CN111281854A - Atorvastatin calcium tablet and preparation process thereof - Google Patents
Atorvastatin calcium tablet and preparation process thereof Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to an atorvastatin calcium tablet and a preparation process thereof. The atorvastatin calcium tablet comprises the following components in parts by weight: 5-15 parts of atorvastatin calcium, 40-70 parts of a filler, 1-5 parts of a binder, 20-35 parts of a disintegrating agent, 1-5 parts of a lubricant and 3-8 parts of an auxiliary agent. The invention has the advantages of good dispersibility, high disintegration rate and dissolution rate and excellent stability of related substances.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an atorvastatin calcium tablet and a preparation process thereof.
Background
Atorvastatin Calcium (Atorvastatin Calcium) belongs to the HMG-CoA reductase inhibitor, reduces the concentration of cholesterol and serum lipoprotein in plasma by inhibiting HMG-COA reductase and cholesterol biosynthesis in liver, and enhances the uptake and metabolism of low density lipoprotein by increasing the hepatic low density lipoprotein receptor on the cell surface. Atorvastatin calcium is effective in lowering plasma total cholesterol, low density lipoprotein cholesterol, apolipoprotein and triglyceride levels in homozygote and heterozygote familial hypercholesterolemia, non-familial hypercholesterolemia and mixed lipid metabolism disorder patients, and raising high density lipoprotein cholesterol and apolipoprotein Al levels to different degrees. The atorvastatin calcium has various specifications of 10mg, 20mg, 40mg, 80mg and the like, and the dosage forms include tablets, dispersible tablets, capsules and the like.
Atorvastatin calcium is a white or off-white crystalline powder, is very slightly soluble in water, a phosphate buffer solution with pH of 7.4 and acetonitrile, is slightly soluble in ethanol and is very easy to dissolve in methanol. The chemical name is [ R- (R ', R')]-2- (4-fluorophenyl) - β, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (anilino) carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate, formula: (C)33H34FN2O5)2Ca·3H2O, molecular weight: 1209.42.
atorvastatin calcium has poor stability, is sensitive to moisture, heat, low pH conditions and the like, and is easy to degrade particularly under the condition of low pH.
Chinese patent CN 1630510A discloses atorvastatin calcium in a pharmaceutical form, a composition thereof and a pharmaceutical preparation containing atorvastatin calcium, wherein a wet granulation technology is adopted, and calcium carbonate is added in a prescription as a stabilizer to ensure that a medicament is in an alkaline environment, so that the medicament degradation is avoided and the medicament dissolution rate is improved.
Chinese patent CN 102920675A discloses an atorvastatin calcium tablet and a preparation method thereof, and the atorvastatin calcium tablet is prepared by wet granulation and tabletting. The tablet comprises the following components in parts by mass: 7.22 parts of main drug atorvastatin calcium, 84.55 parts of filler, 6 parts of disintegrant croscarmellose sodium, 1.33 parts of adhesive hydroxypropyl cellulose, 800.4 parts of cosolvent polysorbate-800.4 and 0.5 part of lubricant magnesium stearate; the filler comprises the following raw materials in parts by mass: 22.01 parts of calcium carbonate, 21.87 parts of lactose and 40.67 parts of microcrystalline cellulose. The patent adds 22.01 parts of calcium carbonate as a filler, and is coated with a film coat, and simultaneously adds polysorbate-800 as a dissolution promoter, wherein the calcium carbonate can play a stabilizing role, but the problem of the rise of related substances in the storage process cannot be completely solved, and the disintegration rate and the dissolution rate of the patent need to be further improved.
Chinese patent CN 103705484A discloses a stable atorvastatin calcium tablet and a preparation method thereof, the tablet comprises a tablet core and a film coating layer, the tablet core is composed of atorvastatin calcium, a filling agent, a disintegrating agent, a lubricating agent and a compound stabilizing agent with a proper dosage, and the film coating layer contains stabilizing agents such as calcium carbonate, magnesium oxide, sodium bicarbonate and the like.
In the above patents, alkaline substances such as calcium carbonate are added, so that atorvastatin calcium is stable under alkaline conditions, and the generation of impurities is reduced. However, a large amount of calcium carbonate reacts with gastric acid, which causes adverse reactions such as constipation, flatulence, dyspepsia and the like.
