A compound furosemide tablet and preparation method thereof

Abstract

The present invention belongs to the technical field of diuretic and anti-edema pharmaceutical preparations, and specifically relates to a compound furosemide tablet and a preparation method thereof. The compound furosemide tablet of the present invention comprises furosemide, amiloride hydrochloride, a stabilizing agent, a filler, a disintegrant, and a lubricant. By optimizing the stabilizing agent, the present invention overcomes the defect of furosemide's easy decomposition and instability, thereby improving the stability of the compound furosemide tablet and the dissolution rate of the compound furosemide tablet, thereby contributing to improved drug efficacy.

Description

Technical Field

[0001] The present invention belongs to the technical field of diuretic and anti-edema pharmaceutical preparations, and particularly relates to a compound furosemide tablet and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Furosemide (C 12 H 11 ClN2O5S) is a highly effective diuretic widely used clinically to treat edematous diseases, hypertension, and acute renal failure. Amiloride hydrochloride (C6H8ClN7O·HCl) is a potassium-sparing diuretic. The combined use of the two can synergistically enhance the diuretic effect and reduce the risk of electrolyte imbalance. Currently, compound furosemide tablets have been included in the 2020 edition of the "Chinese Pharmacopoeia" Part II. Its standard prescription is 20g furosemide and 2.5g amiloride hydrochloride to make 1000 tablets, with appropriate excipients, and quality control is carried out by high-performance liquid chromatography.

[0004] However, existing technologies still suffer from significant drawbacks, such as dissolution and stability issues. Furosemide's solubility is significantly affected by fluctuations in pH, leading to wide variations in absorption rates among different patients and unstable bioavailability. The dissolution standard for existing compound tablets only requires 75% of the labeled amount to be reached within 30 minutes, making it difficult to meet the demand for rapid onset of action. Furthermore, furosemide is highly hygroscopic, and conditions such as high temperature, high humidity, and sunlight may affect its stability, resulting in reduced efficacy or chemical degradation.

[0005] To address these issues, existing technologies have attempted improvements. For example, Chinese patent publication number CN 116492308 A discloses a solid formulation of furosemide and its preparation method. This approach utilizes a porous AERO SIL200Pharma to adsorb furosemide, and then adjusts the pH of the saturated solution surrounding the drug particles with sodium bicarbonate, a microenvironmental pH regulator. This improves drug solubility and dissolution. However, these approaches have yet to achieve synergistic optimization in compound formulations, particularly with insufficient research on the stability of the combination of amiloride hydrochloride and furosemide. Summary of the Invention

[0006] To overcome the deficiencies of the prior art, the present invention provides a compound furosemide tablet with high stability and high solubility, which is composed, by weight, of 15 to 25 parts of furosemide, 1.5 to 3.5 parts of amiloride hydrochloride, 3.5 to 10 parts of a stabilizing agent, 150 to 350 parts of a filler, 10 to 30 parts of a disintegrant, and 0.5 to 3 parts of a lubricant.

[0007] Furthermore, the stabilizing regulator is composed of 2 to 5 parts of sodium alginate, 1 to 3 parts of taurine, and 0.5 to 2 parts of mannitol in parts by weight; the filler is selected from at least one of microcrystalline cellulose, starch, dextrin, sucrose, and lactose; the disintegrant is selected from at least one of sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose; and the lubricant is selected from at least one of talc, magnesium stearate, and micropowdered silica gel.

[0008] The present invention also provides a method for preparing the compound furosemide tablets, comprising the following steps:

[0009] (1) Pretreatment of active ingredients: sieve furosemide and amiloride hydrochloride separately and set aside;

[0010] (2) Pretreatment with a stabilizing agent: taurine and mannitol were mixed, ball-milled with ethanol, and dried to obtain taurine-mannitol cocrystals;

[0011] (3) Mixing the main and auxiliary materials: mix furosemide with taurine-mannitol eutectic, add sodium alginate, mix, add amiloride hydrochloride, filler, and disintegrant, and mix well;

[0012] (4) tableting: add lubricant to the mixture of step (3), mix, and tablet.

[0013] Furthermore, the mass fraction of ethanol is 65% to 75%; the ball milling time in step (2) is 25 to 40 minutes, and the rotation speed is 350 to 450 rpm.

