CN115487162A - Preparation method of isosorbide mononitrate sustained-release tablets - Google Patents
Preparation method of isosorbide mononitrate sustained-release tablets Download PDFInfo
- Publication number
- CN115487162A CN115487162A CN202211253863.0A CN202211253863A CN115487162A CN 115487162 A CN115487162 A CN 115487162A CN 202211253863 A CN202211253863 A CN 202211253863A CN 115487162 A CN115487162 A CN 115487162A
- Authority
- CN
- China
- Prior art keywords
- mixing
- isosorbide mononitrate
- coating
- tablet
- speed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of an isosorbide mononitrate sustained-release tablet, which comprises the following steps: preparing materials: uniformly mixing isosorbide mononitrate and calcium hydrophosphate in a mass ratio of 1:1 to obtain a premix; (2) granulating: premixing hydroxypropyl methylcellulose, microcrystalline cellulose, premix, ethyl cellulose and calcium hydrogen phosphate in a wet mixing granulator for 300S, mixing for the second time for 600S after premixing is finished, starting a peristaltic pump after the second mixing is finished, adding purified water in an atomizing and liquid adding manner, and discharging to obtain wet granules; (3) drying: drying the wet granules until the weight loss is 2.5% -3.5%; (4) finishing the grains: granulating the dried granules by using a granulator; (5) total mixing: mixing the granules and hydroxypropyl methylcellulose at a speed of 8r/min for 5 minutes, adding magnesium stearate and silicon dioxide, and mixing at a speed of 8r/min for 5 minutes to obtain a total mixed material; (6) tabletting; (7) coating; (8) inner packaging; and (9) packaging.
Description
Technical Field
The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of an isosorbide mononitrate sustained-release tablet.
Background
Isosorbide mononitrate (ISMN) is the main biologically active metabolite of isosorbide mononitrate, the main pharmacological effect being relaxation of vascular smooth muscle. ISMN releases Nitric Oxide (NO), which, like endothelial relaxant, activates guanylate cyclase, increasing cyclic guanylate (cGMP) in smooth muscle cells, thereby relaxing vascular smooth muscle, dilating peripheral arteries and veins, and having a stronger effect on the dilation of veins. Venous dilation causes blood retention in the periphery, a reduction in the volume of return blood, a reduction in left ventricular diastolic pressure and pulmonary capillary wedge pressure (preload). The coronary artery dilates to increase the amount of coronary perfusion. The overall effect is to decrease myocardial oxygen consumption, increase oxygen supply and relieve angina pectoris. However, the existing isosorbide mononitrate sustained-release tablets have short action time and poor dissolution behavior.
Disclosure of Invention
In order to solve the problems in the prior art, the application provides a preparation method of an isosorbide mononitrate sustained-release tablet, which is realized by the following scheme:
a preparation method of isosorbide mononitrate sustained-release tablets comprises the following steps: preparing materials: mixing isosorbide mononitrate and calcium hydrophosphate in a mass ratio of 1:1 at the rotating speed of 8rpm for 5min, crushing the mixed materials by a crusher to pass through a 60-mesh sieve, and then mixing at the rotating speed of 8rpm for 5min to obtain a premix; and (2) granulating: premixing hydroxypropyl methylcellulose, microcrystalline cellulose, premix, ethyl cellulose and calcium hydrogen phosphate in a wet mixing granulator for 300S, cleaning the inner wall of the wet mixing granulator after premixing, mixing for 600S for the second time, starting a peristaltic pump after the mixing for the second time is finished, adding purified water in an atomizing and liquid adding manner, and discharging to obtain wet granules; (3) drying: drying the wet granules until the weight loss is 2.5% -3.5%; (4) finishing the grains: granulating the dried granules by using a granulator; (5) total mixing: mixing the granules and hypromellose at 8r/min for 5min, adding magnesium stearate and silicon dioxide, and mixing at 8r/min for 5min to obtain total mixtureFeeding; (6) tabletting: use of
