CN106031713B - Ketoprofen sustained-release pellet and preparation method thereof - Google Patents
Ketoprofen sustained-release pellet and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a ketoprofen sustained-release pellet and a preparation method thereof. The invention is composed of blank pill core, sustained-release coating layer, and coating layer, the invention adopts the process of coating twice and coating the sustained-release coating layer twice, not only controls the content proportion and the coating speed of the two-time medicine application, but also adopts the mode of combining skeleton and membrane controlled release, and adds oil into the sustained-release coating liquid, so that the medicine application efficiency and the coating efficiency are improved, the content uniformity and the process reproducibility are better, the control is easy, the release is uniform, the release energy is basically consistent with the release curve of the reference preparation on the market, the stability of the coating layer is better, the in-vitro release effect similar to the original research is achieved, the production efficiency is improved, and the invention is suitable for large-scale production.
Description
Technical Field
The invention relates to a pharmaceutical preparation containing ketoprofen and a preparation method thereof, in particular to a sustained-release pellet containing ketoprofen and a preparation method thereof.
Background
Ketoprofen, english name: ketoprofen, chemical name: α -methyl-3-benzoyl-phenylacetic acid having the following structural formula:
the molecular formula is as follows: c16H14O3Molecular weight: 254.29.
in daily life, pain is one of the most common reasons for patients to seek medical advice, rheumatism and arthritis are common diseases in the existing living environment, the prevalence rate of only rheumatoid arthritis in China currently reaches about 5 per thousand, and the number of patients suffering from rheumatism and rheumatoid arthritis exceeds 1000 ten thousand.
Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID), also known as ketoprofen, has analgesic and antipyretic properties, is a newer product of ibuprofen, is superior to ibuprofen in therapeutic effects and adverse effects, NSAIDs are generally considered to act by inhibiting Cyclooxygenase (COX), and studies have shown that in vivo COX consists of two enzymes COX1 and COX2, COX1 is present in normal tissues, particularly gastric mucosa and kidney, and maintains normal physiological functions by catalyzing the production of Prostaglandins (PG). And electrophysiology research shows that ketoprofen has a definite central analgesic effect on a human body, and intravenous injection of ketoprofen can quickly penetrate through a blood brain barrier and reduce the threshold of nociceptive reflex caused by spinal cord level. Ketoprofen has more than forty years of clinical use experience, and has better analgesic, anti-inflammatory and anti-inflammatory effects than ibuprofen preparations which are mainstream in the market at present. In the aspect of dosage forms, the ketoprofen sustained release preparation is easy to take and has small adverse reactions, so that patients are easy to accept the ketoprofen sustained release preparation, and therefore, the inventor develops the ketoprofen sustained release preparation.
Through a large number of tests and data research, the existing ketoprofen sustained release preparation related to Chinese patent CN 102000032B and Chinese patent CN 1203787A only disclose the prescription of a sustained release tablet, which belongs to a unit sustained release preparation-tablet, while the multi-unit sustained release pellet is more advantageous and can be taken in multiple doses, and a certain small unit can not generate great influence on the total release, while the tablet is only a unit, one unit directly influences the quality of the product, the generated risk is larger, and the tablet is not suitable for taking multiple doses and is not dominant; the domestic patent does not disclose ketoprofen sustained-release pellets, and the US patent 6613361B 1 discloses a method for preparing ketoprofen sustained-release pellets, which adopts the conventional way of coating blank pellets with a drug and then coating a sustained-release coating, wherein the coating liquid uses Eudragit NE30D, Eudragit RS30D, Eudragit RL30D, talcum powder, colloidal silica and triethyl citrate, but special equipment is needed for production, and a large amount of colloidal silica is used, wherein the colloidal silica is very light and easy to float in the air due to the small density of the colloidal silica, can cause great influence on production and transportation, even possibly cause explosion, and the film-forming material and the framework material are sprayed into a binder and the particularity of the framework material is easy to generate adhesion phenomenon and static electricity in the coating process, the inventor finds that part of the pellets are adhered in the coating process in a repeated test process, the recovery is not easy after heating and cooling, even more anti-sticking agent is added, the environment and equipment requirements are very high, and the process is difficult to control. And the inherent characteristics of the ketoprofen raw material: the problems of the prior art are that the prepared sustained-release pellets need to be correspondingly modified, and a large amount of antistatic auxiliary materials need to be added.
