Tamsulosin preparation containing sustained-release auxiliary materials and preparation method of tamsulosin preparation

Abstract

The invention discloses a tamsulosin preparation containing sustained-release auxiliary materials and a preparation method thereof, and relates to the technical field of sustained-release preparations, in order to improve the medication compliance of patients, tamsulosin hydrochloride is prepared into sustained-release particles, and the sustained-release auxiliary materials are improved. Microcrystalline cellulose and modified cross-linked starch are respectively used as slow-release auxiliary materials; the microcrystalline cellulose has certain pores in the structure and has the crystallization property, so that a network structure can be formed in a concentrated manner and effective components of the medicine can be wrapped, the immersion of water is delayed, the slow release effect of the medicine can be realized, and the starch is subjected to modification treatment, so that the slow release effect of the medicine is improved. By means of cross-linking and surface modification, the size of the starch is increased, dissolution of drugs is delayed, and the defect that slow release time of conventional starch is insufficient is effectively overcome.

Description

Technical Field

[0001] The invention relates to the technical field of sustained-release preparations, in particular to a tamsulosin preparation containing a sustained-release excipient and a preparation method thereof. Background Art

[0002] Benign prostatic hyperplasia (BPH) is a common benign disease in middle-aged and elderly men. After the onset of the disease, as the prostate enlarges, the enlarged prostate will compress the urethra, causing symptoms such as frequent urination, urgency, thinning of urine flow, and incomplete urination. In severe cases, it will significantly affect the patient's daily quality of life. If not treated in time, it may cause a series of serious complications, such as acute urinary retention, stones, renal failure, etc., and even endanger life; Tamsulosin hydrochloride is an α1A receptor antagonist, which specifically blocks the α1A receptors in the prostate and relaxes the prostate smooth muscle, thereby relieving symptoms such as dysuria caused by benign prostatic hyperplasia. However, benign prostatic hyperplasia is a long-term chronic disease that requires patients to take medication continuously for a long time. Tamsulosin hydrochloride has a short half-life in the body and is metabolized rapidly. Therefore, in order to improve the patient's medication compliance, it is necessary to prepare it as a sustained-release agent to facilitate the continuity of patient treatment. Summary of the invention

[0003] The object of the present invention is to provide a tamsulosin preparation containing a sustained-release excipient and a preparation method thereof, so as to solve the problems raised in the prior art.

[0004] To achieve the above object, the present invention provides the following technical solution: a method for preparing a tamsulosin preparation containing a sustained-release excipient, characterized in that it comprises the following steps:

[0005] S1. Preparation of sustained-release pellets;

[0006] S11. After talcum powder is passed through a 40-mesh sieve, it is mixed with a sustained-release excipient and loaded into a high-speed shear granulator. After dry mixing for 10 minutes under low-speed stirring and shear-off state, an aqueous solution of tamsulosin hydrochloride is added thereto within 1.5-2 minutes, and then the state is switched to low-speed stirring and low-speed shear state to granulate the wet material for 30-45 seconds;

[0007] S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion;

[0008] 50% of the volume of the granulation dispersion was added to the high-speed shear granulator within 1 minute, and the material was raked after continuing to stir and shear at low speed for 30-45 seconds. The remaining granulation dispersion was added to the high-speed shear granulator within 1 minute, and the material was raked after continuing to stir and shear at low speed for 30-45 seconds. After passing through a 6.0 mm sieve, the obtained wet granules were transferred to a spheronizer, and pellets were obtained by water spraying and spheronization. The pellets were placed in an environment of 40±5°C and dried until the LOD range was 1-2% m / m, and then sieved to collect the pellet particles of the 14-30 mesh sieve to obtain sustained-release pellets;

[0009] S2. Preparation of coated pellets;

[0010] S21. The methacrylic acid - ethyl acrylate copolymer dispersion was filtered using fine cotton cloth, deionized water was added thereto and stirred evenly, and then triacetin was added and stirred for 15 min, and the resulting mixture was set aside;

[0011] After talcum powder is passed through a 100-mesh sieve, it is mixed with deionized water, and after stirring and dispersing, a talcum powder dispersion is obtained, which is added to the above mixed solution, and stirring and mixing is continued for 30-45 minutes to obtain a coating solution;

[0012] S22. Place the sustained-release pellets in a fluidized bed and heat them to 35±5°C. After the LOD of the sustained-release pellets drops to 0.5-1% m / m, heat them to 35±3°C, spray the sustained-release pellets with the coating solution using the Wurster process, and dry them again until the LOD drops to 0.5-1% m / m again. Heat them to 40±2°C and continue drying and curing for 20-30 minutes. Then, pass them through a 14-mesh sieve to remove lumps to obtain coated pellets.

[0013] S3. After talcum powder and calcium stearate are passed through a 100-mesh sieve and mixed to obtain a lubricating material, the coated micropellets are mixed with the lubricating material, and after blending for 45-60 minutes, the resulting product is loaded into capsules to obtain a tamsulosin preparation containing a sustained-release excipient.

