Furosemide micro-tablet and preparation method thereof

Abstract

The invention discloses a furosemide micro-tablet preparation and a method for preparing the furosemide micro-tablet, furosemide, an adhesive, a diluent and other raw materials are subjected to top spray fluidized bed granulation and other preparation methods to prepare the furosemide micro-tablet with good compressibility, the furosemide micro-tablet can be dosed for multiple times in a small dosage, and the furosemide micro-tablet preparation can be used for preparing the furosemide micro-tablet. Especially for people with large individual metabolism difference, such as old people and infants, the medicine can be taken in a counting manner and is accurately administered, for people with difficulty in taking conventional preparations, the medicine taking compliance can be improved, and the method and the raw materials used by the invention are convenient for industrial production.

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application date of June 21, 2016, application number: 201610450850.0, and invention name: "A kind of furosemide microtablet and its preparation method". Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a furosemide microtablet, and provides a method for preparing the furosemide microtablet. Background Art

[0003] Furosemide, also known as furosemide and furosemide, has a chemical name of 2-[(2-furanmethyl)amino]-5-(sulfamoyl)-4-chlorobenzoic acid, and is a potent diuretic. Furosemide can inhibit the renal tubular reabsorption function and promote the excretion of water, sodium, chloride, potassium, calcium, magnesium, phosphorus, etc. Furosemide can inhibit the activity of prostaglandin degrading enzymes, increase the content of prostaglandin E2, and thus have a vasodilatory effect. Dilate renal blood vessels, reduce renal vascular resistance, and increase renal blood flow, especially deep renal cortical blood flow. The diuretic effect is strong and rapid. Furosemide can dilate pulmonary capacitance veins and reduce pulmonary capillary permeability. In addition to its diuretic effect, it reduces the amount of blood returning to the heart and reduces the left ventricular end-diastolic pressure, which helps in the treatment of acute left heart failure. Furosemide is clinically used for various edematous diseases, such as congestive heart failure, renal edema, cirrhosis ascites, etc. It is also used in emergency situations where elimination is urgent, such as acute renal edema, cerebral edema, and hypertensive crisis. It can be used to accelerate the excretion of poisons in drug poisoning.

[0004] Microtablets refer to miniature tablets with a diameter of 1 to 3 mm that are pressed by a special tablet press. Microtablets are dose-dispersible preparations. After oral administration, microtablets are evenly dispersed in the gastrointestinal tract, reducing irritation to the gastrointestinal tract. The gastrointestinal transport and absorption of drugs are less affected by the gastric emptying rate, so the individual differences are small; the drug release behavior of microtablets is the sum of the drug release behaviors of multiple small units that make up a dose. After oral administration, defects in the preparation process of individual small units will not have a serious impact on the drug release behavior of the overall preparation. For people with large individual differences in drug metabolism, such as the elderly and young children, or for drugs whose dosage needs to be adjusted at any time, microtablets are an ideal dosage form. Patients can count and take microtablets according to individualized medication plans, and the measurement is more accurate. Compared with other multi-unit dosage forms, microtablets have more regular shapes and more uniform sizes. Since microtablets are pressed by fixed molds, they have the characteristics of ordinary tablets. Their tablet weight and size are precisely controllable, and the production reproducibility is good. Each microtablet unit has equal size, the same weight, and the same drug content.

[0005] At present, the oral preparations of furosemide on the market are mainly tablets, and all of them are for adults. However, in clinical application, furosemide usually needs to be adjusted in dosage according to its diuretic effect. When furosemide is used in children, its dosage needs to be calculated according to the child's kilogram body weight. The existing furosemide dosage forms cannot meet the requirements of individualized medication, cannot be conveniently and accurately divided into doses, and cannot achieve precise drug administration. In addition, when taking existing drug dosage forms, due to the large size of the dosage form, the compliance of children, the elderly, and patients who are inconvenient to swallow tablets is poor. Summary of the invention

[0006] To overcome the defects of the prior art, the present invention provides a furosemide microtablet preparation. Through a special granulation formula and preparation process, the furosemide microtablet of the present invention can be accurately administered in small doses, especially for people with large individual metabolic differences, such as the elderly and young children, so that accurate administration can be achieved, thereby ensuring the efficacy of the drug while reducing the occurrence of adverse reactions that may be caused by inaccurate dosage. And for people who have difficulty taking conventional preparations, the microtablet is easy to swallow, which can improve the compliance of taking the medicine.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides a furosemide microtablet preparation, and its prescription raw materials and dosage ratio are as follows:

[0008]

[0009] The furosemide microtablet preparation of the present invention, wherein the raw materials and their dosage ratios in the microtablets are preferably as follows:

[0010]

[0011] The diluent is selected from one or more of starch, pregelatinized starch, dextrin, microcrystalline cellulose, and lactose. The binder is selected from one or more of HPMC, povidone, gelatin, poloxamer, microcrystalline cellulose, and polyvinyl pyrrolidone. The lubricant is selected from one or more of magnesium stearate, talc, corn starch, stearic acid, calcium stearate, talc, and calcium behenate.

[0012] The excipients included in the micro-tablet preparation of the present invention are not limited to the types listed in the content of the invention and the examples, and may also include other pharmaceutical excipients, provided that they do not affect the compression molding of the micro-tablets. For example, a surfactant may also be included, and the surfactant may be selected from: sorbitol, mannitol, sodium lauryl sulfate, fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, etc.

[0013] The spatial shape of the microchip can be selected as required in principle. The microchip in the present invention is preferably cylindrical, elliptical or spherical in spatial shape. It is preferably a cylindrical shape with a height and a diameter of 1 to 4 mm. The height and the diameter can be arbitrarily selected as required, such as the height and the diameter can be 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, etc.

[0014] In the microtablet preparation of the present invention, the surface of the microtablet can also be coated by a known method. For example, the active substance furosemide can be controlled (generally delayed) released in an aqueous medium by coating at least one layer of coating. Suitable controlled release coatings contain water-insoluble waxes or polymers, preferably ethylcellulose.

[0015] In addition to water-insoluble polymers, the release rate of the active substance can also be arbitrarily adjusted by using non-release-controlling substances in an amount of preferably up to 30 wt.%., preferably water-soluble polymers such as polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose, and / or known plasticizers.

[0016] In addition to the controlled release coating, the microtablets of the present invention may also have an additional coating. Thus, a coating containing an active substance may be used from which the active substance can be released in an uncontrolled manner after oral administration.

[0017] In addition to the controllable coating, the microtablet formulation of the present invention may also contain a coating that can dissolve in a pH-dependent manner, for example, to ensure that the microtablet formulation does not dissolve after passing through the stomach and is not released until it reaches the intestine.

[0018] The present invention can also put the furosemide microtablet preparation into a capsule to prepare an oral preparation in the form of a capsule, wherein the capsule contains a certain number of microtablets that can control the release of the drug, and the number of microtablets is determined according to the single release time and the amount of drug to be released. The number of microtablets in the capsule is preferably sufficient for a dose of once or twice a day. The advantage of using this dosage form is that the dose of the active ingredient is subdivided between many directly countable microtablets, but since the dose is already determined in the capsule, the patient does not have to count tediously.

[0019] The micro-tablet preparation of the present invention can be used alone or in combination with a special drug delivery device such as a drug dispensing device to provide more convenient and accurate drug delivery.

[0020] Another object of the present invention is to provide a method for preparing furosemide microtablets, wherein the microtablets can be prepared by fluidized bed top spray granulation, wet granulation, dry granulation or fluidized bed bottom spray granulation.

[0021] For example, when the top spray granulation process is adopted, the preparation method is as follows: furosemide and a binder are added to purified water, and stirred to form a clear and transparent solution as a granulation binder solution for standby use; the diluent is premixed and then placed in the fluidized bed top spray pot; the fluidized bed is opened for blowing, the atomization pressure and the air volume and air inlet temperature are adjusted, and the binder solution is sprayed in for top spray granulation; after the binder solution is sprayed, the particles are taken out and dry granulated; after the obtained dry particles are evenly mixed with the prescribed amount of lubricant, the mixture is transferred to a high-speed rotary tablet press for tableting to obtain finished tablets.

[0022] Alternatively, when a wet granulation process is adopted, the preparation method is as follows: furosemide, a diluent and a binder are placed in the pot of a wet granulator, and after mixing, purified water is sprayed in for wet granulation, wet granulation, and subsequent drying. After drying, the granules are subjected to dry granulation; after the dry granules are uniformly mixed with a prescribed amount of lubricant, the mixture is transferred to a high-speed rotary tablet press for tableting to obtain finished tablets.

