CN111643471A - Atorvastatin calcium tablet and preparation method thereof - Google Patents
Atorvastatin calcium tablet and preparation method thereof Download PDFInfo
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- CN111643471A CN111643471A CN202010633447.8A CN202010633447A CN111643471A CN 111643471 A CN111643471 A CN 111643471A CN 202010633447 A CN202010633447 A CN 202010633447A CN 111643471 A CN111643471 A CN 111643471A
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- 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
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Abstract
The invention relates to an atorvastatin calcium tablet which consists of atorvastatin calcium solid dispersion and other pharmaceutically acceptable auxiliary materials. The atorvastatin calcium solid dispersion consists of atorvastatin calcium, a surfactant and polyvinylpyrrolidone, wherein the weight ratio of the atorvastatin calcium to the surfactant to the polyvinylpyrrolidone in the atorvastatin calcium solid dispersion is 1 (0.05-5) to 1-10. The invention also relates to a preparation method of the atorvastatin calcium tablet. According to the invention, atorvastatin calcium is prepared into a solid dispersion, and a specific mixture ratio is adopted, so that the atorvastatin calcium tablet with good stability and quick dissolution is obtained. The preparation process is simple and is suitable for industrial production.
Description
Technical Field
The invention relates to an atorvastatin calcium tablet and a preparation method thereof.
Background
Cardiovascular and cerebrovascular diseases caused by atherosclerosis are one of diseases seriously harming human life health, and the research and development of blood fat reducing medicines are more and more paid more attention by people. The statins have obvious effect of resisting atherosclerosis, and can obviously reduce the risk and death rate of diseases such as coronary heart disease, angina, cerebrovascular accident and the like.
Atorvastatin calcium is a novel hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, is used as a new generation of statin hypolipidemic, can reduce cholesterol and triglyceride, and has far stronger effect than simvastatin, pravastatin, fluvastatin and lovastatin. The developer is the pfeiy pharmaceutical co ltd and has been approved by the FDA in 1997 for marketing in the united states and was approved for entry into the chinese market in 2000. The clinical use of the medicine shows that the medicine is safe and effective, the tolerance is good, and the adverse reaction is light.
Atorvastatin calcium is poorly stable, sensitive to moist heat, easily degraded at low pH, and insoluble in solutions with pH below 4. Lipitor developed by the pharmaceutical company pfizer shows a phenomenon of low dissolution during storage. How to improve the stability of the preparation and the dissolution rate of the medicine is the key for improving the treatment effect of the medicine.
Chinese patent CN104546775B discloses an atorvastatin calcium tablet, which contains atorvastatin calcium, hydroxypropyl cellulose and fumed silica, wherein the atorvastatin calcium and the hydroxypropyl cellulose are dissolved in diethylene glycol monoethyl ether and ether, the fumed silica is added for adsorption, and then the atorvastatin calcium and the hydroxypropyl cellulose are uniformly mixed with pharmaceutically acceptable auxiliary materials and are pressed by adopting a direct tabletting process.
Chinese patent CN106420645A discloses an atorvastatin calcium tablet and a preparation method thereof, wherein the atorvastatin calcium tablet is prepared by effectively mixing atorvastatin calcium with an alkaline diluent through a reasonable preparation process, adding a certain specific type of disintegrant, adopting an auxiliary material with good fluidity as a filler, increasing the compressibility and fluidity of an intermediate, and directly performing powder tabletting.
Chinese patent CN102139115B discloses a method for preparing atorvastatin cyclodextrin inclusion compound and oral solid preparation thereof, wherein the sulfobutyl-beta-cyclodextrin used has high moisture content, is easy to cause atorvastatin calcium degradation and has poor stability.
