Hydrochlorothiazide micro-tablet and preparation method thereof

Abstract

The invention discloses a novel hydrochlorothiazide dosage form and a method for preparing the novel hydrochlorothiazide dosage form, the novel hydrochlorothiazide dosage form with good compressibility is prepared from hydrochlorothiazide, an adhesive, a filling agent and other raw materials through top spray fluidized bed granulation and other preparation methods, and the novel hydrochlorothiazide dosage form has the advantages that the novel hydrochlorothiazide dosage form has obvious curative effect 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 August 29, 2016, application number: 201610749789.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, most of the drugs on the market for the treatment of hypertension or diabetes insipidus are hydrochlorothiazide-related drugs. Hydrochlorothiazide, with the chemical name of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, is a diuretic and antihypertensive drug. It is mainly used for cardiogenic 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 conventional 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 the medication is poor for children, the elderly and patients who are inconvenient to swallow tablets. 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 purpose of the invention, the present invention provides a hydrochlorothiazide micro-tablet preparation, which is mainly composed of an active ingredient hydrochlorothiazide and pharmaceutical excipients.

[0010] The hydrochlorothiazide microtablet preparation of the present invention, wherein the pharmaceutical excipients include fillers, disintegrants, lubricants and optional binders. The fillers may be selected from one or more of lactose, sucrose, microcrystalline cellulose, starch, mannitol, sorbitol and dextrin; the disintegrants may be selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone and cross-linked sodium carboxymethyl starch; the binders may be selected from one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate, xanthan gum, ethyl cellulose and acrylic resin; the lubricants may be selected from one or more of magnesium stearate, polyethylene glycol, stearic acid, calcium stearate, sodium stearyl fumarate and talc.

[0011] The binder in the microtablet preparation of the present invention is selected from one or more of the binders mentioned above. When preparing microtablets, the prescription may contain a binder or not, depending on different preparation methods. If direct powder tableting is selected, you may choose not to use a binder or you may choose to use a binder. During wet granulation, tableting or top spray granulation and tableting, a binder is required for granulation and then microtablet compression. From the final result, direct powder tableting without a binder and wet granulation and top spray granulation tableting with a binder have no obvious effect on the final forming of the microtablets.

[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 hydrochlorothiazide microtablet preparation of the present invention, wherein the mass percentage of the active ingredient hydrochlorothiazide in the microtablet is 5-50%, preferably 7-25%.

[0014] The hydrochlorothiazide microtablet preparation of the present invention, wherein the mass percentage of the filler in the microtablet is 50-90%, preferably 70-90%; the disintegrant is 2-10%, preferably 3-6%; the lubricant is 0.1-10%, preferably 0.5-5%; the binder is optional, and the mass percentage can be 0-15%, preferably 2-10%.

[0015] 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 3 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, etc.

[0016] 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 coated with at least one layer of coating to achieve the effect of slow release, controlled release or release in different environments in the body.

[0017] The hydrochlorothiazide microtablet preparation of the present invention can be used alone, or the microtablet preparation can be loaded into a capsule to prepare an oral preparation in the form of a capsule. Another object of the present invention is to provide a capsule preparation containing hydrochlorothiazide microtablets, wherein the capsule contains a certain number of hydrochlorothiazide 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.

[0018] In addition to manual counting, the microtablet preparation of the present invention can also be used in conjunction with a special drug delivery device, such as a drug dispensing device, to provide more convenient and accurate drug delivery. For example, a certain number of microtablets can be provided together with a drug dispensing device, such as a tablet counter, as a whole, which can be detachable or inseparable. When the drug dispensing device is inseparable from the microtablets, the drug dispensing device should ensure that the number of microtablets loaded reaches a certain scale, such as enough for patients to use for a period of time (ranging from several weeks to several months).

[0019] Another object of the present invention is to provide a method for preparing hydrochlorothiazide microtablets, wherein the microtablets can be prepared by top spray granulation tableting, wet granulation tableting, or powder direct tableting.

[0020] For example, when top spray granulation and tableting is adopted, the steps include: dissolving the binder in water, ethanol or a mixed solvent of ethanol and water to prepare a binder solution, then putting the active ingredient and the filler into a fluidized bed for top spray granulation, using a 40-mesh screen to sieve the particles, adding a disintegrant and a lubricant to the obtained particles, mixing them and then tableting them.

