A drug-loaded fluid material prepared based on solubilization technology, a preparation method and applications thereof

Abstract

The application belongs to the technical field of pesticide dosage forms, and provides a drug-loaded fluid material prepared based on a solubilization technology, a preparation method and application. The fluid material is prepared from raw material A, raw material B, a surfactant and an organic solvent; the raw material A is any one of gamma-polyglutamic acid (PGA), corn alcohol-soluble protein and wheat alcohol-soluble protein; the raw material B is at least one kind of monomer containing an isocyanate group with a functionality of greater than or equal to 2. The state of the fluid material is regulated by changing the ratio of the two kinds of raw materials to the organic solvent, and the drug loading rate is significantly improved in the fluid state, especially reaching a maximum value in the viscoelastic fluid state; the fluid material preparation method is simple, the raw materials are widely sourced and low in cost, and has wide application in the field of pesticides.

Description

Technical Field

[0001] This invention belongs to the field of pesticide formulation technology, and relates to a drug-loaded fluid material prepared based on solubilization technology, its preparation method, and its application. Background Technology

[0002] In the field of pesticide formulation, developing precise pesticide delivery technologies using materials science and designing functionalized pesticide carriers are important ways to unleash the application potential of existing pesticide varieties, achieve precise and efficient pesticide delivery, and improve the economic benefits of plant protection. Currently, pesticide carrier material research focuses primarily on functional development, neglecting the environmental safety risks posed by the materials themselves. Therefore, developing green and biodegradable pesticide carrier materials, while ensuring the functionality of the carrier application, aligns with the development requirements of current national pesticide industry policies. Traditional polymeric pesticide carriers are mainly based on polymers such as polyurea, polyurethane, and urea-formaldehyde resin. Although these materials have low raw material costs, mature preparation technologies, and excellent mechanical properties, their complete degradation cycle is long (50-200 years), and their initial degradation products also pose environmental pollution and toxicity risks.

[0003] Chinese invention patent application CN107568218A discloses an avermectin B2 microcapsule suspension and its preparation method. First, urea and formaldehyde are reacted in water to generate a urea-formaldehyde resin prepolymer, which is then mixed with a dispersant to obtain an aqueous phase. This aqueous phase is then emulsified with an oil phase containing avermectin B2, and the urea-formaldehyde resin prepolymer undergoes further polymerization via a polymerization reaction, forming urea-formaldehyde resin on the surface of avermectin B2. This urea-formaldehyde resin then encapsulates the avermectin B2 surface, forming a microcapsule suspension. This avermectin B2 microcapsule suspension is a water-based formulation with good dispersibility, good mobility in soil, good efficacy, and long-lasting effect. However, the polyurea resin in the above technology suffers from a long degradation cycle and environmental impact.

[0004] In comparison, natural polymer materials can further improve degradation resistance, rain erosion resistance, photodegradation resistance, and versatility in pesticide delivery. Among these, proteins such as gliadin and zein are natural proteins isolated from cereal seeds, while polymers like polyglutamic acid are water-soluble polyamino acids produced by microbial fermentation in nature, exhibiting excellent biodegradability, biocompatibility, and ease of availability. Furthermore, these materials have the potential to be used to prepare flexible carriers, which facilitates better integration with leaf microstructures, increasing pesticide adhesion and distribution range.

[0005] Chinese invention patent application CN108849887A discloses a hydrophilic gel-coated pesticide product, its preparation method, and its application. The method uses starch as a base material, partially neutralized acrylate and acrylamide as monomers, and N,N... Methylenebisacrylamide crosslinking agents introduce pesticide active ingredients into a free radical polymerization reaction system via emulsion or aqueous solution. The reaction product, after freeze-drying, yields a hydrophilic gel-coated pesticide product. Combining this with traditional pesticide matrix introduction methods can improve pesticide utilization efficiency while reducing total pesticide residues in soil by 10-10%, and can also control the spread of pesticide non-point source pollution to some extent. These natural polymer materials, such as chitosan, starch, and sodium alginate, possess advantages such as biodegradability, biocompatibility, and renewability, and are widely used in hydrogel-based pesticide delivery systems. The flexibility of the gel system allows for better integration with the microstructure of leaf surfaces, improving pesticide spreading and adhesion. However, the poor compatibility between hydrophilic carriers and hydrophobic pesticides often leads to poor drug loading efficiency and versatility, significantly impacting pesticide stability and utilization.

