CN113230225B - Atorvastatin calcium tablet and preparation method and application thereof - Google Patents
Atorvastatin calcium tablet and preparation method and application thereof Download PDFInfo
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- 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
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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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
- A61K9/2009—Inorganic compounds
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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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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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
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention relates to the technical field of medicine technology, in particular to an atorvastatin calcium tablet and a preparation method and application thereof, wherein the atorvastatin calcium tablet comprises a tablet core and a coating coated outside the tablet core, and the tablet core is prepared from the following components in parts by weight: 10-60 parts of atorvastatin calcium; 15-30 parts of a protective agent; 80-120 parts of a filling agent; 4-8 parts of a disintegrating agent; 0.3-1 part of a lubricant; the protective agent comprises anhydrous calcium hydrophosphate and modified hydroxyapatite. The atorvastatin calcium tablet provided by the invention has the advantages of good stability and high dissolution rate. The preparation method of the atorvastatin calcium tablet comprises pretreatment, material weighing, initial mixing, total mixing, tabletting and coating, and the tablet prepared by the preparation method has high dissolution rate and stable drug effect. The atorvastatin calcium tablet prepared by the invention can be applied to capsules, and has the advantages of convenience in dosage adjustment and strong practicability in clinical application.
Description
Technical Field
The invention relates to the technical field of medical technology, in particular to atorvastatin calcium tablets and a preparation method and application thereof.
Background
The atorvastatin calcium tablet is a second-generation statin drug, is a selective and competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is mainly used for treating hypercholesterolemia and coronary heart disease clinically, is a statin blood lipid regulating drug, and has a higher lipid lowering effect than other HMG-CoA reductase inhibitors.
Atorvastatin calcium tablets are inactive, and hydrolysate after oral absorption competitively inhibits a rate-limiting enzyme, namely hydroxymethylglutaryl coenzyme A reductase in the cholesterol synthesis process in vivo, so that the synthesis of cholesterol is reduced, the synthesis of a low-density lipoprotein receptor is increased, blood cholesterol and low-density lipoprotein levels are reduced, the serum triglyceride level is moderately reduced, and the blood high-density lipoprotein level is increased, thereby achieving the effect of reducing blood fat; and can be used for preventing and treating atherosclerosis and coronary heart disease with high blood lipid.
The atorvastatin calcium tablet has definite curative effect and obvious effect in clinical application, but the atorvastatin calcium tablet is extremely slightly soluble in water, has poor stability, is highly sensitive to moisture, heat, light and acid environments, and can be degraded to form corresponding lactone and reduce pharmacological activity particularly in the acid environment. In order to improve the stability of atorvastatin calcium tablets and ensure that the atorvastatin calcium tablets can be stably dissolved in the stomach, related researchers make a lot of attempts, and the currently common technical means is to add a large amount of disintegrants and alkaline stabilizers in a prescription to accelerate the disintegration speed of the medicines and enable the medicines to be in an alkaline medium to reduce the degradation of the medicines and ensure the dissolution rate of the medicines.
Although the technical means enables the finished product of atorvastatin calcium tablets to reach the relevant quality standard, adverse reactions are easily caused by the addition of a large amount of alkaline stabilizing agents and disintegrating agents in clinical application; therefore, atorvastatin calcium tablets with stable drug effect and good dissolution rate are needed.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide atorvastatin calcium tablets having good dissolution rate and stable drug effect.
In order to achieve the purpose, the invention provides an atorvastatin calcium tablet, which comprises a tablet core and a coating coated outside the tablet core, wherein the tablet core is prepared from the following components in parts by weight: 10-60 parts of atorvastatin calcium; 15-30 parts of a protective agent; 80-120 parts of a filling agent; 4-8 parts of a disintegrating agent; 0.3-1 part of a lubricant; the protective agent comprises anhydrous calcium hydrophosphate and modified hydroxyapatite.
Further, the modification operation of the hydroxyapatite is as follows: and (3) placing the hydroxyapatite in a chitosan solution, soaking for 24-48h by ultrasonic waves, centrifuging and drying after soaking.
Furthermore, the weight ratio of the hydroxyapatite in the protective agent to the anhydrous calcium hydrophosphate is 1.5-4.
Further, the filler is one or more of microcrystalline cellulose, lactose, mannitol, starch and dextrin; the disintegrating agent is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, talcum powder and silicon dioxide.
Further, the filler is lactose; the disintegrating agent is croscarmellose sodium, and the lubricating agent is magnesium stearate.