[0014] Furthermore, in step S1, the sustained-release excipient is microcrystalline cellulose or modified cross-linked starch;

[0015] Wherein, the preparation method of the modified cross-linked starch is:

[0016] a. Disperse corn starch in deionized water, heat to 40-50°C, stir for 10-15 minutes, add potassium sulfate and potassium chloride, continue stirring for 10-15 minutes, add phosphorus oxychloride, and add alkali solution to adjust the pH value to 10.5-11. After stirring and reacting for 3 hours, add hydrochloric acid to adjust the pH value to 6.5-7, centrifuge and separate the precipitate, wash the precipitate with deionized water for 3-5 times, vacuum dry to constant weight, and crush it through a 120-mesh sieve to obtain cross-linked starch;

[0017] b. The cross-linked starch was dispersed again in deionized water, sodium acetate was added thereto, the pH value was adjusted to 8.5-9.5, the temperature was raised to 40-50°C, and after stirring and preheating for 20 minutes, glucoamylase and α-amylase were added thereto, the temperature was raised to 45-50°C, and the reaction was stirred for 1.5-4 hours, and then the precipitate was separated by centrifugation, and washed again with deionized water for 3-5 times, vacuum dried to constant weight, and crushed through an 80-mesh sieve to obtain microporous cross-linked starch;

[0018] c. Mix the microporous cross-linked starch with lauric acid, add dimethyl sulfoxide thereto, stir and mix until the lauric acid is completely dissolved, add lipase and deionized water thereto, stir and react at room temperature for 4-12 hours, centrifuge and separate the precipitate, wash the precipitate with anhydrous ethanol for 3-5 times, vacuum dry to constant weight, and crush through a 40-mesh sieve to obtain modified cross-linked starch.

[0019] Furthermore, in step a, the mass ratio of the corn starch, potassium sulfate and potassium chloride is 100:(1.5-2.55):(0.5-5) in parts by weight.

[0020] Furthermore, in step a, the mass ratio of corn starch to phosphorus oxychloride is 100:(0.1-1) in parts by weight.

[0021] Furthermore, in step b, the mass ratio of the cross-linked starch, glucoamylase and α-amylase is 100:(0.5-0.8):(0.3-0.8) in parts by weight.

[0022] Further, in step c, the ratio of the microporous cross-linked starch, lauric acid, and lipase is 100 g: 10-300 g: 0.1-0.5 mL;

[0023] Wherein, the specification of the lipase is 100unit / μL.

[0024] Further, in step S11, the wet material is composed of 7.8-8.5 parts of talc, 120-150 parts of sustained-release excipients and 25-30 parts of tamsulosin hydrochloride aqueous solution;

[0025] Wherein, in the tamsulosin hydrochloride aqueous solution, the concentration of tamsulosin hydrochloride is 0.7-0.73% m / m.

[0026] Furthermore, in step S12, the solid content of the methacrylic acid-ethyl acrylate copolymer dispersion is 27-35%, and the mass ratio of methacrylic acid to ethyl acrylate in the methacrylic acid-ethyl acrylate copolymer is 1:1;

[0027] The granulation dispersion consists of 140-150 parts of methacrylic acid-ethyl acrylate copolymer dispersion and 1-1.5 parts of triacetin.

[0028] Further, in step S21, the mixed solution is composed of 12-15 parts of acrylic acid-ethyl acrylate copolymer dispersion, 65-70 parts of deionized water, and 0.5-0.7 parts of triacetin;

[0029] The talc powder dispersion consists of 0.6-0.9 parts of talc powder and 20-25 parts of deionized water.

[0030] Furthermore, the lubricating material consists of 14.5-16 parts of talc and 1.2-1.8 parts of calcium stearate;

[0031] The mass ratio of the coated pellets to the lubricating material is 20-25:1.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] In order to improve the medication compliance of patients, the present invention prepares tamsulosin hydrochloride into sustained-release microparticles, and improves the sustained-release excipients thereof, and uses microcrystalline cellulose and modified cross-linked starch as sustained-release excipients respectively; microcrystalline cellulose has certain pores in its structure and its own crystallization properties, so that it can form a network structure in the drug microparticles and wrap the active ingredients of the drug, thereby delaying the infiltration of water, so that the drug can achieve a sustained-release effect; starch also has the same structural effect, and starch is widely available, which can effectively reduce the cost of the preparation in the production process, but the sustained-release effect of simple starch is poor, and a long-term sustained-release effect is often not achieved, so the present invention also modifies the starch, and the present invention The invention firstly uses corn starch with smaller particles as raw material, and uses phosphorus oxychloride to cross-link it, thereby increasing the volume of corn starch and increasing the time for water to fully penetrate it. On this basis, the invention also uses amylase to treat it, so that the larger cross-linked starch has more pores, thereby avoiding the decrease in porosity after the volume of the cross-linked starch increases, resulting in a decrease in drug loading. In order to further enhance the sustained-release effect, the invention also uses lipase and lauric acid to treat the starch. In a non-aqueous phase reaction system, lipase can effectively catalyze the esterification between fatty acids and alcohol hydroxyl groups on the surface of starch, thereby improving the surface hydrophilicity of starch, further reducing the penetration of water, and delaying the dissolution of drugs. DETAILED DESCRIPTION

[0034] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without making any creative work shall fall within the scope of protection of the present invention.

[0035] The weight parts of the raw materials used in Examples 1-5 of the present invention and Comparative Examples 1-2 are shown in Table 1 below;

[0036] Table 1.