Therefore, the inventor invents a ketoprofen sustained-release pellet, which can avoid the risk of only one unit of sustained-release tablets and the influence caused by incapability of taking multiple doses, and can also avoid the potential safety hazard caused by using excessive colloidal silicon dioxide. The coating process has the advantages that the production efficiency is guaranteed, meanwhile, the coating can be smoothly completed, the stability of the film layer is guaranteed, the requirements for equipment are reduced, the control degree of the process is improved, and the process is suitable for large-scale production.
The inventor adopts a mode of combining the framework material with the membrane controlled release to carry out medicine application for 2 times and coating for 2 times, namely, a mode of carrying out solid medicine application on a blank pellet core, carrying out first sustained-release coating layer coating, then carrying out second medicine application, and finally carrying out second coating is carried out, so that the content uniformity of the pellet is very good, and the release uniformity is also very high. The first medicine feeding and the second medicine feeding are strictly controlled in the process, the medicine feeding efficiency is high, and the content uniformity of the pellets is not influenced by the medicine feeding speed.
The inventor adds grease into the coating components in the coating process to improve the easy adhesion phenomenon caused by static electricity in the coating process and greatly improve the stability of the slow-release coating layer, and a large number of experiments prove the advantages.
The inventor prepares the ketoprofen sustained-release pellets by the process of the invention without using special equipment, adopts a common centrifugal granulation coating machine, has high production efficiency, good content uniformity and uniform release, and can achieve similar release and more uniform release with a reference preparation.
The method has the advantages of simple process, easy operation, stable process and good repeatability, and is suitable for large-scale production.
Disclosure of Invention
The invention describes a ketoprofen sustained-release pellet and a preparation method thereof, which reduce the risks of batch difference, grain difference and incapability of multi-dose administration caused by few units of ketoprofen sustained-release tablets, solve the problems of low efficiency, poor repeatability and difficult control of the sustained-release pellet in the coating process, improve the medicine application efficiency, can efficiently complete the medicine application and coating processes by adopting a common equipment centrifugal granulation coating machine, have stable process, good repeatability and good content uniformity, prepare the ketoprofen sustained-release pellet with uniform release, solve the defect that common equipment of similar products is difficult to reproduce, greatly shorten the process time and are suitable for large-scale production.
The ketoprofen sustained-release pellet consists of a pellet core, two medicine applying layers and two coating layers;
wherein the pellet core is one of sucrose pellet cores and microcrystalline cellulose pellet cores, and the particle size is 0.35 mm-1.0 mm.
Wherein the coating layer is composed of a slow-release film-forming material, a plasticizer, an anti-sticking agent, a diluent, a wetting agent and oil.
Wherein the oil is soybean oil, peanut oil or medium chain fatty acid triglyceride.
Furthermore, the part of the oil in the coating layer is 2.0-5.0.
Wherein the slow-release film-forming material is one or a combination of Eudragit RL30D and Eudragit RS 30D; the anti-sticking agent is talcum powder, the plasticizer is triethyl citrate, and the wetting agent is water. The twice medicine application amount of the ketoprofen sustained-release pellet is 55-65% of the first medicine application amount, and the second medicine application amount is 70-80%. The medicine loading amount refers to the mass fraction of all the components in the medicine loading layer in the ketoprofen sustained-release pellet. The ketoprofen sustained-release pellet is characterized in that release is controlled by adopting a mode of combining a framework material with membrane controlled release, the framework material is added along with a wetting agent in the process of applying medicine, and then the membrane controlled release is carried out through coating, so that the uniform release of the ketoprofen sustained-release pellet is controlled, the release uniformity is greatly increased, and the burst release phenomenon at each time point is reduced;
the ketoprofen accounts for a large amount of ketoprofen sustained-release pellets, more than 65% of the ketoprofen is ketoprofen, so solid powder application is needed in the process, the inherent characteristics of the ketoprofen raw material are very serious electrostatic phenomenon, easy aggregation and agglomeration and difficult forming, and the sustained-release pellets which are uniform in content, smooth in appearance and uniform in release are very difficult to obtain. At present, no reports and patents related to ketoprofen sustained-release pellets exist in China, and some methods related to the ketoprofen sustained-release pellets in the paper are tried and applied to a pilot stage, and large-scale production cannot be performed at all, while foreign patents can finish the medicine coating process through specially modified equipment. The inventor proves through a large number of experiments that the method can obtain pills with uniform content and smooth appearance and can achieve the aim of uniform release only by using a common equipment, namely a centrifugal granulation coating machine, through twice medicine feeding and twice coating and adopting a production process combining framework materials and membrane controlled release, and the medicine feeding speed is very high and is about 100 plus 150 g/min through adjusting the medicine feeding speed and other parameters, but the slow medicine feeding speed can cause the yield to be low due to long medicine feeding time in the invention, and the medicine feeding rate can reach more than 95% through adjusting various parameters of the medicine feeding coating. Through the combination mode, the content uniformity is very good, the production efficiency is higher, and the release is more uniform.