The circular shallow concave punch presses the total mixed material to obtain a tablet core; (7) coating: installing and connecting a peristaltic pump and a spray gun system, starting compressed air, adjusting a switch of the spray gun to enable sprayed coating liquid to be in a mist shape and a fan shape, adding a tablet to be coated into a coating pot after the spray gun system is well adjusted, starting the coating pot to preheat a tablet core, adjusting the position of the spray gun to enable the spray gun to be perpendicular to a tablet bed and to be 25-40cm away from the tablet bed, starting the peristaltic pump and the spray gun to perform initial coating after the tablet core is preheated for about 10min, increasing the rotating speed and the speed of the peristaltic pump to deepen the coating after the coating is coated for 20-30 min, controlling the temperature of the tablet bed to be 30-45 ℃, increasing the weight of the coating by 2-4%, stopping spraying the liquid, reducing the rotating speed, closing the heating, still starting an air inlet and exhaust system, enabling the coating pot to continuously rotate until the temperature of the tablet bed is consistent with the room temperature and the tablet is dried, and installing a discharging device to obtain the isosorbide mononitrate sustained release tablet; (8) inner packaging: packing with solid medicinal hard polyvinyl chloride/polyvinylidene chloride sheet and medicinal aluminum foil bubble cap; (9) external packing: putting the isosorbide mononitrate sustained release tablets subjected to inner packaging and an instruction into a paper box.
Preferably, the mass ratio of the hypromellose, the microcrystalline cellulose, the premix, the ethylcellulose and the calcium hydrophosphate in the step (2) is 4.5-5.5:7-8:18-22:3-3.5:15-20; the pre-mixing setting parameters are as follows: chopping (800 rpm), stirring (120 rpm); the parameters set by the secondary mixing are as follows: chopping (1800 rpm), stirring speed (200 rpm); the rotating speed of the peristaltic pump is 85-95rpm, the pressure of the atomized liquid is 0.3Mpa, and the time of the atomized liquid is 600S; the mass ratio of the purified water to the premix is 8-10.
Further, in the step (2), the mass ratio of the hydroxypropyl methylcellulose, the microcrystalline cellulose, the premix, the ethyl cellulose and the calcium hydrophosphate is 5.09:7.5:20:3.25:17.64 of; the mass ratio of the purified water to the premix is 9.
Further, the drying temperature in the step (3) is 50-55 ℃.
Furthermore, the aperture of the whole screen mesh in the step (5) is 2mm, and the rotating speed is 500 r/min.
Furthermore, the mass ratio of the hypromellose, magnesium stearate and silicon dioxide added in the step (5) to the isosorbide mononitrate added in the step (1) is 65-70:1.8-2.2:1.8-2.2:45-55.
Furthermore, the mass ratio of the hydroxypropyl methylcellulose, the magnesium stearate and the silicon dioxide added in the step (5) to the isosorbide mononitrate added in the step (1) is 67.85:2:2:50.4.
furthermore, the feeding speed during tabletting in the step (6) is 55-65 rpm, the pressure during tabletting is 13-32 KN, and the tabletting speed is 8-10 ten thousand tablets per hour on a single track.
Further, the coating solution used in the step (7) is prepared as follows: adding the coating powder into purified water, stirring for 45min, and preparing coating solution with mass concentration of 8-12% and sieving with 120 mesh sieve; the preheating process is characterized in that the rotating speed of a coating pan is set to be 2-5 rpm, and the air inlet temperature is set to be 50-70 ℃; the atomization pressure of the initial coating is 0.5-0.7MPa, and the speed of a peristaltic pump is 1.5-4 rpm; when the coating is deepened, the rotating speed of a coating pan is 2-7 rpm, and the speed of a peristaltic pump is 1.5-8 rpm.
Furthermore, the upper heating temperature of the inner packaging and packaging machine in the step (8) is 100-120 ℃, the lower heating temperature is 118-138 ℃, the heat sealing temperature is 180-200 ℃, and the batch number temperature is 150-170 ℃.