[0037]

[0038] Example 1. A method for preparing a tamsulosin preparation containing a sustained-release excipient, comprising the following steps:

[0039] S1. Preparation of sustained-release pellets;

[0040] S11. After talcum powder is passed through a 40-mesh sieve, it is mixed with a sustained-release excipient and loaded into a high-speed shear granulator. After dry mixing for 10 minutes under low-speed stirring and off-shear conditions, an aqueous solution of tamsulosin hydrochloride is added thereto within 2 minutes, and then the state is switched to low-speed stirring at 40 rpm and granulation of the wet material under low-speed shear conditions for 30 seconds;

[0041] Wherein, the sustained-release excipient is microcrystalline cellulose;

[0042] S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion;

[0043] 50% of the volume of the granulation dispersion was added to the high-speed shear granulator within 1 minute, and the material was raked after continuing to stir and shear at low speed for 30 seconds. The remaining granulation dispersion was added to the high-speed shear granulator within 1 minute, and the material was raked after continuing to stir and shear at low speed for 30 seconds. After passing through a 6.0 mm sieve, the obtained wet granules were transferred to a spheronizer, and pellets were obtained by water spraying and spheronization. The pellets were placed in an environment of 40±5°C and dried until the LOD range was 1-2% m / m, and then sieved to collect the pellet particles of the 14-30 mesh sieve to obtain sustained-release pellets;

[0044] S2. Preparation of coated pellets;

[0045] S21. The methacrylic acid - ethyl acrylate copolymer dispersion was filtered using fine cotton cloth, deionized water was added thereto and stirred evenly, and then triacetin was added and stirred for 15 min, and the resulting mixture was set aside;

[0046] After talcum powder is passed through a 100-mesh sieve, it is mixed with deionized water, stirred and dispersed, and then added to the above mixed solution, and the stirring and mixing is continued for 30 minutes to obtain a coating solution;

[0047] S22. Place the sustained-release pellets in a fluidized bed and heat them to 35±5°C. After the LOD of the sustained-release pellets drops to 0.5-1% m / m, heat them to 35±3°C, spray the sustained-release pellets with the coating solution using the Wurster process, and dry them again until the LOD drops to 0.5-1% m / m again. Heat them to 40±2°C and continue drying and curing for 30 minutes. Then, pass them through a 14-mesh sieve to remove lumps to obtain coated pellets.

[0048] S3. After talcum powder and calcium stearate are passed through a 100-mesh sieve and mixed to prepare a lubricating material, the coated micropellets are mixed with the lubricating material, and after blending for 60 minutes, the resulting product is loaded into a gelatin hard capsule to obtain a tamsulosin preparation containing a sustained-release excipient.

[0049] Example 2. A method for preparing a tamsulosin preparation containing a sustained-release excipient, comprising the following steps:

[0050] Compared with Example 1, the type of sustained-release excipients is changed in this example;

[0051] S1. Preparation of sustained-release pellets;

[0052] S11. After talcum powder is passed through a 40-mesh sieve, it is mixed with a sustained-release excipient and loaded into a high-speed shear granulator. After dry mixing for 10 minutes under low-speed stirring and off-shear conditions, an aqueous solution of tamsulosin hydrochloride is added thereto within 2 minutes, and then the state is switched to low-speed stirring at 40 rpm and granulation of the wet material under low-speed shear conditions for 30 seconds;

[0053] Wherein, the sustained-release excipient is modified cross-linked starch, and its preparation method is as follows:

[0054] a. Disperse 100 parts of corn starch in deionized water by weight, heat to 45°C, stir for 15 minutes, add 1.8 parts of potassium sulfate and 1.5 parts of potassium chloride, continue stirring for 10 minutes, add 0.15 parts of phosphorus oxychloride, and add potassium hydroxide dropwise to adjust the pH value to 11. After stirring and reacting for 3 hours, add hydrochloric acid dropwise to adjust the pH value to 6.8, centrifuge and separate the precipitate, wash the precipitate with deionized water 3 times, vacuum dry to constant weight, and crush it through a 120-mesh sieve to obtain cross-linked starch;

[0055] b. 100 parts of cross-linked starch were dispersed again in deionized water, sodium acetate was added thereto, the pH value was adjusted to 9, the temperature was raised to 45°C, and after stirring and preheating for 20 minutes, 0.5 parts of glucoamylase and 0.3 parts of α-amylase were added thereto, the temperature was raised to 45°C, and the reaction was stirred for 3 hours, and then the precipitate was separated by centrifugation, and washed again with deionized water for 5 times, vacuum dried to constant weight, and crushed through an 80-mesh sieve to obtain microporous cross-linked starch;

[0056] c. 100 parts of microporous cross-linked starch were mixed with 30 parts of lauric acid, dimethyl sulfoxide was added thereto, and the mixture was stirred until the lauric acid was completely dissolved, and lipase and deionized water with an equal volume of lipase were added thereto. After stirring and reacting for 4 hours at room temperature, the precipitate was separated by centrifugation, and the precipitate was washed 5 times with anhydrous ethanol, vacuum dried to constant weight, and crushed through a 40-mesh sieve to obtain a modified cross-linked starch;