[0006] Therefore, the market transformation of novel pesticide formulations requires not only meeting the functional requirements of pesticides on the foliar environment, but also selecting environmentally friendly carrier materials and designing simple preparation processes to complete the formulation process. To address these issues, this study utilizes inexpensive and widely available natural polymer materials as carriers, and designs a flexible drug-carrying material based on solubilization technology. This material is simple to prepare, highly efficient in drug loading, has controllable morphology, and strong drug loading versatility, thus developing pesticide formulations that balance control efficacy and safety. Summary of the Invention

[0007] To address the aforementioned problems in existing technologies, this invention provides a drug-loaded fluid material prepared based on solubilization technology, its preparation method, and its application. This fluid material can achieve a viscous fluid state or even a viscoelastic fluid state under specific raw material and solvent ratios. In this state, it ensures better integration with the microstructure of the leaf surface, increases the pesticide's adhesion and distribution range, and improves the pesticide loading rate, thereby significantly enhancing pesticide utilization.

[0008] One of the technical solutions of the present invention is as follows:

[0009] A drug-loaded fluid material prepared based on solubilization technology is provided. The fluid material is prepared from raw material A, raw material B, surfactant and organic solvent. Raw material A is any one of γ-polyglutamic acid PGA, zein and wheat gliadin. Raw material B is at least one monomer containing isocyanate group with a functionality ≥2.

[0010] Further, the monomer containing an isocyanate group with a functionality ≥2 is any one of diphenylmethane diisocyanate MDI, toluene diisocyanate TDI, isophorone diisocyanate IPDI, and dicyclohexylmethane-4-4'-diisocyanate HMDI.

[0011] Furthermore, the organic solvent is at least one selected from toluene, methanol, ethanol, petroleum ether, ethyl acetate, cyclohexanone, tripropylene glycol methyl ether, N'N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and acetonitrile; preferably acetone or tripropylene glycol methyl ether.

[0012] The drug-loaded fluid material described in this invention is a viscoelastic fluid when the organic solvent, raw material A, and raw material B are in a specific ratio. Under viscoelastic fluid ratio conditions, by increasing the amount of organic solvent or decreasing the ratio between raw material A and raw material B, it changes from a viscoelastic fluid to a viscous fluid. Conversely, by decreasing the amount of organic solvent or increasing the ratio between raw material A and raw material B, it changes to an elastic solid. Therefore, by controlling the ratio of organic solvent, raw material A, and raw material B, the state of the fluid material can be effectively regulated.

[0013] Furthermore, when the drug-loaded fluid material is in the state of a viscoelastic fluid, the raw material composition of the drug-loaded fluid material by mass ratio is: organic solvent: γ-polyglutamic acid PGA: raw material B = x: y: z; x = 200, y = 48, z = 41;

[0014] Or organic solvent: zein: raw material B = x:y:z; x = 20, y = 4, z = 1;

[0015] Or organic solvent: gliadin: raw material B = x:y:z; x = 25, y = 5, z = 1.

[0016] Furthermore, when the drug-loaded fluid material is in the state of a viscous fluid, the raw material composition of the drug-loaded fluid material by mass ratio is: organic solvent: γ-polyglutamic acid PGA: raw material B = x: y: z; x = 200, y: z > 48: 41; or z > 200, y: z = 48: 41;

[0017] Or organic solvent: zein: raw material B = x:y:z; x = 20, y:z > 4:1; or x > 20, y:z = 4:1;

[0018] Or organic solvent: gliadin: raw material B = x:y:z; x = 25, y:z > 5:1; or x > 25, y:z = 5:1.

[0019] Furthermore, the γ-polyglutamic acid PGA is an NMP solution of γ-polyglutamic acid PGA; the mass percentage of γ-polyglutamic acid PGA in NMP is 30%.

[0020] The second technical solution of the present invention is as follows:

[0021] A fluid-loaded pesticide formulation is provided, wherein the pesticide formulation is prepared using any of the above-described drug-loaded fluid materials as a carrier.

[0022] The third technical solution of the present invention is as follows:

[0023] A method for preparing the above-mentioned fluid-loaded drug delivery system is provided, comprising the following steps:

[0024] (1) Dissolve the pesticide in an organic solvent, add a surfactant, and stir to obtain mixture 1;

[0025] (2) Add raw material B and raw material A to mixture 1 in sequence, and stir until fully dissolved to obtain mixture 2;

[0026] (3) Add the catalyst, stir until dissolved, and let stand for 2 hours to obtain the product.

