A furosemide solid preparation and its preparation method

Abstract

The present invention provides a furosemide solid preparation and a preparation method thereof, relating to the technical field of medicine. The solid preparation described in the present invention comprises the following components: furosemide, microenvironment pH regulator, preparation porosity regulator, diluent, disintegrant, lubricant. The microenvironment pH regulator is sodium bicarbonate, and the preparation porosity regulator is hydrophilic AEROSIL 200Pharma. In the present invention, porous AEROSIL 200Pharma is used to adsorb furosemide, and then sodium bicarbonate, the microenvironment pH regulator, is used to adjust the pH value of the saturated solution around the drug particles, which can improve the solubility of the drug and increase the drug dissolution.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a furosemide solid preparation and a preparation method thereof. Background Art

[0002] Furosemide is a rapid-acting and highly effective diuretic, also known as frusemide (with aliases such as diuretic sulfonamide, furanphenylalanine, proline, etc.). Furosemide can inhibit the tubular absorption function and promote the excretion of water, sodium, chlorine, potassium, calcium, magnesium, phosphorus, etc. Furosemide can inhibit the activity of prostaglandin-decomposing enzyme, increase the content of prostaglandin E2, and thus has a vasodilating effect. It dilates renal blood vessels, reduces renal vascular resistance, and increases renal blood flow, especially the blood flow in the deep part of the renal cortex. Furosemide can dilate the pulmonary volume veins, reduce the permeability of pulmonary capillaries, and combined with its diuretic effect, reduce the return blood volume and the left ventricular end-diastolic pressure, which helps in the treatment of acute left heart failure. Its dosage forms include tablets, granules, sustained-release tablets, and injections. It has the characteristics of rapid and short diuretic effect, high efficacy, wide indications, and small side effects, and is widely used in the treatment of various diseases such as edema caused by heart, kidney, and liver diseases, dysfunction, or peripheral edema and cerebral edema caused by vascular wall disorders.

[0003] Furosemide is a compound of the furoaniline acid class, with the chemical name of 2-[(2-furfuryl)amino]]-5-(aminosulfonyl)-4-chlorobenzoic acid, and the molecular formula is C 12 H 11 ClN2O5S, and the structural formula is as follows.

[0004]

[0005] Patent CN 1682709 A provides a furosemide orally disintegrating tablet and a preparation method thereof. This orally disintegrating tablet does not require drinking water, which reduces the burden on patients. Moreover, this orally disintegrating tablet successfully solves the problems of large amount of excipients used, insoluble in water, and insoluble substances remaining after disintegration by using the pre-treatment method before tabletting. This orally disintegrating tablet contains furosemide, diluent, disintegrant, and lubricant, and its weight composition is 5-40% of furosemide; 30-80% of diluent; 5-25% of disintegrant; 0.1-5% of lubricant.

[0006] Patent CN 1771933A discloses a furosemide dropping pill and its preparation process. The furosemide dropping pill is prepared by formulating furosemide with a dropping pill matrix. The weight ratio of furosemide to the dropping pill matrix in this invention is 1:1 - 1:10. The dropping pill matrix is one or several combinations of polyethylene glycols, sodium carboxymethyl starch, poloxamer, sodium carboxymethyl cellulose, stearic acid, sodium stearate, polyoxyethylene monostearate, and the content of each combination component is not equal to zero.

[0007] Furosemide is extremely slightly soluble in water, with a solubility of 0.01mg·mL -1, which belongs to weak acid, with a pKa value of 3.9, a LogP value of 0.74, and a CLogP value of 1.9. It belongs to BCS class IV with low solubility and low permeability, and the drug dissolution is the rate-limiting step of drug absorption.

[0008] Furosemide is a weak acidic drug whose solubility increases with the increase of pH. The release of the drug is pH-dependent, rather than the ideal non-pH-dependent release characteristics. Food can also change the pH value of the gastrointestinal tract. Eating will slow down absorption, and there are also significant differences in the gastrointestinal pH of different patients, and there are also differences in the absorption rate and extent. Therefore, strategies need to be developed to overcome the influence of the in vivo pH value on dissolution, to improve the rate and / or extent of drug absorption (Cmax and / or AUC), and to reduce the inter-individual differences.

