WO2020199349A1 - 一种纳米孔道型天然缓控释载体材料及制备方法 - Google Patents

一种纳米孔道型天然缓控释载体材料及制备方法 Download PDF

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WO2020199349A1
WO2020199349A1 PCT/CN2019/091135 CN2019091135W WO2020199349A1 WO 2020199349 A1 WO2020199349 A1 WO 2020199349A1 CN 2019091135 W CN2019091135 W CN 2019091135W WO 2020199349 A1 WO2020199349 A1 WO 2020199349A1
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carrier
shrimp
controlled release
drug
calcium carbonate
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PCT/CN2019/091135
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English (en)
French (fr)
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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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厦门大学
宁波大学
北京紫光英力化工技术有限公司
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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

Definitions

  • the invention belongs to the development and production application field of drug slow and controlled release materials, and specifically relates to the preparation and application field of green safe carriers filled with drugs, fertilizers and other functional chemical substances. Invented a carrier with natural nanoporous channels using natural biomass such as shrimp and crab shells as raw materials and a simple preparation method.
  • Slow and controlled release carriers refer to materials that can control the functional components to be released automatically at a certain speed within a predetermined time to maintain their effective concentration, and can be widely used in animals, plants and microorganisms. Among them, the most important is the slow and controlled release drugs that can control the speed, time and location of the drug release, and the drug slow-release carrier can change the way the drug enters the animal and plant body and its distribution, and can effectively control the release speed and concentration of the drug. Promote drug absorption. Sustained-release drug carriers have outstanding advantages in reducing the number of administrations, reducing the amount of administration, reducing toxic and side effects, and improving efficacy, and are an important direction for drug development.
  • the patent CN107536806A describes the cumulative release curve of methotrexate loaded with chitosan-calcium carbonate carrier, which uses the complex of chitosan-embedded calcium chloride and sodium bicarbonate to produce calcium carbonate as the carrier to absorb
  • the sustained-release effect is not ideal. About 50% is released in about 100 minutes. Under the conditions, the release is basically stopped for 200 minutes, and the sustained release effect is improved under acidic conditions (see Figure 15).
  • Pesticides are the guarantee for the increase and stability of crops. Pest control, weeding and plant growth promotion are the three major functions of pesticides.
  • the existing pesticides use microemulsion (ME), water emulsion (EW), suspending agent (SC), emulsifiable concentrate (EC) and wettable powder (WP) and other formulations, which are only limited to the dispersion and convenient use of pesticides. It can well solve the problem of difficult adsorption on the waxy surface of plants and easy to be washed off by rain. In the process of using pesticides, a series of negative problems such as large dosage, short validity period, damage to the ecological system, serious residue and environmental pollution, and rapid increase of resistance to pests and diseases require effective solutions.
  • the State Council has put forward the "double reduction" requirement of pesticides and fertilizers, which obviously reduces the amount of pesticides used, avoids the loss of pesticides, environmental pollution and damage to the microbial system as much as possible, develops high-efficiency, long-acting and low-toxic pesticides, and develops cost-effective and safe pesticide carriers It is the direction of pesticide development.
  • Pesticide sustained-release agents (BR) are still in the initial stage of research and development, and there is no finished product of sustained and controlled-release pesticides, so the development prospects are huge.
  • Plant growth regulators can significantly promote plant growth and development, increase and stabilize production, improve crop quality, and enhance crop resistance. They can be artificially synthesized or extracted from biomass.
  • Shrimp and crab shells and carriers are naturally derived from crustaceans.
  • Chitosan, chitosan and carboxymethyl chitosan are a kind of plant growth promoters with great development and application value.
  • the existing slow and controlled release technology has a series of problems such as high cost, unstable product performance, low drug loading, poor use effect, use safety and poor biocompatibility, etc.
  • the development of green and safe with biomass as raw material A stable, universal and cost-effective drug carrier is of great significance.
  • Chitin is a natural polymer of amino polysaccharides whose output is second only to cellulose. It is widely used in many fields such as crop cultivation, medicine, food, bioengineering, daily chemical industry, textile printing and dyeing, papermaking and tobacco, water treatment, etc. the use of. Chitosan is a deacetylated derivative of chitin. It is the only alkaline polysaccharide that exists stably in nature.
  • chitosan is known as the key substance that will affect the scientific and technological progress of human society in the 21st century. .
  • Shrimp and crab shell is a natural composite material with regular structure composed of chitin, protein and calcium carbonate. It has a capillary network structure with protein and chitin as the main structural components to meet the needs of body fluid circulation. It is a slow and controlled release Ideal material for carrier.
  • the content of calcium carbonate in the shells of shrimps and crabs is 40%-50%, the content of protein is 20-30%, and the content of chitin is 20%-30%. Due to the difficulty of recycling, most of the shells of shrimps and crabs are discarded. Only the shells of shrimps and crabs produced by processing plants are powdered as feed or fertilizer, and only a very small amount of raw materials are used as raw materials for extracting chitin and producing chitosan.
  • the traditional chitin extraction process has the problems of high material consumption and energy consumption, serious waste water pollution, high production costs, poor enterprise benefits, and environmental constraints on production, making it difficult to produce on a large scale. Therefore, the global annual output of chitin and its derivatives chitosan is less than 200,000 tons, and the development of the industry is greatly restricted.
  • the protein and chitin in the shells of shrimps and crabs not only form the shell structure of shrimps and crabs together with calcium carbonate, but also construct a network system of capillary tubes to ensure the smooth flow of body fluids. It has the potential as a slow and controlled release carrier.
  • the innovative technology of combining protein removal or/and extraction of chitosan and the "one-pot" synthesis of carboxymethyl chitosan can further expand the pores and develop a series of natural carrier materials with nano-pores (see Figure 1), creating a green A new type of slow and controlled release carrier library that is safe, low-cost, and developed for use.
  • the calcium carbonate-carboxymethyl chitosan mixture with nanopores can be obtained through a "one-pot cooking" reaction, and the two products can be separated by dissolving in water. Therefore, according to the difference in the solubility of raw materials or intermediates, products or by-products in acid or alkali or alcohol or water or their mixed solvents, the chitosan calcium carbonate solid complex can be separated and dissolved out of chitosan or carboxymethyl chitosan
  • the main components of post-sugar co-production are calcium carbonate products, carboxymethyl chitosan/calcium carbonate solid mixture, chitosan solution or chitosan products, carboxymethyl chitosan solution or powder and other series of products including A liquid fertilizer raw material with amino acids ⁇ small peptides and potassium acetate as the main components.
  • the new process not only avoids the shell structure damage caused by acid decalcification, the degradation of chitin, a large amount of acid consumption, and the difficult treatment of acid-containing organic wastewater, but also can co-produce a series with an average pore diameter of 10 nanometers
  • Porous natural bio-based materials can completely solve the industry problems of high production cost, high pollution, serious hydrolysis and degradation, poor quality and low productivity of chitosan and its derivatives.
  • the acid-treated protein and chitin may still retain the natural pore structure, and can also be effectively filled with functional chemicals in the solution, and has significant slow and controlled release characteristics. Therefore, the present invention can promote the development of the chitosan industry chain and open up a new type of green and safe slow and controlled release carrier material library.
  • the present invention has developed shrimp and crab shell powder raw materials obtained by simple processing or further alkali or acid treatment using shrimp and crab shells as raw materials, and deproteinized chitosan-calcium carbonate composite materials to separate carboxymethyl chitosan
  • the by-product biological calcium carbonate material and the composite bio-based material of protein and chitin from which calcium carbonate has been removed with acid through scanning electron microscopy, pore size, pore volume, specific surface area, water absorption, different substances, dissolving adsorption system and loading volume and According to the measurement of the release curve, it is found that the other two materials except the composite bio-based material of protein and chitin have a pore structure with an average pore diameter of less than 10 nanometers, and the specific surface area is more than 10 times that of the raw material.
  • bio-based materials with natural nano-pores not only have the unique advantages of abundant raw materials, low production cost, non-toxic and edible, safe and environmentally friendly, and completely biodegradable, but also have the unique advantages of selective adsorption in the solution and large amount
  • the characteristics of storing various functional chemical substances including various drugs can be developed as an ideal controlled release carrier material.
  • SSP refers to Shrimp Shell Powder
  • CSP refers to Crab Shell Powder
  • CS-CaCO 3 refers to chitosan-calcium carbonate composite bio-based material
  • CaCO 3 refers to porous calcium carbonate
  • S- refers to products derived from shrimp shell powder
  • C- refers to products derived from crab shell powder. See the chart for related performance.
  • the present invention is based on the aforementioned patented method and found a natural carrier material library with a large specific surface, pore volume, water absorption doubled and nano-pore structure using shrimp and crab shell powder as raw material. It is found that different carriers have different adaptability and loading capacity. The surface tension of the system, the properties of the carrier and the loading material have a great influence on the loading capacity. The release curves of different drug carrier complexes are significantly different. This discovery is for different needs. The development of slow and controlled release system and optimization of combination have laid the research foundation, showing various possibilities.
  • the heating of the nanocarrier discharges air and moisture, adsorption under reduced pressure, adsorption of saturated or supersaturated solutions, aqueous, organic and mixed solutions, and mixed solvents to improve surface tension filling methods, as well as to increase the filling volume and extend the release period.
  • Re-coating and other methods have been able to make the carrier material with natural nanopores reach a loading capacity of 10-44%.
  • the sustained and controlled release effects of various loaded drugs were determined according to the general analysis method, which proved that they showed good sustained and controlled release characteristics: no burst release, uniform and long-term sustained release, less drug residue, and the carrier itself can be degraded And absorption, safe to use, can greatly reduce the dosage.
  • the Chinese Pharmacopoeia 2005 edition introduced that the half-life of ibuprofen is 1.8 to 2 hours, and it needs to be administered 3 to 4 times a day, and it has disadvantages such as low bioavailability and large dosage.
  • the current common preparations and specifications are: (1) Ibuprofen tablets: 100mg; 200mg; 400mg (2) Ibuprofen sustained-release capsules: 300mg (3) Ibuprofen sustained-release tablets: 200mg (4) Ibuprofen foam Teng tablets: 100mg (5) Ibuprofen liniment: 5mL 250mg.
  • the release amount of the sustained and controlled release product prepared by the present invention in 1 hour, 2 hours, 4 hours and 7 hours is 10% to 35%, 25% to 55%, 50% to 80% and 75% of the pharmacopoeia marked amount.
  • the indicators match.
  • Sodium ibuprofen/porous calcium carbonate (IBU-Na/CaCO 3 ) complex and ibuprofen/chitosan-calcium carbonate complex (IBU/CS-CaCO 3 ) are both effective for slow and controlled release of ibuprofen. Both can control the release of 70% of the drug for about 7 hours, and the latter has a better sustained and controlled release effect.
  • Potassium chloride/chitin-protein-envelope complex (KCl/Ct-Pro) can control the release of potassium chloride only 85% within 10 hours.
  • the weight of a single tablet or a single tablet of drug tablets and capsules is usually 100-200 mg, and the single drug amount of drugs such as hypertension is generally about 5 mg, that is, a loading amount of about 5% can meet the requirements. Therefore, various vectors have development potential.
