Preparation process of instant trimethoprim solid dispersion with content of 35% or 40%

Abstract

The invention discloses a preparation process of an instant trimethoprim solid dispersion with the content of 35% or 40%, the formula of the instant trimethoprim solid dispersion comprises trimethoprim (TMP), a cosolvent and a dispersing agent according to a certain proportion, during preparation, various materials are weighed according to the proportion of the formula, the trimethoprim and the cosolvent are uniformly mixed, and the mixture is put into a mold for molding, so that the instant trimethoprim solid dispersion with the content of 35% or 40% is obtained. And adding purified water, stirring and dissolving the filler, adding the dispersing agent, adding purified water to prepare the material into a solution with the solid content of 15-20%, and drying by adopting a spray dryer to prepare the trimethoprim solid dispersion. The content of trimethoprim in the trimethoprim solid dispersion product is not lower than 35%, the solubility (the content of trimethoprim in the solution) is not lower than 18 mg / mL, and the solubility of trimethoprim is improved under the condition that the content of trimethoprim is guaranteed.

Description

Technical Field

[0001] The present invention relates to the preparation of veterinary drugs, and in particular to a preparation process of a fast-dissolving trimethoprim solid dispersion with a trimethoprim content of 35 percent or 40 percent. Background Art

[0002] Trimethoprim is an antibacterial synergist. It is a lipophilic weak base formed by condensation and cyclization of trimethoxybenzaldehyde. It has antibacterial effects on a variety of Gram-positive and Gram-negative bacteria. Its antibacterial mechanism is mainly that trimethoprim inhibits bacterial dihydrofolate reductase, preventing dihydrofolate from being reduced to tetrahydrofolate, affecting ribonucleic acid synthesis, and ultimately inhibiting bacterial growth and reproduction.

[0003] Trimethoprim is generally used as an antimicrobial synergist in conjunction with antimicrobial drugs, enhancing the antimicrobial effects of various antibiotics, including sulfonamides, fluoroquinolones, penicillins, cephalosporins, and aminoglycosides. It can also be used to enhance the antimicrobial efficacy of traditional Chinese medicines, increasing their efficacy by several to dozens of times. However, due to trimethoprim's extremely poor water solubility (a solubility of only 0.31 mg / mL), the soluble dispersants produced by direct use have extremely low absorption rates in clinical applications (solubility is a fundamental requirement for drug absorption from the gastrointestinal tract and directly affects drug absorption and bioavailability in animals; greater solubility leads to higher absorption rates and bioavailability, and better therapeutic effects). Furthermore, the rapid growth of large-scale animal husbandry has prompted companies to adopt drinking water administration for community prevention and treatment. This prerequisite for drinking water administration requires that the drug's solubility meet the required standards, forcing pharmaceutical companies to address the solubility issues of animal preparations (dispersants).

[0004] Currently, three commonly used solubilization techniques in pharmacy to enhance trimethoprim solubility include surfactant solubilization, β-cyclodextrin inclusion, and solid dispersions. The highest solubilities achieved are 0.37 mg / mL, 7.06 μg / mL, and 3.3 mg / mL, respectively. The first two methods have very limited effects on trimethoprim solubility and are of no value in pharmaceutical formulations. Furthermore, solid dispersion methods, whether using the melting, solvent, or solvent-melting methods, achieve trimethoprim concentrations of less than 17% in solid dispersions. Only the solvent-based method achieves a trimethoprim concentration of 3.3 mg / mL in aqueous solutions of trimethoprim dispersions. The specifications for the most widely used sulfamethoxine preparations in the aquaculture industry, 20% sulfamethoxine sodium and 75% sulfachloropyridazine sodium, are: 20g / 100g sulfamethoxine, 4g / 100g trimethoprim; and 62.5g / 100g sulfachloropyridazine sodium, 12.5g / 100g trimethoprim, respectively. The solubility of the preparations in the water supply dosing system of aquaculture farms is required to be at least 100g / L, which translates to a trimethoprim concentration of at least 4g / L and 12.5g / L, respectively. Therefore, the current production process for trimethoprim dispersions cannot produce products that meet these requirements. The first reason is that the content of trimethoprim in the trimethoprim dispersion is low. For example, in a 75% compound sulfachloropyridazine sodium, sulfachloropyridazine sodium accounts for 62.5%. Even if the remaining components are all trimethoprim solid dispersions, the content of trimethoprim in the solid dispersion must be at least not less than 33.333%. It can be seen that the 17% trimethoprim solid dispersion cannot meet the requirement. Secondly, the solubility requirements of 4g / L and 12.5g / L for the water line dosing device for drinking water administration cannot be met by the existing technology level.