The ketoprofen sustained-release pellet disclosed by the invention has the pellet core content of 16-20%. The content of the main drug in the upper drug layer is 70-80%, and the content of the framework material is 0.4-3.0%. The content of the slow-release framework material in the coating layer is 0.7-3.5%, the content of the plasticizer is 0.4-2.0%, the content of the antisticking agent is 1.0-3.0%, and the content of the oil is 0.4-2.6%. The content means a mass fraction of each solid component in the total of all solid components.
Furthermore, the coating liquid of the coating layer comprises the following components in proportion: 0-30 parts of slow-release film-forming material, 0.5-2.5 parts of plasticizer, 1-4 parts of anti-sticking agent, 2.0-5.0 parts of oil and 80-100 parts of wetting agent.
The invention generally uses a high-shear dispersion emulsifying machine in the process of preparing the coating liquid, and simultaneously, the components of the coating liquid are sheared and dispersed to be uniform, and simultaneously, the oil phase and the water phase are homogenized to form simple emulsion, so that the lubricity is increased, the adhesion phenomenon of pellets in the coating process caused by electrostatic action is improved, and simultaneously, the technology of the invention plays a role of a stabilizer. The ketoprofen sustained-release pellet provided by the invention may not play similar effects in other medicines, and can only play the similar effects when being related to the characteristics of ketoprofen raw materials, and related documents at home and abroad are not reported.
The ketoprofen sustained-release pellet adopts the processes of twice medicine application and twice coating, and the specific processes are as follows: (1) the first medicine applying layer preparation includes weighing pellet core, setting in centrifugal pelletizing and coating machine, weighing ketoprofen material in the grain size of less than 20 microns, regulating the parameters, adding ketoprofen powder while spraying the skeleton material and purified water solution, and matching the medicine adding speed and the liquid spraying speed to ensure the medicine adding speed of 100-150 g/min, low speed to result in material loss, high speed to result in poor content homogeneity and coarse appearance of prepared pellet and to affect the subsequent steps. After the medicine is added, drying the pellets and collecting the pellets with required meshes; (2) preparing a first coating:
preparing a coating solution: weighing the components of each coating solution: stirring for 30 minutes, then shearing for 10-15 minutes by a wetting agent high-shear dispersion emulsifying machine, and keeping the mixture for later use under the stirring state.
Coating: placing the first-time pellet in a centrifugal granulating and coating machine, starting a turntable, adjusting various parameters, controlling the material temperature at 25-45 deg.C, timely adjusting the spray speed according to the material state, and coatingAnd (6) heat treatment. (3) second medicine application: the preparation method is the same as the first medicine application. (4) And (3) coating for the second time: weighing the second pill, and coating the first pill.
The ketoprofen sustained-release pellet prepared by the invention has smooth appearance, uniform release, small inter-particle difference and stable release, and can be finally filled into capsules according to different specifications and dosages to prepare the capsule preparation.
Through a large number of experiments and examination and comparison of typical examples, it can be seen that when the oil occupies a certain proportion in the coating liquid, the electrostatic phenomenon generated in the coating process of the ketoprofen pellet can be reduced, and through twice medicine application and twice coating, the content uniformity and the release uniformity are higher than those of the marketed preparation. The phenomenon and result of pellet coating are better than that of pellets prepared according to the patent proportion of the commercial preparation, and the stability of the coating film is greatly improved. The above effect may not be achieved with other active drug pellets using oil.