[0014] Compared with the prior art, the technical effects of the present invention are:

[0015] The present invention utilizes taurine-mannitol eutectic and sodium alginate as stabilizing regulators, thereby overcoming the defect of furosemide being easily decomposed and unstable, improving the stability of the compound furosemide tablets, and also improving the solubility of the compound furosemide tablets. The active ingredients can quickly and effectively enter the blood circulation, have good bioavailability, and help to improve the efficacy of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 : Furosemide content curve in compound furosemide tablets.

[0017] Figure 2 : Amiloride hydrochloride content curve in compound furosemide tablets. DETAILED DESCRIPTION

[0018] In order to make the purpose and technical solution of the present invention more clear, the present invention is further described below in conjunction with the embodiments, but the scope of protection of the present invention is not limited to these embodiments, and the embodiments are only used to illustrate the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the scope of protection of the present invention.

[0019] Example 1 Compound Furosemide Tablets

[0020] formula:

[0021]

[0022] Preparation method:

[0023] (1) Pretreatment of active ingredients: Furosemide and amiloride hydrochloride were sieved through a 100-mesh sieve and set aside;

[0024] (2) Pretreatment with a stabilizing agent: Taurine and mannitol were added to a planetary ball mill and mixed. 1 ml of 70% ethanol was added and ball-milled for 30 min at a speed of 400 rpm. The mixture was then dried to obtain taurine-mannitol co-crystals.

[0025] (3) Mixing the main and auxiliary materials: mix furosemide with taurine-mannitol eutectic, add sodium alginate, mix, add amiloride hydrochloride, filler, and disintegrant, and mix well;

[0026] (4) tableting: adding a lubricant to the mixture of step (3), mixing, and tableting to obtain the product.

[0027] Example 2 Compound Furosemide Tablets

[0028] formula:

[0029]

[0030]

[0031] Preparation method:

[0032] (1) Pretreatment of active ingredients: Furosemide and amiloride hydrochloride were sieved through a 100-mesh sieve and set aside;

[0033] (2) Pretreatment with a stabilizing agent: Taurine and mannitol were added to a planetary ball mill and mixed. 0.5 ml of 65% ethanol was added and ball-milled for 25 min at a speed of 350 rpm. The mixture was then dried to obtain taurine-mannitol cocrystals.

[0034] (3) Mixing the main and auxiliary materials: mix furosemide with taurine-mannitol eutectic, add sodium alginate, mix, add amiloride hydrochloride, filler, and disintegrant, and mix well;

[0035] (4) tableting: adding a lubricant to the mixture of step (3), mixing, and tableting to obtain the product.

[0036] Example 3 Compound Furosemide Tablets

[0037] formula:

[0038]

[0039]

[0040] Preparation method:

[0041] (1) Pretreatment of active ingredients: Furosemide and amiloride hydrochloride were sieved through a 100-mesh sieve and set aside;

[0042] (2) Pretreatment with a stabilizing agent: Taurine and mannitol were added to a planetary ball mill and mixed. 2 ml of 75% ethanol was added and ball milled for 40 min at 450 rpm. The mixture was dried to obtain taurine-mannitol cocrystals.

[0043] (3) Mixing the main and auxiliary materials: mix furosemide with taurine-mannitol eutectic, add sodium alginate, mix, add amiloride hydrochloride, filler, and disintegrant, and mix well;

[0044] (4) tableting: adding a lubricant to the mixture of step (3), mixing, and tableting to obtain the product.

[0045] Validation of Taurine-Mannitol Cocrystal

[0046] Pure component controls: Prepare single component samples of taurine and mannitol, respectively.

[0047] Physical mixture: Taurine and mannitol were mixed in a mass ratio of 2:1 and uniformly dispersed by ball milling.

[0048] Co-crystal candidate: prepared according to the taurine-mannitol co-crystal in Example 1.

[0049] Differential scanning calorimetry (DSC) was used for verification, with a heating rate of 10°C / min, a test temperature range of 80°C to 350°C, and a nitrogen protection flow rate of 50 ml / min.

