CN109966505A - A kind of natural sustained and controlled release carrier material of nano-pore channel type and preparation method - Google Patents

A kind of natural sustained and controlled release carrier material of nano-pore channel type and preparation method Download PDF

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CN109966505A
CN109966505A CN201910256346.0A CN201910256346A CN109966505A CN 109966505 A CN109966505 A CN 109966505A CN 201910256346 A CN201910256346 A CN 201910256346A CN 109966505 A CN109966505 A CN 109966505A
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carrier
raw material
release
controlled release
chitosan
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CN109966505B (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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TH-UNIS INSIGHT Co Ltd
Xiamen University
Ningbo University
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TH-UNIS INSIGHT Co Ltd
Xiamen University
Ningbo University
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • 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
    • A01N25/10—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N51/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds having the sequences of atoms O—N—S, X—O—S, N—N—S, O—N—N or O-halogen, regardless of the number of bonds each atom has and with no atom of these sequences forming part of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • 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
    • A01N57/20—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing acyclic or cycloaliphatic radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts

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  • Animal Behavior & Ethology (AREA)
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  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

The present invention relates to a kind of natural sustained and controlled release carrier material of nano-pore channel type and preparation methods, using shrimp and crab shells and other natural products with nano pore as carrier, directly or by joint production process production series there is the functional chemical in natural nano duct to delay controlled release carrier and its production and application method.Research finds the fine duct of 10 ran of average pore size, can effectively store the various functional materials of gentle controlled release, provides abundant new support product line and flexible combination to meet the performance requirement of various slow controlled release products.This technique biomass material is from a wealth of sources; it is cheap; the carrier of preparation, which can satisfy, to be simple and efficient; green safe cost performance requirement; this technique will push the application of medicine, pesticide, plant growth regulator slow-release controlled-release and controlled availability fertilizer; by the unapproachable nano pore protection of microorganism, the cheap animal and plant medicine fertilizer new system of efficient long-acting, safety can be developed to avoid by enzyme or microorganism decomposition or loss.

Description

A kind of natural sustained and controlled release carrier material of nano-pore channel type and preparation method
Technical field
The invention belongs to the exploitation of sustained and controlled release medicine material and production application fields, and in particular to filling drug, fertilizer and The green safe carrier preparation and application field of other functional chemicals.It has invented with natural biomass such as shrimp and crab shells as original Material has natural nano duct carrier and simple preparation method.
Background technique
Slow controlled release carrier refers to that controllable functions component is discharged automatically with certain speed to maintain it in the given time The material of effective concentration can be widely used for animals and plants and microorganism.Wherein, it most importantly can control the speed of drug release Degree, time and the sustained and controlled release medicament at position, and slow releasing carrier of medication can change drug and enter the mode of animal and plant body and its divide The rate of release and concentration of drug can be effectively controlled in cloth, promotes drug absorption.Sustained-release drug carrier is reducing administration number of times, drop Low dosage reduces toxic side effect, and it is the important directions of drug development that improving curative effect etc., which has outstanding advantage,.
The research of existing slow releasing carrier of medication is very active always, has formed primary structure: pharmaceutical carrier has developed It out include inorganic matter carrier, natural polymer subcarrier and synthesis macromolecule carrier three categories type, drug coating and controlled-release technology packet Include the carrier models such as microballoon, gel, nanoparticle, film, tablet and solution absorption, embedding (spray drying, emulsified solvent volatilization, Self-emulsifying sovent diffusion, mutually separate) and fill etc. support types two major classes.However, slow controlled-release effect is poor, toxicity and safety issue Or the problems such as high production cost, perplexs always industry development, cost performance is high, and safely and efficiently slow controlled release carrier is still slow controlled release The maximum bottleneck of drug development.
Such as the accumulative release song of the carrier loaded methotrexate (MTX) of chitosan-carbon acid calcium is described in patent CN107536806A Line, for this compound of calcium carbonate for using chitosan imbedded calcium chloride and reaction of sodium bicarbonate to generate as carrier, absorption is anti- The methotrexate (MTX) of tumour, since artificial synthesized calcium carbonate duct and hole size are different, it is difficult to uniform nano pore is obtained, Therefore slow release effect is unsatisfactory, just releases 50% or so at 100 minutes or so, and 200 minutes substantially in neutral conditions It just no longer discharges, slow release effect is just improved (referring to attached drawing 15) in acid condition.Patent CN107375217A description Calcium carbonate-(poly ornithine/fucosan) although carrier can slow releasing pharmaceutical, carrier preparation is complicated, and industrial applications are difficult. As it can be seen that existing pass through the pharmaceutical carrier of the compound with artificial synthesized porous nano calcium carbonate as film forming agent using chitosan There is a problem of that Drug absorbability amount is few and slow release effect is undesirable.
Pesticide is the guarantee of increasing crop yield stable yields, and the prevention and control of plant diseases, pest control, weeding and plant growth promote to be the three big of pesticide Function.Microemulsion (ME), aqueous emulsion (EW), suspending agent (SC), missible oil (EC) and the wettable powder that existing pesticide uses (WP) etc. dosage forms are limited only to the dispersion of pesticide and convenient to use, and it is difficult on the blade face wax surface of plant not yet to solve very well It adsorbs and is easy to wash the problem of falling by rainwater.Dosage during Pesticide use is big, and validity period is short, destroys ecosystem, residual With environmental pollution is serious, the fast equal serial negative issue of the drug resistance of pest and disease damage enhancing needs effective solution.State Council mentions Go out that pesticide, chemical fertilizer are " double to subtract " to be required, it is clear that reduce Pesticide use amount, pesticide is avoided to be lost and environmental pollution and right as far as possible The destruction of microorganism system, develops efficient long-acting low-toxin farm chemicals, and exploitation cost performance height is that pesticide is sent out using safe farm chemical carrier The direction of exhibition, pesticide slow-releasing agent (BR) is at present also just in the research and development primary stage, there are no molding slow controlled release pesticide finished product, because This development prospect is huge.
Plant growth regulator can remarkably promote plant growth and development, realize volume increase stable yields, improve crop quality, enhancing The important pesticide of one kind of crop anti-adversity can be had by oneself originally in shrimp and crab shells and carrier by extracting in artificial synthesized or biomass Chitin, chitosan, carboxymethyl chitosan are exactly the plant growth promoter of a kind of great development and application value.To sum up institute It states, existing slow controlled-release technology is there are at high cost, and properties of product are unstable, and drug loading is few, and using effect is poor, and use is safe And the series of problems such as poor biocompatibility, green, safe and stable, general high performance-price ratio drug is developed as raw material using biomass Carrier is significant.
Shrimp crab whole world yield alreadys exceed 3,000,000 tons within 2018, and shrimp, crab shell amount are up to million tons or more, due to shrimp and crab shells In rich in the valuable components such as chitin, protein, calcium carbonate, be the resource for being worth utilizing.Chitin (Chitin) is yield Be only second to the glycosaminoglycan class natural polymer of cellulose, arviculture, medicine, food, bioengineering, daily-use chemical industry, Many field tools such as textile printing and dyeing, papermaking and tobacco, water process have been widely used.Chitosan is that chitin is turned into through deacetylated Derivative, is a kind of unique alkaline polysaccharide being stabilized of nature, in molecule containing a large amount of active group-OH and- NH2, there is good water imbibition, moisture retention, film forming, metal-chelating, plant growth to promote activity, biocompatibility and can A variety of excellent properties such as degradability, therefore, chitosan are known as the crucial object of 21st century influence human society scientific and technological progress Matter.
Shrimp and crab shells are the natural composite materials of the compound with regular structure constituted with three kinds of chitin, protein and calcium carbonate ingredients, Inherently exist using protein and chitin as the capillary network structure for meeting body fluid circulatory needs of principal structural component, is The ideal material of slow controlled release carrier.
Calcium carbonate content is 40%~50% in shrimp and crab shells, protein content 20~30%, chitin content 20%~ 30%.Since recycling is difficult, most of shrimp and crab shells are discarded, only the shrimp and crab shells of processing factory's by-product broken into powder as feed or Fertilizer, raw material of the only minimal amount of raw material as chitin extraction and production chitosan.But since existing shrimp and crab shells extract first The common processes of shell element remove calcium carbonate using excessive hydrochloric acid, generate the acidic organic wastewater of a large amount of high calcium chloride concentrations, not molten It is organic that alkalinity can be generated again during the material sodium hydroxide solution thermokalite solution removal protein production chitin crude product of acid Waste water.The wastewater flow rate of chitin crude product is up to 300 tons/ton, 10 ton/ton of shrimp and crab shells consumption or so, and acid and alkali consumption amount is also very big. Therefore, traditional chitin extraction technology existence consumption energy consumption is big, and contaminated wastewater is serious, and high production cost, the performance of enterprises is poor, production By environmental restrictions, it is difficult to the problem of large-scale production.Therefore the annual output of global chitin and its derivative chitosan etc. is not no 200,000 tons of foot, industry development is very limited.
