Trimethoprim / polyacrylic resin solid dispersant as well as preparation method and application thereof

Abstract

The invention discloses a trimethoprim / polyacrylic resin solid dispersant as well as a preparation method and application thereof, and belongs to the technical field of veterinary drug preparations. The trimethoprim / polyacrylic resin solid dispersant comprises the following raw materials: trimethoprim and polyacrylic resin, wherein the mass ratio of the trimethoprim to the polyacrylic resin is 0.02 to 0.3; and dissolving the raw materials with an organic solvent, and dialyzing or evaporating to remove the solvent to prepare the trimethoprim / polyacrylic resin solid dispersant. The prepared solid dispersing agent is high in drug loading rate and good in stability, and the formed solid dispersing agent obviously improves the glass transition temperature of trimethoprim. Besides, the preparation method is convenient to operate, simple and easy to implement, and the obtained solid dispersing agent can be compounded with the sulfonamides antibacterial drugs to serve as a synergist of the sulfonamides antibacterial drugs, so that the antibacterial effect of the sulfonamides antibacterial drugs is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of veterinary drug preparations, and in particular relates to a trimethoprim / polyacrylic acid resin solid dispersant, a preparation method and an application thereof. Background Art

[0002] Trimethoprim is a bacterial dihydrofolate reductase inhibitor. Its antibacterial action is based on interfering with bacterial folate metabolism, thereby inhibiting bacterial growth and reproduction. As a widely used antibacterial drug and synergist in veterinary clinical practice, trimethoprim exhibits antibacterial activity against most Gram-positive and Gram-negative bacteria. Pure trimethoprim has a bitter taste and low solubility in aqueous solutions, resulting in low bioavailability. These drawbacks limit its application. Therefore, research into new sustained-release trimethoprim veterinary dosage forms is of great significance.

[0003] In recent years, researchers have been widely using biocompatible materials as carriers to load active pharmaceutical ingredients through encapsulation, embedding, and other methods to improve the water solubility and bioavailability of drugs. For example, patent CN118562028A discloses a method for preparing a trimethoprim-cyclodextrin derivative inclusion compound, which improves the water solubility of trimethoprim and improves the pharmacokinetic properties of trimethoprim in mice. Patent CN115819428B discloses a trimethoprim-octa-cucurbit ring inclusion compound and its preparation and application, which improves the solubility and antibacterial activity of trimethoprim. However, the inclusion compounds prepared by the above two processes have obvious deficiencies in controlling the release site, improving drug stability, achieving enteric dissolution function, adapting to industrial production, and supporting compound medication. Summary of the Invention

[0004] To address the above technical issues, the present invention provides a trimethoprim / polyacrylic acid resin solid dispersant, its preparation method, and its application. Specifically, the solid dispersant prepared by the present invention has good water solubility, is stable in gastric fluid after oral administration, and releases the drug in intestinal fluid, making it useful for treating bacterial infections. Furthermore, the solid dispersant disclosed by the present invention can be compounded with sulfonamides in any proportion to form a composite formulation, expanding its application prospects.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] One of the technical solutions of the present invention:

[0007] A trimethoprim / polyacrylic acid resin solid dispersant, the raw materials of which include trimethoprim and polyacrylic acid resin;

[0008] Wherein, the mass ratio of trimethoprim (TMP) to polyacrylic acid resin (PAA) is 0.02-0.3.

[0009] Optionally, the polyacrylic acid resin is selected from one or more of Eudragit S100, Eudragit L100 or Eudragit L100-55.

[0010] Beneficial Effects: The present invention utilizes carboxyl-containing polyacrylic acid resins, such as Eudragit L100 and S100, as carriers to form a solid dispersion system, significantly improving the dispersibility and solubility of trimethoprim in water. Furthermore, the coating structure formed by the polyacrylic acid resin effectively prevents trimethoprim degradation during storage, extending the drug's shelf life. Furthermore, the solubility characteristics of the polyacrylic acid resins defined in this invention under different pH conditions (e.g., Eudragit L100 dissolves at pH > 6) enable selective release of the drug in the intestinal tract, preventing loss in gastric fluid.

[0011] Optionally, the particle size of the trimethoprim / polyacrylic acid resin solid dispersant is 200 nm-6 μm.

[0012] The second technical solution of the present invention:

[0013] A method for preparing a trimethoprim / polyacrylic acid resin solid dispersant comprises the following steps:

[0014] dissolving trimethoprim and polyacrylic acid resin in an organic solvent, then adding deionized water and stirring uniformly to obtain a mixed solution;

[0015] The mixed solution is dialyzed or evaporated to remove the organic solvent, and then dried to prepare the trimethoprim / polyacrylic acid resin solid dispersant.

[0016] Beneficial Effects: This method uses an organic solvent to dissolve the raw materials and then removes the solvent through dialysis or evaporation. This method is simple to operate and suitable for industrial production. Furthermore, by adjusting the stirring rate, time, and drying method (freeze-drying or spray-drying), the present invention can produce particles ranging from 200 nm to 6 μm, which helps improve drug absorption efficiency. Low-temperature freeze-drying and controllable spray-drying parameters help preserve the chemical structure and antibacterial activity of trimethoprim.

[0017] Optionally, the volume ratio of the organic solvent to deionized water is 1:5-20.

[0018] Furthermore, the organic solvent is selected from one or more of methanol, ethanol, acetone, tetrahydrofuran, dimethyl sulfoxide and N,N-dimethylformamide.

[0019] Optionally, the stirring rate during the stirring process is 500-3000 rpm; the stirring time is 2-24 hours; and the stirring temperature is 25-80°C.

[0020] Optionally, the dialysis conditions are: dialysis in a dialysis bag with a molecular weight cut-off of 8000-14000 for 12-48 hours;

[0021] The evaporation conditions are: distillation on a rotary evaporator at 40-80° C. for 0.5-3 hours to remove the organic solvent.

[0022] Optionally, the drying is freeze-drying or spray-drying.

[0023] Furthermore, the freeze-drying conditions are: freeze-drying at (-40)°C-(-60)°C for 40-80h.

[0024] Furthermore, the spray drying conditions are: flow rate of 20 mL / h, inlet temperature of 100-200°C, and outlet temperature of 80-150°C.

[0025] The third technical solution of the present invention:

[0026] The present invention provides use of the trimethoprim / polyacrylic acid resin solid dispersant in preparing antibacterial drugs.

[0027] Beneficial Effects: The solid dispersion prepared by this invention increases the bioavailability of trimethoprim, thereby enhancing its inhibitory effect against both Gram-positive and Gram-negative bacteria. Furthermore, the dispersion's flexible form facilitates subsequent formulation into a variety of veterinary dosage forms, including oral preparations, sustained-release tablets, and granules. It also provides a good foundation for subsequent combined use with other antibiotics (such as sulfonamides), demonstrating its potential as a "synergistic enhancer."

[0028] The fourth technical solution of the present invention:

[0029] A veterinary drug preparation, the raw materials of which include sulfonamides and the above-mentioned trimethoprim / polyacrylic acid resin solid dispersant.

[0030] Beneficial Effects: The present invention combines trimethoprim with sulfonamides (such as sulfamethazine) to produce a synergistic antibacterial effect. This dual-target mechanism reduces the risk of drug resistance associated with single-drug use.

[0031] The solid dispersant disclosed in the present invention makes the compound preparation easier to process, and the prepared compound preparation has stable efficacy and sustained-release properties, and is more suitable for long-term use in veterinary clinics.

[0032] Optionally, the mass ratio of the sulfonamide drug to the trimethoprim / polyacrylic acid resin solid dispersant is 1:1.

[0033] Furthermore, the sulfonamide drug is sulfamethazine.

[0034] Optionally, the veterinary preparation is an oral preparation, a sustained-release tablet preparation or a granular preparation.

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

[0036] 1. This invention constructs a trimethoprim / polyacrylic acid resin solid dispersion system based on an enteric-coated polyacrylic acid resin with pH-responsive properties. This system remains stable in the low pH environment of the stomach, effectively preventing drug degradation and inactivation in gastric fluid. Furthermore, in the neutral or weakly alkaline environment of the intestine (pH > 6), the resin material rapidly dissolves, enabling targeted drug release. This characteristic significantly improves the bioavailability and therapeutic efficacy of trimethoprim, making it particularly suitable for the development of oral formulations with targeted release.

[0037] 2. The trimethoprim / polyacrylic acid resin solid dispersion prepared by the present invention has a high drug loading rate and excellent physicochemical stability. By uniformly dispersing trimethoprim in the resin matrix, not only is the drug's dispersibility and dissolution rate effectively improved, but its glass transition temperature (Tg) is also significantly increased, indicating that the drug molecule is more stable in the solid state and less prone to crystallization or phase separation. This structural optimization helps extend the drug's shelf life and improve its stability during storage, thereby enhancing the overall quality and clinical application value of the preparation.

[0038] 3. The preparation method provided by the present invention is simple to operate, has a controllable process, and is suitable for industrial continuous production. The resulting solid dispersion can not only be used alone to improve the solubility and bioavailability of trimethoprim, but can also be used in combination with sulfonamide antibiotics. Specifically, when formulated as a solid dispersion, it can more effectively enhance the antibacterial activity of sulfonamides, significantly enhancing their antibacterial activity and reducing the risk of drug resistance, thus showing promising clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The accompanying drawings, which constitute part of the present invention, are intended to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are intended to explain the present invention and do not constitute an undue limitation of the present invention. In the accompanying drawings:

[0040] Figure 1 FTIR spectrum of the trimethoprim / polyacrylic acid resin solid dispersant prepared in Example 1 of the present invention;

[0041] Figure 2 This is the thermogravimetric curve of the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 of the present invention;

[0042] Figure 3 This is the DSC curve of the trimethoprim / polyacrylic acid resin solid dispersant prepared in Example 1 of the present invention;

[0043] Figure 4(a) and (b) are the UV absorption curves and standard curves of trimethoprim (trimethoprim dissolved in ethanol) at different concentrations, respectively; (c) and (d) are the UV absorption curves and potentials of the solid dispersants prepared in Example 1 and Example 8, respectively;

[0044] Figure 5 This is a scanning electron microscope image of the trimethoprim / polyacrylic acid resin solid dispersant prepared in Example 1 of the present invention;

[0045] Figure 6 The drug dissolution curves of the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 of the present invention in gastric juice, intestinal juice and PBS;

[0046] Figure 7 The present invention shows the inhibitory activity of the trimethoprim / polyacrylic acid resin solid dispersant prepared in Example 1 of the present invention against Staphylococcus aureus in vitro; wherein, (a) is a blank control group, (b) shows the mass concentration of the trimethoprim / polyacrylic acid resin solid dispersant prepared in Example 1 in the bacterial solution is 0.01 mg / mL, (c) shows the mass concentration of the trimethoprim / polyacrylic acid resin solid dispersant prepared in Example 1 in the bacterial solution is 0.025 mg / mL, and (d) shows the growth of Staphylococcus aureus colonies formed by compounding the solid dispersant with sulfamethazine in a mass ratio of 1:1 (the mass concentration of the compound drug in the bacterial solution is 0.01 mg / mL). DETAILED DESCRIPTION

[0047] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0048] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between any intermediate value within a stated value or stated range and any other stated value or intermediate value within the stated range is also encompassed by the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0049] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0050] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be exemplary only.

[0051] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0052] The present invention discloses an intestinal sustained-release trimethoprim / polyacrylic acid resin solid dispersion, its preparation method, and application. The trimethoprim / polyacrylic acid resin solid dispersion prepared by the present invention has antibacterial activity and can be combined with sulfonamides to treat diseases caused by bacterial infections.

[0053] Specifically, the present invention discloses a method for preparing a trimethoprim / polyacrylic acid resin solid dispersant, comprising the following steps:

[0054] (1) dissolving trimethoprim and polyacrylic acid resin in an organic solvent in a proportion, wherein the mass ratio of trimethoprim to polyacrylic acid resin is 0.02-0.3 and the mass concentration of the solid is 0.5 mg / mL-20 mg / mL (i.e., the ratio of the sum of the mass of trimethoprim and polyacrylic acid resin to the volume of the organic solvent);

[0055] (2) adding the above solution dropwise to a certain volume of stirred deionized water, wherein the volume ratio of the organic solution to water is (1:5)-(1:20); stirring speed is 500-3000 rpm, stirring time is 2-24 hours, and stirring temperature is 25-80°C;

[0056] (3) The mixed solution was dialyzed in a dialysis bag with a molecular weight cut-off of 8000-14000 for 12-48 hours.

[0057] or,

[0058] The mixed solution was distilled on a rotary evaporator at 40-80°C for 0.5-3 hours to remove the organic solvent;

[0059] (4) Freeze-dry the solution after removing the organic solvent at (-40)-(-60)°C for 40-80h.

[0060] or,

[0061] The spray drying was carried out under the conditions of a flow rate of 20 mL / h, an inlet temperature of 100-200° C., and an outlet temperature of 80-150° C. to finally obtain a trimethoprim / polyacrylic acid resin solid dispersant.

[0062] In some optional embodiments, the polyacrylic acid resin is selected from one or more of Eudragit S100, Eudragit L100 or Eudragit L100-55.

[0063] The Eudragit L / S polyacrylic acid resins defined in the present invention contain carboxyl groups that react with alkali in water to form salts, leading to dissolution. Eudragit L100 dissolves in solutions with a pH greater than 6, while Eudragit S100 dissolves in solutions with a pH greater than 7. Therefore, the present invention combines Eudragit L100 or Eudragit S100 with trimethoprim to protect the drug (trimethoprim) in the stomach while dissolving and releasing it in the intestines.

[0064] In some optional embodiments, the organic solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, dimethyl sulfoxide and N,N-dimethylformamide.

[0065] The embodiment of the present invention further discloses a trimethoprim / polyacrylic acid resin solid dispersant prepared by the above preparation method.

[0066] In some optional embodiments, the particle size of the trimethoprim / polyacrylic acid resin solid dispersion is 200 nm-6 μm.

[0067] The raw materials used in the present invention are all purchased from the market.

[0068] The technical solution of the present invention is further illustrated by the following examples.

[0069] Example 1

[0070] 0.002 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.02) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 500 rpm and a temperature of 25°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; then freeze-dried (-40°C, 40 hours) to obtain a solid dispersion with a size of approximately 200 nm.

[0071] Example 2

[0072] Dissolve 0.03g of trimethoprim and 0.10g of Eudragit S100 (mass ratio 0.3) in 20mL of methanol. Once completely dissolved, add the mixture dropwise to 100mL of deionized water at 25°C at a stirring rate of 500rpm. Stir for 2 hours. Then, distill the mixture on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent. Freeze-dry (-40°C for 40 hours) to obtain a solid dispersion approximately 300 nanometers in size.

[0073] Example 3

[0074] Dissolve 0.03g of trimethoprim and 0.10g of Eudragit S100 (mass ratio 0.3) in 20mL of methanol. Once completely dissolved, add the mixture dropwise to 100mL of deionized water at 25°C at a stirring rate of 500rpm. Stir for 2 hours. Then, distill the mixture on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent. Freeze-dry (-40°C for 40 hours) to obtain a solid dispersion approximately 360 nanometers in size.

[0075] Example 4

[0076] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 3000 rpm and a temperature of 25°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; and freeze-dried (-40°C, 40 hours) to obtain a solid dispersant with a size of approximately 680 nanometers.

[0077] Example 5

[0078] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 1000 rpm and a temperature of 80°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; and freeze-dried (-40°C, 40 hours) to obtain a solid dispersant with a size of approximately 720 nm.

[0079] Example 6

[0080] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 ml of deionized water at a stirring rate of 1000 rpm and a temperature of 50°C. After stirring for 24 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; and freeze-dried (-40°C, 40 hours) to obtain a solid dispersion with a size of approximately 330 nm.

[0081] Example 7

[0082] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 1000 rpm and a temperature of 50°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 80°C for 0.5 hours to remove the organic solvent; and freeze-dried (-40°C, 40 hours) to obtain a solid dispersant with a size of approximately 260 nanometers.

[0083] Example 8

[0084] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 1000 rpm and a temperature of 50°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 3 hours to remove the organic solvent; and freeze-dried (-40°C, 40 hours) to obtain a solid dispersion with a size of approximately 430 nm.

[0085] Example 9

[0086] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 1000 rpm and a temperature of 50°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; the mixed solution was dialyzed in a dialysis bag with a molecular weight cutoff of 8000 for 12 hours and freeze-dried (-40°C, 40 hours) to obtain a solid dispersion with a size of approximately 400 nm.

[0087] Example 10

[0088] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 1000 rpm and a temperature of 50°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; the mixed solution was dialyzed in a dialysis bag with a molecular weight cutoff of 14,000 for 48 hours and freeze-dried (-40°C, 40 hours) to obtain a solid dispersion with a size of approximately 400 nm.