[0050] Table 1 Taurine-mannitol cocrystal verification

[0051] sample Absorption peak temperature (℃) Absorption peak characteristics Taurine Single Component 301 Sharp single peak Mannitol single component 167 Single peak physical mixture 166，301 Twin Peaks Cocrystal candidates 221 New single peak, no original component peak

[0052] As shown in Table 1, the taurine component exhibits a single endothermic peak at approximately 301°C, and the mannitol component exhibits an endothermic peak at approximately 167°C. The DSC curve of the physical mixture in which no eutectic is formed shows a superposition of the endothermic peaks of taurine and mannitol, and the peak shape and position are basically consistent with those of the single components. However, the DSC curve of the eutectic candidate exhibits a melting peak (221°C) different from that of the pure components, and the characteristic peaks of orthotaurine and mannitol disappear, indicating that the taurine-mannitol eutectic is indeed formed.

[0053] Comparative Example 1 Compound Furosemide Tablets

[0054] formula:

[0055]

[0056]

[0057] Preparation method:

[0058] (1) Pretreatment of active ingredients: Furosemide and amiloride hydrochloride were sieved through a 100-mesh sieve and set aside;

[0059] (2) Mixing the main and auxiliary materials: Evenly mix furosemide, amiloride hydrochloride, filler, and disintegrant;

[0060] (4) tableting: adding a lubricant to the mixture of step (3), mixing, and tableting to obtain the product.

[0061] Comparative Example 2 Compound Furosemide Tablets

[0062] formula:

[0063]

[0064] Preparation method:

[0065] (1) Pretreatment of active ingredients: Furosemide and amiloride hydrochloride were sieved through a 100-mesh sieve and set aside;

[0066] (2) Pretreatment with a stabilizing agent: taurine and mannitol were added to a planetary ball mill and mixed to obtain a taurine-mannitol physical mixture;

[0067] (3) Mixing the main and auxiliary materials: mix furosemide with the taurine-mannitol physical mixture, add sodium alginate, mix, add amiloride hydrochloride, filler, and disintegrant, and mix well;

[0068] (4) tableting: adding a lubricant to the mixture of step (3), mixing, and tableting to obtain the product.

[0069] Comparative Example 3 Compound Furosemide Tablets

[0070] formula:

[0071]

[0072] Preparation method:

[0073] (1) Pretreatment of active ingredients: Furosemide and amiloride hydrochloride were sieved through a 100-mesh sieve and set aside;

[0074] (2) Pretreatment with a stabilizing agent: Taurine and mannitol were added to a planetary ball mill and mixed. 1 ml of 70% ethanol was added and ball-milled for 30 min at a speed of 400 rpm. The mixture was then dried to obtain taurine-mannitol co-crystals.

[0075] (3) Mixing the main and auxiliary materials: Mix furosemide with taurine-mannitol eutectic, add amiloride hydrochloride, filler, and disintegrant, and mix well;

[0076] (4) tableting: adding a lubricant to the mixture of step (3), mixing, and tableting to obtain the product.

[0077] Stability Verification of Compound Furosemide Tablets

[0078] Determine the contents of furosemide and amiloride hydrochloride according to the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0512) by high-performance liquid chromatography. Test solution: Take 20 tablets of this product, accurately weigh them, and grind them into a fine powder. Accurately weigh an appropriate amount (approximately equivalent to 40 mg of furosemide and 5 mg of amiloride hydrochloride) and place them in a 200-ml volumetric flask. Add 15 ml of methanol and 2 ml of 0.1 mol / L hydrochloric acid solution. Ultrasonicate for approximately 15 minutes to dissolve the furosemide and amiloride hydrochloride. Cool, dilute to the mark with mobile phase, shake well, filter, and collect the filtrate. Reference solution: Take amiloride hydrochloride reference, accurately weigh it, dissolve it in methanol and quantitatively dilute it to make a solution containing about 1 mg per 1 ml as reference solution (1); take about 40 mg of furosemide reference, accurately weigh it, place it in a 200 ml volumetric flask, add 15 ml of methanol and 2 ml of 0.1 mol / L hydrochloric acid solution, sonicate for about 15 minutes, let it cool, then accurately add 5 ml of reference solution (1), dilute it to the mark with mobile phase, and shake it well. Chromatographic conditions: use octadecylsilane bonded silica gel as the filler; use water-methanol-phosphate buffer (take 13.6 g of potassium dihydrogen phosphate, add 80 ml of water to dissolve it, adjust the pH value to 3.0 with phosphoric acid, and dilute it to 100 ml with water) (50:49:1) as the mobile phase; the detection wavelength is 286 nm; the injection volume is 20 μl. System suitability requirements: The number of theoretical plates calculated based on the furosemide peak must be no less than 2000, and the resolution between the furosemide and amiloride peaks must meet the required resolution. Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph, and record the chromatograms. Calculate the furosemide and amiloride hydrochloride contents, respectively, based on the peak areas, using the external standard method. Test conditions: Temperature 40 ± 2°C, relative humidity 75% ± 5%, illumination 4500 lx ± 500 lx.