Summary of the invention
Crack existing drug and slow-released carrier there are high production cost, performance is unstable, dosage is big, effective component release Speed is fast, drug effect efficiency time is short, bioavilability is low, toxicity is big, and safety is poor, and environmental pollution is big, slow controlled-release effect difference etc. Industry problems, developing biology base sustained and controlled release medicament carrier safe and efficient, that cost performance is good is important directions.Shrimp and crab shells raw material is original Just can be used as food or feed, have it is safe and non-toxic, enrich cheap resources advantage.Chitosan is also always the slow control being expected Release vector envelope material.Protein and chitin in shrimp and crab shells not only together form the shell body knot of shrimp crab with calcium carbonate Structure, but also the smooth capillary microtubular network system of guarantee body fluid has been constructed, inherently have as slow controlled release carrier potentiality, such as It can be further in conjunction with the innovative technology for removing isolating protein or/and extract chitosan and " one kettle way " synthesis carboxymethyl chitosan Duct is extended, the natural carrier material (referring to attached drawing 1) that series has nano pore is developed, starts green safe, at low cost Honest and clean, purposes exploitation novel slow controlled release carrier library.
This seminar is in patent " a kind of shell-fish raw material clean manufacturing chitosan and carboxymethyl chitosan new process Following new process is founded in CN104788584A ": by shrimp and crab shells powder in isopropanol~sodium hydroxide~water mixed system Basic fluxing raction is carried out under boiling temperature, can under conditions of less alkali number fast hydrolyzing protein and deacetylate simultaneously, it is convenient Obtain eliminating the compound of 90% or more protein and chitin acetyl group --- calcium carbonate-chitosan with nano pore Compound bio sill.If monoxone is added without isolation to react the carbon that can obtain having nano pore by " treating different things alike " Sour calcium-carboxymethyl chitosan mixture may separate out two products with water dissolution.Therefore, according to raw material or intermediate, product or Byproduct, can be with isolated chitosan calcium carbonate solid in the difference of acid or alkali or alcohol or water or its in the mixed solvent solubility The main component of coproduction is the product of calcium carbonate, carboxymethyl chitosan/carbon after compound, dissolution chitosan or carboxymethyl chitosan The series of products such as sour calcium solid mixture, chitosan solution or chitosan product, carboxymethyl chitosan solution or powder and including Amino acid~small peptide, potassium salt Liquid Fertilizer raw material as main component.
We have found that new process not only avoids the destruction of shell structurre caused by sour decalcification, chitin drop in furtheing investigate Solution, a large amount of consumptions are sour and containing series of problems such as the refractory reasons of sour organic wastewater, and can be with what coproduction had 10 nm average pore diameters Porous natural biological sill is arranged, can thoroughly crack that chitosan and its derivative high production cost, pollution is big, hydrolytic degradation is tight The low industry problems of weight, poor quality, production capacity, push the development of chitosan industrial chain, and can open up green safe novel Sustained and controlled release carrier material library.
By above-mentioned patent, it is raw material by simple processing or further alkali or acid processing that the present invention, which is developed using shrimp and crab shells, The shrimp and crab shells powder raw material of acquisition, Deproteinated chitosan-carbon acid calcium composite material separate the by-product biology of carboxymethyl chitosan Calcium carbonate material and deviate from the protein of calcium carbonate and the compound bio sill of chitin with acid, passes through scanning electron microscope, hole Diameter, Kong Rong, specific surface area, water absorption and different material and dissolution absorption system and load capacity and release profiles measurement, discovery remove Other two kinds of materials outside the compound bio sill of protein and chitin all have the duct within 10 nanometers of average pore size Structure, specific surface area increase by 10 times or more than raw material.The bio-based materials in this four kinds of included natural nano ducts, not only have Abundant raw material, production cost are low, nontoxic edible, the unique advantage of safety and environmental protection, fully biodegradable, and have molten The characteristic of the various functional chemicals of selective absorption and relatively large storage including various drugs, can be used as in liquid Ideal controlled release carrier material exploitation.
Deeper into research also found, the adsorbance significant difference of different carriers material, and close with the surface tension of feed liquid Cut phase is closed, the easier load of the smaller system of surface tension, and load capacity can be significantly improved by carrying out absorption under reduced pressure.No The material easily loaded can be embedded, and compound has significant control-release function slow for a long time, can meet the function such as medicine and pesticide The slow controlled release requirement of energy property product.SSP refers to shrimp shell meal (Shrimp Shell Powder)；CSP refers to crab shell powder (Crab Shell Powder)；Ct-Pro fingernail element-protein compound bio sill；CS-CaCO3Refer to chitosan-carbon acid calcium compound bio base Material；CaCO3Refer to that porous calcium carbonate, S- refer to that the product in shrimp shell meal source, C- refer to the product in crab shell powder source.Correlated performance please join See chart.
The present invention is based on aforementioned patent method, it was found that there is Large ratio surface, Kong Rong, water absorption to be multiplied and receive Rice cellular structure is using shrimp and crab shells powder as the natural carrier material depot of raw material.Have found that different carriers have different adaptability and bear Carrying capacity, the property of the surface tension of system, carrier and loaded article influence load capacity very big, and different drug carrier complex are released The curve significant difference put, this is found to be the exploitation of the slow control delivery of different demands and Combinatorial Optimization has established research base Plinth, it is shown that various possibility.Air and moisture content, decompression absorption, saturated solution or supersaturation is discharged by the heating of nano-carrier Solution, aqueous solution, organic solution and mixed solution absorption, mixed solvent improve the fill method of surface tension, and to increase Loading and extended release phase carry out the modes such as coating again, it is already possible to reach the carrier material with natural nano duct 10~44% load capacity.Slow controlled-release effect measurement is carried out to a variety of carrying medicaments by general analysis method, it was demonstrated that their tables Show slow controlled release characteristics well: not being released, can be uniformly long lasting for release, dose remaining is few, and carrier itself can be dropped Solution and absorption, use is safe, can greatly reduce dosage.
It is described in Chinese Pharmacopoeia 2005 editions two, the half-life period of brufen is 1.8~2h, and 3~4 need to be administered daily The disadvantages of secondary, and that there are bioavilabilities is low, and taking dose is big.Preparation and specification common at present has: (1) Nuprin Tablets: 100mg；200mg；400mg (2) ibuprofen sustained release capsules: 300mg (3) Ibumetin Retavd: 200mg (4) ibuprofen effervescent tablets: 100mg (5) brufen liniment: 5mL 250mg.The slow controlled release produced at present 1 hour, 2 hours, 4 hours with release in 7 hours Amount and 10%~35%, 25%~55%, 50%~80% and 75% or more of pharmacopeia labelled amount.
Sodium ibuprofen/porous calcium carbonate (IBU-Na/CaCO3) compound and brufen/chitosan-carbon acid calcium complexes (IBU/CS-CaCO3) 7 hours or so 70% drugs of release, the slow control of the latter all can control to the sustained and controlled release medicament of brufen It is more preferable to release effect.Potassium chloride/chitin-protein-coating compound (KCl/Ct-Pro) can be controlled in potassium chloride 10 hours Interior release 85%.The monolithic or simple grain quality of drug tablet and capsule are usually 100~200mg, the list of the drugs such as hypertension For piece medication amount generally in 5mg or so, i.e., 5% or so load capacity can satisfy requirement.Therefore, various carriers all have out Send out potentiality.
