Disclosure of Invention
Based on the problems of the existing nicergoline tablets, the invention provides a preparation method of nicergoline tablets, which comprises the steps of firstly granulating microcrystalline cellulose and sodium carboxymethyl cellulose in a formula, mixing the prepared microcrystalline cellulose-sodium carboxymethyl cellulose granules with nicergoline, calcium hydrophosphate and magnesium stearate, directly tabletting, coating and carrying out aluminum-plastic packaging to obtain the nicergoline tablets. The nicergoline tablet prepared by the method provided by the invention can be rapidly and completely disintegrated, so that the aim of rapid dissolution is fulfilled.
Experiments prove that if the method provided by the invention is not adopted, the nicergoline tablet prepared by directly tabletting the nicergoline, the microcrystalline cellulose, the sodium carboxymethylcellulose, the calcium hydrophosphate and the magnesium stearate powder or by mixing the main drug and the auxiliary material together and then carrying out wet granulation cannot realize the purposes of quick disintegration and quick dissolution.
The invention provides a direct compression process of nicergoline tablets without traditional disintegrants, and nicergoline tablets prepared by the process provided by the invention are rapidly disintegrated and have good stability.
The microcrystalline cellulose and the sodium carboxymethylcellulose in the prescription are granulated, so that the prescription which cannot be completely disintegrated and is slowly dissolved is changed into the prescription which can be quickly and completely disintegrated and quickly dissolved. The method provided by the invention does not contain the traditional disintegrating agent, ensures the stability of the product, and realizes the rapid disintegration and dissolution of the nicergoline tablets.
The invention discloses a preparation method of a rapidly disintegrating nicergoline tablet, which mainly comprises the following steps:
step one
The preparation method comprises the specific steps of granulating microcrystalline cellulose and sodium carboxymethylcellulose in a prescription by adopting a wet granulation process, drying the prepared microcrystalline cellulose-sodium carboxymethylcellulose granules, and controlling the particle size of the dried granules to obtain the composite auxiliary material granules with the rapid disintegration property.
Step two
Mixing: mixing the prepared microcrystalline cellulose-sodium carboxymethyl cellulose particles, nicergoline, calcium hydrogen phosphate and magnesium stearate for a certain number of revolutions to obtain total mixed powder.
Step three
Tabletting: and (3) placing the prepared total mixed powder into a tabletting machine for tabletting, and monitoring related parameters to obtain the nicergoline tablets.
Step four
Coating: and (3) placing the prepared nicergoline tablets in a high-efficiency coating pot for film coating to obtain nicergoline coated tablets.
Step five
And (3) aluminum-plastic packaging: and packaging the nicergoline coated tablet to obtain a finished product. The package refers to an aluminum-plastic package and is made of PVC-aluminum or PVDC-PVC-aluminum.
The invention is further improved in that:
in the first step, the weight ratio of microcrystalline cellulose to sodium carboxymethyl cellulose is 10: 1-30: 1; the wet granulation process of the microcrystalline cellulose and the sodium carboxymethyl cellulose comprises a wet mixing granulation process and a boiling granulation process; drying the microcrystalline cellulose-sodium carboxymethyl cellulose particles by an oven and boiling, wherein the drying temperature is 30-70 ℃; the particle size of the microcrystalline cellulose-sodium carboxymethyl cellulose particles is controlled by adopting a sieve with 18-200 meshes to carry out size stabilization on the microcrystalline cellulose-sodium carboxymethyl cellulose particles.
The mixing in the second step comprises two steps of premixing and total mixing. The premixing is to mix microcrystalline cellulose-carboxymethyl cellulose sodium particles, nicergoline and calcium hydrophosphate; the total mixing is to add magnesium stearate into the premixed powder for total mixing.
The monitoring related parameters in the third step refer to the monitoring of the thickness, weight difference and hardness of the tablet in the tabletting process.