The specific implementation mode is as follows:
example 1:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription amount of the embodiment 1, stirring for 45 minutes to prepare a suspension as a binding agent for later use, weighing medicinal pellet cores (sucrose type, 0.35-0.55 mm) of the prescription amount, placing the medicinal pellet cores into a centrifugal granulation coating machine, weighing ketoprofen raw material of the prescription amount, wherein the particle size D90 of the raw material is less than 20 mu m, starting the machine, adjusting various parameters, spraying the binding agent in a spraying manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100 plus one piece, adding the medicine, drying until the water content is less than or equal to 3.0 percent, collecting pellets of the required mesh number, and carrying out the next step. (2) Preparing a first coating: weighing each coating liquid component according to the proportion and the prescription in the embodiment 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standby under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid-spraying speed according to the material state, and carrying out heat treatment after coating. (3) second medicine application: weighing Eudragit NE30D and purified water according to the prescription in the example 1, stirring for 45 minutes for standby, placing the first coated pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription in the example 1, starting the machine, adjusting various parameters, adding adhesive in a spray manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, performing the same preparation method as the first medicine application, drying until the water content is less than or equal to 3.0%, and collecting the pellets with the required mesh number for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the example 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating.
Example 1
Example 2:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription of the embodiment 2, stirring for 45 minutes to prepare a suspension as a binder for standby, weighing a medicinal pellet core (microcrystalline cellulose pellet core, 0.35-0.55 mm) of the prescription, placing the medicinal pellet core in a centrifugal granulation coating machine, weighing a ketoprofen raw material of the prescription, wherein the particle size D90 of the raw material is less than 20 mu m, starting the machine, adjusting various parameters, adding the binder in a spraying manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100 plus, drying after the medicine adding is finished until the moisture is less than or equal to 3.0%, collecting pellets of required meshes, and carrying out the next step. (2) Preparing a first coating: weighing each coating liquid component according to the example 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) second medicine application: weighing Eudragit NE30D and purified water according to the prescription of the embodiment 2, stirring for 45 minutes for standby, placing the first coating pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of the embodiment 1, starting the machine, adjusting various parameters, adding an adhesive in a spraying manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished, drying until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the example 2, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating.
Example 3:
(1) preparing a first medicine applying layer: weighing hypromellose (5 cp) and purified water according to the prescription in the embodiment 3, stirring for 45 minutes to prepare a solution as an adhesive for standby, weighing a blank pellet core (starch type, particle size: 0.5-0.6 mm) for medical use according to the prescription, placing the blank pellet core in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription, wherein the particle size D90 of the raw material is less than 20 mu m, starting the machine, adjusting various parameters, adding the adhesive in a spraying manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100 plus materials, adding the medicine, drying until the water content is less than or equal to 3.0%, and collecting pellets with required meshes for the next step. (2) Preparing a first coating: weighing each coating liquid component according to the example 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) second medicine application: weighing Eudragit NE30D and purified water according to the prescription of the embodiment 3, stirring for 45 minutes for standby, placing the first coating pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of the embodiment 1, starting the machine, adjusting various parameters, adding an adhesive in a spraying manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished, drying until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the example 3, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating.
Example 4:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription of example 4, stirring for 45 minutes to prepare a suspension as a binder for standby, weighing a medicinal pellet core (sucrose type, 0.8-1.0 mm) of the prescription, placing the medicinal pellet core in a centrifugal granulation coating machine, weighing a ketoprofen raw material of the prescription, wherein the particle size D90 of the raw material is less than 20 microns, starting the machine, adjusting various parameters, adding the binder in a spray manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100-. (2) Preparing a first coating: weighing each coating liquid component according to the example 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) second medicine application: weighing Eudragit NE30D and purified water according to the prescription in the example 1, stirring for 45 minutes for standby, placing the first coating pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription in the example 1, starting the machine, adjusting various parameters, adding an adhesive in a spray manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished, drying until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the example 4, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating.
Example 5:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription of example 5, stirring for 45 minutes to prepare a suspension as a binder for standby, weighing a medicinal pellet core (starch type, 0.7-0.8 mm) of the prescription, placing the medicinal pellet core in a centrifugal granulation coating machine, weighing a ketoprofen raw material of the prescription, wherein the particle size D90 of the raw material is less than 20 microns, starting the machine, adjusting various parameters, adding the binder in a spray manner, controlling various parameters according to actual conditions, controlling the drug adding speed at 150 g/min of 100-. (2) Preparing a first coating: weighing each coating liquid component according to the example 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) second medicine application: weighing Eudragit NE30D and purified water according to the prescription of example 5, stirring for 45 minutes for standby, placing the first coated pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of example 5, starting the machine, adjusting various parameters, adding an adhesive in a spray manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished, drying until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the example 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating.