[0057] Wherein, the addition amount of the lipase is 0.1mL / 100g microporous cross-linked starch; the specification of the lipase is 100unit / μL;

[0058] S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion;

[0059] 50% of the volume of the granulation dispersion was added to the high-speed shear granulator within 1 minute, and the material was raked after continuing to stir and shear at low speed for 30 seconds. The remaining granulation dispersion was added to the high-speed shear granulator within 1 minute, and the material was raked after continuing to stir and shear at low speed for 30 seconds. After passing through a 6.0 mm sieve, the obtained wet granules were transferred to a spheronizer, and pellets were obtained by water spraying and spheronization. The pellets were placed in an environment of 40±5°C and dried until the LOD range was 1-2% m / m, and then sieved to collect the pellet particles of the 14-30 mesh sieve to obtain sustained-release pellets;

[0060] S2. Preparation of coated pellets;

[0061] S21. The methacrylic acid - ethyl acrylate copolymer dispersion was filtered using fine cotton cloth, deionized water was added thereto and stirred evenly, and then triacetin was added and stirred for 15 min, and the resulting mixture was set aside;

[0062] After talcum powder is passed through a 100-mesh sieve, it is mixed with deionized water, stirred and dispersed, and then added to the above mixed solution, and the stirring and mixing is continued for 30 minutes to obtain a coating solution;

[0063] S22. Place the sustained-release pellets in a fluidized bed and heat them to 35±5°C. After the LOD of the sustained-release pellets drops to 0.5-1% m / m, heat them to 35±3°C, spray the sustained-release pellets with the coating solution using the Wurster process, and dry them again until the LOD drops to 0.5-1% m / m again. Heat them to 40±2°C and continue drying and curing for 30 minutes. Then, pass them through a 14-mesh sieve to remove lumps to obtain coated pellets.

[0064] S3. After talcum powder and calcium stearate are passed through a 100-mesh sieve and mixed to prepare a lubricating material, the coated micropellets are mixed with the lubricating material, and after blending for 60 minutes, the resulting product is loaded into a gelatin hard capsule to obtain a tamsulosin preparation containing a sustained-release excipient.

[0065] Example 3. A method for preparing a tamsulosin preparation containing a sustained-release excipient, comprising the following steps:

[0066] Compared with Example 2, this example increases the amount of phosphorus oxychloride added in step a;

[0067] S1. Preparation of sustained-release pellets;

[0068] S11. After talcum powder is passed through a 40-mesh sieve, it is mixed with a sustained-release excipient and loaded into a high-speed shear granulator. After dry mixing for 10 minutes under low-speed stirring and off-shear conditions, an aqueous solution of tamsulosin hydrochloride is added thereto within 2 minutes, and then the state is switched to low-speed stirring at 40 rpm and granulation of the wet material under low-speed shear conditions for 30 seconds;

[0069] Wherein, the sustained-release excipient is modified cross-linked starch, and its preparation method is as follows:

[0070] a. Disperse 100 parts of corn starch in deionized water by weight, heat to 45°C, stir for 15 minutes, add 1.8 parts of potassium sulfate and 1.5 parts of potassium chloride, continue stirring for 10 minutes, add 0.8 parts of phosphorus oxychloride, and add potassium hydroxide dropwise to adjust the pH value to 11. After stirring and reacting for 3 hours, add hydrochloric acid dropwise to adjust the pH value to 6.8, centrifuge and separate the precipitate, wash the precipitate with deionized water 3 times, vacuum dry to constant weight, and crush it through a 120-mesh sieve to obtain cross-linked starch;

[0071] b. 100 parts of cross-linked starch were dispersed again in deionized water, sodium acetate was added thereto, the pH value was adjusted to 9, the temperature was raised to 45°C, and after stirring and preheating for 20 minutes, 0.5 parts of glucoamylase and 0.3 parts of α-amylase were added thereto, the temperature was raised to 45°C, and the reaction was stirred for 3 hours, and then the precipitate was separated by centrifugation, and washed again with deionized water for 5 times, vacuum dried to constant weight, and crushed through an 80-mesh sieve to obtain microporous cross-linked starch;

[0072] c. 100 parts of microporous cross-linked starch were mixed with 30 parts of lauric acid, dimethyl sulfoxide was added thereto, and the mixture was stirred until the lauric acid was completely dissolved, and lipase and deionized water with an equal volume of lipase were added thereto. After stirring and reacting for 4 hours at room temperature, the precipitate was separated by centrifugation, and the precipitate was washed 5 times with anhydrous ethanol, vacuum dried to constant weight, and crushed through a 40-mesh sieve to obtain a modified cross-linked starch;

[0073] Wherein, the addition amount of the lipase is 0.1mL / 100g microporous cross-linked starch; the specification of the lipase is 100unit / μL;

[0074] S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion;

[0075] 50% of the volume of the granulation dispersion was added to the high-speed shear granulator within 1 minute, and the material was raked after continuing to stir and shear at low speed for 30 seconds. The remaining granulation dispersion was added to the high-speed shear granulator within 1 minute, and the material was raked after continuing to stir and shear at low speed for 30 seconds. After passing through a 6.0 mm sieve, the obtained wet granules were transferred to a spheronizer, and pellets were obtained by water spraying and spheronization. The pellets were placed in an environment of 40±5°C and dried until the LOD range was 1-2% m / m, and then sieved to collect the pellet particles of the 14-30 mesh sieve to obtain sustained-release pellets;