" the performance of mesoporous activated carbon avermectin drug-loading system in " Pesticide Science journal " the 12nd phase in 2012 such as Sun Changjiao A described in the text in research ": the mesoporous activated carbon avermectin that average grain diameter is 814nm carries medicine absorbent charcoal carrier to Avermectin The drugloading rate of element is 18.07%, and drug release time is up to 672h or more, shows good slow release effect.Li Zhuzhu etc. is in " agriculture Acta Pharmaceutica Sinica " the 7th phase in 2005 " preparation of Novel Abamectin nano controlled release agent and performance study " described in the text: it is hollow Porous SiO2Nano particle can reach 62.5% to the drugloading rate of avermectin, and avermectin nanometer controlled release agent (Av-PHSN) exists Control release time in the dissolution medium successively stirred is 33h.Liu Qi etc. was " ecological environment journal " 2009 Volume 18 " surface modification of silica and its to avermectin absorption and and sustained release performance " in show: modified SiO2It is right Avermectin drugloading rate is in 7.02%-35.96%.The extension of avermectin-silica dioxide nano particle drug release rate at any time increases Add slowly, arrive 14h or so, dissolution basically reaches balance.But only about 50% or so avermectin dissolution, avermectin-two Silica nanoparticle drug release rate is held essentially constant, and can continue 80h or so.Li Jia is really equal in " the Journal of Hainan University's nature Scientific version " the 4th phase of volume 24 " with the preparation and property of the Abamectin that polymer/diatomite is slow controlled-release material Can research " in show: using polymer/diatomite be the Abamectin of controlled-release material in 60h, cumulative release 50% Avermectin, just basically reach balance when being 80%, 150h when 100h, show good slow release effect.It can be seen that nothing Machine porous material active carbon, SiO2, polymer/diatomite as pharmaceutical carrier there is preferable slow controlled-release effect, but it is existing Residual dose is excessive (residual dose close to half~one third), and not degradable etc. there are serious Environmental security hidden danger to ask Topic, need to cautiously use.
The study found that the avermectin that the various carrier adsorption methods that shrimp and crab shells powder and processing obtain obtain delays control delivery, Avermectin/chitosan-carbon acid calcium complexes (AVM/CS-CaCO3) in 200h, 50% or so Avermectin of cumulative release Element, 260h are 80% or so, basically reach balance later, show better slow release effect；Avermectin/porous calcium carbonate is multiple Close object (AVM/CaCO3) in 150h, 50% avermectin of cumulative release, 300h 80% is shown brilliant slow Release effect；Avermectin/chitin-protein complex (AVM/Ct-Pro) is in 150h, 50% Avermectin of cumulative release Element, the time for needing 240h to be up to 10 days or more can discharge completely substantially.
Control agent release of the glyphosate isopropyl amine salt/shrimp shell meal (NPPMG/SSP) in the dissolution medium successively stirred Time basically reaches balance when 100h, 120h；Glyphosate isopropyl amine salt/chitosan-carbon acid calcium complexes (NPPMG/CS- CaCO3) 96h when it is accumulative release 50% glyphosate isopropyl salt, when 300h is accumulative release 88% glyphosate isopropyl amine salt, Balance is basically reached, has reached pesticide and has preferably delayed controlled release requirement；Glyphosate isopropyl amine salt/chitin-protein complex (NPPMG/Ct-Pro) equilibrium state is basically reached in 72h or so to the release of glyphosate isopropyl amine salt, also there is certain delay Release effect；Glyphosate isopropyl amine salt/porous calcium carbonate compound (NPPMG/CaCO3) 90% is being released in 300 hours Glyphosate isopropyl amine salt has reached the requirement of ideal slow controlled release pesticide.Glyphosate/chitosan-carbon acid calcium complexes (PMG/ CS-CaCO3) up to the glyphosate isopropyl amine salt for releasing 90% in 370h, also reach wanting for ideal slow controlled release pesticide It asks.Equally, imidacloprid/chitin-protein complex (Imidacloprid/Ct-Pro) is being up in 400h only imidacloprid 75% imidacloprid is released, slow controlled-release effect is more significant.Slow controlled release pesticide require the dosage per acre of highly effective pesticide mostly 50g with Under, slow controlled release support type pesticide can greatly save raw medicine dosage, reduction or pollution remission, extend drug effect, therefore actual amount Too big increase is not had.
Cost can be equally produced as sustained-controll-release fertiliser carrier and dosage increases little efficient and controlled availability fertilizer.Cause This, this discards powder as raw material using shrimp and crab shells, delays controlled release as functional chemical using its natural nano duct and carries Body can meet very well and be simple and efficient, green safe cost performance requirement, and other tangerine bar powder do not have slow controlled-release effect, and bamboo is fine It is poor to tie up effect.
In conclusion achievement of the present invention will will push medicine, pesticide, plant growth regulator sustained release, the control of various drugs Release and the application of concentrated fertilizer, have the protection of the unapproachable nano pore of microorganism, more preferably drug can be avoided by enzyme Or microorganism decomposition or loss, guarantee the long-term effect of drug, the natural degradable characteristic of carrier, it is ensured that drug safety.Therefore, The present invention is by the exploitation for pushing long-term safety, cheap animal and plant medicine fertilizer and other functional slow controlled release new systems and builds It is vertical.
Specifically, the present invention be supplied to it is a kind of using shrimp and crab shells be raw material by or construct nano pore exploitation natural drug The method of carrier selects the solid of any one of following (1)~(4) step step according to different systems and specific requirement Or mixtures thereof product is used as pharmaceutical carrier, can satisfy bioelectric detecting by the production of solution adsorption supporting method and needs to have slow control The drug, fertilizer or plant growth promoter series of products of function are released, the specific preparation method of carrier is as follows:
(1) shrimp and crab shells raw material is cleaned, boils removal soluble matter, dried, be ground into the powder of 200 mesh or more, be sieved, it is standby With can be directly as one of sustained and controlled release carrier material；
(2) it is added to product made from step (1) as raw material in isopropanol~potassium hydroxide~aqueous systems, in reflux temperature Lower heating alkaline hydrolysis 3 hours or so of degree, makes chitin removing acetyl group become chitosan, and protein degradation is that amino acid and small peptide are molten In in the mixed solvent, solid powder is filtered out from reaction mixture, solid powder is washed to neutrality, and drying obtains chitosan- Calcium carbonate compound bio sill, as one of sustained and controlled release carrier material, filtrate is as amino acid and potash fertilizer raw material；
(3) mixture that step (2) reaction is completed is directly added into monoxone without isolation, then heating carries out chitosan Carboxymethylation reaction, reaction mixture filtering, obtained filtrate can be used as amino acid and potash fertilizer raw material, obtained solid mixing Object is washed to neutrality by isopropanol washing filtering, the carboxymethyl chitosan that is dissolved in water, the byproduct calcium carbonate solid filtered out, It can obtain the porous calcium carbonate with nano pore structure, filtering drying, as one of nanometer sustained and controlled release carrier material, aqueous solution Alcohol is added to be precipitated out carboxymethyl chitosan solid product；
(4) shrimp and crab shells raw material or the processing dissolution of the powder material acid solution of step (1) are directly removed into calcium carbonate, filtered, Washing grinds sieving with pulverizer after drying, chitin-protein compound bio sill is obtained, as biology base to neutrality One of sustained and controlled release carrier material.
Preferably, in the above method, it is characterised in that the shrimp and crab shells raw material powder is in isopropanol~potassium hydroxide~water body In system be stirred to react temperature be 50~90 DEG C, the reaction time 1~20 hour, or with boiling temperature stirring 3 hours or so；Step (3) in, carboxymethylation reaction temperature is 50~70 DEG C, the reaction time 0.5~10 hour.
Preferably, in the above method, it is characterised in that the mass ratio of the isopropanol and raw material is 1~5: 1, water and raw material Mass ratio be 0.1~0.5: 1, the mass ratio of potassium hydroxide and raw material is 7~8: 15, in step (3), monoxone and raw material Mass ratio 1: 5~7, monoxone can continuous or point 3~7 additions.
Preferably, in the above method, it is characterised in that the isopropyl of the protein hydrolyzate recycling being separated by filtration Alcoholic solvent is recycled, and the protein hydrolyzate being concentrated to get is as liquid potash fertilizer raw material.
Preferably, in the above method, it is characterised in that the acid solution in the step (4) is hydrochloric acid, citric acid or paddy ammonia Acid, reaction temperature are 30~60 DEG C, and the reaction time is 1~10 hour, it is preferred that raw material uses the raw material of 100~200 mesh, instead It should not be changed with pH and be terminal less than 4.
Preferably, in the above method, it is characterised in that rapid (1) to the various carrier materials that step (4) obtains have Nano pore structure, specific surface area are 2~100m2·g-1, it is preferred that the carrier specific surface area that step (2), (3) and (4) obtains For 40~50m2·g-1, can be used as the carrier application with higher load amount.