  • Glyphosate isopropylamine salt/shrimp shell powder (NPPMG/SSP) in the continuously stirred dissolution medium has a controlled release time of up to 100h, and basically reaches equilibrium at 120h; glyphosate isopropylamine salt/chitosan-carbonic acid Calcium complex (NPPMG/CS-CaCO 3 ) released 50% of glyphosate isopropyl salt in 96h, and 88% of glyphosate isopropylamine salt in 300h, which basically reached the balance and reached the ideal pesticide Sustained and controlled release requirements; Glyphosate isopropylamine salt/chitin-protein complex (NPPMG/Ct-Pro) releases glyphosate isopropylamine salt at about 72 hours and basically reaches equilibrium, and it also has a certain slow-release effect; The glyphosate isopropylamine salt/porous calcium carbonate complex (NPPMG/CaCO 3 ) can release 90% glyphosate iso
  • the glyphosate/chitosan-calcium carbonate complex (PMG/CS-CaCO 3 ) releases 90% of glyphosate isopropylamine salt within 370 hours, which also meets the requirements of an ideal sustained and controlled release pesticide.
  • the imidacloprid/chitin-protein complex (Imidacloprid/Ct-Pro) releases only 75% imidacloprid for up to 400 hours, and the slow and controlled release effect is more significant.
  • Slow- and controlled-release pesticides require the dosage of high-efficiency pesticides to be less than 50g per acre. Slow- and controlled-release loaded pesticides can greatly save the amount of original medicine, reduce or alleviate pollution, and prolong the efficacy. Therefore, the actual dosage will not increase much.
  • the results of the present invention will promote the application of medicines, pesticides, plant growth regulators slow release, controlled release of various drugs, and high-efficiency fertilizers.
  • the protection of nanopores in which microorganisms cannot enter it can better prevent drugs from being damaged. Enzymes or microorganisms are decomposed or lost to ensure the long-term effect of the drug, and the natural degradability of the carrier can ensure the safety of the drug. Therefore, the present invention will promote the development and establishment of long-term, safe, low-cost animal and plant fertilizers and other functional slow and controlled release new systems.
  • the present invention provides a method for developing natural drug carriers by using shrimp and crab shells as raw materials by using or constructing nanopores. According to different systems and specific requirements, any one of the following steps (1) to (4) is selected
  • the solid product or its mixture is used as a drug carrier to produce a series of drugs, fertilizers or plant growth promoters that can meet the needs of biological regulation by the solution adsorption loading method with a slow and controlled release function.
  • the specific method for obtaining the carrier is as follows:
  • step (2) Add the product obtained in step (1) as the raw material of shrimp and crab shell powder to the isopropanol ⁇ potassium hydroxide ⁇ water system, and heat it for alkaline hydrolysis at boiling temperature for about 3 hours, preferably 2-4 hours,
  • the acetyl group of chitin is removed to become chitosan
  • the protein is degraded into amino acids and small peptides are dissolved in a mixed solvent to obtain a reaction mixture
  • the solid powder is filtered from the reaction mixture, the solid powder is washed to neutrality, and dried to obtain chitosan -Calcium carbonate composite bio-based material, as one of the slow and controlled release carrier materials, and the filtrate as the raw material of amino acid and potash fertilizer;
  • step (3) The reaction mixture obtained in step (2) is directly added to chloroacetic acid without separation, and then heated to carry out the carboxymethylation reaction of chitosan, the reaction mixture is filtered, and the obtained filtrate can be used as the raw material of amino acid and potash fertilizer, and the obtained solid
  • the mixture is washed and filtered with isopropanol, added with water to dissolve carboxymethyl chitosan, and the filtered by-product calcium carbonate solid is washed with water to neutrality, and porous calcium carbonate with nano-pore structure can be obtained, filtered and dried, and used as a nano-controlled release carrier
  • One of the materials, the aqueous solution and alcohol can precipitate solid carboxymethyl chitosan products;
  • step (1) Directly treat the shrimp and crab shell raw materials or the shrimp and crab shell powder raw materials of step (1) with an acid solution to dissolve calcium carbonate, filter, wash until neutral, dry, grind and sieve with a grinder to obtain chitin -Protein composite bio-based material, as one of the bio-based slow and controlled release carrier materials.
  • the above method is characterized in that the stirring reaction temperature of the shrimp and crab shell raw material powder in the isopropanol-potassium hydroxide-water system is 50-90°C, the reaction time is 1-20 hours, or the boiling temperature Stir for about 3 hours, preferably 2.5-3.5 hours; in step (3), the carboxymethylation reaction temperature is 50-70°C, and the reaction time is 0.5-10 hours.
  • the 3 hours or so means that the time fluctuates by 1 hour or 0.5 hours, that is, 3 ⁇ 1 or 3 ⁇ 0.5 hours.
  • about 3 hours can also be understood as 3 ⁇ 1 hour, preferably 3 ⁇ 0.5 hour can also refer to 2 hours to 4 hours, preferably 2.5 to 3.5 hours.
  • the mass ratio of the isopropanol to the raw material is 1 to 5:1
  • the mass ratio of water to the raw material is 0.1 to 0.5:1
  • the mass ratio of potassium hydroxide to the raw material is 7 ⁇ 8:15.
  • the mass ratio of chloroacetic acid to chitosan-calcium carbonate composite bio-based material is 1:5-7. Chloroacetic acid can be added continuously or in multiple times, preferably in 3-7 times .
  • 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.
  • the acid solution in the step (4) is hydrochloric acid, citric acid or glutamic acid
  • the reaction temperature is 30-60°C
  • the reaction time is 1-10 hours
  • the reaction is performed at a pH Change and less than 4 is the end point.
  • the various carrier materials obtained in the steps (1) to (4) have a nanoporous structure and a specific surface area of 2-100m 2 ⁇ g -1 .
  • the step (2) The specific surface area of the carrier obtained in (3) and (4) is 40-50m 2 ⁇ g -1 , and the carrier is determined to have a loading capacity of 10%-50% after adsorption by a conventional adsorption method.
  • the above method is characterized in that the steps of the solution adsorption loading method are: obtaining the powder sample carrier material according to steps (1) to (4), then drying to remove water, and quickly adding the liquid medicine while it is hot. Decompression adsorption and other measures all increase the drug loading to reduce the air and moisture remaining in the pores, and immerse in the excessively saturated or supersaturated aqueous or organic solution or mixed solution of the substance to be adsorbed for full adsorption, and the temperature can be heated to a slightly boiling state if necessary.
  • the method further comprises drying the carrier material obtained in step (1) to step (4) at 160°C for 3 ⁇ 0.5 hours.
  • the present invention also provides the use of the carrier material prepared by the above method as a product after adsorbing one or more components of medicines, pesticides, fertilizers, disinfectants, preservatives, flavors and fragrances, feed and food additives, characterized in that the above steps
  • the sustained and controlled release carrier material obtained from (1) to step (4) adsorbs the one or more components.
  • the ingredients are selected from medicines, health care products, nutritional ingredients, preferably, the ingredients are selected from Chinese and Western medicines, nutritional ingredients, vitamins, pesticides, disinfectants, preservatives, flavors and fragrances
  • the ingredients are glyphosate isopropylamine salt, ibuprofen sodium, imidacloprid, abamectin, potassium chloride, amino acids, plant resin accelerators.
  • the present invention also provides a carrier material prepared by using shrimp and crab shells as a raw material to develop a natural drug carrier by means of or constructing nanopores.
  • the carrier material is through steps (1) to (4) in the above method.
  • the prepared carrier material has a specific surface area of 2-100 m 2 ⁇ g -1 .
  • the specific surface area of the carrier obtained in steps (2), (3) and (4) is 40-50 m 2 ⁇ g -1 .
  • the present invention also provides a variety of functional products prepared by the above-mentioned carrier material.
  • the carrier may also be bamboo fiber with nanopores and other biomass materials with nanopores.
  • the present invention also provides a method for preparing a drug carrier using shrimp and crab shells as raw materials, the method adopts one of the following steps (1)-(4):
  • step (2) Heat the shrimp and crab shell powder raw material product obtained in step (1) in the isopropanol ⁇ potassium hydroxide ⁇ water system to reflux boiling temperature, filter the solid powder from the reaction mixture, and wash the solid powder until the washing liquid is Neutralize and dry to obtain drug carrier materials, especially drug sustained and controlled release carrier materials;
  • step (3) Mix the reaction mixture obtained in step (2) with chloroacetic acid, then heat the reaction, filter the mixture, and wash the resulting solid mixture with isopropanol, then add water to mix, filter out the calcium carbonate solid, and wash with water until the washing liquid is Neutral, to obtain porous calcium carbonate with nano-pore structure, filter and dry it, as a drug carrier material, especially a nano-scale controlled release carrier material;
  • step (1) Treat the shrimp and crab shell raw materials or the shrimp and crab shell powder powder raw materials of step (1) with an acid solution, dissolve and remove calcium carbonate, filter, wash until the washing liquid is neutral, and grind with a grinder after drying Sieve to obtain a chitin-protein composite bio-based material as a bio-based drug carrier material, especially a bio-based slow and controlled release carrier material.
  • the present invention also provides a drug carrier, which is prepared by step (1), step (2), step (3) and/or step (4) in the above method.
  • the shrimp and crab shells are washed and dried with water, they are placed in a 5-12% citric acid solution, at 30-80°C, keeping the pH below 4, electric stirring for 1-10 hours, filtered, washed until neutral, and dried. Grind through a 200-mesh sieve with a pulverizer to obtain the chitin-protein composite bio-based material after removing calcium carbonate, which is then dried for use.
  • the shrimp and crab shells are washed and dried with water, they are ground in a crusher through a 200-mesh sieve and dried for later use.
  • Use Kjeldahl method to digest, distill, absorb, and titrate. For sample analysis, see Tables 1 to 5.
  • chloroacetic acid to the mixture after the reaction is completed for further carboxymethylation.
  • the chloroacetic acid is added in 3-7 times.
  • the carboxymethylation reaction temperature is 50-70°C and the reaction time is 0.5-10 hours.
  • the solid after the reaction is washed with isopropanol to neutrality, dissolved in water, filtered, washed, and dried to obtain porous calcium carbonate.
  • the solid product of carboxymethyl chitosan can be precipitated by adding alcohol to the aqueous solution.
  • the results show that the specific surface area of the sample obtained by the alcohol-alkali-water process has increased by about 20 times, has an average pore of about 10 nanometers, and the pore volume has increased a lot. It has the basic conditions as a drug carrier.
  • the scanning electron micrograph in Figure 2 shows that the alkali-treated carrier has obvious pores, and the acid-treated carrier has almost no pores.
  • Control experiment Weigh the drug-loaded powder, coat the drug-loaded powder with different concentrations of ethyl cellulose (EC)/hydroxypropyl methyl cellulose (HPMC), and prepare a 3% EC ethyl acetate solution with mass concentration 5g/L HPMC, HPMC is the inner coating swelling layer, and EC is the outer layer controlled release coating material. The drug release is controlled by controlling the weight gain of the swelling layer and the coating layer.