Chinese patent CN1911209A discloses a rapidly disintegrating atorvastatin calcium tablet and a preparation method thereof, wherein the atorvastatin calcium tablet is prepared by wet granulation, and a large amount of disintegrant is added in the formula. However, a problem with a large amount of disintegrant is that it tends to absorb moisture, resulting in degradation of atorvastatin calcium. Furthermore, a certain amount of sodium dodecyl sulfate is added into the formula to improve the in vitro dissolution rate, but the addition of the surfactant can bring about gastrointestinal tract stimulation.
The Chinese patent CN102309462A provides an atorvastatin calcium tablet, which adopts a dry secondary granulation technology, has a complex process and poor stability, and cannot be completely dissolved in acid.
Chinese patent CN102138910A discloses an atorvastatin calcium tablet and a preparation method thereof, wherein a direct tabletting technology is adopted, atorvastatin calcium and croscarmellose sodium in the amount of a prescription are respectively sieved by a 120-mesh sieve and then are uniformly mixed, then are uniformly mixed with lactose (80M) in the amount of the prescription by an equivalent progressive method, and are uniformly mixed with magnesium stearate in the amount of the prescription and then are tabletted to obtain the atorvastatin calcium tablet. However, the tablet was only 60% dissolved in acid for 30min, and was not completely and rapidly dissolved. Meanwhile, lactose is a meta-acidic substance, which can cause the degradation of atorvastatin calcium.
Therefore, it is very necessary to develop atorvastatin calcium tablets and a preparation process thereof, which can solve the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an atorvastatin calcium tablet which has good dispersibility, high disintegration rate and dissolution rate and excellent stability of related substances and a preparation process thereof.
The invention is realized by the following technical scheme:
the atorvastatin calcium tablet comprises the following components in parts by weight: 5-15 parts of atorvastatin calcium, 40-70 parts of a filler, 1-5 parts of a binder, 20-35 parts of a disintegrating agent, 1-5 parts of a lubricant and 3-8 parts of an auxiliary agent.
Preferably, the particle size composition of the atorvastatin calcium is as follows: 30-40 μm: 5-10 μm ═ 3-8: 1. Namely, the mass ratio of the atorvastatin calcium particles with the particle size of 30-40 mu m to the atorvastatin calcium particles with the particle size of 5-10 mu m is 3-8: 1.
Preferably, the filler is at least one of mannitol, microcrystalline cellulose, starch and dextrin.
More preferably, the filler is a mixture of mannitol, microcrystalline cellulose and hydroxypropyl- β -cyclodextrin.
More preferably, the mass ratio of the mannitol, the microcrystalline cellulose and the hydroxypropyl- β -cyclodextrin is 4-6:2-3: 1.
Preferably, the binder is one or more of hydroxypropyl cellulose, hypromellose, povidone, and gelatin.
More preferably, the binder is a mixture of gelatin and hypromellose.
More preferably, the mass ratio of the gelatin to the hypromellose is 1: 1-2.
Preferably, the disintegrant is one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and microcrystalline cellulose.
More preferably, the disintegrant is a mixture of croscarmellose sodium, microcrystalline cellulose and low substituted hydroxypropylcellulose.
More preferably, the mass ratio of the croscarmellose sodium to the microcrystalline cellulose to the low-substituted hydroxypropylcellulose is 1:3-6: 2-4.
More preferably, the microcrystalline cellulose is an external disintegrant, the croscarmellose sodium is an internal disintegrant and an external disintegrant, and the low-substituted hydroxypropylcellulose is an internal disintegrant.
More preferably, the mass ratio of the inner disintegrant to the outer disintegrant in the croscarmellose sodium is 1-2: 1.
Preferably, the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, talcum powder, silicon dioxide and silica micropowder.
Preferably, the auxiliary agent is at least one of polyethylene glycol-4000 and polyethylene glycol-6000.
Preferably, the atorvastatin calcium tablet further comprises 1-5 parts of a flavoring agent.
More preferably, the flavoring agent is one or more of sweet orange powder essence, aspartame, sodium cyclamate, glycyrrhizin, stevioside and saccharin.