Example 6:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription of example 6, stirring for 45 minutes to prepare a suspension as a binder for standby, weighing a medicinal pellet core (sucrose type, 0.5-0.6 mm) of the prescription, placing the medicinal pellet core in a centrifugal granulation coating machine, weighing a ketoprofen raw material of the prescription, wherein the particle size D90 of the raw material is less than 20 microns, starting the machine, adjusting various parameters, adding the binder in a spray manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100-. (2) Preparing a first coating: weighing each coating liquid component according to the example 6, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) second medicine application: weighing Eudragit NE30D and purified water according to the prescription of example 6, stirring for 45 minutes for standby, placing the first coated pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of example 1, starting the machine, adjusting various parameters, adding an adhesive in a spray manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the example 6, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating.
Example 7:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription of example 7, stirring for 45 minutes to prepare a suspension as a binder for later use, weighing a medicinal pellet core (sucrose type, 0.8-1.0 mm) of the prescription, placing the medicinal pellet core in a centrifugal granulation coating machine, weighing a ketoprofen raw material of the prescription, wherein the particle size D90 of the raw material is less than 20 microns, starting the machine, adjusting various parameters, adding the binder in a spray manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100-. (2) Preparing a first coating: weighing each coating liquid component according to the example 7, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) second medicine application: weighing Eudragit NE30D and purified water according to the prescription of example 7, stirring for 45 minutes for standby, placing the first coated pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of example 7, starting the machine, adjusting various parameters, adding an adhesive in a spray manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: taking each coating liquid component according to the example 7, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating.
Example 8:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription in example 8, stirring for 45 minutes to prepare a suspension as a binder for later use, weighing a medicinal pellet core (sucrose type, 0.5-0.6 mm) of the prescription, placing the medicinal pellet core in a centrifugal granulation coating machine, weighing a ketoprofen raw material of the prescription, wherein the particle size D90 of the raw material is less than 20 microns, starting the machine, adjusting various parameters, adding the binder in a spray manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100-. (2) Preparing a first coating: taking each coating liquid component according to the example 8, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) second medicine application: weighing Eudragit NE30D and purified water according to the prescription of the embodiment 8, stirring for 45 minutes for standby, placing the first coating pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of the embodiment 8, starting the machine, adjusting various parameters, adding an adhesive in a spraying manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished, drying until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the embodiment 8, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating.
Example 9:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription in example 9, stirring for 45 minutes to prepare a suspension as a binder for standby, weighing a medicinal pellet core (sucrose type, 0.5-0.6 mm) according to the prescription, placing the medicinal pellet core in a centrifugal granulation coating machine, weighing a ketoprofen raw material according to the prescription, wherein the particle size D90 of the raw material is less than 20 microns, starting the machine, adjusting various parameters, adding the binder in a spray manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min, drying after the medicine adding is finished, drying until the water content is less than or equal to 3.0%, and collecting pellets with required meshes for the next step. (2) Preparing a first coating: weighing each coating liquid component according to the example 9, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) And (3) medicine application for the second time: weighing Eudragit NE30D and purified water according to the prescription of example 9, stirring for 45 minutes for standby, placing the first coated pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of example 9, starting the machine, adjusting various parameters, adding an adhesive in a spray manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished, drying until the moisture of the pellets is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: taking each coating liquid component according to the example 9, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after the coating is finished.
Example 10:
(1) preparing a first medicine applying layer: weighing Eudragit NE30D and purified water according to the prescription of example 10, stirring for 45 minutes to prepare a suspension as a binder for standby, weighing a medicinal pellet core (sucrose type, 0.5-0.6 mm) of the prescription, placing the medicinal pellet core in a centrifugal granulation coating machine, weighing a ketoprofen raw material of the prescription, wherein the particle size D90 of the raw material is less than 20 microns, starting the machine, adjusting various parameters, adding the binder in a spray manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100-. (2) Preparing a first coating: taking each coating liquid component according to the example 10, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) And (3) medicine application for the second time: weighing Eudragit NE30D and purified water according to the prescription of the embodiment 10, stirring for 45 minutes for standby, placing the first-time coated pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of the embodiment 10, starting the machine, adjusting various parameters, adding an adhesive in a spraying manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed to be 100-150 g/min, drying after the medicine adding is finished, drying until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the embodiment 10, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after the coating is finished.