The atorvastatin calcium tablet has the beneficial effects that:
1. the formula system of the invention contains a protective agent, the protective agent comprises anhydrous calcium hydrophosphate and hydroxyapatite, the hydroxyapatite is an adduct of calcium phosphate and calcium hydroxide, is alkaline, can replace the traditional alkaline stabilizers such as calcium carbonate and the like, and has the advantage of difficult adverse reaction generation; the hydroxyapatite is a porous structure substance, has a large holding capacity for the main drug, and can adsorb the atorvastatin calcium in the inner pore channel after being mixed with the atorvastatin calcium, so that the contact between the atorvastatin calcium and the external environment is avoided or reduced, and the stability of the atorvastatin calcium tablet is further improved; meanwhile, the hydroxyapatite contains a large amount of hydroxyl groups, and is compatible with anhydrous calcium hydrophosphate for use, so that disintegration can be further promoted, the addition amount of a disintegrating agent is reduced, and the atorvastatin calcium tablet finished product has a relatively good dissolution rate.
2. According to the invention, the hydroxyapatite is coated and modified by chitosan, is not easy to cohere, and can form a structure of hydroxyapatite surface layer-chitosan adhesion layer-mixed drug layer on the surface or in the holes after being mixed with other components in the formula, so that the stability of the drug is improved, meanwhile, atorvastatin calcium in the hydroxyapatite can be fully dissolved out, and the finished drug is ensured to reach the relevant quality standard.
The invention also aims to provide a preparation method of the atorvastatin calcium tablet.
The preparation method of the atorvastatin calcium tablet specifically comprises the following steps: (1) pretreatment: modifying hydroxyapatite, weighing hydroxyapatite and anhydrous calcium hydrophosphate according to a proportion, mixing, sieving by a 30-mesh sieve, and preparing a protective agent for later use; weighing materials: weighing atorvastatin calcium, a protective agent, a filling agent, a disintegrating agent and a lubricating agent according to the formula, wherein the atorvastatin calcium passes through a 80-mesh sieve for later use; (3) primary mixing: mixing atorvastatin calcium, a protective agent and a part of disintegrating agent, and placing the mixture in a fluidized bed to ensure that the mixed material is in a fluidized state; (4) total mixing: adding the filler, the rest of the disintegrating agent and the lubricant into the mixture obtained in the step (3), and uniformly mixing for later use; and (5) tabletting: tabletting the mixture obtained in the step (4); and (6) coating.
Furthermore, the dosage of the disintegrating agent in the step (3) is 20-40% of the total amount.
The preparation method of the atorvastatin calcium tablet has the beneficial effects that: the preparation method has simple process, the hydroxyapatite is sieved by a sieve with 30 meshes, the main drug atorvastatin calcium is sieved by a sieve with 80 meshes, the mixture is mixed by a fluidized bed, and finally other components are added, and the atorvastatin calcium tablet is prepared by tabletting.
Another object of the present invention is to provide the use of the atorvastatin calcium tablets of claims 1 to 5 as a filling agent for capsules for preparing atorvastatin calcium capsules.
Further, the atorvastatin calcium capsule comprises a capsule shell and at least 2 atorvastatin calcium tablets filled in the capsule shell.
The invention has the beneficial effects that: the atorvastatin calcium tablet disclosed by the invention is not limited to tablets, and can be used as an internal filling agent of a capsule; the capsule filled with the atorvastatin calcium tablet has the advantages of the atorvastatin calcium tablet, is convenient for adjusting the dosage, can realize accurate medication, and has strong practicability in clinical application.
Detailed Description
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Preparation example
Preparation example 1
Weighing hydroxyapatite, sieving with a 30-mesh sieve, and placing into a chitosan solution with the mass fraction of 0.5% and the pH value of 6.50 for ultrasonic soaking for 24h, wherein stirring is not stopped in the process; and after soaking, centrifuging and drying to prepare hydroxyapatite coated with chitosan for later use.
Preparation example 2
Weighing hydroxyapatite, sieving with a 30-mesh sieve, placing into a chitosan solution with the mass fraction of 0.5% and the pH value of 6.50, ultrasonically soaking for 36h, centrifuging, filtering, and drying to obtain the hydroxyapatite coated with chitosan for later use.
Preparation example 3
Weighing hydroxyapatite, sieving with a 30-mesh sieve, placing into a chitosan solution with the mass fraction of 0.5% and the pH value of 6.50, ultrasonically soaking for 48h, centrifuging, filtering, and drying to obtain the hydroxyapatite coated with chitosan for later use.
