Doxazosin mesylate sustained release tablet and preparation method thereof

Abstract

The invention relates to a doxazosin mesylate corrosion type skeleton sustained-release tablet and a preparation method thereof. The tablet is prepared from the following components in percentage by mass: 2-3% of doxazosin mesylate, 54-69% of corrosion type skeleton sustained-release material, 8-12% of pore-foaming agent and the balance of conventional auxiliary materials. The preparation process comprises the following steps: melting and granulating the raw material medicines, the sustained-release material and the pore-foaming agent at 80-95 DEG C through a double-screw extruder, adding the filling agent, the flow aid and the lubricant, and tabletting. The content of genotoxic substances such as methyl methanesulfonate and ethyl methanesulfonate is reduced by optimizing the ratio of raw materials and auxiliary materials and parameters in the granulation process, and the prepared tablet achieves a dissolution curve similar to that of a commercially available preparation. The sustained release preparation provided by the invention can keep effective and stable blood concentration within 24 hours and reduce side effects. The preparation process is simple, good in stability and process reproducibility and suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to pharmaceutical preparation technology in the medical field, and more specifically to a doxazosin mesylate erosion-type skeleton sustained-release tablet and a preparation method thereof. Background Art

[0002] Doxazosin mesylate is a selective long-acting α1 adrenergic receptor blocker. Compared with similar drugs, it has strong antihypertensive effect, low toxicity and good tolerance. It is the first-line drug for the clinical treatment of primary hypertension. It can also effectively improve patients' benign prostatic hyperplasia. This product is a white or off-white crystalline powder; odorless and tasteless. It dissolves in dimethyl sulfoxide and is slightly soluble in water, methanol or ethanol. The chemical name is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxane-2-formyl)piperazine mesylate. Its molecular formula is C 23 H 25 N5O5·CH4SO3, molecular weight is 547.59, chemical structure is as follows:

[0003]

[0004] This product is rapidly absorbed in the gastrointestinal tract, and age and gender have no effect on absorption. In 1988, Pfizer developed doxazosin mesylate tablets and launched them in Denmark. Ordinary tablets have a pain point in dosage adjustment during clinical use, so Pfizer used osmotic pump controlled release technology to improve it and developed a sustained-release preparation of this variety. ( XL), achieved more stable plasma drug concentration parameters, reduced side effects, showed good clinical superiority, and was successively launched in Europe, the United States and China.

[0005] Listed products It is a double-layer tablet core structure, using polyoxyethylene as a suspending and swelling functional auxiliary material, and sodium chloride as an osmogen to achieve the controlled release effect of the drug. Although the quality is stable and the efficacy is definite. However, the prescription and process of the preparation still have certain defects. Polyoxyethylene has a low melting point, and the rotation of the paddle during the mixing and granulation process is prone to agglomeration. The heat between the dies during the tableting process is prone to cause sticking. Double-layer tableting poses certain challenges to both equipment and workers. In the process of industrialization, it is often encountered that the two layers are mixed and the tablets are scattered. Color mixing makes it difficult to distinguish between the two layers, thereby increasing the error rate of punching. The use of a large amount of organic solvents in the coating process has certain operational risks and is not environmentally friendly.

[0006] In order to avoid the risk of tablet production brought by polyethylene oxide, patent CN101439026B provides a controlled release preparation of doxazosin or its salts, in which the drug-containing layer carrier is a vinyl pyrrolidone homopolymer / copolymer. The melting point of vinyl pyrrolidone homopolymer / copolymer is significantly higher, which broadens the controllable parameter range of granulation and tableting processes. The booster layer adopts a combination of disintegrant and penetration-promoting polymer to increase the driving force of the booster layer. However, the controlled release preparation does not simplify the complex production process, and a large amount of organic solvents are still used in the coating process.