Example 11:
(1) preparing a first medicine applying layer: eudragit NE30D and purified water are weighed according to the prescription in example 11, mixed for 45 minutes to prepare a suspension as a binder for standby, a medicinal pellet core (sucrose type, 0.5-0.6 mm) is weighed and placed in a centrifugal granulation coating machine, a ketoprofen raw material with the prescription is weighed, the particle size D90 of the raw material is less than 20 microns, the machine is started, various parameters are adjusted, the binder is added by spraying, various parameters are controlled according to actual conditions, the medicine adding speed is controlled at 150 g/min of 100-. (2) Preparing a first coating: weighing each coating liquid component according to the example 11, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) And (3) medicine application for the second time: weighing Eudragit NE30D and purified water according to the prescription of the embodiment 11, stirring for 45 minutes for standby, placing the first coating pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of the embodiment 11, starting the machine, adjusting various parameters, adding an adhesive in a spraying manner, simultaneously controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished, drying until the water content is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to the example 11, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after the coating is finished.
Example 12:
the release results of example 1 of marketed ketoprofen slow release capsules in US 6613361B 1 are substantially identical to those of marketed ketoprofen slow release capsules, so we coated the weight ratio of the coating ingredients in example 1 (Eudragit RS 30D: Eudragit RL 30D: trietyl citrate: aerosol 200: talc ═ 1.83%: 0.21%: 0.40%: 0.49%), comparing with other examples of the present invention, the process still uses twice-coating of the present invention, the preparation method is as follows
(1) The first preparation of the upper medicine layer comprises the steps of weighing Eudragit NE30D and purified water according to the prescription amount in the example 12, stirring for 45 minutes to prepare a suspension as a binder for later use, weighing the medicinal pellet cores (sucrose type, 0.5-0.6 mm) of the prescription amount in a centrifugal granulation coating machine, weighing the ketoprofen raw material of the prescription amount, wherein the particle size D90 of the raw material is less than 20 mu m, starting the machine, adjusting various parameters, adding the binder in a spraying manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100-. (2) Preparing a first coating: weighing each coating liquid component according to the example 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) And (3) medicine application for the second time: weighing Eudragit NE30D and purified water according to the prescription of the embodiment 1, stirring for 45 minutes for standby, placing the first coating pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of the embodiment 1, starting the machine, adjusting various parameters, adding an adhesive in a spraying manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 150 g/min of 100-. (4) And (3) coating for the second time: weighing each coating liquid component according to the example 12, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the second-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after the coating is finished.
Example 13:
the coating solution of example 1 in US patent 6613361B 1 contains increased amounts of talc and colloidal silica as anti-sticking agents, and the coating solution is coated twice with the two-time medicine application of the present invention.
(1) The first preparation of the medicine applying layer comprises weighing Eudragit NE30D and purified water according to the prescription amount in example 13, stirring for 45 minutes to prepare a suspension as a binder for standby, weighing the medicinal pellet cores (sucrose type, 0.5-0.6 mm) according to the prescription amount, placing the medicinal pellet cores into a centrifugal granulation coating machine, weighing the ketoprofen raw material according to the prescription amount, wherein the particle size D90 of the raw material is less than 20 mu m, starting the machine, adjusting various parameters, adding the binder by spraying, controlling various parameters according to the actual situation, controlling the medicine adding speed at 150 g/min of 100 minus one plus. (2) Preparing a first coating: weighing each coating liquid component according to the example 1, firstly stirring for 30 minutes, then shearing for 10-15 minutes by a high shear dispersion emulsifying machine, standing by under the stirring state, placing the first-time medicine-applying pellets in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and carrying out heat treatment after coating. (3) And (3) medicine application for the second time: weighing Eudragit NE30D and purified water according to the prescription of the embodiment 13, stirring for 45 minutes for standby, placing the first coating pellets in a centrifugal granulation coating machine, weighing ketoprofen raw material according to the prescription of the embodiment 1, starting the machine, adjusting various parameters, adding an adhesive in a spraying manner, controlling various parameters according to actual conditions, controlling the medicine adding speed at 100-150 g/min, drying after the medicine adding is finished, drying until the moisture of the pellets is less than or equal to 3.0%, and collecting the pellets with required meshes for the next process. (4) And (3) coating for the second time: weighing each coating liquid component according to example 13, stirring for use, placing the second pill in a centrifugal granulation coating machine, starting the machine to adjust various parameters, controlling the material temperature at 25-45 ℃, timely adjusting the liquid spraying speed according to the material state, and performing heat treatment after coating.
