CN113287608B

CN113287608B - Drug solubilization system and application thereof in pesticide preparation

Info

Publication number: CN113287608B
Application number: CN202110512409.1A
Authority: CN
Inventors: 翟晚娜; 蒋园佳; 付媛丽; 王纯洁; 金志敏; 龚国华
Original assignee: Zhejiang Longyou Dongfang Anasaike Crop Technology Co ltd; Zhejiang University of Technology ZJUT
Current assignee: Zhejiang Longyou Dongfang Anasaike Crop Technology Co ltd; Zhejiang University of Technology ZJUT
Priority date: 2021-05-11
Filing date: 2021-05-11
Publication date: 2022-05-17
Anticipated expiration: 2041-05-11
Also published as: CN113287608A

Abstract

The invention discloses a drug solubilizing system and application thereof in pesticide preparations, wherein the drug solubilizing system is formed by compounding hydroxymethylated rosin and poloxamer, and the mass ratio of the hydroxymethylated rosin to the poloxamer is 1: 1-6. The pesticide is a poorly soluble drug, the poorly soluble drug is compounded with a drug solubilization system to form a pesticide preparation, and the mass ratio of the poorly soluble drug in the pesticide preparation is 10-50%. According to the invention, hydroxymethylated rosin and poloxamer are compounded to form a solubilization system, so that insoluble drugs are solubilized. The poloxamer converts the insoluble medicine crystals into amorphous bodies, the amphipathy of hydroxymethylated rosin acid greatly stabilizes the distribution of the insoluble medicine in water, and the hydroxymethylated rosin and the poloxamer form a stable system through hydrogen bonding, so that the stability of the medicinal preparation is further improved.

Description

Drug solubilization system and application thereof in pesticide preparation

Technical Field

The invention belongs to the field of medicinal preparations, and particularly relates to a medicament solubilization system and application thereof in a pesticide preparation.

Background

Pharmaceutical preparations are an important part of the market for drugs, and the processing of the same agricultural pharmaceutical dosage forms, whether human or animal, is also important. The raw material medicaments are prepared into specific dosage forms through a plurality of processes so as to be used in the market. As for the traditional pesticide formulations, mainly aqueous solution, water dispersible granules, wettable powder and missible oil are available. The traditional pesticide has many defects, wastes of a large amount of medicines and potential harm to the environment, and a lot of environment-friendly pesticide aqueous emulsions, microemulsions, suspending agents and the like are gradually developed.

The preparation method of the water-soluble medicine in agriculture is simple, and the cost is relatively low. However, most of pesticides are poorly water-soluble drugs, and the formulation of the drugs is always the focus of the research on the pesticide formulation. More than half of the formulations on the market at present are wettable powder and missible oil. The wettable powder is a powdery preparation prepared by mixing and grinding raw material medicaments and other auxiliary agents, and mainly improves the dispersibility, wettability and suspensibility to improve the bioavailability. Micron-sized dust is generated in the preparation process of the wettable powder, so that the wettable powder has great harm to human bodies and is easy to cause cross contamination in workshops. The emulsifiable solution is prepared by dissolving high-concentration raw material medicines in an ester-soluble solvent and then adding an emulsifying agent for emulsification, so that the emulsifiable solution can form a stable emulsion in water. The main drawback of emulsifiable concentrates is that large amounts of organic solvents are used in the formulation process, which inevitably places a great burden on the environment.

The requirements on the pesticide industry are more and more strict while the national attention on environmental protection is paid, the promotion of pesticide preparations and the process and method are also more and more required, and the water-based solidification, dust-free solidification and green formation of pesticide preparations are inevitable trends in development.

The pesticide is a poorly soluble drug, is selected from cyazofamid, thiamethoxam, difenoconazole, trifloxystrobin, phenylthionura, nereistoxin, abamectin, pyridaben, imazaquin, phenylpyrazole, indoxacarb, azoxystrobin or cyhalothrin, is a commonly used agricultural insecticide or bactericide, is a conventional dosage form such as a suspending agent and missible oil, and is a solid dispersion dosage form which is a dispersion system in a solid form formed by highly dispersing the drug in a solid carrier. The particle size of the drug in the carrier is 0.001-0.1 mm, and the carrier is mainly used for accelerating and increasing the dissolution of the insoluble drug and improving the bioavailability of the insoluble drug. Compared with the traditional preparation form, the solid dispersion preparation form has the advantages of environmental protection and no pollution. However, solid dispersions have their inevitable disadvantages, which are: the stability of the dispersed state of the medicine is not high, and the aging phenomenon is easy to generate after long-term storage.

