Tamsulosin hydrochloride sustained release preparation and preparation method thereof

Abstract

The invention provides a tamsulosin hydrochloride sustained release preparation and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: spraying an ethanol water solution of tamsulosin hydrochloride on a mesoporous silica carrier, and drying to obtain a drug-containing carrier; mixing the drug-containing carrier, an auxiliary carrier, an adhesive and water, and carrying out wet granulation to obtain a drug-containing soft material; extruding and rounding the medicine-containing soft material to obtain a medicine-containing pellet core; coating the drug-containing pellet core with a coating solution to obtain a coated pellet core; the coating liquid comprises an enteric-coated material and a plasticizer; and mixing the coated pellet core with a lubricant to obtain the tamsulosin hydrochloride sustained release preparation. The tamsulosin hydrochloride sustained-release preparation prepared by the method is good in drug content stability, stable in main drug release, simple in process, high in controllability and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a sustained-release formulation of tamsulosin hydrochloride and its preparation method. Background Technology

[0002] Benign prostatic hyperplasia (BPH) is a common male disease, especially prevalent in elderly men. The enlarged prostate compresses the urethra, leading to urinary symptoms such as urgency and frequency, severely impacting the quality of life for middle-aged and elderly men. BPH symptoms are related to bladder outlet obstruction. Tamsulosin, an alpha-receptor blocker, selectively acts on alpha-1 receptors in the prostate. Blocking these receptors relaxes the smooth muscle located along the bladder meridian and in the prostate, increasing urine flow rate and alleviating BPH symptoms. Tamsulosin hydrochloride has high selectivity for prostatic smooth muscle, and its oral formulation is rapidly absorbed and has a fast onset of action. Very low doses of tamsulosin hydrochloride can achieve therapeutic effects. Developing it into a sustained-release formulation can reduce the frequency of administration, improve patient compliance, and has broad clinical application prospects.

[0003] Related technologies disclose methods for preparing tamsulosin hydrochloride sustained-release formulations. Specifically, tamsulosin hydrochloride tablets are first prepared, followed by sustained-release coating to form a controlled-release film to control the release of tamsulosin hydrochloride. However, if the controlled-release film is broken or incomplete, there is a risk of dose dumping within a short period after administration of tamsulosin hydrochloride, leading to adverse reactions. Other related technologies disclose methods for preparing tamsulosin hydrochloride sustained-release capsules. Specifically, blank pellet cores are coated with a drug-containing coating solution, followed by a sustained-release coating solution, and then capsule filling. However, this method uses a coating method for drug loading, and variations in coating efficiency can lead to unstable drug content in the formulation. Furthermore, the preparation steps are cumbersome and unsuitable for industrial production. Additionally, some technologies use a drug-containing sustained-release coating solution to coat the surface of blank pellet cores, forming a drug-containing sustained-release layer. This method also suffers from the drawback of unstable drug content in the formulation due to variations in coating efficiency. Summary of the Invention

[0004] The purpose of this invention is to provide a tamsulosin hydrochloride sustained-release formulation and its preparation method. The tamsulosin hydrochloride sustained-release formulation prepared by the method of this invention has good drug content stability, stable release of the active drug, simple and highly controllable process, and is suitable for industrial production.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing a sustained-release formulation of tamsulosin hydrochloride, comprising the following steps: An ethanol-water solution of tamsulosin hydrochloride was sprayed onto a mesoporous silica support and dried to obtain a drug-containing carrier. The drug-containing carrier, auxiliary carrier, and binder are mixed with water and wet granulated to obtain a drug-containing soft material. The drug-containing soft material is extruded and spherical to obtain a drug-containing pellet core; The drug-containing pellet core is coated with a coating solution to obtain a coated pellet core; the coating solution includes an enteric coating material and a plasticizer; The coated pellet core is mixed with a lubricant to obtain the tamsulosin hydrochloride sustained-release formulation.

[0006] Preferably, the mass ratio of tamsulosin hydrochloride to mesoporous silica support is 0.01~1:0.5~20; the particle size of the mesoporous silica support is 20~40μm, and the mesoporous pore size is 3~5nm; The concentration of tamsulosin hydrochloride in the ethanol aqueous solution is 0.18~0.22 g / mL, and the volume fraction of ethanol is 70~80%.

[0007] Preferably, the spraying and drying conditions include: a spraying rate of 8-12 mL / min, an air inlet temperature of 38-42°C, a weight gain of 32-33%, and a moisture content of the drug carrier ≤2.5 wt%.

[0008] Preferably, the mass ratio of tamsulosin hydrochloride to the auxiliary carrier is 0.01~1:0.01~20; the auxiliary carrier includes one or more of microcrystalline cellulose, starch, sucrose and dextrin. The mass ratio of tamsulosin hydrochloride to the adhesive in the adhesive solution is 0.01~1:0.1~20; the adhesive includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and microcrystalline cellulose; the concentration of the adhesive solution is 3~5 wt%.