After the step (5) is finished, calculating the balance rate of the total mixed materials to be 97-100% and the yield to be 96-100%;
after the step (6) is finished, calculating the balance rate of the tablet core to be 98-100% and the yield to be 97-100%;
after the step (7) is finished, calculating the equilibrium rate of the isosorbide mononitrate sustained release tablets to be 95-100% and the yield to be 95-100%;
after the step (9) is finished, calculating the balance rate of the total raw materials to be 93-100%;
the company for calculating the material balance rate and yield of the application is as follows:
material balance rate = (weight of material after treatment + weight of waste product)/weight of material before treatment x 100%;
yield = weight of material after treatment/weight of material before treatment × 100%.
Has the advantages that: (1) The isosorbide mononitrate sustained-release tablet prepared by the application has long dissolution time, an aqueous medium is used as a dissolution medium, dissolution investigation is carried out by adopting a basket method at 50 revolutions per minute, and the dissolution amounts of the compressed tablet at 1 hour, 4 hours and 8 hours are respectively marked
And 75%;
(2) The isosorbide mononitrate sustained release tablet can quickly take effect at the early administration stage, and can maintain effective blood concentration after reaching the effective blood concentration;
(3) By adding magnesium stearate and silicon dioxide, the problems of sticking and low tablet hardness in the tabletting process are avoided, the stability of the effective components is improved, the stability of the medicine can be effectively improved, and the release effect is optimized;
(4) The method has reasonable design, and obtains high equilibrium rate and high yield by optimizing the preparation process.
Detailed Description
To make the objects, technical solutions and advantages of the present application more clear, the following detailed description will be made of embodiments of the present application.
Example 1
A preparation method of isosorbide mononitrate sustained-release tablets is characterized by comprising the following steps:
(1) Preparing materials: mixing 50kg of isosorbide mononitrate and 50kg of calcium hydrogen phosphate at the rotating speed of 8rpm for 5min, crushing the mixed materials by a crusher, sieving the crushed materials with a 60-mesh sieve, and then mixing the crushed materials at the rotating speed of 8rpm for 5min to obtain a premix;
(2) And (3) granulating: 25.45kg of hypromellose, 37.5kg of microcrystalline cellulose, 100.0kg of premix, 16.25kg of ethyl cellulose and 88.2kg of calcium hydrophosphate are premixed in a wet mixing granulator for 300S, and the set parameters are 'chopping (800 rpm) and stirring (120 rpm)'; after premixing, cleaning the inner wall of the wet mixing granulator, secondarily mixing for 600S, setting parameters of cutting (1800 rpm) and stirring speed (200 rpm), starting a peristaltic pump after secondary mixing is finished, adding 45kg of purified water in an atomizing liquid adding mode (the pressure is 0.3 Mpa), and discharging to obtain wet granules;
(3) And (3) drying: putting the wet granules into a drying hopper of an intelligent boiling granulator, setting the air inlet temperature to be 55 ℃, and drying until the weight loss is 3%;
(4) Straightening: granulating the dried granules by using a granulator, wherein the aperture of a screen is 2mm, and the rotating speed is 500 r/min;
(5) Total mixing: mixing the granules and hydroxypropyl methylcellulose at a speed of 8r/min for 5 minutes, adding magnesium stearate and silicon dioxide, and mixing at a speed of 8r/min for 5 minutes to obtain a total mixed material; detecting the mixed particles, wherein the properties of the particles are white or white-like particles or powder, the appearance of the particles is free from foreign points, and the content of isosorbide mononitrate (C6H 9NO 6) in the particles is 140.1-154.7 mg/g;
(6) Tabletting: tabletting the total mixed material by using a round dimple punch with phi =8mm to obtain a tablet core with isosorbide mononitrate content of 40mg, wherein the feeding speed during tabletting is 55-65 rpm, the pressure during tabletting is 13-32 KN, and the tabletting speed is 8-10 ten thousand tablets per hour of single track; the hardness of the tablet obtained by tabletting is 70-110N, the weight difference is +/-5%, the friability is less than or equal to 1%, and the dissolution amount of each tablet in 1 hour, 4 hours and 8 hours is respectively marked after the tabletting is finished by sampling and detecting
