Hydrochlorothiazide micro-tablet and preparation method thereof

Abstract

The invention discloses a hydrochlorothiazide micro-tablet preparation and a method for preparing hydrochlorothiazide micro-tablets, the hydrochlorothiazide micro-tablets with good compressibility are prepared from hydrochlorothiazide, an adhesive, a filling agent and other raw materials through top-spraying fluidized bed granulation and other preparation methods, and the hydrochlorothiazide micro-tablets have the advantages that the hydrochlorothiazide micro-tablets have no toxic or side effects on patients suffering from edema, hypertension and diabetes insipidus; according to the present invention, the pharmaceutical composition can be subjected to multiple administration at a small dose, can be subjected to counting administration especially for people with large individual metabolism difference, such as old people and children, can achieve accurate administration, can improve the medication compliance for people with difficulty in taking conventional preparations, and has characteristics of simple method, easily available raw materials, and easy 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: 201610453878.X, and invention name: "A kind of hydrochlorothiazide micro-tablet and its preparation method". Technical Field

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

[0003] The symptoms of hypertension vary from person to person. In the early stage, there may be no symptoms or the symptoms are not obvious. The blood pressure will only rise after fatigue, mental stress, and emotional fluctuations, and return to normal after rest. As the course of the disease prolongs, the blood pressure continues to rise significantly, and various symptoms will gradually appear. This is called slow-progressive hypertension. Common clinical symptoms of slow-progressive hypertension include headache, dizziness, inattention, memory loss, limb numbness, increased nocturia, palpitations, chest tightness, fatigue, etc. When the blood pressure suddenly rises to a certain level, there may even be severe headache, vomiting, palpitations, dizziness and other symptoms. In severe cases, unconsciousness and convulsions may occur. This belongs to rapid hypertension and critical hypertension, which often causes serious damage and lesions to the heart, brain, kidneys and other organs in a short period of time, such as stroke, myocardial infarction, renal failure, etc. There is no consistent relationship between the symptoms and the level of blood pressure increase.

[0004] Diabetes insipidus is a group of clinical syndromes caused by hypothalamic-neurophyaloid lesions, which lead to different symptoms of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), or due to various lesions that cause kidney sensitivity defects to AVP, resulting in dysfunction of renal tubular reabsorption of water. The former is central diabetes insipidus (CDI) and the latter is nephrogenic diabetes insipidus (NDI), which are clinically characterized by polyuria, polydipsia, low specific gravity urine or hypoosmotic urine. Diabetes insipidus is common in young and middle-aged people, with a male to female ratio of 2:1. Hereditary NDI is more common in children.

[0005] At present, the drugs on the market for the treatment of hypertension or diabetes insipidus are mostly hydrochlorothiazide-related drugs, which are diuretics and antihypertensive drugs. They are mainly suitable for cardiac edema, hepatic edema and renal edema, such as nephrotic syndrome, acute glomerulonephritis, chronic renal failure, and edema, hypertension and diabetes insipidus caused by excessive adrenal cortex hormones and estrogen.

[0006] 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.

[0007] At present, the oral preparations of hydrochlorothiazide on the market are mainly tablets, and all of them are dosage specifications for adults. However, in clinical application, the dosage of hydrochlorothiazide usually needs to be adjusted according to the effect. When hydrochlorothiazide is used for children, its dosage needs to be calculated according to the child's kilogram body weight. The existing hydrochlorothiazide dosage form cannot meet the requirements of individualized medication, and the dosage cannot be conveniently and accurately divided, and precise medication cannot be achieved. In addition, when the existing drug dosage form is taken, 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

[0008] In order to overcome the defects of the prior art, the present invention provides a hydrochlorothiazide microtablet preparation for treating hypertension and its related symptoms. Through a special granulation formula and preparation process, the hydrochlorothiazide 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. In addition, for people who have difficulty taking conventional preparations, the microtablet is easy to swallow and can improve the compliance of taking the medicine.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides a hydrochlorothiazide micro-tablet preparation, and its prescription raw materials and their dosage ratios are as follows:

[0010]

[0011] The hydrochlorothiazide microtablet preparation of the present invention, wherein the raw materials and their usage ratios in the microtablets are preferably as follows:

[0012]

[0013] Another preferred formulation of the hydrochlorothiazide microtablet preparation of the present invention includes the following raw materials and dosage ratios:

[0014]

[0015] The filler 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. The disintegrant is selected from one or more of cross-linked povidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, effervescent disintegrant, sodium alginate, etc.