[0023] When the dry granulation process is adopted, the preparation method is as follows: after the main drug furosemide and other auxiliary materials except the lubricant are mixed evenly, the mixed material is added to the dry granulator to obtain suitable dry granules; after the granules and the lubricant are evenly mixed, the mixed material is transferred to a high-speed rotary tablet press for tableting to obtain finished tablets. DETAILED DESCRIPTION

[0024] Embodiment 1:

[0025] name Dosage Furosemide 4mg Microcrystalline cellulose 102 16mg Lactose granulac200 4mg HPMC E3 4mg Magnesium Stearate 0.28mg

[0026] The preparation process is as follows: furosemide, microcrystalline cellulose 102, lactose granulac 200 and HPMC E3 are placed in a multiphase mixer and uniformly mixed, and then magnesium stearate is added and mixed for 3 minutes, and the mixture is transferred to a high-speed rotary tablet press for tableting to obtain finished tablets. The finished furosemide micro-tablets are obtained.

[0027] Embodiment 2:

[0028]

[0029]

[0030] The preparation process is as follows: furosemide, lactose granulac200 and HPMC E3 are placed in the pot of a wet granulator, and the paddles are turned on for initial mixing for 10 minutes. After the mixing is completed, the paddles are turned on and purified water is sprayed in for wet granulation; after the purified water is sprayed, granulation is continued for 5 minutes; then the obtained wet granules are wet-granulated, and then placed in a fluidized bed for drying. After drying, the granules are dry-granulated; after the dry granules are uniformly mixed with the prescribed amount of magnesium stearate, the mixed material is transferred to a high-speed rotary tablet press for tableting to obtain the finished furosemide micro-tablets.

[0031] Embodiment 3:

[0032]

[0033] Preparation process: After furosemide, microcrystalline cellulose 102 and HPMC E3 are evenly mixed, the mixture is added to a dry granulator to obtain suitable dry granules; after the granules and magnesium stearate are evenly mixed, the mixture is transferred to a high-speed rotary tablet press for tableting to obtain finished tablets.

[0034] Example 4

[0035]

[0036]

[0037] Preparation process: Add furosemide and povidone K30 into purified water, stir until a clear and transparent solution is formed as a granulation binder solution for later use; pre-mix microcrystalline cellulose 102 and dextrin and put them into the fluidized bed top spray pot; turn on the fluidized bed blower, adjust the atomization pressure and air volume and inlet temperature, and spray the binder solution for top spray granulation; after the binder solution is sprayed, take out the particles and dry granulate; after uniformly mixing the obtained dry particles with the prescribed amount of magnesium stearate, transfer the mixture to a high-speed rotary tablet press for tableting to obtain a finished micro-tablet preparation.

Claims

1. A furosemide microtablet, Features The raw materials and their usage ratios in the micro-sheets are as follows:

2. The microchip according to claim 1, Features The raw materials and their usage ratios in the micro-sheets are as follows:

3. The microtablet according to claim 1 or 2, wherein the diluent is selected from one or more of starch, pregelatinized starch, dextrin, microcrystalline cellulose, and lactose.

4. The microtablet according to any one of claims 1 to 3, wherein the binder is selected from one or more of HPMC, povidone, gelatin, poloxamer, microcrystalline cellulose, and polyvinyl pyrrolidone, preferably HPMC E3.

5. The microtablet according to any one of claims 1 to 4, wherein the lubricant is selected from one or more of magnesium stearate, talc, corn starch, stearic acid, calcium stearate, talc, and calcium behenate, preferably stearic acid. 6 . The microplate according to claim 1 , wherein the microplate has a cylindrical, elliptical or spherical spatial shape.

7. The microplate according to any one of claims 1 to 6, wherein the microplate is in a cylindrical shape with a height of 1 to 3 mm and a diameter of 1 to 3 mm.

8. A method for preparing the furosemide microtablets according to any one of claims 1 to 7, Features The micro-tablets are prepared by fluidized bed top spray granulation, wet granulation, dry granulation, direct powder tableting or fluidized bed bottom spray granulation.

9. The microtablet according to any one of claims 1 to 7, wherein the microtablet is further coated with one or more functional coating layers.

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