  • EC ethyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • FIG 1a Shrimp shell powder (SSP), b: Chitin-protein composite bio-based material (S-Ct/Pro), c: Chitosan-Calcium carbonate composite bio-based material (S-CS/CaCO 3 ), d :TEM image of porous calcium carbonate (S-CaCO 3 )
  • FIG. 2a Shrimp shell powder (SSP), b: Chitin-protein composite bio-based material (S-Ct/Pro), c: Chitosan-Calcium carbonate composite bio-based material (S-CS/CaCO 3 ), d :SEM image of porous calcium carbonate (S-CaCO 3 )
  • FIG 3a Crab shell powder (CSP), b: Chitin-protein composite bio-based material (C-Ct/Pro), c: Chitosan-calcium carbonate composite (C-CS/CaCO 3 ), d: porous SEM image of calcium carbonate (C-CaCO 3 )
  • Figure 8a 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
  • Figure 9 Cumulative release curve of shrimp shell powder, chitosan-calcium carbonate composite bio-based material, porous calcium carbonate, chitin-protein bio-based material to glyphosate isopropylamine salt
  • Figure 10 Cumulative release curves of shrimp shell powder, chitosan-calcium carbonate composite bio-based materials, and chitin-protein composite bio-based materials on potassium chloride drugs
  • Figure 12 The cumulative release curve of chitosan-calcium carbonate composite bio-based material on ibuprofen
  • Figure 13 The cumulative release curve of chitosan-calcium carbonate composite bio-based material on glyphosate
  • Figure 15 The cumulative release curve of chitosan-embedded synthetic calcium carbonate compound methotrexate disclosed in patent CN107536806A
  • Figure 17 The release curve of hollow porous SiO 2 nanoparticles to abamectin reported in the literature "Surface Modification of Nano-Silica and Its Absorption and Sustained Release Performance for Abamectin"
  • Figure 18 The cumulative release curve of chitosan-calcium carbonate composite bio-based materials, porous calcium carbonate, and chitin-protein bio-based materials to abamectin
  • FIG. 19 The production flow chart of several carriers using shrimp and crab shells as raw materials
  • SSP refers to Shrimp Shell Powder
  • CSP refers to Crab Shell Powder
  • CS-CaCO 3 refers to chitosan-calcium carbonate composite Bio-based materials
  • CaCO 3 refers to porous calcium carbonate
  • S- refers to products derived from shrimp shell powder
  • C- refers to products derived from crab shell powder.
  • the isopropanol solvent After recycling the isopropanol solvent, it can be used as liquid amino acids and potassium fertilizer raw materials. Determine the degree of deacetylation by acid-base titration or infrared spectroscopy, dilute hydrochloric acid to dissolve chitosan and calcium carbonate, ethanol reverse precipitation of chitosan, repeated washing with 70% ethanol aqueous solution to remove calcium chloride to obtain pure chitosan. The degree of deacetylation is 88%.
  • Example 4 Dissolution of the soluble matter of the carrier in water
  • EC ethyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • HPMC the inner coating swelling layer
  • EC the outer layer controlled release coating material
  • the drug release is controlled by controlling the swelling layer and the coating layer.
  • EC ethyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • HPMC the inner coating swelling layer
  • EC the outer layer controlled release coating material
  • the drug release is controlled by controlling the swelling layer and coating layer.
  • NPPMG is added to the 1.0g activated carrier (see the table below for details), heated to reflux for 2 hours, filtered, washed and dried. Appropriately increasing the amount of NPPMG will help increase the landfill rate.
  • Example 22 The influence of temperature and solvent on the landfill rate of abamectin

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Abstract

一种纳米孔道型天然缓控释载体材料及其制备方法，以虾蟹壳及其它天然具有纳米孔道的产品为载体，直接或通过联产工艺生产系列具有天然纳米孔道的功能性化学物质缓控释载体。所述载体能够用于医药、农药、植物生长调节剂的缓释、控释、以及长效肥料，借助微生物无法进入的纳米孔道保护，避免被酶或微生物分解或流失。

Description

一种纳米孔道型天然缓控释载体材料及制备方法 技术领域
本发明属于药物缓控释材料的开发及生产应用领域，具体涉及填充药物、肥料及其它功能性化学物质的绿色安全载体制备与应用领域。发明了以虾蟹壳等天然生物质为原料的具有天然纳米孔道载体及简单制备方法。
背景技术
缓控释载体是指可控制功能性组分在预定时间内自动以一定速度释放以维持其有效浓度的材料，可广泛用于动植物及微生物。其中，最为重要的是可控制药物释放的速度、时间及部位的缓控释药物，而药物缓释载体可以改变药物进入动植物体的方式及其分布，可有效控制药物的释放速度和浓度，促进药物吸收。缓释药物载体在减少给药次数、降低给药量、降低毒副作用、提高疗效等方面具有突出优势，是药物发展的重要方向。