[0076] S2. Preparation of coated pellets;

[0077] S21. The methacrylic acid - ethyl acrylate copolymer dispersion was filtered using fine cotton cloth, deionized water was added thereto and stirred evenly, and then triacetin was added and stirred for 15 min, and the resulting mixture was set aside;

[0078] After talcum powder is passed through a 100-mesh sieve, it is mixed with deionized water, stirred and dispersed, and then added to the above mixed solution, and the stirring and mixing is continued for 30 minutes to obtain a coating solution;

[0079] S22. Place the sustained-release pellets in a fluidized bed and heat them to 35±5°C. After the LOD of the sustained-release pellets drops to 0.5-1% m / m, heat them to 35±3°C, spray the sustained-release pellets with the coating solution using the Wurster process, and dry them again until the LOD drops to 0.5-1% m / m again. Heat them to 40±2°C and continue drying and curing for 30 minutes. Then, pass them through a 14-mesh sieve to remove lumps to obtain coated pellets.

[0080] S3. After talcum powder and calcium stearate are passed through a 100-mesh sieve and mixed to prepare a lubricating material, the coated micropellets are mixed with the lubricating material, and after blending for 60 minutes, the resulting product is loaded into a gelatin hard capsule to obtain a tamsulosin preparation containing a sustained-release excipient.

[0081] Example 4. A method for preparing a tamsulosin preparation containing a sustained-release excipient, comprising the following steps:

[0082] Compared with Example 3, this example increases the amount of two types of amylase added in step b;

[0083] S1. Preparation of sustained-release pellets;

[0084] S11. After talcum powder is passed through a 40-mesh sieve, it is mixed with a sustained-release excipient and loaded into a high-speed shear granulator. After dry mixing for 10 minutes under low-speed stirring and off-shear conditions, an aqueous solution of tamsulosin hydrochloride is added thereto within 2 minutes, and then the state is switched to low-speed stirring at 40 rpm and granulation of the wet material under low-speed shear conditions for 30 seconds;

[0085] Wherein, the sustained-release excipient is modified cross-linked starch, and its preparation method is as follows:

[0086] a. Disperse 100 parts of corn starch in deionized water by weight, heat to 45°C, stir for 15 minutes, add 1.8 parts of potassium sulfate and 1.5 parts of potassium chloride, continue stirring for 10 minutes, add 0.8 parts of phosphorus oxychloride, and add potassium hydroxide dropwise to adjust the pH value to 11. After stirring and reacting for 3 hours, add hydrochloric acid dropwise to adjust the pH value to 6.8, centrifuge and separate the precipitate, wash the precipitate with deionized water 3 times, vacuum dry to constant weight, and crush it through a 120-mesh sieve to obtain cross-linked starch;

[0087] b. 100 parts of cross-linked starch were dispersed again in deionized water, sodium acetate was added thereto, the pH value was adjusted to 9, the temperature was raised to 45°C, and after stirring and preheating for 20 minutes, 0.8 parts of glucoamylase and 0.8 parts of α-amylase were added thereto, the temperature was raised to 45°C, and the reaction was stirred for 3 hours, and then the precipitate was separated by centrifugation, and washed again with deionized water for 5 times, vacuum dried to constant weight, and crushed through an 80-mesh sieve to obtain microporous cross-linked starch;

[0088] c. 100 parts of microporous cross-linked starch were mixed with 30 parts of lauric acid, dimethyl sulfoxide was added thereto, and the mixture was stirred until the lauric acid was completely dissolved, and lipase and deionized water with an equal volume of lipase were added thereto. After stirring and reacting for 4 hours at room temperature, the precipitate was separated by centrifugation, and the precipitate was washed 5 times with anhydrous ethanol, vacuum dried to constant weight, and crushed through a 40-mesh sieve to obtain a modified cross-linked starch;

[0089] Wherein, the addition amount of the lipase is 0.1mL / 100g microporous cross-linked starch; the specification of the lipase is 100unit / μL;

[0090] S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion;

[0091] 50% volume of the granulation dispersion was added to the high-speed shear granulator within 1 min, and the material was raked after continuing low-speed stirring and low-speed shearing for 30 s. The remaining granulation dispersion was added to the high-speed shear granulator within 1 min, and low-speed stirring and low-speed shearing were continued for 30 s. After passing through a 6.0 mm sieve, the obtained wet granules were transferred to a spheronizer, and pellets were obtained by water spray spheronization. The pellets were placed in an environment of 40±5°C and dried until the LOD range was 1-2% m / m, and then sieved to collect the pellet particles of the 14-30 mesh sieve to obtain sustained-release pellets.