[0009] Preferably, the extrusion spheroidizing conditions include: the extrusion spheroidizing is carried out at a temperature of 20~30℃ and a relative humidity of 40~60%; the extrusion spheroidizing includes sequential extrusion and spheroidizing processes; the extrusion processing conditions include: an extrusion speed of 20~40 rpm and an extrusion orifice diameter of 0.8 mm; the spheroidizing processing conditions include: an air inlet speed of 200~500 rpm, a spheroidizing speed of 500~1500 rpm, and a spheroidizing time of 7~9 min; the particle size of the cored pellet is 0.2~2 mm and the polydispersity index is ≤0.25.

[0010] Preferably, the mass ratio of tamsulosin hydrochloride to enteric material is 0.01~1:0.5~35; the enteric material includes one or more of Eudragit L100-55, Eudragit L30-55, Kollicoat MAE30DP, Kollicoat MAElOOP and Acryl-EZE 93A; The mass ratio of tamsulosin hydrochloride to plasticizer is 0.01~1:0.05~50; the plasticizer includes one or more of polyethylene glycol, propylene glycol, diethyl phthalate, triethyl citrate, triethyl triacetate, castor oil, silicone oil and oleic acid; The coating solution further includes a sustained-release material, wherein the mass ratio of the sustained-release material to the enteric material is 1:1 to 8; the sustained-release material includes one or more of Eudragit NE30D, Eudragit NE40D, Eudragit RS30D, Kollicoat SR30D, Eudragit RL30D, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, Surelease E-7-19040, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, methylcellulose, cellulose acetate, sodium carboxymethyl cellulose, carbomer, sodium alginate, chitosan, and poloxamer.

[0011] Preferably, the solid content of the coating liquid is 15-20 wt%; the coating conditions include: an inlet air temperature of 37-39°C, a spraying rate of 7-9 g / min, and a weight gain of 11-16%.

[0012] Preferably, the mass ratio of tamsulosin hydrochloride to lubricant is 0.01~1:0.05~50; the lubricant includes magnesium stearate.

[0013] The present invention provides a sustained-release formulation of tamsulosin hydrochloride prepared by the preparation method described above, comprising a coated pellet core and a lubricant. The coated pellet core comprises a drug-containing pellet core and a coating layer covering the surface of the drug-containing pellet core. The components of the drug-containing pellet core include tamsulosin hydrochloride, a mesoporous silica carrier, an auxiliary carrier, and a binder. The components of the coating layer include an enteric material and a plasticizer.

[0014] Beneficial Effects: This invention utilizes a direct mixing process with a high-adsorption carrier to spray an ethanol-water solution of tamsulosin hydrochloride onto a mesoporous silica carrier. The mesoporous silica carrier adsorbs tamsulosin hydrochloride through its mesopores, which helps increase the drug loading of the product. This invention employs an extrusion-spheroidization process, which, compared to centrifugal granulation and drug coating methods, more easily produces pellets of uniform size and regular shape (nearly spherical). This uniformity of pellets helps ensure the stability and controllability of the subsequent coating process, improves coating quality, and results in good stability of drug content in the formulation, thereby ensuring the uniformity and controllability of drug release.

[0015] This invention employs a single-layer coating to achieve enteric coating, which avoids premature drug release in the stomach, ensures drug release in the intestine, improves bioavailability, and reduces gastric irritation. Furthermore, this invention can employ a single-layer composite coating, combining enteric-coating materials with sustained-release materials to achieve simultaneous sustained release and enteric coating, further improving the sustained-release effect.

[0016] In summary, the tamsulosin hydrochloride sustained-release formulation prepared by the method of this invention has good uniformity of active ingredients, high utilization rate, stable release of the main drug, and a simple and highly controllable process, making it suitable for industrial production. Detailed Implementation

[0017] This invention provides a method for preparing a sustained-release formulation of tamsulosin hydrochloride, comprising the following steps: An ethanol-water solution of tamsulosin hydrochloride was sprayed onto a mesoporous silica support and dried to obtain a drug-containing carrier. The drug-containing carrier, auxiliary carrier, and binder are mixed with water and wet granulated to obtain a drug-containing soft material. The drug-containing soft material is extruded and spherical to obtain a drug-containing pellet core; The drug-containing pellet core is coated with a coating solution to obtain a coated pellet core; the coating solution includes an enteric coating material and a plasticizer; The coated pellet core is mixed with a lubricant to obtain the tamsulosin hydrochloride sustained-release formulation.

[0018] In this invention, unless otherwise specified, all raw materials used are commercially available products well known to those skilled in the art or prepared using methods well known to those skilled in the art.