[0007] Patent CN101167728B discloses a kind of doxazosin mesylate controlled-release tablets with a single-layer core structure, which is granulated once, has a single-layer core, and a small hole is punched on the upper and lower sides of the tablet after being coated with a semipermeable film, which simplifies the production process to a certain extent. However, this technology is subject to certain restrictions on the use of drugs with poor water solubility, and drug solubilization means must be used, such as adding surfactants or salt formation, etc., which may produce irrelevant impurities. In addition, the single-layer osmotic pump technology may have shortcomings such as incomplete drug release. In the preparation method, doxazosin mesylate, citric acid, sodium dodecyl sulfate, 100,000 molecular weight polyethylene oxide, gum arabic, sodium alginate, lactose, sucrose, and starch are crushed separately, sieved, mixed evenly, ethanol is used as a wetting agent to make a soft material, 20 mesh sieves are granulated, wet granules are dried, 18 mesh sieves are granulated, and then the dry granules are mixed with magnesium stearate and tableted to obtain a core.

[0008] CN 101439026 B provides a controlled release preparation of doxazosin or its salt, which comprises a drug-containing layer and a push layer in a weight ratio of 1:0.5-3, wherein the drug-containing layer comprises doxazosin or its salt and a carrier, wherein the carrier is a vinylpyrrolidone polymer accounting for 40-99% of the weight of the drug-containing layer; the push layer at least comprises a permeation-promoting polymer accounting for 10-80% of the weight of the push layer, a water-insoluble polymer accounting for 10-80% and an osmotic pressure enhancer accounting for 3-60% of the weight of the push layer; the doxazosin or its pharmaceutically acceptable salt of the invention can release the drug at a controlled rate, so that the preparation can achieve the purpose of releasing doxazosin or its pharmaceutically acceptable salt within about 24 hours by once-daily administration. The method for preparing the drug-containing layer comprises the following steps: passing doxazosin or its salt and 40-99% of vinylpyrrolidone polymer through a 60-mesh sieve, mixing them uniformly by an equal amount incremental method, adding them to a fluidized bed, spraying an ethanol-water solution of not less than 40%, granulating, drying, adding magnesium stearate, and mixing. In the above two technical solutions for the production and granulation process, ethanol is added, and methanesulfonic acid reacts with lower alcohols such as ethanol to easily produce genotoxic substances such as methyl methanesulfonate and ethyl methanesulfonate, which increases the risk of cancer after medication.

[0009] CN111388439B provides a tablet containing doxazosin mesylate for quick release and sustained release and a preparation method thereof; the preparation method is to prepare the raw material and its pharmaceutically acceptable auxiliary materials into a quick release layer and a sustained release layer intermediate respectively, and press them into a double-layer tablet, and the outermost layer of the tablet core is coated with a quick release film; wherein the sustained release layer contains a solid dispersion prepared by the raw material and polyethylene glycol, dichloromethane, dimethyl sulfoxide and purified water, and the doxazosin mesylate quick release and sustained release tablets prepared by the present invention can avoid the risk of using ethanol to produce genotoxic impurities in the existing preparation of sustained release tablets, reduce the difficulty of production technology and shorten the production time, and the tablet of the present invention releases quickly in the early stage and quickly plays a hypotensive effect, and releases stably in the later stage through the sustained release part, so that the blood drug concentration in the human body is stable, and plays a role in stabilizing the hypotensive effect. And mesylate and polyethylene glycol (PEG) are also easy to produce esterification reaction to generate harmful substances such as polyethylene glycol dimesylate.

[0010] Patent CN106727406B discloses a controlled-release composition of doxazosin with a single-hole, single-layer core structure, which improves the solubility of doxazosin by using solid dispersion technology, and increases the drug loading of doxazosin in the tablet by more than 1 times. The combination design of suspending agents and retardants prolongs the duration of constant-rate drug release. However, the preparation process of solid dispersions is cumbersome, involving processes such as melting, dissolving, organic solvent volatilization, and freeze drying, and industrialization is difficult.

