Fusemide micro-tablet convenient to take and capable of treating edema diseases of children and preparation method of fusemide micro-tablet

Abstract

The invention provides a furosemide micro-tablet which is convenient to take and is used for treating edema diseases of children and a preparation method of the furosemide micro-tablet. The furosemide micro-tablet is prepared from an active ingredient, a filling agent, an anti-sticking agent and a lubricating agent, the active component is furosemide; the invention also provides a preparation method of the furosemide micro-tablet. Compared with the existing furosemide tablet, the furosemide micro-tablet has the characteristics of low dosage, convenience in swallowing, improvement of children administration compliance and the like. The furosemide micro-tablet process is controllable, easy to operate and suitable for commercial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a furosemide microplate and its preparation method. Technical Background

[0002] Furosemide, chemically known as 2-[(2-furanmethyl)amino]-5-(aminosulfonyl)-4-chlorobenzoic acid, has the molecular formula C2. 12 H 11 ClN₂O₅S, with a molecular weight of 330.75, has the following chemical structural formula:

[0003]

[0004] Furosemide was developed by Sanofi and first launched in Japan in May 1965 under the brand name "Furxamide". The dosage forms included 40mg tablets and 20mg injections. Later, 20mg tablets (1981), 10mg tablets (2011), 4% fine granules (1988), and 100mg injections (1981) were launched in Japan.

[0005] In 1966, Sanofi's furosemide tablets were approved by the FDA under the brand name "..." The specifications include 20mg, 40mg, and 80mg, with the 80mg being an FDA Orange Book designated RLD. Furosemide is one of the most commonly used potent diuretics in clinical practice. It has a strong excretory effect on various substances such as water, sodium, potassium, and chloride, and it has a rapid onset of action. Therefore, it is often used in clinical treatment of various acute and chronic edematous diseases, such as acute and chronic heart failure, renal insufficiency, and acute cerebral edema. It is also one of the drugs commonly used in clinical practice to treat essential hypertension.

[0006] Furosemide tablets are a potent diuretic that quickly helps the body eliminate excess water. Its core function is to promote kidney urination. By promoting the kidneys' excretion of water and salt, this drug effectively reduces swelling throughout the body. For example, leg swelling caused by weakened heart function or abdominal edema due to cirrhosis can be relieved through urination. It can also quickly relieve stress in sudden dangerous situations such as fluid accumulation in the brain or lungs. In treating hypertension, furosemide tablets work by regulating the body's water and salt balance. However, it also has adverse reactions, common ones including nausea, vomiting, heartburn, decreased appetite, abdominal pain, diarrhea, or constipation. Numerous patents exist for furosemide tablets, but each has its own set of issues.

[0007] Patent CN104490753A discloses a furosemide composition freeze-dried tablet and its preparation method, which uses a two-down-two-up freeze-drying process to improve tablet formability and dissolution rate. However, this patented process is complex and uncontrollable, with a long production cycle, and is not suitable for industrial production.

[0008] Patent CN120093702A discloses a compound furosemide tablet and its preparation method, which uses taurine-mannitol co-products and sodium alginate as stabilizers to improve the stability and dissolution of the compound furosemide tablet. However, the patent formulation contains a wide variety of excipients, the process is complex and uncontrollable, and the organic solvent ethanol is used in the preparation process, making it unsuitable for industrial production.

[0009] Patent CN110538157A discloses a furosemide tablet and its preparation method. The method involves mixing furosemide, corn starch, lactose, purified water, sodium carboxymethyl starch, and magnesium stearate in a specific ratio. The corn starch is dissolved in purified water, and the mixture is then granulated with the dry mixture and processed into tablets. While this patented process is simple and easy to implement, its large dosage results in tablets of a certain size, which is not user-friendly for children or patients with swallowing difficulties.

[0010] It is evident that current research on furosemide tablets focuses primarily on improving the original furosemide tablets or compound furosemide tablets, and is not suitable for use in children or patients with dysphagia.