[0019] This invention involves spraying an ethanol-water solution of tamsulosin hydrochloride onto a mesoporous silica support, followed by drying to obtain a drug-containing carrier. In one embodiment, the concentration of tamsulosin hydrochloride in the ethanol-water solution can be 0.18~0.22 g / mL, specifically 0.2 g / mL; the volume fraction of ethanol can be 70~80%, specifically 75%. Specifically, in this embodiment, tamsulosin hydrochloride is mixed with an ethanol-water solution to obtain the ethanol-water solution of tamsulosin hydrochloride. By limiting the composition of the ethanol-water solution of tamsulosin hydrochloride to the above range, this invention ensures that tamsulosin hydrochloride is efficiently embedded in the mesoporous structure of the mesoporous silica support and achieves uniform distribution. This facilitates the formation of a stable drug-loaded system, improves the reliability of sustained-release performance, and prevents crystallization or aggregation of tamsulosin hydrochloride during processing or storage, providing a good foundation for subsequent formulation processes.

[0020] In one embodiment of the present invention, the mass ratio of tamsulosin hydrochloride to mesoporous silica support can be 0.01~1:0.5~20, more preferably 0.1~0.8:0.7~10, and even more preferably 0.3~0.5:0.8~5, specifically 0.4:0.85~1; the mesoporous silica support may include one or more of Prosolv® HD, Syloid® 244FP, XDP, Aerosil® 200, and Aerosil® 300, specifically Syloid® 244FP; the particle size of the mesoporous silica support can be 20~40μm, and the mesopore size can be 3~5nm. In one embodiment of the present invention, the spraying and drying conditions include: a spraying rate of 8-12 mL / min, specifically 10 mL / min; an inlet air temperature of 38-42°C, specifically 40°C; a weight gain of 32-33%; and a moisture content of the drug-containing carrier of ≤2.5 wt%, further ≤1.5 wt%. Specifically, the spraying and drying are carried out in a fluidized bed. The present invention uses a high-adsorption carrier direct mixing process to spray an ethanol-water solution of tamsulosin hydrochloride onto a mesoporous silica carrier. The mesoporous silica carrier adsorbs tamsulosin hydrochloride through mesopores, which is beneficial for increasing the drug loading of the product. In the embodiments of the present invention, spraying and drying are carried out under the above conditions. By controlling the spraying rate, temperature control, and drying and adsorption endpoints during the adsorption process, it is beneficial to ensure that the product has a high drug loading.

[0021] After obtaining the drug-containing carrier, the present invention mixes the drug-containing carrier, auxiliary carrier, binder, and water, and performs wet granulation to obtain a drug-containing soft material. As one embodiment of the present invention, the mass ratio of tamsulosin hydrochloride to the auxiliary carrier can be 0.01~1:0.01~20, more further, 0.1~0.8:0.05~1, even more further, 0.3~0.5:0.08~0.5, specifically 0.4:0.1; the auxiliary carrier can include one or more of microcrystalline cellulose, starch, sucrose, and dextrin, specifically microcrystalline cellulose, and the microcrystalline cellulose can specifically be pH102. In one embodiment of the present invention, the mass ratio of tamsulosin hydrochloride to the binder can be 0.01~1:0.1~20, more further, 0.1~0.8:0.1~5, and even more further, 0.3~0.5:0.3~1, specifically 0.4:0.55; the binder may include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and microcrystalline cellulose, specifically hydroxypropyl methylcellulose, which may specifically be HPMC E5. In this embodiment, the binder is mixed with water to obtain an aqueous binder solution; then the drug-containing carrier, auxiliary carrier, and the aqueous binder solution are mixed for wet granulation; the concentration of the aqueous binder solution can be 3~5 wt%, specifically 3 wt%, 4 wt%, or 5 wt%. The present invention does not specifically limit the conditions for wet granulation; conditions well known to those skilled in the art can be used.

[0022] After obtaining the drug-containing soft material, the present invention extrudes and spheroidizes the drug-containing soft material to obtain drug-containing pellet cores. In one embodiment of the present invention, the extrusion and spheroidization can be carried out at a temperature of 20-30°C and a relative humidity of 40-60%, and the extrusion and spheroidization includes sequential extrusion and spheroidization. In one embodiment of the present invention, the extrusion conditions include: an extrusion speed of 20-40 rpm, specifically 30 rpm; and an orifice diameter of 0.8 mm for the extrusion plate. In one embodiment of the present invention, the spheroidization conditions include: an air inlet speed of 200-500 rpm, specifically 350 rpm; a spheroidization speed of 500-1500 rpm, specifically 1000 rpm; and a spheroidization time of 7-9 min, specifically 8 min. In one embodiment of the present invention, the particle size of the drug-containing pellet core is 0.2-2 mm, more specifically 0.8-1.2 mm; and the polydispersity index (PDI) is ≤0.25. This invention employs an extrusion-spheronization process, which, compared to centrifugal granulation and drug coating, more easily produces pellets with uniform size and regular shape (nearly spherical). This uniformity in pellet size helps ensure the stability and controllability of the coating process, improves coating quality, and thus ensures the uniformity and controllability of drug release. In the embodiments of this invention, extrusion-spheronization is performed under the aforementioned conditions, which facilitates obtaining pellets with uniform size, regular shape, and uniform drug content, thereby improving the quality of subsequent coating and ensuring the uniformity of drug release.