Example 14:
examples 1-13 were examined for release and compared to the marketed formulation. The specific implementation method comprises the following steps: the dissolution rate determination method comprises the following steps: taking the product, encapsulating according to the specification of 0.2g for measurement, measuring according to a release rate measuring method (a first method of appendix X D of the second part of 2010 edition of Chinese pharmacopoeia), adopting a device of the second method of the dissolution rate measuring method, taking 900ml of phosphate buffer solution with the pH value of 6.9 as a dissolution medium, performing a slurry method at the rotating speed of 75 revolutions per minute, operating according to the method, measuring the absorbance at the wavelength of 260nm by using 0.5, 1, 2, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18 and 24 hours, and sampling 10 ml by using a spectrophotometry method (appendix IV A of the second part of 2010 edition of Chinese pharmacopoeia), measuring and calculating the release rate of 12 granules at each time point by using an external standard method, and finally evaluating by using a release rate result, a similar factor and an RSD value of release uniformity. The results are shown in the attached tables III and IV. The results show that: the dissolution release of the invention can achieve the release effect similar to that of the preparation on the market. The observation result of the coating process phenomenon shows that: examples 1, 2, 3, 4, 5, 6, 7 and 10, which use the coating solution of the present invention, have been found to exhibit a low blocking phenomenon during coating and a release similar to that of the commercially available preparations. Examples 8, 9, 11, in which oil was used in a smaller, larger or non-added amount, resulted in coating adhesion, and examples 8, 9, 11 were only typical examples in which oil was present in the coating solution in an amount of 2-5% (w/w) except for slow release film material, and were not included in the screening process, although more slow release film forming material was added, the release was not similar to that of the commercial preparations. Examples 12 and 13 refer to the coating solution components and proportions patented by the manufacturers of the commercial preparations, and since colloidal silica is used, the adhesion phenomenon is improved in the coating process, and the adhesion does not cause film breakage, so that the release can be close to that of the commercial preparations, but from the release uniformity, the thickness of the film is not uniform due to the adhesion, and the release uniformity is poor.
Example 15:
the processes of examples 1 to 13 were monitored, the coating phenomenon was observed and evaluated, the contents of the drug in each layer and the uniformity of the contents of the final pellets were comprehensively analyzed, and the bulk density of the finally obtained pellets was measured. The specific implementation method comprises the following steps: (1) content uniformity: taking 10 samples of each of the first application and the second application of each example, grinding the samples respectively, precisely weighing an appropriate amount (about 60mg of ketoprofen), placing the samples in a 200ml measuring flask, adding about 150ml of water-methanol (1:3), sufficiently shaking to dissolve the ketoprofen, adding water-methanol (1:3) to dilute the solution to a scale, shaking uniformly, filtering, precisely weighing an appropriate amount of subsequent filtrate, adding about 6 mug of the solution in each 1ml of the solution, measuring the absorbance at the 257nm wavelength according to a spectrophotometry (appendix IV A of the second part of the 2010 edition of Chinese pharmacopoeia, precisely weighing an appropriate amount of a ketoprofen control which is dried to a constant weight under reduced pressure at 60 ℃, adding about 6 mug of the solution in each 1ml of the solution, measuring the absorbance by the same method, calculating the content of each sample by an external standard method, the Relative Standard Deviation (RSD) of the content was calculated for each example as content uniformity, and evaluated. (2) Bulk density: the final sample of each example was weighed into a 10 ml measuring cylinder, the 10 ml sample was weighed, the bulk density was calculated, and a comparison of each example was made. The results are shown in the attached tables I and II. The results show that: the bulk density of the final product without oil in the coating solution and with the proportion of oil in the coating solution out of the range in the examples can meet the requirements, but the bulk density is smaller than that of the example with the oil in the range (2-5%) in the coating solution, and the content uniformity of the obtained pellets is better than that of a reference preparation after a certain amount (2-5%) of oil is added in the coating solution.
Example 16:
the stability of the coatings of examples 1-13 was evaluated in combination, and the results are shown in the accompanying table five, wherein each example was examined for 3 and 6 months at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 5%, respectively, and the change of the release rate of each example under the conditions was examined, and compared with the release rate of each example at 0 month.
The results show that: the stability of the sustained-release coating film is greatly improved by adding oil in the coating liquid, but the stability of the examples (the examples 8 and 9 are less than 2 percent, and the example 11 is more than 5 percent) outside the range does not reach the expected value within a certain range, and the small stability is better than that of the coating liquid according to the examples of the U.S. patent after coating.
Example 17:
in examples 1-13, the appearance of pellets obtained from each coating was observed during two coating processes, and the adhesion phenomenon during the coating process was evaluated by the method shown in the attached table, i.e., the small notes, and the results shown in the attached table, i.e., the oil added to the coating solution in a certain range was used to improve the coating appearance and the adhesion phenomenon due to static electricity.