The invention also relates to a preparation method of the atorvastatin calcium tablet, which comprises the following steps:
(1) mixing atorvastatin calcium, a filling agent, a part of a lubricating agent and a disintegrating agent to obtain a substance A;
(2) adding an adhesive and an auxiliary agent into the purified water to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 16-18 mesh sieve to obtain wet granules;
(4) drying the wet granules, and sieving with a 20-mesh sieve to obtain dry granules;
(5) adding the rest lubricant into the dry granules, and tabletting.
Preferably, the portion of the lubricant in step (1) is 10-20% of the lubricant.
Preferably, the step (1) includes the steps of: mixing atorvastatin calcium, a filling agent, 10-20 wt% of a lubricant and a disintegrating agent in sequence, stirring for 5-10min at 50-100r/min, and then stirring for 10-20min at 300r/min at 200-.
The invention optimizes the stirring process, slowly stirs and then rapidly stirs in stages, and compared with direct rapid stirring, the disintegration time limit and dissolution rate effect are obviously improved.
Preferably, the step (2) includes the steps of: heating purified water to 40-50 ℃, and adding an adhesive and an auxiliary agent according to the mass ratio of 1:3-10 to obtain a substance B.
Namely, the mass ratio of the mass of the purified water to the total mass of the adhesive and the auxiliary agent is 1: 3-10.
Preferably, the step (4) includes the steps of: drying the wet granules at 40-60 deg.C, controlling water content to be less than 2%, sieving with 20 mesh sieve, and grading to obtain dry granules.
The invention also relates to a preparation method of the atorvastatin calcium tablet, which comprises the following steps:
(1) mixing atorvastatin calcium, a filling agent, a part of a lubricating agent and an internal disintegrating agent to obtain a substance A;
(2) adding an adhesive and an auxiliary agent into the purified water to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 16-18 mesh sieve to obtain wet granules;
(4) drying the wet granules, and sieving with a 20-mesh sieve to obtain dry granules;
(5) adding the rest lubricant and external disintegrating agent into the dry granules, and tabletting.
Preferably, the portion of the lubricant in step (1) is 10-20% of the lubricant.
Preferably, the step (1) includes the steps of: mixing atorvastatin calcium, a filling agent, 10-20 wt% of a lubricant and an internal disintegrating agent, stirring for 5-10min at 50-100r/min, and then stirring for 10-20min at 300r/min at 200-.
Preferably, the step (2) includes the steps of: heating purified water to 40-50 ℃, and adding an adhesive and an auxiliary agent according to the mass ratio of 1:3-10 to obtain a substance B.
Namely, the mass ratio of the mass of the purified water to the total mass of the adhesive and the auxiliary agent is 1: 3-10.
Preferably, the preparation method comprises the following steps:
(1) mixing atorvastatin calcium, a filling agent, 10-20% of a lubricant and an internal disintegrating agent, stirring for 5-10min at 50-100r/min, and then stirring for 10-20min at 300r/min at 200-;
(2) heating purified water to 40-50 ℃, and adding an adhesive and an auxiliary agent according to the mass ratio of 1:3-10 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 16-18 mesh sieve to obtain wet granules;
(4) drying the wet granules at 40-60 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding the rest lubricant and external disintegrating agent into the dry granules, and tabletting.
The invention has the beneficial effects that:
the invention optimizes the particle size composition of the atorvastatin calcium, and the atorvastatin calcium particles with two different particle sizes form a spatial scale effect, thereby being beneficial to the rapid disintegration and dissolution of the atorvastatin calcium.
The invention optimizes the components and the proportion thereof, and obviously improves the disintegration rate, the dissolution rate and the stability of related substances, especially when the filling agent is a mixture of mannitol, microcrystalline cellulose and hydroxypropyl- β -cyclodextrin, the improvement of each performance is obvious, although the fluidity of the mannitol is poor, the dissolution rate of the atorvastatin calcium and the stability of the related substances are obviously improved by combining the mannitol with the microcrystalline cellulose and the hydroxypropyl- β -cyclodextrin, and even when the atorvastatin calcium is in two particle size systems, the dissolution rate of the two particle size systems and the stability of the related substances can be obviously improved.
In addition, the invention does not adopt calcium carbonate stabilizing agent and a large amount of disintegrating agent, thereby avoiding stimulating gastrointestinal tract.
