Preparation process of spirolactone tablets
By using microcrystalline cellulose, dextrin and starch in spirolactone tablets, combined with ethanol solution and sustained-release layer coating technology, spirolactone tablets were prepared, which solved the problem of excessively fast release rate of existing tablets and achieved the The slow and continuous release of the drug has improved the efficacy and scope of application.
Patent Information
- Application Number
- CN202411390585.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-08
- Publication Date
- 2024-12-17
AI Technical Summary
The drug release rate of existing spironolactone tablets is too fast, causing large fluctuations in blood drug concentrations, limiting their applicable population and efficacy, and may cause health risks.
Microcrystalline cellulose, dextrin and starch as fillers, combined with ethanol solution and sustained-release layer coating technology, micropills are prepared by centrifugation fluidized bed, and dried in a drying chamber and pressed into tablets to control the slowness of the drug and Continuous release.
The stable and full release of spironolactone was achieved, smoothed the fluctuations in blood concentration, improved the efficacy, expanded the applicable population, and reduced health risks.
Smart Images
Figure BDA0005072297960000101
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug dosage form development, and particularly relates to a preparation process of spironolactone tablets. Background Art
[0002] Spironolactone is a steroid compound with the chemical name 17β-hydroxy-3-oxo-7α-(acetylthio)-17α-pregnane-4-ene-21-carboxylic acid-γ-lactone. It is mainly used as a low-efficiency diuretic. The pharmacological action of spironolactone is that its structure is similar to aldosterone. It can act as a competitive inhibitor of aldosterone, acting on the distal convoluted tubules and collecting ducts of the kidney, thereby blocking the Na + -K + and Na + -H + exchange, resulting in Na + , Cl - and water excretion increased, while K + Mg 2+ and H + This effect makes spironolactone particularly suitable for the treatment of diseases associated with increased aldosterone levels, such as congestive heart failure, ascites due to cirrhosis, edematous diseases such as nephrotic syndrome, as well as hypertension and primary aldosteronism. In addition, spironolactone can also be used to prevent hypokalemia that may occur when used in combination with thiazide diuretics.
[0003] Spironolactone preparations currently on the market mostly adopt the form of common tablets, which have the advantages that the production technology is very mature, the manufacturing cost is relatively low, and it is convenient for patients to swallow. However, a significant disadvantage of this type of common tablets is that the drug release rate is high, which causes the drug concentration in the patient's blood to rise rapidly in a short period of time after taking the medicine, and then rapidly declines, causing significant fluctuations in blood drug concentration. For some patients who cannot tolerate rapid diuresis or may cause health risks due to rapid changes in blood drug concentration, the application and effect of common spironolactone tablets are greatly limited. Summary of the invention
[0004] In view of the shortcomings of the prior art, the present invention provides a preparation process of spironolactone tablets, aiming to provide spironolactone tablets with stable release and high release rate, which can achieve slow and continuous drug release in clinical use and smooth blood drug concentration fluctuations, thereby helping to expand the applicable population, improve efficacy and reduce potential risks.
[0005] The preparation process of the spironolactone tablets provided by the present invention comprises the following steps:
[0006] Step S1: mixing microcrystalline cellulose, dextrin and starch in a mass ratio of (20-35):(15-35):100 to form a filler;
[0007] Step S2: uniformly mixing the spironolactone API and ethanol in a mass ratio of (3-10):1000 to form an ethanol solution of spironolactone;
[0008] Step S3: putting the filler prepared in step S1 into a centrifugal fluidized bed, and then spraying the spironolactone ethanol solution prepared in step S2 to prepare micropellets;
[0009] Step S4: coating the pellets with a sustained-release layer, wherein the coating solution comprises polyvinyl alcohol, tributyl citrate and ethanol in a mass ratio of (10-25):(5-8):100;
[0010] Step S5: pressing the tableting powder containing the pellets obtained in step S4 into tablets to obtain the spironolactone tablets.
[0011] As a further optimization scheme for the preparation process of spironolactone tablets, in step S1, microcrystalline cellulose, dextrin and starch are respectively passed through a 300-mesh sieve and then mixed evenly.
[0012] As a further optimization scheme for the preparation process of spironolactone tablets, in step S2, the spironolactone API is added to anhydrous ethanol, stirred and ultrasonically oscillated to form a uniform solution.