Examples
In the following examples, lactose is used as filler, and in actual production, the filler can be any one or more of microcrystalline cellulose, lactose, mannitol, starch and dextrin.
In the following examples, croscarmellose sodium is used as the disintegrant, and in actual production, the disintegrant may be any one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.
Magnesium stearate is used as a lubricant in the following examples, and in actual production, the lubricant can be any one or more of magnesium stearate, sodium stearate fumarate, talcum powder and silicon dioxide.
Example 1
(1) Pretreatment: weighing the hydroxyapatite and the anhydrous calcium hydrophosphate prepared in the preparation example 1 according to the proportion of 1.5;
(2) Weighing: weighing 10g of atorvastatin calcium, 15g of protective agent, 80g of filler, 4g of disintegrant and 0.3g of lubricant, wherein the atorvastatin calcium is sieved by a sieve of 80 meshes for later use;
(3) Primary mixing: mixing atorvastatin calcium, a protective agent and 20% of a disintegrating agent, and placing the mixture in a fluidized bed to ensure that the mixed material is in a fluidized state, wherein the parameters of the fluidized bed are as follows: the air inlet temperature is 45-50 ℃, the spraying pressure is set to be 0.5MPa, the temperature of the mixed material is controlled to be 35-40 ℃, and the air outlet temperature is 35-40 ℃;
(4) Total mixing: adding the filler, the rest of the disintegrant and the lubricant into the mixture obtained in the step (3), and uniformly mixing for later use;
(5) Tabletting: tabletting the mixture obtained in the step (4);
(6) And (4) coating.
Example 2
(1) Pretreatment: weighing the hydroxyapatite and the anhydrous calcium hydrogen phosphate prepared in the preparation example 2 according to the proportion of 2.5;
(2) Weighing: weighing 10g of atorvastatin calcium, 15g of protective agent, 80g of filler, 4g of disintegrant and 0.3g of lubricant, wherein the atorvastatin calcium is sieved by a sieve of 80 meshes for later use;
(3) Primary mixing: mixing atorvastatin calcium, a protective agent and 20% of a disintegrating agent, placing the mixture in a fluidized bed, and enabling the mixture to be in a fluidized state, wherein the parameters of the fluidized bed are as follows: the air inlet temperature is 45-50 ℃, the spraying pressure is set to be 0.5MPa, the temperature of the mixed material is controlled to be 35-40 ℃, and the air outlet temperature is 35-40 ℃;
(4) Total mixing: adding the filler, the rest of the disintegrant and the lubricant into the mixture obtained in the step (3), and uniformly mixing for later use;
(5) Tabletting: tabletting the mixture obtained in the step (4);
(6) And (4) coating.
Example 3
(1) Pretreatment: weighing the hydroxyapatite and the anhydrous calcium hydrogen phosphate prepared in the preparation example 3 according to the proportion of 4;
(2) Weighing: weighing 10g of atorvastatin calcium, 15g of protective agent, 80g of filler, 4g of disintegrant and 0.3g of lubricant, wherein the atorvastatin calcium is sieved by a sieve of 80 meshes for later use;
(3) Primary mixing: mixing atorvastatin calcium, a protective agent and 20% of a disintegrating agent, and placing the mixture in a fluidized bed to ensure that the mixed material is in a fluidized state, wherein the parameters of the fluidized bed are as follows: the air inlet temperature is 45-50 ℃, the spraying pressure is set to be 0.5MPa, the temperature of the mixed material is controlled to be 35-40 ℃, and the air outlet temperature is 35-40 ℃;
(4) Total mixing: adding the filler, the rest of the disintegrant and the lubricant into the mixture obtained in the step (3), and uniformly mixing for later use;
(5) Tabletting: tabletting the mixture obtained in the step (4);
(6) And (4) coating.
Example 4
(1) Pretreatment: weighing the hydroxyapatite and the anhydrous calcium hydrophosphate prepared in the preparation example 2 according to the proportion of 2.5;
(2) Weighing: weighing 40g of atorvastatin calcium, 25g of protective agent, 100g of filling agent, 6g of disintegrating agent and 0.6g of lubricating agent, wherein the atorvastatin calcium is sieved by a 80-mesh sieve for later use;
(3) Primary mixing: mixing atorvastatin calcium, a protective agent and 30% of a disintegrating agent, placing the mixture in a fluidized bed, and enabling the mixture to be in a fluidized state, wherein the parameters of the fluidized bed are as follows: the air inlet temperature is 45-50 ℃, the spraying pressure is set to be 0.5MPa, the temperature of the mixed material is controlled to be 35-40 ℃, and the air outlet temperature is 35-40 ℃;
(4) Total mixing: adding the filler, the rest of the disintegrating agent and the lubricant into the mixture obtained in the step (3), and uniformly mixing for later use;
(5) Tabletting: tabletting the mixture obtained in the step (4);
(6) And (4) coating.