[0016] 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.

[0017] 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.

[0018] 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 hydrochlorothiazide 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] The present invention can also encapsulate the hydrochlorothiazide microtablet preparation 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 dosage of once or twice daily administration. The advantage of using this dosage form is that the dosage of the active ingredient is subdivided between many directly countable microtablets, but since the dosage has been determined in the capsule, the patient does not need to count tediously.

[0023] 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.

[0024] Another object of the present invention is to provide a method for preparing hydrochlorothiazide microtablets, wherein the microtablets can be prepared by fluidized bed top spray granulation, wet granulation, dry granulation or fluidized bed bottom spray granulation.

[0025] For example, when the top spray granulation process is adopted, the preparation method is as follows: hydrochlorothiazide 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 filler 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 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.

[0026] Alternatively, when a wet granulation process is adopted, the preparation method is as follows: hydrochlorothiazide, a filler 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.

[0027] When the dry granulation process is adopted, the preparation method is as follows: after the main drug hydrochlorothiazide and other auxiliary materials except the lubricant are evenly mixed, 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

[0028] Embodiment 1:

[0029] name Dosage Hydrochlorothiazide 2mg Microcrystalline cellulose 102 9.46mg Lactose Flawlac100 9.44mg Sodium carboxymethyl starch 0.66mg Magnesium Stearate 0.44mg

[0030] The preparation process is as follows: weigh hydrochlorothiazide, microcrystalline cellulose 102, lactose Flawlac 100 and sodium carboxymethyl starch and mix them evenly, then add magnesium stearate and mix for 2 to 5 minutes, transfer the mixture to a high-speed rotary tablet press for tableting, and obtain the finished hydrochlorothiazide micro-tablets.

[0031] Embodiment 2:

[0032] name Dosage Hydrochlorothiazide 2mg Microcrystalline Cellulose 101 9.22mg Lactose granulac200 20mg Sodium carboxymethyl starch 0.66mg Povidone K30 0.66mg Magnesium Stearate 0.44mg

[0033] The preparation process is as follows: povidone K30 is prepared into a 3% to 8% solution, hydrochlorothiazide, lactose granulac200 and sodium carboxymethyl starch are placed in the pot of a wet granulator, and after mixing, the paddle is turned on and the povidone K30 solution is sprayed in simultaneously for wet granulation, granulation, 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 mixture is transferred to a high-speed rotary tablet press for tableting to obtain finished hydrochlorothiazide micro-tablets.

[0034] Embodiment 3:

[0035] name Dosage Hydrochlorothiazide 3mg Microcrystalline Cellulose 101 20.5mg Crospovidone 1mg Magnesium Stearate 0.8mg

[0036] Preparation process: After hydrochlorothiazide, microcrystalline cellulose 101 and cross-linked polyvinylpyrrolidone 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.

[0037] Example 4

[0038]

[0039] Preparation process: Add hydrochlorothiazide 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 cross-linked carboxymethyl cellulose sodium 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 perform dry granulation; 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 hydrochlorothiazide microtablet, Features The raw materials and their dosage 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 microchip according to claim 1, Features The raw materials and their usage ratios in the micro-sheets are as follows:

4. The microtablet according to any one of claims 1 to 3, wherein the filler is selected from one or more of starch, pregelatinized starch, dextrin, microcrystalline cellulose and lactose.

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

6. The microtablet according to any one of claims 1 to 5, 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.

7. The microchip according to any one of claims 1 to 6, wherein the microchip is in a cylindrical, elliptical or spherical spatial shape, and the microchip is preferably in a cylindrical shape with a height of 1 to 3 mm and a diameter of 1 to 3 mm.

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

9. A method for preparing the hydrochlorothiazide microtablets according to any one of claims 1 to 8, 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.

10. A capsule, It is characterized in that The capsule contains the hydrochlorothiazide microtablets according to any one of claims 1 to 8.

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