[0011] In order to overcome the above defects, the inventors tried to use skeleton sustained-release materials such as beeswax, carnauba wax, stearic acid, etc. to reduce the content of genotoxic substances such as methyl methanesulfonate and ethyl methanesulfonate, and adopted granulation process design to simplify the production process to obtain a sustained-release tablet of doxazosin mesylate similar to the original research. The drug release is also stable in the sustained-release formulation. Summary of the invention

[0012] In view of the deficiencies of the prior art, the inventors provide a skeleton-type doxazosin mesylate sustained-release tablet with low genotoxic substance content, simplified and environmentally friendly process, high controllability, and relatively few prescription components. The present invention, under the premise of fully considering the properties of the raw material drug, takes a different approach and cleverly combines the technical advantages of the twin-screw extruder with the physicochemical properties of the dissolution-type skeleton material, performs melt granulation, and then adds conventional drug excipients to directly compress the tablet to obtain the desired preparation. It has certain advantages in terms of production capacity, cost, safety, and environmental protection in industrial production.

[0013] The invention is specifically implemented through the following scheme:

[0014] In one aspect, the present invention provides a doxazosin mesylate sustained-release tablet. In a preferred embodiment, the doxazosin mesylate sustained-release tablet comprises the following components in parts by weight:

[0015]

[0016] In a preferred embodiment of the present invention, the erosion-type skeleton sustained-release material is one or more of beeswax, carnauba wax, and stearic acid.

[0017] In a preferred embodiment of the present invention, the porogen is one or more of polyvinyl pyrrolidone, copovidone, and hydroxypropyl cellulose.

[0018] In a preferred embodiment of the present invention, the filler is one or more of microcrystalline cellulose, lactose, cellulose lactose, silicified microcrystalline cellulose, pregelatinized starch, and colloidal silicon dioxide.

[0019] In a preferred embodiment of the present invention, the glidant is one or more of micro-powdered silica gel and talc.

[0020] In a preferred embodiment of the present invention, the lubricant is selected from one or more of the following: magnesium stearate, zinc stearate, sodium stearyl fumarate and hydrogenated castor oil.

[0021] On the other hand, the present invention provides a method for preparing the above-mentioned doxazosin mesylate sustained-release tablets, comprising the following steps:

[0022] (1) mixing doxazosin mesylate, a dissolution skeleton sustained-release material and a pore-forming agent uniformly;

[0023] (2) in the granulation (TSG) mode of the twin-screw extruder, the barrel temperature is set to 80-95° C., the screw element configuration and the screw speed are adjusted to control the particle size and hardness of the particles, and the mixed powder in step (1) is melt-granulated;

[0024] (3) mixing the cooled particles with a filler, a glidant, and a lubricant to obtain a mixed powder;

[0025] (4) Compressing the mixed powder obtained in step (3) into tablets.

[0026] Furthermore, the screw configuration in step (2) has at least one mixing zone consisting of 7 mixing elements with an offset angle of 60°.

[0027] Furthermore, in step (2), the screw speed of the extruder during stable operation is above 100 rpm.

[0028] Compared with the prior art, the present invention has the following advantages:

[0029] (1) Use skeleton sustained-release materials such as beeswax, carnauba wax, stearic acid, etc., and avoid using auxiliary materials such as ethanol and polyethylene glycol to reduce the content of genotoxic substances such as methyl methanesulfonate and ethyl methanesulfonate.

[0030] (2) The preparation process is simplified and the process controllability is higher. The doxazosin mesylate sustained-release tablets of the present invention are one-step granulation and single-layer tableting, and do not require coating, which reduces the labor intensity of workers and reduces the requirements on workers' skills and literacy.

[0031] (3) Energy saving and environmental protection, cost reduction and efficiency improvement. The granulation process does not require the addition of any solvent, does not require drying, does not have a complicated coating process, and the batch production time is shortened. The API is overdosed by 5%, but there is no overdosing of API in the present invention.

[0032] (4) The demand for high-performance / special equipment is reduced, and the production threshold is lowered. In the present invention, except for the twin-screw extruder, the mixer, tablet press, etc. are all conventional equipment of pharmaceutical companies.