And 75%, in the tabletting process, 10 tablets are taken from each tablet outlet every 30min to detect the properties, appearance, tablet weight and weight difference of the isosorbide mononitrate sustained-release tablets; in addition, after each shutdown and when process parameters are changed, properties, appearance, weight difference, hardness and friability are checked, and if abnormal conditions occur, deviation programs need to be executed;
and (3) dissolution rate determination: taking an aqueous medium as a dissolution medium, and performing dissolution investigation by adopting a basket method at 50 revolutions per minute;
(7) Coating: adding coating powder into purified water, stirring for 45min, preparing coating liquid with the mass concentration of 8-12% and passing through a 120-mesh sieve, installing and connecting a peristaltic pump and a spray gun system, starting compressed air, adjusting the spray gun to enable the sprayed coating liquid to be in a mist shape and a fan shape, adding tablets to be coated into a coating pan after the spray gun system is adjusted, starting the coating pan to preheat tablet cores, setting the rotation speed of the coating pan to be 2-5 rpm and the inlet air temperature to be 50-70 ℃ in the preheating process, adjusting the position of the spray gun to enable the spray gun to be perpendicular to a tablet bed and to be 25-40cm away from the tablet bed, starting the peristaltic pump and the spray gun after the tablet cores are preheated for about 10min, controlling the atomization pressure to be 0.5-0.7MPa, controlling the peristaltic pump speed to be 1.5-4 rpm, increasing the rotation speed and the peristaltic speed of the coating pan and the peristaltic pump after the coating is 20-30 min, enabling the rotation speed of the coating pan to be 2-7 rpm and the pump speed to be 1.5-8 rpm, controlling the tablet bed temperature of the tablet bed to be 30-45 ℃, controlling the coating pan to be 2-4% and achieving the required appearance weight gain, stopping, turning off, continuing to turn on the heating system, and installing a spray gun to enable the spray drying device to be consistent with the temperature of the isosorbide tablet cores to be the tablet cores, and installing of the single spray gun, and drying device, and obtaining the isosorbide tablet;
(8) Inner packaging: packing the solid medicinal composite hard sheet of polyvinyl chloride/polyvinylidene chloride and the medicinal aluminum foil blister by a packing machine, wherein the upper heating temperature of the packing machine is 100-120 ℃, the lower heating temperature is 118-138 ℃, the heat sealing temperature is 180-200 ℃, and the batch temperature is 150-170 ℃; production operators check the appearance, batch number and validity period every 30 minutes until the printing condition is reached, and reject out unqualified products in time and store the unqualified products separately;
(9) And (3) outer packaging: putting the isosorbide mononitrate sustained-release tablets subjected to inner packaging and an instruction into a paper box.
After the step (5) is finished, calculating the balance rate of the total mixed materials = (total mixed materials + waste product weight)/(whole granules + hypromellose + magnesium stearate + silicon dioxide) to be 99%, and the yield is 97%;
after the step (6) is finished, calculating the equilibrium rate of the tablet core to be 99 percent and the yield to be 98 percent;
after the step (7), calculating that the equilibrium rate of the isosorbide mononitrate sustained-release tablets is 99% and the yield is 98%;
and (4) calculating the equilibrium rate of the total raw materials to be 99% after the step (9) is finished.
Evaluation of biological equivalent research result of isosorbide mononitrate sustained-release tablets
Through the bioequivalence research of the isosorbide mononitrate sustained-release tablet on one of Chinese adult healthy subjects, wherein the isosorbide mononitrate sustained-release tablet is administered randomly, openly, fasting and once after meal, two preparations, two sequences and two cycles are crossed, the pharmacokinetic parameters of the two preparations are analyzed, the bioequivalence and the safety of the two preparations are evaluated, and a reference basis is provided for the declaration and clinical medication of the isosorbide mononitrate sustained-release tablet.
1. Fasting bioequivalence research results
Fasting test a total of 28 subjects (14 in each of the TR and RT groups) were included and all completed the two-cycle test. All 28 subjects were included in the total analysis set (FAS), safety analysis set (SS), PK concentration set (PKCS), PK parameters set (PKPS), and equivalence analysis set (BES).