[0011] Furosemide tablets offer flexible and accurate dosing, providing precise dosages based on the child's age or weight. Once opened, the appropriate dose is dispensed according to the child's weight, making it easy to administer.

[0012] Mini-tablets are typically less than 3 mm in diameter and are generally multi-unit formulations. They offer advantages such as easy swallowing, accurate dosing, and flexible dosage adjustment, making them suitable for children and patients with swallowing difficulties. Depending on clinical needs, mini-tablets can be developed into immediate-release, sustained-release, or enteric-coated forms; they can be used alone or filled into capsules, pouches, or bottles, and can be equipped with tablet counters to measure the number of tablets administered.

[0013] Compared to regular tablets, microcapsules have the following advantages: ① They are easy to swallow and suitable for children and the elderly; ② They have a small diameter, smooth surface, and precise dosage; ③ The preparation process is simple, with less coating material and high efficiency; ④ They are small in size and convenient to transport, carry, and store; ⑤ They combine the advantages of ordinary tablets and microcapsules; ⑥ The masking technology for unpleasant tastes such as bitterness and astringency is relatively simple.

[0014] Based on dosage form characteristics and clinical treatment needs, the selection of excipients should focus on functional indicators affecting their flowability and compressibility. For active pharmaceutical ingredients (APIs), indicators affecting flowability, such as crystal form, density, particle size, and distribution, should be considered. For applications requiring improved palatability, altered drug dissolution behavior, or other production needs, microtablets can be coated. The production process for microtablets is similar to that of ordinary tablets, typically employing processes such as direct powder compression, wet granulation compression, and dry granulation compression.

[0015] Micro-tablet production and quality control have higher requirements than ordinary tablets. In particular, the content uniformity of small-sized micro-tablets is a technical challenge. Using the above-mentioned preparation process makes it difficult to control the content uniformity of micro-tablets, which can easily lead to the production of products with unqualified content uniformity.

[0016] Therefore, providing furosemide microtablets with stable product quality, reliable efficacy, qualified content uniformity, reasonable dissolution, and simple preparation process to meet the medication needs of children and patients with dysphagia has significant economic and social benefits. Summary of the Invention

[0017] This invention addresses the problems existing in the prior art by providing a furosemide microtablet, its preparation method, and its application. This invention discloses for the first time a furosemide microtablet and its preparation method. The furosemide microtablet has a diameter of 1mm to 3mm, is easy to swallow, provides accurate dosage, and allows for flexible dosage adjustment; it offers good medication adherence and is suitable for children and patients with swallowing difficulties. The furosemide microtablet avoids the inaccuracies in weight and content, instability, and microbial contamination problems associated with breaking furosemide tablets for dosage dispensing, as well as the occupational exposure risks associated with dispensing medication to pharmacists.

[0018] The furosemide microtablets of this invention are composed of an active ingredient, a filler, an anti-adhesion agent, and a lubricant. The active ingredient is furosemide, with a unit dose of 1 mg to 5 mg. The preparation method employs a powder mixing and tableting process; the active ingredient, anti-adhesion agent, and filler are mixed uniformly in a mixer, and then a lubricant is added for final mixing, followed by tableting to obtain furosemide microtablets. The filler described in this invention is a composite excipient, which, compared to traditional oral solid dosage form excipients, has excellent flowability and disintegration properties, solving problems such as poor tableting, uneven mixing, and slow dissolution and disintegration. Compared to the mixing method of ordinary three-dimensional mixers, this invention uses a dual high-speed mechanical mixing method in both horizontal and vertical directions, effectively encapsulating and uniformly dispersing the active ingredient. This allows for the preparation of furosemide microtablets with good content uniformity and stability while ensuring product quality consistent with the original furosemide tablets.

[0019] To achieve the above objectives, the present invention provides the following technical solution:

[0020] A convenient-to-take furosemide microtablet for treating childhood edema and its preparation method, wherein each 1000 furosemide microtablets are composed of the following weight ratio:

[0021] Active ingredient 1g~5g, filler 14.8g~19.8g, anti-adhesive 0.1g~0.5g, lubricant 0.1g~0.5g.