[0092] Example 5. A method for preparing a tamsulosin preparation containing a sustained-release excipient, comprising the following steps:

[0093] Compared with Example 4, this example increases the amount of lauric acid added in step c;

[0094] S1. Preparation of sustained-release pellets;

[0095] S11. After talcum powder is passed through a 40-mesh sieve, it is mixed with a sustained-release excipient and loaded into a high-speed shear granulator. After dry mixing for 10 minutes under low-speed stirring and off-shear conditions, an aqueous solution of tamsulosin hydrochloride is added thereto within 2 minutes, and then the state is switched to low-speed stirring at 40 rpm and granulation of the wet material under low-speed shear conditions for 30 seconds;

[0096] Wherein, the sustained-release excipient is modified cross-linked starch, and its preparation method is as follows:

[0097] a. Disperse 100 parts of corn starch in deionized water by weight, heat to 45°C, stir for 15 minutes, add 1.8 parts of potassium sulfate and 1.5 parts of potassium chloride, continue stirring for 10 minutes, add 0.8 parts of phosphorus oxychloride, and add potassium hydroxide dropwise to adjust the pH value to 11. After stirring and reacting for 3 hours, add hydrochloric acid dropwise to adjust the pH value to 6.8, centrifuge and separate the precipitate, wash the precipitate with deionized water 3 times, vacuum dry to constant weight, and crush it through a 120-mesh sieve to obtain cross-linked starch;

[0098] b. 100 parts of cross-linked starch were dispersed again in deionized water, sodium acetate was added thereto, the pH value was adjusted to 9, the temperature was raised to 45°C, and after stirring and preheating for 20 minutes, 0.8 parts of glucoamylase and 0.8 parts of α-amylase were added thereto, the temperature was raised to 45°C, and the reaction was stirred for 3 hours, and then the precipitate was separated by centrifugation, and washed again with deionized water for 5 times, vacuum dried to constant weight, and crushed through an 80-mesh sieve to obtain microporous cross-linked starch;

[0099] c. 100 parts of microporous cross-linked starch and 300 parts of lauric acid were mixed, dimethyl sulfoxide was added thereto, and the mixture was stirred until the lauric acid was completely dissolved, and lipase and deionized water with an equal volume of lipase were added thereto. After stirring and reacting for 4 hours at room temperature, the precipitate was separated by centrifugation, and the precipitate was washed 5 times with anhydrous ethanol, vacuum dried to constant weight, and crushed through a 40-mesh sieve to obtain a modified cross-linked starch;

[0100] Wherein, the addition amount of the lipase is 0.1mL / 100g microporous cross-linked starch; the specification of the lipase is 100unit / μL;

[0101] S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion;

[0102] 50% volume of the granulation dispersion was added to the high-speed shear granulator within 1 min, and the material was raked after continuing low-speed stirring and low-speed shearing for 30 s. The remaining granulation dispersion was added to the high-speed shear granulator within 1 min, and low-speed stirring and low-speed shearing were continued for 30 s. After passing through a 6.0 mm sieve, the obtained wet granules were transferred to a spheronizer, and pellets were obtained by water spray spheronization. The pellets were placed in an environment of 40±5°C and dried until the LOD range was 1-2% m / m, and then sieved to collect the pellet particles of the 14-30 mesh sieve to obtain sustained-release pellets.

[0103] Example 6. A method for preparing a tamsulosin preparation containing a sustained-release excipient, comprising the following steps:

[0104] Compared with Example 5, this example increases the amount of lipase added in step c;

[0105] S1. Preparation of sustained-release pellets;

[0106] S11. After talcum powder is passed through a 40-mesh sieve, it is mixed with a sustained-release excipient and loaded into a high-speed shear granulator. After dry mixing for 10 minutes under low-speed stirring and off-shear conditions, an aqueous solution of tamsulosin hydrochloride is added thereto within 2 minutes, and then the state is switched to low-speed stirring at 40 rpm and granulation of the wet material under low-speed shear conditions for 30 seconds;

[0107] Wherein, the sustained-release excipient is modified cross-linked starch, and its preparation method is as follows:

[0108] a. Disperse 100 parts of corn starch in deionized water by weight, heat to 45°C, stir for 15 minutes, add 1.8 parts of potassium sulfate and 1.5 parts of potassium chloride, continue stirring for 10 minutes, add 0.8 parts of phosphorus oxychloride, and add potassium hydroxide dropwise to adjust the pH value to 11. After stirring and reacting for 3 hours, add hydrochloric acid dropwise to adjust the pH value to 6.8, centrifuge and separate the precipitate, wash the precipitate with deionized water 3 times, vacuum dry to constant weight, and crush it through a 120-mesh sieve to obtain cross-linked starch;

[0109] b. 100 parts of cross-linked starch were dispersed again in deionized water, sodium acetate was added thereto, the pH value was adjusted to 9, the temperature was raised to 45°C, and after stirring and preheating for 20 minutes, 0.8 parts of glucoamylase and 0.8 parts of α-amylase were added thereto, the temperature was raised to 45°C, and the reaction was stirred for 3 hours, and then the precipitate was separated by centrifugation, and washed again with deionized water for 5 times, vacuum dried to constant weight, and crushed through an 80-mesh sieve to obtain microporous cross-linked starch;

[0110] c. 100 parts of microporous cross-linked starch and 300 parts of lauric acid were mixed, dimethyl sulfoxide was added thereto, and the mixture was stirred until the lauric acid was completely dissolved, and lipase and deionized water with an equal volume of lipase were added thereto. After stirring and reacting for 4 hours at room temperature, the precipitate was separated by centrifugation, and the precipitate was washed 5 times with anhydrous ethanol, vacuum dried to constant weight, and crushed through a 40-mesh sieve to obtain a modified cross-linked starch;