In the step four, the selected coating material is a film coating premix which comprises HPMC type and PVA type.
And in the fifth step, the aluminum-plastic package is made of PVDC-PVC-aluminum material.
The invention is further improved in that:
in the first step, the weight ratio of microcrystalline cellulose to sodium carboxymethyl cellulose is 15: 1-20: 1; selecting a wet mixing granulation process as the wet granulation process of the microcrystalline cellulose and the sodium carboxymethyl cellulose; drying the microcrystalline cellulose-carboxymethylcellulose sodium particles at the temperature of 40-60 ℃; the particle size of the microcrystalline cellulose-sodium carboxymethylcellulose particles is controlled by adopting a 24-100-mesh screen to carry out particle size stabilization on the microcrystalline cellulose-sodium carboxymethylcellulose particles.
The invention is further improved in that:
and in the step one, the grain size of the microcrystalline cellulose-sodium carboxymethyl cellulose particles is controlled by adopting a 40-80 mesh screen to carry out size stabilization on the microcrystalline cellulose-sodium carboxymethyl cellulose particles.
The film coating in the fourth step is HPMC type film coating premix, which mainly comprises the following components: HPMC, titanium dioxide, and polyethylene glycol.
Due to the adoption of the technical scheme, the technical progress of the invention is as follows:
(1) the invention provides a novel method for improving the disintegration of nicergoline tablets, and no report that microcrystalline cellulose and sodium carboxymethylcellulose are granulated so as to improve the disintegration is provided before the method. The microcrystalline cellulose-carboxymethylcellulose sodium particles prepared by the method can be used for other tablets needing to be quickly disintegrated besides the nicergoline tablets.
(2) The microcrystalline cellulose-carboxymethylcellulose sodium particles prepared by adopting the key steps have the main effects of quickly disintegrating the prepared nicergoline tablets in the prescription and also have the effects of an adhesive and a filler. Experiments prove that if the method provided by the invention is not adopted, the nicergoline tablet prepared by directly tabletting the nicergoline, the microcrystalline cellulose, the sodium carboxymethylcellulose, the calcium hydrophosphate and the magnesium stearate powder or by mixing the main drug and the auxiliary material together and then carrying out wet granulation cannot realize the purposes of quick disintegration and quick dissolution.
(3) The nicergoline tablet prepared by the technical scheme does not contain a traditional disintegrating agent, and the prepared nicergoline tablet is not easy to absorb moisture in the preparation process and the storage process and has good stability.
Detailed Description
The invention will now be described in the following examples, which are intended to be illustrative only and not limiting to the scope of protection.
The raw materials and auxiliary materials used in the following examples are, unless otherwise specified, those which are generally commercially available. The main equipment used is a wet mixing granulator, manufacturer: shenzhen, Xinyite science and technology Limited, model: G10. rotary tablet press, manufacturer: shanghai information source pharmaceutical machinery ltd, model number: ZPS 8. Three-dimensional mixer, manufacturer: chat to Wanhe Industrial manufacturing Co., Ltd, model number: SBH-10. Small size coating machine, manufacturer: shanghai yellow sea medical testing instrument, type: BY 300A. Tablet hardness tester, manufacturer: tianjin, Tianda Tiankui science and technology Limited, model: YD-20 KZ. Intelligent disintegration tester, manufacturer: tianjin, Tianda Tiankui science and technology Limited, model: 2B-2E. Dissolution tester, manufacturer: tianjin, Tianda Tiankui science and technology Limited, model: RC8 MD. High performance liquid chromatograph, manufacturer: shimadzu, Kaisha, type: LC-2030C.