[0009] Based on the above problems, the present invention provides a furosemide solid preparation, aiming to overcome the problem that the dissolution of furosemide is affected by the in vivo pH value, resulting in differences in the rate and / or extent of drug absorption in different patients. Taking Summary of the Invention

[0010] In view of the above problems, the present invention provides a furosemide solid preparation and its preparation method. Taking

[0011] as the reference preparation, through human bioequivalence test research, the furosemide tablets prepared by the present invention are bioequivalent to the reference preparation, and the individual differences are smaller than those of the reference preparation.

[0012] On the one hand, the present invention provides a furosemide solid preparation, and the solid preparation comprises the following components: furosemide, microenvironment pH regulator, preparation porosity regulator, diluent, disintegrant, lubricant. The microenvironment pH regulator is sodium bicarbonate, and the preparation porosity regulator is hydrophilic AEROSIL 200Pharma.

[0013] Preferably, the weight parts of the components can be: 18-23 parts of furosemide, 12-18 parts of microenvironment pH regulator, 3-7 parts of preparation porosity regulator, 45-54 parts of diluent, 5-11 parts of disintegrant, 0.1-3 parts of lubricant.

[0014] More preferably, the weight parts of the components can be: 19-21 parts of furosemide, 14-16 parts of microenvironment pH regulator, 4-6 parts of preparation porosity regulator, 18-52 parts of diluent, 6-9 parts of disintegrant, 0.5-2 parts of lubricant.

[0015] More preferably, the parts by weight of the components may be: 20 parts of furosemide, 15 parts of microenvironment pH regulator, 5 parts of preparation porosity regulator, 50.5 parts of diluent, 8 parts of disintegrant, and 1.5 parts of lubricant.

[0016] More preferably, the parts by weight of the components may be: 20 parts of furosemide, 15 parts of microenvironment pH regulator, 5 parts of preparation porosity regulator, 51 parts of diluent, 8 parts of disintegrant, and 1 part of lubricant.

[0017] Preferably, the diluent comprises at least one of sucrose, lactose, starch, microcrystalline cellulose, and mannitol. Further preferably, the diluent may be lactose.

[0018] Preferably, the disintegrant comprises at least one of croscarmellose sodium, sodium carboxymethyl starch, and pregelatinized starch; further preferably, the disintegrant may be pregelatinized starch.

[0019] Preferably, the lubricant comprises at least one of magnesium stearate, silicon dioxide, and talcum powder; further preferably, the lubricant comprises at least one of magnesium stearate and talcum powder.

[0020] On the other hand, the preparation method of the above solid preparation comprises at least one of powder direct compression and dry granulation, and preferably, it is powder direct compression.

[0021] The present invention provides a powder direct compression preparation method for a furosemide solid preparation, comprising the following steps:

[0022] 1) Mix the prescribed amount of furosemide and microenvironment pH regulator for 3 - 8 minutes and then pass through a sieve to obtain mixture 1;

[0023] 2) Weigh the prescribed amount of AEROSIL 200Pharma and mix it with mixture 1 for 3 - 8 minutes, then pass through a sieve mesh, and mix for another 5 - 10 minutes, and pass through a sieve to obtain mixture 2;

[0024] 3) Pass the diluent and disintegrant through a sieve and weigh them according to the prescribed amount, mix them with mixture 2 for 3 - 8 minutes to obtain mixture 3;

[0025] 4) Pass the lubricant through a sieve and weigh it according to the prescribed amount, mix it with mixture 3 for 3 - 8 minutes to obtain mixture 4;

[0026] 5) Tablet pressing: Use a tablet press to press the mixture obtained in 4) into tablets with a weight of 100 mg per tablet, and thus obtain furosemide tablets.