[0033] (5) The finished product has good controllability and higher drug safety. The single-layer tablet of the present invention has easy-to-control tablet weight and more accurate tablet content. No coating is required and no organic solvent residue is left. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The drawings in the specification, which constitute a part of the present application, are used to provide further understanding of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute improper limitations on the present application.

[0035] Figure 1 Examples 1-5 and the original commercially available preparation Dissolution curve of

[0036] Figure 2 For comparison of Examples 1-2 and the original commercially available preparation dissolution curve. DETAILED DESCRIPTION

[0037] The beneficial effects of the present invention are further described below by way of examples. It should be correctly understood that the examples of the present invention are provided only for the purpose of illustrating the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope of protection claimed in the present invention.

[0038] Embodiment (prescription quantity is calculated based on 1000 tablets)

[0039] Example 1

[0040] 1) Prescription

[0041]

[0042] 2) Preparation process

[0043] (a) Add the prescribed amount of doxazosin mesylate, carnauba wax and K30 into a mixing barrel and mix for 20 minutes.

[0044] (b) The mixed powder in step (a) is added into a twin-screw extruder through a feeder, the barrel temperature is set at 80-95° C., the rotation speed is 100 rpm, melt granulation is performed, and the granules are naturally cooled.

[0045] (c) Add the granulated mixed powder, microcrystalline cellulose, lactose and talcum powder into a mixing barrel and mix for 30 minutes.

[0046] (d) Add magnesium stearate and mix thoroughly for 5 minutes.

[0047] (e) tabletting the total mixed granules by a rotary tablet press, controlling the hardness to be appropriate, to obtain doxazosin mesylate sustained-release tablets.

[0048] Example 2

[0049] 1) Prescription

[0050]

[0051]

[0052] 2) Preparation process

[0053] (a) Add the prescribed amount of doxazosin mesylate, carnauba wax, stearic acid and hydroxypropyl cellulose into a mixing bucket and mix for 20 minutes.

[0054] (b) The mixed powder in step (a) is added into a twin-screw extruder through a feeder, the barrel temperature is set at 80-95° C., the rotation speed is 120 rpm, and melt granulation is performed, and the granules are naturally cooled.

[0055] (c) Add the granulated mixed powder, silicified microcrystalline cellulose, lactose and talcum powder into a mixing barrel and mix for 30 minutes.

[0056] (d) Add sodium stearyl fumarate and mix thoroughly for 5 minutes.

[0057] (e) tabletting the total mixed granules by a rotary tablet press, controlling the hardness to be appropriate, to obtain doxazosin mesylate sustained-release tablets.

[0058] Example 3

[0059] 1) Prescription

[0060]

[0061] 2) Preparation process

[0062] (a) Add the prescribed amount of doxazosin mesylate, carnauba wax, beeswax, copovidone and hydroxypropyl cellulose into a mixing bucket and mix for 20 minutes.

[0063] (b) The mixed powder in step (a) is added into a twin-screw extruder through a feeder, the barrel temperature is set at 80-95° C., the rotation speed is 150 rpm, melt granulation is performed, and the granules are naturally cooled.

[0064] (c) Add the granulated mixed powder, cellulose lactose and colloidal silicon dioxide into a mixing barrel and mix for 10 minutes.

[0065] (d) Use a swing granulator to granulate the mixed powder in step (c) and sieve it through a 16-mesh screen.

[0066] (e) Mix the granulated powder and the mixed powder for 20 minutes.

[0067] (f) Add magnesium stearate and mix thoroughly for 5 minutes.

[0068] (g) tabletting the total mixed granules by a rotary tablet press, controlling the hardness to be appropriate, to obtain doxazosin mesylate sustained-release tablets.

[0069] Example 4

[0070] 1) Prescription

[0071]

[0072] 2) Preparation process

[0073] (a) Add the prescribed amount of doxazosin mesylate, stearic acid, beeswax, copovidone and K30 into a mixing bucket and mix for 20 minutes.

[0074] (b) The mixed powder in step (a) is added into a twin-screw extruder through a feeder, the barrel temperature is set at 80-95° C., the rotation speed is 170 rpm, and melt granulation is performed, and the granules are naturally cooled.