[0022] The furosemide microplates mentioned above contain furosemide as their active ingredient.

[0023] The filler may be selected from one of the following: starch-mannitol complex, mannitol microcrystalline cellulose complex, lactose microcrystalline cellulose complex, starch microcrystalline cellulose complex, and starch-lactose complex.

[0024] Preferably, the filler is a mannitol microcrystalline cellulose complex. The component ratio of the complex is 20-30:80-70.

[0025] The ratio of the first component to the last component in the complex is 20-30:80-70, preferably a mannitol microcrystalline cellulose complex, in which the ratio of mannitol to microcrystalline cellulose is 25:75.

[0026] The anti-adhesive can be selected from one of magnesium stearate, silica, starch, talc, and micronized silica.

[0027] Preferably, the anti-adhesion agent is talc.

[0028] The lubricant may be selected from one of magnesium stearate, calcium stearate, stearic acid, talc, hydrogenated vegetable oil, polyethylene glycol, and sodium stearate fumarate.

[0029] Preferably, the lubricant is magnesium stearate.

[0030] Furthermore, each 1000 furosemide microplates are composed of the following weight ratio:

[0031] Active ingredient 1g-5g, mannitol microcrystalline cellulose complex 14.8g-19.8g, talc 0.1g-0.5g, magnesium stearate 0.1g-0.5g.

[0032] The method for preparing furosemide microplates includes the following steps:

[0033] Step 1: Add the active ingredient, anti-adhesive, and filler to the mixer and mix thoroughly; after mixing, add the lubricant and mix thoroughly.

[0034] Step 2: Press the mixed materials from Step 1 into tablets using a rotary tablet press.

[0035] Furthermore, the method for preparing furosemide microplates includes the following steps, which can be described as follows:

[0036] Step 1: Add furosemide, talc, and mannitol microcrystalline cellulose complex into a mixer; set the stirring speed to 200 rpm and the blade speed to 600 rpm, turn on the stirring and blade to mix for 5 minutes; after mixing, add magnesium stearate and mix for 2 minutes;

[0037] Step 2: Compress the mixed materials from Step 1 into tablets using a rotary tablet press with a 3.0mm round shallow concave die, controlling the tablet hardness to 2-4 kg.

[0038] The method for preparing furosemide microplates yields furosemide microplates with a diameter of 1 mm to 3 mm.

[0039] The furosemide microtablets of the present invention obtained by using the above technical solution can ideally produce the objectives and technical effects to be achieved by the present invention. Specifically, the drug of the present invention, which is convenient for patients to take, can produce:

[0040] (1) The preparation method has strong applicability, stable process, and strong quality reproducibility;

[0041] (2) Furosemide micro tablets are smaller in diameter than regular tablets, making them more convenient for children and patients with difficulty swallowing to take.

[0042] Compared with the prior art, the beneficial effects of the present invention are:

[0043] 1. The furosemide microtablet preparation method of the present invention produces furosemide microtablets with good content uniformity and stability, resulting in good medication compliance and making them suitable for children and patients with dysphagia. The present invention adopts a powder mixing and tableting process, which is simple and easy to operate, suitable for commercial production, and can continuously and effectively produce this product.

[0044] 2. The furosemide microplates prepared by the present invention through a simple preparation process have a highly similar dissolution behavior to commercially available formulations in a distinguishing medium, and also have a good dissolution effect in a standard medium.

[0045] 3. The furosemide microtablets of the present invention are multi-unit formulations that combine the advantages of ordinary tablets and microcapsules. They provide precise dosage, are easy to swallow, and can improve patient compliance. They are especially suitable for the elderly and children. Compared with microcapsules, microtablets have higher product quality and economic benefits.

[0046] 4. The furosemide microplates of the present invention have small diameter, smooth surface, and small volume, making them convenient to transport, carry, and store.

[0047] 5. The furosemide microtablets of the present invention are not inferior to the original furosemide tablets in terms of quality and efficacy.