[0023] After obtaining the drug-containing pellet core, the present invention uses a coating solution to coat the drug-containing pellet core to obtain a coated pellet core; the coating solution includes an enteric coating material and a plasticizer. As one embodiment of the present invention, the mass ratio of tamsulosin hydrochloride to the enteric coating material can be 0.01~1:0.5~35, further can be 0.1~0.8:0.8~5, even further can be 0.3~0.5:1~3, specifically 0.4:1.44; the enteric coating material can include one or more of Eudragit L100-55, Eudragit L30-55, Kollicoat MAE30DP, Kollicoat MAElOOP, and Acryl-EZE 93A, specifically Eudragit L100-55. In one embodiment of the present invention, the mass ratio of tamsulosin hydrochloride to plasticizer can be 0.01~1:0.05~50, more preferably 0.1~0.8:0.08~1, and even more preferably 0.3~0.5:0.1~0.5, specifically 0.4:0.36; the plasticizer may include one or more of polyethylene glycol, propylene glycol, diethyl phthalate, triethyl citrate, triethyl triacetate, castor oil, silicone oil, and oleic acid, specifically triethyl citrate.

[0024] In one embodiment of the present invention, the coating solution may further include a sustained-release material, wherein the mass ratio of the sustained-release material to the enteric-coating material may be 1:1 to 8, specifically 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8; the sustained-release material may include one or more of Eudragit NE30D, Eudragit NE40D, Eudragit RS30D, Kollicoat SR30D, Eudragit RL30D, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, Surelease E-7-19040, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, methylcellulose, cellulose acetate, sodium carboxymethyl cellulose, carbomer, sodium alginate, chitosan, and poloxamer, specifically ethylcellulose. The present invention, by employing the above-mentioned types and amounts of sustained-release materials, enables simultaneous sustained release and enteric coating, which is beneficial for further improving the sustained-release effect of the drug.

[0025] In one embodiment of the present invention, the coating solution may further include an additive, wherein the mass ratio of tamsulosin hydrochloride to the additive may be 0.01~1:0.5~50, more further may be 0.1~0.8:0.8~10, and even more further may be 0.3~0.5:0.5~2; the additive may include an anti-adhesion agent and / or a pore-forming agent, wherein the anti-adhesion agent may include talc and / or magnesium stearate, and the pore-forming agent may include polyethylene glycol and / or polyvinylpyrrolidone.

[0026] In one embodiment of the present invention, the solid content of the coating solution can be 15-20 wt%, specifically 18 wt%; the solvent of the coating solution can be water; the coating conditions include: the inlet air temperature can be 37-39°C, specifically 38°C; the spraying rate can be 7-9 g / min, specifically 8 g / min; the weight gain can be 11-16%, specifically 11%, 12%, 13%, 14%, 15% or 16%, and in the examples 12%±0.3% or 15%±0.3%.

[0027] After obtaining the coated pellet core, the present invention mixes the coated pellet core with a lubricant to obtain the tamsulosin hydrochloride sustained-release formulation. As one embodiment of the present invention, the mass ratio of tamsulosin hydrochloride to the lubricant can be 0.01~1:0.05~50, more further, 0.1~0.8:0.006~0.1, and even more further, 0.3~0.5:0.008~0.05, specifically 0.4:0.01; the lubricant may include magnesium stearate.

[0028] As one embodiment of the present invention, the tamsulosin hydrochloride sustained-release formulation can be a tamsulosin hydrochloride capsule sustained-release formulation. Specifically, the coated pellet core can be mixed with a lubricant and then filled into capsules to obtain the tamsulosin hydrochloride capsule sustained-release formulation. The capsule filling preferably uses #2 capsules, and the fill weight of the tamsulosin hydrochloride capsule sustained-release formulation is preferably 200 mg / capsule.

[0029] The tamsulosin hydrochloride matrix-type sustained-release formulations disclosed in related technologies are either single-release systems or multi-unit sustained-release microsphere release systems. In single-release systems, factors such as matrix particle size, tableting pressure fluctuations, membrane control agents, coating films, and changes in release pores significantly affect drug release behavior, leading to defects such as large batch-to-batch differences and poor reproducibility in low-dose tamsulosin hydrochloride sustained-release formulations. Multi-unit sustained-release microspheres are typically prepared by coating a core containing tamsulosin hydrochloride with a sustained-release film, which results in insufficient initial drug release. This invention utilizes a high-adsorption carrier direct mixing process to spray an ethanol-water solution of tamsulosin hydrochloride onto a mesoporous silica carrier. After drying, the solution is directly extruded and spheroidized to obtain a drug-containing core, which is then coated with a single layer to achieve enteric coating (or, further, a single-layer composite coating, simultaneously achieving enteric coating and sustained release). The tamsulosin hydrochloride sustained-release formulation prepared using this method exhibits good uniformity of active ingredients, high utilization rate, stable drug release, and strong process controllability, making it suitable for industrial production.