[0075] (c) Add the granulated mixed powder, silicified microcrystalline cellulose, pregelatinized starch and talcum powder into a mixing barrel and mix for 30 minutes.

[0076] (d) Add zinc stearate and mix thoroughly for 5 minutes.

[0077] (e) tabletting the total mixed granules by a rotary tablet press, controlling the hardness to be appropriate, to obtain doxazosin mesylate sustained-release tablets.

[0078] Example 5

[0079] 1) Prescription

[0080]

[0081]

[0082] 2) Preparation process

[0083] (a) Add the prescribed amount of doxazosin mesylate, carnauba wax and hydroxypropyl cellulose into a mixing bucket and mix for 20 minutes.

[0084] (b) The mixed powder in step (a) is added into a twin-screw extruder through a feeder, the barrel temperature is set at 80-95° C., the rotation speed is 200 rpm, melt granulation is performed, and the granules are naturally cooled.

[0085] (c) The granulated mixed powder is mixed with microcrystalline cellulose, pregelatinized starch and colloidal silicon dioxide and added into a mixing barrel and mixed for 10 minutes.

[0086] (d) Use a swing granulator to granulate the mixed powder in step (c) and sieve it through a 16-mesh screen.

[0087] (e) Mix the granulated powder and the mixed powder for 20 minutes.

[0088] (f) Add magnesium stearate and mix thoroughly for 5 minutes.

[0089] (g) tabletting the total mixed granules by a rotary tablet press, controlling the hardness to be appropriate, to obtain doxazosin mesylate sustained-release tablets.

[0090] Comparative Example (prescription amount is calculated based on 1000 tablets)

[0091] Comparative Example 1

[0092] The formulation of Example 1 was granulated by wet method to prepare doxazosin mesylate sustained-release tablets.

[0093] 1) Prescription

[0094]

[0095] 2) Preparation process

[0096] (a) The prescribed amount of doxazosin mesylate, carnauba wax, polyethylene glycol and K30 were added to a mixing barrel, mixed for 20 minutes, and granulated with 60% ethanol.

[0097] (b) The granules prepared in step (a) are added with magnesium stearate and mixed for 5 minutes.

[0098] (c) tabletting the total mixed granules by a rotary tablet press, controlling the hardness to be appropriate, to obtain doxazosin mesylate sustained-release tablets.

[0099] Comparative Example 2

[0100] Reference Prescription, and the preparation process of double-layer controlled-release tablets of patent CN103877061, to prepare doxazosin mesylate sustained-release tablets.

[0101] 1) Prescription

[0102] Drug-containing layer

[0103]

[0104] Booster layer

[0105]

[0106] Semipermeable membrane coating liquid composition

[0107] Cellulose acetate 40.0g

[0108] Macrogol 4000 1.7g

[0109] Acetone:water (95:5) 2000mL

[0110] film coat

[0111] Opadry II White Appropriate amount

[0112] 2) Preparation process

[0113] (a) Preparation of drug-layered particles

[0114] Doxazosin mesylate, polyoxyethylene, hydroxypropyl methylcellulose and red iron oxide in the formula are mixed evenly by equal amount, placed in a mixer and mixed evenly, and then 75% ethanol aqueous solution is added to prepare a soft material, granulated with a 20-mesh sieve, and dried at 50°C for more than 2 hours. Then magnesium stearate is added and mixed evenly.

[0115] (b) Preparation of boost layer particles

[0116] Place polyoxyethylene, hydroxypropyl methylcellulose, sodium chloride and red iron oxide in a mixer and mix them. After mixing evenly, add 75% ethanol aqueous solution to prepare a soft material, sieve 20 meshes to granulate, and dry at 50°C for more than 2 hours. Add magnesium stearate and mix evenly.

[0117] (c) Tableting

[0118] A double-layer tablet press is used to compress double-layer tablets with a tablet diameter of 8 mm to produce tablet cores of appropriate hardness.