Example 5
(1) Pretreatment: weighing the hydroxyapatite and the anhydrous calcium hydrophosphate prepared in the preparation example 2 according to the proportion of 2.5;
(2) Weighing: weighing 60g of atorvastatin calcium, 30g of protective agent, 120g of filling agent, 8g of disintegrating agent and 1g of lubricant, wherein the atorvastatin calcium is sieved by a 80-mesh sieve for later use;
(3) Primary mixing: mixing atorvastatin calcium, a protective agent and 40% of a disintegrating agent, and placing the mixture in a fluidized bed to ensure that the mixed material is in a fluidized state, wherein the parameters of the fluidized bed are as follows: the air inlet temperature is 45-50 ℃, the spraying pressure is set to be 0.5MPa, the temperature of the mixed material is controlled to be 35-40 ℃, and the air outlet temperature is 35-40 ℃;
(4) Total mixing: adding the filler, the rest of the disintegrating agent and the lubricant into the mixture obtained in the step (3), and uniformly mixing for later use;
(5) Tabletting: tabletting the mixture obtained in the step (4);
(6) And (4) coating.
Comparative example
Comparative example 1
The preparation process of comparative example 1 was the same as that of example 4 except that 25g of hydroxyapatite, which was prepared in preparation example 2, was added as the protective agent.
Comparative example 2
Comparative example 2 was prepared by the same procedure as in example 4 except that 25g of anhydrous dibasic calcium phosphate was added as the protecting agent.
Comparative example 3
Comparative example 3 was prepared by the same procedure as in example 4 except that hydroxyapatite added thereto was not modified.
Comparative example 4
The raw material composition of comparative example 4 is the same as that of example 4, except that the initial mixing operation is different, and the specific preparation process is as follows:
(1) Pretreatment: weighing the hydroxyapatite and the anhydrous calcium hydrogen phosphate prepared in the preparation example 2 according to the proportion of 2.5;
(2) Weighing: weighing 60g of atorvastatin calcium, 30g of protective agent, 120g of filler, 8g of disintegrant and 1g of lubricant, wherein the atorvastatin calcium is sieved by a 80-mesh sieve for later use;
(3) Primary mixing: mixing atorvastatin calcium, a protective agent and 40% of a disintegrating agent, and uniformly stirring for later use;
(4) Total mixing: adding the filler, the rest of the disintegrant and the lubricant into the mixture obtained in the step (3), and stirring and mixing uniformly for later use;
(5) Tabletting: tabletting the mixture obtained in the step (4);
(6) And (4) coating.
Comparative example 5
The application number is CN112451498A, and the atorvastatin calcium tablet corresponding to the formula 1 in the example 1 is disclosed as well as a preparation method thereof.
The atorvastatin calcium tablet raw and auxiliary materials of the formula 1 comprise the following components in parts by weight: 10mg of atorvastatin calcium, 30mg of calcium carbonate, 3mg of magnesium oxide, 81.8mg of microcrystalline cellulose lactose complex, 6mg of aerosil, 5mg of sodium dodecyl sulfate, 5mg of croscarmellose sodium, 0.6mg of polysorbate 80, 3mg of hydroxypropyl cellulose, 0.75mg of magnesium stearate, and 4.5mg of Opadry coating powder (white) YS-I-7040.
Comparative example 6
The atorvastatin calcium tablet has the specification of 40mg, and the manufacturer is Beijing Jialin pharmaceutical industry Co.
Inspection and characterization
The properties and contents of the atorvastatin calcium tablets prepared in examples 1-5 (high performance liquid chromatography determination, general guideline 0512) are shown in table 1:
TABLE 1 Properties of atorvastatin calcium tablets in examples 1 to 5
| Group of | Traits | Content (c) of(％) |
| Example 1 | White intact tablet, and developing white color after removing coating | 100.3 |
| Example 2 | White whole tablet, appearing white after removing coating | 99.8 |
| Example 3 | White whole tablet, appearing white after removing coating | 99.9 |
| Example 4 | White whole tablet, appearing white after removing coating | 100.1 |
| Example 5 | White intact tablet, and developing white color after removing coating | 99.7 |
As can be seen from the table 1, the atorvastatin calcium tablets prepared in the embodiments 1 to 5 of the present invention have complete tablets, the content of the main drug is 95 to 105.0%, and the tablets meet the quality standards in pharmacopoeia.