The disintegrating agent is divided into an inner disintegrating agent and an outer disintegrating agent, the composition and the proportion of the inner disintegrating agent and the outer disintegrating agent are optimized, and the dispersing effect, the disintegrating rate and the dissolution rate of the tablet are remarkably improved.
The auxiliary agent is added in the invention, and the auxiliary agent and other components have synergistic effect, thus being beneficial to improving the dispersibility, disintegration rate and dissolution rate of the tablet and improving the stability of related substances.
The invention optimizes the adding sequence and the stirring process of the raw materials, and adds the lubricant twice, thereby improving the dispersibility of the raw materials, avoiding the moisture absorption of the atorvastatin calcium, accelerating the disintegration of the tablet and improving the stability of related substances.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Example 1
The atorvastatin calcium tablet comprises the following components in parts by weight: 5 parts of atorvastatin calcium with the particle size of 30-40 mu m, 40 parts of starch, 1 part of povidone, 20 parts of crospovidone, 1 part of magnesium stearate and 03 parts of polyethylene glycol-40003.
The atorvastatin calcium tablet is prepared by the following method:
(1) mixing atorvastatin calcium, starch, 10% magnesium stearate and crospovidone, stirring at 50r/min for 5min, and then stirring at 200r/min for 10min to obtain a substance A;
(2) heating purified water to 40 ℃, and adding povidone and polyethylene glycol-4000 according to the mass ratio of 1:3 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 16-mesh sieve to obtain wet granules;
(4) drying the wet granules at 40 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding the rest 90% of magnesium stearate into the dry granules, and tabletting.
Example 2
The atorvastatin calcium tablet comprises the following components in parts by weight: 15 parts of atorvastatin calcium with the particle size of 30-40 mu m, 70 parts of mannitol, 5 parts of hydroxypropyl cellulose, 35 parts of sodium carboxymethyl starch, 5 parts of sodium stearate fumarate and 60008 parts of polyethylene glycol.
The atorvastatin calcium tablet is prepared by the following method:
(1) mixing atorvastatin calcium, mannitol, 20% sodium fumarate stearate and sodium carboxymethyl starch, stirring at 100r/min for 10min, and then at 300r/min for 20min to obtain a substance A;
(2) heating purified water to 50 ℃, and adding hydroxypropyl cellulose and polyethylene glycol-6000 according to the mass ratio of 1:10 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 18-mesh sieve to obtain wet granules;
(4) drying the wet granules at 60 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding the rest 80% of sodium fumarate stearate into the dry granules, and tabletting.
Example 3
The atorvastatin calcium tablet comprises the following components in parts by weight: 5 parts of atorvastatin calcium, 40 parts of microcrystalline cellulose, 1 part of adhesive, 20 parts of disintegrant, 1 part of silicon dioxide, 40003 parts of polyethylene glycol-40003 parts of and 1 part of aspartame.
The particle size composition of the atorvastatin calcium is as follows: 30-40 μm: 5-10 μm ═ 3: 1;
the adhesive is a mixture of gelatin and hydroxypropyl methylcellulose, and the mass ratio of the gelatin to the hydroxypropyl methylcellulose is 1: 1;
the disintegrating agent is a mixture of croscarmellose sodium, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and the mass ratio of the croscarmellose sodium to the microcrystalline cellulose to the low-substituted hydroxypropyl cellulose is 1:3: 2; the microcrystalline cellulose is an external disintegrating agent, the croscarmellose sodium is an internal disintegrating agent and an external disintegrating agent (the mass ratio of the internal disintegrating agent to the external disintegrating agent is 1:1), and the low-substituted hydroxypropyl cellulose is an internal disintegrating agent.
The atorvastatin calcium tablet is prepared by the following method:
(1) mixing atorvastatin calcium, microcrystalline cellulose, 10% silicon dioxide and all internal disintegrants, stirring at 50r/min for 5min, and then stirring at 200r/min for 10min to obtain a substance A;
(2) heating purified water to 40 ℃, and adding an adhesive and polyethylene glycol-4000 according to the mass ratio of 1:3 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 16-mesh sieve to obtain wet granules;
(4) drying the wet granules at 40 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding the rest silicon dioxide, all external disintegrating agents and aspartame into the dry granules, and tabletting to obtain the finished product.