[0027] The present invention provides a dry granulation preparation method for a furosemide solid preparation, comprising the following steps:

[0028] 1) Mix the prescribed amount of furosemide and the microenvironment pH regulator for 3 - 8 minutes, then sieve to obtain Mixture 1;

[0029] 2) Weigh the prescribed amount of AEROSIL 200Pharma and mix it with Mixture 1 for 3 - 8 minutes, then sieve through a sieve mesh, mix for another 5 - 10 minutes, and sieve to obtain Mixture 2;

[0030] 3) Sieve the diluent and disintegrant, then weigh them according to the prescription amount, and mix them with Mixture 2 for 3 - 8 minutes to obtain Mixture 3;

[0031] 4) Sieve the lubricant, then weigh it according to the prescription amount, and mix it with Mixture 3 for 3 - 8 minutes to obtain Mixture 4;

[0032] 5) Dry - press and crush Mixture 4 with a dry granulator, sieve it, and then mix it with 0.5 - 1.5 g of the sieved lubricant for 5 - 10 minutes to obtain intermediate granules.

[0033] 6) Tablet - making: Use a tableting machine to press the intermediate granules obtained in 5) into tablets at a heavy pressure of 100 mg per tablet to obtain furosemide tablets.

[0034] Preferably, the pH of the aqueous solution of Mixture 1 obtained in step 1) described in the above two preparation methods can be 5.8 - 8.0; Further preferably, the pH of the aqueous solution of Mixture 1 obtained in step 1) can be 6.8 - 7.2.

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

[0036] The porosity of AEROSIL 200Pharma has a high loading capacity. The present invention uses porous AEROSIL 200Pharma to adsorb furosemide, and then uses the 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 drug dissolution. Detailed Embodiments

[0037] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the following specific embodiments are used to further clarify the present invention. However, the following embodiments are only the preferred embodiments of the present invention, not all of them. Based on the embodiments in the implementation manners, other embodiments obtained by those skilled in the art without creative efforts all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all ordinary commercially available products, and no specific limitation is made on their sources. The technical and scientific terms used in the embodiments have the same meanings as those commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0038] Example 1

[0039] Preparation of Furosemide Tablets by Direct Compression of Powder

[0040] The prescription composition is as follows (total of 1000 tablets are prepared):

[0041] Raw and auxiliary materials Weight (g) Function Furosemide 20 Active ingredient Sodium bicarbonate 15 Microenvironment pH regulator AEROSIL 200Pharma 5 Porosity regulator Lactose 51 Diluent Pregelatinized starch 8 Disintegrant Magnesium stearate 1 Lubricant

[0042] Preparation process:

[0043] 1) Weigh 20 g of furosemide and 15 g of the microenvironment pH regulator sodium bicarbonate, mix for 5 min, and then pass through an 80-mesh sieve for standby;

[0044] 2) Weigh 5 g of AEROSIL 200Pharma and mix it with the mixture obtained in 1) for 5 min, then pass through an 80-mesh sieve. After mixing for another 5 min, pass through an 80-mesh sieve again for standby;

[0045] 3) Pass lactose and pregelatinized starch through a 60-mesh sieve, then weigh 51 g and 8 g respectively, and mix them with the mixture obtained in 2) for 5 min for standby;

[0046] 4) Pass magnesium stearate through a 20-mesh sieve, then weigh 1 g, and mix it with the mixture obtained in 3) for 5 min to obtain uniformly mixed intermediate granules;

[0047] 5) Use a tableting machine to press the intermediate granules obtained in 4) into tablets at a weight of 100 mg per tablet to obtain furosemide tablets by direct compression of powder, and the pH of its solution is 7.0.

[0048] Example 2

[0049] Preparation of Furosemide Tablets by Dry Granulation Process

[0050] The prescription composition is as follows (total of 1000 tablets are prepared):

[0051]

[0052]

[0053] Preparation process:

[0054] 1) Weigh 20 g of furosemide and 15 g of the microenvironment pH regulator sodium bicarbonate, mix for 5 min, and then pass through an 80-mesh sieve for standby;

[0055] 2) Weigh 5 g of AEROSIL 200Pharma and mix it with the mixture obtained in 1) for 5 min, then pass through an 80-mesh sieve. After mixing for another 5 min, pass through an 80-mesh sieve again for standby;