[0030] This invention provides a sustained-release formulation of tamsulosin hydrochloride prepared by the above-described technical solution, comprising a coated pellet core and a lubricant. The coated pellet core includes a drug-containing pellet core and a coating layer covering the surface of the drug-containing pellet core. The components of the drug-containing pellet core include tamsulosin hydrochloride, a mesoporous silica carrier, an auxiliary carrier, and a binder. The components of the coating layer include an enteric coating material and a plasticizer (in this case, the coating layer is an enteric coating layer). As one embodiment of this invention, the components of the coating layer may further include a sustained-release material (in this case, the coating layer is an enteric sustained-release coating layer). The mass ratio of the sustained-release material to the enteric coating material is 1:1 to 8, specifically 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8. As one embodiment of this invention, the particle size of the drug-containing pellet core can be 0.2 to 2 mm, more specifically 0.8 to 1.2 mm; the polydispersity index (PDI) is ≤0.25. In one embodiment of the present invention, the mesoporous silica support may have a pore size of 3-5 nm. The types and amounts of each component in the tamsulosin hydrochloride sustained-release formulation of the present invention are preferably consistent with the above-described technical solution, and will not be repeated here.

[0031] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0032] Example 1 0.4 g of tamsulosin hydrochloride was dissolved in 2 mL of 75 vol% ethanol aqueous solution to obtain an ethanol aqueous solution of tamsulosin hydrochloride with a concentration of 0.2 g / mL. The ethanol aqueous solution of tamsulosin hydrochloride was sprayed onto 0.85 g of mesoporous silica support (Syloid® 244FP, particle size 20~40 μm, pore size 3~5 nm) and dried to obtain a drug-containing carrier. The spraying and drying were carried out in a fluidized bed under the following conditions: spraying rate of 10 mL / min, inlet air temperature of 40 °C, and weight gain of 32~33%. The moisture content of the drug-containing carrier was controlled below 1.5 wt%. The drug-containing carrier was mixed with 0.1 g of microcrystalline cellulose (PH102) for 5 min, and then a 5 wt% aqueous solution of binder (hydroxypropyl methylcellulose, HPMC E5, 0.55 g) was added. The resulting mixture was wet-granulated to obtain a drug-containing soft material. The drug-containing soft material was extruded and spheroidized at a temperature of 25±2℃ and a relative humidity of 50±5% to obtain a drug-containing pellet core. The extrusion and spheroidization process included extrusion using an extruder and spheroidization using a spheroidizing machine. The extrusion conditions included an extrusion speed of 30 rpm and a sieve aperture of 0.8 mm. The spheroidization conditions included an air inlet speed of 350 rpm, a spheroidization speed of 1000 rpm, and a spheroidization time of 8 min. The particle size of the drug-containing pellet core was 0.8~1.2 mm (polydispersity index (PDI) ≤ 0.25). 1.44g of enteric coating material (Eudragit L100-55), 0.36g of sustained-release material (ethyl cellulose), and 0.36g of plasticizer (triethyl citrate) were mixed with water to obtain an enteric coating solution with a solid content of 18wt%. The drug-containing pellet core was coated with the enteric coating solution to obtain a coated pellet core. The coating conditions included: an inlet air temperature of 38℃, a spraying rate of 8g / min, and a weight gain of 12.0%±0.3%. The coated pellet core was mixed with 0.01g of lubricant (magnesium stearate) and then filled into #2 capsules to obtain a sustained-release capsule formulation with a content of 200mg / capsule.

[0033] Example 2 0.4 g of tamsulosin hydrochloride was dissolved in 2 mL of 75 vol% ethanol aqueous solution to obtain an ethanol aqueous solution of tamsulosin hydrochloride with a concentration of 0.2 g / mL. The ethanol aqueous solution of tamsulosin hydrochloride was sprayed onto 1 g of mesoporous silica support (Syloid® 244FP, particle size 20~40 μm, pore size 3~5 nm) and dried to obtain a drug-containing carrier. The spraying and drying were carried out in a fluidized bed under the following conditions: spraying rate of 10 mL / min, inlet air temperature of 40 °C, and weight gain of 32~33%. The moisture content of the drug-containing carrier was controlled below 2.5 wt%. The drug-containing carrier was mixed with 0.1 g of microcrystalline cellulose (PH102) for 5 min, and then a 5 wt% aqueous solution of binder (hydroxypropyl methylcellulose, HPMC E5, 0.55 g) was added. The resulting mixture was wet-granulated to obtain a drug-containing soft material. The drug-containing soft material was extruded and spheroidized at a temperature of 25±2℃ and a relative humidity of 50±5% to obtain a drug-containing pellet core. The extrusion and spheroidization process included extrusion using an extruder and spheroidization using a spheroidizing machine. The extrusion conditions included an extrusion speed of 30 rpm and a sieve aperture of 0.8 mm. The spheroidization conditions included an air inlet speed of 350 rpm, a spheroidization speed of 1000 rpm, and a spheroidization time of 8 min. The particle size of the drug-containing pellet core was 0.8~1.2 mm (polydispersity index (PDI) ≤ 0.25). 1.44g of enteric coating material (Eudragit L100-55), 0.36g of sustained-release material (ethyl cellulose), and 0.36g of plasticizer (triethyl citrate) were mixed with water to obtain an enteric coating solution with a solid content of 18wt%. The drug-containing pellet core was coated with the enteric coating solution to obtain a coated pellet core. The coating conditions included: an inlet air temperature of 38℃, a spraying rate of 8g / min, and a weight gain of 12.0%±0.3%. The coated pellet core was mixed with 0.01g of lubricant (magnesium stearate) and then filled into #2 capsules to obtain a sustained-release capsule formulation with a content of 200mg / capsule.