The prescription, the composition and the preparation process of the fast disintegrating nicergoline tablet comprise the following steps:
example 1
TABLE 1 example 1 prescription composition (10mg standard) in preparation of nicergoline tablets
Note: 1. the microcrystalline cellulose, the sodium carboxymethylcellulose and the purified water are added by 5 percent according to the prescription amount so as to offset the loss in the granulation process; 2. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
2. Preparation process
(1) Granulation of microcrystalline cellulose and sodium carboxymethylcellulose
And (3) granulating: weighing microcrystalline cellulose and sodium carboxymethylcellulose according to 105% of the formula amount, placing the weighed materials in a wet mixing granulator, setting the rotating speed of a stirring paddle and the rotating speed of a shearing paddle, starting the wet mixing granulator, and performing dry mixing for 2 minutes. And after the dry mixing time is up, keeping the wet mixing granulator in an open state, and clicking an atomization water adding button to atomize and add water. After the atomization and water addition are finished, the wet mixing granulator is kept in an open state, and granulation is continued for 2 minutes. And clicking a discharging button after the granulating time reaches the preset time, discharging, and closing the wet mixing granulator after the discharging is finished.
And (3) drying: uniformly spreading the prepared microcrystalline cellulose-carboxymethylcellulose sodium particles in a baking pan, placing in a drying oven, setting the temperature to be 40-60 ℃, starting timing when the temperature is reached, sampling about 1g every 0.5h after drying for 3.5h, measuring the moisture by using a rapid moisture tester, stopping drying after the requirements are met, closing the drying oven, and recording the drying time.
Straightening: the microcrystalline cellulose-carboxymethylcellulose sodium particles were sized using a screen of a selected mesh number, and the particles above the screen were pulverized so that all of them passed through the screen of the selected mesh number. After the whole grains are finished, the obtained microcrystalline cellulose-carboxymethyl cellulose sodium grains are placed in a clean material bag and sealed for later use.
(2) Mixing
Premixing: weighing the microcrystalline cellulose-carboxymethylcellulose sodium particles, the nicergoline and the calcium hydrophosphate in the prescription amount and placing the mixture in a mixer. And (4) covering the hopper cover, starting the mixer, and performing premixing operation, wherein the mixing revolution is 150-300 revolutions.
Total mixing: weighing magnesium stearate in a prescription amount, placing the magnesium stearate in a premixing mixer, covering a hopper cover, opening the mixing machine, and carrying out total mixing operation, wherein the mixing revolution is 100-200 revolutions. And discharging the total mixed particles in the mixer into a clean material bag, sampling, sealing, and taking out a sample to be used for measuring the total mixed powder content.
(3) Tabletting
The total mixed powder is added into a hopper of a tablet press at one time, the tablet press is started, the rotating speed of the tablet press is set to be 20rpm for tabletting operation, and the mouth of a clean material bag for containing tablets is tied on a discharge port of the tablet press by a silica gel elastic band in the tabletting process, so that the tablets are prevented from being exposed. Appearance, tablet weight and tablet thickness were monitored during the compression. Sampling and inspecting after tabletting. And after sampling, sealing the clean material bag filled with the plain sheets, placing the clean material bag in an aluminum-plastic composite bag, sealing, and storing the mark for later use.
(4) Coating film
Preparing a coating solution: weighing the film coating premix and purified water according to 110% of the formula amount, placing the coating premix in the purified water in a stirring state, quickly stirring to disperse formed lumps, reducing the stirring speed to almost eliminate vortex, and continuously stirring for 45 minutes for later use.
And (3) coating process: and installing the coating machine, and adjusting the pressure of compressed air to 0.05-0.3 mpa. Setting the rotating speed of the coating pan to be 15-25 rpm, setting the air inlet temperature to be 40-70 ℃, and adjusting the air inlet angle to ensure that the temperature of the slice bed is 40-55 ℃. Adding the plain tablets into a coating pot, starting a coating machine, preheating for 10-30 minutes, sampling, and weighing the tablets before coating. And setting the rotating speed of a peristaltic pump to enable the flow rate of the coating liquid to be 5-15 g/min, and coating. The appearance of the coated tablets was checked during the coating process. And after coating, closing the peristaltic pump, continuously drying for 10-30 minutes, sampling, weighing the coated tablets, and calculating the weight gain of the coating. And (5) sampling after coating is finished, and detecting the water content, the content and the dissolution curve. After the coated tablets are cooled, discharging into a clean plastic bag, and sealing.