Chinese patent CN104306343B discloses an atorvastatin calcium tablet and a preparation method thereof, wherein atorvastatin calcium is dissolved in methanol, fine powder of potassium polacrilin IRP-88 is added for ultrasonic treatment, the mixture is dried under reduced pressure and crushed to obtain atorvastatin calcium solid dispersion, swollen carbomer 971P is added, the pH value is adjusted to 9-11, spray drying is carried out to obtain atorvastatin calcium pellets, the obtained pellets are placed in a fluidized bed, acrylic resin IV and ethyl cellulose coating liquid are sprayed in the pellets for coating to obtain the atorvastatin calcium pellets, and finally the atorvastatin calcium pellets are uniformly mixed with other pharmaceutically acceptable auxiliary materials and tabletted to obtain the atorvastatin calcium tablet. The atorvastatin calcium solid dispersion prepared by the solvent deposition technology greatly improves the drug solubility, reduces the side effects such as stomach discomfort and the like by the semipermeable membrane coating, but has complex process and high cost, and is not suitable for industrial production.
At present, the research on atorvastatin calcium in the prior art mainly focuses on two aspects of improving the stability of atorvastatin calcium and enhancing the dissolution performance of atorvastatin calcium. However, in order to improve the dissolution rate of atorvastatin calcium, the prior art mainly increases the dosage of a disintegrant or uses a super disintegrant, and the phenomena of higher impurities and slower dissolution are easy to occur in the storage process of a pharmaceutical preparation. The problem that how to ensure the dissolution rate of the atorvastatin calcium pharmaceutical preparation and ensure the stability of the atorvastatin calcium pharmaceutical preparation is still the problem to be solved in the field.
Disclosure of Invention
Aiming at the defects in the prior art, the atorvastatin calcium tablet with good stability and quick dissolution is prepared by preparing atorvastatin calcium into a solid dispersion and adopting a specific mixture ratio. The preparation process is simple and is suitable for industrial production.
Specifically, the invention is realized by the following technical means:
the atorvastatin calcium tablet is characterized by consisting of atorvastatin calcium solid dispersion and other pharmaceutically acceptable auxiliary materials. The atorvastatin calcium solid dispersion consists of atorvastatin calcium, a surfactant and polyvinylpyrrolidone, wherein the weight ratio of the atorvastatin calcium to the surfactant to the polyvinylpyrrolidone in the atorvastatin calcium solid dispersion is 1 (0.05-5) to 1-10.
As a preferred technical scheme, the pharmaceutically acceptable auxiliary materials are selected from one or more of fillers, binders, disintegrants, lubricants, alkalizers and coating materials
As a preferable technical scheme, the weight ratio of each component is 1 part of atorvastatin calcium, 2-12 parts of filling agent, 0.05-3 parts of adhesive, 0.02-3 parts of disintegrating agent, 0.02-1 part of lubricant, 1-8 parts of alkalizer and 0.05-2 parts of coating material.
As a preferred technical scheme, the filler is selected from one or more of lactose monohydrate, microcrystalline cellulose, starch, sucrose, dextrin, mannitol and pre-crosslinked starch.
As a preferable technical solution, the binder is selected from one or more of hydroxypropyl cellulose, polyvinylpyrrolidone, methylcellulose, hypromellose, sodium carboxymethylcellulose, ethylcellulose and polyethylene glycol.
As a preferable technical scheme, the disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone.
As a preferred technical scheme, the lubricant is selected from one or more of magnesium stearate, hydrogenated vegetable oil, calcium stearate and sodium stearyl fumarate.
As a preferred technical scheme, the alkalizer is selected from one or more of calcium carbonate, calcium hydrogen phosphate, calcium hydroxide and calcium oxide.
As a preferable technical solution, the coating material is selected from one or more of hypromellose, methylcellulose, hydroxyethyl cellulose, glycerol, propylene glycol, polyethylene glycol, talc, silicon dioxide, opadry.
A process for the preparation of atorvastatin calcium tablets comprising the steps of:
adding polyvinylpyrrolidone into a proper amount of methanol, stirring until the polyvinylpyrrolidone is completely dissolved, adding atorvastatin calcium and a surfactant, continuously stirring until the atorvastatin calcium and the surfactant are fully dissolved and uniformly mixed, drying under reduced pressure to remove the solvent, crushing to obtain an atorvastatin calcium solid dispersion, mixing with other pharmaceutically acceptable auxiliary materials, tabletting, and coating to obtain the atorvastatin calcium solid dispersion, wherein the weight ratio of the atorvastatin calcium to the surfactant to the polyvinylpyrrolidone in the atorvastatin calcium solid dispersion is 1 (0.05-5) to (1-10).