现有药物缓释载体的研究一直非常活跃，已经形成基本体系：药物载体已经发展出包括无机物载体、天然高分子载体和合成高分子载体三大类型，药物包膜及控释技术包括微球、凝胶、纳米粒子、膜剂、片剂等载体型及溶液吸附、包埋(喷雾干燥、乳化溶剂挥发、自乳化溶剂扩散、相分离)和填充等负载型两大类。然而，缓控释效果差、毒性和安全性问题或生产成本高等问题一直困扰行业发展，性价比高，安全高效的缓控释载体仍然是缓控释药物开发的最大瓶颈。
例如专利CN107536806A中描述了壳聚糖-碳酸钙载体负载甲氨蝶呤的累计释放曲线，其采用壳聚糖包埋氯化钙与碳酸氢钠反应生成的碳酸钙这一复合物作为载体，吸附抗肿瘤的甲氨蝶呤，由于人工合成的碳酸钙孔道和孔洞大小不一，难以得到均匀的纳米孔道，因此缓释效果并不理想，在100分钟左右就释放了50％左右，在中性条件下200分钟基本上就不再释放，在酸性条件下缓释效果才得到改善(参见附图15)。专利CN107375217A描述的碳酸钙(聚鸟氨酸/岩藻聚糖)载体虽然能够缓释药物，但是载体制备复杂，工业化应用难。现有采用壳聚糖作为成膜剂通过人工合成的多孔纳米碳酸钙复合物的药物载体，同样存在药物吸附量少和缓释效果不理想的问题。
农药是农作物增产稳产的保证，病虫害防治、除草及植物生长促进是农药的三大功能。现有的农药采用的微乳剂(ME)、水乳剂(EW)、悬浮剂(SC)、乳油(EC)和可湿性粉剂(WP)等剂型，仅局限于农药的分散和方便使用，尚未能很好解决在植物的叶面蜡质表面难吸附和容易被雨水洗落的问题。农药使用过程中的用量大，有效期短，破坏生态体系，残留和环境污染严重，病虫害的抗药性增强快等系列负面问题需要有效的解决方案。国务院提 出了农药、化肥“双减”要求，显然减少农药使用量，尽可能避免农药流失和对环境污染及对微生物体系的破坏，发展高效长效低毒农药，开发性价比高使用安全的农药载体是农药发展的方向，农药缓释剂(BR)目前还刚处于研发初级阶段，还没有成型的缓控释农药成品，因此发展前景巨大。
植物生长调节剂可以显著促进植物生长发育，实现增产稳产、改善作物品质、增强作物抗逆性的一类重要农药，可由人工合成或生物质中提取，虾蟹壳及载体中本来自有的甲壳素、壳聚糖、羧甲基壳聚糖就是一类极具开发和应用价值的植物生长促进剂。综上所述，现有的缓控释技术存在成本高，产品性能不稳定，药物负载量少，使用效果差，使用安全及生物相容性差等系列问题，以生物质为原料开发绿色、安全、稳定、通用的高性价比药物载体意义重大。
2018年虾蟹全球产量已经超过300万吨，虾、蟹壳量高达百万吨以上，由于虾蟹壳中富含甲壳素、蛋白质、碳酸钙等有价值成分，是值得利用的资源。甲壳素(Chitin)是产量仅次于纤维素的氨基多糖类天然高分子，在农作物栽培、医药、食品、生物工程、日用化工、纺织印染、造纸和烟草、水处理等许多领域具有广泛的用途。壳聚糖是甲壳质经脱乙酰化作用的衍生物，是自然界唯一一种稳定存在的碱性多糖，其分子中含有大量活性基团-OH和-NH 2，具有良好的吸水性、保湿性、成膜性、金属螯合性、植物生长促进活性、生物相容性和可降解性等多种优异性能，因此，壳聚糖被誉为二十一世纪影响人类社会科技进步的关键物质。
虾蟹壳是以甲壳素、蛋白质和碳酸钙三种成分构成的结构规整的天然复合材料，本身就存在以蛋白质和甲壳素为主要结构成分的满足体液循环需要的毛细管网络结构，是缓控释载体的理想材料。
虾蟹壳中碳酸钙含量在40％～50％，蛋白质含量20～30％，甲壳素含量在20％～30％。由于回收困难，大部分虾蟹壳被废弃，只有加工厂副产的虾蟹壳被打成粉作为饲料或肥料，仅有极少量的原料作为提取甲壳素和生产壳聚糖的原料。但由于现有虾蟹壳提取甲壳素的通用工艺使用过量盐酸脱除碳酸钙，产生大量高浓度氯化钙的酸性有机废水，未溶于酸的物料用氢氧化钠溶液热碱解去除蛋白质生产甲壳素粗品过程中又会产生碱性有机废水。甲壳素粗品的废水量高达300吨/吨，虾蟹壳消耗量10吨/吨左右，酸碱消耗量也很大。因此，传统甲壳素提取工艺存在物耗能耗大，废水污染严重，生产成本高，企业效益差，生产受到环境限制，难以大规模生产的难题。因此全球甲壳素及其衍生物壳聚糖等的年产量不足二十万吨，行业发展受到很大限制。
发明内容
破解现有药物及缓释载体存在生产成本高、性能不稳定、用药量大、有效成分释放速度快、药效持效时间短、生物利用度低、毒性大，安全性差，环境污染大，缓控释效果差等行业难题，开发安全高效、性价比好的生物基缓控释药物载体是重要方向。虾蟹壳原料本来就可作为食品或饲料，具有安全无毒，丰富廉价的资源优势。壳聚糖也一直是被看好的缓控释载体包膜材料。虾蟹壳中的蛋白质和甲壳素不但与碳酸钙共同形成了虾蟹的壳层体结构，而且还构筑了保障体液畅通的毛细微管网络系统，本身就具有作为缓控释载体潜力，如再结合去除蛋白质或/和提取壳聚糖及“一锅法”合成羧甲基壳聚糖的创新工艺可以进一步扩展孔道，开发出系列具有纳米孔道的天然载体材料(参见附图1)，开创绿色安全、成本低廉、用途开发的新型缓控释载体库。
本课题组在专利“一种甲壳类原料清洁生产壳聚糖及羧甲基壳聚糖新工艺CN104788584A”中创立了以下新工艺方法：将虾蟹壳粉在异丙醇～氢氧化钠～水混合体系沸腾温度下进行碱解反应，可在更少碱量的条件下快速水解蛋白质和同时去乙酰基，方便得到去除了90％以上蛋白质和甲壳素乙酰基的复合物——具有纳米孔道的碳酸钙-壳聚糖复合生物基材料。如果不经分离加入氯乙酸可通过“一锅煮”反应可得到具有纳米孔道的碳酸钙-羧甲基壳聚糖混合物，用水溶解可分离出两个产品。因此，根据原料或中间体、产品或副产品在酸或碱或醇或水或其混合溶剂中溶解度的差异，可以分离得到壳聚糖碳酸钙固体复合物，溶出壳聚糖或羧甲基壳聚糖后联产的主要成分是碳酸钙的产品，羧甲基壳聚糖/碳酸钙固体混合物、壳聚糖溶液或壳聚糖产品、羧甲基壳聚糖溶液或粉体等系列产品及包括氨基酸～小肽、乙酸钾盐为主要成分的液体肥原料。
我们深入研究中发现，新工艺不但避免了酸脱钙造成的壳层结构破坏、甲壳素降解、大量耗酸及含酸有机废水难治理等系列问题，而且可以联产具有10纳米平均孔径的系列多孔天然生物基材料，可彻底破解壳聚糖及其衍生物生产成本高、污染大、水解降解严重、品质差、产能低的行业难题。同时发现，酸处理过的蛋白质和甲壳素可能仍然保留了天然的孔道结构，在溶液中同样可有效装填功能性化学品，具有显著的缓控释特性。因此，本发明可以推动壳聚糖产业链的发展，开辟绿色安全的新型缓控释载体材料库。
借助上述专利，本发明开发了以虾蟹壳为原料经过简单加工或进一步碱或酸处理获得的虾蟹壳粉原料、脱蛋白的壳聚糖-碳酸钙复合材料，分离羧甲基壳聚糖的副产物生物碳酸钙材料及用酸脱出了碳酸钙的蛋白质与甲壳素的复合生物基材料，通过扫描电镜、孔径、孔容、比表面积、吸水量及不同物质及溶解吸附体系和负载量及释放曲线测定，发现除蛋白质与甲壳素的复合生物基材料外的其它二种材料均具有平均孔径10纳米以内的孔道结构，比表面积 比原料增加10倍以上。这种四种自带天然纳米孔道的生物基材料，不但具有原料丰富、生产成本低、无毒可食用，安全环保、可完全生物降解的独特优势，而且具有在溶液中选择性吸附和较大量储存包括各种药物在内的各种功能性化学物质的特性，可以作为理想的控释载体材料开发。
更深入的研究还发现，不同载体材料的吸附量差异显著，并与料液的表面张力密切相关，表面张力越小的体系越容易负载，在减压情况下进行吸附可以显著提高负载量。不易负载的物料可进行包埋，复合物具有显著的长时间缓控释功能，可满足医药和农药等功能性产品的缓控释要求。SSP指虾壳粉(Shrimp Shell Powder)；CSP指蟹壳粉(Crab Shell Powder)；Ct-Pro指甲壳素-蛋白质复合生物基材料；CS-CaCO 3指壳聚糖-碳酸钙复合生物基材料；CaCO 3指多孔碳酸钙，S-指虾壳粉来源的产品，C-指蟹壳粉来源的产品。相关性能请参见图表。
本发明正是基于前述专利方法，发现了具有大比表面、孔容、吸水量成倍增加及纳米孔道结构以虾蟹壳粉为原料的天然载体材料库。发现了不同载体具有不同的适应性和负载量，体系的表面张力、载体及负载物的性质对负载量影响很大，不同的药物载体复合物释放的曲线差异显著，这一发现为不同需求的缓控释体系的开发和组合优化奠定了研究基础，显示了各种可能。通过纳米载体的加热排出空气和水分，减压吸附，饱和溶液或过饱和溶液，水溶液、有机溶液及混合溶液吸附、混合溶剂改善表面张力的填充方法，以及为增加填充量和延长释放期，进行再包膜等方式，已经可以使具有天然纳米孔道的载体材料达到10～44％的负载量。按通用的分析方法对多种负载药物进行缓控释效果测定，证明它们表现了很好的缓控释特性：没有突释，可均匀长时间持续释放，药量残存少，载体自身可被降解和吸收，使用安全，可大大减少用药量。
中国药典2005版二部的中介绍了，布洛芬的半衰期为1.8～2h，每天需给药3～4次，且存在生物利用度低，服用剂量大等缺点。目前常见的制剂和规格有：(1)布洛芬片：100mg；200mg；400mg(2)布洛芬缓释胶囊：300mg(3)布洛芬缓释片：200mg(4)布洛芬泡腾片：100mg(5)布洛芬搽剂：5mL 250mg。本发明制备的缓控释产品在1小时、2小时、4小时与7小时的释放量与药典标示量的10％～35％、25％～55％、50％～80％和75％以上的指标相符。
布洛芬钠/多孔碳酸钙(IBU-Na/CaCO 3)复合物及布洛芬/壳聚糖-碳酸钙复合物(IBU/CS-CaCO 3)均对布洛芬的缓控释药物都均可控制7小时左右释放70％药物，后者缓控释效果更好。氯化钾/甲壳素-蛋白质-包膜复合物(KCl/Ct-Pro)对氯化钾可控制在10小时内只释放85％。药物片粒及胶囊的单片或单粒质量通常为100～200mg，高血压等药物的单片药物 量一般在5mg左右，即5％左右的负载量已经可以满足要求。因此，各种载体都具有开发潜力。