Equivalence analysis Using the ABE method, the AUC of the proto-drug isosorbide mononitrate in the plasma of 28 subjects enrolled in the BES pool 0-t 、AUC 0-∞ And C max The 90% confidence interval of the Geometric Mean Ratio (GMR) of the test and reference formulations of (A) falls well within the bioequivalent acceptable range of 80.00% to 125.00%, AUC 0-t 、AUC 0-∞ 、C max The 90% confidence intervals for the Geometric Mean Ratio (GMR) are in order: 91.00% -96.25%, 91.14% -96.44% and 88.64% -95.64%. The results show that: after the test preparation and the reference preparation are taken by a subject in a single dose or a single time in an oral way in the fasting state, the two preparations have bioequivalence.
28 subjects who included the fasting test SS group had 12 (42.86%, 12/28) and 14 AEs together during the study, with 4 (14.29%, 4/28) and 4 AEs together in subjects taking the test formulation and 9 (32.14%, 9/28) and 10 in subjects taking the reference formulation. Of these, 6 (21.43%, 6/28) 7 AE cases were judged to be possibly unrelated to the causal relationship between the test drugs, and 1 (3.57%, 1/28) 2 AE cases and 5 (17.86%, 5/28) 5 AE cases were judged to be positively related and possibly related to the test drugs. The vast majority (32.14%, 9/28, 10 occurrences) of AEs were mild, only 3 (10.71%, 3/28) of 4 of the 4-moderate AEs occurred, and no AEs and SAEs resulting in subject withdrawal occurred. All AEs were followed to "improve/alleviate" or "recovered/healed". The result shows that the product has good safety.
2. Results of a postprandial bioequivalence study
The postprandial test is composed of 28 subjects (14 cases in each of TR and RT sequences), 25 of which complete two-cycle tests according to the scheme, and 3 of which are withdrawn halfway (1 case in RT sequence and 2 cases in TR sequence). All 28 subjects were included in the safety data set (SS); all 28 subjects were enrolled in the pharmacokinetic concentration set (PKCS), with only the first cycle concentration data for subjects with random number 218 and subjects with random number 228; the 27 subjects were included in the pharmacokinetic parameter set (PKPS) and bioequivalence set (BES), with subjects with a random number of 205 not included in PKPS and BES due to vomiting withdrawal from the trial after 1h of blood draw in the first cycle.
Equivalence analysis Using the ABE method, the AUC of the proto-drug isosorbide mononitrate in the plasma of 27 subjects enrolled in the BES pool 0-t 、AUC 0-∞ And C max The 90% confidence intervals for the Geometric Mean Ratio (GMR) for both the test and reference formulations fall well within the acceptable range of 80.00% to 125.00% bioequivalence, AUC 0-t 、AUC 0-∞ 、C max The 90% confidence intervals for the Geometric Mean Ratio (GMR) are in order: 97.89% -5754% of zxft 5754%, 97.94% -3252% of zxft 3252% and 3532% of zxft 3532% -3425% of zxft 3425%. The results show that: after the test preparation and the reference preparation are taken by a single dose or a single time in an oral way under the postprandial state of a subject, the two preparations have bioequivalence.
28 subjects enrolled in the post-meal trial SS group had 14 (50.00%, 14/28) total AEs during the study, with 7 (25.93%, 7/27) total AEs occurring in subjects taking the test formulation and 8 (30.77%, 8/26) total AEs occurring in subjects taking the reference formulation. The causal relationship between 8 (28.57%, 8/28) 9 AE cases and the test drug is judged to be possibly irrelevant, and the correlations between 1 (3.57%, 1/28) AE case 1, 5 (17.86%, 5/28) AE cases 7 and 1 (3.57%, 1/28) AE case 1 and the test drug are respectively judged to be positive, possibly relevant and possibly relevant. The vast majority of AEs (42.86%, 12/28, 16 occurrences) were mild, with only 1 (3.57%, 1/28) occurrence of 1 AE resulting in withdrawal from the subject (vomiting, relationship with study drug judged as "likely related"), and no SAE occurring. All AEs were followed to "improvement/remission" or "recovered/recovered" except for 1 possible AE outcome of the study drug as "unknown/lost visit". The result shows that the product has good safety.