Compared with the prior art, the invention has the following advantages:
(1) the invention can improve the dissolution speed and solubility of atorvastatin calcium by dispersing the insoluble atorvastatin calcium in the water-soluble solid carrier to ensure that the atorvastatin calcium is highly dispersed.
(2) The solid dispersion technology is adopted to improve the dispersion degree of the atorvastatin calcium raw material, and the prepared atorvastatin calcium tablet has good stability, low impurity content and no obvious change in dissolution rate in the storage process.
(3) The preparation process is simple and easy to implement, and is suitable for industrial production.
The above-described and other features, aspects, and advantages of the present application will become more apparent with reference to the following detailed description.
Drawings
Figure 1 is a dissolution profile of atorvastatin calcium tablets in water.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs. The use of "first," "second," and similar terms in the description and claims of the present application do not denote any order, quantity, or importance, but rather the terms are used to distinguish one element from another. Also, the use of the terms "a" or "an" and the like do not denote a limitation of quantity, but rather denote the presence of at least one.
The invention aims to provide a preparation method of an atorvastatin calcium tablet. The preparation process is simple and is suitable for industrial production.
The atorvastatin calcium tablet consists of atorvastatin calcium solid dispersion and other pharmaceutically acceptable supplementary material. The atorvastatin calcium solid dispersion consists of atorvastatin calcium, a surfactant and polyvinylpyrrolidone, and the pharmaceutically acceptable auxiliary materials are selected from one or more of fillers, binders, disintegrants, lubricants, alkalinizing agents and coating materials.
The weight ratio of the atorvastatin calcium to the surfactant to the polyvinylpyrrolidone in the atorvastatin calcium solid dispersion is 1:0.05-5: 1-10. Wherein the weight ratio of each component is 1 part of atorvastatin calcium, 2-12 parts of filling agent, 0.05-3 parts of binding agent, 0.02-3 parts of disintegrating agent, 0.02-1 part of lubricating agent, 1-8 parts of alkalizer and 0.05-2 parts of coating material.
The filler is selected from one or more of lactose monohydrate, microcrystalline cellulose, starch, sucrose, dextrin, mannitol and pre-crosslinked starch.
The adhesive is selected from one or more of hydroxypropyl cellulose, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, ethyl cellulose and polyethylene glycol.
The disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone.
The lubricant is selected from one or more of magnesium stearate, hydrogenated vegetable oil, calcium stearate and sodium stearyl fumarate.
The alkalizer is one or more selected from calcium carbonate, calcium hydrogen phosphate, calcium hydroxide and calcium oxide.
The coating material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, glycerol, propylene glycol, polyethylene glycol, talcum powder, silicon dioxide and Opadry.
A process for the preparation of atorvastatin calcium tablets comprising the steps of:
adding polyvinylpyrrolidone into a proper amount of methanol, stirring until the polyvinylpyrrolidone is completely dissolved, adding atorvastatin calcium and a surfactant, continuously stirring until the atorvastatin calcium and the surfactant are fully dissolved and uniformly mixed, drying under reduced pressure to remove the solvent, crushing to obtain an atorvastatin calcium solid dispersion, mixing with other pharmaceutically acceptable auxiliary materials, tabletting, and coating to obtain the atorvastatin calcium solid dispersion.
