Doxazosin mesylate sustained-release tablet and preparation process thereof

Abstract

The invention discloses a doxazosin mesylate sustained-release tablet and a preparation process thereof, and relates to the technical field of doxazosin mesylate sustained-release tablets.The sustained-release tablet comprises a double-layer tablet core composed of a first sustained-release layer and a second sustained-release layer; the double-layer tablet core is prepared from the following components in parts by mass: a first slow-release layer and a second slow-release layer; the first slow-release layer is prepared from the following components in parts by mass: 2.4 parts of chitosan-TPP modified doxazosin mesylate, 10 to 12.5 parts of citric acid-cassava starch, 12.5 to 15 parts of magnesium aluminum silicate-cassava starch, 40 to 60 parts of microcrystalline cellulose and 3 to 4 parts of magnesium stearate; the second slow-release layer is prepared from the following components in parts by weight: 2.4 parts of chitosan-TPP modified doxazosin mesylate, 1.44 to 3.36 parts of carrageenan, 130 to 140 parts of polyethylene oxide, 30 to 40 parts of sodium alginate, 55 to 65 parts of citric acid, 67 to 77 parts of microcrystalline cellulose and 3 to 4 parts of magnesium stearate.

Description

Technical Field

[0001] This invention relates to the field of doxazosin mesylate sustained-release tablets, specifically a doxazosin mesylate sustained-release tablet and its preparation process. Background Technology

[0002] Doxazosin mesylate (DOX) is a commonly used drug for treating benign prostatic hyperplasia and hypertension. Its pharmacological effects depend on maintaining a stable blood drug concentration. Because DOX is a weakly basic drug salt, its solubility and release behavior are highly sensitive to the pH environment of the gastrointestinal tract. As the pH of the gastrointestinal tract increases, the drug release rate decreases significantly, thereby affecting the drug's bioavailability and therapeutic efficacy.

[0003] Sustained-release tablets have become an important direction in the development of DOX formulations due to their ability to achieve sustained drug release, reduce dosing frequency, and minimize fluctuations in blood drug concentration. However, existing sustained-release formulations face challenges in addressing pH-dependent release issues. For example, the initial release rate may be too rapid, leading to fluctuations in blood drug concentration, or the release rate may be too slow in the alkaline environment of the intestine, making it difficult to maintain an effective therapeutic concentration, thereby affecting patient compliance and treatment efficacy.

[0004] Therefore, developing a sustained-release tablet that can maintain stable release behavior and balance the initial release rate with the sustained release effect in different pH environments of the gastrointestinal tract is of great significance for improving the clinical application value of DOX. Summary of the Invention

[0005] The purpose of this invention is to provide a doxazosin mesylate sustained-release tablet and its preparation process to solve the problems raised in the prior art.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A doxazosin mesylate sustained-release tablet, the sustained-release tablet comprising a double-layer core composed of a first sustained-release layer and a second sustained-release layer; the double-layer core is composed of the following by weight: the first sustained-release layer comprises: 2.4 parts chitosan-TPP modified doxazosin mesylate, 10-12.5 parts citric acid-cassava starch, 12.5-15 parts magnesium aluminum silicate-cassava starch, 40-60 parts microcrystalline cellulose, and 3-4 parts magnesium stearate; The second sustained-release layer consists of: 2.4 parts of chitosan-TPP modified doxazosin mesylate, 1.44-3.36 parts of carrageenan, 130-140 parts of polyethylene oxide, 30-40 parts of sodium alginate, 55-65 parts of citric acid, 67-77 parts of microcrystalline cellulose, and 3-4 parts of magnesium stearate.

[0007] Furthermore, the method for preparing the citric acid-cassava starch includes the following steps: Tapioca starch was added to a citric acid solution and heated to 100-105℃ for 30-45 minutes. The product was washed with deionized water, dried under vacuum at 50-55℃, ground, and sieved to obtain citric acid-tapioca starch.

[0008] Furthermore, in the preparation process of the citric acid-cassava starch, the concentration of the citric acid solution is 40-50% w / w.