[0021] Alternatively, when a wet granulation process is adopted, it includes the following steps: one method is to dissolve the binder in water, ethanol or a mixed solvent of ethanol and water to prepare a binder solution, then put the active ingredient and the filler into a wet granulator, premix them first, then add the binder solution to granulate, dry the obtained granules, sieve them with a 40-mesh screen, add a disintegrant and a lubricant to mix them, and then compress them into tablets. When a wet granulation process is adopted, the active ingredient, the filler and the binder can also be put into a wet granulator together for premixing, then use water, ethanol or a mixed solvent of ethanol and water as a wetting agent to wet granulate, then dry the obtained granules, sieve them with a 40-mesh screen, add a disintegrant and a lubricant to mix them, and then compress them into tablets.

[0022] When direct tableting of powder is adopted, it includes the following steps: respectively weighing the prescribed amount of excipients and active pharmaceutical ingredients, fully mixing the excipients and active pharmaceutical ingredients except lubricants until they are evenly mixed, adding lubricants to mix evenly, then determining the content of the intermediate, and calculating the tablet weight according to the content of the intermediate for tableting. DETAILED DESCRIPTION

[0023] Embodiment 1:

[0024]

[0025]

[0026] The preparation process is as follows: weigh the auxiliary materials and the main drug hydrochlorothiazide separately, fully mix the auxiliary materials except magnesium stearate and the main drug until they are evenly mixed, add magnesium stearate and mix evenly, then determine the content of the intermediate, calculate the tablet weight based on the content of the intermediate, and then press the tablet.

[0027] Embodiment 2:

[0028] Hydrochlorothiazide 2mg Lactose Flawlac100 5mg Microcrystalline cellulose 102 9.46mg Sodium carboxymethyl starch 0.66mg Magnesium Stearate 0.44mg

[0029] Preparation process: Same as Example 1.

[0030] Embodiment 3:

[0031] Hydrochlorothiazide 2mg Lactose Flawlac100 15mg Microcrystalline cellulose 102 9.46mg Sodium carboxymethyl starch 0.66mg Magnesium Stearate 0.44mg

[0032] Preparation process: Same as Example 1.

[0033] Embodiment 4:

[0034] Hydrochlorothiazide 2mg Lactose Flawlac100 9.44mg Microcrystalline cellulose 102 5mg Sodium carboxymethyl starch 0.66mg Magnesium Stearate 0.44mg

[0035] Preparation process: Same as Example 1.

[0036] Embodiment 5:

[0037] Hydrochlorothiazide 2mg Lactose Flawlac100 9.44mg Microcrystalline cellulose 102 15mg Sodium carboxymethyl starch 0.66mg Magnesium Stearate 1.2mg

[0038] Preparation process: Same as Example 1.

[0039] Embodiment 6:

[0040]

[0041] Preparation process: Same as Example 1.

[0042] Embodiment 7:

[0043] Hydrochlorothiazide 2mg starch 9.44mg Microcrystalline cellulose 102 9.46mg Sodium carboxymethyl starch 1.4mg Magnesium Stearate 0.44mg

[0044] Preparation process: Same as Example 1.

[0045] Embodiment 8:

[0046] Hydrochlorothiazide 2mg Lactose Flawlac100 9.02mg Microcrystalline cellulose 102 9.22mg Sodium carboxymethyl starch 0.66mg Povidone K30 0.66mg Magnesium Stearate 0.44mg

[0047] Preparation process: Povidone K30 is dissolved in a mixed solvent of ethanol and water to prepare a binder solution, hydrochlorothiazide, lactose Flawlac 100, microcrystalline cellulose 102 and the binder solution are put into a wet granulator for premixing, and then wet granulation is carried out using water as a wetting agent. The prepared granules are dried, sieved with a 40-mesh screen, and sodium carboxymethyl starch and magnesium stearate are added and mixed before tableting.

[0048] Embodiment 9:

[0049] Hydrochlorothiazide 2mg Lactose Flawlac100 9.02mg Microcrystalline cellulose 102 9.22mg Sodium carboxymethyl starch 0.66mg Povidone K30 0.66mg Magnesium Stearate 0.44mg

[0050] Preparation process: Povidone K30 is dissolved in water to prepare an adhesive solution as a top-spray adhesive solution, and then the main drug hydrochlorothiazide, lactose Flawlac100, and microcrystalline cellulose 102 are put into a fluidized bed for top-spray granulation, and granulated with a 40-mesh screen. The obtained granules are added with sodium carboxymethyl starch and magnesium stearate and mixed for tableting.