[0056] 3) Pass lactose and pregelatinized starch through a 60-mesh sieve, then weigh 50.5 g and 8 g respectively, and mix them with the mixture obtained in 2) for 5 min for standby;

[0057] 4) Weigh 0.5 g of talcum powder after passing through a 20-mesh sieve, mix it with the mixture obtained in 3) for 5 min, and set aside;

[0058] 5) Dry-press and crush the material obtained in 4) with a dry granulator, pass it through a 20-mesh sieve, and then mix it with 1 g of magnesium stearate that has passed through a 20-mesh sieve for 5 minutes to obtain uniformly mixed intermediate granules;

[0059] 6) Use a tableting machine to press the intermediate granules obtained in 5) into tablets at a weight of 100 mg per tablet to obtain dry granulation furosemide tablets, and the pH value of its solution is 7.0.

[0060] Comparative Example 1

[0061] Preparation of direct powder compression furosemide tablets:

[0062] The prescription composition is as follows (a total of 1000 tablets are prepared):

[0063] Raw and auxiliary materials Weight (g) Function Furosemide 20 Active ingredient Starch 15 Diluent AEROSIL 200Pharma 5 Porosity regulator Lactose 51 Diluent Pregelatinized starch 8 Disintegrant Magnesium stearate 1 Lubricant

[0064] Preparation process:

[0065] 1) Weigh 20 g of furosemide and 5 g of AEROSIL 200 Pharma, mix them for 5 min, and then pass through an 80-mesh sieve, and set aside;

[0066] 2) Pass lactose, starch, and pregelatinized starch through a 60-mesh sieve, weigh 51 g, 15 g, and 8 g respectively, mix them with the mixture obtained in 1) for 5 min, and set aside;

[0067] 3) Weigh 1 g of magnesium stearate after passing through a 20-mesh sieve, mix it with the mixture obtained in 2) for 5 min to obtain uniformly mixed intermediate granules;

[0068] 4) Use a tableting machine to press the intermediate granules obtained in 3) into tablets at a weight of 100 mg per tablet to obtain direct powder compression furosemide tablets, and the pH value of its solution is 4.5.

[0069] Comparative Example 2

[0070] Preparation of furosemide tablets by direct powder compression process:

[0071] The prescription composition is as follows (a total of 1000 tablets are prepared):

[0072] Raw and auxiliary materials Weight (g) Function Furosemide 20 Active ingredient Sodium bicarbonate 15 Microenvironment pH regulator Lactose 56 Diluent Pregelatinized starch 8 Disintegrant Magnesium stearate 1 Lubricant

[0073] Preparation process:

[0074] 1) Weigh 20 g of furosemide and 15 g of the microenvironment pH regulator sodium bicarbonate, mix them for 5 min, and then pass through an 80-mesh sieve, and set aside;

[0075] 2) After passing lactose and pregelatinized starch through a 60-mesh sieve, weigh 56 g and 8 g respectively, mix with the mixture obtained in 1) for 5 min, and set aside;

[0076] 3) After passing magnesium stearate through a 20-mesh sieve, weigh 1 g, mix with the mixture obtained in 2) for 5 min, and obtain uniformly mixed intermediate granules;

[0077] 4) Using a tableting machine, tablet the intermediate granules obtained in 3) at a tablet weight of 100 mg to obtain powder direct compression furosemide tablets, and the pH value of its solution is 7.0.

[0078] Comparative Example 3

[0079] Preparation of powder direct compression furosemide tablets:

[0080] The prescription composition is as follows (a total of 1000 tablets are prepared):

[0081] Raw and auxiliary materials Weight (g) Function Furosemide 20 Active ingredient Starch 15 Diluent Lactose 56 Diluent Pregelatinized starch 8 Disintegrant Magnesium stearate 1 Lubricant

[0082] Preparation process:

[0083] 1) Pass furosemide through an 80-mesh sieve, pass starch, lactose and pregelatinized starch through a 60-mesh sieve, and pass magnesium stearate through a 20-mesh sieve, and set aside;

[0084] 2) Weigh 20 g of furosemide, 15 g of starch, 56 g of lactose and 8 g of pregelatinized starch in 1) and mix for 10 min, and set aside;

[0085] 3) Weigh 1 g of magnesium stearate in 1), mix with the mixture obtained in 2) for 5 min, and obtain uniformly mixed intermediate granules;

[0086] 4) Using a tableting machine, tablet the intermediate granules obtained in 3) at a tablet weight of 100 mg to obtain powder direct compression furosemide tablets, and the pH value of its solution is 4.5.