[0009] Furthermore, the preparation method of the magnesium aluminum silicate-cassava starch includes the following steps: Tapioca starch was added to deionized water and heated to 75-80℃ and stirred for 10-15 minutes to obtain a gelled tapioca starch dispersion. Magnesium aluminum silicate was added to deionized water and ultrasonically dispersed to obtain a magnesium aluminum silicate dispersion. The gelled tapioca starch dispersion and the magnesium aluminum silicate dispersion were added to a reaction vessel in proportion, mixed evenly, and spray-dried to obtain magnesium aluminum silicate-tapioca starch.

[0010] Furthermore, in the preparation process of the magnesium aluminum silicate-cassava starch, the mass ratio of cassava starch to magnesium aluminum silicate is 1:(0.5-0.8); the solid content of the gelled cassava starch dispersion and the magnesium aluminum silicate dispersion after mixing is 2-3% w / v; the spray drying parameters include: inlet temperature of 230-240℃, feed air pressure of 300-400kPa, and feed rate of 16-20mL / min.

[0011] Furthermore, the preparation method of the chitosan-TPP modified doxazosin mesylate includes the following steps: Chitosan and doxazosin mesylate were added to a 1% w / v acetic acid solution and stirred until homogeneous to obtain a cationic solution. Sodium tripolyphosphate was added to water and stirred until homogeneous to obtain an anionic solution. Under stirring, the anionic solution was added to the cationic solution, and then poloxamer 188 was added. The mixture was homogenized, centrifuged, washed, and freeze-dried to obtain chitosan-TPP modified doxazosin mesylate.

[0012] Furthermore, in the preparation process of the chitosan-TPP modified doxazosin mesylate, the chitosan concentration is 1-1.2 mg / mL, the doxazosin mesylate concentration is 0.95-1 mg / mL, the sodium tripolyphosphate concentration is 0.8-1 mg / mL, and the poloxamer 188 concentration is 10-12 mg / mL; in the homogenization process, the homogenization rate is 18000-22000 rpm, and the homogenization time is 1-3 min; the anion solution addition rate is 0.4-0.5 mL / min.

[0013] A process for preparing doxazosin mesylate sustained-release tablets includes the following steps: S1: Preparation of first sustained-release layer particles: Chitosan-TPP modified doxazosin mesylate and microcrystalline cellulose are mixed for 15-30 min, then citric acid-tapioca starch and magnesium aluminum silicate-tapioca starch are added, mixed evenly, sieved, and finally magnesium stearate is added and mixed evenly to obtain the first sustained-release layer particles; S2: Preparation of the second sustained-release layer particles: Chitosan-TPP modified doxazosin mesylate and carrageenan are mixed for 10-15 min, deionized water is added to form a paste, vacuum dried at 45-50℃, ground, and sieved to obtain a solid dispersion; the solid dispersion, polyethylene oxide, sodium alginate, citric acid, and microcrystalline cellulose are mixed evenly, sieved, magnesium stearate is added, and mixed evenly to obtain the second sustained-release layer particles; S3: Preparation of doxazosin mesylate sustained-release tablets: The first sustained-release layer particles and the second sustained-release layer particles are sequentially filled into a rotary tablet press for compression to obtain doxazosin mesylate sustained-release tablets.

[0014] Furthermore, in the doxazosin mesylate sustained-release tablets, the thickness of the first sustained-release layer is 4.0-4.2 mm, the thickness of the second sustained-release layer is 4.6-4.8 mm, and the hardness of a single tablet is 9-11 kp.

[0015] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention uses self-made citric acid-cassava starch and magnesium aluminum silicate-cassava starch together for the disintegration of the first sustained-release layer, rapidly releasing chitosan-TPP modified doxazosin mesylate with sustained-release and bioavailability properties in the acidic environment of gastric juice. Although this invention also rapidly releases doxazosin mesylate, it differs from traditional doxazosin mesylate immediate-release tablets, which have an excessively fast release rate and cause specific side effects in patients due to a rapid increase in blood drug concentration at the initial administration. The doxazosin mesylate released after the disintegration of the first sustained-release layer of this invention, under the modification of chitosan-TPP, has a blood drug concentration higher than that of traditional sustained-release tablets but lower than that of traditional immediate-release tablets. The purpose is to ensure that the blood drug concentration after the release of the subsequent second sustained-release layer is in a continuously stable state, greatly improving patient compliance.