Rosin is a rich natural renewable resource, has a large yield and a low price, and mainly comprises resin acid with a molecular formula C₁₉H₂₉COOH is classified into four types, i.e., abietic acid type, pimaric acid type, isopimaric acid, and thiodan type resin acid (or called as a bicyclic acid) according to its structural characteristics, and is widely used in industrial production, including soap industry, paper industry, ink industry, rubber industry, and food industry. Rosin-based has great potential for solubilizing insoluble drugs, and has natural affinity with most ester-soluble drugs, but rosin acid has too high rigidity of chemical structure, and has weak affinity when directly adding water-soluble compounds, so that a formed system is unstable. To modify this situation, hydroxymethyl groups are attached to the 7, 12, 14 positions of the abietic acid by hydroxymethylation, flexible groups are added to the rigid phenanthrene ring and more active sites are created. Hydroxymethylated rosin only appears in reports as an intermediate, and has not been studied and applied deeply, and has not been reported in agriculture. The hydroxymethylated rosin and the flexible water-soluble polymer are used together to increase the dissolution rate of the insoluble drug and improve the bioavailability of the drug.

Poloxamers (poloxamers) are non-patent names for polyoxyethylene-polyoxypropylene copolymers. The product manufactured by BASF corporation in germany is sold under the trade name Pluronic chemical book in which polyoxyethylene chains are relatively hydrophilic and polyoxypropylene chains are relatively lipophilic and therefore are nonionic polymeric surfactants, primarily used as emulsifiers and solubilizers in pharmaceutical formulations.

Disclosure of Invention

The invention aims to provide a medicament solubilization system and application thereof in pesticide preparations aiming at the defects of the solid dispersion, and solves the problems that the medicament is difficult to dissolve in water, the dispersed water solution is unstable and the like.

The technical scheme adopted by the invention is as follows: the drug solubilization system is formed by compounding hydroxymethylated rosin and poloxamer, and the mass ratio of the hydroxymethylated rosin to the poloxamer is 1: 1-6.

Another technical solution is as follows: the pesticide is an insoluble drug and is selected from cyazofamid, thiamethoxam, difenoconazole, trifloxystrobin, phenylureide, nereistoxin, abamectin, pyridaben, imazaquin, phenylpyrazole, indoxacarb, azoxystrobin or cyhalothrin; the insoluble drug and the drug solubilization system are compounded to form a pesticide preparation, and the mass ratio of the insoluble drug in the pesticide preparation is 10-50%.

The application comprises the following steps: the poloxamer and the hydroxymethylated rosin are stirred magnetically for 0.5-2 hours in an oil bath at 50-85 ℃ by a hot melting method to obtain a uniform and stable hot melt; and adding the insoluble drug, continuing to magnetically stir for 10-30 min to obtain a uniform system, and cooling to obtain the pesticide preparation.

The preparation of hydroxymethylated rosin refers to the experiments of Zhangang and the like (Zhangang, Zhouyonghong, Lishulong, et al. Prins addition reaction research on rosin resin acid and formaldehyde [ J ]. Fine chemical engineering, 2008, (02):195-200.), and is slightly improved on the basis, 16.2g of 37 percent formaldehyde solution is taken into a round-bottom flask, 0.16g of p-toluenesulfonic acid is added, and after stirring and dissolving, 10.2g of rosin is added and then fully stirred; heating and stirring in an oil bath at 120 ℃, stopping heating after reacting for 4 hours, and naturally cooling to room temperature. Adding a proper amount of acetone into the reactant for dissolving, filtering, carrying out vacuum drying, adding a proper amount of cyclohexane solution into the obtained solid for dissolving at 70 ℃, filtering, and carrying out vacuum drying at 60 ℃ to obtain hydroxymethyl rosin for later use.

According to the invention, hydroxymethylated rosin and poloxamer are compounded to form a solubilization system, so that insoluble drugs are solubilized. Poloxamer which is often used as a solid dispersion carrier is used for converting insoluble drug crystals into amorphous substances, the amphipathy of hydroxymethylated abietic acid greatly stabilizes the distribution of the insoluble drug in water, and hydroxymethylated rosin and poloxamer form a stable system through hydrogen bond combination. After the nano-scale particles are distributed in water, the particle size reaches the nano level, the average hydrated particle size is 100-200 nm, and the potential is-15-20 mV, so that the stability of the pharmaceutical preparation is further improved.

Detailed Description

Example 1

Selecting poloxamer high-molecular polymer, magnetically stirring poloxamer and hydroxymethylated rosin for 1.5h in an oil bath at 80 ℃ by a hot melting method to obtain a uniform and stable hot melt, adding azoxystrobin and cyhalothrin, continuously magnetically stirring for 30min to obtain a uniform system, and cooling to obtain the drug-loaded solid dispersion. The experimental components are shown in table 1.

TABLE 1

Example 2

Selecting PEG 6000 high molecular polymer, magnetically stirring PEG 6000 and hydroxymethylated rosin for 1.5h in an oil bath at 80 ℃ by a hot melting method to obtain a uniform and stable hot melt, adding azoxystrobin and cyhalothrin, continuously magnetically stirring for 30min to obtain a uniform system, and cooling to obtain a drug-loaded solid dispersion, wherein the experimental components are shown in Table 2.

TABLE 2

1g of the solid dispersion obtained was placed in a beaker, 250ml of hard water was added thereto, and the mixture was stirred at 25 ℃ on a magnetic stirrer at 100 r/min. Record the complete disintegration time of the drug solids in the beaker. Diluting the completely disintegrated medicinal liquid by 100 times, standing, collecting supernatant, introducing sample through 0.45 μm microporous filter membrane, measuring its peak area by HPLC, and calculating the dissolved amount of the medicine in water according to standard curve.

Example 3

PVP K30 high-molecular polymer is selected, PVP K30 and hydroxymethylated rosin are dissolved by methanol through a solvent volatilization method, azoxystrobin and cyhalothrin are added, magnetic stirring is carried out for 30min, a uniform system is obtained after the solvent is volatilized, cooling is carried out, and the drug-loaded solid dispersion is obtained, wherein experimental components are shown in Table 3.

TABLE 3

The results obtained for the above examples are shown in table 4:

TABLE 4

Group of	Disintegration time(s)	Cumulative dissolution rate (%)	Saturated solubility (mg/ml)
				S1	60	101.02	8.2
S2	100	65.13	6.6
				S3	246	50	1.27
S4	89	99.21	17.96
				S5	98	70.21	5.22
S6	110	42.1	0.62
				S7	88	100.02	7.3
S8	150	90.13	4.7
				S9	97	80.2	4.93
S10	129	99.21	14.96
				S11	196	85.2	5.78
S12	250	42.1	0.83
				S13	219	89.21	10.2
S14	356	40.2	6.1

The result shows that the insoluble drug solid dispersion prepared by taking hydroxymethylated rosin-high polymer as a drug carrier has high disintegration speed, and excellent accumulative dissolution rate and saturated solubility, such as: the water solubility of azoxystrobin was increased from 0.006mg/ml to 8.2 mg/ml. The solubility of the cyhalothrin in water is about 0.005mg/ml, the solubility of the azoxystrobin in water is about 17.96mg/ml, and the solubility solubilization system of the insoluble drugs is increased by about 800-3000 times.

Claims

1. The application of the drug solubilizing system in the pesticide preparation is characterized in that: the drug solubilization system is formed by compounding hydroxymethylated rosin and poloxamer, and the mass ratio of the hydroxymethylated rosin to the poloxamer is 0.35: 0.65; the pesticide is an insoluble drug and is selected from azoxystrobin or cyhalothrin; the insoluble drug and the drug solubilization system are compounded to form a pesticide preparation, and the mass ratio of the insoluble drug in the pesticide preparation is 10-50%.

2. The use of claim 1, wherein: comprises the following steps: the poloxamer and the hydroxymethylated rosin are stirred magnetically for 0.5-2 hours in an oil bath at 50-85 ℃ by a hot melting method to obtain a uniform and stable hot melt; and adding the insoluble drug, continuing to magnetically stir for 10-30 min to obtain a uniform system, and cooling to obtain the pesticide preparation.