孙长娇等在《农药学学报》2012年第12期的“介孔活性炭阿维菌素载药系统的性能研究”中一文中描述了：平均粒径为814nm的介孔活性炭阿维菌素载药活性炭载体对阿维菌素的载药量为18.07％，释药时间长达672h以上，表现出了良好的缓释效果。李珠柱等在《农药学学报》2005年第7期“新型阿维菌素纳米控释剂的制备及性能研究”一文中描述了：空心多孔SiO 2纳米颗粒对阿维菌素的载药量可达到62.5％，阿维菌素纳米控释剂(Av-PHSN)在连续不断搅拌的溶出介质中的控制释放时间可长达33h。刘琪等在《生态环境学报》2009年第18卷“纳米二氧化硅表面改性及其对阿维菌素吸附和及缓释性能”中表明：改性的SiO 2对阿维菌素载药量在7.02％-35.96％。阿维菌素-二氧化硅纳米粒释药速度随时间的延长增加缓慢，到14h左右，溶出基本达到平衡。但仅有约50％左右的阿维菌素溶出，阿维菌素-二氧化硅纳米粒释药速度基本保持不变，可以持续80h左右。李嘉诚等在《海南大学学报自然科学版》的第24卷第4期的“以聚合物/硅藻土为缓控释材料的阿维菌素颗粒剂的制备及性能研究”中表明：以聚合物/硅藻土为控释材料的阿维菌素颗粒剂在60h时，累积释放了50％的阿维菌素，100h时为80％，150h时才基本达到平衡，表现出良好的缓释效果。可以看出，无机多孔材料活性炭、SiO 2、聚合物/硅藻土作为药物载体具有较好的缓控释效果，但存在的残药量过多(残药量接近二分之一～三分之一)，不易降解等存在严重的环境安全隐患问题，需慎重使用。
研究发现，虾蟹壳粉及加工得到的各种载体吸附法得到的阿维菌素缓控释体系，阿维菌素/壳聚糖-碳酸钙复合物(AVM/CS-CaCO 3)在200h时，累积释放了50％左右的阿维菌素，260h为80％左右，之后基本达到平衡，表现出更好的缓释效果；阿维菌素/多孔碳酸钙复合物(AVM/CaCO 3)在150h时，累积释放了50％的阿维菌素，300h为80％，表现出了卓越的缓释效果；阿维菌素/甲壳素-蛋白质复合物(AVM/Ct-Pro)在150h，累积释放了50％的阿维菌素，需要240h即长达10天以上的时间才基本释放完全。
草甘膦异丙胺盐/虾壳粉(NPPMG/SSP)在连续不断搅拌的溶出介质中的控剂释放时间长达100h，120h时基本达到平衡；草甘膦异丙胺盐/壳聚糖-碳酸钙复合物(NPPMG/CS-CaCO 3)96h时累计释放了50％的草甘膦异丙盐，300h时累计释放了88％的草甘膦异丙胺盐，基本达到平衡，达到了农药理想的缓控释要求；草甘膦异丙胺盐/甲壳素-蛋白质复合物(NPPMG/Ct-Pro)对草甘膦异丙胺盐的释放在72h左右时基本达到平衡状态，也有一定的缓释效果；草甘膦异丙胺盐/多孔碳酸钙复合物(NPPMG/CaCO 3)在长达300小时内释放出90％草甘膦异丙胺盐，达到了理想的缓控释农药的要求。草甘膦/壳聚糖-碳酸钙复合物 (PMG/CS-CaCO 3)在长达370h内释放了90％的草甘膦异丙胺盐，也达到了理想的缓控释农药的要求。同样，吡虫啉/甲壳素-蛋白质复合物(Imidacloprid/Ct-Pro)对吡虫啉在长达400h内仅释放出75％吡虫啉，缓控释效果更显著。缓控释农药要求高效农药的每亩用量大多在50g以下，缓控释负载型农药可以大大节省原药用量，减少或缓解污染，延长药效，因此实际用量不会有太大的增加。
作为缓控释肥料载体同样可以生产出成本和用量增加不大的高效和长效肥料。因此，这一以虾蟹壳废弃物粉体为原料，利用其天然纳米孔道作为功能性化学物质缓控释载体，可以很好满足简单高效，绿色安全的性价比要求。实验结果表明，桔杆粉并不具缓控释效果，竹纤维缓控释效果较差。
综上所述，本发明成果将会推动医药、农药、植物生长调节剂缓释、各种药物控制释放及高效肥料的应用，有了微生物无法进入的纳米孔道的保护，可以更好避免药物被酶或微生物分解或流失，保证药物的长效性，载体的天然可降解特性，可保证用药安全。因此，本发明将推动长效安全、价格低廉的动植物药肥及其它功能性缓控释新体系的开发和建立。
具体的，本发明提供给了一种以虾蟹壳为原料借助或构筑纳米孔道开发天然药物载体的方法，根据不同的体系和具体要求选用以下(1)～(4)步骤中的任何一个步骤的固体产品或其混合物作为药物载体，通过溶液吸附负载法生产能够满足生物调控需要具有缓控释功能的药物、肥料或植物生长促进剂系列产品，载体的具体获得方法如下：
(1)将虾蟹壳原料洗净，煮沸去除可溶物，烘干，粉碎成200目以上的虾蟹壳粉末原料，过筛，备用，可直接作为缓控释载体材料之一；
(2)将步骤(1)制得的产品作为虾蟹壳粉末原料加到异丙醇～氢氧化钾～水体系中，在沸腾温度下加热碱解3小时左右，优选2-4小时，使甲壳素脱除乙酰基成为壳聚糖，蛋白质降解为氨基酸和小肽溶于混合溶剂中得到反应混合物，从反应混合物中过滤出固体粉末，固体粉末洗涤至中性，烘干，得到壳聚糖-碳酸钙复合生物基材料，作为缓控释载体材料之一，滤液作为氨基酸及钾肥原料；
(3)将步骤(2)获得的反应混合物不经分离直接加入氯乙酸，然后加热进行壳聚糖的羧甲基化反应，反应混合物过滤，得到的滤液可作为氨基酸及钾肥原料，得到的固体混合物经过异丙醇洗涤过滤，加水溶解羧甲基壳聚糖、过滤出的副产品碳酸钙固体水洗至中性，可得到具有纳米孔道结构的多孔碳酸钙，过滤烘干，作为纳米缓控释载体材料之一，水溶液加醇可沉淀出羧甲基壳聚糖固体产品；
(4)直接将虾蟹壳原料或步骤(1)的虾蟹壳粉末原料用酸溶液处理溶解除碳酸钙，过滤，洗涤至中性，烘干后用粉碎机磨碎过筛，得到甲壳素-蛋白质复合生物基材料，作为生物基缓 控释载体材料之一。
优选的，上述方法中，其特征在于所述虾蟹壳原料粉在异丙醇～氢氧化钾～水体系中的搅拌反应温度为50～90℃，反应时间1～20小时，或以沸腾温度搅拌3小时左右，优选2.5-3.5小时；步骤(3)中，羧甲基化反应温度为50～70℃，反应时间0.5～10小时。
本发明的上下文中，所述3小时左右是指时间上下浮动1小时或0.5小时，也就是3±1或3±0.5小时，同样，3小时左右也可以理解为3±1小时，优选3±0.5小时，也可以是指2小时到4小时，优选2.5到3.5小时之间。
优选的，上述方法中，其特征在于所述异丙醇与原料的质量比为1～5∶1，水与原料的质量比为0.1～0.5∶1，氢氧化钾与原料的质量比为7～8∶15，步骤(3)中，氯乙酸与壳聚糖-碳酸钙复合生物基材料的质量比1∶5～7，氯乙酸可连续或分多次加入，优选分3-7次加入。
优选的，上述方法中，其特征在于所述过滤分离得到的蛋白质水解液回收的异丙醇溶剂循环使用，浓缩得到的蛋白质水解液作为液体钾肥原料。
优选的，上述方法中，其特征在于所述步骤(4)中的酸溶液为盐酸、柠檬酸或谷氨酸，反应温度为30～60℃，反应时间为1～10小时，反应以pH不变化且小于4为终点。
优选的，上述方法中，其特征在于所述骤(1)至步骤(4)得到的各种载体材料具有纳米孔道结构，比表面积为2～100m 2·g -1，优选的，步骤(2)、(3)和(4)得到的载体比表面积为40～50m 2·g -1，用常规吸附法吸附后测定载体具有10％～50％的负载量。
优选的，上述方法中，其特征在于溶液吸附负载法的步骤为：按步骤(1)～(4)分别得到粉末样品载体材料，然后烘干除去水分，趁热迅速投入药液，也可通过减压吸附等措施都提高载药量减少孔道中空气和水分残留，浸没在过量饱和或过饱和的待吸附物质的水溶液或有机溶液或混合溶液进行充分吸附，必要时可升温至微沸状态，室温或回流状态下搅拌0.5～24小时，尽可能排除纳米孔道中的空气和溶剂，过滤和用去离子水或相应溶剂冲洗，减压干燥至恒重，可得到缓控释产品颗粒，具体条件可以根据药物特性，进行加热或减压吸附或选择合适溶剂优化确定。
优选地，上述方法中，所述方法还包括将步骤(1)至步骤(4)所得到的载体材料在160℃下烘干3±0.5小时。
本发明还提供了上述方法制备的载体材料吸附医药、农药、肥料、消毒剂、保鲜剂、香精香料、饲料及食品添加剂中一种或多种成分后作为产品的用途，其特征在于将上述步骤(1)至步骤(4)所得到的缓控释载体材料吸附所述一种或多种成分。
优选的，上述用途中，其特征在于所述成分选自药物，保健品、营养成分，优选的，所述成分选自中西药、营养成分、维生素、农药、、消毒剂、保鲜剂、香精香料中的一种或多 种，优选的，成分为草甘膦异丙胺盐、布洛芬钠、吡虫啉、阿维菌素、氯化钾、氨基酸、植物树脂促进剂。
本发明还提供了一种以虾蟹壳为原料借助或构筑纳米孔道开发天然药物载体的方法所制备得到的载体材料，所述载体材料为通过上述方法中的步骤(1)至步骤(4)所制备得到的载体材料，所述载体材料的比表面积为2～100m 2·g -1，优选的，步骤(2)、(3)和(4)得到的载体比表面积为40～50m 2·g -1。
本发明还提供了一种通过上述载体材料制备得到的各种功能性产品。优选的，上述方法中，所述载体也可以是具有纳米孔道的竹纤维等其它具有纳米孔道的生物质材料。
为解决上述技术问题，本发明还提供了一种以虾蟹壳为原料制备药物载体的方法，所述方法采用下列步骤(1)-(4)之一：
(1)将虾蟹壳原料于水中煮沸，去除可溶物，获取固体物并烘干，粉碎成200目以上的虾蟹壳粉末原料，直接作为药物载体，特别是药物缓控释载体材料；
(2)将步骤(1)制得的虾蟹壳粉末原料产品于异丙醇～氢氧化钾～水体系中加热回流沸腾温度，从反应混合物中过滤出固体粉末，固体粉末洗涤至洗涤液为中性，烘干，得到药物载体材料，特别是药物缓控释载体材料；
(3)将步骤(2)获得的反应混合物与氯乙酸混合，然后加热反应，过滤混合物，得到的固体混合物用异丙醇洗涤，随后加水混合，过滤出碳酸钙固体，用水洗涤至洗涤液呈中性，得到具有纳米孔道结构的多孔碳酸钙，过滤烘干，作为药物载体材料，特别是纳米缓控释载体材料；
(4)将虾蟹壳原料或步骤(1)的虾蟹壳粉末粉体原料用酸溶液处理，溶解除去碳酸钙，过滤，洗涤至洗涤液呈中性，烘干后用粉碎机磨碎过筛，得到甲壳素-蛋白质复合生物基材料，作为生物基药物载体材料，特别是生物基缓控释载体材料。
本发明还提供了一种药物载体，所述药物载体通过上述方法中的步骤(1)、步骤(2)、步骤(3)和/或步骤(4)制备而得。
具体地，以虾蟹壳为原料获得天然多孔载体甲壳素-蛋白质复合生物基材料、壳聚糖-碳酸钙复合生物基材料、多孔碳酸钙可采取以下通用方法：
通法一 甲壳素-蛋白质复合生物基材料的制备
虾蟹壳经水洗干燥后，置于5～12％柠檬酸溶液中，30～80℃下，保持pH在4以下条件下，电动搅拌1～10小时，过滤，洗涤至中性，干燥处理后用粉碎机磨碎过200目筛，得到除碳酸钙后的甲壳素-蛋白质复合生物基材料，再经干燥备用。
通法二 壳聚糖-碳酸钙复合生物基材料的制备
虾蟹壳经水洗干燥后，在粉碎机中磨碎过200目筛后干燥备用。将烘干的虾蟹粉、固体KOH、异丙醇、水四种物质按质量比3∶1.4∶6.3∶0.7投入反应器中，常压回流温度(或称作沸腾温度)，例如65℃，或3±0.5小时，也就是3小时左右，冷却、过滤、去离子水洗涤、烘干，最后干燥得到壳聚糖-碳酸钙复合生物基材料。用凯氏定氮法通过消化、蒸馏、吸收、滴定，样品分析情况参见表1～5。