The specific implementation mode is as follows:
example 1
Preparation of 1000 atorvastatin calcium tablets
Atorvastatin calcium 10.0g
Poloxamer 18810.0 g
Polyvinylpyrrolidone K3020.0 g
Lactose monohydrate 65.0g
Hydroxypropyl cellulose LXF 7.5g
Croscarmellose sodium 4.5g
Magnesium stearate 3.0g
Calcium carbonate 30.0g
Opadry YS-1-70406.5 g
The preparation process comprises the following steps:
weighing polyvinylpyrrolidone K30 with the formula amount, adding the polyvinylpyrrolidone K30 into 500ml of methanol, stirring until the polyvinylpyrrolidone K30 is completely dissolved, adding 10g of atorvastatin calcium and 18810 g of poloxamer, continuously stirring until the atorvastatin calcium and the poloxamer are fully dissolved and uniformly mixed, drying at 50 ℃ under reduced pressure to remove the methanol, crushing, and sieving with a 80-mesh sieve to obtain the atorvastatin calcium solid dispersion. Adding the atorvastatin calcium solid dispersion, lactose monohydrate, hydroxypropyl cellulose LXF, croscarmellose sodium, magnesium stearate and calcium carbonate into a hopper mixer in sequence, mixing for 15 minutes, calculating the weight of tablets, tabletting, weighing the Opadry according to the prescription amount and a proper amount of purified water to prepare a coating solution, and coating.
Comparative example 1
Preparation of 1000 atorvastatin calcium tablets
Atorvastatin calcium 10.0g
Lactose monohydrate 95.0g
Hydroxypropyl cellulose LXF 7.5g
Croscarmellose sodium 4.5g
Magnesium stearate 3.0g
Calcium carbonate 30.0g
Opadry YS-1-70406.5 g
The preparation process comprises the following steps:
weighing atorvastatin calcium according to a prescription amount, sieving the atorvastatin calcium by a 80-mesh sieve, sequentially adding the sieved atorvastatin calcium, lactose monohydrate, hydroxypropyl cellulose LXF, croscarmellose sodium, magnesium stearate and calcium carbonate into a hopper mixer, mixing for 15 minutes, calculating the weight of tablets, tabletting, weighing opadry according to the prescription amount and a proper amount of purified water to prepare coating liquid, and coating.
Comparative example 2
Preparation of 1000 atorvastatin calcium tablets
Atorvastatin calcium 10.0g
Poloxamer 18810.0 g
Polyvinylpyrrolidone K305.0g
Lactose monohydrate 80.0g
Hydroxypropyl cellulose LXF 7.5g
Croscarmellose sodium 4.5g
Magnesium stearate 3.0g
Calcium carbonate 30.0g
Opadry YS-1-70406.5 g
The preparation process comprises the following steps:
weighing polyvinylpyrrolidone K30 with the formula amount, adding the polyvinylpyrrolidone K30 into 500ml of methanol, stirring until the polyvinylpyrrolidone K30 is completely dissolved, adding 10g of atorvastatin calcium and 18810 g of poloxamer, continuously stirring until the atorvastatin calcium and the poloxamer are fully dissolved and uniformly mixed, drying at 50 ℃ under reduced pressure to remove the methanol, crushing, and sieving with a 80-mesh sieve to obtain the atorvastatin calcium solid dispersion. Adding the atorvastatin calcium solid dispersion, lactose monohydrate, hydroxypropyl cellulose LXF, croscarmellose sodium, magnesium stearate and calcium carbonate into a hopper mixer in sequence, mixing for 15 minutes, calculating the weight of tablets, tabletting, weighing the Opadry according to the prescription amount and a proper amount of purified water to prepare a coating solution, and coating.
Comparative example 3
Preparation of 1000 atorvastatin calcium tablets
Atorvastatin calcium 10.0g
Poloxamer 18810.0 g
Polyvinylpyrrolidone K30120.0g
Lactose monohydrate 65.0g
Hydroxypropyl cellulose LXF 7.5g
Croscarmellose sodium 4.5g
Magnesium stearate 3.0g
Calcium carbonate 30.0g
Opadry YS-1-704010.8 g
The preparation process comprises the following steps:
weighing polyvinylpyrrolidone K30 with the formula amount, adding the polyvinylpyrrolidone K30 into 500ml of methanol, stirring until the polyvinylpyrrolidone K30 is completely dissolved, adding 10g of atorvastatin calcium and 18810 g of poloxamer, continuously stirring until the atorvastatin calcium and the poloxamer are fully dissolved and uniformly mixed, drying at 50 ℃ under reduced pressure to remove the methanol, crushing, and sieving with a 80-mesh sieve to obtain the atorvastatin calcium solid dispersion. Adding the atorvastatin calcium solid dispersion, lactose monohydrate, hydroxypropyl cellulose LXF, croscarmellose sodium, magnesium stearate and calcium carbonate into a hopper mixer in sequence, mixing for 15 minutes, calculating the weight of tablets, tabletting, weighing the Opadry according to the prescription amount and a proper amount of purified water to prepare a coating solution, and coating.
Measurement of dissolution curve of atorvastatin calcium tablet
Taking 6 atorvastatin calcium tablets (specification 10mg) prepared in example 1 of the invention and comparative examples 1, 2 and 3 and 6 commercially available atorvastatin calcium tablets (lipitor, specification 10mg) respectively, operating according to a dissolution rate determination method (second method of 0931 in the fourth general rule of China pharmacopoeia 2015 edition) with 900ml of water solvent and 50 revolutions per minute, taking a proper amount of solution after 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes, filtering, and taking a subsequent filtrate as a sample solution; and taking an appropriate amount of an atorvastatin calcium reference substance (about equivalent to 25mg of atorvastatin calcium), precisely weighing, placing in a 25ml measuring flask, adding methanol for dissolving and diluting to a scale, shaking uniformly, precisely measuring 1ml, placing in a 100ml measuring flask, adding water for diluting to the scale, shaking uniformly, and taking as a reference substance solution. The two solutions were taken and measured for absorbance at a wavelength of 241nm by spectrophotometry (0401 in the fourth pharmacopoeia 2015 edition) to calculate the amount of elution of each tablet.
As can be seen from FIG. 1, the dissolution rates of the atorvastatin calcium tablets prepared in example 1 of the present invention are significantly higher than those of the atorvastatin calcium tablets prepared in comparative examples 1, 2 and 3 and commercially available atorvastatin calcium tablets (lipitor) at 5min, 10min and 15 min. When the weight ratio of the atorvastatin calcium, the surfactant and the polyvinylpyrrolidone in the atorvastatin calcium solid dispersion is out of 1 (0.05-5) to 1-10, the medicine dissolution is close to or slightly lower than that of the atorvastatin calcium raw material which is used singly. The weight ratio of the atorvastatin calcium, the surfactant and the polyvinylpyrrolidone in the atorvastatin calcium solid dispersion and the preparation method thereof provided by the invention can obviously improve the dissolution rate of the atorvastatin calcium.
Stability test
Atorvastatin calcium tablets (specification 10mg) prepared in the invention example 1 and the comparative example 1 and commercially available atorvastatin calcium tablets (lipitor, specification 10mg) are placed under an accelerated test (40 ℃ +/-2 ℃ and relative humidity of 75% +/-5%) to examine the content, related substances and change conditions of the related substances.
Content determination method of atorvastatin calcium tablets
Taking 20 atorvastatin calcium tablets (specification 10mg) prepared in example 1 of the invention and 20 atorvastatin calcium tablets (marketed) (lipitor, specification 10mg), precisely weighing, grinding, precisely weighing a proper amount (about equivalent to 10mg of atorvastatin), placing the atorvastatin calcium tablets in a 50 ml measuring flask, adding a proper amount of ethanol, fully shaking to dissolve atorvastatin calcium, adding ethanol to dilute to a scale, shaking uniformly, filtering, precisely measuring 2ml of subsequent filtrate, placing the subsequent filtrate in a 25ml measuring flask, adding ethanol to dilute the scale, and shaking uniformly to obtain a sample solution; and taking a proper amount of an atorvastatin calcium reference substance, precisely weighing, and adding ethanol to prepare a solution containing 16 mu g of atorvastatin calcium per 1ml, wherein the solution is used as a reference substance solution. Determining absorbance at 246nm wavelength according to spectrophotometry (four parts of pharmacopoeia 2015 edition 0401), and calculating to obtain final product
Determination of atorvastatin calcium tablet related substances
The measurement is carried out according to high performance liquid chromatography (the four-part general regulation 0512 in the 2015 edition of Chinese pharmacopoeia). Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent, acetonitrile-tetrahydrofuran-0.05 mol/L citric acid solution (0.05 mol/L citric acid is adjusted to pH value of 4.0 by ammonia water) (30:20: 50) is used as a mobile phase, and the detection wavelength is 244 nm. The number of theoretical plates should not be less than 3500 calculated as atorvastatin peak. The separation degree of the atorvastatin peak and each impurity peak is in accordance with the requirement. The determination method comprises the following steps: weighing atorvastatin calcium tablets (specification 10mg) prepared in example 1 and comparative example 1 of the invention and a proper amount (about equivalent to atorvastatin 12.5 mg) of commercially available atorvastatin calcium tablets (lipitor, specification 10mg) into a 25ml measuring flask, adding a proper amount of acetonitrile-tetrahydrofuran-0.05 mol/L citric acid solution (0.05 mol/L citric acid is adjusted to pH value of 4.0 by ammonia water) (50: 50), dissolving atorvastatin calcium by ultrasonic treatment for 5 minutes, cooling, diluting to scale with the solvent, shaking uniformly, filtering with a 0.45 mu m filter membrane, and taking the filtrate as a test solution; precisely measuring a proper amount of a test solution, adding the solvent to dilute the test solution into a solution containing 15 mu g of the test solution per lml, and taking the solution as a control solution; and (3) taking 20 mul of the reference solution, injecting the reference solution into a liquid chromatograph, adjusting the detection sensitivity to ensure that the peak height of the chromatographic peak of the main component is 25 percent of the full range of the recorder, carefully measuring 20 mul of the test solution and the reference solution respectively, injecting the test solution and the reference solution into the liquid chromatograph respectively, and recording the chromatogram until the retention time of the main component is 3 times. The chromatogram of the test solution shows impurity peaks, and the sum of the peak areas of the impurities is not larger than the main peak area (3.0%) of the control solution.
Dissolution rate determination method of atorvastatin calcium tablets
Taking 6 atorvastatin calcium tablets (specification 10mg) prepared in example 1 of the invention and comparative example 1 and 6 commercially available atorvastatin calcium tablets (lipitor, specification 10mg) respectively, operating according to a dissolution rate determination method (0931 second method of the four general rules of the pharmacopoeia 2015 edition) by using 900ml of water solvent at the rotating speed of 50 revolutions per minute, taking a proper amount of solution after 45 minutes, filtering, and taking a subsequent filtrate as a sample solution; and taking an appropriate amount of an atorvastatin calcium reference substance (about equivalent to 25mg of atorvastatin calcium), precisely weighing, placing in a 25ml measuring flask, adding methanol for dissolving and diluting to a scale, shaking uniformly, precisely measuring 1ml, placing in a 100ml measuring flask, adding water for diluting to the scale, shaking uniformly, and taking as a reference substance solution. The two solutions are taken, and absorbance is measured at 241nm wavelength according to spectrophotometry (0401 in the four parts of the Chinese pharmacopoeia 2015 edition), and the dissolution amount of each tablet is calculated, wherein the limit is 80% of the labeled amount and is in line with the specification.
As can be seen from the above table, through the accelerated stability test, the impurity level of the atorvastatin calcium tablet prepared in example 1 of the present invention is significantly better than that of comparative example 1 and the commercially available product (lipitor), the dissolution rate of the comparative example 1 and the commercially available product (lipitor) is significantly reduced during the accelerated stability period, but the content and the dissolution rate of the atorvastatin calcium tablet prepared in example 1 of the present invention have no significant change compared with 0 day, which indicates that the atorvastatin calcium tablet prepared by the solid dispersion technology of the present invention has good stability.
Through the investigation of the dissolution curve and the stability, the atorvastatin calcium tablet and the preparation method thereof provided by the invention can effectively improve the dissolution of atorvastatin calcium and solve the problems of impurity increase and dissolution reduction during the stability period.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and the description is given here only for clarity, and those skilled in the art should integrate the description, and the embodiments may be combined appropriately to form other embodiments understood by those skilled in the art.