[0111] Wherein, the addition amount of the lipase is 0.5mL / 100g microporous cross-linked starch; the specification of the lipase is 100unit / μL;

[0112] S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion;

[0113] 50% volume of the granulation dispersion was added to the high-speed shear granulator within 1 min, and the material was raked after continuing low-speed stirring and low-speed shearing for 30 s. The remaining granulation dispersion was added to the high-speed shear granulator within 1 min, and low-speed stirring and low-speed shearing were continued for 30 s. After passing through a 6.0 mm sieve, the obtained wet granules were transferred to a spheronizer, and pellets were obtained by water spray spheronization. The pellets were placed in an environment of 40±5°C and dried until the LOD range was 1-2% m / m, and then sieved to collect the pellet particles of the 14-30 mesh sieve to obtain sustained-release pellets.

[0114] Comparative Example 1. A method for preparing a tamsulosin preparation containing a sustained-release excipient, comprising the following steps:

[0115] Compared with Example 2, this comparative example did not perform step c treatment;

[0116] S1. Preparation of sustained-release pellets;

[0117] S11. After talcum powder is passed through a 40-mesh sieve, it is mixed with a sustained-release excipient and loaded into a high-speed shear granulator. After dry mixing for 10 minutes under low-speed stirring and off-shear conditions, an aqueous solution of tamsulosin hydrochloride is added thereto within 2 minutes, and then the state is switched to low-speed stirring at 40 rpm and granulation of the wet material under low-speed shear conditions for 30 seconds;

[0118] Wherein, the sustained-release excipient is modified cross-linked starch, and its preparation method is as follows:

[0119] a. Disperse 100 parts of corn starch in deionized water by weight, heat to 45°C, stir for 15 minutes, add 1.8 parts of potassium sulfate and 1.5 parts of potassium chloride, continue stirring for 10 minutes, add 0.15 parts of phosphorus oxychloride, and add potassium hydroxide dropwise to adjust the pH value to 11. After stirring and reacting for 3 hours, add hydrochloric acid dropwise to adjust the pH value to 6.8, centrifuge and separate the precipitate, wash the precipitate with deionized water 3 times, vacuum dry to constant weight, and crush it through a 120-mesh sieve to obtain cross-linked starch;

[0120] b. 100 parts of cross-linked starch were dispersed again in deionized water, sodium acetate was added thereto, the pH value was adjusted to 9, the temperature was raised to 45°C, and after stirring and preheating for 20 minutes, 0.5 parts of glucoamylase and 0.3 parts of α-amylase were added thereto, the temperature was raised to 45°C, and the reaction was stirred for 3 hours, and then the precipitate was separated by centrifugation, and washed again with deionized water for 5 times, vacuum dried to constant weight, and crushed through an 80-mesh sieve to obtain microporous cross-linked starch;

[0121] c. 100 parts of microporous cross-linked starch were mixed with 30 parts of lauric acid, dimethyl sulfoxide was added thereto, and the mixture was stirred until the lauric acid was completely dissolved, and lipase and deionized water with an equal volume of lipase were added thereto. After stirring and reacting for 4 hours at room temperature, the precipitate was separated by centrifugation, and the precipitate was washed 5 times with anhydrous ethanol, vacuum dried to constant weight, and crushed through a 40-mesh sieve to obtain a modified cross-linked starch;

[0122] Wherein, the addition amount of the lipase is 0.1mL / 100g microporous cross-linked starch; the specification of the lipase is 100unit / μL;

[0123] S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion;

[0124] 50% volume of the granulation dispersion was added to the high-speed shear granulator within 1 min, and the material was raked after continuing low-speed stirring and low-speed shearing for 30 s. The remaining granulation dispersion was added to the high-speed shear granulator within 1 min, and low-speed stirring and low-speed shearing were continued for 30 s. After passing through a 6.0 mm sieve, the obtained wet granules were transferred to a spheronizer, and pellets were obtained by water spray spheronization. The pellets were placed in an environment of 40±5°C and dried until the LOD range was 1-2% m / m, and then sieved to collect the pellet particles of the 14-30 mesh sieve to obtain sustained-release pellets.

[0125] Test: The capsules prepared in Examples 1-6 and Comparative Example 1 were subjected to dissolution tests. The test results are shown in Table 2 below;

[0126] Table 2.

[0127]