(II) stability test
The atorvastatin calcium tablets prepared in the embodiments 1 to 5 and the comparative examples 1 to 6 are placed at the temperature of 25 +/-2 ℃ and the relative humidity of 60%, the change conditions of related substances and dissolution rates of the atorvastatin calcium tablets are respectively measured by high performance liquid chromatography (general rule 0512) in 0 day, 6 months, 18 months, 24 months and 36 months, and the test results are shown in tables 2 and 3:
table 2 results of stability test of atorvastatin calcium tablets in examples 1 to 5
Table 3 results of stability test of atorvastatin calcium tablets in comparative examples 1 to 6
The data in the table 2 show that the content of the related substances in the atorvastatin calcium tablet prepared by the invention is less than 1.5%, the dissolution rate is more than 85%, and the atorvastatin calcium tablet still has excellent stability and dissolution rate after being stored for 6 months, 18 months, 24 months and 36 months, and meets the relevant quality standard.
Combining tables 2 and 3, the specific analysis is as follows:
comparing the data of examples 1 to 5 with the data of comparative example 1, it can be seen that only adding modified hydroxyapatite in the formulation does not change the content of the related substances in the drug obviously with time, and the drug has excellent stability but the dissolution rate is reduced.
Comparing the data of examples 1 to 5 with that of comparative example 2, it can be seen that anhydrous dibasic calcium phosphate, which is alkaline when added to the formulation, also acts as an alkaline protectant temporarily, but the content of the relevant substances in the drug increases significantly after a certain period of storage due to its extreme water absorption.
Comparing the data of examples 1 to 5 with the data of comparative example 3, it can be seen that the addition of unmodified hydroxyapatite in the formulation still has superior stability but the dissolution rate is significantly reduced by virtue of the alkaline property and porous structure of hydroxyapatite; further, compared with the example 4, the comparative example 1 and the comparative example 2, the modified hydroxyapatite and the anhydrous calcium phosphate are compatible for use, and when the modified hydroxyapatite and the anhydrous calcium phosphate are added into the formula of the atorvastatin calcium tablet, the atorvastatin calcium tablet prepared by the method has the advantages of good stability and good dissolution rate.
Comparing the data of examples 1 to 5 with the data of comparative example 4, it can be seen that the preparation process of the present invention allows the main drug and the protective agent to be fully mixed, the prepared finished product has excellent stability and dissolution rate, the mixing effect is poor only by stirring and mixing, the structure of the hydroxyapatite cannot be fully utilized, and the main drug cannot be fully protected.
Comparing the data of examples 1 to 5 with the data of comparative example 5, it can be seen that, compared with the prior art, the content of the disintegrant in the formula system of the present invention is reduced, and adverse reactions are not easily caused in clinical application; meanwhile, compared with comparative example 5, the stability and dissolution rate are better.
Comparing the data of examples 1 to 5 with the data of comparative example 6, it can be seen that the atorvastatin calcium tablet prepared by the invention has better stability and dissolution rate and clinical application value compared with the commercial product.
In conclusion, the atorvastatin calcium tablet prepared by the invention has the advantages of good stability and good dissolution rate.
It should be added that the dosage form of the atorvastatin calcium tablet of the present invention is not limited to tablet, but can also be used as an internal filling agent of a capsule. The atorvastatin calcium capsule comprises a capsule shell and at least 2 atorvastatin calcium tablets filled in the capsule shell, and the capsule has all the advantages of the atorvastatin calcium tablets prepared by the invention; meanwhile, compared with the traditional capsule preparation, the preparation has the advantages of being convenient to adjust the dosage and capable of realizing accurate medication.