[0027] Further, the surfactant is a quaternary ammonium salt cationic surfactant and / or a sulfonate anionic surfactant; the quaternary ammonium salt cationic surfactant includes at least one of: dicedyldimethylammonium chloride, tetradecyldimethylbenzylammonium chloride and gemini quaternary ammonium salt surfactant; the sulfonate anionic surfactant includes any one of: calcium dodecylbenzenesulfonate, α-olefin sulfonate and petroleum sulfonate.

[0028] Furthermore, the mass ratio of raw material A to surfactant is 1:0.25-2.

[0029] Since excessive organic solvents in fluid materials can have a certain impact on the plants to which pesticide formulations act, this invention reduces the amount of organic solvents used. The amount of organic solvents used in raw materials A and B is relatively increased. Introducing surfactants during the preparation process can effectively improve the solubility of raw material A.

[0030] In some embodiments of the present invention, the ratio of γ-polyglutamic acid PGA to surfactant is 1:0.25-0.5; preferably 1:0.25.

[0031] In some embodiments of the present invention, the ratio of zein to surfactant is 1:0.5-2; preferably 1:1.5-2; and more preferably 1:2.

[0032] In some embodiments of the present invention, the ratio of gliadin to surfactant is 1:1.5-2; preferably 1:1.5.

[0033] Furthermore, the pesticide is any one of abamectin, pyraclostrobin, thiamethoxam, or lambda-cyhalothrin.

[0034] Furthermore, the catalyst is dibutyltin dilaurate and / or tin 2-ethylhexanoate.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] (1) Compared with traditional rigid pesticide loading systems, the fluid material of the present invention achieves morphological control by selecting raw material A and controlling the proportion of each component. This system can form a stronger flow and spreading state at the interface and has great potential to improve pesticide utilization.

[0037] (2) This invention solves the problem of dissolving natural polymer materials such as γ-polyglutamic acid PGA, corn lysin, and wheat lysin in conventional solvents based on surfactant solubilization technology;

[0038] (3) The fluid materials prepared in this invention have high pesticide binding efficiency, with a pesticide loading rate of over 97% for viscoelastic fluid carriers and over 89% for viscous fluid carriers.

[0039] (4) The present invention uses natural polymer materials, which are widely available, inexpensive, environmentally compatible, and biodegradable;

[0040] (5) The preparation method provided by the present invention is simple and efficient and can be industrialized. Attached Figure Description

[0041] Figure 1 The image shows the appearance morphology of the fluid-loaded drug preparation according to an embodiment of the present invention.

[0042] Figure 2 This is a morphological image of the fluid-loaded drug preparation prepared in the comparative example of this invention. Detailed Implementation

[0043] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention. Those skilled in the art can make various changes and modifications to the invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention. It is worth noting that the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0044] The following sources of raw materials are provided as examples:

[0045] γ-Polyglutamic acid (PGA) was purchased from Guangzhou Hongyi Food Additives Co., Ltd.; item number: bbbm1243; molecular weight: 500,000.

[0046] The zein was purchased from Bid Pharmaceuticals, product number BD157001;

[0047] The gliadin was purchased from Shanxi Beisheng Biotechnology Co., Ltd., product number BSSW-0630-002;

[0048] Polymer MDI (PM200), purchased from Wanhua Chemical Group Co., Ltd.; Product No.: BS293.

[0049] Examples 1-4

[0050] Prepare fluid-loaded drug delivery agents according to the raw materials and dosages described in Table 1;

[0051] Table 1. Raw material list for fluid-loaded drug delivery systems in Examples 1-4

[0052]

[0053]

[0054] Preparation method (taking Example 1 as an example):

[0055] (1) Add 1.2g PGA to 2.8g NMP solution to prepare 30% PGA (NMP) solution and stir to dissolve. Add 1g D1021, mix well and then add 5g cyclohexanone and stir until the solution is clear to prepare mixture 1.

[0056] (2) Add 1.025g PM200 to mixture 1 and dissolve it completely to make mixture 2. Stir for 1 hour.

[0057] (3) Add 0.22g of abamectin to the mixture 2 and stir for an appropriate time until fully dissolved. Add 0.05g of dilauric acid-dibutyltin and stir until fully reacted. Let stand for 10 minutes until the solution is stable.

[0058] The preparation methods for other embodiments are the same as those for Embodiment 1.

[0059] Examples 5-10

[0060] Prepare fluid-loaded drug delivery agents according to the raw materials and dosages described in Table 1;

[0061] Table 2. Raw material list for fluid-loaded drug delivery systems in Examples 5-8

[0062]

[0063]

[0064] Preparation method (taking Example 5 as an example):

[0065] (1) Add 1g of zein to 5g of cyclohexanone and 2g of 1427, mix well to make mixture 1;

[0066] (2) Add 0.3g PM200 to mixture 1 and dissolve it completely to make mixture 2. Stir for 1 hour.

