Compound furosemide tablet and preparation method thereof

Abstract

The invention belongs to the technical field of diuretic and anti-edema medicinal preparations, and particularly relates to a compound furosemide tablet and a preparation method thereof. The compound furosemide tablet comprises furosemide, amiloride hydrochloride, a stable regulator, a filler, a disintegrating agent and a lubricant. According to the compound furosemide tablet disclosed by the invention, by optimizing the stability regulator, the defect that furosemide is easy to decompose and unstable is overcome, the stability of the compound furosemide tablet is improved, the dissolution rate of the compound furosemide tablet is also improved, and the medicine effect is favorably improved.

Description

Technical Field

[0001] The invention belongs to the technical field of diuretic and anti-edema drug 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 the 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 a person skilled in the art.

[0003] Furosemide (C 12 H 11 C1N 2 O 5 As a highly effective diuretic, amiloride hydrochloride (C 6 H 8 C1N 7 O·HCl) is a potassium-sparing diuretic. The combined use of the two can synergistically enhance the diuretic effect and reduce the risk of electrolyte disturbances. At present, compound furosemide tablets have been included in the 2020 edition of the Chinese Pharmacopoeia, Part II. Its standard prescription is 1,000 tablets made of 20g furosemide and 2.5g amiloride hydrochloride, with appropriate amounts of excipients, and quality control by high-performance liquid chromatography.

[0004] However, the existing technology still has the following significant defects, for example, dissolution and stability issues. The solubility of furosemide is significantly affected by the fluctuation of pH value in the body, resulting in large differences in absorption rates among different patients and unstable bioavailability. The dissolution standard of existing compound tablets only requires that 75% of the labeled amount be reached within 30 minutes, which is difficult to meet the demand for rapid onset of action. In addition, furosemide is highly hygroscopic, and conditions such as high temperature, high humidity, and light may affect the stability of furosemide, resulting in reduced efficacy or chemical degradation.

[0005] In view of the above problems, existing technologies have attempted to improve them. For example, the Chinese patent with publication number CN 116492308 A discloses a furosemide solid preparation and its preparation method, which uses porous AERO SIL200Pharma to adsorb furosemide, and then uses microenvironment pH regulator sodium bicarbonate to adjust the pH value of the saturated solution around the drug particles, which can improve the solubility of the drug and increase the dissolution of the drug. However, these schemes have not yet achieved synergistic optimization in compound preparations, especially the lack of research on the compatibility stability of amiloride hydrochloride and furosemide. Summary of the invention

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

[0007] Furthermore, the stabilizing agent 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; the lubricant is selected from at least one of talc, magnesium stearate, and micro-powdered 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 for later use;

[0010] (2) Pretreatment with a stabilizing agent: taurine and mannitol were mixed, ethanol was added for ball milling, and dried to obtain taurine-mannitol co-crystals;

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

[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 that furosemide is 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 clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain 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 protection scope 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 respectively for later use;

[0024] (2) Pretreatment with a stabilizing agent: taurine and mannitol were added to a planetary ball mill and mixed, and 1 ml of 70% ethanol was added and ball milled for 30 min at a speed of 400 rpm, and 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 respectively for later use;

[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, and dried to obtain taurine-mannitol co-crystals;

[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 respectively for later use;

[0042] (2) Pretreatment with a stabilizing agent: taurine and mannitol were added to a planetary ball mill and mixed, and 2 ml of 75% ethanol was added and ball milled for 40 min at a speed of 450 rpm, and dried to obtain taurine-mannitol co-crystals;

[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 has a single endothermic peak at about 301°C, and the mannitol component has an endothermic peak at about 167°C. The DSC curve of the physical mixture that did not form a eutectic showed a superposition of the endothermic peaks of taurine and mannitol, and the peak shape and position were basically consistent with those of the single components. However, a melting peak (221°C) different from that of the pure components appeared in the DSC curve of the eutectic candidate, and the characteristic peaks of orthotaurine and mannitol disappeared, indicating that the taurine-mannitol eutectic was 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 respectively for later use;