[0051] Embodiment 10:

[0052] Hydrochlorothiazide 2mg Lactose Flawlac100 9.02mg Microcrystalline cellulose 102 9.22mg Sodium carboxymethyl starch 0.66mg Hydroxypropyl methylcellulose 2.0mg talcum powder 0.44mg

[0053] Preparation process: Same as Example 9

[0054] Assay methods and results for content, content uniformity and dissolution:

[0055] 1. Methods:

[0056] Content uniformity Take 1 tablet of this product, place it in a 100ml volumetric flask, add an appropriate amount of mobile phase to disintegrate it, add 5ml of methanol-acetonitrile (1:1), dissolve it by ultrasound, dilute it to the scale with mobile phase, shake well, filter, take the filtrate as the test solution, and determine the content according to the method under the content determination item.

[0057] Content Take 80 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount of fine powder (equivalent to about 20 mg of hydrochlorothiazide), put it in a 100ml volumetric flask, add 5ml of methanol-acetonitrile (1:1), shake, add an appropriate amount of mobile phase to dissolve by ultrasound, dilute to scale with mobile phase, shake well, accurately measure 5ml and put it in a 50ml volumetric flask, dilute to scale with mobile phase, shake well, as the test solution, accurately measure 25μl and inject it into the liquid chromatograph, record the chromatogram; take an appropriate amount of hydrochlorothiazide reference substance, accurately weigh, add 5ml of methanol-acetonitrile (1:1) to dissolve by ultrasound, dilute with mobile phase to make a solution containing about 20μg of hydrochlorothiazide per 1ml, and determine in the same way. Calculate by peak area according to the external standard method.

[0058] Dissolution: Take this product, and follow the dissolution and release determination method, with 500ml of 0.1mol / L hydrochloric acid solution (take 8.5ml of hydrochloric acid, add water to 1000ml, mix well, and obtain) as the dissolution medium, and the speed is 100 revolutions per minute. Operate according to the method. After 15 minutes, take the solution and filter it. According to the chromatographic conditions under the content determination item, accurately measure 25μl of the filtrate, inject it into the liquid chromatograph, and record the chromatogram; accurately weigh an appropriate amount of hydrochlorothiazide reference substance, add 4ml of methanol and ultrasonically dissolve it, dilute it with the release medium to make a solution containing about 4μg per 1ml, and determine it in the same way. Calculate the dissolution amount of each tablet by the peak area according to the external standard method. The limit is 80% of the labeled amount, which should meet the regulations.

[0059] (II) Results:

[0060] Content and content uniformity:

[0061]

[0062] Dissolution:

[0063]

[0064]

[0065] From the experimental results, the content and content uniformity results of Examples 1 to 10 all meet the requirements. Among the dissolution rates of Examples 1 to 10, except for Example 6 which has a slower dissolution rate, the dissolution rates of other Examples can reach more than 85% in 15 minutes, which meets the requirements of rapid dissolution.

Claims

1. A hydrochlorothiazide microtablet, Features The micro-tablet is mainly composed of an active ingredient, hydrochlorothiazide, and pharmaceutical excipients.

2. The micro-tablet according to claim 1, wherein the mass percentage of the active ingredient hydrochlorothiazide in the micro-tablet is 5 to 50%, preferably 7 to 25%.

3. The microtablet according to any one of claims 1 to 2, wherein the pharmaceutical excipients include a filler, a disintegrant, a lubricant and optionally a binder.

4. The microtablet according to any one of claims 1 to 3, wherein the components and mass percentages in the microtablet are as follows: hydrochlorothiazide 5-50%, preferably 7-25%; filler 50-90%, preferably 70-90%; disintegrant 2-10%, preferably 3-6%; lubricant 0.1-10%, preferably 0.5-5%; binder 0-15%, preferably 2-10%.

5. The microtablet according to any one of claims 1 to 4, wherein the filler is selected from one or more of lactose, sucrose, microcrystalline cellulose, starch, mannitol, sorbitol, and dextrin; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and cross-linked sodium carboxymethyl starch; the lubricant is selected from one or more of magnesium stearate, polyethylene glycol, stearic acid, calcium stearate, sodium stearyl fumarate, and talc; the binder is selected from one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate, xanthan gum, ethyl cellulose, and acrylic resin.

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

7. The microtablet according to any one of claims 1 to 6, wherein the microtablet is further coated with one or more functional coatings.

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

9. A hydrochlorothiazide capsule, It is characterized in that The capsule contains the hydrochlorothiazide microtablets according to any one of claims 1 to 7.

10. A drug delivery device, It is characterized in that The hydrochlorothiazide micro-tablets according to any one of claims 1 to 7 are contained therein.

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