Claims (10)
1. The atorvastatin calcium tablet is characterized by consisting of atorvastatin calcium solid dispersion and other pharmaceutically acceptable auxiliary materials. The atorvastatin calcium solid dispersion consists of atorvastatin calcium, a surfactant and polyvinylpyrrolidone, wherein the weight ratio of the atorvastatin calcium to the surfactant to the polyvinylpyrrolidone in the atorvastatin calcium solid dispersion is 1 (0.05-5) to 1-10.
2. The atorvastatin calcium tablet of claim 1, wherein the pharmaceutically acceptable excipients are selected from one or more of fillers, binders, disintegrants, lubricants, alkalinizing agents and coating materials.
3. The atorvastatin calcium tablet of claim 1, wherein the atorvastatin calcium tablet consists of the following components: 1 part by weight of atorvastatin calcium, 2-12 parts by weight of filler, 0.05-3 parts by weight of adhesive, 0.02-3 parts by weight of disintegrant, 0.02-1 part by weight of lubricant, 1-8 parts by weight of alkalizer and 0.05-2 parts by weight of coating material.
4. The atorvastatin calcium tablet of claim 2, wherein the filler is selected from one or more of lactose monohydrate, microcrystalline cellulose, starch, sucrose, dextrin, mannitol, pre-crosslinked starch.
5. The atorvastatin calcium tablet of claim 2, wherein the binder is selected from one or more of hydroxypropyl cellulose, polyvinylpyrrolidone, methylcellulose, hypromellose, sodium carboxymethylcellulose, ethylcellulose and polyethylene glycol.
6. The atorvastatin calcium tablet of claim 2, wherein the disintegrant is one or more selected from the group consisting of sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone.
7. The atorvastatin calcium tablet of claim 2, wherein the lubricant is selected from one or more of magnesium stearate, hydrogenated vegetable oil, calcium stearate and sodium stearyl fumarate.
8. The atorvastatin calcium tablet of claim 2, wherein the alkalizer is selected from one or more of calcium carbonate, calcium hydrogen phosphate, calcium hydroxide and calcium oxide.
9. The atorvastatin calcium tablet of claim 2, wherein the coating material is selected from one or more of hypromellose, methylcellulose, hydroxyethylcellulose, glycerol, propylene glycol, polyethylene glycol, talc, silicon dioxide, opadry.
10. A process for the preparation of atorvastatin calcium tablets comprising the steps of:
adding polyvinylpyrrolidone into a proper amount of methanol, stirring until the polyvinylpyrrolidone is completely dissolved, adding atorvastatin calcium and a surfactant, continuously stirring until the atorvastatin calcium and the surfactant are fully dissolved and uniformly mixed, drying under reduced pressure to remove the solvent, crushing to obtain an atorvastatin calcium solid dispersion, mixing with other pharmaceutically acceptable auxiliary materials, tabletting, and coating to obtain the atorvastatin calcium solid dispersion, wherein the weight ratio of the atorvastatin calcium to the surfactant to the polyvinylpyrrolidone in the atorvastatin calcium solid dispersion is 1 (0.05-5) to (1-10).
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|---|---|---|---|---|
| CN113230225A (en) * | 2021-05-17 | 2021-08-10 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method and application thereof |
| CN113546050A (en) * | 2021-07-07 | 2021-10-26 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107998085A (en) * | 2017-11-29 | 2018-05-08 | 乐普制药科技有限公司 | A kind of tablet containing Atorvastatin calcium alkali solid dispersion and preparation method thereof |
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2020
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| CN107998085A (en) * | 2017-11-29 | 2018-05-08 | 乐普制药科技有限公司 | A kind of tablet containing Atorvastatin calcium alkali solid dispersion and preparation method thereof |
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| LIANDONG HU等: ""Investigation of Solid Dispersion of Atorvastatin Calcium in Polyethylene Glycol 6000 and Polyvinylpyrrolidone"", 《TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH》 * |
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| 鲍佳音等: ""塞来昔布增溶技术研究进展"", 《浙江化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113230225A (en) * | 2021-05-17 | 2021-08-10 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method and application thereof |
| CN113546050A (en) * | 2021-07-07 | 2021-10-26 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method thereof |
| CN113546050B (en) * | 2021-07-07 | 2022-11-29 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN111643471B (en) | 2023-03-07 |
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