[0013] As a further optimization scheme for the preparation process of spironolactone tablets, in step S3, the filler prepared in step S1 is put into a centrifuge fluidized bed and blown to form a vortex rotating particle flow, and the spironolactone ethanol solution prepared in step S2 is sprayed into the centrifuge fluidized bed through a spray gun, so that the powder is condensed into micropills in the centrifuge fluidized bed.
[0014] As a further optimization scheme for the preparation process of spironolactone tablets, in step S3, the micropellets condensed in the centrifuge fluidized bed are dried in a drying oven at 60° C. to obtain dried micropellets.
[0015] As a further optimization scheme for the preparation process of spironolactone tablets, in step S4, the pellets with a particle size of 0.3 mm to 0.6 mm are screened out from the pellets prepared in step S3 for coating.
[0016] As a further optimization scheme for the preparation process of spironolactone tablets, in step S4, a fluidized bed is used to coat the pellets with a sustained-release layer, and the inlet air temperature is maintained at 75±2°C and the coating liquid temperature is maintained at 40±2°C.
[0017] As a further optimization scheme for the preparation process of spironolactone tablets, in step S4, the coating weight gain is 18-25%.
[0018] As a further optimization scheme for the preparation process of spironolactone tablets, in step S5, the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethyl cellulose, magnesium stearate, and microcrystalline cellulose prepared in step S4 are uniformly mixed and then pressed into tablets to obtain the spironolactone tablets.
[0019] As a further optimization scheme for the preparation process of spironolactone tablets, in step S5, the mass ratio of coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethyl cellulose, magnesium stearate, and microcrystalline cellulose is (70-90):(4-8):(10-25):(0.6-1.2):100.
[0020] Beneficial Effects
[0021] The spironolactone tablets provided by the present invention control the sustained, stable and sufficient release of spironolactone, avoiding the large fluctuation of blood drug concentration caused by the rapid release of ordinary tablets, which is beneficial to improving the efficacy of the drug, reducing the tolerance risk, and further expanding the applicable population of spironolactone. DETAILED DESCRIPTION
[0022] The present invention is further illustrated by specific examples below. These examples are exemplary and are intended to illustrate the problem and explain the present invention, but are not intended to be limiting.
[0023] Preparation of Spironolactone Tablets
[0024] Step S1: pass microcrystalline cellulose, dextrin and starch through a 300-mesh sieve respectively and mix them evenly in a mass ratio of (20-35):(15-35):100.
[0025] Step S2: accurately weighing the spironolactone API and anhydrous ethanol according to a mass ratio of (3-10):1000, adding the spironolactone API into the anhydrous ethanol, stirring and ultrasonically oscillating to form a uniform solution.
[0026] Step S3: The filler prepared in step S1 is put into a centrifuge fluidized bed and blown. Under the action of centrifugal force and friction, the powder forms a vortex rotational particle flow on the curved surface of the stator and the rotor, so that the particles can be tumbled and stirred evenly, and the spironolactone ethanol solution prepared in step S2 is sprayed into the powder through a spray gun. The mass ratio of the ethanol solution to the filler is (20-40):100, so that the powder is condensed into micropills, and then dried in a drying oven at 60°C for 24 hours to obtain dried micropills.
[0027] Step S4: Screening out micropellets with a particle size of 0.3 mm to 0.6 mm and coating them with a sustained-release layer in a fluidized bed, wherein the inlet air temperature is maintained at 75±2° C., the coating solution temperature is maintained at 40±2° C., and the coating weight gain is 18-25%; the coating solution is prepared by mixing polyvinyl alcohol, tributyl citrate, and ethanol in a mass ratio of (10-25):(5-8):100.
[0028] Step S5: The coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose prepared in step S4 are mixed and uniformly pressed into tablets to obtain the spironolactone tablets. The mass ratio of the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose is (70-90):(4-8):(10-25):(0.6-1.2):100.
[0029] Example 1
[0030] Step S1: pass microcrystalline cellulose, dextrin and starch through a 300-mesh sieve respectively and mix them evenly in a mass ratio of 20:15:100.
[0031] Step S2: accurately weighing the spironolactone API and anhydrous ethanol at a mass ratio of 3:1000, adding the spironolactone API into the anhydrous ethanol, stirring and ultrasonically oscillating to form a uniform solution.
[0032] Step S3: The filler prepared in step S1 is put into a centrifuge fluidized bed and blown. Under the action of centrifugal force and friction, the powder forms a vortex rotational particle flow on the curved surface of the stator and the rotor, so that the particles can be tumbled and stirred evenly, and the spironolactone ethanol solution prepared in step S2 is sprayed into the powder through a spray gun. The mass ratio of the ethanol solution to the filler is 20:100, so that the powder is condensed into micropills, and then dried in a drying oven at 60°C for 24 hours to obtain dry micropills.