Finally, the above embodiments are only used for illustrating the technical solutions of the present application and not for limiting, although the present application is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present application without departing from the spirit and scope of the technical solutions of the present application, and all the technical solutions of the present application should be covered by the claims of the present application.
Claims (10)
1. A preparation method of isosorbide mononitrate sustained-release tablets is characterized by comprising the following steps: preparing materials: mixing isosorbide mononitrate and calcium hydrophosphate in a mass ratio of 1:1 at the rotating speed of 8rpm for 5min, crushing the mixed materials by a crusher to pass through a 60-mesh sieve, and then mixing at the rotating speed of 8rpm for 5min to obtain a premix; (2) granulating: premixing hydroxypropyl methylcellulose, microcrystalline cellulose, premix, ethyl cellulose and calcium hydrogen phosphate in a wet mixing granulator for 300S, cleaning the inner wall of the wet mixing granulator after premixing, mixing for 600S for the second time, starting a peristaltic pump after the mixing for the second time is finished, adding purified water in an atomizing and liquid adding manner, and discharging to obtain wet granules; (3) drying: drying the wet granules until the weight loss is 2.5% -3.5%; (4) finishing the grains: granulating the dried granules by using a granulator; (5) total mixing: mixing the granules and hydroxypropyl methylcellulose at a speed of 8r/min for 5 minutes, adding magnesium stearate and silicon dioxide, and mixing at a speed of 8r/min for 5 minutes to obtain a total mixed material; (6) tabletting: use of
The circular shallow concave punch presses the total mixed material to obtain a tablet core; (7) coating: installing and connecting a peristaltic pump and a spray gun system, starting compressed air, adjusting a switch of the spray gun to enable sprayed coating liquid to be in a mist shape and a fan shape, adding a tablet to be coated into a coating pot after the spray gun system is well adjusted, starting the coating pot to preheat a tablet core, adjusting the position of the spray gun to enable the spray gun to be perpendicular to a tablet bed and to be 25-40cm away from the tablet bed, starting the peristaltic pump and the spray gun to perform initial coating after the tablet core is preheated for about 10min, increasing the rotating speed and the speed of the peristaltic pump to deepen the coating after the coating is coated for 20-30 min, controlling the temperature of the tablet bed to be 30-45 ℃, increasing the weight of the coating by 2-4%, stopping spraying the liquid, reducing the rotating speed, closing the heating, still starting an air inlet and exhaust system, enabling the coating pot to continuously rotate until the temperature of the tablet bed is consistent with the room temperature and the tablet is dried, and installing a discharging device to obtain the isosorbide mononitrate sustained release tablet; (8) inner packaging: packing with solid medicinal hard polyvinyl chloride/polyvinylidene chloride sheet and medicinal aluminum foil bubble cap; (9) external packing: putting the isosorbide mononitrate sustained-release tablets subjected to inner packaging and an instruction into a paper box.
2. The preparation method of isosorbide mononitrate sustained release tablets as claimed in claim 1, wherein the mass ratio of hypromellose, microcrystalline cellulose, premix, ethyl cellulose and calcium hydrogen phosphate in step (2) is 4.5-5.5:7-8:18-22:3-3.5:15-20 parts of; the pre-mixing setting parameters are as follows: chopping (800 rpm), stirring (120 rpm); the parameters set by the secondary mixing are as follows: chopping (1800 rpm), stirring speed (200 rpm); the rotating speed of the peristaltic pump is 85-95rpm, the pressure of the atomized liquid is 0.3Mpa, and the time of the atomized liquid is 600S; the mass ratio of the purified water to the premix is 8-10.