[0048] It should be noted that, in order to enable those skilled in the art to more clearly understand the inventive content and technical connotation of this invention, the inventors of this invention provide the following explanations regarding the technical terms, symbols, reagents, consumables, and instruments used:

[0049] "0 days": refers to the time when sample preparation was completed;

[0050] "Acceleration conditions" refer to a temperature of 40℃±2℃ and a relative humidity of 75%±5%. Detailed Implementation

[0051] To facilitate understanding of the present invention by those skilled in the art, the following specific embodiments are provided to further illustrate the furosemide microplates and their preparation method. Unless otherwise specified, the technical means used in this invention are all methods known to those skilled in the art. Furthermore, the embodiments should be understood as illustrative, not limiting the scope of the invention; the essence and scope of the invention are defined only by the claims. For those skilled in the art, various changes or modifications to the material composition and dosage in these embodiments without departing from the essence and scope of the invention are also within the protection scope of this invention. To facilitate understanding of the present invention by those skilled in the art, the following specific embodiments are provided to further illustrate the convenient patient-administered drug and its preparation method:

[0052] Example 1

[0053] prescription

[0054] Raw material names Unit dose (mg) Furosemide 5 Mannitol microcrystalline cellulose complex 14.4 talcum powder 0.3 magnesium stearate 0.3 total 20

[0055] Preparation method:

[0056] 1. Add furosemide, talc, and mannitol microcrystalline cellulose complex into a mixer; set the stirring speed to 200 rpm and the cutter speed to 600 rpm, turn on the stirring and cutter to mix for 5 minutes; after mixing, add magnesium stearate and mix for 2 minutes.

[0057] 2. Compress the mixed materials into tablets using a rotary tablet press with a 3.0mm round shallow concave die, controlling the tablet hardness to 2-4 kg.

[0058] Example 2

[0059] prescription

[0060] Raw material names Unit dose (mg) Furosemide 1 Starch-lactose complex 18.5 talcum powder 0.3 magnesium stearate 0.2 total 20

[0061] Preparation method:

[0062] 1. Add furosemide, talc, and starch-lactose complex to a mixer; set the stirring speed to 200 rpm and the blade speed to 600 rpm, turn on the stirring and blade to mix for 5 minutes; after mixing, add magnesium stearate and mix for 2 minutes.

[0063] 2. Compress the mixed materials into tablets using a rotary tablet press with a 3.0mm round shallow concave die, controlling the tablet hardness to 2-4 kg.

[0064] Example 3

[0065] prescription

[0066] Raw material names Unit dose (mg) Furosemide 2 Mannitol starch complex 17 talcum powder 0.5 magnesium stearate 0.5 total 20

[0067] Preparation method:

[0068] 1. Add furosemide, talc, and mannitol starch complex to a mixer; set the stirring speed to 200 rpm and the cutter speed to 600 rpm, turn on the stirring and cutting to mix for 5 minutes; after mixing, add magnesium stearate and mix for 2 minutes.

[0069] 2. Compress the mixed materials into tablets using a rotary tablet press with a 3.0mm round shallow concave die, controlling the tablet hardness to 2-4 kg.

[0070] Example 4

[0071] prescription

[0072] Raw material names Unit dose (mg) Furosemide 3 lactose microcrystalline cellulose complex 16.5 talcum powder 0.1 magnesium stearate 0.4 total 20

[0073] Preparation method:

[0074] 1. Add furosemide, talc, and lactose microcrystalline cellulose complex to a mixer; set the stirring speed to 200 rpm and the blade speed to 600 rpm, turn on the stirring and blade to mix for 5 minutes; after mixing, add magnesium stearate and mix for 2 minutes.

[0075] 2. Compress the mixed materials into tablets using a rotary tablet press with a 3.0mm round shallow concave die, controlling the tablet hardness to 2-4 kg.

[0076] Comparative Example 1

[0077] prescription

[0078] Raw material names Unit dose (mg) Furosemide 5 lactose 9 corn starch 4.5 Povidone K30 0.5 talcum powder 0.35 silicon dioxide 0.35 magnesium stearate 0.3 Purified water Appropriate amount total 20

[0079] Preparation method:

[0080] 1. Add furosemide, corn starch, povidone K30, talc, and lactose into a wet granulator. Set the stirring speed to 200 rpm and the shearing speed to 1000 rpm. Start the stirring and shearing process and mix for 5 minutes. After mixing, add purified water and continue granulation for 2 minutes. During granulation, control the stirring speed at 400 rpm and the shearing speed at 1500 rpm. Perform wet granulation at the discharge point using a 10*10mm square mesh screen at a granulation speed of 300 rpm.

[0081] 2. The obtained granules are dried in a fluidized bed, with the inlet air temperature controlled at 55-65℃ and the fan frequency at 30-40Hz. The bag is shaken periodically during the drying process, and the drying is stopped when the moisture content of the granules is below 4%.

[0082] 3. The obtained granules are sized using a 1.0mm round hole sieve at a sizing speed of 500 rpm;

[0083] 4. Put the granulated particles into a mixer, add silica and magnesium stearate, set the speed to 10 r / min, and mix for 5 minutes;

[0084] 5. Compress the mixed materials into tablets using a rotary tablet press with a 3.0mm round shallow concave die, controlling the tablet hardness to 2-4 kg.

[0085] Comparative Example 2

[0086] prescription

[0087] Raw material names Unit dose (mg) Furosemide 5 Microcrystalline cellulose pH 102 10.8 Mannitol 3.6 talcum powder 0.3 magnesium stearate 0.3 total 20

[0088] Preparation method:

[0089] 1. Add furosemide, talc, mannitol, and microcrystalline cellulose (pH 102) to a mixer, set the speed to 10 rpm, and mix for 10 minutes. After mixing, add magnesium stearate and mix for 2 minutes.

[0090] 2. Compress the mixed materials into tablets using a rotary tablet press with a 3.0mm round shallow concave die, controlling the tablet hardness to 2-4 kg.

[0091] Test Example 1

[0092] Content uniformity check:

[0093] Test method: Determine the absorbance using ultraviolet-visible spectrophotometry (General Rule 0401). Take one tablet of this product, place it in a 100ml volumetric flask, add approximately 60ml of solvent (0.4% sodium hydroxide solution), shake for 10 minutes to dissolve the furosemide, dilute to the mark with solvent, shake well, filter, accurately measure 5ml of the filtrate, place it in a 100ml volumetric flask, dilute to the mark with solvent, and shake well to obtain the test solution. Take the test solution and measure the absorbance at a wavelength of 271nm, according to C. 12H 11 Absorption coefficient of ClN2O5S Calculated for 580.

[0094] The content uniformity of samples from Examples 1-4, Comparative Examples 1-2, and commercially available formulations was checked, and the results are as follows:

[0095] Testing items Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Commercially available formulations Average content % 99 99 99 99 98 98 99 A+2.2S 3.98 4.33 4.29 4.12 8.53 9.64 6.85

[0096] The data in the table above show that the furosemide content uniformity in the furosemide microplates prepared according to Examples 1-4 of this invention is good, and the results are far less than the requirement of A+2.2S≤15.0 specified in the current Chinese Pharmacopoeia. This is superior to commercially available formulations and comparative examples 1-2.

[0097] Test Example 2

[0098] Dissolution test:

[0099] Test method: Take this product and determine its dissolution and release according to the method for determination of dissolution and release (General Rule 0931, Method II). Use 1000 ml of phosphate buffer (pH 5.8) as the dissolution medium, rotate at 50 rpm, and operate according to the method. Take a sample after 30 minutes. Take 10 ml of the dissolution solution, filter it through a 0.45 μm filter membrane, accurately measure 5 ml of the filtrate, place it in a 10 ml volumetric flask, dilute to the mark with 0.8% sodium hydroxide solution, and shake well. Take the test solution and measure the absorbance at a wavelength of 271 nm according to the ultraviolet-visible spectrophotometry method (General Rule 0401), according to C. 12 H 11 Absorption coefficient of ClN2O5S The dissolution rate per tablet for 580 should be no less than 75% of the labeled amount.

[0100] Dissolution tests were performed on samples from Examples 1-4, Comparative Examples 1-2, and commercially available formulations. Results

[0101] as follows:

[0102]

[0103] As shown in the table above, the furosemide microplates prepared according to Examples 1-4 of the present invention have a dissolution rate of over 95% in the standard medium after 30 minutes. The dissolution performance is better than that of commercially available formulations and comparative examples 1-2, and has a better dissolution effect.

[0104] Test Example 3

[0105] Based on the dissolution behavior of furosemide microplates from Examples 1-4 and commercially available formulations in a highly discriminative pH 4.0 acetate buffer, the dissolution behavior of the products was evaluated using a similarity factor f2.

[0106] time min Example 1 Example 2 Example 3 Example 4 Commercially available formulations 5 24.8 21.7 27.4 27.2 26.1 10 38.8 37.5 41.4 39.9 38.7 15 48.8 45.8 50.1 48.2 47.4 30 63.3 62.8 66.1 61.0 62.5 45 73.0 71.9 73.7 69.8 72.3 60 79.0 77.9 78.3 75.4 78.6 90 85.8 85.7 84.4 81.4 86.9 Dissolution similarity f2 93 83 80 77 /

[0107] As can be seen from the table above, the furosemide microplates prepared according to Examples 1-4 of the present invention exhibit dissolution behavior in a distinguishing medium that is highly similar to that of commercially available formulations.

[0108] Test Example 4

[0109] Stability assessment:

[0110] Samples from Examples 1-4 and Comparative Examples 1-2 were packaged in commercially available packaging and placed under accelerated conditions along with commercially available formulations. They were retrieved at 0 and 6 months, and their properties, content, dissolution rate, and related substances were tested to assess sample stability. The results are as follows:

[0111]

[0112]

[0113] The results in the table above show that after 6 months of accelerated storage, the properties, content, and dissolution of the samples prepared in Examples 1-4 showed virtually no significant changes compared to day 0; the amounts of related substances and impurities showed virtually no increase. However, the commercially available formulation and samples from Comparative Examples 1-2 showed a decrease in dissolution and a significant increase in the amounts of related substances after 6 months of accelerated storage. This demonstrates that the preparation method described in this patent can improve the stability of furosemide microplates.

[0114] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A convenient-to-take furosemide microtablet for treating edema in children, characterized in that, The furosemide microplates are composed of the following weight ratio per 1000 tablets: Active ingredient 1g~5g, filler 14.8g~19.8g, anti-adhesive 0.1g~0.5g, lubricant 0.1g~0.5g. The furosemide microplates mentioned above contain furosemide as the active ingredient, with a unit dose of 1 mg to 5 mg. The filler can be selected from one of starch-mannitol complex, mannitol microcrystalline cellulose complex, lactose microcrystalline cellulose complex, starch microcrystalline cellulose complex, and starch-lactose complex, and the ratio of the first component to the second component in the complex is 20-30:80-70. The anti-adhesion agent is talc. The lubricant is magnesium stearate.

2. The furosemide microplates according to claim 1, wherein the preparation method comprises the following steps: Step 1: Add the active ingredients, anti-sticking agent, and filler to the mixer; set the stirring speed to 200 rpm and the cutter speed to 600 rpm, turn on the stirring and cutting to mix for 5 minutes; after mixing, add the lubricant and mix for 2 minutes; Step 2: Compress the mixed materials from Step 1 into tablets using a rotary tablet press, controlling the tablet hardness to 2-4 kg.

3. The furosemide microplates prepared by the method described in claim 2 have a diameter of 1 mm to 3 mm.

4. The use of furosemide microplates as described in claims 1 to 3 in medicaments for children and patients with dysphagia.

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