[0033] Step S4: Screening out micropellets with a particle size of 0.3 mm to 0.6 mm and coating them with a sustained-release layer in a fluidized bed, maintaining the inlet air temperature at 75±2°C, the coating solution temperature at 40±2°C, and the coating weight gain at 18%; the coating solution is prepared by mixing polyvinyl alcohol, tributyl citrate, and ethanol in a mass ratio of 10:5:100.
[0034] Step S5: The coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose prepared in step S4 are mixed and uniformly pressed into tablets to obtain the spironolactone tablets. The mass ratio of the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose is 70:4:10:0.6:100.
[0035] Example 2
[0036] Step S1: pass microcrystalline cellulose, dextrin and starch through a 300-mesh sieve respectively and mix them evenly in a mass ratio of 25:20:100.
[0037] Step S2: accurately weighing the spironolactone API and anhydrous ethanol at a mass ratio of 5:1000, adding the spironolactone API into the anhydrous ethanol, stirring and ultrasonically oscillating to form a uniform solution.
[0038] Step S3: The filler prepared in step S1 is put into a centrifuge fluidized bed and blown. Under the action of centrifugal force and friction, the powder forms a vortex rotational particle flow on the curved surface of the stator and the rotor, so that the particles can be tumbled and stirred evenly, and the spironolactone ethanol solution prepared in step S2 is sprayed into the powder through a spray gun. The mass ratio of the ethanol solution to the filler is 25:100, so that the powder is condensed into micropills, and then dried in a drying oven at 60°C for 24 hours to obtain dry micropills.
[0039] Step S4: Screening out micropellets with a particle size of 0.3 mm to 0.6 mm and coating them with a sustained-release layer in a fluidized bed, maintaining the inlet air temperature at 75±2°C, the coating solution temperature at 40±2°C, and the coating weight gain at 20%; the coating solution is prepared by mixing polyvinyl alcohol, tributyl citrate, and ethanol in a mass ratio of 15:6:100.
[0040] Step S5: The coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose prepared in step S4 are uniformly mixed and pressed into tablets to obtain the spironolactone tablets. The mass ratio of the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose is 75:6:15:0.8:100.
[0041] Example 3
[0042] Step S1: pass microcrystalline cellulose, dextrin and starch through a 300-mesh sieve respectively and mix them evenly in a mass ratio of 30:25:100.
[0043] Step S2: accurately weighing the spironolactone API and anhydrous ethanol in a mass ratio of 8:1000, adding the spironolactone API into the anhydrous ethanol, stirring and ultrasonically oscillating to form a uniform solution.
[0044] Step S3: The filler prepared in step S1 is put into a centrifuge fluidized bed and blown. Under the action of centrifugal force and friction, the powder forms a vortex rotational particle flow on the curved surface of the stator and the rotor, so that the particles can be tumbled and stirred evenly, and the spironolactone ethanol solution prepared in step S2 is sprayed into the powder through a spray gun. The mass ratio of the ethanol solution to the filler is 30:100, so that the powder is condensed into micropills, and then dried in a drying oven at 60°C for 24 hours to obtain dry micropills.
[0045] Step S4: Screening out micropellets with a particle size of 0.3 mm to 0.6 mm and coating them with a sustained-release layer in a fluidized bed, with the inlet air temperature maintained at 75±2°C, the coating solution temperature maintained at 40±2°C, and the coating weight gain being 22%; the coating solution is prepared by mixing polyvinyl alcohol, tributyl citrate, and ethanol in a mass ratio of 20:6:100.
[0046] Step S5: The coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose prepared in step S4 are mixed and uniformly pressed into tablets to obtain the spironolactone tablets. The mass ratio of the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose is 80:6:20:1.0:100.
[0047] Example 4
[0048] Step S1: pass microcrystalline cellulose, dextrin and starch through a 300-mesh sieve respectively and mix them evenly in a mass ratio of 30:30:100.
[0049] Step S2: accurately weighing the spironolactone API and anhydrous ethanol in a mass ratio of 8:1000, adding the spironolactone API into the anhydrous ethanol, stirring and ultrasonically oscillating to form a uniform solution.