[0016] 2. Magnesium aluminum silicate in magnesium aluminum silicate-cassava starch has a layered structure and strong water absorption capacity. It forms a nanocomposite network with gelatinized cassava starch through hydrogen bonds, which significantly improves the swelling capacity of the material in acidic media. After swelling, it forms an erosive gel layer. Drug release is achieved through a dual mechanism of diffusion and gel erosion. In conjunction with the high hydrophilicity and dissociation characteristics of citric acid-cassava starch under acidic conditions, it can promote the fragmentation of the gel layer and accelerate the disintegration process. The negatively charged surface of magnesium aluminum silicate-cassava starch may form a weak electrostatic interaction with the carboxyl groups of citric acid-cassava starch, which stabilizes the particle dispersion, reduces pre-disintegration agglomeration, and ensures disintegration uniformity.

[0017] 3. The chitosan-TPP modified doxazosin mesylate prepared in this invention exhibits a structure in which chitosan molecules undergo an ionic gelation reaction with negatively charged sodium tripolyphosphate to form a cross-linked network structure, encapsulating the drug doxazosin mesylate within. The small size and large specific surface area of ​​the nanoparticles increase the drug's solubility and dissolution rate, promoting drug absorption. Simultaneously, the adhesiveness of chitosan facilitates close contact between the nanoparticles and the intestinal mucosa, prolonging the drug's residence time at the absorption site and further improving absorption efficiency. Mixing chitosan-TPP modified doxazosin mesylate with carrageenan results in ionic interactions between the two, forming an in-situ complex that further enhances sustained-release performance while preventing the release of the second sustained-release layer in the acidic environment of gastric juice.

[0018] 4. Since doxazosin mesylate is a weakly basic drug salt, its solubility is greatly affected by pH. An increase in pH in the intestine will reduce its release rate. This invention selects to add citric acid as a pH adjuster to the polyethylene oxide-sodium alginate matrix to maintain a low pH value inside the tablet during drug release in intestinal fluid, thereby achieving drug release of doxazosin mesylate sustained-release tablets in the intestinal fluid environment. Detailed Implementation

[0019] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] In the following examples, the method for preparing citric acid-cassava starch includes the following steps: Tapioca starch was added to a 40% w / w citric acid solution, heated to 100°C and reacted for 30 min. The product was washed with deionized water, dried under vacuum at 50°C, ground, and sieved to obtain citric acid-tapioca starch.

[0021] The preparation method of magnesium aluminum silicate-cassava starch includes the following steps: Add 1g of cassava starch to deionized water, heat to 75℃ and stir for 10min to obtain a gelled cassava starch dispersion; add 0.6g of magnesium aluminum silicate to deionized water and ultrasonically disperse to obtain a magnesium aluminum silicate dispersion; add the gelled cassava starch dispersion and the magnesium aluminum silicate dispersion to a reaction vessel in proportion, mix evenly, and spray dry to obtain magnesium aluminum silicate-cassava starch.

[0022] The spray drying parameters include: inlet temperature of 230℃, feed air pressure of 300kPa, and feed rate of 16mL / min.

[0023] The preparation method of chitosan-TPP modified doxazosin mesylate includes the following steps: Chitosan and doxazosin mesylate were added to a 1% w / v acetic acid solution and stirred until homogeneous to obtain a cationic solution. Sodium tripolyphosphate was added to water and stirred until homogeneous to obtain an anionic solution. Under stirring, the anionic solution was added to the cationic solution, and then poloxamer 188 was added. The mixture was homogenized, centrifuged, washed, and freeze-dried to obtain chitosan-TPP modified doxazosin mesylate.

[0024] The concentrations of chitosan, doxazosin mesylate, sodium tripolyphosphate, and poloxamer 188 were 10 mg / mL. The homogenization process was carried out at a homogenization rate of 18,000 rpm for 2 min. The anion exchange solution was added at a rate of 0.4 mL / min.