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Claims (6)
1. The atorvastatin calcium tablet comprises a tablet core and a coating coated outside the tablet core, and is characterized in that the tablet core is prepared from the following components in parts by weight:
10-60 parts of atorvastatin calcium;
15-30 parts of a protective agent;
80-120 parts of a filling agent;
4-8 parts of a disintegrating agent;
0.3-1 part of a lubricant;
the protective agent comprises anhydrous calcium hydrophosphate and modified hydroxyapatite;
the weight ratio of the modified hydroxyapatite in the protective agent to the anhydrous calcium hydrophosphate is 1.5-4;
the modification operation of the hydroxyapatite comprises the following steps: putting hydroxyapatite into chitosan solution, ultrasonically soaking for 24-48h, centrifuging and drying after soaking;
the preparation method of the atorvastatin calcium tablet specifically comprises the following steps:
(1) Pretreatment: modifying hydroxyapatite, weighing hydroxyapatite and anhydrous calcium hydrophosphate according to a proportion, mixing, sieving by a 30-mesh sieve, and preparing a protective agent for later use;
(2) Weighing: weighing atorvastatin calcium, a protective agent, a filling agent, a disintegrating agent and a lubricating agent according to the formula, wherein the atorvastatin calcium passes through a 80-mesh sieve for later use;
(3) Primary mixing: mixing atorvastatin calcium, a protective agent and a part of disintegrating agent, and placing the mixture in a fluidized bed to ensure that the mixed material is in a fluidized state;
(4) Total mixing: adding the filler, the rest of the disintegrant and the lubricant into the mixture obtained in the step (3), and uniformly mixing for later use;
(5) Tabletting: tabletting the mixture obtained in the step (4);
(6) And (4) coating.
2. The atorvastatin calcium tablet of claim 1, wherein the filler is one or more of microcrystalline cellulose, lactose, mannitol, starch, dextrin; the disintegrating agent is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, talcum powder and silicon dioxide.
3. The atorvastatin calcium tablet of claim 2, wherein the filler is lactose; the disintegrating agent is croscarmellose sodium, and the lubricating agent is magnesium stearate.
4. The atorvastatin calcium tablet of claim 1, wherein the amount of disintegrant used in step (3) is 20 to 40% of the total amount.
5. Use of the atorvastatin calcium tablet of any one of claims 1 to 4 as a filler for capsules for the preparation of atorvastatin calcium capsules.
6. The use of the atorvastatin calcium tablet of claim 5, wherein the atorvastatin calcium capsule comprises a capsule shell and at least 2 atorvastatin calcium tablets filled in the capsule shell.
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| CN114042052A (en) * | 2021-11-24 | 2022-02-15 | 海南皇隆制药股份有限公司 | Pitavastatin calcium tablet and preparation method thereof |
| CN115006358B (en) * | 2022-06-07 | 2023-05-23 | 石家庄市普力制药有限公司 | Engliflozin oral tablet and preparation method thereof |
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| US7411075B1 (en) * | 2000-11-16 | 2008-08-12 | Teva Pharmaceutical Industries Ltd. | Polymorphic form of atorvastatin calcium |
| EA018606B1 (en) * | 2006-01-05 | 2013-09-30 | Велоксис Фармасьютикалз А/С | Disintegrating loadable tablets |
| CN101979091B (en) * | 2010-11-04 | 2012-01-25 | 中国科学院上海硅酸盐研究所 | Preparation method of calcium phosphate nano medicament-carrying systems |
| CN104069502B (en) * | 2013-03-29 | 2018-02-16 | 北京罗诺强施医药技术研发中心有限公司 | Compound skeleton material and its pharmaceutical composition |
| CN105343024B (en) * | 2015-11-05 | 2018-03-30 | 石家庄市华新药业有限责任公司 | A kind of atorvastatin agent and preparation method thereof |
| CN106491554B (en) * | 2016-11-29 | 2019-08-09 | 乐普制药科技有限公司 | A kind of atorvastatin agent and preparation method thereof |
| TR201702101A2 (en) * | 2017-02-13 | 2018-08-27 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | ATORVASTATIN CALCIUM AND EZETIMIBIN PHARMACEUTICAL TWO-LAYER TABLET COMPOSITION |
| CN109453135A (en) * | 2018-12-29 | 2019-03-12 | 成都恒瑞制药有限公司 | Atorvastatin and preparation method thereof |
| CN111643471B (en) * | 2020-07-04 | 2023-03-07 | 上海安必生制药技术有限公司 | Atorvastatin calcium tablet and preparation method thereof |
| CN114042052A (en) * | 2021-11-24 | 2022-02-15 | 海南皇隆制药股份有限公司 | Pitavastatin calcium tablet and preparation method thereof |
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Denomination of invention: Atorvastatin calcium tablets and their preparation method and use Effective date of registration: 20230920 Granted publication date: 20221014 Pledgee: Qingdao Qishun Investment Management Co.,Ltd. Pledgor: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980057940 |