[0119] (d) Semipermeable membrane coating

[0120] The tablet cores that have passed the above inspection are coated with a semipermeable membrane coating solution. The coated products should be dried at 50°C for 5 hours and then the acetone residue should be measured.

[0121] (e) Use a laser puncher to punch a small hole of about 0.6 mm on the surface of the drug layer of the coated tablets that have passed the inspection.

[0122] (f) After film coating, doxazosin mesylate sustained-release tablets are obtained.

[0123] Verification Example

[0124] 1. Determination of alkyl methanesulfonate content in tablets

[0125] HPLC conditions: Shim-pack GIST C18 (2.1mm×100mm, 2μm); column temperature: 40℃; sample tray temperature: 15℃; flow rate: 0.4mL / min; mobile phase A: 0.1% formic acid solution, mobile phase B: acetonitrile; gradient elution program: 0-3min, 5%-5% mobile phase B; 3-10min, 5%-35% mobile phase B; 10-15min, 35%-95% mobile phase B; 15-19min, 95%-95% mobile phase B; 19-19.1min, 95%-5% mobile phase B; 19.1-23min, 5%-5% mobile phase B.

[0126] Mass spectrometry conditions: ion source: electrospray ion source (ESI); detector voltage: relative tuning voltage is 0.2 kV; ion source temperature is 250°C; interface temperature: 300°C; DL temperature: 250°C; nebulizer flow rate: 3 L / min; drying gas flow rate: 10 L / min; heating gas flow rate: 10 L / min; collision gas: argon, 230 kPa.

[0127] References: Huang Bing, Lu Chao, Cheng Tao, et al. Determination of sulfonate in doxazosin mesylate by liquid chromatography-mass spectrometry[J]. Shandong Chemical Industry, 2023, 52(05): 151-153.

[0128] Test solution: Take appropriate amount of samples of Examples 1-5 and Comparative Examples 1-2, grind them, add diluent (water-acetonitrile (600:400, by volume) to dissolve and quantitatively dilute to make a solution containing about 2 mg per 1 mL, accurately measure 0.5 mL of the above solution and 0.5 mL of the derivatization reagent, put them into an injection vial, cover and seal, shake to dissolve, react at 60°C for 3 h, and inject directly after cooling.

[0129] Reference solution: Take appropriate amount of methyl methanesulfonate reference substance, ethyl methanesulfonate reference substance and butyl methanesulfonate reference substance, dissolve in diluent and quantitatively dilute to make a solution containing approximately 374 ng of methyl methanesulfonate, ethyl methanesulfonate and butyl methanesulfonate per 1 mL. Accurately measure 0.5 mL of the above solution and 0.5 mL of the derivatization reagent, place in an injection vial, cover and seal, shake to dissolve, react at 60°C for 3 h, and inject directly after cooling.

[0130] The results are shown in Table 1.

[0131] Table 1 Content of alkyl methanesulfonate in tablets (ppm)

[0132] sample Methyl methanesulfonate Ethyl methanesulfonate Butyl methanesulfonate Example 1 Not detected Not detected Not detected Example 2 0.5 Not detected Not detected Example 3 Not detected 0.8 Not detected Example 4 Not detected Not detected Not detected Example 5 Not detected Not detected Not detected Comparative Example 1 1.2 2.0 1.8 Comparative Example 2 1.5 1.9 2.3

[0133] As can be seen from the above table, the contents of methyl methanesulfonate, ethyl methanesulfonate and butyl methanesulfonate in the doxazosin mesylate sustained-release tablets of Examples 1-5 are extremely low or undetectable, while methyl methanesulfonate, ethyl methanesulfonate and butyl methanesulfonate can be detected in Comparative Examples 1 and 2, indicating that this may be related to the use of ethanol granulation or the presence of polyethylene glycol in the prescription.

[0134] 2. Control the uniformity of dosage units in the tablet core

[0135] According to the Technical Guidance for the Study of Mixing Uniformity and Unit Uniformity of Central Control Dosage for Chemical Oral Solid Preparations, the tablet cores of the Examples and Comparative Examples were sampled and tested. The tablet pressing process was sampled 20 times, and at least 3 tablets were tested each time.

