC) with different concentrations to prepare ethyl acetate solution with 3% EC, HPMC with mass concentration of 5g/L, HPMC as an inner coating swelling layer, EC as an outer controlled-release coating material, and controlling the release degree of the medicine by controlling the swelling layer and the coating layer.
3. Potassium chloride Release test 1
Accurately weighing 2.0g of drug-loaded powder, loading the drug-loaded powder into a dialysis bag after coating treatment, adding 2mL of water, clamping two ends of the drug-loaded powder, placing the drug-loaded powder into a beaker, adding 500mL of water, releasing the drug-loaded powder at 37 ℃, sampling at regular time, and measuring by using conductivity. The sustained and controlled release profile was determined and is shown in FIG. 10 for KCl/SSP-Coating.
4. Potassium chloride Release test 2
Accurately weighing 2.0g of drug-loaded powder in a dialysis bag, adding 2mL of water, clamping two ends of the drug-loaded powder, placing the drug-loaded powder in a beaker, adding 500mL of water, releasing the drug-loaded powder at 37 ℃, sampling at regular time and measuring by using electric conductivity. The sustained and controlled release profile was determined and is shown in FIG. 10 as KCl/SSP.
Example 11 Potassium chloride/Chitosan-calcium carbonate (KCl/CS-CaCO)3) Preparation of the complexes and determination of the Release Profile
1. Potassium chloride load test
Preparing saturated potassium chloride solution in a single-neck flask at room temperature, accurately weighing 5g of chitosan-calcium carbonate composite bio-based material, drying at 160 ℃ for 2h, cooling to below 100 ℃, rapidly pouring, slowly heating to a slightly boiling state, stirring and refluxing for 2h, cooling to room temperature, filtering, washing with certain mass of water for three times, and drying to constant weight. The drug loading was measured to be 9.4%.
2. Drug-loaded powder coating treatment
Weighing 2g of medicine-carrying powder, spraying a proper amount of ethyl cellulose solution and hydroxypropyl methyl cellulose solution, drying and weighing.
Weighing medicine-carrying powder, coating the medicine-carrying powder with Ethyl Cellulose (EC)/hydroxypropyl methyl cellulose (HPMC) with different concentrations to prepare ethyl acetate solution with 3% EC, HPMC with mass concentration of 5g/L, HPMC as an inner coating swelling layer, EC as an outer controlled-release coating material, and controlling the release degree of the medicine by controlling the swelling layer and the coating layer.
3. Potassium chloride Release test 1
Accurately weighing 2.0g of drug-loaded powder, loading the drug-loaded powder into a dialysis bag after coating treatment, adding 2mL of water, clamping two ends of the drug-loaded powder, placing the drug-loaded powder into a beaker, adding 500mL of water, releasing the drug-loaded powder at 37 ℃, sampling at regular time, and measuring by using conductivity. The sustained and controlled release profile was determined and is shown in FIG. 10 for KCl/CS-CaCO3-Coating。
4. Potassium chloride Release test 2
Accurately weighing 2.0g of drug-loaded powder in a dialysis bag, adding 2mL of water, clamping two ends of the drug-loaded powder, placing the drug-loaded powder in a beaker, adding 500mL of water, releasing the drug-loaded powder at 37 ℃, sampling at regular time and measuring by using electric conductivity. The sustained and controlled release profile was determined and is shown in FIG. 10 for KCl/CS-CaCO3。
Example 12 preparation of Imidacloprid/chitin-protein (Imidacloprid/Ct-Pro) complexes and Release Curve determination
1. Imidacloprid load experiment
Accurately weighing 3.0g imidacloprid insecticide with the mass fraction of 10%, dissolving with dichloromethane, pouring into a single-neck flask, accurately weighing 5.0g chitin-protein complex, drying at 160 ℃ for 2 hours, cooling to below 100 ℃, pouring rapidly, slowly heating to a slightly boiling state, stirring for 1 hour, filtering, washing with a large amount of water for three times, and drying to constant weight. The drug loading was found to be 16.8%.
2. Imidacloprid release test
Accurately weighing 1.5g of medicine-carrying powder, performing coating treatment, placing in a beaker, adding 500mL of water, releasing at 30 ℃, sampling at regular time, centrifuging to obtain supernatant, filtering with a 0.45-micron filter membrane, diluting, performing ultrasonic treatment for 20min, and characterizing by high performance liquid chromatography. The sustained and controlled release profile was determined and is shown in figure 11.
Example 13 ibuprofen/Chitosan-calcium carbonate (IBU/CS-CaCO)3) Preparation of the complexes and determination of the Release Profile
1. Ibuprofen Loading experiment
1.0g of IBU was accurately weighed out and dissolved in 20mL of 50 ℃ deionized water, and 1mol/L NaOH solution was slowly added with vigorous stirring until the IBU was completely dissolved. Adding 4.0g of chitosan-calcium carbonate composite bio-based material, heating and stirring at 70 ℃, adjusting the pH value to be neutral by using 10% hydrochloric acid solution, stirring for 1h, and drying at 50 ℃. The drug loading was found to be 10.8%.
2. Ibuprofen Release test
Accurately weighing 1.0g of drug-loaded powder in a dialysis bag, adding 2mL of water, clamping two ends of the drug-loaded powder, placing the drug-loaded powder in a beaker, adding 500mL of water, releasing the drug-loaded powder at 37 ℃, sampling at regular time, centrifuging to obtain supernatant, filtering the supernatant through a 0.45-micron filter membrane, diluting and performing ultrasonic treatment for 20min, and characterizing the drug-loaded powder by using high performance liquid chromatography. The sustained and controlled release profile was determined and is shown in figure 12.
Example 14 Glyphosate/Chitosan-calcium carbonate (PMG/CS-CaCO)3) Preparation of the complexes and determination of the Release Profile
1. Glyphosate load experiment
Accurately weighing 3.0g of 95% glyphosate crystal powder, placing the powder into a single-neck flask, adding 20mL of deionized water to dissolve the powder, weighing 5.0g of chitosan-calcium carbonate composite bio-based material, drying the material at 160 ℃ for 2 hours, cooling the material to below 100 ℃, quickly pouring the material into glyphosate solution, slowly heating the material to a slightly boiling state, stirring the material for one hour, cooling the material to room temperature, decompressing the glyphosate preparation to evaporate water to the greatest extent until crystals are separated out, filtering the product, washing the product with water of certain mass for three times, and drying the product. The drug loading was measured to be 31.1%.
2. Glyphosate release test
Accurately weighing 2.0g of drug-loaded powder in a dialysis bag, adding 2mL of water, clamping two ends of the drug-loaded powder, placing the drug-loaded powder in a beaker, adding 500mL of water, releasing the drug-loaded powder at 30 ℃, sampling at regular time, centrifuging to obtain supernatant, filtering the supernatant with a 0.45 mu m filter membrane, diluting and ultrasonically treating for 20min, and then filtering with a 0.45 mu m filter membrane, and characterizing the drug-loaded powder by high performance liquid chromatography. The sustained-release curve was determined, and is shown in FIG. 13.
Example 15 sodium ibuprofen/porous calcium carbonate (IBU-Na/CaCO)3) Preparation of the complexes and determination of the Release Profile
1. Sodium ibuprofen Loading experiment
Accurately weighing 0.2g of sodium hydroxide solid (40.0, 1eq), and adding 25mL of water to prepare a sodium hydroxide solution; weighing 1g of Ibuprofen (IBU) (206.2, 1eq), pouring into a prepared sodium hydroxide solution, stirring and dissolving the ibuprofen (neutralization reaction), adding 4.0g of porous calcium carbonate, slowly heating to a slightly boiling state, stirring for one hour, cooling to room temperature, washing with water of certain mass for three times, and drying at 60 ℃ to obtain the drug-loading rate of 16.6%.
2. Sodium ibuprofen Release test
Accurately weighing 1.0g of drug-loaded powder in a dialysis bag, adding 2mL of water, clamping two ends of the drug-loaded powder, placing the drug-loaded powder in a beaker, adding 500mL of water, releasing the drug-loaded powder at 37 ℃, sampling at regular time, centrifuging to obtain supernatant, filtering the supernatant through a 0.45-micron filter membrane, diluting and performing ultrasonic treatment for 20min, and characterizing the drug-loaded powder by using high performance liquid chromatography. The sustained and controlled release profile was determined and is shown in figure 14. The determination result proves that the ibuprofen sodium/the porous calcium carbonate (IBU-Na/CaCO)3) The compound completely meets the sustained and controlled release requirements of pharmacopoeia.
EXAMPLE 16 preparation of Avermectin/shrimp Shell powder (AVM/SSP)
Accurately weighing 1.0g of shrimp shell powder, activating for 2h at 160 ℃, cooling to below 100 ℃, quickly adding into a 50mL round-bottom flask, respectively adding 10.0g of 10% abamectin solution in acetone, chloroform and ethanol, refluxing in a water bath for 24h, cooling, filtering, washing with acetone, and drying to obtain the drug-loading rates of 26.87%, 2.87% and 2.24%.
Example 17 Avermectin/Chitosan-calcium carbonate (AVM/CS-CaCO)3) Preparation of the Complex
Accurately weighing 1.0g of chitosan-calcium carbonate composite bio-based material, activating the material at 160 ℃ for 2h, cooling the material to below 100 ℃, quickly adding the material into a 50mL round-bottom flask, respectively adding 10.0g of 10% abamectin solution in acetone, chloroform and ethanol into the round-bottom flask, refluxing the material in a water bath for 24h, cooling the material, filtering the material, washing the material with acetone, and drying the material to obtain the drug-loading rate of 36.54%, 3.58% and 0.96%.
Weighing 1.0g of abamectin/shrimp shell powder (AVM/CS-CaCO)336.54 percent of drug loading amount), clamping the two sides, placing the dialysis bag into a wide-mouth bottle with a ground mouth, adding 100mL of absolute ethyl alcohol, releasing at room temperature, sampling at regular time, centrifuging, passing through a 0.45 mu m powder filter membrane, characterizing by high performance liquid chromatography, and determining a sustained and controlled release curve, which is shown as AVM/CS-CaCO in figure 183。
Example 18 Avermectin/porous calcium carbonate (AVM/CaCO)3) Preparation of
Accurately weighing 1.0g of porous calcium carbonate, activating at 160 ℃ for 2h, cooling to below 100 ℃, quickly adding into a 50mL round-bottom flask, respectively adding 10.0g of 10% abamectin solution in acetone, chloroform and ethanol, refluxing in a water bath for 24h, cooling, filtering, washing with acetone, and drying to obtain drug-loading rates of 44.68%, 6.19% and 0.
Weighing 1.0g of abamectin/shrimp shell powder (AVM/CaCO)344.68%) in dialysis bag, clamping the two sides, placing in ground jar, adding 100mL anhydrous ethanol, releasing at room temperature, sampling at regular time, centrifuging, filtering with 0.45 μm powder filter membrane, characterizing with high performance liquid chromatography, and determining sustained-release curve (see AVM/CaCO in FIG. 18)3。
EXAMPLE 19 preparation of Abamectin/chitin-protein (AVM/Ct-Pro) Complex
Accurately weighing 1.0g of chitin-protein composite bio-based material, activating at 160 ℃ for 2h, cooling to below 100 ℃, quickly adding into a 50mL round-bottom flask, respectively adding 10.0g of 10% abamectin solution in acetone, chloroform and ethanol into the round-bottom flask, refluxing in a water bath for 24h, cooling, filtering, washing with chloroform, drying, and measuring the drug-loading rate to be 0, 25.89% and 0.