Preferably, in the above method, it is characterised in that the step of the solution adsorption supporting method are as follows: press step (1)~(4) Powder sample carrier material is obtained, then drying removes moisture content to reduce air and moisture content residual in duct, is immersed in excessive full And/or the aqueous solution or organic solution or mixed solution of oversaturated substance to be adsorbed are sufficiently adsorbed, and can be warming up to when necessary It is stirred 0.5~24 hour under slight boiling condition, room temperature or reflux state, filtering is rinsed with deionized water or coordinative solvent, and decompression is dry Dry to obtain slow controlled release product particle to constant weight, actual conditions can be heated or be depressurized absorption or choosing according to medicinal property Suitable solvent optimization is selected to determine.
The present invention also provides the above method preparation carrier material absorption medicine, pesticide, fertilizer, disinfectant, antistaling agent, Application in flavors and fragrances, feed and food additives after one or more ingredients as product, it is characterised in that right The step of seeking any one of 1-6 (1) to the obtained sustained and controlled release carrier material of step (4) adsorbs one or more ingredients.
Preferably, in above-mentioned application, it is characterised in that the ingredient is selected from drug, health care product, nutritional ingredient, it is preferred that The ingredient be selected from Chinese and Western medicine, nutritional ingredient, vitamin, pesticide, plant growth promoter, amino acid, disinfectant, antistaling agent, One of flavors and fragrances is a variety of, it is preferred that ingredient be glyphosate isopropyl amine salt, Sodium ibuprofen, imidacloprid, avermectin, Potassium chloride.
The present invention also provides it is a kind of using shrimp and crab shells as raw material by or construct nano pore and develop natural drug carrier The preparation-obtained carrier material of method, the carrier material be step (1) in any one of claim 1-6 the method extremely Step (4) preparation-obtained carrier material, the specific surface area of the carrier material are 2~100m2·g-1, it is preferred that step (2), the carrier specific surface area that (3) and (4) obtain is 40~50m2·g-1, the various functional products of the carrier and production.
Preferably, in the above method, the carrier is also possible to have bamboo fibre of nano pore etc. is other to have nanometer The biological material in duct.
Specifically, natural porous carrier chitin-protein compound bio sill is obtained using shrimp and crab shells as raw material, shell gathers Sugar-calcium carbonate compound bio sill, porous calcium carbonate can take following universal method:
The preparation of logical one chitin of method-protein compound bio sill
Shrimp and crab shells are placed in 5~12% citric acid solutions after washing and drying, at 30~80 DEG C, keep pH item below 4 Under part, electric stirring 1~10 hour, filtering, washing to neutrality was used milled 200 mesh of pulverizer, is removed after drying process Chitin-protein compound bio sill after calcium carbonate, then through drying for standby.
The preparation of logical two chitosan-carbon acid calcium compound bio sill of method
Shrimp shell is after washing and drying, the drying for standby after milled 200 mesh in pulverizer.By the shrimp crab powder of drying, admittedly Body KOH, isopropanol, four kinds of substances of water in mass ratio 3: 1.4: 6.3: 0.7 are put into reactor, atmospheric pressure reflux (65 DEG C) (boiling) 3h or so, cooling, filtering, deionized water washing, drying, is finally dried to obtain chitosan-carbon acid calcium compound bio sill.With Kjeldahl's method is by digestion, distillation, absorption, titration, and sample analysis situation is referring to table 1~5.
The preparation of logical method thricarbonate calcium carrier and carboxymethyl chitosan
By in the mixture of logical method two after the reaction was completed, it is added monoxone further progress carboxy methylation, monoxone point 3~ 7 additions, carboxymethylation reaction temperature are 50~70 DEG C, the reaction time 0.5~10 hour.Solid after reaction is washed through isopropanol It washs to neutrality, is dissolved in water, be filtered, washed, be dried to obtain porous calcium carbonate, aqueous solution adds alcohol to be precipitated out carboxymethyl chitosan Solid product.
Protein content analysis in 1 raw material of table and carrier
As it can be seen that the removal rate of protein is up to 95% or more in shrimp and crab shells in the case where retaining calcium carbonate skeleton structure.
The constituent content analysis of 2 raw material of table and carrier
Shrimp and crab shells C, H, N content after alkali process are remarkably decreased, and illustrate to prove that most of protein is removed.
The analysis of the water absorption of 3 raw material of table and carrier
The carrier water absorption of isolating protein is gone to increase one times, it was demonstrated that pore-creating reaming effect is obvious.
The deacetylation situation of 4 infrared spectroscopic determination sample of table
90% or more chitin has had changed into chitosan in carrier.
The specific surface area and Kong Rong and pore size determination of 5 shrimp and crab shells sample of table
The result shows that: the sample specific surface area that alcohol~alkali~hydraulic art obtains increases 20 times or so, has 10 nanometers of left sides Right average duct, hole, which holds, to be increased very much, has the primary condition as pharmaceutical carrier.
On the contrary, the sample obtained with acid processing either specific surface area or Kong Rong significantly become smaller, illustrate to lack carbon The protein of sour calcium support and the compound bio sill of chitin are easier to associate due to space limits and eliminates.But in aqueous systems In can restore porous structure and can also serve as pharmaceutical carrier.It is unable to carrying medicament with straw powder, but with nano pore Bamboo fibre can a small amount of carrying medicament, it was demonstrated that only the carrier of the structure of nano pore could carrying medicament.
Scanning electron microscope (SEM) photograph shows that the carrier hole of alkali process is obvious in attached drawing 2, and the carrier of acid processing is substantially without hole.
Logical four solution adsorption method drug loading of method
Powder sample is obtained by logical method 1~3, is dried at 160 DEG C and is removed within 2 hours moisture content as far as possible and be cooled to 100 DEG C hereinafter, subtracting In less porous road under air and the remaining situation of moisture content, submerged excessive saturation or oversaturated substance to be adsorbed aqueous solution or Then organic solution or mixed solution are slowly ramped to slight boiling condition, magnetic agitation 1~24 hour under reflux state, filter, and use Deionized water or dehydrated alcohol flush three times, and are dried under reduced pressure to constant weight, analyze drugloading rate, spare.
Logical method five delays controlled release properties measurement
The load medicinal powder end prepared is accurately weighed in bag filter, 2mL water is added, both ends clamp, are placed in a beaker, and are added 500mL water or PBS solution or dehydrated alcohol are discharged, timing sampling at 37 DEG C, carry out centrifuging and taking supernatant liquor, are used Ultraviolet specrophotometer or high performance liquid chromatography characterization.Drugloading rate is 10~44% after tested, and the preparation of drug exists 80%, there is certain drugloading rate, there is good slow release effect.
Control experiment, which weighs, carries medicinal powder end, with ethyl cellulose (EC)/hydroxypropyl methyl cellulose of various concentration (HPMC) load medicinal powder end is coated, prepares the acetic acid ethyl fluid of 3%EC, the HPMC of mass concentration 5g/L, HPMC are interior packet Clothing swell layer, EC are outer layer release controlling coating material, are increased weight by control swell layer and coatings, carry out Drug controlled release degree.
Carry out the quantitative assessment of drugloading rate and slow controlled-release effect.
The present embodiment has carried out several representative drugs such as potassium chloride, brufen, Sodium ibuprofen and avermectin, pyrrole worm The load and release conditions evaluation of several representative pesticides such as quinoline, glyphosate, glyphosate isopropyl amine salt, cypermethrin, it was demonstrated that The load capacity of carrier can have preferable slow controlled-release effect in 10%~44% range.
The present invention sufficiently show it is following the utility model has the advantages that
Using the shrimp and crab shells for enriching inexpensive safe green as raw material, full price may be implemented by process for cleanly preparing and height is additional Value utilizes, and it is multiple to prepare the chitosan-carbon acid calcium with natural nano duct, large specific surface area and Kong Rong and larger drugloading rate Closing bio-based materials, porous calcium carbonate, chitin-protein compound bio sill etc. is all the carrier material with great potential Material, for improve various functions substance long-term effect, reduce dosage and toxic side effect, develop safe and efficient animals and plants and micro- Biological medicine fertilizer system opened up a new way.