[0136] Determined by high performance liquid chromatography (General Rule 0512).

[0137] Take 10 tablets of the product for test solution, place them in a 100ml volumetric flask, add an appropriate amount of mobile phase, dissolve them by ultrasonication, let cool, dilute to the scale with mobile phase, shake well, filter, and take the filtrate.

[0138] Reference solution: Take the reference substance, weigh it accurately, add the mobile phase to dissolve it and quantitatively dilute it to make a solution containing about 40 μg of doxazosin per 1 ml.

[0139] The determination method uses octadecylsilane bonded silica gel as filler; methanol-phosphate buffer (take 3.4g of potassium dihydrogen phosphate, add 800ml of water and 4.0ml of triethylamine to dissolve, adjust the pH value to 4.5 with phosphoric acid, and dilute with water to 1000ml) (55:45) as mobile phase; detection wavelength is 245nm; injection volume is 20μ1. Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0140] Table 2. Results of uniformity test of tablet core in-dose control unit

[0141]

[0142] It can be seen from the above table that the single-layer tablets compressed after granulation have better controllability of content uniformity than mixed powder direct compression and double-layer tablets, the unit dose content of the product is more accurate, and the patient's medication is safer.

[0143] 3. Dissolution

[0144] Determine according to the dissolution and release method (General Rule 0931 Method 2).

[0145] The dissolution conditions were 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, the rotation speed was 75 rpm, and the operation was carried out according to the law. Samples were taken at 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 16 hours. The release amount of the doxazosin mesylate preparation was determined, and the results were compared with those of the commercial preparation. The dissolution results were compared.

[0146] Table 3 Dissolution data of doxazosin mesylate sustained-release tablets at 37°C in 0.01 mol hydrochloric acid medium

[0147]

[0148]

[0149] It can be seen from the above table that the doxazosin mesylate sustained-release tablets of the present invention can achieve a dissolution curve similar to that of the original commercially available sustained-release tablets.

[0150] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A doxazosin mesylate sustained-release tablet, characterized in that: It is composed of the following components in parts by weight:

2. The doxazosin mesylate sustained-release tablet according to claim 1, characterized in that: The dissolution-type skeleton sustained-release material is one or more of beeswax, carnauba wax and stearic acid.

3. The doxazosin mesylate sustained-release tablet according to claim 1, characterized in that: The pore-forming agent is one or more of polyvinyl pyrrolidone, copovidone, and hydroxypropyl cellulose.

4. The doxazosin mesylate sustained-release tablet according to claim 1, characterized in that: The filler is one or more of microcrystalline cellulose, lactose, cellulose lactose, silicified microcrystalline cellulose, pregelatinized starch, and colloidal silicon dioxide.

5. The doxazosin mesylate sustained-release tablet according to claim 1, characterized in that: The glidant is one or more of micro-powdered silica gel and talcum powder.

6. The doxazosin mesylate sustained-release tablet according to claim 1, characterized in that: The lubricant is selected from one or more of the following: magnesium stearate, zinc stearate, sodium stearyl fumarate and hydrogenated castor oil.

7. A sustained-release tablet containing doxazosin mesylate according to any one of claims 1 to 6, characterized in that: The preparation method comprises the following steps: (1) mixing doxazosin mesylate, a dissolution skeleton sustained-release material and a pore-forming agent uniformly; (2) in the granulation (TSG) mode of the twin-screw extruder, the barrel temperature is set to 80-95° C., the screw element configuration and the screw speed are adjusted to control the particle size and hardness of the particles, and the mixed powder in step (1) is melt-granulated; (3) mixing the cooled particles with a filler, a glidant, and a lubricant to obtain a mixed powder; (4) tableting the mixed powder obtained in step (3); Further, the screw configuration in step (2) has at least one mixing zone consisting of 7 mixing elements offset at an angle of 60°; Furthermore, in step (2), the screw speed of the extruder during stable operation is above 100 rpm.

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