通法三 碳酸钙载体及羧甲基壳聚糖的制备
按通法二反应完成后的混合物中，加入氯乙酸进一步进行羧甲基化，氯乙酸分3～7次加入，羧甲基化反应温度为50～70℃，反应时间0.5～10小时。反应后的固体经异丙醇洗涤至中性，加水溶解，过滤、洗涤、干燥得到多孔碳酸钙，水溶液加醇可沉淀出羧甲基壳聚糖固体产品。
表1 原料及载体中的蛋白质含量分析
Figure PCTCN2019091135-appb-000001
可见，在保留碳酸钙骨架结构的情况下，虾蟹壳中蛋白质的去除率高达95％以上。
表2 原料及载体的元素含量分析
Figure PCTCN2019091135-appb-000002
Figure PCTCN2019091135-appb-000003
虾蟹壳经过碱处理后，元素分析仪分析结果表明C、H、N含量显著下降，证明大部分蛋白质被去除。
表3 原料及载体的吸水量分析
Figure PCTCN2019091135-appb-000004
利用增重法测得去除蛋白质的载体吸水量增加了一倍，证明造孔扩孔作用明显。
表4 红外光谱法测定样品的脱乙酰度情况
Figure PCTCN2019091135-appb-000005
载体中90％以上的甲壳素已经变成了壳聚糖。
表5 虾蟹壳样品的比表面积及孔容和孔径测定
Figure PCTCN2019091135-appb-000006
Figure PCTCN2019091135-appb-000007
结果表明：醇～碱～水工艺获得的样品比表面积增加了20倍左右，具有10纳米左右的平均孔道，孔容增加很多，具备作为药物载体的基本条件。
相反，用酸处理得到的样品无论是比表面积、还是孔容都显著变小了，说明缺乏碳酸钙支撑的蛋白质与甲壳素的复合生物基材料更容易因空间限制消除而缔合。但在水体系中可以恢复多孔结构同样可以作为药物载体。用秸秆粉不能负载药物，但具有纳米孔道的竹纤维可以少量负载药物，证明只有纳米孔道的结构的载体才能负载药物。
附图2中扫描电镜图显示碱处理的载体孔洞明显，酸处理的载体基本没有孔洞。
通法四 溶液吸附法药物负载
按通法1～3得到粉末样品，160℃下烘2小时尽可能除去水分和冷至100℃以下，减少孔道中空气和水分残留的情况下，将其浸没过量饱和或过饱和的待吸附物质的水溶液或有机溶液或混合溶液，然后慢慢升温至微沸状态，回流状态下磁力搅拌1～24小时，过滤，用去离子水或无水乙醇冲洗三次，减压干燥至恒重，分析载药量，备用。
通法五 缓控释性能测定
准确称取制备好的载药粉末于透析袋中，加入2mL水，两端夹紧，置于烧杯中，加入500mL水或PBS溶液或者无水乙醇，在37℃下进行释放，定时取样，进行离心取上层清液，用紫外分光光度计或者高效液相色谱表征。经测试载药量为10～44％，药物的累积释放率在80％，具有一定的载药量，具有良好的缓慢释放效果。
对照实验 称取载药粉末，用不同浓度的乙基纤维素(EC)/羟丙基甲基纤维素(HPMC)对载药粉末进行包衣，配制3％EC的乙酸乙酯液，质量浓度5g/L的HPMC，HPMC为内包衣溶胀层，EC为外层控释包衣材料，通过控制溶胀层和包衣层增重，来控制药物释放度。
进行载药量及缓控释效果的定量评价。
本实施例进行了氯化钾、布洛芬、布洛芬钠等几种代表性药物及阿维菌素、吡虫啉、草甘膦、草甘膦异丙胺盐、氯氰菊酯等几种代表性农药的负载及释放情况评价，证明了载体的负载量可在10％～44％范围具有较好的缓控释效果。
本发明充分显示了以下有益效果：
以丰富价廉安全绿色的虾蟹壳为原料，通过清洁生产工艺可以实现全价及高附加值利用，制备出具有天然纳米孔道、较大比表面积和孔容及较大载药量的壳聚糖-碳酸钙复合生物基材料、多孔碳酸钙、甲壳素-蛋白质复合生物基材料等都是具有巨大潜力的载体材料，为提高各种功能的物质的长效性，减少用量及毒副作用，开发安全、高效的动植物及微生物药肥体系开辟了新途径。
附图说明
图1a：虾壳粉(SSP)、b：甲壳素-蛋白质复合生物基材料(S-Ct/Pro)、c：壳聚糖-碳酸钙复合生物基材料(S-CS/CaCO 3)、d：多孔碳酸钙(S-CaCO 3)的TEM图
图2a：虾壳粉(SSP)、b：甲壳素-蛋白质复合生物基材料(S-Ct/Pro)、c：壳聚糖-碳酸钙复合生物基材料(S-CS/CaCO 3)、d：多孔碳酸钙(S-CaCO 3)的SEM图
图3a：蟹壳粉(CSP)、b：甲壳素-蛋白质复合生物基材料(C-Ct/Pro)、c：壳聚糖-碳酸钙复合材料(C-CS/CaCO 3)、d：多孔碳酸钙(C-CaCO 3)的SEM图
图4虾壳粉的N 2吸附-脱附等温线和对应的孔径分布图
图5甲壳素-蛋白质复合生物基材料的N 2吸附-脱附等温线和对应的孔径分布图
图6壳聚糖-碳酸钙复合生物基材料的N 2吸附-脱附等温线和对应的孔径分布图
图7多孔碳酸钙(S-CaCO 3)的N 2吸附-脱附等温线和对应的孔径分布图
图8a：虾壳粉、b：甲壳素-蛋白质复合生物基材料、c：壳聚糖-碳酸钙复合生物基材料、d：多孔碳酸钙的FT-IR图谱
图9虾壳粉、壳聚糖-碳酸钙复合生物基材料、多孔碳酸钙、甲壳素-蛋白质生物基材料对草甘膦异丙胺盐的累积释放曲线
图10虾壳粉、壳聚糖-碳酸钙复合生物基材料、甲壳素-蛋白质复合生物基材料对氯化钾药物的累积释放曲线
图11甲壳素-蛋白质复合生物基材料对吡虫啉的累积释放曲线
图12壳聚糖-碳酸钙复合生物基材料对布洛芬的累积释放曲线
图13壳聚糖-碳酸钙复合生物基材料对草甘膦的累积释放曲线
图14多孔碳酸钙(S-CaCO 3)对布洛芬钠的累积释放曲线
图15专利CN107536806A中公开的壳聚糖包埋的合成碳酸钙复合甲氨蝶呤的累计释放曲线
图16文献《布洛芬缓释片的制备及体外释放研究》报道的布洛芬缓释片的制备及体外释放曲线
图17文献《纳米二氧化硅表面改性及其对阿维菌素吸附合缓释性能》报道的空心多孔SiO 2纳米颗粒对阿维菌素的释放曲线
图18壳聚糖-碳酸钙复合生物基材料、多孔碳酸钙、甲壳素-蛋白质生物基材料对阿维菌素的累积释放曲线
图19虾蟹壳为原料的几种载体制取流程图
图表中，SSP指虾壳粉(Shrimp Shell Powder)；CSP指蟹壳粉(Crab Shell Powder)；Ct-Pro指甲壳素-蛋白质复合生物基材料；CS-CaCO 3指壳聚糖-碳酸钙复合生物基材料；CaCO 3指多孔碳酸钙，S-指虾壳粉来源的产品，C-指蟹壳粉来源的产品。
具体实施方式
下面结合具体实施例，进一步阐述本发明的技术方案。这些实施例仅用于说明本发明而不用于限制本发明的范围。
在实施例和对比例中所使用的各种材料均是市售可得的，或可通过本领域技术人员已知的方法获得。
实施例1 用虾壳制备甲壳素-蛋白质复合生物基材料
先将虾壳冲洗干净置于160℃下烘干，取出加入安装有电动搅拌器的单口烧瓶中，配制10％浓度的柠檬酸溶液，其中虾壳与柠檬酸溶液的质量比为1∶10，加热至50℃，保温处理4小时进行脱钙，选50℃温水用网筛进行过滤，将滤液中的柠檬酸钙回收，将所得的过滤物按相同的实验条件进行二次脱钙，最后用网筛进行过滤，将过滤物用适量的蒸馏水多次冲洗至中性，烘干后用粉碎机粉碎至200目即为甲壳素-蛋白质复合生物基材料。再次烘干至恒重，待用。参照GB5009.4-2016《食品安全国家标准食品中灰分的测定》中的方法检测灰分为0.26％。
实施例2 用虾壳制备壳聚糖-碳酸钙复合生物基材料
向安装有电动搅拌器的三口烧瓶中加入150.0g虾壳粉，另将80.0g氢氧化钾固体与40.0g水混合溶解后加入400mL异丙醇，搅拌均匀后倒入三口烧瓶，在回流温度条件下反应3.0h，充分水解蛋白和脱除乙酰基，过滤，将得到的固体用200mL异丙醇在常温下搅拌0.5h，过滤、再用清水洗涤三次、烘干至恒重，得到壳聚糖-碳酸钙复合生物基材料。过滤得到的蛋白质水解液，含有氨基酸、小肽和氢氧化钾，回收异丙醇溶剂循环使用后，可作为液体氨基酸及钾肥原料。通过酸碱滴定法或红外光谱法测定脱乙酰度，稀盐酸溶解壳聚糖和碳酸钙，乙醇反沉淀出壳聚糖，用70％乙醇水溶液反复洗涤除去氯化钙得纯品壳聚糖，脱乙酰度88％。
实施例3 用虾壳制备碳酸钙粗品
向安装有电动搅拌器的三口烧瓶中加入150.0g虾壳粉，另将80.0g氢氧化钾固体与40.0g水混合溶解后加入400mL异丙醇，搅拌均匀后倒入三口烧瓶，回流温度条件下反应3.0h，充分水解蛋白和脱除乙酰基，再加入25.0g氯乙酸，分5次加入，60℃保温条件下反应3.0h，对壳聚糖进行羧甲基化，过滤分离得到羧甲基壳聚糖、碳酸钙混合物，混合物加水溶解，过滤得到副产多孔碳酸钙。滤液可加入80％乙醇反沉淀出羧甲基壳聚糖产品。
实施例4 载体在水中的可溶物溶出情况
准确称取1.0g左右的载体(虾壳粉SSP、壳聚糖-碳酸钙复合生物基材料CS-CaCO 3、多孔碳酸钙CaCO 3、甲壳素-蛋白质复合生物基材料Ct-Pro)倒入50mL的圆底烧瓶中，在圆底烧瓶中加入10g的水，升温至微沸，保持此温度2h，过滤，烘干。SSP失重2.91％，CS-CaCO 3失重4.89％，CaCO 32.77％，Ct-Pro失重6.88％。各载体中的极性大的物质会在此条件下溶解于水中。
实施例5 草甘膦异丙胺盐/虾壳粉(NPPMG/SSP)复合物的制备及释放曲线测定
1.草甘膦异丙胺盐负载实验
准确称取1.0g虾壳粉样品SSP(以下实施例中所用的载体用品均为上述表1至表5中所述性能的样品)，160℃下烘干至恒重，冷至100℃以下迅速倒入单口烧瓶中，加入10.0g 41％的草甘膦异丙胺盐溶液(边加NPPMG溶液边摇动反应瓶)，补加5.0g去离子水使反应体系有流动性，室温、搅拌0.5小时，过滤，洗涤三次，干燥至恒重。测得载药量(即草甘膦异丙胺盐百分含量)为35.0％。
2.草甘膦异丙胺盐释放测试
准确称取1.0g载药粉末(载药量35.0％)于透析袋中，两端夹紧，置于烧杯中，分别加入500mL水，在30℃下进行释放，定时取样，进行离心取上层清液，过0.45μm的滤膜，稀释、超声20min，用高效液相色谱表征，测定缓控释曲线，见图9中NPPMG/SSP。
实施例6 草甘膦异丙胺盐/多孔碳酸钙(NPPMG/CaCO 3)复合物的制备及释放曲线测定
1.草甘膦异丙胺盐负载实验
准确称取3.0g多孔碳酸钙，160℃下烘干至恒重，冷至100℃以下迅速倒入单口烧瓶中，加入30g 41％的草甘膦异丙胺盐溶液(边加NPPMG溶液边摇动反应瓶)，补加5.0g去离子水使反应体系有流动性，室温、搅拌0.5小时，过滤，洗涤，干燥至恒重。测得载药量为43.0％。