Weighing 1.0g of abamectin/shrimp shell powder (AVM)/Ct-Pro with drug loading of 25.9%) in dialysis bag, clamping the two sides, placing in ground jar, adding 100mL absolute ethanol, releasing at room temperature, sampling at regular time, centrifuging, filtering with 0.45 μm powder filter membrane, characterizing by high performance liquid chromatography, and determining sustained-release curve, see AVM/Ct-Pro in FIG. 18.
Example 20 landfill of different Carriers, different pH vs. KCl
Accurately weighing about 1.0g of carrier (shrimp shell powder SSP, chitosan-calcium carbonate composite bio-based material CS-CaCO)3Porous calcium carbonate CaCO3And the chitin-protein composite bio-based material Ct-Pro) is added into saturated potassium chloride solutions with different pH values, the mixture is heated to slight boiling, the slight boiling is kept for 4 hours, and the mixture is filtered and dried. As can be seen from the following table of landfill rates, the weight loss of various carriers varied with the change of pH, and CS-CaCO was observed at pH 12 and 133、CaCO3Has a certain landfill rate.
TABLE 6 Effect of different carriers on carrier landfill Rate at different pH conditions
Figure BDA0002012611750000181
Example 21 Effect of NPPMG (Glyphosate isopropylamine salt) dosing on landfill Rate
Adding NPPMG (see the table below) with a certain mass into 1.0g of the activated carrier, heating and refluxing for 2h, filtering, washing and drying. The appropriate increase of the dosage of NPPMG is beneficial to improving the landfill rate.
TABLE 7 Effect of the quality of Glyphosate isopropylamine salt on Carrier landfill Rate
Figure BDA0002012611750000182
Figure BDA0002012611750000191
Example 22 Effect of temperature, solvent on the landfill rate of Avermectin
Respectively adding 1.0g of activated carrier into 10% abamectin chloroform solution, ethanol solution and acetone solution, refluxing at room temperature or for 24h, filtering, washing and drying. SSP, CS-CaCO3、CaCO3The three carriers can obtain higher landfill rate in an abamectin acetone solution, the landfill rate in a chloroform and ethanol solution is lower, but the Ct-Pro carrier can obtain higher landfill rate in chloroform reflux, and other solvents are basically not loaded. It can be seen that the carrier, solvent and temperature conditions all significantly affect the landfill effect.
TABLE 8 influence of temperature, solvent on the landfill rate of Avermectin
Figure BDA0002012611750000192
EXAMPLE 23 landfill of sodium ibuprofen with different vehicles and different solvents
10g of 10% ibuprofen acetone solution and 0.68g of 30% sodium hydroxide (0.2 g of sodium hydroxide) solution are respectively added into the ethanol solution to change the ibuprofen into the ibuprofen sodium solution, 1.0g of activated carrier is added, the temperature is increased, the reflux is carried out for 24h, and the filtration and the washing are carried out. CS-CaCO3And CaCO3The carrier amount in acetone solution can reach a certain amount, and the effect in ethanol solution is poor. However, the ethanol solution can make Ct-Pro be better loaded.
TABLE 9 Effect of different carriers and different solvents on the sodium ibuprofen landfill rate
Figure BDA0002012611750000193
Figure BDA0002012611750000201
EXAMPLE 24 filling Effect of various vehicles on Soybean oil
Adding 10g soybean oil into 1.0g activated carrier, adding under different pressures, stirring under different pressures for 2h, filtering, washing with ethanol, and oven drying. Multiple supports all show good loading potential, and the reduced pressure can significantly increase the loading capacity.
TABLE 10 Effect of pressure on Carrier landfill Rate
Figure BDA0002012611750000202
The loading effect of the natural plant raw materials bamboo powder and sunflower stalk powder as the carriers is not ideal in the comparison example
Respectively adding 10g of 41% glyphosate isopropylamine salt, 10g of 30% KCl solution, 10g of 30% urea solution and 6g of 75% glyphosate ammonium salt into 1g of activated carrier, heating, refluxing for 4h, filtering, washing and drying. Therefore, the bamboo fiber with the nanometer pore canal has certain loading capacity, and the straw powder with the larger pore canal has no loading capacity.