[0034] Example 3 The procedure was performed according to Example 1, except that the sustained-release material was omitted from the enteric coating solution and the weight gain during coating was 15% ± 0.3%.

[0035] Comparative Example 1 In this comparative example, the mesoporous silica carrier is omitted from Example 1. The specific steps are as follows: 0.4 g of tamsulosin hydrochloride was mixed with 1.2 g of microcrystalline cellulose (PH102) for 5 min, and then a 5 wt% aqueous solution of binder (hydroxypropyl methylcellulose, HPMC E5, 0.55 g) was added. The resulting mixture was wet-granulated to obtain a drug-containing soft mass. The drug-containing soft mass was extruded and spheroidized at a temperature of 25±2℃ and a relative humidity of 50±5% to obtain a drug-containing pellet core. The extrusion and spheroidization process included extrusion using an extruder and spheroidization using a spheroidizing machine. The extrusion conditions included an extrusion speed of 30 rpm and a sieve aperture of 0.8 mm. The spheroidization conditions included an air inlet speed of 350 rpm, a spheroidization speed of 1000 rpm, and a spheroidization time of 8 min. The particle size of the drug-containing pellet core was 0.8~1.2 mm (polydispersity index (PDI) ≤0.25). 1.44g of enteric coating material (Eudragit L100-55), 0.36g of sustained-release material (ethyl cellulose), and 0.36g of plasticizer (triethyl citrate) were mixed with water to obtain an enteric coating solution with a solid content of 18wt%. The drug-containing pellet core was coated with the enteric coating solution to obtain a coated pellet core. The coating conditions included: an inlet air temperature of 38℃, a spraying rate of 8g / min, and a weight gain of 12.0%±0.3%. The coated pellet core was mixed with 0.01g of lubricant (magnesium stearate) and then filled into #2 capsules to obtain a sustained-release capsule formulation with a content of 200mg / capsule.

[0036] Comparative Example 2 In this comparative example, blank pellet core coating was performed based on Example 1. The specific steps are as follows: 0.4 g tamsulosin hydrochloride, 0.36 g sustained-release material (ethyl cellulose), and 0.36 g plasticizer (triethyl citrate) were mixed with water to obtain a first coating solution with a solid content of 18 wt%. 1.44 g enteric coating material (Eudragit L100-55) and 0.36 g plasticizer (triethyl citrate) were mixed with water to obtain a second coating solution with a solid content of 18 wt%. Blank sucrose pellets (0.7 mm in diameter) were coated with the first coating solution, and then coated again with the second coating solution to obtain coated pellets. The conditions for the first coating included: an inlet air temperature of 40°C, a spraying rate of 40 g / min, and a weight gain of 8.0%. The conditions for the second coating included: an inlet air temperature of 45°C, a spraying rate of 50 g / min, and a weight gain of 6.0%. The coated pellet core was mixed with 0.01g of lubricant (magnesium stearate) and then filled into #2 capsules to obtain a sustained-release capsule formulation with a content of 200mg / capsule.

[0037] Comparative Example 3 0.6g of microcrystalline cellulose and 0.6g of lactose were premixed and fed into a fluidized bed granulator. 0.55g of 5wt% HPMCE5 aqueous solution was used as a binder, and 0.4g of tamsulosin hydrochloride was added to prepare a drug loading liquid. The spraying rate was set to 3g / min, the inlet air temperature to 65℃, and the atomization pressure to 1Bar for granulation and coating to prepare drug-containing granules. 1.44g of enteric-coating material (Eudragit L100-55), 0.36g of sustained-release material (ethyl cellulose), and 0.36g of plasticizer (triethyl citrate) were mixed with water to obtain a coating solution with a solid content of 18wt%. The drug-containing granules were coated with the coating solution to obtain coated pellet cores. The coating conditions included: an inlet air temperature of 38℃, a spraying rate of 8g / min, and a weight gain of 12.0%±0.3%. The coated pellet core was mixed with 0.01g of lubricant (magnesium stearate) and then filled into #2 capsules to obtain a sustained-release capsule formulation with a content of 200mg / capsule.