[0089] Example 11

[0090] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 1000 rpm and a temperature of 50°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; the mixed solution was dialyzed in a dialysis bag with a molecular weight cutoff of 14,000 for 48 hours and freeze-dried (-60°C, 80 hours) to obtain a solid dispersion with a size of approximately 420 nanometers.

[0091] Example 12

[0092] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at a stirring rate of 1000 rpm and a temperature of 50°C. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; the mixed solution was dialyzed in a dialysis bag with a molecular weight cutoff of 14,000 for 48 hours, and spray-dried at a flow rate of 20 mL / h, an inlet temperature of 100°C, and an outlet temperature of 80°C to finally obtain a solid dispersant with a size of approximately 1.2 microns.

[0093] Example 13

[0094] 0.03 g of trimethoprim and 0.10 g of Eudragit S100 (mass ratio 0.3) were dissolved in 20 mL of methanol. After complete dissolution, the mixture was added dropwise to 100 mL of deionized water at 50°C and stirred at 1000 rpm. After stirring for 2 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent. The mixed solution was dialyzed in a dialysis bag with a molecular weight cutoff of 14,000 for 48 hours and spray-dried at a flow rate of 20 mL / h, an inlet temperature of 200°C, and an outlet temperature of 150°C to obtain a solid dispersion with a size of approximately 3.0 μm.

[0095] Example 14

[0096] 0.03 g of trimethoprim and 0.10 g of Eudragit L100 (mass ratio 0.3) were dissolved in 10 mL of methanol. After complete dissolution, the mixture was added dropwise to 200 mL of deionized water at a stirring rate of 500 rpm and a temperature of 25°C. After stirring for 5 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; and freeze-dried (-40°C, 40 hours) to obtain a solid dispersion with a size of approximately 370 nanometers.

[0097] Example 15

[0098] 0.03 g of trimethoprim and 0.10 g of Eudragit L100-55 (mass ratio 0.3) were dissolved in 10 mL of methanol. After complete dissolution, the mixture was added dropwise to 200 mL of deionized water at a stirring rate of 500 rpm and a temperature of 25°C. After stirring for 5 hours, the mixed solution was distilled on a rotary evaporator at 40°C for 0.5 hours to remove the organic solvent; and freeze-dried (-40°C, 40 hours) to obtain a solid dispersant with a size of approximately 260 nanometers.

[0099] Effect verification

[0100] Figure 1 This is the FTIR spectrum of the trimethoprim / polyacrylic acid resin solid dispersant prepared in Example 1 of the present invention. It can be seen from the figure that the main characteristic absorption peaks of pure trimethoprim are located at 1668 and 1563 cm -1 , corresponding to the C=N stretching vibration and -NH2 bending vibration on the pyrimidine ring. 1450, 1112 cm and 3448 cm -1 The peaks at 2968 and 1733 cm-1 are C=C, COC and -OH stretching vibrations respectively. -1 In addition to the stretching vibration peaks of the alkyl and carbon groups of Eudragit S100, the spectrum of the solid dispersant also shows the stretching vibration peaks of the alkyl and carbon groups at 1668 and 1303 cm -1 The absorption peak of trimethoprim appeared, indicating that the characteristic signal of trimethoprim appeared in the formed dispersant, proving that trimethoprim was successfully loaded.

[0101] Figure 2 Thermogravimetric curve of the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 of the present invention; Figure 2As can be seen in the figure, pure trimethoprim exhibits rapid and slow weight loss at 250-350°C and 350-700°C, corresponding to oxidative condensation of functional groups and carbonization of the compound, respectively. Pure polyacrylic acid resin also exhibits rapid weight loss between 400-480°C, due to polymer combustion. Solid dispersants exhibit rapid and slow weight loss at 320-380°C and 380-500°C, respectively.

[0102] Figure 3 This is the DSC curve of the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 of the present invention. DSC analysis shows that the glass transition temperature of the trimethoprim technical is approximately 200°C, while the glass transition temperature of pure polyacrylic acid resin is approximately 400°C. The glass transition temperatures of trimethoprim and polyacrylic acid resin in the solid dispersion are increased to 260°C and 450°C, respectively.

[0103] Figure 4 (a) and (b) are the UV absorption curves and standard curves of trimethoprim at different concentrations, respectively. (c) and (d) are the UV absorption curves and potentials of the solid dispersions prepared in Examples 1 and 8, respectively. Analysis indicates that the trimethoprim loadings (calculated using the standard curve method, i.e., UV absorption of the solid dispersions tested and substituting this into the standard curve) in the solid dispersions prepared in Examples 1 and 8 are 4% and 10%, respectively. The potential of the solid dispersions does not change dramatically over time, demonstrating good stability.

[0104] Figure 5 This is a scanning electron microscope image of the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 of the present invention. The SEM image shows that the prepared solid dispersion has a large, bulky morphology, free of large particles and other irregular solids, indicating that the trimethoprim is completely dispersed in the polyacrylic acid resin.

[0105] Figure 6 The drug dissolution curves of the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 of the present invention in gastric juice, intestinal juice, and PBS show that after 48 hours, the dissolution rates of the dispersion in gastric juice, intestinal juice, and PBS are 0.32, 0.48, and 0.65, respectively, indicating good gastric juice retention.

[0106] Figure 7The in vitro inhibitory activity of the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 of the present invention against Staphylococcus aureus is shown in Figure 1. (a) represents the blank control group, (b) represents the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 at a concentration of 0.01 mg / mL in the bacterial solution, (c) represents the trimethoprim / polyacrylic acid resin solid dispersion prepared in Example 1 at a concentration of 0.025 mg / mL in the bacterial solution, and (d) represents the growth of Staphylococcus aureus colonies using a compounded drug formed by combining the solid dispersant with sulfamethazine in a 1:1 mass ratio (the compounded drug had a concentration of 0.01 mg / mL in the bacterial solution). As can be seen from the figure, the antibacterial activity of the drug-dosed group was significantly stronger than that of the control group, and the solid dispersant can be combined with sulfonamide antibacterial drugs to act as a synergist, enhancing the antibacterial effect of sulfonamide drugs.

[0107] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A trimethoprim / polyacrylic acid resin solid dispersant, characterized in that: The raw materials include trimethoprim and polyacrylic acid resin; Wherein, the mass ratio of the trimethoprim to the polyacrylic acid resin is 0.02-0.

3.

2. A trimethoprim / polyacrylic acid resin solid dispersant according to claim 1, characterized in that: The polyacrylic acid resin is selected from one or more of Eudragit S100, Eudragit L100 or Eudragit L100-55.

3. The trimethoprim / polyacrylic acid resin solid dispersant according to claim 1, characterized in that: The particle size of the trimethoprim / polyacrylic acid resin solid dispersant is 200 nm to 6 μm.

4. A method for preparing a trimethoprim / polyacrylic acid resin solid dispersant, characterized in that: The following steps are involved: dissolving trimethoprim and polyacrylic acid resin in an organic solvent, then adding water and stirring uniformly to obtain a mixed solution; The mixed solution is dialyzed or evaporated to remove the organic solvent, and then dried to prepare the trimethoprim / polyacrylic acid resin solid dispersant according to any one of claims 1 to 3.

5. The method for preparing a trimethoprim / polyacrylic acid resin solid dispersant according to claim 4, wherein: The volume ratio of the organic solvent to water is 1:5-20.

6. The method for preparing a trimethoprim / polyacrylic acid resin solid dispersant according to claim 4, wherein: The stirring rate during the stirring process is 500 to 3000 rpm; the stirring time is 2 to 24 hours; and the stirring temperature is 25 to 80° C.

7. The method for preparing a trimethoprim / polyacrylic acid resin solid dispersant according to claim 4, wherein: The drying is freeze drying or spray drying.

8. The method for preparing a trimethoprim / polyacrylic acid resin solid dispersant according to claim 7, characterized in that: The freeze-drying conditions are: freeze-drying at (-40) to (-60)°C for 40 to 80 hours; The spray drying conditions are: flow rate of 20 mL / h, inlet temperature of 100-200° C., and outlet temperature of 80-150° C.

9. Use of the trimethoprim / polyacrylic acid resin solid dispersion according to any one of claims 1 to 3 in the preparation of antibacterial drugs.

10. A veterinary drug preparation, the raw materials of which include sulfonamides and the trimethoprim / polyacrylic acid resin solid dispersant according to any one of claims 1 to 3.

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