[0087] Comparative Example 4

[0088] Preparation of powder direct compression furosemide tablets:

[0089] The prescription composition is as follows (a total of 1000 tablets are prepared):

[0090] Raw and auxiliary materials Weight (g) Function Furosemide 20 Active ingredient Sodium bicarbonate 15 Microenvironment pH regulator Lactose 54 Diluent Pregelatinized starch 8 Disintegrant Magnesium stearate 1 Lubricant AEROSIL 200Pharma 2 Glidant

[0091] Preparation process:

[0092] 1) Weigh 20 g of furosemide and 15 g of microenvironment pH regulator sodium bicarbonate, mix for 5 min, and then pass through an 80-mesh sieve, and set aside;

[0093] 2) After passing lactose and pregelatinized starch through a 60-mesh sieve, weigh 54 g and 8 g respectively, mix with the mixture obtained in 1) for 5 min, and set aside;

[0094] 3) Pass magnesium stearate and AEROSIL 200 Pharma through a 20-mesh sieve, then weigh 1 g and 2 g respectively, and mix them with the mixture obtained in 2) for 5 min to obtain uniformly mixed intermediate granules;

[0095] 4) Using a tableting machine, press the intermediate granules obtained in 3) into tablets at a weight of 100 mg per tablet to obtain powder direct compression furosemide tablets, and the pH value of its solution is 7.0.

[0096] Test Example 1

[0097] Dissolution determination

[0098] Take this product, according to the dissolution determination method (General Chapter 0931, Method 2, Volume IV of Chinese Pharmacopoeia 2020 Edition), use 900 mL of pH 4.0 acetate buffer solution as the dissolution medium, rotate at a speed of 50 revolutions per minute, operate according to the law. At 5, 10, 15, 20, 30, 45, 60, 90 and 120 minutes, take 5 mL of the solution each time, and immediately supplement the same temperature and the same volume of the dissolution medium, filter. At 5, 10 and 15 minutes, take the subsequent filtrate as the test solution; at 20, 30, 45, 60, 90 and 120 minutes, accurately measure 2 mL of the subsequent filtrate, place it in a 5 mL volumetric flask, dilute it to the mark with the dissolution medium, shake well, and use it as the test solution. According to the ultraviolet-visible spectrophotometry (General Chapter 0401, Volume IV of Chinese Pharmacopoeia 2020 Edition), measure the absorbance at the wavelength of 274 nm respectively.

[0099] Determine the dissolution (%) of the samples of Examples 1-2, Comparative Examples 1-4 and the reference preparation The experimental results are as follows:

[0100]

[0101] Dissolution factor F2 of Examples 1-2 and Comparative Examples 1-4

[0102] Examples <![CDATA[F2]]> Example 1 62.26 Example 2 60.84 Comparative Example 1 40.06 Comparative Example 2 46.68 Comparative Example 3 36.98 Comparative Example 4 47.07

[0103] As can be seen from the results analysis of the above table: In the present invention, porous AEROSIL 200Pharma is used to adsorb furosemide, and then sodium bicarbonate, a microenvironment pH regulator, is used to adjust the pH value of the saturated solution around the drug particles, which can improve the solubility of the drug and increase the drug dissolution. The F2 values of the samples in Example 1 and Example 2 and the reference preparation are 62.26 and 60.84 respectively, and the dissolution curves are consistent with that of the reference preparation. In Comparative Example 1, only the porosity regulator AEROSIL 200Pharma is added, and the microenvironment pH regulator is not added, so the effect of improving the drug solubility cannot be achieved, and the dissolution is slower than that of the reference preparation, with an F2 of 40.06; in Comparative Example 2, only the microenvironment pH regulator sodium bicarbonate is added, and the porosity regulator is not added. The dissolution is slightly faster than that in Comparative Example 1, but still significantly slower than that of the reference preparation, and it still cannot be completely dissolved within 2 hours, with an F2 of 46.68; in Comparative Example 3, neither the porosity regulator nor the microenvironment pH regulator is added, and the dissolution is significantly slower than that of the reference preparation, with an F2 of only 36.98; in Comparative Example 4, AEROSIL 200Pharma is used as an external lubricant, which cannot increase the drug dissolution, and the dissolution is still significantly slower than that of the reference preparation, with an F2 of 47.07.