Table one observation of double coating phenomena in each example
Note: the appearance symbol represents: the method comprises the following steps of: + + + +; appearance: bright and clean ++; appearance: generally, the finish is poor;
the blocking phenomenon is symbolized as: adhesion is less than 2%: + + + + +; adhesion 2-5%, + + +; ③ 5-9% of adhesion phenomenon, and ++; (ii) a The blocking phenomenon is more than 10%: +.
Table two measurement results of drug content, final uniformity and bulk density of each layer of the examples
Table three examples cumulative release results:
injecting: the smaller the f2 value compared to the marketed formulation, the less similar the indication, and meeting above 50 demonstrates similarity.
TABLE four 12 granule Release homogeneity
(determination of% in capsules of size 0.2 g)
TABLE V results of the stability study of the film after coating (accelerated test, similar factor f2 compared to 0 month)
| Compared with 0 month | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | Example 8 | Example 9 | Example 10 | Example 11 | Example 12 | Example 13 |
| 3 months old | 98.6 | 98.4 | 98.8 | 98.7 | 98.1 | 99.5 | 98.4 | 75.2 | 74.1 | 97.7 | 79.6 | 94.5 | 95.6 |
| 6 months old | 98.5 | 98.8 | 98.7 | 98.9 | 98.5 | 99.1 | 95.8 | 52.3 | 56.8 | 94.6 | 55.1 | 85.5 | 82.1 |
Claims (6)
1. A ketoprofen sustained-release pellet is characterized by consisting of a blank pellet core, two medicine applying layers and two coating layers; the upper medicine layer consists of ketoprofen as a main medicine, a framework material and a wetting agent; the coating layer is composed of a slow-release film-forming material, a plasticizer, an anti-sticking agent, a wetting agent and oil; the oil is soybean oil, peanut oil or medium-chain fatty acid triglyceride, and the content of the oil is 0.5 to 2.5 percent.
2. The ketoprofen sustained-release pellet according to claim 1, wherein the pellet core is a sucrose pellet core or a microcrystalline cellulose pellet core, and the content of the pellet core is 16-20%.
3. The ketoprofen sustained-release pellet as claimed in claim 1, wherein the content of the main drug ketoprofen is 70-80%, and the content of the matrix material is 0.4-3.0%.
4. The ketoprofen sustained-release pellet according to claim 1, wherein the sustained-release film-forming material is contained in an amount of 0.7 to 3.5%, the plasticizer is contained in an amount of 0.5 to 2.0%, and the anti-adhesion agent is contained in an amount of 1.0 to 3.0%.
5. The ketoprofen sustained-release pellet according to claim 1, wherein each coating layer comprises the following components in percentage by weight: 0-30 parts of slow-release film-forming material, 0.5-2.5 parts of plasticizer, 1-4 parts of anti-sticking agent, 2.0-5.0 parts of oil and 80-100 parts of wetting agent.
6. The ketoprofen sustained-release pellet according to claim 1, wherein the sustained-release film-forming material is one or a combination of Eudragit RL30D or Eudragit rs 30D; the anti-sticking agent is talcum powder, and the plasticizer is triethyl citrate; the wetting agent is purified water; the oil is soybean oil, peanut oil or medium-chain fatty acid triglyceride.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6613361B1 (en) * | 1999-04-22 | 2003-09-02 | Laboratoires Des Produits Ethiques Ethypharm | Ketoprofen microgranules, method for preparing same and pharmaceutical compositions |
| CN101279091A (en) * | 2007-04-04 | 2008-10-08 | 常州市第四制药厂有限公司 | Pancreatic enzymes enteric coated pellets and preparation |
| CN103989638A (en) * | 2014-04-29 | 2014-08-20 | 常州市第四制药厂有限公司 | Mesalazine slow-release granules and preparation method thereof |
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2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6613361B1 (en) * | 1999-04-22 | 2003-09-02 | Laboratoires Des Produits Ethiques Ethypharm | Ketoprofen microgranules, method for preparing same and pharmaceutical compositions |
| CN101279091A (en) * | 2007-04-04 | 2008-10-08 | 常州市第四制药厂有限公司 | Pancreatic enzymes enteric coated pellets and preparation |
| CN103989638A (en) * | 2014-04-29 | 2014-08-20 | 常州市第四制药厂有限公司 | Mesalazine slow-release granules and preparation method thereof |
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