(5) Plastic-aluminum package
And (3) aluminum-plastic packaging: and (3) installing an aluminum-plastic blister packaging machine, opening compressed air, starting a water cooling machine, setting the temperature of each heating plate to be 140 +/-20 ℃, setting the heat sealing temperature to be 180 +/-20 ℃, switching on a power supply, and preheating for 20-30 minutes. And (3) pouring tablets into a hopper, starting the host machine and the leakage detection device after the temperature of each heating plate reaches a set value, running the empty machine, and starting a blanking switch to work formally after determining that the bubble hole forming, the heat sealing, the batch number imprinting and the blanking are normal. After normal packaging, the quality is periodically checked and recorded. Unqualified tablets such as black spots, color spots, loose pieces, splinters and the like are removed at any time in the packaging process, and abnormal/unqualified aluminum-plastic tablets are removed. And after the packaging is finished, randomly taking the packaged sample, and detecting according to the internal control quality standard.
The following preparation processes of examples 2 to 5 were identical to those of example 1, and the formulation compositions were different.
Example 2
TABLE 2 example 2 prescription composition (5mg standard) in preparation of nicergoline tablets
Note: 1. the microcrystalline cellulose, the sodium carboxymethylcellulose and the purified water are added by 5 percent according to the prescription amount so as to offset the loss in the granulation process; 2. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
Example 3
TABLE 3 example 3 prescription composition (30mg standard) in preparation of nicergoline tablets
Note: 1. the microcrystalline cellulose, the sodium carboxymethylcellulose and the purified water are added by 5 percent according to the prescription amount so as to offset the loss in the granulation process; 2. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
Example 4
TABLE 4 example 4 prescription composition (10mg standard) in preparation of nicergoline tablets
Note: 1. the microcrystalline cellulose, the sodium carboxymethylcellulose and the purified water are added by 5 percent according to the prescription amount so as to offset the loss in the granulation process; 2. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
Example 5
TABLE 5 example 5 prescription composition (10mg standard) in preparation of nicergoline tablets
Note: 1. the microcrystalline cellulose, the sodium carboxymethylcellulose and the purified water are added by 5 percent according to the prescription amount so as to offset the loss in the granulation process; 2. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
Comparative example:
the samples of the comparative examples were prepared by a powder direct compression process and a wet granulation process, respectively.
Comparative example 1
TABLE 6 comparison example 1 prescription composition (10mg standard) in preparation of nicergoline tablets
Note: 1. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
Preparation process
(1) Mixing
Premixing: weighing nicergoline, microcrystalline cellulose, sodium carboxymethylcellulose and calcium hydrogen phosphate according to the prescription amount, and placing the materials in a mixer. And (4) covering the hopper cover, starting the mixer, and performing premixing operation, wherein the mixing revolution is 150-300 revolutions.
Total mixing: weighing magnesium stearate in a prescription amount, placing the magnesium stearate in a premixing mixer, covering a hopper cover, opening the mixing machine, and carrying out total mixing operation, wherein the mixing revolution is 100-200 revolutions. And discharging the total mixed particles in the mixer into a clean material bag, sampling, sealing, and taking out a sample to be used for measuring the total mixed powder content.
(2) Tabletting
The total mixed powder is added into a hopper of a tablet press at one time, the tablet press is started, the rotating speed of the tablet press is set to be 20rpm for tabletting operation, and the mouth of a clean material bag for containing tablets is tied on a discharge port of the tablet press by a silica gel elastic band in the tabletting process, so that the tablets are prevented from being exposed. Appearance, tablet weight and tablet thickness were monitored during the compression. Sampling and inspecting after tabletting. And after sampling, sealing the clean material bag filled with the plain sheets, placing the clean material bag in an aluminum-plastic composite bag, sealing, and storing the mark for later use.
(3) Coating film
Preparing a coating solution: weighing the film coating premix and purified water according to 110% of the formula amount, placing the coating premix in the purified water in a stirring state, quickly stirring to disperse formed lumps, reducing the stirring speed to almost eliminate vortex, and continuously stirring for 45 minutes for later use.
And (3) coating process: and installing the coating machine, and adjusting the pressure of compressed air to 0.05-0.3 mpa. Setting the rotating speed of the coating pan to be 15-25 rpm, setting the air inlet temperature to be 40-70 ℃, and adjusting the air inlet angle to ensure that the temperature of the slice bed is 40-55 ℃. Adding the plain tablets into a coating pot, starting a coating machine, preheating for 10-30 minutes, sampling, and weighing the tablets before coating. And setting the rotating speed of a peristaltic pump to enable the flow rate of the coating liquid to be 5-15 g/min, and coating. The appearance of the coated tablets was checked during the coating process. And after coating, closing the peristaltic pump, continuously drying for 10-30 minutes, sampling, weighing the coated tablets, and calculating the weight gain of the coating. And (5) sampling after coating is finished, and detecting the water content, the content and the dissolution curve. After the coated tablets are cooled, discharging into a clean plastic bag, and sealing.
(4) Plastic-aluminum package
And (3) aluminum-plastic packaging: and (3) installing an aluminum-plastic blister packaging machine, opening compressed air, starting a water cooling machine, setting the temperature of each heating plate to be 140 +/-20 ℃, setting the heat sealing temperature to be 180 +/-20 ℃, switching on a power supply, and preheating for 20-30 minutes. And (3) pouring tablets into a hopper, starting the host machine and the leakage detection device after the temperature of each heating plate reaches a set value, running the empty machine, and starting a blanking switch to work formally after determining that the bubble hole forming, the heat sealing, the batch number imprinting and the blanking are normal. After normal packaging, the quality is periodically checked and recorded. Unqualified tablets such as black spots, color spots, loose pieces, splinters and the like are removed at any time in the packaging process, and abnormal/unqualified aluminum-plastic tablets are removed. And after the packaging is finished, randomly taking the packaged sample, and detecting according to the internal control quality standard.
The following comparative example 2 was prepared in accordance with comparative example 1.
Comparative example 2
TABLE 7 comparison example 2 prescription composition (10mg standard) in preparation of nicergoline tablets
Note: 1. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
Comparative example 3
TABLE 8 comparison example 3 prescription composition (10mg standard) in preparation of nicergoline tablets
Note: 1. the microcrystalline cellulose, the sodium carboxymethylcellulose, the calcium hydrophosphate and the purified water are all added by 5 percent according to the prescription amount so as to offset the loss in the granulation process; 2. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
Preparation process
(1) Wet granulation of auxiliary materials
And (3) granulating: weighing microcrystalline cellulose, sodium carboxymethylcellulose and calcium hydrogen phosphate according to 105% of the formula amount, placing the materials in a wet mixing granulator, setting the rotating speed of a stirring paddle and the rotating speed of a shearing paddle, starting the wet mixing granulator, and performing dry mixing for 2 minutes. And after the dry mixing time is up, keeping the wet mixing granulator in an open state, and clicking an atomization water adding button to atomize and add water. After the atomization and water addition are finished, the wet mixing granulator is kept in an open state, and granulation is continued for 5 minutes. And clicking a discharging button after the granulating time reaches the preset time, discharging, and closing the wet mixing granulator after the discharging is finished.
And (3) drying: uniformly spreading the prepared auxiliary material particles in a baking pan, placing the baking pan in a drying oven at the set temperature of 40-60 ℃, starting timing when the temperature reaches, sampling about 1g every 0.5h after drying for 4.0h, measuring the moisture by using a rapid moisture tester, stopping drying after the requirement is met, closing the drying oven, and recording the drying time.