[0025] Example 1: A preparation process for doxazosin mesylate sustained-release tablets, comprising the following steps: S1: Preparation of the first sustained-release layer particles: 2.4 parts of chitosan-TPP modified doxazosin mesylate and 40 parts of microcrystalline cellulose are mixed for 15 min, then 12.5 parts of citric acid-cassava starch and 12.5 parts of magnesium aluminum silicate-cassava starch are added, mixed evenly, sieved, and finally 3 parts of magnesium stearate are added and mixed evenly to obtain the first sustained-release layer particles; S2: Preparation of the second sustained-release layer particles: 2.4 parts of chitosan-TPP modified doxazosin mesylate and 1.44 parts of carrageenan were mixed for 10 min, deionized water was added to form a paste, vacuum dried at 45℃, ground, and sieved to obtain a solid dispersion; the solid dispersion, 130 parts of polyethylene oxide, 30 parts of sodium alginate, 55 parts of citric acid, and 77 parts of microcrystalline cellulose were mixed evenly, sieved, and 3 parts of magnesium stearate were added and mixed evenly to obtain the second sustained-release layer particles; S3: Preparation of doxazosin mesylate sustained-release tablets: The first sustained-release layer particles and the second sustained-release layer particles are sequentially filled into a rotary tablet press for compression to obtain doxazosin mesylate sustained-release tablets.

[0026] Furthermore, in the doxazosin mesylate sustained-release tablets, the thickness of the first sustained-release layer is 4.0 mm, the thickness of the second sustained-release layer is 4.6 mm, and the hardness of a single tablet is 9 kp.

[0027] Example 2: A preparation process of doxazosin mesylate sustained-release tablets, comprising the following steps: S1: Preparation of the first sustained-release layer particles: 2.4 parts of chitosan-TPP modified doxazosin mesylate and 40 parts of microcrystalline cellulose are mixed for 15 min, then 10 parts of citric acid-cassava starch and 15 parts of magnesium aluminum silicate-cassava starch are added, mixed evenly, sieved, and finally 3 parts of magnesium stearate are added and mixed evenly to obtain the first sustained-release layer particles; The remaining steps are the same as in Example 1.

[0028] Example 3: A preparation process for doxazosin mesylate sustained-release tablets, comprising the following steps: S2: Preparation of second sustained-release layer particles: 2.4 parts of chitosan-TPP modified doxazosin mesylate and 2.4 parts of carrageenan are mixed for 10 min, deionized water is added to form a paste, vacuum dried at 45°C, ground, and sieved to obtain a solid dispersion; the solid dispersion, 130 parts of polyethylene oxide, 30 parts of sodium alginate, 65 parts of citric acid, and 67 parts of microcrystalline cellulose are mixed evenly, sieved, and 3 parts of magnesium stearate are added and mixed evenly to obtain the second sustained-release layer particles; The remaining steps are the same as in Example 2.

[0029] Comparative Example 1: A preparation process for doxazosin mesylate sustained-release tablets, comprising the following steps: The preparation method of citric acid-cassava starch includes the following steps: Tapioca starch was added to a 20% w / w citric acid solution, heated to 100°C and reacted for 30 min. The product was washed with deionized water, dried under vacuum at 50°C, ground, and sieved to obtain citric acid-tapioca starch. The remaining steps are the same as in Example 1.

[0030] Comparative Example 2: A preparation process of doxazosin mesylate sustained-release tablets, comprising the following steps: S1: Preparation of the first sustained-release layer particles: 2.4 parts of doxazosin mesylate and 40 parts of microcrystalline cellulose are mixed for 15 min, then 12.5 parts of citric acid-cassava starch and 12.5 parts of magnesium aluminum silicate-cassava starch are added, mixed evenly, sieved, and finally 3 parts of magnesium stearate are added and mixed evenly to obtain the first sustained-release layer particles; The remaining steps are the same as in Example 1.