[0079] Figure 1 This is the furosemide content curve in compound furosemide tablets. Figure 2 The figure shows the amiloride hydrochloride content in compound furosemide tablets. Comparing the experimental data from compound furosemide tablets in Examples 1 to 3, it was found that the combination of sulfonic acid-mannitol cocrystal and sodium alginate prevents the decomposition or deterioration of the components in the compound furosemide tablets, thereby extending the drug's shelf life and ensuring its stability during its shelf life, thereby maintaining its effectiveness in the body.

[0080] Dissolution

[0081] Determine according to the dissolution and release determination method (General Rule 0931 Method 2) of the 2020 edition of the "Chinese Pharmacopoeia". Dissolution conditions: Use 900ml of phosphate buffer (pH 5.8) as the dissolution medium, the rotation speed is 50 revolutions per minute, operate according to the law, and take samples after 30 minutes. Test solution: Take an appropriate amount of dissolution solution, filter, and take the filtrate. Reference solution: Accurately measure 5ml of the reference solution under the content determination item, place it in a 50ml volumetric flask, dilute to the scale with the dissolution medium, and shake well. Chromatographic conditions and system suitability requirements: See under the content determination item. Determination method: See under the content determination item. Calculate the solubility of each tablet of furosemide and amiloride hydrochloride respectively.

[0082] Table 2 Dissolution of furosemide and amiloride hydrochloride (%)

[0083]

[0084]

[0085] As shown in Table 2, the drug in the compound furosemide tablets of Examples 1 to 3 of the present invention is released relatively completely, can quickly and effectively enter the blood circulation, has good bioavailability, and helps to improve drug efficacy.

Claims

1. A compound furosemide tablet, characterized in that: The compound furosemide tablets are composed, by weight, of 15-25 parts of furosemide, 1.5-3.5 parts of amiloride hydrochloride, 3.5-10 parts of a stabilizing agent, 150-350 parts of a filler, 10-30 parts of a disintegrant, and 0.5-3 parts of a lubricant; the stabilizing agent is composed, by weight, of 2-5 parts of sodium alginate, 1-3 parts of taurine, and 0.5-2 parts of mannitol. The preparation method of the compound furosemide tablets comprises the following steps: (1) Pretreatment of active ingredients: sieve furosemide and amiloride hydrochloride separately and set aside; (2) Pretreatment with a stabilizing agent: taurine and mannitol were mixed, ball-milled with ethanol, and dried to obtain taurine-mannitol cocrystals; (3) Mixing the main and auxiliary materials: mix furosemide with taurine-mannitol eutectic, add sodium alginate, mix, add amiloride hydrochloride, filler, disintegrant, and mix evenly; (4) Tableting: Add lubricant to the mixture in step (3), mix, and tablet.

2. The compound furosemide tablets according to claim 1, characterized in that The filler is selected from at least one of microcrystalline cellulose, starch, dextrin, sucrose and lactose.

3. The compound furosemide tablets according to claim 1, characterized in that The disintegrant is selected from at least one of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose.

4. The compound furosemide tablets according to claim 1, characterized in that The lubricant is selected from at least one of talc, magnesium stearate, and micro-powder silica gel.

5. The compound furosemide tablets according to claim 1 or 2, characterized in that: The stabilizing regulator is composed of 4 parts of sodium alginate, 2 parts of taurine and 1 part of mannitol in parts by weight.

6. The compound furosemide tablets according to claim 1, characterized in that The compound furosemide tablets are composed, calculated by weight, of 20 parts of furosemide, 2.5 parts of amiloride hydrochloride, 7 parts of a stabilizing agent, 251 parts of a filler, 18 parts of a disintegrant, and 1.5 parts of a lubricant.

7. The compound furosemide tablets according to claim 1, characterized in that The mass fraction of the ethanol is 65% to 75%.

8. The compound furosemide tablets according to claim 1, characterized in that In the step (2), the ball milling time is 25-40 min and the rotation speed is 350-450 rpm.

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