[0104] Test Example 2

[0105] Postprandial bioequivalence experiment with the reference preparation

[0106] Take the reference preparation The samples prepared in Examples 1-2 and Comparative Examples 1-4 were subjected to a postprandial bioequivalence experiment, with C max and AUC as the main pharmacokinetic indices to investigate whether they are bioequivalent to the reference preparation. The experimental results are as follows:

[0107] PK parameter data of the subjects in the postprandial test after taking the reference preparation

[0108]

[0109] PK parameter data of the subjects in the postprandial test after taking Example 1

[0110]

[0111] PK parameter data of the subjects in the postprandial test after taking Example 2 PK parameter data of the subjects in the postprandial test after taking Comparative Example 1

[0112]

[0113] PK parameter data of the subjects in the postprandial test after taking Comparative Example 2

[0114]

[0115]

[0116] PK parameter data of the subjects in the postprandial test after taking Comparative Example 3

[0117]

[0118] PK parameter data of the subjects in the postprandial test after taking Comparative Example 4 Pharmacokinetic indices of furosemide tablets in vivo after postprandial administration

[0119]

[0120]

[0121] It can be seen from the above bioequivalence test results that the 90% confidence intervals of Comparative Examples 1-4 do not fall within the range of 80%-125% required by the FDA for bioequivalence; the relative bioavailability is also not within the required range of 80%-120%, both are relatively low. It is further confirmed that the release of Comparative Examples 1-4 in vivo is slower than that of the reference preparation, resulting in bioinequivalence. While the 90% confidence intervals of Example 1 and Example 2 are both within the range of 80%-125%, and the relative bioavailability is also within the required range of 80%-120%, which are bioequivalent to the reference preparation, and the SD values of the PK parameter data of 12 subjects are all smaller than those of the reference preparation, indicating that the furosemide tablets prepared by adsorbing furosemide with porous AEROSIL 200Pharma and then adjusting the pH value of the saturated solution around the drug particles with the microenvironment pH regulator sodium bicarbonate according to the present invention can not only increase the release and absorption of the drug in vivo, but also overcome the influence of the difference in the pH value in different patients on drug dissolution, and reduce the inter-individual difference.

[0122] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A furosemide solid preparation, characterized in that, The solid preparation described above comprises the following components: furosemide, microenvironment pH regulator, preparation porosity regulator, diluent, disintegrant, lubricant. The microenvironment pH regulator is sodium bicarbonate, and the preparation porosity regulator is hydrophilic AEROSIL 200 Pharma; The diluent described above comprises at least one of sucrose, lactose, starch, microcrystalline cellulose, and mannitol; The disintegrant described above comprises at least one of croscarmellose sodium, sodium carboxymethyl starch, and pregelatinized starch; The lubricant described above comprises at least one of magnesium stearate, silica, and talc powder; The weight parts of the components described above are: 18 - 23 parts of furosemide, 12 - 18 parts of microenvironment pH regulator, 3 - 7 parts of preparation porosity regulator, 45 - 54 parts of diluent, 5 - 11 parts of disintegrant, and 0.1 - 3 parts of lubricant; The dry granulation preparation method of the furosemide solid preparation described above comprises the following steps: 1) Mix the prescribed amount of furosemide and microenvironment pH regulator for 3 - 8 min and then pass through a sieve to obtain mixture 1; 2) Weigh the prescribed amount of AEROSIL 200 Pharma and mix it with mixture 1 for 3 - 8 min, then pass through a sieve mesh, mix for another 5 - 10 min, and pass through a sieve to obtain mixture 2; 3) Pass the diluent and disintegrant through a sieve and weigh them according to the prescription amount, and mix them with mixture 2 for 3 - 8 min to obtain mixture 3; 4) Pass the lubricant through a sieve and weigh it according to the prescription amount, and mix it with mixture 3 for 3 - 8 min to obtain mixture 4; 5) Dry - press and crush mixture 4 with a dry granulator, pass through a sieve, and then mix it with 0.5 - 1.5 g of the sieved lubricant in total for 5 - 10 min to obtain intermediate granules; 6) Tablet - making, use a tableting machine to press - tablet the intermediate granules obtained in 5) at a weight of 100 mg per tablet to obtain furosemide tablets; The powder direct - compression preparation method of the furosemide solid preparation described above comprises the following steps: S1: Mix the prescribed amount of furosemide and microenvironment pH regulator for 3 - 8 min and then pass through a sieve to obtain mixture 1; S2: Weigh the prescribed amount of AEROSIL 200 Pharma and mix it with mixture 1 for 3 - 8 min, then pass through a sieve mesh, mix for another 5 - 10 min, and pass through a sieve to obtain mixture 2; S3: Pass the diluent and disintegrant through a sieve and weigh them according to the prescription amount, and mix them with mixture 2 for 3 - 8 min to obtain mixture 3; S4: Pass the lubricant through a sieve and weigh it according to the prescription amount, and mix it with mixture 3 for 3 - 8 min to obtain mixture 4; S5: Use a tableting machine to press - tablet the mixture obtained in S4 at a weight of 100 mg per tablet to obtain furosemide tablets.

2. The solid preparation according to claim 1, characterized in that, The weight parts of the components described above are: 20 parts of furosemide, 15 parts of microenvironment pH regulator, 5 parts of preparation porosity regulator, 51 parts of diluent, 8 parts of disintegrant, and 1 part of lubricant.

3. A dry granulation preparation method for the furosemide solid preparation according to claim 1, characterized in that, Comprises the following steps: 1) Mix the prescribed amount of furosemide and microenvironment pH regulator for 3 - 8 min and then pass through a sieve to obtain mixture 1; 2) Weigh the prescribed amount of AEROSIL 200 Pharma and mix it with mixture 1 for 3 - 8 min, then pass through a sieve mesh, mix for another 5 - 10 min, and pass through a sieve to obtain mixture 2; 3) Sieve the diluent and disintegrant, weigh them according to the prescription amount, and mix them with mixture 2 for 3 - 8 min to obtain mixture 3; 4) Sieve the lubricant, weigh it according to the prescription amount, and mix it with mixture 3 for 3 - 8 min to obtain mixture 4; 5) Dry - press and crush mixture 4 by a dry granulator, sieve it, and then mix it with 0.5 - 1.5 g of the sieved lubricant for 5 - 10 min to obtain intermediate granules; 6) Tablet - making, using a tableting machine, press the intermediate granules obtained in 5) into tablets at a weight of 100 mg per tablet to obtain furosemide tablets.

4. A method for directly compressing the powder of the furosemide solid preparation according to claim 1, characterized in that, Comprising the following steps: 1) Mix the furosemide and the micro - environment pH regulator in the prescription amount for 3 - 8 min and then sieve to obtain mixture 1; 2) Weigh the AEROSIL 200 Pharma in the prescription amount, mix it with mixture 1 for 3 - 8 min, then pass through a sieve mesh, mix for another 5 - 10 min, and sieve to obtain mixture 2; 3) Sieve the diluent and disintegrant, weigh them according to the prescription amount, and mix them with mixture 2 for 3 - 8 min to obtain mixture 3; 4) Sieve the lubricant, weigh it according to the prescription amount, and mix it with mixture 3 for 3 - 8 min to obtain mixture 4; 5) Using a tableting machine, press the mixture obtained in 4) into tablets at a weight of 100 mg per tablet to obtain furosemide tablets.

5. The preparation method according to any one of claims 3-4, characterized in that, The pH of mixture 1 obtained in step 1) is 5.8 - 8.0.

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