[0031] Comparative Example 3: A preparation process for a doxazosin mesylate sustained-release tablet, comprising the following steps: S2: Preparation of the second sustained-release layer particles: 2.4 parts of chitosan-TPP modified doxazosin mesylate are added to deionized water to form a paste, which is then vacuum dried at 45°C, ground, and sieved to obtain a solid dispersion; the solid dispersion, 130 parts of polyethylene oxide, 30 parts of sodium alginate, 55 parts of citric acid, and 77 parts of microcrystalline cellulose are mixed evenly, sieved, and 3 parts of magnesium stearate are added and mixed evenly to obtain the second sustained-release layer particles; The remaining steps are the same as in Example 1.

[0032] Comparative Example 4: A preparation process for doxazosin mesylate sustained-release tablets, comprising the following steps: S2: Preparation of second sustained-release layer particles: 2.4 parts of chitosan-TPP modified doxazosin mesylate and 1.44 parts of carrageenan are mixed for 10 min, deionized water is added to form a paste, vacuum dried at 45℃, ground, and sieved to obtain a solid dispersion; the solid dispersion, 130 parts of polyethylene oxide, 30 parts of sodium alginate, and 132 parts of microcrystalline cellulose are mixed evenly, sieved, and 3 parts of magnesium stearate are added and mixed evenly to obtain the second sustained-release layer particles; The remaining steps are the same as in Example 1.

[0033] Comparative Example 5: Commercially available Coca-Cola.

[0034] Experiment: The USP paddle method was used, employing a dissolution testing station and a heater / circulator. Tests were conducted in 900 mL of simulated gastric and intestinal fluids, with a paddle rotation speed of 75 rpm and a temperature maintained at 37 ± 0.5°C. Dissolution progress was monitored at predetermined time intervals of 2, 4, 6, 8, 16, and 24 hours. Each time, 5 mL of dissolution medium was removed, filtered, and then 5 mL of fresh medium was added. The release of doxazosin mesylate was determined by HPLC.

[0035]

[0036] Note: The above dissolution rate is calculated based on the content of the first sustained-release layer (simulating gastric juice). Conclusion: The first sustained-release layer prepared by this invention has a release rate that is different from the rapid release rate of traditional doxazosin mesylate immediate-release tablets. It can avoid the occurrence of specific side effects in patients due to a rapid increase in blood drug concentration at the initial administration. The blood drug concentration is higher than that of traditional sustained-release tablets but lower than that of traditional immediate-release tablets. The purpose is to ensure that the blood drug concentration after the release of the second sustained-release layer is in a continuous and stable state, which greatly improves patient compliance.

[0037]

[0038] Note: The above dissolution rates are calculated based on the content of the second sustained-release layer (simulating intestinal fluid). Conclusion: The second sustained-release layer prepared by this invention uses citric acid as a pH adjuster added to a polyethylene oxide-sodium alginate matrix to maintain a low pH value inside the tablet during drug release in intestinal fluid, thereby achieving drug release of doxazosin mesylate sustained-release tablets in the intestinal fluid environment.

[0039] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A doxazosin mesylate sustained-release tablet, characterized in that: The sustained-release tablet comprises a double-layer core consisting of a first sustained-release layer and a second sustained-release layer; by weight, the double-layer core is composed as follows: the first sustained-release layer consists of: 2.4 parts of chitosan-TPP modified doxazosin mesylate, 10-12.5 parts of citric acid-cassava starch, 12.5-15 parts of magnesium aluminum silicate-cassava starch, 40-60 parts of microcrystalline cellulose, and 3-4 parts of magnesium stearate; The second sustained-release layer consists of: 2.4 parts of chitosan-TPP modified doxazosin mesylate, 1.44-3.36 parts of carrageenan, 130-140 parts of polyethylene oxide, 30-40 parts of sodium alginate, 55-65 parts of citric acid, 67-77 parts of microcrystalline cellulose, and 3-4 parts of magnesium stearate.

2. The doxazosin mesylate sustained-release tablet according to claim 1, characterized in that: The method for preparing the citric acid-cassava starch includes the following steps: Tapioca starch was added to a citric acid solution and heated to 100-105℃ for 30-45 minutes. The product was washed with deionized water, dried under vacuum at 50-55℃, ground, and sieved to obtain citric acid-tapioca starch.