[0038] Test Example 1 (1) Determination of drug loading Sample processing and detection: Accurately weigh approximately 0.1 g of the capsule sustained-release formulation prepared in each example and comparative example, add 50 mL of acidic methanol (containing 0.1 wt% hydrochloric acid), and sonicate for 30 min at a power of 300 W and a temperature of 25 °C. After centrifugation, collect the supernatant as the test solution for HPLC detection. The chromatographic column used is a C18 column (4.6 × 150 mm, 5 μm), and the mobile phase is acetonitrile-phosphate buffer (pH = 3.0), with a volume ratio of acetonitrile to phosphate buffer of 55:45. The flow rate of the mobile phase is 1.0 mL / min, and the detection wavelength is 225 nm.

[0039] (2) Dissolution test The paddle method (USP Apparatus 2) was used for determination at a rotation speed of 50 rpm. The medium was 900 mL of phosphate buffer solution with pH=6.8, and the temperature was 37±0.5℃. The sampling time points were 15 min, 20 min, 25 min, 30 min, and 45 min. The specific operation steps were as follows: after drug administration, 10 mL of medium was drawn at each sampling time (immediately replenished with an equal volume of pre-warmed medium), filtered through a 0.45 μm filter membrane, and the filtrate was collected as the test solution for HPLC detection (under the same conditions as drug loading determination). The dissolution standard was: the dissolution amount should reach more than 80% of the labeled amount at 20 min.

[0040] (3) AUC 0-24 (Area under curve) determination Experimental Design - Animal Models: ① Healthy beagle dogs (n=6) were given a single oral dose of the preparation after fasting for 12 hours (dosage: 0.2 mg / kg). ② Blood sample collection: The collection time points were 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h; whole blood was collected in heparin anticoagulant tubes and plasma was separated by centrifugation (3000g×10min); Blood drug concentration testing: LC-MS / MS method was used (ion source: ESI) + The ion pair was determined to be m / z 409→228 (tamsulosin), and the AUC was calculated using WinNonlin software. 0-24 (Non-room model).

[0041] The test results are shown in Table 1. As can be seen from Table 1, the drug loading of the products prepared by using Syloid® 244FP type silica as a carrier in Examples 1 and 2 of this invention is 32.1~35.2%, which is significantly higher than the drug loading (≤25%) when only microcrystalline cellulose was used in Comparative Example 1. This indicates that the method of this invention can significantly improve the drug loading efficiency, and the mesopores (3~5nm) of silica can accurately adsorb drug molecules and effectively prevent drug leakage.

[0042] Furthermore, in Example 1 of this invention, a single-layer composite coating method (i.e., using enteric-coated material + sustained-release material) was adopted, simultaneously achieving enteric triggering and sustained-release control. In a medium with pH=6.8, the release rate was 92.3% within 20 minutes (100% at 45 minutes). Compared to Example 3, which used a single coating method (i.e., using enteric-coated material), this method can more effectively control the drug release rate. In contrast, in Comparative Example 1, when only microcrystalline cellulose was used, the drug dissolution rate was low, with only 80% released at 45 minutes. The release rate of the product in Example 1 was increased by 1.25 times compared to Comparative Example 1 (based on the release rate at 45 minutes). In Comparative Example 2, only a single sustained-release material (such as ethyl cellulose) was used for coating, resulting in low drug dissolution rate. This indicates that the lack of enteric coating protection led to premature drug release in gastric juice, failing to achieve the synergistic effect of intestinal targeting and sustained release. In Comparative Example 3, a fluidized bed granulation coating process was used to prepare the sustained-release formulation, and the drug loading and release rate at 45 minutes were both lower than those in Example 1.

[0043] Meanwhile, the bioavailability of the product in Example 1 of this invention is significantly improved, and the AUC is... 0-24 It reached 3.5 μg·h / mL, which is 106% higher than the product in Comparative Example 1 (1.7 μg·h / mL).

[0044] Table 1. Performance test results of products prepared in each embodiment and comparative example.

[0045] Test Example 2 The relevant substances in the products of each embodiment and comparative example were tested, as follows: Chromatographic column: octadecylsilane-bonded silica gel (C18 column); detection wavelength: 225 nm; mobile phase A: 0.02 mol / L ammonium acetate solution (pH adjusted to 4.0 with glacial acetic acid); mobile phase B: acetonitrile; flow rate: 1.0 mL / min; column temperature: 30℃; accurately measure the test solution and control solution, inject them separately into the liquid chromatograph, and record the chromatograms. If impurity peaks are present in the chromatogram of the test solution, calculate the content of each impurity using the main component self-comparison method.