Detailed description of the invention
Fig. 1 a: shrimp shell meal (SSP), b: chitin-protein compound bio sill (S-Ct/Pro), c: chitosan-carbon Sour calcium compound bio sill (S-CS/CaCO3), d: porous calcium carbonate (S-CaCO3) TEM figure
Fig. 2 a: shrimp shell meal (SSP), b: chitin-protein compound bio sill (S-Ct/Pro), c: chitosan-carbon Sour calcium compound bio sill (S-CS/CaCO3), d: porous calcium carbonate (S-CaCO3) SEM figure
Fig. 3 a: crab shell powder (CSP), b: chitin-protein compound bio sill (C-Ct/Pro), c: chitosan-carbon Sour calcium composite material (C-CS/CaCO3), d: porous calcium carbonate (C-CaCO3) SEM figure
The N of Fig. 4 shrimp shell meal2Adsorption-desorption isothermal and corresponding graph of pore diameter distribution
Fig. 5 chitin-protein compound bio sill N2Adsorption-desorption isothermal and corresponding graph of pore diameter distribution
The N of Fig. 6 chitosan-carbon acid calcium compound bio sill2Adsorption-desorption isothermal and corresponding graph of pore diameter distribution
Fig. 7 porous calcium carbonate (S-CaCO3) N2Adsorption-desorption isothermal and corresponding graph of pore diameter distribution
Fig. 8 a: shrimp shell meal, b: chitin-protein compound bio sill, c: chitosan-carbon acid calcium compound bio substrate Material, d: the FT-IR map of porous calcium carbonate
Fig. 9 shrimp shell meal, chitosan-carbon acid calcium compound bio sill, porous calcium carbonate, chitin-protein bio base Cumulative release curve of the material to glyphosate isopropyl amine salt
Figure 10 shrimp shell meal, chitosan-carbon acid calcium compound bio sill, chitin-protein compound bio sill pair The cumulative release curve of potassium-potassium chloride drug
Cumulative release curve of Figure 11 chitin-protein compound bio sill to imidacloprid
Cumulative release curve of Figure 12 chitosan-carbon acid calcium compound bio sill to brufen
Cumulative release curve of Figure 13 chitosan-carbon acid calcium compound bio sill to glyphosate
Figure 14 porous calcium carbonate (S-CaCO3) to the cumulative release curve of Sodium ibuprofen
The Cumulative release profile of the compound methotrexate (MTX) of chitosan imbedded synthetic calcium carbonate of Figure 15 patent disclosure
The preparation of Figure 16 Ibumetin Retavd reported in the literature and In-vitro release curves
Figure 17 hollow porous SiO reported in the literature2Release profiles of the nano particle to avermectin
Figure 18 chitosan-carbon acid calcium compound bio sill, porous calcium carbonate, chitin-protein bio sill pair The cumulative release curve of avermectin
Figure 19 shrimp and crab shells are several carrier preparing flow charts of raw material
In chart, SSP refers to shrimp shell meal (Shrimp Shell Powder)；CSP refers to crab shell powder (Crab Shell Powder)；Ct-Pro fingernail element-protein compound bio sill；CS-CaCO3Refer to chitosan-carbon acid calcium compound bio base Material；CaCO3Refer to that porous calcium carbonate, S- refer to that the product in shrimp shell meal source, C- refer to the product in crab shell powder source.
Specific embodiment
The technical solution that present invention will be further explained below with reference to specific examples.These embodiments are merely to illustrate this It invents rather than limits the scope of the invention.
Embodiment 1 prepares chitin-protein compound bio sill with shrimp shell
First shrimp shell is rinsed well to be placed at 160 DEG C and is dried, addition is taken out and is equipped in the single-necked flask of electric mixer, The citric acid solution of 10% concentration is prepared, wherein the mass ratio of shrimp shell and citric acid solution is 1: 10, is heated to 50 DEG C, at heat preservation Progress decalcification in 4 hours is managed, 50 DEG C of warm water is selected to be filtered with mesh screen, the calcium citrate in filtrate is recycled, by resulting filtering Object carries out secondary decalcification by identical experiment condition, is finally filtered with mesh screen, and filtrate is multiple with suitable distilled water It rinses to neutrality, being crushed to 200 mesh with pulverizer after drying is chitin-protein compound bio sill.It dries again To constant weight, for use.Referring to the method detection in GB5009.4-2016 " measurement of ash content in national food safety standard food " Ash content is 0.26%.
Embodiment 2 prepares chitosan-carbon acid calcium compound bio sill with shrimp shell
150.0g shrimp shell meal is added into the three-necked flask for be equipped with electric mixer, separately by 80.0g potassium hydroxide solid With addition 400mL isopropanol after 40.0g water mixed dissolution, three-necked flask is poured into after mixing evenly, it is anti-under reflux conditions 3.0h is answered, albumen and removing acetyl group are fully hydrolyzed, filtering stirs obtained solid with 200mL isopropanol at normal temperature 0.5h, filtering, again with clear water wash three times, drying to constant weight, obtain chitosan-carbon acid calcium compound bio sill.It filters The protein hydrolyzate arrived can be used as liquid after recycling isopropanol solvent recycling containing amino acid, small peptide and potassium hydroxide Body amino acid and potash fertilizer raw material.By acid-base titration or infrared spectroscopic determination deacetylation, diluted hydrochloric acid dissolution chitosan and Calcium carbonate, ethyl alcohol is counter to be settled out chitosan, washs removing calcium chloride repeatedly with 70% ethanol water and obtains sterling chitosan, takes off second Acyl degree 88%.
Embodiment 3 prepares calcium carbonate crude product with shrimp shell
150.0g shrimp shell meal is added into the three-necked flask for be equipped with electric mixer, separately by 80.0g potassium hydroxide solid With addition 400mL isopropanol after 40.0g water mixed dissolution, three-necked flask is poured into after mixing evenly, is reacted under reflux conditions 3.0h is fully hydrolyzed albumen and removing acetyl group, adds 25.0g monoxone, point 5 additions, reacts under 60 DEG C of heat-retaining conditions 3.0h carries out carboxy methylation to chitosan, is separated by filtration to obtain carboxymethyl chitosan, calcium carbonate mixture, mixture adds water-soluble Solution, is obtained by filtration by-product porous calcium carbonate.Filtrate can be added that 80% ethyl alcohol is counter to be settled out carboxymethyl chitosan sugar product.
The soluble matter of 4 carrier of embodiment in water dissolves out situation
Accurately weigh carrier (the shrimp shell meal SSP, chitosan-carbon acid calcium compound bio sill CS-CaCO of 1.0g or so3、 Porous calcium carbonate CaCO3, chitin-protein compound bio sill Ct-Pro) pour into the round-bottomed flask of 50mL, in round bottom The water of 10g is added in flask, is warming up to slightly boiled, keeps this temperature 2h, filters, drying.SSP weightlessness 2.91%, CS-CaCO3It loses Weigh 4.89%, CaCO32.77%, Ct-Pro weightlessness 6.88%.The big substance of polarity in each carrier can dissolve with this condition Yu Shuizhong.
The preparation of 5 glyphosate isopropyl amine salts of embodiment/shrimp shell meal (NPPMG/SSP) compound and release profiles measurement
1. glyphosate isopropyl amine salt load test
Accurately weighing 1.0g shrimp shell meal sample SSP, (carrier articles used in following embodiment are above-mentioned table 1 to table 5 Described in performance sample), drying to constant weight at 160 DEG C, is cooled to 100 DEG C or less and pours into single-necked flask rapidly, and 10.0g is added 41% glyphosate isopropyl amine salt solution (shaking reaction flask when adding NPPMG solution), adding 5.0g deionized water makes reactant There are mobility, room temperature, stirring 0.5 hour in system, and filtering is washed three times, dry to constant weight.Measure drugloading rate (i.e. glyphosate isopropyl Amine salt percentage composition) it is 35.0%.
2. glyphosate isopropyl amine salt release test
It accurately weighs 1.0g and carries medicinal powder last (drugloading rate 35.0%) in bag filter, both ends clamp, and are placed in a beaker, respectively 500mL water is added, is discharged at 30 DEG C, timing sampling, centrifuging and taking supernatant liquor is carried out, crosses 0.45 μm of filter membrane, dilute, Ultrasonic 20min, is characterized with high performance liquid chromatography, is measured slow controlled-release profile, is seen NPPMG/SSP in Fig. 9.
6 glyphosate isopropyl amine salts of embodiment/porous calcium carbonate (NPPMG/CaCO3) compound preparation and release profiles survey It is fixed
1. glyphosate isopropyl amine salt load test
Accurately weigh 3.0g porous calcium carbonate, drying to constant weight at 160 DEG C, is cooled to 100 DEG C or less and pours into single port burning rapidly Bottle in, be added 30g 41% glyphosate isopropyl amine salt solution (shaking reaction flask when adding NPPMG solution), add 5.0g go from Sub- water makes reaction system have mobility, and room temperature, stirring 0.5 hour are filtered, washing, dry to constant weight.Measuring drugloading rate is 43.0%.