Straightening: the granules of the auxiliary material are granulated with a sieve having a selected mesh number, and the granules above the sieve are pulverized so that all of them pass through the sieve having the selected mesh number. And after finishing the granulation, placing the obtained auxiliary material particles in a clean material bag, and sealing for later use.
(2) Mixing, (3) tabletting, (4) coating, and (5) plastic-aluminum packaging are the same as in example 1.
Comparative example 4
TABLE 9 comparative example 4 prescription composition (5mg size) in preparation of nicergoline tablets
Note: 1. when the coating solution is prepared, 10% more is prepared to offset the loss in the coating process.
Preparation process
(1) Wet granulation
And (3) granulating: weighing nicergoline, microcrystalline cellulose, sodium carboxymethylcellulose and calcium hydrogen phosphate according to the prescription amount, placing the nicergoline, the microcrystalline cellulose, the sodium carboxymethylcellulose and the calcium hydrogen phosphate in a wet mixing granulator, setting the rotating speed of a stirring paddle and the rotating speed of a shearing paddle, starting the wet mixing granulator, and performing dry mixing for 2 minutes. And after the dry mixing time is up, keeping the wet mixing granulator in an open state, and clicking an atomization water adding button to atomize and add water. After the atomization and water addition are finished, the wet mixing granulator is kept in an open state, and granulation is continued for 5 minutes. And clicking a discharging button after the granulating time reaches the preset time, discharging, and closing the wet mixing granulator after the discharging is finished.
And (3) drying: uniformly spreading the prepared auxiliary material particles in a baking pan, placing the baking pan in a drying oven at the set temperature of 40-60 ℃, starting timing when the temperature reaches, sampling about 1g every 0.5h after drying for 4.0h, measuring the moisture by using a rapid moisture tester, stopping drying after the requirement is met, closing the drying oven, and recording the drying time.
Straightening: the granules of the auxiliary material are granulated with a sieve having a selected mesh number, and the granules above the sieve are pulverized so that all of them pass through the sieve having the selected mesh number. And after finishing the granulation, placing the obtained auxiliary material particles in a clean material bag, and sealing for later use.
(2) Mixing, (3) tabletting, (4) coating, and (5) plastic-aluminum packaging are the same as in example 1.
Quality study
The samples prepared according to examples 1 to 5 and comparative examples 1 to 4 were tested according to established quality standards, in particular comparing the dissolution curves of the samples according to examples 1 to 5 and comparative examples 1 to 4 in different media.
TABLE 10 examination results of samples prepared in examples 1 to 5 and comparative example
It can be seen from the data in Table 10 that the samples of examples 1-5 prepared by the method provided by the present invention have significantly higher dissolution in media at pH6.8 than the samples prepared in comparative examples 1-4. Disintegration time period examination showed that the samples prepared in examples 1-5 all disintegrated completely and rapidly, while the samples in comparative example 1 and comparative example 2 did not disintegrate, and the samples in comparative example 3 and comparative example 4 did not disintegrate completely.
The samples prepared in examples 1 to 5 all disintegrated rapidly within 1min in the above 3 media, showing rapid dissolution. The samples of the comparative example 1 and the comparative example 2 are dissolved in the pH1.2 medium and the pH4.0 medium gradually because the calcium hydrophosphate in the formula is dissolved in the pH1.2 medium and the pH4.0 medium, the samples are slowly dissolved but not disintegrated, and the dissolution is slow; in the medium of pH6.8, calcium hydrogen phosphate did not dissolve, and the sample of the comparative example did not disintegrate and could not be dissolved. The samples of comparative examples 3 and 4 showed slow dissolution in the above 3 media, which were slow and incomplete in disintegration and no longer continued after disintegration into large pieces, and the amount of dissolution in the same time was significantly less than in the examples.