[0005] Therefore, under the condition of ensuring the content of trimethoprim, improving the solubility of trimethoprim is a technical problem that needs to be solved urgently. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a process for preparing a fast-dissolving trimethoprim solid dispersion having a trimethoprim content of 35% or 40%, wherein the process ensures that the trimethoprim content in the trimethoprim solid dispersion product is not less than 35% and the solubility (trimethoprim content in the solution) is not less than 18 mg / mL.

[0007] To solve the above technical problems, the technical solution adopted by the present invention is: a process for preparing a fast-soluble trimethoprim solid dispersion with a content of 35% or 40%, wherein the formula of the fast-soluble trimethoprim solid dispersion with a content of 35% is: trimethoprim (TMP): cosolvent: dispersant: filler is 5:2:3:4.3, and the formula of the fast-soluble trimethoprim solid dispersion with a content of 40% is: trimethoprim (TMP): cosolvent: dispersant: filler is 5:2:3:2.5. Various materials are weighed according to the above formula ratios, trimethoprim and cosolvent are uniformly mixed, purified water and filler are added, stirred and dissolved, and then the dispersant is added. Purified water is added to make the materials into a solution with a solid content of 15%-20%, and the materials are dried using a spray dryer to prepare the trimethoprim solid dispersion.

[0008] The spray dryer conditions are set as follows: inlet temperature of 190°C-220°C, outlet temperature of 80°C-90°C, material concentration of 15%-20%, temperature of 80°C, and feed rate of 10mL / min-20mL / min.

[0009] The cosolvent is tartaric acid, malic acid or salicylic acid, the dispersant is carboxymethyl cellulose, hydroxypropyl methyl cellulose or polyvinyl pyrrolidone, and the filler is instant starch, dextrin, anhydrous glucose or maltose.

[0010] The process principle of the present invention is to utilize the alkalinity of the amino group on the pyrimidine ring of trimethoprim. This reacts with a weak acid cosolvent to increase its molecular surface charge, enhance polarizability, and thus alter its solubility, enabling trimethoprim solution concentrations to reach above 40 mg / mL. This allows trimethoprim to exist in the solution as molecules (or charged molecular groups), rather than as insoluble nanoparticles suspended in a solution (suspension) as in dispersions produced by ball milling or coating techniques. This results in a solution rather than a suspension. An appropriate amount of colloidal dispersant and readily soluble filler excipient are then added to the solution. After sufficient dissolution (which may be heated), the resulting solution is spray-dried under predetermined conditions to produce a trimethoprim solid dispersion. The spray-drying principle involves first dispersing a liquid (solution) into numerous fine droplets using a high-pressure pump or centrifugal spray device. The atomized droplets then come into contact with hot air in a drying chamber, rapidly evaporating the water and completing the drying process. The resulting powder or granules are uniform in their components and, like snow, porous, increasing their specific surface area and enabling rapid dissolution upon contact with water. The colloidal dispersant prevents hydrolysis of the trimethoprim solid dispersion during dissolution, which occurs due to a decrease in concentration and an increase in pH, leading to precipitation of the trimethoprim. The addition of a fast-dissolving filler is intended to increase the disintegration rate during dissolution (colloidal dispersant solutions can melt during spray drying, forming a dense surface that prevents solvent penetration and affects the dissolution rate. The addition of a fast-dissolving filler addresses this problem by dissolving first and causing disintegration), thereby increasing the dissolution rate of the trimethoprim dispersion.

[0011] The present invention adopts the above-mentioned process for preparing a fast-dissolving trimethoprim solid dispersion having a trimethoprim content of 35% or 40%, so that the trimethoprim content in the trimethoprim solid dispersion product is not less than 35%, and the solubility (the content of trimethoprim in the solution) is not less than 18 mg / mL. The preparation process of the present invention is simple and improves the solubility of trimethoprim while ensuring the trimethoprim content. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 It is the ultraviolet scanning spectrum of the wavelength of the trimethoprim standard reference substance of the present invention;

[0013] Figure 2 This is a wavelength ultraviolet scanning spectrum of the 40% trimethoprim solid dispersion of the present invention;

[0014] Figure 3 This is the liquid chromatography identification spectrum of the trimethoprim reference substance of the present invention;

[0015] Figure 4 This is a liquid chromatography identification spectrum of the trimethoprim solid dispersion of the present invention;

[0016] Figure 5is the hydrogen NMR spectrum of trimethoprim and solid dispersion of the present invention;

[0017] Figure 6 is the carbon NMR spectrum of trimethoprim and solid dispersion of the present invention;

[0018] Figure 7 This is the dissolution curve for detecting and identifying trimethoprim of the present invention. DETAILED DESCRIPTION

[0019] The following is a detailed description of the preparation process of a fast-dissolving trimethoprim solid dispersion containing 35% or 40% trimethoprim in conjunction with the accompanying drawings.

[0020] The present invention provides a process for preparing a 40% instant trimethoprim solid dispersion. The instant trimethoprim solid dispersion has a formula of trimethoprim (TMP): cosolvent: dispersant: filler in a ratio of 5:2:3:2.5. A 35% instant trimethoprim solid dispersion has a formula of trimethoprim (TMP): cosolvent: dispersant: filler in a ratio of 5:2:3:4.3. The various materials are weighed according to the aforementioned ratios. The trimethoprim and cosolvent are uniformly mixed. Purified water and filler are added, stirred to dissolve, and then the dispersant is added. Purified water is added to form a solution with a solid content of 15%-20%. The solution is then dried using a spray dryer to prepare the trimethoprim solid dispersion.

[0021] The cosolvent is tartaric acid, malic acid, or salicylic acid; the dispersant is carboxymethyl cellulose, hydroxypropyl methyl cellulose, or polyvinyl pyrrolidone; and the filler is instant starch, dextrin, anhydrous glucose, or maltose. Spray dryer conditions are: inlet temperature 150°C-190°C, outlet temperature 80°C-90°C, material concentration 15%-20%, temperature 80°C, and feed rate 10mL / min-20mL / min.

[0022] Example 1,

[0023] The invention discloses a process for preparing a fast-dissolving trimethoprim solid dispersion with a solid content of 35%. The formula of the fast-dissolving trimethoprim solid dispersion is as follows: 10 g of trimethoprim (TMP), 4 g of tartaric acid, 6 g of hydroxypropyl methylcellulose, and 8.6 g of dextrin. Various materials are weighed according to the formula, the trimethoprim and tartaric acid are uniformly mixed, purified water and dextrin are added, the materials are stirred and dissolved, hydroxypropyl methylcellulose is added, and purified water is added to prepare a solution with a solid content of 15%-20%. The solution is dried using a spray dryer to prepare the trimethoprim solid dispersion.

[0024] The spray dryer conditions were set as follows: inlet temperature of 170°C, outlet temperature of 85°C, material concentration of 18%, liquid temperature of 80°C, and feed rate of 15 mL / min.

[0025] Example 2,

[0026] The present invention provides a process for preparing a fast-dissolving trimethoprim solid dispersion with a solid content of 35%. The formula of the fast-dissolving trimethoprim solid dispersion is as follows: 10g of trimethoprim (TMP), 4g of malic acid, 6g of carboxymethyl cellulose, and 8.6g of dextrin. Various materials are weighed according to the formula, the trimethoprim and malic acid are uniformly mixed, purified water and dextrin are added, and the materials are stirred and dissolved. After that, carboxymethyl cellulose is added, and purified water is added to prepare a solution with a solid content of 15%. The solution is dried using a spray dryer to prepare the trimethoprim solid dispersion.

[0027] The spray dryer conditions were set as follows: inlet temperature of 170°C, outlet temperature of 85°C, material concentration of 18%, liquid temperature of 80°C, and feed rate of 15 mL / min.

[0028] Example 3,

[0029] The present invention provides a process for preparing a fast-dissolving trimethoprim solid dispersion with a solid content of 35%. The formula of the fast-dissolving trimethoprim solid dispersion is as follows: 10g of trimethoprim (TMP), 4g of tartaric acid, 6g of polyvinyl pyrrolidone, and 8.6g of anhydrous glucose. Various materials are weighed according to the formula, the trimethoprim and tartaric acid are uniformly mixed, purified water and anhydrous glucose are added, the materials are stirred and dissolved, and then polyvinyl pyrrolidone is added. Purified water is added to prepare a solution with a solid content of 18%, and the solution is dried using a spray dryer to prepare the trimethoprim solid dispersion.

[0030] The spray dryer conditions were set as follows: inlet temperature of 160°C, outlet temperature of 80°C, material concentration of 20%, liquid temperature of 80°C, and feed rate of 20 mL / min.

[0031] Example 4,

[0032] The present invention provides a process for preparing a fast-dissolving trimethoprim solid dispersion with a solid content of 40%. The formula of the fast-dissolving trimethoprim solid dispersion is: 10g of trimethoprim (TMP), 4g of tartaric acid, 6g of polyvinyl pyrrolidone, and 5g of dextrin. Various materials are weighed according to the formula, the trimethoprim and tartaric acid are uniformly mixed, purified water and dextrin are added, and the materials are stirred and dissolved. After that, polyvinyl pyrrolidone is added, and purified water is added to prepare a solution with a solid content of 18%. The solution is dried using a spray dryer to prepare the trimethoprim solid dispersion.

[0033] The spray dryer conditions were set as follows: inlet temperature of 170°C, outlet temperature of 80°C, material concentration of 18%, liquid temperature of 80°C, and feed rate of 20 mL / min.

[0034] Example 5,

[0035] The present invention provides a process for preparing a fast-dissolving trimethoprim solid dispersion with a solid content of 40%. The formula of the fast-dissolving trimethoprim solid dispersion is: 10g of trimethoprim (TMP), 4g of malic acid, 6g of polyvinyl pyrrolidone, and 5g of dextrin. Various materials are weighed according to the formula, the trimethoprim and malic acid are uniformly mixed, purified water and dextrin are added, the materials are stirred and dissolved, and then polyvinyl pyrrolidone is added. Purified water is added to prepare a solution with a solid content of 15%, and the solution is dried using a spray dryer to prepare the trimethoprim solid dispersion.

[0036] The spray dryer conditions were set as follows: inlet temperature of 180°C, outlet temperature of 80°C, material concentration of 15%, liquid temperature of 80°C, and feed rate of 20 mL / min.

[0037] Example 6,

[0038] The present invention provides a process for preparing a fast-dissolving trimethoprim solid dispersion with a solid content of 40%. The formula of the fast-dissolving trimethoprim solid dispersion is as follows: 10g of trimethoprim (TMP), 4g of tartaric acid, 6g of polyvinyl pyrrolidone, and 5g of anhydrous glucose. Various materials are weighed according to the formula, the trimethoprim and tartaric acid are uniformly mixed, purified water and anhydrous glucose are added, and the materials are stirred and dissolved. After that, polyvinyl pyrrolidone is added, and purified water is added to prepare a solution with a solid content of 18%. The solution is dried using a spray dryer to prepare the trimethoprim solid dispersion.

[0039] The spray dryer conditions were set as follows: inlet temperature of 160°C, outlet temperature of 80°C, material concentration of 16%, feed liquid temperature of 80°C, and feed rate of 20 mL / min.

[0040] The present invention detects and identifies as follows:

[0041] The trimethoprim solid dispersion samples obtained in the six examples above were numbered and their properties were measured, and the corresponding numbers were designated as sample 1, sample 2, sample 3, sample 4, sample 5, and sample 6. The raw material trimethoprim was used as a reference substance, and commercially available trimethoprim lactate was used as a reference substance.

[0042] 1. Determination of trimethoprim content

[0043] Refer to the detection method of trimethoprim in the standard of compound sulfamethoxazole sodium soluble powder in the 2020 edition of the Chinese Veterinary Pharmacopoeia, and determine it by ultraviolet spectrophotometry. Accurately weigh an appropriate amount of TMP solid dispersion (approximately equivalent to 2 mg of trimethoprim) and place it in a separatory funnel filled with an appropriate amount of water. Shake it to dissolve it completely; add 25 ml of 0.1 mol / L sodium hydroxide solution, shake it well, extract it twice with chloroform (25 ml and 20 ml), combine the chloroform solution, and place it in 50 ml. 10ml of the filtrate was accurately measured and placed in a 100ml volumetric flask, 10ml of dilute acetic acid was added, and the solution was diluted to the mark with water. The absorbance was measured at a wavelength of 271nm according to the UV-visible spectrophotometry method (Appendix 0401). The absorption coefficient of C14H18N4O3 was 0. Calculate it as 204 to get the trimethoprim content.

[0044] 2. Determination of solubility

[0045] Weigh an excess of TMP or its solid dispersion into a 50 mL volumetric flask. Add distilled water and shake at 25 ± 2°C until fully dissolved. Dilute to the mark and allow to stand to obtain a supersaturated solution. Filter the resulting solution, accurately measure 2 mL of the filtrate into a 50 mL volumetric flask, dilute with distilled water, and dilute to the mark to obtain a solution. Measure the absorbance at 271 nm using distilled water as the blank solvent to calculate the solution concentration.

[0046] 3. Determination of dissolution rate of trimethoprim solid dispersion system

[0047] Weigh a sample containing approximately 1g of TMP and use the basket method in the appendix of the 2020 edition of the Chinese Pharmacopoeia. Select 900mL of distilled water as the dissolution medium, temperature: 37±0.5℃, rotation speed: 50r / min. Take 5mL of samples at 1, 3, 5, 10, 15, 20, and 30min respectively, and add an equal volume of dissolution solution. Filter the sample through a 0.45um microporous membrane, discard the initial filtrate, take 1mL of the filtrate, and measure the absorbance at a wavelength of 271nm. According to the absorption coefficient of C14H18N4O3 Calculate the cumulative dissolution amount for 204. Perform the same test on samples 2 and 5, and trimethoprim lactate for comparison. Create a dissolution curve for each sample, plotting time on the horizontal axis and dissolution rate on the vertical axis.

[0048] 4. UV scanning

[0049] Accurately weigh 0.050 g of TMP reference substance into a 25 mL volumetric flask, dissolve it in dilute acetic acid, and dilute to the mark. Shake well and filter to obtain a 2 mg / mL TMP standard solution. Measure 2 mL of this TMP standard solution into a 100 mL volumetric flask, dilute to the mark, and filter to prepare a trimethoprim solution with a concentration of approximately 0.04 mg / mL. Perform a UV scan in the 200-400 nm wavelength range. Select one of samples 1-6 to prepare a solution containing 0.04 mg / mL TMP and perform the same UV scan.

[0050] 5. Liquid chromatography identification

[0051] Weigh a reference substance containing approximately 1g of TMP and use the method of determining the content of related substances in trimethoprim in the 2020 edition of the Chinese Pharmacopoeia. Select sample No. 5 and perform the same operation.

[0052] 6. Nuclear magnetic resonance spectrum identification

[0053] Weigh an appropriate amount of trimethoprim and dissolve it in a DMSO-D6 and D2O NMR tube, and measure its hydrogen and carbon spectra at 400 MHz; select sample No. 5 and perform the same operation.

[0054] The detection and identification results of the present invention

[0055] 1. Content and solubility

[0056] As shown in Table 1, it can be seen from Table 1 that the solubility of the trimethoprim solid dispersion is higher than that of trimethoprim lactate, regardless of the 35% sample or the 40% sample. They both increase the solubility of trimethoprim by more than 50 times; the solubility of the 35% trimethoprim solid dispersion is slightly higher than that of the 40% sample.