2. glyphosate isopropyl amine salt release test
It accurately weighs 1.0g and carries medicinal powder last (drugloading rate 43.0%) in bag filter, both ends clamp, and are placed in a beaker, respectively 500mL water is added, is discharged at 30 DEG C, timing sampling, centrifuging and taking supernatant liquor is carried out, crosses 0.45 μm of filter membrane, dilute, Ultrasonic 20min, is characterized with high performance liquid chromatography.Slow controlled-release profile is measured, sees the NPPMG/CaCO in Fig. 93。
7 glyphosate isopropyl amine salts of embodiment/chitosan-carbon acid calcium (NPPMG/CS-CaCO3) compound preparation and release Curve determination
The chitosan-carbon acid calcium compound bio sill of 1.0g is accurately weighed in 160 DEG C of activation 2h, is cooled to 100 DEG C or less It is quickly adding into the round-bottomed flask of 100mL, under room temperature, stirring, the glyphosate isopropyl amine of 10.0g 41% is added portionwise Salting liquid adds the water of 5.0g after finishing, 0.5h is stirred at room temperature, and filters, washing, and 120 DEG C of drying, measuring drugloading rate is 40.90%.
It accurately weighing 1.0g and carries medicinal powder last (drugloading rate 40.90%) in bag filter, both ends clamp, it is placed in a beaker, point Not Jia Ru 500mL water, discharged at 30 DEG C, timing sampling, carry out centrifuging and taking supernatant liquor, cross 0.45 μm of filter membrane, it is dilute It releases, ultrasound 20min, is characterized with high performance liquid chromatography.Slow controlled-release profile is measured, sees the NPPMG/CS-CaCO in Fig. 93。
The preparation of 8 glyphosate isopropyl amine salts of embodiment/chitin-protein (NPPMG/Ct-Pro) compound and release are bent Line measurement
Chitin-protein compound bio sill of 1.0g is accurately weighed in 160 DEG C of activation 2h, is cooled to 100 DEG C or less It is quickly adding into the round-bottomed flask of 100mL, under room temperature, stirring, the glyphosate isopropyl amine of 10.0g 41% is added portionwise Salting liquid adds the water of 5.0g, 0.5h is stirred at room temperature, is filtered, washed after finishing, 120 DEG C of drying, measuring drugloading rate is 41.99%.
It accurately weighing 1.0g and carries medicinal powder last (drugloading rate 41.99%) in bag filter, both ends clamp, it is placed in a beaker, point Not Jia Ru 500mL water, discharged at 30 DEG C, timing sampling, carry out centrifuging and taking supernatant liquor, cross 0.45 μm of filter membrane, it is dilute It releases, ultrasound 20min, is characterized with high performance liquid chromatography.Slow controlled-release profile is measured, sees the NPPMG/Ct-Pro in Fig. 9.
The preparation of 9 potassium chloride of embodiment/chitin-protein (KCl/Ct-Pro) compound and release profiles measurement
1. potassium chloride load test
Saturated potassium chloride solution is prepared at room temperature in single-necked flask, accurately weighs 5g chitin-protein compound bio Sill dries 2 hours at 160 DEG C, is cooled to 100 DEG C or less and pours into rapidly, is slowly ramped to slight boiling condition, stirs one hour, cold But to room temperature, filtering is flushed three times with certain mass water, dry to constant weight.Measuring drugloading rate is 17.3%.
2. carrying the processing of medicinal powder end coating
It weighs 2g and carries the appropriate ethyl cellulose solution of medicine powder spray and Gonak, dry, weighing.
It weighs and carries medicinal powder end, with ethyl cellulose (EC)/hydroxypropyl methyl cellulose (HPMC) of various concentration to load medicine Powder is coated, and prepares the acetic acid ethyl fluid of 3%EC, and the HPMC of mass concentration 5g/L, HPMC are interior coating swell layer, and EC is Outer layer release controlling coating material passes through control swell layer and coatings Drug controlled release degree.
3. chlorination K released is tested
Accurately weigh 2.0g carry medicinal powder end, carry out coating processing after, be placed in a beaker, be added 500mL water, at 37 DEG C into Row release, timing sampling use conductance measurement.Slow controlled release release profiles are measured, see the KCl/Ct-Pro-Coating in Figure 10.
The preparation of 10 potassium chloride of embodiment/shrimp shell meal (KCl/SSP) compound and release profiles measurement
1. potassium chloride load test
Saturated potassium chloride solution is prepared at room temperature in single-necked flask, is accurately weighed 5.0g shrimp shell meal, is dried 2h at 160 DEG C, It is cooled to 100 DEG C or less to pour into rapidly, is slowly ramped to slight boiling condition, is stirred at reflux 2h, be cooled to room temperature, filters, with certain matter Amount water flushes three times, dry to constant weight.Measuring drugloading rate is 3.9%.
2. carrying the processing of medicinal powder end coating
It weighs 2g and carries the appropriate ethyl cellulose solution of medicine powder spray and Gonak, dry, weighing.
Specific experiment step: it weighs and carries medicinal powder end, with ethyl cellulose (EC)/hydroxypropyl methyl cellulose of various concentration (HPMC) load medicinal powder end is coated, prepares the acetic acid ethyl fluid of 3%EC, the HPMC of mass concentration 5g/L, HPMC are interior packet Clothing swell layer, EC are outer layer release controlling coating material, pass through control swell layer and coatings Drug controlled release degree.
3. chlorination K released test 1
It accurately weighs 2.0g load medicinal powder end to be loaded into bag filter after carrying out coating processing, 2mL water, both ends folder is added Tightly, it is placed in a beaker, 500mL water is added, is discharged at 37 DEG C, timing sampling uses conductance measurement.Slow controlled release is measured to release Curve is put, sees the KCl/SSP-Coating in Figure 10.
4. chlorination K released test 2
It accurately weighs 2.0g and carries medicinal powder end in bag filter, 2mL water is added, both ends clamp, are placed in a beaker, and are added 500mL water, is discharged at 37 DEG C, and timing sampling uses conductance measurement.Slow controlled release release profiles are measured, are seen in Figure 10 KCl/SSP。
11 potassium chloride of embodiment/chitosan-carbon acid calcium (KCl/CS-CaCO3) compound preparation and release profiles measurement
1. potassium chloride load test
Saturated potassium chloride solution is prepared at room temperature in single-necked flask, accurately weighs 5g chitosan-carbon acid calcium compound bio Sill dries 2h at 160 DEG C, is cooled to 100 DEG C or less and pours into rapidly, be slowly ramped to slight boiling condition, be stirred at reflux 2h, be cooled to Room temperature, filtering, is flushed three times with certain mass water, dry to constant weight.Measuring drugloading rate is 9.4%.
2. carrying the processing of medicinal powder end coating
It weighs 2g and carries the appropriate ethyl cellulose solution of medicine powder spray and Gonak, dry, weighing.
It weighs and carries medicinal powder end, with ethyl cellulose (EC)/hydroxypropyl methyl cellulose (HPMC) of various concentration to load medicine Powder is coated, and prepares the acetic acid ethyl fluid of 3%EC, and the HPMC of mass concentration 5g/L, HPMC are interior coating swell layer, and EC is Outer layer release controlling coating material passes through control swell layer and coatings Drug controlled release degree.
3. chlorination K released test 1
It accurately weighs 2.0g load medicinal powder end to be loaded into bag filter after carrying out coating processing, 2mL water, both ends folder is added Tightly, it is placed in a beaker, 500mL water is added, is discharged at 37 DEG C, timing sampling uses conductance measurement.Slow controlled release is measured to release Curve is put, sees the KCl/CS-CaCO in Figure 103-Coating。
4. chlorination K released test 2
It accurately weighs 2.0g and carries medicinal powder end in bag filter, 2mL water is added, both ends clamp, are placed in a beaker, and are added 500mL water, is discharged at 37 DEG C, and timing sampling uses conductance measurement.Slow controlled release release profiles are measured, are seen in Figure 10 KCl/CS-CaCO3。
The preparation of 12 imidacloprids of embodiment/chitin-protein (Imidacloprid/Ct-Pro) compound and release are bent Line measurement
1. imidacloprid load test
3.0g Imidacloprid Insecticide mass fraction 10% is accurately weighed, is poured into single-necked flask after being dissolved with methylene chloride, 5.0g chitin-protein complex is accurately weighed again, is dried 2 hours at 160 DEG C, is cooled to 100 DEG C or less and pours into rapidly, then slowly Slowly it is warming up to slight boiling condition, is stirred 1 hour, filtering is flushed three times with a large amount of water, dry to constant weight.Measuring drugloading rate is 16.8%.
2. imidacloprid release test
Accurately weigh 1.5g carry medicinal powder end, carry out coating processing after, be placed in a beaker, be added 500mL water, at 30 DEG C into Row release, timing sampling carry out centrifuging and taking supernatant liquor, cross 0.45 μm of filter membrane, and high-efficient liquid phase color is used in dilution, ultrasound 20min Stave sign.Slow controlled release release profiles are measured, see Figure 11.
13 brufens of embodiment/chitosan-carbon acid calcium (IBU/CS-CaCO3) compound preparation and release profiles measurement
1. brufen load test
It accurately weighs 1.0g IBU to be dissolved in 20mL50 DEG C of deionized water, under strong stirring, slowly plus 1mol/LNaOH is molten Liquid is completely dissolved until IBU.Chitosan-carbon acid calcium compound bio sill 4.0g is taken to be added, 70 DEG C of heating stirrings, with 10% salt Acid solution tune pH value stirs 1h, 50 DEG C of drying to neutrality.Measuring drugloading rate is 10.8%.
2. brufen release test
It accurately weighs 1.0g and carries medicinal powder end in bag filter, 2mL water is added, both ends clamp, are placed in a beaker, and are added 500mL water is discharged, timing sampling at 37 DEG C, carries out centrifuging and taking supernatant liquor, crosses 0.45 μm of filter membrane, dilution, ultrasound 20min is characterized with high performance liquid chromatography.Slow controlled release release profiles are measured, see Figure 12.
14 glyphosates of embodiment/chitosan-carbon acid calcium (PMG/CS-CaCO3) compound preparation and release profiles measurement
1. glyphosate load test
It accurately weighs 95% glyphosate crystal powder 3.0g to be placed in single-necked flask, 20mL deionized water dissolving is added, then Weigh 5.0g chitosan-carbon acid calcium compound bio sill, dried 2 hours at 160 DEG C, be cooled to 100 DEG C or less pour into rapidly grass it is sweet In phosphine solution, it is slowly ramped to slight boiling condition, is stirred one hour, is cooled to room temperature, glyphosate formulation is first depressurized and is steamed as far as possible Water is until having crystal precipitation, and filtering is washed three times with certain mass water logging, drying.Measuring drugloading rate is 31.1%.
2. glyphosate release test
It accurately weighs 2.0g and carries medicinal powder end in bag filter, 2mL water is added, both ends clamp, are placed in a beaker, and are added 500mL water is discharged, timing sampling at 30 DEG C, carries out centrifuging and taking supernatant liquor, crosses 0.45 μm of filter membrane, dilution, ultrasound 20min is characterized after 0.45 μm of filter membrane with high performance liquid chromatography.Slow controlled-release profile is measured, sees Figure 13.
15 Sodium ibuprofens of embodiment/porous calcium carbonate (IBU-Na/CaCO3) compound preparation and release profiles measurement
1. Sodium ibuprofen load test
It accurately weighs 0.2g sodium hydrate solid (40.0,1eq), 25mL water is added, is made into sodium hydroxide solution；It weighs again 1g brufen (IBU) (206.2,1eq) pours into the sodium hydroxide solution prepared, and brufen (neutralization reaction) is dissolved in stirring, then 4.0g porous calcium carbonate is added, is slowly ramped to slight boiling condition, stirs one hour, is cooled to room temperature, is washed with certain mass water logging Three times, 60 DEG C of drying, measuring drugloading rate is 16.6%.
2. Sodium ibuprofen release test
It accurately weighs 1.0g and carries medicinal powder end in bag filter, 2mL water is added, both ends clamp, are placed in a beaker, and are added 500mL water is discharged, timing sampling at 37 DEG C, carries out centrifuging and taking supernatant liquor, crosses 0.45 μm of filter membrane, dilution, ultrasound 20min is characterized with high performance liquid chromatography.Slow controlled release release profiles are measured, see Figure 14.Measurement result proof Sodium ibuprofen/porous Calcium carbonate (IBU-Na/CaCO3) compound fully meets the slow controlled release requirement of pharmacopeia.
The preparation of 16 avermectin of embodiment/shrimp shell meal (AVM/SSP)
The shrimp shell meal for accurately weighing 1.0g activates 2h at 160 DEG C, is cooled to 100 DEG C or less the round bottoms for being quickly adding into 50mL In flask, it is separately added into the acetone, chloroform, ethanol solution of the avermectin of 10.0g 10% in round-bottomed flask, in water-bath For 24 hours, cooled and filtered, acetone washing, drying, measuring drugloading rate is 26.87%, 2.87%, 2.24% for reflux.
17 avermectin of embodiment/chitosan-carbon acid calcium (AVM/CS-CaCO3) compound preparation
The chitosan-carbon acid calcium compound bio sill for accurately weighing 1.0g activates 2h at 160 DEG C, be cooled to 100 DEG C with Under be quickly adding into the round-bottomed flask of 50mL, be separately added into round-bottomed flask the avermectin of 10.0g 10% acetone, Chloroform, ethanol solution flow back for 24 hours in water-bath, cooled and filtered, acetone washing, obtain drugloading rate after drying and are 36.54%, 3.58%, 0.96%.
Weigh avermectin/shrimp shell meal (AVM/CS-CaCO of 1.0g3, drugloading rate 36.54%) and in bag filter, two While stepping up, it is placed in the wide-mouth bottle of ground, the dehydrated alcohol of 100mL is added, is discharged at room temperature, timing sampling carries out Centrifugation is crossed 0.45 μm of powder filter membrane, is characterized with high performance liquid chromatography, measures slow controlled-release profile, sees the AVM/CS-CaCO in Figure 183。
18 avermectin of embodiment/porous calcium carbonate (AVM/CaCO3) preparation
The porous calcium carbonate for accurately weighing 1.0g activates 2h at 160 DEG C, is cooled to 100 DEG C or less and is quickly adding into 50mL's In round-bottomed flask, the acetone, chloroform, ethanol solution of the avermectin of 10.0g 10%, water-bath are separately added into round-bottomed flask It flows back for 24 hours in pot, cooled and filtered, acetone washing, drying, measuring drugloading rate is 44.68%, 6.19%, 0.
Weigh avermectin/shrimp shell meal (AVM/CaCO of 1.0g3, drugloading rate 44.68%) and in bag filter, both sides add Tightly, it being placed in the wide-mouth bottle of ground, the dehydrated alcohol of 100mL is added, is discharged at room temperature, timing sampling is centrifuged, 0.45 μm of powder filter membrane is crossed, is characterized with high performance liquid chromatography, slow controlled-release profile is measured, sees the AVM/CaCO in Figure 183。
The preparation of 19 avermectin of embodiment/chitin-protein (AVM/Ct-Pro) compound
Chitin-protein compound bio the sill for accurately weighing 1.0g activates 2h at 160 DEG C, be cooled to 100 DEG C with Under be quickly adding into the round-bottomed flask of 50mL, round-bottomed flask respectively in be added 10.0g 10% avermectin acetone, Chloroform, ethanol solution flow back for 24 hours in water-bath, cooled and filtered, chloroform, drying, measure drugloading rate be 0,25.89%, 0。
Weigh avermectin/shrimp shell meal (AVM of 1.0g/Ct-Pro, drugloading rate 25.9%) in bag filter, both sides add Tightly, it being placed in the wide-mouth bottle of ground, the dehydrated alcohol of 100mL is added, is discharged at room temperature, timing sampling is centrifuged, 0.45 μm of powder filter membrane is crossed, is characterized with high performance liquid chromatography, slow controlled-release profile is measured, sees the AVM/Ct-Pro in Figure 18.
20 different carriers of embodiment, difference pH are to the landfill situation of KCl
Accurately weigh carrier (the shrimp shell meal SSP, chitosan-carbon acid calcium compound bio sill CS-CaCO of 1.0g or so3、 Porous calcium carbonate CaCO3, chitin-protein compound bio sill Ct-Pro) the saturation potassium chloride that is added under different pH is molten It in liquid, is warming up to slightly boiled, keeps slightly boiled 4h, filter, drying.From the variation known to the landfill rate of following table with pH, various carriers It is weightless also can be with fluctuation, the CS-CaCO at 12,13 pH3、CaCO3There is certain landfill rate.
Influence under 6 different carriers of table, condition of different pH to carrier landfill rate
21 NPPMG of embodiment (glyphosate isopropyl amine salt) is with the influence for comparing landfill rate
NPPMG (specifically see the table below), the temperature rising reflux 2h of certain mass are added in carrier after 1.0g activation, filtering is washed Wash drying.The appropriate dosage for increasing NPPMG is conducive to improve landfill rate.