[0050] Step S3: The filler prepared in step S1 is put into a centrifuge fluidized bed and blown. Under the action of centrifugal force and friction, the powder forms a vortex rotational particle flow on the curved surface of the stator and the rotor, so that the particles can be tumbled and stirred evenly, and the spironolactone ethanol solution prepared in step S2 is sprayed into the powder through a spray gun. The mass ratio of the ethanol solution to the filler is 35:100, so that the powder is condensed into micropills, and then dried in a drying oven at 60°C for 24 hours to obtain dried micropills.
[0051] Step S4: Screening out micropellets with a particle size of 0.3 mm to 0.6 mm and coating them with a sustained-release layer in a fluidized bed, with the inlet air temperature maintained at 75±2°C, the coating solution temperature maintained at 40±2°C, and the coating weight gain being 25%; the coating solution is prepared by mixing polyvinyl alcohol, tributyl citrate, and ethanol in a mass ratio of 25:5:100.
[0052] Step S5: The coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose prepared in step S4 are mixed and uniformly pressed into tablets to obtain the spironolactone tablets. The mass ratio of the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose is 85:6:20:1.2:100.
[0053] Example 5
[0054] Step S1: pass microcrystalline cellulose, dextrin and starch through a 300-mesh sieve respectively and mix them evenly in a mass ratio of 20:35:100.
[0055] Step S2: accurately weighing the spironolactone API and anhydrous ethanol at a mass ratio of 3:1000, adding the spironolactone API into the anhydrous ethanol, stirring and ultrasonically oscillating to form a uniform solution.
[0056] Step S3: The filler prepared in step S1 is put into a centrifuge fluidized bed and blown. Under the action of centrifugal force and friction, the powder forms a vortex rotational particle flow on the curved surface of the stator and the rotor, so that the particles can be tumbled and stirred evenly, and the spironolactone ethanol solution prepared in step S2 is sprayed into the powder through a spray gun. The mass ratio of the ethanol solution to the filler is 20:100, so that the powder is condensed into micropills, and then dried in a drying oven at 60°C for 24 hours to obtain dry micropills.
[0057] Step S4: Screening out micropellets with a particle size of 0.3 mm to 0.6 mm and coating them with a sustained-release layer in a fluidized bed, with the inlet air temperature maintained at 75±2°C, the coating solution temperature maintained at 40±2°C, and the coating weight gain being 25%; the coating solution is prepared by mixing polyvinyl alcohol, tributyl citrate, and ethanol in a mass ratio of 25:8:100.
[0058] Step S5: The coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose prepared in step S4 are mixed and uniformly pressed into tablets to obtain the spironolactone tablets. The mass ratio of the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose is 90:6:10:0.8:100.
[0059] Example 6
[0060] Step S1: pass microcrystalline cellulose, dextrin and starch through a 300-mesh sieve respectively and mix them evenly in a mass ratio of 35:35:100.
[0061] Step S2: accurately weighing the spironolactone API and anhydrous ethanol at a mass ratio of 10:1000, adding the spironolactone API into the anhydrous ethanol, stirring and ultrasonically oscillating to form a uniform solution.
[0062] Step S3: The filler prepared in step S1 is put into a centrifuge fluidized bed and blown. Under the action of centrifugal force and friction, the powder forms a vortex rotational particle flow on the curved surface of the stator and the rotor, so that the particles can be tumbled and stirred evenly, and the spironolactone ethanol solution prepared in step S2 is sprayed into the powder through a spray gun. The mass ratio of the ethanol solution to the filler is 40:100, so that the powder is condensed into micropills, and then dried in a drying oven at 60°C for 24 hours to obtain dry micropills.
[0063] Step S4: Screening out micropellets with a particle size of 0.3 mm to 0.6 mm and coating them with a sustained-release layer in a fluidized bed, with the inlet air temperature maintained at 75±2°C, the coating solution temperature maintained at 40±2°C, and the coating weight gain being 25%; the coating solution is prepared by mixing polyvinyl alcohol, tributyl citrate, and ethanol in a mass ratio of 25:8:100.
[0064] Step S5: The coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose prepared in step S4 are mixed and uniformly pressed into tablets to obtain the spironolactone tablets. The mass ratio of the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose, magnesium stearate, and microcrystalline cellulose is 90:8:25:1.2:100.