TABLE 11 landfill rate analysis of different samples with bamboo powder and sunflower powder
Figure BDA0002012611750000203

Claims (8)

1. The application of the sustained and controlled release carrier material prepared by taking shrimp and crab shells as raw materials in preparing medicines, fertilizers or plant growth promoters is characterized in that the carrier material is prepared by any one of the following methods:
(1) cleaning raw materials of shrimp and crab shells, boiling to remove soluble substances, drying, pulverizing into powder of more than 200 meshes, and sieving for later use to directly serve as one of sustained and controlled release carrier materials; or
(2) Adding the product prepared in the step (1) as a raw material into an isopropanol-potassium hydroxide-water system, heating and carrying out alkaline hydrolysis for 3 hours at a reflux temperature to remove acetyl of chitin to form chitosan, degrading protein into amino acid and small peptide, dissolving the amino acid and the small peptide in a mixed solvent, filtering solid powder from a reaction mixture, washing the solid powder to be neutral, and drying to obtain a chitosan-calcium carbonate composite bio-based material serving as one of slow-release carrier materials; or
(3) Directly adding chloroacetic acid into the mixture obtained by the reaction in the step (2) without separation, then heating to perform carboxymethylation reaction of chitosan, filtering the reaction mixture, taking the obtained filtrate as the raw materials of amino acid and potassium fertilizer, washing and filtering the obtained solid mixture by isopropanol, adding water to dissolve carboxymethyl chitosan, washing the filtered byproduct calcium carbonate solid to be neutral, obtaining porous calcium carbonate with a nano-pore structure, filtering and drying, and taking the porous calcium carbonate as one of nano sustained and controlled release carrier materials; or
(4) Directly treating and dissolving shrimp and crab shell raw materials or powder raw materials in the step (1) by using an acid solution to remove calcium carbonate, filtering, washing to be neutral, drying, grinding by using a grinder and sieving to obtain the chitin-protein composite biological base material serving as one of the biological base slow-release carrier materials.
2. The use according to claim 1, in the step (2), the shrimp and crab shell raw material powder is stirred in an isopropanol-potassium hydroxide-water system for 3 hours at a boiling temperature; in the step (3), the temperature of carboxymethylation reaction is 50-70 ℃, and the reaction time is 0.5-10 hours.
3. The use according to claim 1, wherein in the step (2), the mass ratio of the isopropanol to the raw material is 1-5: 1, the mass ratio of the water to the raw material is 0.1-0.5: 1, the mass ratio of the potassium hydroxide to the raw material is 7-8: 15, and in the step (3), the chloroacetic acid is continuously or in 3-7 times.
4. The use according to claim 1, wherein in the step (2), the isopropanol solvent recovered from the protein hydrolysate obtained by filtration and separation is recycled, and the protein hydrolysate obtained by concentration is used as the liquid potash fertilizer raw material.
5. Use according to claim 1, characterized in that: the acid solution in the step (4) is hydrochloric acid, citric acid or glutamic acid, the reaction temperature is 30-60 ℃, the reaction time is 1-10 hours, the raw material is 100-200 meshes, and the reaction is ended when the pH is not changed and is less than 4.
6. The use of claim 1, wherein the various support materials obtained in the steps (1) to (4) have a nano-pore structure and a specific surface area of 2-100 m2·g-1。
7. The use of claim 6, wherein the specific surface area of the carrier obtained by the steps (2), (3) and (4) is 40-50 m2·g-1。
8. The use as claimed in claim 1, wherein the medicament is selected from one or more of glyphosate isopropylamine salt, sodium ibuprofen, imidacloprid and abamectin, and the fertilizer is selected from potassium chloride.
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