Influence of the quality of 7 glyphosate isopropyl amine salt of table to carrier landfill rate
22 temperature of embodiment, solvent influence the landfill rate of avermectin
10% avermectin chloroformic solution, ethanol solution are separately added into the carrier after 1.0g activation, room in acetone soln Temperature or reflux for 24 hours, are filtered, and are washed, drying.SSP,CS-CaCO3、CaCO3Three kinds of carriers are to can in avermectin acetone soln Obtain higher landfill rate, and landfill rate is lower in chloroform and ethanol solution, but Ct-Pro carrier can be obtained in chloroform reflux compared with High landfill rate, and do not loaded substantially in other solvents.As it can be seen that carrier, solvent and temperature condition can all significantly affect landfill effect Fruit.
8 temperature of table, solvent influence the landfill rate of avermectin
23 different carriers of embodiment, different solvents are to the landfill situation of Sodium ibuprofen
30% sodium hydroxide of 0.68g (hundred hydrogen-oxygens of folding are separately added into the brufen acetone soln of 10g10%, ethanol solution Change sodium 0.2g) solution, so that brufen is become Sodium ibuprofen solution, the carrier after 1.0g activation is added, heating flows back for 24 hours, filtering Washing.CS-CaCO3And CaCO3It can achieve certain carrier amount in acetone soln, the effect is relatively poor in ethanol solution.But Ethanol solution can be such that Ct-Pro preferably loads.
9 different carriers of table, influence of the different solvents to Sodium ibuprofen landfill rate
Filling effect of the various carriers of embodiment 24 to soybean oil
The soya-bean oil of 10g is added in carrier after 1.0g activation, feeds, is stirred under different pressure at various pressures 2h, filtering, ethanol washing, drying.Multiple carriers, which all show load potentiality, decompression well, can significantly improve its load Amount.
Influence of 10 pressure of table to carrier landfill rate
Reference examples natural plant raw material bamboo powder, Sunflower Pole powder are undesirable as carrier loaded effect
The glyphosate isopropyl amine salt of 10g 41%, KCl solution, the 10g of 10g30% are separately added into carrier after 1g activation The ammonium glyphosate of 30% urea liquid, 6g 75%, heating, flow back 4h, is filtered, washed, dries.As it can be seen that having nano-pore Certain load capacity is presented in the bamboo fibre in road, and the biggish straw powder in duct does not just have load capacity.
11 bamboo powder of table and sunflower powder analyze the landfill rate of different samples

Claims (11)

1. it is a kind of using shrimp and crab shells as raw material by or construct nano pore develop natural drug carrier method, according to different bodies System and specific requirement select or mixtures thereof any one of following (1)~(4) step solid product of step to be used as drug Carrier can satisfy drug, fertilizer or the plant that bioelectric detecting needs to have slow control-release function by the production of solution adsorption supporting method The specific preparation method of object growth promoter series of products, carrier is as follows:
(1) shrimp and crab shells raw material is cleaned, boils removal soluble matter, dried, be ground into the powder of 200 mesh or more, sieve for subsequent use, It can be directly as one of sustained and controlled release carrier material；
(2) it is added to product made from step (1) as raw material in isopropanol~potassium hydroxide~aqueous systems, at a reflux temperature Heating alkaline hydrolysis 3 hours or so makes chitin removing acetyl group become chitosan, and it is mixed that protein degradation is that amino acid and small peptide are dissolved in In bonding solvent, solid powder is filtered out from reaction mixture, solid powder is washed to neutrality, drying, obtains chitosan-carbon acid Calcium compound bio sill, as one of sustained and controlled release carrier material, filtrate is as amino acid and potash fertilizer raw material；
(3) mixture that step (2) reaction is completed is directly added into monoxone without isolation, then heating carries out the carboxylic of chitosan Methylation reaction, reaction mixture filtering, obtained filtrate can be used as amino acid and potash fertilizer raw material, obtained solid mixture warp Isopropanol washing filtering is crossed, the carboxymethyl chitosan that is dissolved in water, the byproduct calcium carbonate solid filtered out are washed to neutrality, can obtain To the porous calcium carbonate with nano pore structure, filtering drying, as one of nanometer sustained and controlled release carrier material, aqueous solution adds alcohol It is precipitated out carboxymethyl chitosan solid product；
(4) shrimp and crab shells raw material or the processing dissolution of the powder material acid solution of step (1) are directly removed into calcium carbonate, filtered, washing To neutrality, sieving is ground with pulverizer after drying, obtains chitin-protein compound bio sill, as the slow control of biology base Release one of carrier material.
2. shrimp and crab shells raw material powder is in isopropanol~potassium hydroxide~aqueous systems method according to claim 1, in step (2) In be stirred to react temperature be 50~90 DEG C, the reaction time 1~20 hour, or with boiling temperature stirring 3 hours or so；Step (3) in, carboxymethylation reaction temperature is 50~70 DEG C, the reaction time 0.5~10 hour.
3. method according to claim 1, in step (2), the mass ratio of isopropanol and raw material is 1~5: 1, water and raw material Mass ratio is 0.1~0.5: 1, and the mass ratio of potassium hydroxide and raw material is 7~8: 15, in step (3), the matter of monoxone and raw material Ratio 1: 5~7 is measured, monoxone can continuous or point 3~7 additions.
4. method according to claim 1, in step (2), the isopropanol for the protein hydrolyzate recycling being separated by filtration Solvent is recycled, and the protein hydrolyzate being concentrated to get is as liquid potash fertilizer raw material.
5. method according to claim 1, it is characterised in that: the acid solution in the step (4) is hydrochloric acid, citric acid or paddy Propylhomoserin, reaction temperature are 30~60 DEG C, and the reaction time is 1~10 hour, it is preferred that raw material uses the raw material of 100~200 mesh, Reaction is not changed with pH and is terminal less than 4.
6. the various carrier materials that method according to claim 1, step (1) to step (4) obtains have nano pore knot Structure, specific surface area are 2~100m2·g-1, it is preferred that the carrier specific surface area that step (2), (3) and (4) obtains be 40~ 50m2·g-1, can be used as the carrier application with higher load amount.
7. according to the method described in claim 1, it is characterized in that the step of solution adsorption supporting method are as follows: press step (1)~(4) Powder sample carrier material is obtained, then drying removes moisture content, puts into medical fluid rapidly, and the measures such as decompression absorption can improve load Dose reduces air and moisture content residual in duct, is immersed in the aqueous solution or organic of excessive saturation or oversaturated substance to be adsorbed Solution or mixed solution are sufficiently adsorbed, and can be warming up to slight boiling condition when necessary, be stirred 0.5~24 under room temperature or reflux state Hour, the air and solvent in nano pore are excluded as far as possible, are filtered and are rinsed with deionized water or coordinative solvent, are dried under reduced pressure To constant weight, slow controlled release product particle can be obtained, actual conditions can be heated or be depressurized absorption or selection according to medicinal property Suitable solvent optimization determines.
8. the carrier material of any one of -6 the method preparations adsorbs medicine, pesticide, fertilizer, disinfectant, guarantor according to claim 1 Application in fresh dose, flavors and fragrances, feed and food additives after one or more ingredients as product, it is characterised in that will weigh Benefit require the step of any one of 1-6 (1) to step (4) obtained sustained and controlled release carrier material absorption it is described it is one or more at Point.
9. application according to claim 8, it is characterised in that the ingredient be selected from drug, health care product, nutritional ingredient, preferably , the ingredient is selected from Chinese and Western medicine, nutritional ingredient, vitamin, pesticide, plant growth promoter, amino acid, disinfectant, fresh-keeping One of agent, flavors and fragrances are a variety of, it is preferred that ingredient is glyphosate isopropyl amine salt, Sodium ibuprofen, imidacloprid, Avermectin Element, potassium chloride.
10. it is a kind of using shrimp and crab shells as raw material by or construct nano pore develop natural drug carrier method it is preparation-obtained Carrier material, the carrier material are that the step (1) in any one of claim 1-6 the method is obtained to step (4) is prepared The carrier material arrived, and 3 hours obtained carrier materials with nano pore structure, the carrier material are dried at 160 DEG C Specific surface area be 2~100m2·g-1, it is preferred that the carrier specific surface area that step (2), (3) and (4) obtains be 40~ 50m2·g-1, the various functional products of the carrier and production.
11. method according to claim 1, slow controlled release carrier is also possible to have bamboo fibre of nano pore etc. is other to have The biological material of nano pore.
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CN110420346B (en) * 2019-08-30 2021-09-21 华南理工大学 Corn stalk/chitin composite hemostatic sponge and preparation method and application thereof
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