[0128] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a tamsulosin preparation containing a sustained-release excipient, characterized in that: The following steps are involved: S1. Preparation of sustained-release pellets; S11. After sieving the talc, mix it with the sustained-release excipients, put it into a high-speed shear granulator, dry mix it under low-speed stirring and off-shear state, add the tamsulosin hydrochloride aqueous solution within 1.5-2 minutes, and then switch the state to low-speed stirring and low-speed shear state to granulate the wet material for 30-45 seconds; S12. After filtering the methacrylic acid - ethyl acrylate copolymer dispersion using fine cotton cloth, triacetin was added thereto, and the mixture was mixed evenly to obtain a granulation dispersion; Add 50% volume of the granulation dispersion to the high-speed shear granulator, continue to stir and shear at low speed for 30-45 seconds to loosen the material, add the remaining granulation dispersion to the high-speed shear granulator, continue to stir and shear at low speed for 30-45 seconds, sieve, transfer the obtained wet granules to the spheronizer, spray water to spheronize to obtain micropellets, dry the micropellets to an LOD range of 1-2% m / m, sieve, collect the micropellet particles, and obtain sustained-release micropellets; S2. Preparation of coated pellets; S21. The methacrylic acid - ethyl acrylate copolymer dispersion was filtered using fine cotton cloth, deionized water was added thereto and stirred evenly, triacetin was added and stirred, and the resulting mixture was set aside; After sieving talcum powder, mix it with deionized water, stir and disperse it to obtain a talcum powder dispersion, add it to the above mixed solution, continue to stir and mix, and obtain a coating solution; S22. Place the sustained-release pellets in a fluidized bed and heat them to 35±5°C. After the LOD of the sustained-release pellets drops to 0.5-1% m / m, heat them to 35±3°C, spray the sustained-release pellets with the coating solution, and dry them again until the LOD drops to 0.5-1% m / m again. Heat them to 40±2°C and continue drying and curing for 20-30 minutes. Sieve them to remove lumps to obtain coated pellets. S3. After sieving talcum powder and calcium stearate, mix them to prepare a lubricating material, mix the coated micropellets with the lubricating material, blend them, and load the resulting product into capsules to obtain a tamsulosin preparation containing a sustained-release excipient.

2. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 1, characterized in that: In step S1, the sustained-release excipient is microcrystalline cellulose or modified cross-linked starch; Wherein, the preparation method of the modified cross-linked starch is: a. Disperse corn starch in deionized water, heat to 40-50°C, stir for 10-15 minutes, add potassium sulfate and potassium chloride, continue stirring for 10-15 minutes, add phosphorus oxychloride, and add alkali solution to adjust the pH value to 10.5-11. After stirring and reacting for 3 hours, add hydrochloric acid to adjust the pH value to 6.5-7, centrifuge and separate the precipitate, wash the precipitate with deionized water for 3-5 times, vacuum dry to constant weight, and crush it through a 120-mesh sieve to obtain cross-linked starch; b. The cross-linked starch was dispersed again in deionized water, sodium acetate was added thereto, the pH value was adjusted to 8.5-9.5, the temperature was raised to 40-50°C, and after stirring and preheating for 20 minutes, glucoamylase and α-amylase were added thereto, the temperature was raised to 45-50°C, and the reaction was stirred for 1.5-4 hours, and then the precipitate was separated by centrifugation, and washed again with deionized water for 3-5 times, vacuum dried to constant weight, and crushed through an 80-mesh sieve to obtain microporous cross-linked starch; c. Mix the microporous cross-linked starch with lauric acid, add dimethyl sulfoxide thereto, stir and mix until the lauric acid is completely dissolved, add lipase and deionized water thereto, stir and react at room temperature for 4-12 hours, centrifuge and separate the precipitate, wash the precipitate with anhydrous ethanol for 3-5 times, vacuum dry to constant weight, and crush through a 40-mesh sieve to obtain modified cross-linked starch.

3. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 2, characterized in that: In step a, the mass ratio of the corn starch, potassium sulfate and potassium chloride is 100:(1.5-2.55):(0.5-5) in parts by weight.

4. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 2, characterized in that: In step a, the mass ratio of corn starch to phosphorus oxychloride is 100:(0.1-1) in parts by weight.

5. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 2, characterized in that: In step b, the mass ratio of the cross-linked starch, glucoamylase and α-amylase is 100:(0.5-0.8):(0.3-0.8) in parts by weight.

6. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 2, characterized in that: In step c, the ratio of the microporous cross-linked starch, lauric acid, and lipase is 100 g: 10-300 g: 0.1-0.5 mL; Wherein, the specification of the lipase is 100unit / μL.

7. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 1, characterized in that: In step S11, the wet material consists of 7.8-8.5 parts of talc, 120-150 parts of sustained-release excipients and 25-30 parts of tamsulosin hydrochloride aqueous solution; Wherein, in the tamsulosin hydrochloride aqueous solution, the concentration of tamsulosin hydrochloride is 0.7-0.73% m / m.

8. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 1, characterized in that: In step S12, the solid content of the methacrylic acid-ethyl acrylate copolymer dispersion is 27-35%, and the mass ratio of methacrylic acid to ethyl acrylate in the methacrylic acid-ethyl acrylate copolymer is 1:1; The granulation dispersion consists of 140-150 parts of methacrylic acid-ethyl acrylate copolymer dispersion and 1-1.5 parts of triacetin.

9. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 1, characterized in that: In step S21, the mixed solution is composed of 12-15 parts of acrylic acid-ethyl acrylate copolymer dispersion, 65-70 parts of deionized water, and 0.5-0.7 parts of triacetin; The talc powder dispersion consists of 0.6-0.9 parts of talc powder and 20-25 parts of deionized water.

10. The method for preparing a tamsulosin preparation containing a sustained-release excipient according to claim 1, characterized in that: The lubricating material is composed of 14.5-16 parts of talc and 1.2-1.8 parts of calcium stearate; The mass ratio of the coated pellets to the lubricating material is 20-25:1.

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