[0059] (2) Mixing the main and auxiliary materials: uniformly mixing 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 respectively for later use;

[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 respectively for later use;

[0074] (2) Pretreatment with a stabilizing agent: taurine and mannitol were added to a planetary ball mill and mixed, and 1 ml of 70% ethanol was added and ball milled for 30 min at a speed of 400 rpm, and 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 content of furosemide and amiloride hydrochloride according to the HPLC method (General Rule 0512) of the 2020 edition of the Chinese Pharmacopoeia. Test solution: Take 20 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 40 mg furosemide and 5 mg amiloride hydrochloride), place in a 200 ml volumetric flask, add 15 ml methanol and 2 ml 0.1 mol / L hydrochloric acid solution, sonicate for about 15 minutes to dissolve furosemide and amiloride hydrochloride, cool, dilute to scale with mobile phase, shake well, filter, and take the filtrate. Reference solution: Take amiloride hydrochloride reference, weigh accurately, dissolve in methanol and quantitatively dilute to make a solution containing about 1 mg per 1 ml as reference solution (1); take about 40 mg of furosemide reference, weigh accurately, put 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, cool, then accurately add 5 ml of reference solution (1), dilute to scale with mobile phase, and shake well. Chromatographic conditions: octadecylsilane bonded silica gel is used as filler; water-methanol-phosphate buffer (take 13.6 g of potassium dihydrogen phosphate, add 80 ml of water to dissolve, adjust pH to 3.0 with phosphoric acid, and dilute to 100 ml with water) (50:49:1) is used as mobile phase; detection wavelength is 286 nm; injection volume is 20 μl. System suitability requirements: The number of theoretical plates calculated based on the furosemide peak is not less than 2000, and the separation between the furosemide peak and the amiloride peak should meet the requirements. Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate the contents of furosemide and amiloride hydrochloride by peak area according to the external standard method. Test conditions: temperature 40±2℃, relative humidity 75%±5%, illumination 4500lx±500lx.

[0079] Figure 1 This is the furosemide content curve in compound furosemide tablets. Figure 2 The curve of amiloride hydrochloride content in the compound furosemide tablets. By comparing the experimental data of the compound furosemide tablets of Example 1 to the compound furosemide tablets of Example 3, it is found that the sulfonic acid-mannitol eutectic is used in combination with sodium alginate to prevent the components in the compound furosemide tablets from decomposing or deteriorating, thereby extending the shelf life of the drug, ensuring that the drug remains stable during its shelf life, and ensuring its effect 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 900 ml 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 5 ml of the reference solution under the content determination item, place it in a 50 ml 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 more completely, can quickly and effectively enter the blood circulation, has good bioavailability, and helps to improve the efficacy.

Claims

1. A compound furosemide tablet, characterized in that: The compound furosemide tablets are 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 regulator, 150 to 350 parts of a filler, 10 to 30 parts of a disintegrant, and 0.5 to 3 parts of a lubricant.

2. The compound furosemide tablets according to claim 1, characterized in that: 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.

3. 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.

4. 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.

5. 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.

6. 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 terms of weight.

7. The compound furosemide tablets according to claim 1, characterized in that: The compound furosemide tablets are composed, 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.

8. A method for preparing the compound furosemide tablets according to claim 1, characterized in that: The method comprises the following steps: (1) Pretreatment of active ingredients: sieve furosemide and amiloride hydrochloride separately for later use; (2) Pretreatment with a stabilizing agent: taurine and mannitol were mixed, ethanol was added for ball milling, and dried to obtain taurine-mannitol co-crystals; (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; (4) tableting: adding a lubricant to the mixture of step (3), mixing, and tableting to obtain the product.

9. The method according to claim 8, characterized in that The mass fraction of the ethanol is 65% to 75%.

10. The method according to claim 8, characterized in that In the step (2), the ball milling time is 25 to 40 minutes and the rotation speed is 350 to 450 rpm.

Images