[0057] Table 1

[0058]

[0059] 2. Dissolution curve

[0060] See also Figure 7 ,Depend on Figure 7 As shown, in distilled water, the TMP solid dispersion dissolved 85% in 1 minute and 92.5% in 5 minutes. The cumulative dissolution rate of the API was 10% in 5 minutes, while the cumulative dissolution rate of trimethoprim lactate was 50% in 5 minutes. Compared with the API, the solubility of the TMP solid dispersion was greatly improved and was superior to that of trimethoprim lactate.

[0061] 3. UV scanning spectrum

[0062] See also Figure 1 and Figure 2The UV spectrum wavelength scanning results showed that the two characteristic absorption peaks of trimethoprim solid dispersion (226.95nm and 270.40nm) were very close to those of the reference substance (226.35nm and 270.65nm), indicating that the trimethoprim in the solid dispersion had the same structure as the reference substance trimethoprim and was the same substance.

[0063] 4. Liquid chromatography identification spectrum

[0064] See also Figure 3 and Figure 4 The liquid chromatography spectrum showed that the elution time of the trimethoprim solid dispersion solution was 15.815 minutes, which was almost identical to the elution time of trimethoprim at 15.905 minutes, confirming that they were identical substances. This indicates that no chemical changes occurred during the manufacturing process, and the properties of the trimethoprim in the solid dispersion remained unchanged.

[0065] 5. Nuclear Magnetic Resonance Hydrogen and Carbon Spectra (NMR)

[0066] See also Figure 5 and Figure 6 The nuclear magnetic resonance spectrum showed that the carbon spectrum signals of each group of trimethoprim and its solid dispersion were consistent, while the signals of the two amino groups on the pyrimidine ring of trimethoprim in the hydrogen spectrum were different, indicating that in the solid dispersion of trimethoprim, the amino groups on the pyrimidine ring reacted with weak acid to form a salt, thereby changing its solubility properties. However, the carbon spectrum signals were consistent, indicating that no changes occurred in the properties of trimethoprim.

[0067] The present invention utilizes a spray drying method to prepare a trimethoprim solid dispersion. Ultraviolet, liquid chromatography, and nuclear magnetic resonance (NMR) characterizations demonstrate that the trimethoprim solid dispersion obtained by this process is physically bound, without altering TMP properties. Its solubility and dissolution rate are both higher than those of trimethoprim lactate, demonstrating superior solubility performance. Compared to other solubilization techniques, such as surfactant solubilization, β-cyclodextrin inclusion, solvent-based solid dispersions, and melt-based solid dispersions, the trimethoprim solid dispersion produced by this technique exhibits advantages such as high content, rapid dissolution rate, and significant solubilization effect. This overcomes the challenges of poor water solubility, low absorption rate, and poor bioavailability that have plagued high-concentration compound sulfonamide dispersants.

Claims

1. A process for preparing a fast-dissolving trimethoprim solid dispersion containing 35% or 40% trimethoprim, characterized in that: The formula of a 35% instant trimethoprim solid dispersion is as follows: trimethoprim (TMP): cosolvent: dispersant: filler in a ratio of 5:2:3:4.

3. The formula of a 40% instant trimethoprim solid dispersion is as follows: trimethoprim (TMP): cosolvent: dispersant: filler in a ratio of 5:2:3:2.

5. Various materials are weighed according to the above proportions, trimethoprim and cosolvent are uniformly mixed, purified water and filler are added, stirred and dissolved, and then the dispersant is added. Purified water is added to form a solution with a solid content of 15%-20%, and the solution is dried using a spray dryer to prepare the trimethoprim solid dispersion.

2. The process for preparing a fast-dissolving trimethoprim solid dispersion containing 35% or 40% trimethoprim according to claim 1, characterized in that The spray dryer conditions are set as follows: inlet temperature of 190°C-220°C, outlet temperature of 80°C-90°C, material concentration of 15%-20%, temperature of 80°C, and feed rate of 10mL / min-20mL / min.

3. The process for preparing a fast-dissolving trimethoprim solid dispersion containing 35% or 40% trimethoprim according to claim 1, wherein The cosolvent is tartaric acid, malic acid or salicylic acid, the dispersant is carboxymethyl cellulose, hydroxypropyl methyl cellulose or polyvinyl pyrrolidone, and the filler is instant starch, dextrin, anhydrous glucose or maltose.

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