[0046] Table 2 shows the relevant substance test results of the products in each embodiment and comparative example (where 0 corresponds to the newly prepared product). As can be seen from Table 2, the relevant substance test results of the product in Example 1 under accelerated conditions are better than those of each comparative example, and the relevant substance test results of the product in Example 1 under accelerated conditions are also better than those of Examples 2-3, indicating that the formulation and overall process stability are good.

[0047] Table 2. Related substance test results of products in each embodiment and comparative example.

[0048] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a sustained-release formulation of tamsulosin hydrochloride, comprising the following steps: An ethanol-water solution of tamsulosin hydrochloride was sprayed onto a mesoporous silica support and dried to obtain a drug-containing carrier. The drug-containing carrier, auxiliary carrier, and binder are mixed with water and wet granulated to obtain a drug-containing soft material. The drug-containing soft material is extruded and spherical to obtain a drug-containing pellet core; The drug-containing pellet core is coated with a coating solution to obtain a coated pellet core; the coating solution includes an enteric coating material and a plasticizer; The coated pellet core is mixed with a lubricant to obtain the tamsulosin hydrochloride sustained-release formulation.

2. The preparation method according to claim 1, characterized in that, The mass ratio of tamsulosin hydrochloride to mesoporous silica support is 0.01~1:0.5~20; the particle size of the mesoporous silica support is 20~40μm, and the mesoporous pore size is 3~5nm; The concentration of tamsulosin hydrochloride in the ethanol aqueous solution is 0.18~0.22 g / mL, and the volume fraction of ethanol is 70~80%.

3. The preparation method according to claim 2, characterized in that, The conditions for spraying and drying include: spraying rate of 8-12 mL / min, air inlet temperature of 38-42℃, weight gain of 32-33%, and moisture content of the drug carrier ≤2.5 wt%.

4. The preparation method according to claim 1, characterized in that, The mass ratio of tamsulosin hydrochloride to the auxiliary carrier is 0.01~1:0.01~20; the auxiliary carrier includes one or more of microcrystalline cellulose, starch, sucrose and dextrin. The mass ratio of tamsulosin hydrochloride to the adhesive in the adhesive solution is 0.01~1:0.1~20; the adhesive includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and microcrystalline cellulose; the concentration of the adhesive solution is 3~5 wt%.

5. The preparation method according to claim 1 or 4, characterized in that, The extrusion spheroidization is carried out at a temperature of 20~30℃ and a relative humidity of 40~60%, and the extrusion spheroidization includes extrusion treatment and spheroidization treatment in sequence. The extrusion processing conditions include: an extrusion speed of 20-40 rpm and an extrusion plate aperture of 0.8 mm; the rounding processing conditions include: an air inlet speed of 200-500 rpm, a rounding speed of 500-1500 rpm, and a rounding time of 7-9 min; the particle size of the cored pellet is 0.2-2 mm and the polydispersity index is ≤0.

25.

6. The preparation method according to claim 1, characterized in that, The mass ratio of tamsulosin hydrochloride to enteric material is 0.01~1:0.5~35; the enteric material includes one or more of Eudragit L100-55, Eudragit L30-55, Kollicoat MAE30DP, Kollicoat MAElOOP and Acryl-EZE 93A; The mass ratio of tamsulosin hydrochloride to plasticizer is 0.01~1:0.05~50; the plasticizer includes one or more of polyethylene glycol, propylene glycol, diethyl phthalate, triethyl citrate, triethyl triacetate, castor oil, silicone oil and oleic acid; The coating solution further includes a sustained-release material, wherein the mass ratio of the sustained-release material to the enteric material is 1:1 to 8; the sustained-release material includes one or more of Eudragit NE30D, Eudragit NE40D, Eudragit RS30D, Kollicoat SR30D, Eudragit RL30D, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, Surelease E-7-19040, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, methylcellulose, cellulose acetate, sodium carboxymethyl cellulose, carbomer, sodium alginate, chitosan, and poloxamer.

7. The preparation method according to claim 1 or 6, characterized in that, The solid content of the coating solution is 15-20 wt%; the coating conditions include: inlet air temperature of 37-39℃, spraying rate of 7-9 g / min, and weight gain of 11-16%.

8. The preparation method according to claim 1, characterized in that, The mass ratio of tamsulosin hydrochloride to lubricant is 0.01~1:0.05~50; the lubricant includes magnesium stearate.

9. The tamsulosin hydrochloride sustained-release formulation prepared by the preparation method according to any one of claims 1 to 8 comprises a coated pellet core and a lubricant, wherein the coated pellet core comprises a drug-containing pellet core and a coating layer covering the surface of the drug-containing pellet core; the drug-containing pellet core comprises tamsulosin hydrochloride, a mesoporous silica carrier, an auxiliary carrier and a binder, and the coating layer comprises an enteric material and a plasticizer.

10. The tamsulosin hydrochloride sustained-release formulation according to claim 9, characterized in that, The coating layer also includes a sustained-release material.

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