2.草甘膦异丙胺盐释放测试
准确称取1.0g载药粉末(载药量43.0％)于透析袋中，两端夹紧，置于烧杯中，分别加入500mL水，在30℃下进行释放，定时取样，进行离心取上层清液，过0.45μm的滤膜， 稀释、超声20min，用高效液相色谱表征。测定缓控释曲线，见图9中的NPPMG/CaCO 3。
实施例7 草甘膦异丙胺盐/壳聚糖-碳酸钙(NPPMG/CS-CaCO 3)复合物的制备及释放曲线测定
准确称取1.0g的壳聚糖-碳酸钙复合生物基材料在160℃活化2h，冷至100℃以下迅速加入到100mL的圆底烧瓶中，室温、搅拌状态下，分批加入10.0g 41％的草甘膦异丙胺盐溶液，加毕后补加5.0g的水，室温搅拌0.5h，过滤，洗涤，120℃烘干，测得载药量为40.90％。
准确称取1.0g载药粉末(载药量40.90％)于透析袋中，两端夹紧，置于烧杯中，分别加入500mL水，在30℃下进行释放，定时取样，进行离心取上层清液，过0.45μm的滤膜，稀释、超声20min，用高效液相色谱表征。测定缓控释曲线，见图9中的NPPMG/CS-CaCO 3。
实施例8 草甘膦异丙胺盐/甲壳素-蛋白质(NPPMG/Ct-Pro)复合物的制备及释放曲线测定
准确称取1.0g的甲壳素-蛋白质复合生物基材料在160℃活化2h，冷至100℃以下迅速加入到100mL的圆底烧瓶中，室温、搅拌状态下，分批加入10.0g 41％的草甘膦异丙胺盐溶液，加毕后补加5.0g的水，室温搅拌0.5h，过滤、洗涤，120℃烘干，测得载药量为41.99％。
准确称取1.0g载药粉末(载药量41.99％)于透析袋中，两端夹紧，置于烧杯中，分别加入500mL水，在30℃下进行释放，定时取样，进行离心取上层清液，过0.45μm的滤膜，稀释、超声20min，用高效液相色谱表征。测定缓控释曲线，见图9中的NPPMG/Ct-Pro。
实施例9 氯化钾/甲壳素-蛋白质(KCl/Ct-Pro)复合物的制备及释放曲线测定
1.氯化钾负载实验
室温下配制饱和氯化钾溶液于单口烧瓶中，准确称取5g甲壳素-蛋白质复合生物基材料，160℃下烘2小时，冷至100℃以下迅速倒入，慢慢升温至微沸状态，搅拌一小时，冷却至室温，过滤，用一定质量水冲洗三次，干燥至恒重。测得载药量为17.3％。
2.载药粉末包膜处理
称取2g载药粉末喷涂适量乙基纤维素溶液和羟丙基甲基纤维素溶液，烘干，称重。
称取载药粉末，用不同浓度的乙基纤维素(EC)/羟丙基甲基纤维素(HPMC)对载药粉末进行包衣，配制3％EC的乙酸乙酯液，质量浓度5g/L的HPMC，HPMC为内包衣溶胀层，EC为外层控释包衣材料，通过控制溶胀层和包衣层控制药物释放度。
3.氯化钾释放测试
准确称取2.0g载药粉末，进行包膜处理后，置于烧杯中，加入500mL水，在37℃下进行释放，定时取样，用电导率测定。测定缓控释释放曲线，见图10中的KCl/Ct-Pro-Coating。
实施例10 氯化钾/虾壳粉(KCl/SSP)复合物的制备及释放曲线测定
1.氯化钾负载实验
室温下配制饱和氯化钾溶液于单口烧瓶中，准确称取5.0g虾壳粉，160℃下烘2h，冷至100℃以下迅速倒入，慢慢升温至微沸状态，搅拌回流2h，冷却至室温，过滤，用一定质量水冲洗三次，干燥至恒重。测得载药量为3.9％。
2.载药粉末包膜处理
称取2g载药粉末喷涂适量乙基纤维素溶液和羟丙基甲基纤维素溶液，烘干，称重。
具体实验步骤：称取载药粉末，用不同浓度的乙基纤维素(EC)/羟丙基甲基纤维素(HPMC)对载药粉末进行包衣，配制3％EC的乙酸乙酯液，质量浓度5g/L的HPMC，HPMC为内包衣溶胀层，EC为外层控释包衣材料，通过控制溶胀层和包衣层控制药物释放度。
3.氯化钾释放测试1
准确称取2.0g载药粉末，进行包膜处理后，装载入透析袋中，加入2mL水，两端夹紧，置于烧杯中，加入500mL水，在37℃下进行释放，定时取样，用电导率测定。测定缓控释释放曲线，见图10中的KCl/SSP-Coating。
4.氯化钾释放测试2
准确称取2.0g载药粉末于透析袋中，加入2mL水，两端夹紧，置于烧杯中，加入500mL水，在37℃下进行释放，定时取样，用电导率测定。测定缓控释释放曲线，见图10中的KCl/SSP。
实施例11 氯化钾/壳聚糖-碳酸钙(KCl/CS-CaCO 3)复合物的制备及释放曲线测定
1.氯化钾负载实验
室温下配制饱和氯化钾溶液于单口烧瓶中，准确称取5g壳聚糖-碳酸钙复合生物基材料，160℃下烘2h，冷至100℃以下迅速倒入，慢慢升温至微沸状态，搅拌回流2h，冷却至室温，过滤，用一定质量水冲洗三次，干燥至恒重。测得载药量为9.4％。
2.载药粉末包膜处理
称取2g载药粉末喷涂适量乙基纤维素溶液和羟丙基甲基纤维素溶液，烘干，称重。
称取载药粉末，用不同浓度的乙基纤维素(EC)/羟丙基甲基纤维素(HPMC)对载药粉末进行包衣，配制3％EC的乙酸乙酯液，质量浓度5g/L的HPMC，HPMC为内包衣溶胀层，EC为外层控释包衣材料，通过控制溶胀层和包衣层控制药物释放度。
3.氯化钾释放测试1
准确称取2.0g载药粉末，进行包膜处理后，装载入透析袋中，加入2mL水，两端夹紧，置于烧杯中，加入500mL水，在37℃下进行释放，定时取样，用电导率测定。测定缓控释释放曲线，见图10中的KCl/CS-CaCO 3-Coating。
4.氯化钾释放测试2
准确称取2.0g载药粉末于透析袋中，加入2mL水，两端夹紧，置于烧杯中，加入500mL水，在37℃下进行释放，定时取样，用电导率测定。测定缓控释释放曲线，见图10中的KCl/CS-CaCO 3。
实施例12 吡虫啉/甲壳素-蛋白质(Imidacloprid/Ct-Pro)复合物的制备及释放曲线测定
1.吡虫啉负载实验
准确称取3.0g吡虫啉杀虫剂质量分数10％，用二氯甲烷溶解后倒入单口烧瓶中，再准确称取5.0g甲壳素-蛋白质复合物，160℃下烘2小时，冷至100℃以下迅速倒入，然后慢慢升温至微沸状态，搅拌1小时，过滤，用大量水冲洗三次，干燥至恒重。测得载药量为16.8％。
2.吡虫啉释放测试
准确称取1.5g载药粉末，进行包膜处理后，置于烧杯中，加入500mL水，在30℃下进行释放，定时取样，进行离心取上层清液，过0.45μm的滤膜，稀释、超声20min，用高效液相色谱表征。测定缓控释释放曲线，见图11。
实施例13 布洛芬/壳聚糖-碳酸钙(IBU/CS-CaCO 3)复合物的制备及释放曲线测定
1.布洛芬负载实验
准确称取1.0g IBU溶于20mL50℃去离子水中，强烈搅拌下，缓慢加1mol/LNaOH溶液直到IBU完全溶解。取壳聚糖-碳酸钙复合生物基材料4.0g加入，70℃加热搅拌，用10％盐酸溶液调pH值至中性，搅拌1h，50℃烘干。测得载药量为10.8％。
2.布洛芬释放测试
准确称取1.0g载药粉末于透析袋中，加入2mL水，两端夹紧，置于烧杯中，加入500mL水，在37℃下进行释放，定时取样，进行离心取上层清液，过0.45μm的滤膜，稀释、超声20min，用高效液相色谱表征。测定缓控释释放曲线，见图12。
实施例14 草甘膦/壳聚糖-碳酸钙(PMG/CS-CaCO 3)复合物的制备及释放曲线测定
1.草甘膦负载实验
准确称取95％草甘膦结晶粉末3.0g置于单口烧瓶中，加入20mL去离子水溶解，再称取5.0g壳聚糖-碳酸钙复合生物基材料，160℃下烘2小时，冷至100℃以下迅速倒入草甘膦溶液中，慢慢升温至微沸状态，搅拌一小时，冷却至室温，对草甘膦制剂先减压尽量蒸出水至有晶体析出为止，过滤，用一定质量水浸洗三次，烘干。测得载药量为31.1％。
2.草甘膦释放测试
准确称取2.0g载药粉末于透析袋中，加入2mL水，两端夹紧，置于烧杯中，加入500mL 水，在30℃下进行释放，定时取样，进行离心取上层清液，过0.45μm的滤膜，稀释、超声20min，再过0.45μm的滤膜，用高效液相色谱表征。测定缓控释曲线，见图13。
实施例15 布洛芬钠/多孔碳酸钙(IBU-Na/CaCO 3)复合物的制备及释放曲线测定
1.布洛芬钠负载实验
准确称取0.2g氢氧化钠固体(40.0，1eq)，加入25mL水，配成氢氧化钠溶液；再称取1g布洛芬(IBU)(206.2，1eq)，倒入配好的氢氧化钠溶液，搅拌、溶解布洛芬(中和反应)，再加入4.0g多孔碳酸钙，慢慢升温至微沸状态，搅拌一小时，冷却至室温，用一定质量水浸洗三次，60℃烘干，测得载药量为16.6％。
2.布洛芬钠释放测试
准确称取1.0g载药粉末于透析袋中，加入2mL水，两端夹紧，置于烧杯中，加入500mL水，在37℃下进行释放，定时取样，进行离心取上层清液，过0.45μm的滤膜，稀释、超声20min，用高效液相色谱表征。测定缓控释释放曲线，见图14。测定结果证明布洛芬钠/多孔碳酸钙(IBU-Na/CaCO 3)复合物完全满足药典的缓控释要求。
实施例16 阿维菌素/虾壳粉(AVM/SSP)的制备
准确称取1.0g的虾壳粉在160℃下活化2h，冷至100℃以下迅速加入到50mL的圆底烧瓶中，在圆底烧瓶中分别加入10.0g 10％的阿维菌素的丙酮、氯仿、乙醇溶液，水浴锅中回流24h，冷却后过滤，丙酮洗涤，烘干，测得载药量为26.87％、2.87％、2.24％。
实施例17 阿维菌素/壳聚糖-碳酸钙(AVM/CS-CaCO 3)复合物的制备
准确称取1.0g的壳聚糖-碳酸钙复合生物基材料在160℃下活化2h，冷至100℃以下迅速加入到50mL的圆底烧瓶中，在圆底烧瓶中分别加入10.0g 10％的阿维菌素的丙酮、氯仿、乙醇溶液，水浴锅中回流24h，冷却后过滤，丙酮洗涤，烘干后即得到载药量为36.54％、3.58％、0.96％。
称取1.0g的阿维菌素/虾壳粉(AVM/CS-CaCO 3，载药量为36.54％)于透析袋中，两边加紧，置于磨口的广口瓶中，加入100mL的无水乙醇，在室温下进行释放，定时取样，进行离心，过0.45μm的滤膜，用高效液相色谱表征，测定缓控释曲线，见图18中的AVM/CS-CaCO 3。
实施例18 阿维菌素/多孔碳酸钙(AVM/CaCO 3)制备