3. The method for preparing isosorbide mononitrate sustained release tablets according to claim 2, wherein the mass ratio of hypromellose, microcrystalline cellulose, premix, ethyl cellulose and calcium hydrogen phosphate in step (2) is 5.09:7.5:20:3.25:17.64; the mass ratio of the purified water to the premix is 9.
4. The method for preparing an isosorbide mononitrate sustained release tablet as claimed in claim 1, wherein the drying temperature in step (3) is 50-55 ℃.
5. The method for preparing isosorbide mononitrate sustained release tablets according to claim 1, wherein the whole mesh of the sieve in step (5) has a pore size of 2mm and the rotation speed of 500 rpm.
6. The method for preparing the isosorbide mononitrate sustained release tablet as claimed in claim 1, wherein the mass ratio of the hypromellose, magnesium stearate and silicon dioxide added in step (5) to the isosorbide mononitrate added in step (1) is 65-70:1.8-2.2:1.8-2.2:45-55.
7. The method for preparing the isosorbide mononitrate sustained release tablet of claim 6, wherein the mass ratio of the hypromellose, magnesium stearate and silicon dioxide added in step (5) to the isosorbide mononitrate added in step (1) is 67.85:2:2:50.4.
8. the method for preparing isosorbide mononitrate sustained release tablets according to claim 1, wherein the feeding speed during tabletting in step (6) is 55-65 rpm, the pressure during tabletting is 13-32 KN, and the tabletting speed is 8-10 ten thousand tablets/h per single track.
9. The method for preparing isosorbide mononitrate sustained release tablets according to claim 1, wherein the coating solution used in step (7) is prepared as follows: adding the coating powder into purified water, stirring for 45min, and preparing coating solution with mass concentration of 8-12% and sieving with 120 mesh sieve; the preheating process is characterized in that the rotating speed of a coating pan is set to be 2-5 rpm, and the air inlet temperature is set to be 50-70 ℃; the atomization pressure of the initial coating is 0.5-0.7MPa, and the speed of a peristaltic pump is 1.5-4 rpm; when the coating is deepened, the rotating speed of a coating pan is 2-7 rpm, and the speed of a peristaltic pump is 1.5-8 rpm.
10. The method for preparing isosorbide mononitrate sustained release tablets of claim 1, wherein the upper heating temperature of the inner packaging and packaging machine in step (8) is 100-120 ℃, the lower heating temperature is 118-138 ℃, the heat sealing temperature is 180-200 ℃ and the batch number temperature is 150-170 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211253863.0A CN115487162B (en) | 2022-10-13 | 2022-10-13 | Preparation method of isosorbide mononitrate sustained release tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211253863.0A CN115487162B (en) | 2022-10-13 | 2022-10-13 | Preparation method of isosorbide mononitrate sustained release tablet |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115487162A true CN115487162A (en) | 2022-12-20 |
| CN115487162B CN115487162B (en) | 2023-10-13 |
Family
ID=84475279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211253863.0A Active CN115487162B (en) | 2022-10-13 | 2022-10-13 | Preparation method of isosorbide mononitrate sustained release tablet |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115487162B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4812316A (en) * | 1985-10-15 | 1989-03-14 | Eurand Italia S.P.A. | Process for the preparation of stabilized isosorbide-5-mononitrate tablets, being also of sustained release, and formulations thus obtained |
| US5451409A (en) * | 1993-11-22 | 1995-09-19 | Rencher; William F. | Sustained release matrix system using hydroxyethyl cellulose and hydroxypropyl cellulose polymer blends |
| WO1998005306A1 (en) * | 1996-08-02 | 1998-02-12 | Cal International Limited | Controlled release tablet formulation of isosorbide-5-mononitrate |
| CN1679536A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Single nitrate isosorbide delayed-release tablets |
| CN101181259A (en) * | 2007-11-19 | 2008-05-21 | 青岛黄海制药有限责任公司 | Sustained-release agent of nitric acid dinitrate and preparation method thereof |