[0067] (3) Add 1g of abamectin to the mixture 2 and stir for an appropriate time until fully dissolved. Add 0.05g of dilauric acid-dibutyltin and stir until fully reacted. Let stand for 10 minutes until the solution is stable.

[0068] The preparation methods for other embodiments are the same as in Embodiment 5.

[0069] Comparative Examples 1-3

[0070] Prepare fluid-loaded drug delivery agents according to the raw materials and dosages described in Table 3;

[0071] Table 3. Raw material list of fluid-loaded drug agents for comparative examples 1-3

[0072]

[0073] The preparation method of Comparative Example 1 is the same as that of Example 1;

[0074] The preparation methods for Comparative Examples 2-3 are the same as those for Example 5.

[0075] Effect evaluation:

[0076] (1) Morphological characterization of fluid-loaded drug preparations prepared in each comparative example:

[0077] The sample vials containing different pesticide formulations were tilted at a 30° angle to the horizontal plane. The changes in the appearance of the pesticide carriers inside the sample vials were observed and photographed. See the example for the appearance. Figure 1 See the comparison of the appearance. Figure 2 The results are shown in Table 4.

[0078] Table 4. State of drug delivery in different fluids

[0079]

[0080] (2) Viscosity measurement parameters of pesticide formulations prepared in the comparative examples of each embodiment:

[0081] Take an appropriate amount of pesticide formulation and measure it using an SNB-4 digital viscometer at a constant test temperature of 25℃; the results are shown in Table 5.

[0082] Table 5 Viscosity test results of fluid-loaded drugs

[0083]

[0084]

[0085] As shown in Table 5, the pesticide formulations prepared in Examples 1-10 all exhibit a viscosity effect; and the closer the material ratio is to the limit state, the greater the viscosity; while the pesticide formulations prepared in Comparative Examples 1-3 are in crystalline state, and their viscosity cannot be obtained.

[0086] (3) Test of pesticide loading rate of pesticide formulations prepared in each example comparative example:

[0087] The pesticide loading rate (LE, c / c) of the pesticide-loaded material was determined by high performance liquid chromatography (HPLC).

[0088] Chromatographic conditions for avermectin detection: C18 reverse-phase column (250 mm × 4.6 mm id, 5 μm), column temperature 30 ℃, mobile phase acetonitrile:water (80:20, v / v), flow rate 1 mL / min, injection volume 20 μL, UV detection wavelength 244 nm; retention time approximately 17 min.

[0089] Chromatographic conditions for pyraclostrobin detection: C18 reverse-phase column (250 mm × 4.6 mm id, 5 μm), column temperature 30 ℃, mobile phase acetonitrile:water (85 / 15, v / v) mixture, flow rate 1 mL / min, injection volume 20 μL, UV detection wavelength 277 nm; retention time approximately 4.5 min.

[0090] (3-1) Establishing a standard curve: Accurately weigh 10 mg (±0.001 g) of pesticide standard, sonicate it in the corresponding mobile phase at room temperature, transfer it to a 50 mL volumetric flask with a glass rod and accurately dilute it to obtain a mother liquor with a pesticide concentration of 200 mg / L. Then, continue to use the mixed solution to serially dilute the mother liquor to prepare standard solutions with concentrations of 10.0 mg / L, 5.0 mg / L, 2.5 mg / L, 1.0 mg / L and 0.5 mg / L, respectively. Use a 0.22 μm organic filter membrane to filter impurities. Finally, perform high performance liquid chromatography analysis, use Origin 2018 software to linearly fit the peak area of ​​the pesticide and plot the standard curve.

[0091] (3-2) Accurately weigh 0.1g of pesticide formulation and place it in a 50mL centrifuge tube. Add 20mL of cyclohexanone and shake for 30s. After centrifugation, take 0.5mL of supernatant. Dilute the supernatant 50 times with the corresponding mobile phase. Filter the impurities using a 0.22μm organic filter membrane. Then perform high performance liquid chromatography analysis to obtain the concentration C1 of free pesticide not loaded by the material.

[0092] (3-3) After removing the supernatant, add 20 mL of acetonitrile to the remaining pesticide formulation after centrifugation, sonicate for 30 min and then extract by shaking for 5 min. After centrifugation, take 0.5 mL of supernatant and dilute it 50 times with a mixture of acetonitrile and water (80:20, v / v). Filter the impurities using a 0.22 μm organic filter membrane and then perform high performance liquid chromatography analysis. Using the curve of the standard sample as a reference, obtain the concentration C0 of abamectin loaded on the material.

[0093] (3-4) Calculate the pesticide loading efficiency of the pesticide-loaded material according to the following formula: LE(%)=C1 / (C0+C1)×100%; the results are shown in Table 6;

[0094] Table 6 Results of pesticide loading rates for pesticide formulations

[0095]

[0096] As shown in Table 6, the pesticide loading rate of the pesticide formulations in this system is above 88%, and the pesticide loading rate is higher when the material ratio is closer to the limit. The pesticide loading rate in the viscoelastic fluid state is as high as 96% or more. However, in the elastic solid state, the pesticide cannot spread due to the limitation of the loaded pesticide state. Even if the pesticide loading rate reaches the current technology level, its use is still limited.

[0097] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A drug-loaded fluid material prepared based on solubilization technology, characterized in that, The fluid material is prepared from raw material A, raw material B, surfactant, and organic solvent; raw material A is any one of γ-polyglutamic acid PGA, zein, and wheat gliadin; raw material B is at least one monomer containing an isocyanate group with a functionality ≥2; the monomer containing an isocyanate group with a functionality ≥2 is any one of diphenylmethane diisocyanate MDI, toluene diisocyanate TDI, isophorone diisocyanate IPDI, and dicyclohexylmethane-4-4'-diisocyanate HMDI; The drug-loaded fluid material is a viscoelastic fluid, and its raw material composition by mass ratio is as follows: Organic solvent: γ-polyglutamic acid PGA: raw material B = x:y:z; x = 200, y = 48, z = 41; Or organic solvent: zein: raw material B = x:y:z; x = 20, y = 4, z = 1; Or organic solvent: gliadin: raw material B = x: y: z; x = 25, y = 5, z = 1; Alternatively, the fluid material may be in the state of a viscous fluid, and the raw material composition by mass ratio is as follows: Organic solvent: γ-polyglutamic acid PGA: raw material B = x:y:z; x = 200, y:z > 48:41; or z > 200, y:z = 48:41; Or organic solvent: zein: raw material B = x:y:z; x = 20, y:z > 4:1; or x > 20, y:z = 4:1; Or organic solvent: gliadin: raw material B = x:y:z; x = 25, y:z > 5:1; or x > 25, y:z = 5:

1.

2. The drug-loaded fluid material according to claim 1, characterized in that, The organic solvent is at least one selected from toluene, methanol, ethanol, petroleum ether, ethyl acetate, cyclohexanone, tripropylene glycol methyl ether, N'N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and acetonitrile.

3. The drug-loaded fluid material according to claim 2, characterized in that, The organic solvent is N-methylpyrrolidone or cyclohexanone.

4. The drug-loaded fluid material according to claim 1, characterized in that, The γ-polyglutamic acid PGA is an NMP solution of γ-polyglutamic acid PGA; the mass percentage of γ-polyglutamic acid PGA in NMP is 30%.

5. A fluid-loaded drug delivery system, characterized in that, The fluid-loaded drug agent is prepared using the drug-loaded fluid material described in any one of claims 1-4 as a carrier.

6. The method for preparing a fluid-loaded drug delivery system according to claim 5, characterized in that, Includes the following steps: (1) Dissolve the pesticide in an organic solvent, add a surfactant, and stir to obtain mixture 1; (2) Add raw material B and raw material A to mixture 1 in sequence, and stir until fully dissolved to obtain mixture 2; (3) Add the catalyst, stir until dissolved, and let stand for 2 hours to obtain the product.

7. The preparation method according to claim 6, characterized in that, The surfactant is a quaternary ammonium salt cationic surfactant and / or a sulfonate anionic surfactant; the quaternary ammonium salt cationic surfactant includes at least one of: diecryldimethylammonium chloride, tetradecyldimethylbenzylammonium chloride, and gemini quaternary ammonium salt surfactant; the sulfonate anionic surfactant includes any one of: calcium dodecylbenzenesulfonate, α-olefin sulfonate, and petroleum sulfonate; the pesticide is any one of abamectin, pyraclostrobin, thiamethoxam, or lambda-cyhalothrin; the catalyst is dibutyltin dilaurate and / or tin 2-ethylhexanoate.

8. The preparation method according to claim 6, characterized in that, The mass ratio of raw material A to surfactant is 1:0.25-2.

Images