[0065] The samples prepared in the above embodiments were tested for dissolution performance. According to the dissolution and release determination method of "Chinese Pharmacopoeia" 0931, a phosphate buffer solution with a pH value of 6.8 was used as a solvent medium, with a volume of 900 ml, and placed in a dissolution cup. During the experiment, the solvent temperature was maintained within the standard human body temperature, i.e., (37 ± 0.5) ° C, and the speed was controlled to 100 rpm using a paddle stirrer. At predetermined time points, i.e., 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, and 24 hours, 8 ml of solvent sample was extracted from the dissolution cup, and the same volume and temperature of solvent was added to the dissolution cup immediately to maintain the consistency of the dissolution environment. The extracted sample was filtered through a filter membrane with a pore size of 0.45 microns to remove possible particulate matter. After the filtered solution was diluted, its absorbance value was determined by a UV-visible spectrophotometer. The reference substance was accurately weighed and the absorbance was determined by the same method to calculate the cumulative release percentage of the drug in different time periods.
[0066] Table 1 Dissolution performance test results
[0067]
[0068] The results show that the spironolactone tablets prepared in each embodiment show excellent drug release characteristics. Within the first 2 hours, the drug release of all embodiments is between 15% and 18%, with a more reasonable initial release rate. In the mid-term release stage, by 6 hours, the drug release reaches 42%-46%, and the drug can still be released continuously and stably after a certain period of time. By 8 hours, the drug release is close to or exceeds 50%. By 24 hours, the drug release of all embodiments exceeds 90%, and the best can exceed 97%, almost completely released. It can be seen that the sample release process of each embodiment has no obvious sudden release, the release rate is stable, and the release is sufficient.
[0069] The above embodiments are exemplary, and their purpose is to illustrate the technical concept and features of the present invention so that people familiar with the technology in this field can understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.
Claims
1. A preparation process of spironolactone tablets, characterized in that: The following steps are involved: Step S1: mixing microcrystalline cellulose, dextrin and starch in a mass ratio of (20-35):(15-35):100 to form a filler; Step S2: uniformly mixing the spironolactone API and ethanol in a mass ratio of (3-10):1000 to form an ethanol solution of spironolactone; Step S3: putting the filler prepared in step S1 into a centrifugal fluidized bed, and then spraying the spironolactone ethanol solution prepared in step S2 to prepare micropellets; Step S4: coating the pellets with a sustained-release layer, wherein the coating solution comprises polyvinyl alcohol, tributyl citrate and ethanol in a mass ratio of (10-25):(5-8):100; Step S5: pressing the tableting powder containing the pellets obtained in step S4 into tablets to obtain the spironolactone tablets.
2. The preparation process of spironolactone tablets according to claim 1, characterized in that: In step S1, microcrystalline cellulose, dextrin and starch are respectively passed through a 300-mesh sieve and then mixed evenly.
3. The preparation process of spironolactone tablets according to claim 1, characterized in that: In step S2, the spironolactone API is added into anhydrous ethanol, stirred and ultrasonically vibrated to form a uniform solution.
4. The preparation process of spironolactone tablets according to claim 1, characterized in that: In step S3, the filler prepared in step S1 is put into a centrifuge fluidized bed and blown to form a vortexing particle flow, and the spironolactone ethanol solution prepared in step S2 is sprayed into the fluidized bed through a spray gun to condense the powder into micro-pellets in the centrifuge fluidized bed.
5. The preparation process of spironolactone tablets according to claim 4, characterized in that: In step S3, the micropellets condensed in the centrifuge fluidized bed are dried in a drying oven at 60°C to obtain dried micropellets.
6. The preparation process of spironolactone tablets according to claim 1, characterized in that: In step S4, the pellets with a particle size of 0.3 mm to 0.6 mm are screened out from the pellets obtained in step S3 for coating.
7. The preparation process of spironolactone tablets according to claim 6, characterized in that: In step S4, the micropellets are coated with a sustained-release layer using a fluidized bed, the inlet air temperature is maintained at 75±2°C, and the coating liquid temperature is maintained at 40±2°C.
8. The preparation process of spironolactone tablets according to claim 7, characterized in that: In step S4, the coating weight gain is 18-25%.
9. The preparation process of spironolactone tablets according to claim 1, characterized in that: In step S5, the coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethyl cellulose, magnesium stearate and microcrystalline cellulose prepared in step S4 are uniformly mixed and pressed into tablets to obtain the spironolactone tablets.
10. The preparation process of spironolactone tablets according to claim 9, characterized in that: In step S5, the mass ratio of coated pellets, hydroxypropyl methylcellulose, cross-linked sodium carboxymethyl cellulose, magnesium stearate, and microcrystalline cellulose is (70-90):(4-8):(10-25):(0.6-1.2):100.