Example 4
The atorvastatin calcium tablet comprises, by weight, 15 parts of atorvastatin calcium, 70 parts of hydroxypropyl- β -cyclodextrin, 5 parts of an adhesive, 35 parts of a disintegrant, 5 parts of superfine silica gel powder, 60008 parts of polyethylene glycol and 5 parts of glycyrrhizin.
The particle size composition of the atorvastatin calcium is as follows: 30-40 μm: 5-10 μm ═ 8: 1;
the adhesive is a mixture of gelatin and hydroxypropyl methylcellulose, and the mass ratio of the gelatin to the hydroxypropyl methylcellulose is 1: 2;
the disintegrating agent is a mixture of croscarmellose sodium, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and the mass ratio of the croscarmellose sodium to the microcrystalline cellulose to the low-substituted hydroxypropyl cellulose is 1:6: 4; the microcrystalline cellulose is an external disintegrating agent, the croscarmellose sodium is an internal disintegrating agent and an external disintegrating agent (the mass ratio of the internal disintegrating agent to the external disintegrating agent is 2:1), and the low-substituted hydroxypropyl cellulose is an internal disintegrating agent.
The atorvastatin calcium tablet is prepared by the following method:
(1) mixing atorvastatin calcium, hydroxypropyl- β -cyclodextrin, 20% micropowder silica gel and all internal disintegrants, stirring at 100r/min for 10min, and then at 300r/min for 20min to obtain a substance A;
(2) heating purified water to 50 ℃, and adding an adhesive and polyethylene glycol-6000 according to the mass ratio of 1:10 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 18-mesh sieve to obtain wet granules;
(4) drying the wet granules at 60 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding the rest micropowder silica gel and all external disintegrating agents and glycyrrhizin into the dry granules, and tabletting.
Example 5
The atorvastatin calcium tablet comprises the following components in parts by weight: 10 parts of atorvastatin calcium, 55 parts of microcrystalline cellulose, 3 parts of a binder, 30 parts of a disintegrant, 3 parts of silicon dioxide, 05 parts of polyethylene glycol-40005 and 3 parts of stevioside.
The particle size composition of the atorvastatin calcium is as follows: 30-40 μm: 5-10 μm ═ 6: 1;
the adhesive is a mixture of gelatin and hydroxypropyl methylcellulose, and the mass ratio of the gelatin to the hydroxypropyl methylcellulose is 1: 1.5;
the disintegrating agent is a mixture of croscarmellose sodium, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and the mass ratio of the croscarmellose sodium to the microcrystalline cellulose to the low-substituted hydroxypropyl cellulose is 1:4: 3; the microcrystalline cellulose is an external disintegrating agent, the croscarmellose sodium is an internal disintegrating agent and an external disintegrating agent (the mass ratio of the internal croscarmellose sodium to the external disintegrating agent is 1.5:1), and the low-substituted hydroxypropyl cellulose is an internal disintegrating agent;
the atorvastatin calcium tablet is prepared by the following method:
(1) mixing atorvastatin calcium, microcrystalline cellulose, 15% silicon dioxide and all internal disintegrants, stirring at 75r/min for 7min, and then stirring at 250r/min for 15min to obtain a substance A;
(2) heating purified water to 45 ℃, and adding an adhesive and polyethylene glycol-4000 according to the mass ratio of 1:6 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 18-mesh sieve to obtain wet granules;
(4) drying the wet granules at 50 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding the rest silicon dioxide, all external disintegrating agent and stevioside into the dry granules, and tabletting.
Example 6
The difference from example 5 is only that the dosage of atorvastatin calcium is unchanged, the particle size composition is only 30-40 μm, and the rest conditions are the same.
Comparative example 1
The difference from the embodiment 5 is only that the microcrystalline cellulose is an external disintegrating agent, the croscarmellose sodium is an internal disintegrating agent and an external disintegrating agent (the mass ratio of the internal croscarmellose sodium to the external disintegrating agent is 1:2), and the low-substituted hydroxypropyl cellulose is an internal disintegrating agent.
Comparative example 2
The difference from the embodiment 5 is only that the microcrystalline cellulose is an internal disintegrating agent, the croscarmellose sodium is an internal disintegrating agent and an external disintegrating agent (the mass ratio of the internal disintegrating agent to the external disintegrating agent of the croscarmellose sodium is 1.5:1), the low-substituted hydroxypropyl cellulose is an external disintegrating agent, and the rest conditions are the same.
Comparative example 3
The difference from example 5 is only that polyethylene glycol-4000 is replaced by polysorbate-800 of equal mass, and the rest conditions are the same.
Comparative example 4
The difference from the embodiment 5 is only that the adhesive is a mixture of gelatin and hypromellose, the mass ratio of the gelatin to the hypromellose is 2:1, and the rest conditions are the same.
Comparative example 5
The difference from example 5 is only that the lubricant is added at one time, which is different from the preparation method of the atorvastatin calcium tablet, and specifically comprises the following steps:
(1) mixing atorvastatin calcium, a filling agent and all internal disintegrating agents, stirring at 75r/min for 7min, and then stirring at 250r/min for 15min to obtain a substance A;
(2) heating purified water to 45 ℃, and adding an adhesive and polyethylene glycol-4000 according to the mass ratio of 1:6 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 18-mesh sieve to obtain wet granules;
(4) drying the wet granules at 50 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding lubricant, external disintegrating agent, and stevioside into the dry granules, and tabletting.
Comparative example 6
The difference from the example 5 is only that the adding sequence of the raw materials is different, and the specific steps are as follows:
(1) mixing atorvastatin calcium, a filling agent, all internal disintegrating agents, 15% of a lubricant and polyethylene glycol-4000, stirring at 75r/min for 7min, and then stirring at 250r/min for 15min to obtain a substance A;
(2) heating purified water to 45 ℃, and adding an adhesive according to the mass ratio of 1:6 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 18-mesh sieve to obtain wet granules;
(4) drying the wet granules at 50 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding the rest 85% of lubricant, all external disintegrating agent and stevioside into the dry granules, and tabletting.
Test example 1
Testing of disintegration time limit: 6 atorvastatin calcium tablets (specification 10mg) prepared in examples 1-6 and comparative examples 1-6 were taken respectively, tested by an LB-881B model six-tube disintegrator (Tianjin Ming medicine device), 1000ml of purified water at 37 +/-1 ℃ was used as a medium, and the time for the 6 tablets to completely disintegrate and pass through a screen with the aperture of 2.0mm was measured. The test results are shown in Table 1.
TABLE 1 disintegration time test of examples 1-6 and comparative examples 1-6
Test example 2
Dissolution testing: measured according to the dissolution determination method (second method of 0931 in the general rules of the chinese pharmacopoeia 2015). Taking 12 atorvastatin calcium tablets (specification 10mg) prepared in example 2, example 5, example 6 and comparative examples 1-3 of the invention, respectively, taking pH 1.2 hydrochloric acid and 900ml of water as solvents, respectively, and operating according to the method, taking appropriate amount of solution and filtering at 5 minutes, 10 minutes and 20 minutes respectively to obtain test solution; and precisely weighing about 25mg of an atorvastatin calcium reference substance, putting the atorvastatin calcium reference substance into a 25ml measuring flask, adding a proper amount of acetonitrile, performing ultrasonic treatment to dissolve the atorvastatin calcium reference substance, diluting the atorvastatin calcium reference substance to a scale, and shaking up the atorvastatin calcium reference substance. Precisely measuring 1ml, placing into a 100ml measuring flask, adding dissolution medium, diluting to scale, and shaking to obtain reference solution. Taking the test solution and the reference solution respectively, measuring absorbance at 244nm according to Chinese pharmacopoeia 2015, Nianmian Feidao 0401 ultraviolet-visible spectrophotometry, and calculating the dissolution rate. The test results are shown in tables 2 and 3.
Table 2 dissolution test results in water
| 5min/％ | 10min/％ | 20min/％ | |
| Example 2 | 93.1 | 98.6 | 99.8 |
| Example 5 | 95.7 | 99.5 | 99.9 |
| Example 6 | 94.0 | 99.1 | 99.7 |
Table 3 dissolution test results in hydrochloric acid pH 1.2
Test example 3
Test on the stability of the substances: atorvastatin calcium tablets (specification 10mg) prepared in example 5 of the present invention and comparative examples 1-2 and 5-6 were taken for stability examination under accelerated conditions (40 ℃, 75% RH).
The related substance detection method comprises the following steps: refer to high performance liquid chromatography (China pharmacopoeia 2015 edition general rules 0512).
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica was used as a filler, mixed organic phase [ acetonitrile-tetrahydrofuran without stabilizer (25:75) ] -ammonium dihydrogen phosphate buffer solution [5.75g/L of aqueous ammonium dihydrogen phosphate solution ], pH was adjusted to 4.3. + -. 0.05 (42:58) with glacial acetic acid (10%, v/v) or aqueous ammonia (10%, v/v) to give mobile phase A, and methanol-mixed organic phase-ammonium dihydrogen phosphate buffer solution (60:20:20) to give mobile phase B, and gradient elution was performed as shown in Table 4. The detection wavelength was 244 nm.
TABLE 4 gradient elution conditions
| Time (minutes) | Mobile phase A | Mobile phase B | Flow rate (ml/min) |
| 0 | 100 | 0 | 1.8 |
| 30 | 100 | 0 | 1.8 |
| 45 | 25 | 75 | 1.5 |
And (3) testing the applicability of the system: taking a proper amount of an atorvastatin calcium reference substance, an atorvastatin diastereoisomer (impurity B) reference substance, an atorvastatin lactone (impurity H) reference substance and an atorvastatin epoxide (impurity D) reference substance, adding N-N dimethylformamide for dissolving, and diluting to prepare a mixed solution of which each 1ml contains atorvastatin calcium, the impurity B, the impurity H and the impurity D with the concentrations of 60 mu g, 50 mu g, 10 mu g and 0.5 mu g respectively as a system applicability solution. And (3) injecting 20 mu l of the system applicability solution into a liquid chromatograph, and recording a chromatogram, wherein the separation degree of the atorvastatin impurity B and the atorvastatin is not lower than 1.4, the tailing factor of the atorvastatin peak is not higher than 1.5, the relative standard deviation of the atorvastatin peak is not higher than 5%, and the signal-to-noise ratio of the atorvastatin impurity D is not lower than 10.
The determination method comprises the following steps: taking 20 tablets of the product, grinding, precisely weighing a proper amount of fine powder (about equivalent to 50mg of atorvastatin), putting the fine powder into a 50ml measuring flask, adding about 30ml of solvent [ N, N-dimethylformamide ], mechanically shaking for 15 minutes, diluting the mixture to a scale with the solvent, shaking uniformly, filtering, and taking the subsequent filtrate as a sample solution. And precisely weighing a proper amount of an atorvastatin calcium reference substance, adding a solvent to dissolve and dilute the atorvastatin calcium reference substance to a solution containing 5 mu g of atorvastatin calcium per 1ml, and taking the solution as a reference solution. Precisely measuring 20 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording chromatogram. If an impurity peak exists in the chromatogram of the test solution, the content of each impurity is calculated according to the area of the peak of the atorvastatin peak in the reference solution, and the total impurity should not exceed 2.0 percent. The results of the test on the total content of the relevant substances are shown in Table 5.
TABLE 5 test results for related substances
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (10)
1. The atorvastatin calcium tablet is characterized by comprising the following components in parts by weight: 5-15 parts of atorvastatin calcium, 40-70 parts of a filler, 1-5 parts of a binder, 20-35 parts of a disintegrating agent, 1-5 parts of a lubricant and 3-8 parts of an auxiliary agent.
2. The atorvastatin calcium tablet of claim 1, wherein the particle size composition of the atorvastatin calcium is as follows: 30-40 μm: 5-10 μm ═ 3-8: 1.
3. The atorvastatin calcium tablet of claim 1, wherein the filler is at least one of mannitol, microcrystalline cellulose, starch, dextrin; the adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and gelatin; the disintegrating agent is one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose; the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, talcum powder, silicon dioxide and superfine silica powder; the auxiliary agent is at least one of polyethylene glycol-4000 and polyethylene glycol-6000; the atorvastatin calcium tablet further comprises 1-5 parts of a flavoring agent.
4. The atorvastatin calcium tablet of claim 3, wherein the adhesive is a mixture of gelatin and hypromellose, and preferably the mass ratio of the gelatin to the hypromellose is 1: 1-2.
5. The atorvastatin calcium tablet of claim 3, wherein the flavoring agent is one or more of sweet orange powder essence, aspartame, sodium cyclamate, glycyrrhizin, stevioside and saccharin.