准确称取1.0g的多孔碳酸钙在160℃下活化2h，冷至100℃以下迅速加入到50mL的圆底烧瓶中，在圆底烧瓶中分别加入10.0g 10％的阿维菌素的丙酮、氯仿、乙醇溶液，水浴锅中回流24h，冷却后过滤，丙酮洗涤，烘干，测得载药量为44.68％、6.19％、0。
称取1.0g的阿维菌素/虾壳粉(AVM/CaCO 3，载药量为44.68％)于透析袋中，两边加紧，置于磨口的广口瓶中，加入100mL的无水乙醇，在室温下进行释放，定时取样，进行离心，过0.45μm的滤膜，用高效液相色谱表征，测定缓控释曲线，见图18中的AVM/CaCO 3。
实施例19 阿维菌素/甲壳素-蛋白质(AVM/Ct-Pro)复合物的制备
准确称取1.0g的甲壳素-蛋白质复合生物基材料在160℃下活化2h，冷至100℃以下迅速加入到50mL的圆底烧瓶中，在圆底烧瓶分别中加入10.0g 10％的阿维菌素的丙酮、氯仿、乙醇溶液，水浴锅中回流24h，冷却后过滤，氯仿洗涤，烘干，测得载药量为0、25.89％、0。
称取1.0g的阿维菌素/虾壳粉(AVM /Ct-Pro，载药量为25.9％)于透析袋中，两边加紧，置于磨口的广口瓶中，加入100mL的无水乙醇，在室温下进行释放，定时取样，进行离心，过0.45μm的滤膜，用高效液相色谱表征，测定缓控释曲线，见图18中的AVM/Ct-Pro。
实施例20 不同载体、不同pH对KCl的填埋情况
准确称取1.0g左右的载体(虾壳粉SSP、壳聚糖-碳酸钙复合生物基材料CS-CaCO 3、多孔碳酸钙CaCO 3、甲壳素-蛋白质复合生物基材料Ct-Pro)加到不同pH下的饱和氯化钾溶液中，升温至微沸，保持微沸4h，过滤，烘干。从下表的填埋率可知随着pH的变化，各种载体的失重也会随着波动，在pH 12、13时CS-CaCO 3、CaCO 3有一定的填埋率。
表6 不同载体、不同pH条件下对载体填埋率的影响
Figure PCTCN2019091135-appb-000008
实施例21 NPPMG(草甘膦异丙胺盐)配比对填埋率的影响
1.0g活化后的载体中加入一定质量的NPPMG(具体见下表)，升温回流2h，过滤，洗涤烘干。适当增加NPPMG的用量有利于提高填埋率。
表7 草甘膦异丙胺盐的质量对载体填埋率的影响
Figure PCTCN2019091135-appb-000009
Figure PCTCN2019091135-appb-000010
实施例22 温度、溶剂对阿维菌素的填埋率影响
10％的阿维菌素氯仿溶液、乙醇溶液、丙酮溶液中分别加入1.0g活化后的载体，室温或者回流24h，过滤，洗涤，烘干。SSP、CS-CaCO 3、CaCO 3三种载体对阿维菌素丙酮溶液中可获得较高填埋率，而氯仿和乙醇溶液中填埋率较低，但Ct-Pro载体在氯仿回流中能获得较高的填埋率，而其他溶剂中基本不负载。可见，载体、溶剂和温度条件都会显著影响填埋效果。
表8 温度、溶剂对阿维菌素的填埋率影响
Figure PCTCN2019091135-appb-000011
实施例23 不同载体、不同溶剂对布洛芬钠的填埋情况
10g10％的布洛芬丙酮溶液、乙醇溶液中分别加入0.68g 30％氢氧化钠(折百氢氧化钠0.2g)溶液，使布洛芬变成布洛芬钠溶液，加入1.0g活化后的载体，升温，回流24h，过滤洗涤。CS-CaCO 3和CaCO 3在丙酮溶液中可以达到一定的载体量，在乙醇溶液中效果比较差。但乙醇溶液可以使Ct-Pro较好负载。
表9 不同载体、不同溶剂对布洛芬钠填埋率的影响
Figure PCTCN2019091135-appb-000012
Figure PCTCN2019091135-appb-000013
实施例24 各种载体对大豆油的填充效果
1.0g活化后的载体中加入10g的豆油，在不同的压力下加料，不同的压力下搅拌2h，过滤、乙醇洗涤，烘干。多个载体都显示了很好的负载潜力，减压可以显著提高其负载量。
表10 压力对载体填埋率的影响
Figure PCTCN2019091135-appb-000014
对照例 天然植物原料竹粉、葵花杆粉作为载体负载效果不理想
1g活化后的载体中分别加入10g41％的草甘膦异丙胺盐、10g30％的KCl溶液、10g 30％的尿素溶液、6g75％的草甘膦铵盐，升温，回流4h，过滤、洗涤、烘干。可见，具有纳米孔道的竹纤维呈现一定的负载能力，而孔道较大的秸秆粉就不具有负载能力。
表11 竹粉和葵花粉对不同样品的填埋率分析
Figure PCTCN2019091135-appb-000015

Claims (13)

  1. 一种以虾蟹壳为原料借助或构筑纳米孔道开发天然药物载体的方法，根据不同的体系和具体要求选用以下(1)-(4)步骤中的任何一个步骤的固体产品或其混合物作为药物载体，通过溶液吸附负载法生产能够满足生物调控需要具有缓控释功能的药物、肥料或植物生长促进剂系列产品，载体的具体获得方法如下：
    (1)将虾蟹壳原料洗净，煮沸去除可溶物，烘干，粉碎成200目以上的虾蟹壳粉末原料，过筛，备用，可直接作为缓控释载体材料之一；
    (2)将步骤(1)制得的产品作为原料加到异丙醇～氢氧化钾～水体系中，在沸腾温度下加热碱解2-4小时，使甲壳素脱除乙酰基成为壳聚糖，蛋白质降解为氨基酸和小肽溶于混合溶剂中得到反应混合物，从反应混合物中过滤出固体粉末，固体粉末洗涤至中性，烘干，得到壳聚糖-碳酸钙复合生物基材料，作为缓控释载体材料之一，滤液作为氨基酸及钾肥原料；
    (3)将步骤(2)获得的反应混合物不经分离直接加入氯乙酸，然后加热进行壳聚糖的羧甲基化反应，反应混合物过滤，得到的滤液可作为氨基酸及钾肥原料，得到的固体混合物经过异丙醇洗涤过滤，加水溶解羧甲基壳聚糖、过滤出的副产品碳酸钙固体水洗至中性，可得到具有纳米孔道结构的多孔碳酸钙，过滤烘干，作为纳米缓控释载体材料之一，水溶液加醇可沉淀出羧甲基壳聚糖固体产品；
    (4)直接将虾蟹壳原料或步骤(1)的虾蟹壳粉末原料用酸溶液处理，溶解除去碳酸钙，过滤，洗涤至中性，烘干后用粉碎机磨碎过筛，得到甲壳素-蛋白质复合生物基材料，作为生物基缓控释载体材料之一。
  2. 根据权利要求1所述方法，步骤(2)中，虾蟹壳粉末原料在异丙醇～氢氧化钾～水体系中的搅拌反应温度为50～90℃，反应时间1～20小时，或以沸腾温度下搅拌2.5-3.5小时；步骤(3)中，羧甲基化反应温度为50～70℃，反应时间0.5～10小时。
  3. 根据权利要求1所述方法，步骤(2)中，异丙醇与虾蟹壳粉末原料的质量比为1～5∶1，水与虾蟹壳粉末原料的质量比为0.1～0.5∶1，氢氧化钾与虾蟹壳粉末原料的质量比为7～8∶15，步骤(3)中，氯乙酸与壳聚糖-碳酸钙复合生物基材料的质量比1∶5～7，氯乙酸可连续或分多次加入。
  4. 根据权利要求1所述方法，步骤(2)中，将过滤分离得到的蛋白质水解液回收的异丙醇溶剂循环使用，浓缩得到的蛋白质水解液作为液体钾肥原料。
  5. 根据权利要求1所述方法，其特征在于：所述步骤(4)中的酸溶液为盐酸、柠檬酸或谷氨酸，反应温度为30～60℃，反应时间为1～10小时，反应以pH不变化且小于4为终点。
  6. 根据权利要求1所述方法，步骤(1)至步骤(4)得到的各种载体材料具有纳米孔道结构，比表面积为2～100m 2·g -1，优选的，步骤(2)、(3)和(4)得到的载体比表面积为40～50m 2·g -1，用常规吸附法吸附后测得载体具有10重量％～50重量％范围的负载量，基于载体的重量计。
  7. 根据权利要求1所述的方法，其特征在于溶液吸附负载法的步骤为：按步骤(1)～(4)分别得到粉末样品载体材料，然后烘干除去水分，迅速投入药液，减压吸附以提高载药量减少孔道中空气和水分残留，浸没在过量饱和或过饱和的待吸附物质的水溶液或有机溶液或混合溶液进行充分吸附，必要时可升温至微沸状态，室温或回流状态下搅拌0.5～24小时，尽可能排除纳米孔道中的空气和溶剂，过滤和用去离子水或相应溶剂冲洗，减压干燥至恒重，可得到缓控释产品颗粒，具体条件可以根据药物特性，进行加热或减压吸附或选择合适溶剂优化确定。
  8. 根据权利要求1所述的方法，其特征在于还包括将步骤(1)至步骤(4)所得到的载体材料在160℃下烘干3±0.5小时，所述载体材料的比表面积为2～100m 2·g -1，优选的，步骤(2)、(3)和(4)得到的载体比表面积为40～50m 2·g -1。
  9. 根据权利要求1-8任一项所述的方法制备的载体材料用于吸附医药、农药、肥料、消毒剂、保健品、保鲜剂、香精香料、饲料及食品添加剂中的一种或多种成分的用途，其特征在于将权利要求1-8任一项的步骤(1)至步骤(4)所得到的缓控释载体材料吸附所述一种或多种成分。
  10. 根据权利要求9所述的用途，其特征在于所述成分选自药物，保健品、营养成分，优选的，所述成分选自中西药、营养成分、维生素、农药、消毒剂、保鲜剂、香精香料中的一种或多种，优选的，成分为草甘膦异丙胺盐、布洛芬钠、吡虫啉、阿维菌素、氯化钾、氨基酸、植物生长促进剂。
  11. 根据权利要求1所述方法，缓控释载体也可以是具有纳米孔道的竹纤维等其它具有纳米孔道的生物质材料。
  12. 一种以虾蟹壳为原料制备药物载体的方法，所述方法采用下列步骤(1)-(4)之一：
    (1)将虾蟹壳原料于水中煮沸，去除可溶物，获取固体物并烘干，粉碎成200目以上的虾蟹壳粉末原料，直接作为药物载体，特别是药物缓控释载体材料；
    (2)将步骤(1)制得的虾蟹壳粉末原料于异丙醇～氢氧化钾～水体系中加热沸腾温度，从反应混合物中过滤出固体粉末，固体粉末洗涤至洗涤液为中性，烘干，得到药物载体材料，特别是药物缓控释载体材料；
    (3)将步骤(2)获得的反应混合物与氯乙酸混合，然后加热反应，过滤混合物，得到的 固体混合物用异丙醇洗涤，随后加水混合，过滤出碳酸钙固体，用水洗涤至洗涤液呈中性，得到具有纳米孔道结构的多孔碳酸钙，过滤烘干，作为药物载体材料，特别是纳米缓控释载体材料；
    (4)将虾蟹壳原料或步骤(1)的虾蟹壳粉末原料用酸溶液处理，溶解除去碳酸钙，过滤，洗涤至洗涤液呈中性，烘干后用粉碎机磨碎过筛，得到甲壳素-蛋白质复合生物基材料，作为生物基药物载体材料，特别是生物基缓控释载体材料。
  13. 一种药物载体，根据权利要求12的方法中的步骤(1)、步骤(2)、步骤(3)或步骤(4)制备而得。
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