3. The doxazosin mesylate sustained-release tablet according to claim 2, characterized in that: In the preparation of citric acid-cassava starch, the concentration of citric acid solution is 40-50% w / w.

4. The doxazosin mesylate sustained-release tablet according to claim 1, characterized in that: The preparation method of the magnesium aluminum silicate-cassava starch includes the following steps: Tapioca starch was added to deionized water and heated to 75-80℃ and stirred for 10-15 minutes to obtain a gelled tapioca starch dispersion. Magnesium aluminum silicate was added to deionized water and ultrasonically dispersed to obtain a magnesium aluminum silicate dispersion. The gelled tapioca starch dispersion and the magnesium aluminum silicate dispersion were added to a reaction vessel in proportion, mixed evenly, and spray-dried to obtain magnesium aluminum silicate-tapioca starch.

5. The doxazosin mesylate sustained-release tablet according to claim 4, characterized in that: In the preparation process of magnesium aluminum silicate-cassava starch, the mass ratio of cassava starch to magnesium aluminum silicate is 1:(0.5-0.8); the solid content of the gelled cassava starch dispersion and the magnesium aluminum silicate dispersion is 2-3% w / v; the spray drying parameters include: inlet temperature of 230-240℃, feed air pressure of 300-400kPa, and feed rate of 16-20mL / min.

6. The doxazosin mesylate sustained-release tablet according to claim 1, characterized in that: The preparation method of the chitosan-TPP modified doxazosin mesylate includes the following steps: Chitosan and doxazosin mesylate were added to a 1% w / v acetic acid solution and stirred until homogeneous to obtain a cationic solution. Sodium tripolyphosphate was added to water and stirred until homogeneous to obtain an anionic solution. Under stirring, the anionic solution was added to the cationic solution, and then poloxamer 188 was added. The mixture was homogenized, centrifuged, washed, and freeze-dried to obtain chitosan-TPP modified doxazosin mesylate.

7. The doxazosin mesylate sustained-release tablet according to claim 6, characterized in that: In the preparation of chitosan-TPP modified doxazosin mesylate, the concentration of chitosan is 1-1.2 mg / mL, the concentration of doxazosin mesylate is 0.95-1 mg / mL, the concentration of sodium tripolyphosphate is 0.8-1 mg / mL, and the concentration of poloxamer 188 is 10-12 mg / mL; in the homogenization process, the homogenization rate is 18000-22000 rpm, and the homogenization time is 1-3 min; the anion solution is added at a rate of 0.4-0.5 mL / min.

8. The preparation process of a doxazosin mesylate sustained-release tablet according to any one of claims 1-7, characterized in that: Includes the following steps: S1: Preparation of the first sustained-release layer particles: Chitosan-TPP modified doxazosin mesylate and microcrystalline cellulose are mixed for 15-30 minutes, then citric acid-cassava starch and magnesium aluminum silicate-cassava starch are added, mixed evenly, sieved, and finally magnesium stearate is added and mixed evenly to obtain the first sustained-release layer particles. S2: Preparation of the second sustained-release layer particles: Chitosan-TPP modified doxazosin mesylate and carrageenan are mixed for 10-15 min, deionized water is added to form a paste, vacuum dried at 45-50℃, ground, and sieved to obtain a solid dispersion; the solid dispersion, polyethylene oxide, sodium alginate, citric acid, and microcrystalline cellulose are mixed evenly, sieved, magnesium stearate is added, and mixed evenly to obtain the second sustained-release layer particles; S3: Preparation of doxazosin mesylate sustained-release tablets: The first sustained-release layer particles and the second sustained-release layer particles are sequentially filled into a rotary tablet press for compression to obtain doxazosin mesylate sustained-release tablets.

9. The preparation process of doxazosin mesylate sustained-release tablets according to claim 8, characterized in that: In the doxazosin mesylate sustained-release tablets, the thickness of the first sustained-release layer is 4.0-4.2 mm, the thickness of the second sustained-release layer is 4.6-4.8 mm, and the hardness of a single tablet is 9-11 kp.

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