Spirolactone micro-tablet and preparation method thereof

Abstract

The invention discloses a spirolactone micro-tablet preparation for treating edema diseases and cardiovascular and cerebrovascular diseases and a method for preparing the spirolactone micro-tablet, the spirolactone micro-tablet with good compressibility is prepared from raw materials such as spirolactone, an adhesive, a diluent and the like through preparation methods such as top-spraying fluidized bed granulation and the like, and the spirolactone micro-tablet is used for treating the edema diseases and the cardiovascular and cerebrovascular diseases. The spirolactone micro-tablet can be administrated in a small dosage for multiple times, especially for people with large individual metabolism difference, such as old people and infants, the spirolactone micro-tablet can be taken in a counting mode, accurate administration is achieved, and for people with difficulty in taking conventional preparations, the medicine taking compliance can be improved.

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application date of June 21, 2016, application number: 201610447667.5, and invention name: "A spironolactone microtablet and its preparation method". Technical Field

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

[0003] Spironolactone (Spironolactone, Antisterone, Aldatine, Aldonar, Verospiron, Spirolang) is chemically named 17β-hydroxy-3-oxo-7α-(acetylthio)-17α-pregnane-4-ene-21-carboxylic acid γ-lactone. It is similar in structure to aldosterone and is a competitive inhibitor of aldosterone. Its conventional use is as a diuretic. Studies in recent years have found that spironolactone also has significant therapeutic effects on the treatment of cardiovascular and cerebrovascular diseases such as heart failure and hypertension. The clinical indications of spironolactone are as follows: 1. Edema diseases are used in combination with other diuretics to treat edema diseases such as congestive edema, ascites of liver cirrhosis, and renal edema. The purpose is to correct the secondary aldosterone secretion associated with the above diseases and counteract the potassium excretion effect of other diuretics. It is also used in the treatment of idiopathic edema. 2. Hypertension is an auxiliary drug for the treatment of hypertension. 3. Primary aldosteronism can be used for the diagnosis and treatment of this disease. 4. Prevention of hypokalemia: Used in combination with thiazide diuretics to enhance the diuretic effect and prevent hypokalemia.

[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] Spironolactone preparations prepared by existing technologies include common dosage forms such as tablets and capsules for oral use, and all of them are dosage specifications for adults. In situations where small doses must be administered, such as for children who are given by kilograms, or where the dose needs to be adjusted at any time, such as for the elderly, the existing spironolactone dosage forms cannot meet the requirements of individualized medication and cannot achieve precise medication. In addition, when the existing drug dosage forms are taken, due to the large volume of the dosage forms, the compliance of special populations, especially children, is poor. Summary of the invention

[0006] In order to overcome the defects of the prior art, the present invention provides a spironolactone microtablet preparation. Through a special granulation formula and preparation process, the spironolactone microtablet of the present invention can be administered multiple times in small doses, especially for people with large individual metabolic differences, such as the elderly and young children, the dosage can be counted to achieve accurate dosing, and for people who have difficulty taking conventional preparations, the compliance of taking medicine can be improved.

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

[0008]

[0009] The spironolactone microtablet preparation of the present invention, wherein the raw materials and their usage 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 known methods. For example, the active substance spironolactone can be controlled (generally delayed) released in an aqueous medium by applying at least one 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 encapsulate the described spironolactone microtablet preparation, be prepared as the oral preparation of capsule form, contain the microtablet of a certain number of controlled release medicine in the capsule, the number of microtablet is determined according to the single release time and the amount of medicine that will complete release. The number of microtablets is preferably enough to the dosage of daily administration once or twice in the capsule. The advantage of this dosage form is: the dosage of active ingredient is subdivided between many directly countable microtablets, but because dosage has been determined in the capsule, the patient does not need to count trivially.

[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 spironolactone 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: spironolactone 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 at the same time 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: spironolactone, a diluent and a binder are placed in a 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. DETAILED DESCRIPTION

[0023] Embodiment 1:

[0024] name Dosage Spironolactone 4mg Microcrystalline cellulose 102 16mg Lactose granulac200 4mg HPMC E3 4mg Magnesium Stearate 0.28mg

[0025] The preparation process is as follows: spironolactone, 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. Finished spironolactone micro tablets are obtained.

[0026] Embodiment 2:

[0027]

[0028] The preparation process is as follows: spironolactone, 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 spironolactone micro-tablets.

[0029] Embodiment 3:

[0030]

[0031] Preparation process: After spironolactone, 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.

[0032] Example 4

[0033] name Dosage Spironolactone 0.7mg Microcrystalline cellulose 102 3.0mg dextrin 4.8mg Povidone K30 0.4mg Magnesium Stearate 0.05mg

[0034] Preparation process: Add spironolactone and povidone K30 into purified water, stir until a clear and transparent solution is formed as a granulation binder solution for standby 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 the 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 spironolactone microtablet, characterized in that The raw materials and their dosage in the micro-sheets are as follows:

2. The microchip according to claim 1, characterized in that 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 magnesium stearate. 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. The method for preparing the spironolactone microtablets according to any one of claims 1 to 7, characterized in that 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. A capsule, characterized in that: The capsule comprises the spironolactone microtablet according to any one of claims 1 to 7.

Images