6. The atorvastatin calcium tablet of claim 3, wherein the disintegrant is a mixture of croscarmellose sodium, microcrystalline cellulose and low substituted hydroxypropyl cellulose, and preferably the mass ratio of the croscarmellose sodium, the microcrystalline cellulose and the low substituted hydroxypropyl cellulose is 1:3-6: 2-4.
7. The atorvastatin calcium tablet of claim 6, wherein the microcrystalline cellulose is an external disintegrant, the croscarmellose sodium is an internal disintegrant and an external disintegrant, and the mass ratio of the internal disintegrant to the external disintegrant is 1-2: 1; the low-substituted hydroxypropyl cellulose is an internal disintegrating agent.
8. A process for the preparation of atorvastatin calcium tablets as defined in any one of claims 1 to 7 comprising the steps of:
(1) mixing atorvastatin calcium, a filling agent, a part of a lubricating agent and an internal disintegrating agent to obtain a substance A;
(2) adding an adhesive and an auxiliary agent into the purified water to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 16-18 mesh sieve to obtain wet granules;
(4) drying the wet granules, and sieving with a 20-mesh sieve to obtain dry granules;
(5) adding the rest lubricant and external disintegrating agent into the dry granules, and tabletting.
9. The method of claim 8, wherein the portion of the lubricant in step (1) is 10-20% lubricant; the step (2) comprises the following steps: heating purified water to 40-50 ℃, and adding an adhesive and an auxiliary agent according to the mass ratio of 1:3-10 to obtain a substance B.
10. The method of claim 8, comprising the steps of:
(1) mixing atorvastatin calcium, a filling agent, 10-20% of a lubricating agent and an internal disintegrating agent to obtain a substance A;
(2) heating purified water to 40-50 ℃, and adding an adhesive and an auxiliary agent according to the mass ratio of 1:3-10 to obtain a substance B;
(3) mixing the substance A and the substance B, and sieving with a 16-18 mesh sieve to obtain wet granules;
(4) drying the wet granules at 40-60 ℃, controlling the moisture content to be less than 2%, and sieving with a 20-mesh sieve for grading to obtain dry granules;
(5) adding the rest lubricant and external disintegrating agent into the dry granules, and tabletting.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112263560A (en) * | 2020-10-10 | 2021-01-26 | 湖南迪诺制药股份有限公司 | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof |
| CN113230223A (en) * | 2021-05-13 | 2021-08-10 | 宜昌人福药业有限责任公司 | Preparation method of atorvastatin calcium film coated tablet |
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| CN102309462A (en) * | 2011-07-16 | 2012-01-11 | 南京正宽医药科技有限公司 | Atorvastatin calcium tablet |
| CN102920675A (en) * | 2012-11-29 | 2013-02-13 | 河南润弘制药股份有限公司 | Atorvastatin calcium tablet and preparation method thereof |
| CN106176658A (en) * | 2016-06-29 | 2016-12-07 | 扬子江药业集团四川海蓉药业有限公司 | A kind of atorvastatin and preparation method thereof |
| CN106420645A (en) * | 2016-11-24 | 2017-02-22 | 浙江新东港药业股份有限公司 | Calcium tablet containing atorvastatin and preparation method |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309462A (en) * | 2011-07-16 | 2012-01-11 | 南京正宽医药科技有限公司 | Atorvastatin calcium tablet |
| CN102920675A (en) * | 2012-11-29 | 2013-02-13 | 河南润弘制药股份有限公司 | Atorvastatin calcium tablet and preparation method thereof |
| CN106176658A (en) * | 2016-06-29 | 2016-12-07 | 扬子江药业集团四川海蓉药业有限公司 | A kind of atorvastatin and preparation method thereof |
| CN106420645A (en) * | 2016-11-24 | 2017-02-22 | 浙江新东港药业股份有限公司 | Calcium tablet containing atorvastatin and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112263560A (en) * | 2020-10-10 | 2021-01-26 | 湖南迪诺制药股份有限公司 | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof |
| CN113230223A (en) * | 2021-05-13 | 2021-08-10 | 宜昌人福药业有限责任公司 | Preparation method of atorvastatin calcium film coated tablet |
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