| CN103127000A (en) * | 2013-02-27 | 2013-06-05 | 中国药科大学 | Isosorbide mononitrate chronopharmacological sustained release pellet drug delivery system and its preparation method |
| CN110403911A (en) * | 2018-04-26 | 2019-11-05 | 鲁南制药集团股份有限公司 | A kind of isosorbide mononitrate sustained release tablets and preparation method thereof |
-
2022
- 2022-10-13 CN CN202211253863.0A patent/CN115487162B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4812316A (en) * | 1985-10-15 | 1989-03-14 | Eurand Italia S.P.A. | Process for the preparation of stabilized isosorbide-5-mononitrate tablets, being also of sustained release, and formulations thus obtained |
| US5451409A (en) * | 1993-11-22 | 1995-09-19 | Rencher; William F. | Sustained release matrix system using hydroxyethyl cellulose and hydroxypropyl cellulose polymer blends |
| WO1998005306A1 (en) * | 1996-08-02 | 1998-02-12 | Cal International Limited | Controlled release tablet formulation of isosorbide-5-mononitrate |
| CN1679536A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Single nitrate isosorbide delayed-release tablets |
| CN101181259A (en) * | 2007-11-19 | 2008-05-21 | 青岛黄海制药有限责任公司 | Sustained-release agent of nitric acid dinitrate and preparation method thereof |
| CN103127000A (en) * | 2013-02-27 | 2013-06-05 | 中国药科大学 | Isosorbide mononitrate chronopharmacological sustained release pellet drug delivery system and its preparation method |
| CN110403911A (en) * | 2018-04-26 | 2019-11-05 | 鲁南制药集团股份有限公司 | A kind of isosorbide mononitrate sustained release tablets and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115487162B (en) | 2023-10-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9907780B2 (en) | Low-dose doxepin formulations and methods of making and using the same | |
| CN102917697B (en) | For the water solublity of high dose and the controlled release form of hygroscopic drugs | |
| CN103976972B (en) | Orally taken pulsed controlled-release administrating system of Zolpidemtar Trate and preparation method thereof | |
| CN108042503B (en) | High-efficiency potassium sodium dehydroandroan drographolide succinate enteric-coated tablet and preparation method thereof | |
| CN115487162A (en) | Preparation method of isosorbide mononitrate sustained-release tablets | |
| CN101485639B (en) | Huperzine A double-layer osmotic pump controlled release tablets | |
| CN113288905A (en) | Pharmaceutical composition containing dortavir sodium, lamivudine and norfovir disoproxil fumarate | |
| CN105168168B (en) | A kind of preparation method of kallidinogenase enteric coatel tablets | |
| CN113476416B (en) | Pharmaceutical composition for treating vasodilatation | |
| CN104434855B (en) | Memantine hydrochloride tablet and preparation method thereof | |
| CN111759849B (en) | Anti-angina pectoris pharmaceutical composition and preparation method and application thereof | |
| CN102349880A (en) | Isradipine controlled-release tablets and preparation method thereof | |
| CN102038642A (en) | Ginkgolide B solid dispersoid and preparation method thereof | |
| CN102512395B (en) | Huperzine osmotic-pump controlled release tablet | |
| CN109288836B (en) | Compound dihydralazine sulfate preparation as well as preparation method and application thereof | |
| CN115501194A (en) | Preparation method of isosorbide mononitrate tablet | |
| CN101385718B (en) | Osmotic pump preparation composition for treating hyperlipemia | |
| CN111643462A (en) | Formula and process for producing cyproheptadine hydrochloride tablets with high curative effect | |
| CN106692706A (en) | Preparation method for medicine used for treating vertigo | |
| CN103908437B (en) | A kind of Bezafibrate sustained-release preparation and preparation method thereof | |
| CN105663074A (en) | Enteric-coated sustained release tablet of serotonin reuptake inhibitor and preparation method of enteric-coated sustained release tablet | |
| CN111419814B (en) | Febuxostat tablet and preparation process thereof | |
| CN1389208A (en) | Orally taken pulsed releasing system of phenyl diazepine medicine and its prepn. | |
| CN108309949A (en) | A kind of preparation method and products thereof of morphine osmotic pump tablet | |
| CN103181886A (en) | Artemisinin or its derivative sustained release preparation, and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |