CN118078768A - Amlodipine atorvastatin calcium tablet and preparation method thereof - Google Patents

Abstract

The invention relates to an amlodipine atorvastatin calcium tablet and a preparation method thereof, wherein the amlodipine atorvastatin calcium tablet is a core-in-package tablet and comprises an inner tablet core containing atorvastatin calcium and an outer tablet layer containing amlodipine besylate, and the inner tablet core also comprises meglumine and sodium laurylsulfate. According to the invention, the amlodipine besylate and the atorvastatin calcium are prepared into the core-in-package tablet, so that the effective isolation of two active ingredients in the same tablet is realized, and the compatibility of the atorvastatin calcium and the amlodipine besylate is obviously improved; meanwhile, as the tablet-coating core is separately granulated at the inner layer and the outer layer before tabletting, the problem of poor mixing uniformity of total mixed particles in the conventional tablet preparation process is effectively solved; in addition, when the inner layer tablet core is prepared, by adding meglumine and sodium laurylsulfate, the dissolution rate of atorvastatin calcium is further improved, the product quality is further ensured, and the stability and safety of the product are improved.

Description

Amlodipine atorvastatin calcium tablet and preparation method thereof

Technical Field

The invention belongs to the technical field of medicinal preparations, and in particular relates to an amlodipine atorvastatin calcium tablet and a preparation method thereof.

Background

The chemical name of atorvastatin calcium is (3R, 5R) -7- [2- (4-fluorophenyl) -3-phenyl-4- (phenylcarbamoyl) -5-isopropyl pyrrol-1-yl ] -3,5 dihydroxyheptanoic acid calcium trihydrate, and the structural formula is as follows:

Atorvastatin calcium is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Atorvastatin calcium is inactive, and hydrolysate after oral administration can competitively inhibit the speed-limiting enzyme, namely, hydroxymethylglutaryl coenzyme A reductase, in the cholesterol synthesis process in vivo, so that the synthesis of cholesterol is reduced, and simultaneously, the synthesis of a low-density lipoprotein receptor is increased, and the atorvastatin calcium is mainly used for treating hypercholesterolemia and coronary heart disease.

The chemical name of amlodipine besylate is (+ -) -2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid-3-ethyl ester-5-methyl ester benzenesulfonate, and the structural formula is as follows:

Amlodipine is a dihydropyridine calcium channel blocker, can inhibit calcium ions from flowing into vascular smooth muscle and cardiac muscle through a membrane, reduces the concentration of calcium ions in cells, expands blood vessels by reducing the contraction of the vascular smooth muscle, increases the permeability of the blood vessels, and reduces peripheral vascular resistance and blood pressure; on the other hand, the heart muscle contraction force and heart rate are reduced, and the oxygen consumption of the heart muscle is reduced, so that the heart burden is lightened, and the traditional Chinese medicine composition is mainly used for treating hypertension and coronary heart disease.

The amlodipine atorvastatin calcium tablet is developed for Pfizer inc at the earliest time, is marketed in the United states for the first time in 1 month and 30 days in 2004, has the commodity name of CADUET, and is a compound preparation for treating patients with hyperlipidemia accompanied by hypertension or coronary heart disease, wherein amlodipine is suitable for hypertension, coronary heart disease and the like, and atorvastatin is suitable for hyperlipidemia. The successful development of the compound preparation realizes that one medicine simultaneously produces the synergistic effect of reducing blood pressure and blood lipid, effectively simplifies the combined medicine condition of patients, avoids the phenomenon of missed taking of patients, effectively improves the compliance of taking medicine of patients and has good clinical application value.

The existing dosage forms and preparation technology mainly comprise descriptions of common tablets, capsules and preparation methods of double-layer tablets of amlodipine and atorvastatin calcium. Common tablets and capsules of amlodipine atorvastatin calcium and methods for preparing the same (mainly comprising a wet granulation tabletting method and a powder mixing direct tabletting method) are described in the patent application publication numbers CN105012258A, CN104644633A and CN 102274224A. The application publication numbers CN104825449A and CN201572341U both describe a double-layer tablet of amlodipine and atorvastatin calcium and a preparation method thereof, wherein the atorvastatin calcium layer mainly adopts a wet granulation process, and the amlodipine layer mainly adopts a powder direct mixing process.

Because amlodipine besylate is not stable enough under the conditions of illumination and damp heat, and certain incompatibility exists between the amlodipine besylate and atorvastatin calcium as well as a corresponding alkaline protective agent, the impurity level of the preparation is obviously increased by adopting a conventional wet granulation method after the amlodipine besylate and the atorvastatin calcium are directly mixed. The common tablets of amlodipine and atorvastatin calcium disclosed in the above patent are mainly prepared by adopting a process of wet granulating atorvastatin calcium and then mixing the granules with amlodipine for tabletting, or are directly prepared into double-layer tablets. However, the above trial production process cannot ensure complete isolation of the two APIs, and cannot radically and thoroughly solve the problems of compatibility of the two APIs and high impurity content of the preparation. Furthermore, in the process of imitation development of amlodipine and atorvastatin calcium tablets, the surprise of the company finds that the tablet has serious sticking and cracking problems after amlodipine besylate and atorvastatin calcium are directly mixed, and when the process of mixing and tabletting the atorvastatin calcium and amlodipine after wet granulation is performed for trial production, the uniformity of mixing of total mixed particles (and the content uniformity of corresponding tablets) is poor because the granularity difference between the atorvastatin calcium layer particles and the amlodipine layer particles is larger; when preparing a bilayer tablet, this tends to result in poor uniformity of the content of API in the second layer of the tablet and reduced overall tablet yield. Therefore, the production process and the formulation development of the amlodipine atorvastatin calcium tablet need to be further developed and are rich and perfected.

Disclosure of Invention

The invention aims to solve the technical problem of providing an amlodipine atorvastatin calcium tablet with high dissolution and low impurity content and a preparation method thereof.

In order to achieve the above purpose, the invention adopts the following technical scheme:

The first aspect of the invention provides an amlodipine atorvastatin calcium tablet which is a core-in-package tablet and comprises an inner tablet core containing atorvastatin calcium and an outer tablet layer containing amlodipine besylate, wherein the inner tablet core comprises meglumine and sodium lauryl sulfate.

According to some specific and preferred embodiments, the mass ratio of meglumine to sodium lauryl sulfate is 0.5-5: 1, for example 0.5:1, 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1 or 5:1.

According to some specific and preferred embodiments, the meglumine comprises 1-3% of the total mass of the inner layer tablet core, such as 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.2%, 2.4%, 2.6%, 2.8% or 3%.

According to some specific and preferred embodiments, the composition of the inner core further comprises a filler in an amount of 35% to 45% of the total mass of the inner core, such as 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44% or 45%.

According to some specific and preferred embodiments, the composition of the inner core further comprises a stabilizer in an amount of, for example, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37% or 38% of the total mass of the inner core.

According to some specific and preferred embodiments, the composition of the inner core further comprises a disintegrant in an amount of, for example, 2%, 3%, 4%, 5%, 6%, 7% or 8% of the total mass of the inner core.

According to some specific and preferred embodiments, the composition of the inner sheet core further comprises 1-5% binder, e.g. 1%, 2%, 3%, 4% or 5% binder, based on the total mass of the inner sheet core.

According to some specific and preferred embodiments, the composition of the inner core further comprises 0.1% -1% of surfactant, e.g. 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% of the total mass of the inner core.

According to some specific and preferred embodiments, the composition of the inner core further comprises 0.5% -2% of a lubricant, e.g. 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% or 2% of the total mass of the inner core.

According to some specific and preferred embodiments, the composition of the inner tablet core further comprises a coating material comprising 2% to 5% of the total mass of the inner tablet core.

Further, in the inner sheet core, the filler includes one or more of microcrystalline cellulose, lactose, and pregelatinized starch; the stabilizer comprises one or more of calcium carbonate, magnesium carbonate and magnesium oxide; the disintegrating agent comprises one or more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch; the binder comprises hydroxypropyl cellulose and/or povidone K30; the surfactant comprises one or more of polysorbate 80, poloxamer and span 20; the lubricant comprises magnesium stearate and/or sodium hard fumarate; the coating material is a composition of titanium dioxide, talcum powder, polyethylene glycol and polyvinyl alcohol.

According to some specific and preferred embodiments, the composition of the outer layer sheet comprises a filler in an amount of 80-92% by total mass of the outer layer sheet, for example 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% or 92%.

According to some specific and preferred embodiments, the composition of the outer layer tablet layer further comprises a disintegrant in an amount of 2-12% of the total mass of the outer layer tablet layer, e.g. 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11% or 12%.

According to some specific and preferred embodiments, the composition of the outer layer sheet further comprises 0.5-2.5% of a lubricant, e.g. 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4% or 2.5% of the total mass of the outer layer sheet.

Further, in the outer ply layer, the filler includes one or more of microcrystalline cellulose, pregelatinized starch, anhydrous dibasic calcium phosphate, and corn starch; the disintegrating agent comprises one or more of carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium and corn starch; the lubricant comprises magnesium stearate and/or colloidal silica.

According to some specific and preferred embodiments, the atorvastatin calcium accounts for 9% -11% of the total mass of the inner tablet core, and the amlodipine besylate accounts for 3% -4% of the total mass of the outer tablet core.

The second aspect of the invention provides a preparation method of the amlodipine atorvastatin calcium tablet, which is characterized in that: the method comprises the following steps:

(1) Mixing and granulating the materials of the inner layer tablet cores, tabletting and coating to obtain the inner layer tablet cores;

(2) Mixing the materials of the outer layer sheet layer to obtain mixed powder;

(3) And pressing the mixed powder and the inner layer tablet core according to standard tablet weight and hardness setting parameters to obtain the core-spun tablet.

According to some specific and preferred embodiments, in step (1), the parameters controlling the tabletting are: tabletting speed is 3-6 ten thousand tablets/hour, feeding frequency is 25-40 Hz, and main pressure is 5-8 kN; the weight difference in the tabletting process is controlled to be +/-5.0%, the average hardness range of 10 tablets is 60+/-15N, the disintegration time limit is less than or equal to 5min, and the friability is less than or equal to 0.8% of the weight loss.

According to some specific and preferred embodiments, in step (3), the parameters controlling the pressing are: the tabletting speed is 2-4 ten thousand tablets/hour, the feeding frequency of the inner layer tablet core is 25-40 Hz, the feeding frequency of the mixed powder is 25-40 Hz, and the main pressure is 8-12 kN; the weight difference in the pressing process is controlled to be +/-5.0%, the average hardness range of 10 tablets is 120+/-15N, the disintegration time is less than or equal to 6min, and the friability is less than or equal to 0.8% of the weight loss.

According to some specific and preferred embodiments, in step (3), the compacting is performed using a core-in-core tablet press, installing a tablet die, and then sequentially adding the powder blend and the inner core tablet.

Wherein, standard tablet weight (g) =amlodipine mark amount/amlodipine content% + atorvastatin calcium coated tablet average tablet weight); average sheet weight control range: standard tablet weight (1±2.0%).

According to some specific and preferred embodiments, the specific steps of step (1) comprise:

1.1, adding a surfactant, meglumine and an adhesive into water, stirring and dissolving;

1.2, adding a filler, a stabilizer, atorvastatin calcium and a disintegrating agent into a wet granulator for premixing;

1.3, starting a wet granulator, and adding the solution prepared in the step 1.1 to prepare wet granules;

1.4, carrying out wet granulation on the prepared wet granules, and discharging;

1.5, drying the wet granules after finishing in a fluidized bed;

1.6, placing the dried particles, sodium laurylsulfate and a lubricant into a column mixer, and mixing to obtain total mixed particles;

1.7, tabletting the total mixed particles by adopting a tablet press;

and 1.8, coating the tablet cores subjected to tabletting by adopting a coating machine to obtain inner-layer tablet cores.

Further, in the step 1.1, the temperature of the water is controlled to be 50-60 ℃, so that the preparation requirement can be well met.

Further, in step 1.1, the prepared solution is cooled to below 40 ℃ for standby.

Further, in the step 1.1, the ratio of the feeding mass of water to the total feeding mass of the surfactant, meglumine, sodium lauryl sulfate and the adhesive is 25:0.5-4.

Further, in step 1.2, parameters for controlling mixing are: the stirring speed is 50-100 rpm, the granulating knife speed is 200-400 rpm, and the mixing time is 4-10 min.

Further, in the step 1.3, the solution prepared in the step 1.1 is added under the conditions of stirring rotation speed of 100-150 rpm and granulating knife rotation speed of 200-400 rpm, and the liquid adding time is controlled to be 2-3 min.

Further, in the step 1.4, after the liquid adding is completed, the granulation is carried out for 1 to 3 minutes under the conditions of the stirring rotation speed of 100 to 150rpm and the granulating knife rotation speed of 800 to 1200 rpm. Then, a square stainless steel screen mesh with the diameter of (3-5) x (3-5) mm is adopted, the grain finishing rotating speed is 800-1000 rpm, the wet grain finishing is carried out on the materials, and the materials are discharged.

Further, in the step 1.5, the air inlet temperature is set to be 55-75 ℃, and the air exhaust frequency conversion is adjusted to be 30-50% according to the materials. When the temperature of the material reaches 45-55 ℃, sampling and detecting the drying weight loss, and when the drying weight loss is less than or equal to 3.0%, finishing drying and discharging.

Further, in step 1.6, the mixture is mixed at a mixing speed of 6 to 8rpm for 8 to 12 minutes.

Wherein, the atorvastatin calcium total mixed particles are white or white-like powder, the drying weight loss is less than or equal to 3.0 percent, and the content is 9.50 to 10.50 percent.

Further, in step 1.7, a full-automatic rotary tablet press is adopted, and a tablet pressing die is arranged to press the inner layer tablet core.

Further, in the step 1.8, the rotating speed of the pot body is set to be 2-6 rpm, the atomization pressure is 0.5-0.5 MPa, the rotating speed of the liquid spraying peristaltic pump is 10-20 rpm, and the coating is started. The temperature of the tablet bed is maintained between 38 and 48 ℃ in the coating process, and the weight gain range of the coated tablet is controlled between 2.5 and 4.0 percent.

According to some specific and preferred embodiments, the specific steps of step (2) comprise:

2.1, firstly adding a disintegrating agent and amlodipine besylate into a mixer for premixing to obtain mixed powder I;

2.2, putting 1/2 prescription amount of filler and the mixed powder I into a mixer for premixing to obtain mixed powder II;

2.3, placing the rest filler and the mixed powder II into a mixer for premixing to obtain mixed powder III;

And 2.4, mixing the mixed powder III with a lubricant to obtain the mixed powder.

Further, in the step 2.1, the mixture is mixed for 12 to 18 minutes at a rotation speed of 4 to 10 rpm.

Further, in the step 2.2, the mixture is mixed for 8 to 12 minutes at a rotation speed of 4 to 10 rpm.

Further, in the step 2.3, the mixture is mixed for 18 to 22 minutes at a rotation speed of 4 to 10 rpm.

Further, in the step 2.4, the mixture is mixed for 8 to 12 minutes at a rotation speed of 4 to 10 rpm.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

According to the invention, the amlodipine atorvastatin calcium is prepared into the core-in-package tablet, so that effective isolation of two active ingredients in the same tablet is realized, and the compatibility of the atorvastatin calcium and amlodipine besylate is obviously improved; meanwhile, as the tablet-coating core is separately granulated at the inner layer and the outer layer before tabletting, the problem of poor mixing uniformity of total mixed particles in the conventional tablet preparation process is effectively solved; in addition, when the inner layer tablet core is prepared, by adding meglumine and sodium laurylsulfate, the dissolution rate of atorvastatin calcium is further improved, the product quality is further ensured, and the stability and safety of the product are improved. The chip has the advantages of good uniformity of product content, high dissolution rate, low impurity content and the like, and has great market application value.

The preparation method has good mixing uniformity in the preparation process and the product quality is easy to control.

Detailed Description

The existing preparation method of the amlodipine atorvastatin calcium tablet mainly comprises the following steps: 1. wet granulating atorvastatin calcium, mixing with amlodipine layer material, and directly pressing into common tablet; 2. the atorvastatin calcium and the amlodipine are respectively granulated (or mixed) and then pressed into double-layer tablets. The former trial-produced product has poorer dissolution and content uniformity and higher impurity level; the second layer of the product has poor API content uniformity and low product yield.

In order to thoroughly solve the defects of common tablets and double-layer tablets of amlodipine and atorvastatin calcium, simultaneously promote the continuous improvement of the stability of the product and further promote and ensure the quality of the product, the invention firstly carries out wet granulation on atorvastatin calcium, adds proper cosolvent combination in the granulation process, then presses the tablet core independently, and carries out isolation coating on the tablet core; then, the amlodipine is singly granulated by adopting a powder direct mixing process; and finally, pressing the mixture into a packaged chip by a packaged chip tablet press. The invention skillfully utilizes the formulation advantages and the structural characteristics of the tablet, designs and tests the amlodipine atorvastatin calcium tablet into the tablet, not only fundamentally solves the compatibility problem of two APIs, further improves the stability of the product, but also effectively avoids the problem of poor mixing uniformity of total mixed particles (and content uniformity of corresponding tablets), and simultaneously ensures the yield of the product. In addition, because the atorvastatin calcium is a poorly soluble drug, even though micronization is still difficult to achieve the optimal dissolution, the preparation of the invention obviously improves the dissolution of the atorvastatin calcium and further improves the comprehensive quality of the product by increasing the combination of meglumine and sodium lauryl sulfate in the preparation process. The problems of API compatibility, product stability, product dissolution rate/content uniformity and product yield are solved simultaneously compared with common tablets and double-layer tablets. Therefore, in the large-scale commercial production and popularization process of the product, the chip has obvious quality and technical advantages. Therefore, the invention has wide market application value.

Specifically:

(1) The amlodipine atorvastatin calcium tablet utilizes the advantages and structural characteristics of a tablet form, distributes two APIs on an inner layer and an outer layer respectively and uniformly, and performs isolation coating treatment on an inner layer tablet core, so that the two APIs can be completely isolated, the compatibility problem of the two APIs is effectively and thoroughly solved, the impurity level of the preparation is reduced, the stability is further improved, and the safety in the use process is further ensured;

(2) When the amlodipine and atorvastatin calcium tablet is designed and tested to be prepared into a core-in-package tablet, the inner layer and the outer layer of granules are respectively and independently tested before the whole tablet is pressed, then the atorvastatin calcium layer is firstly pressed into a tablet core and coated, and finally the core-in-package tablet is pressed into the core-in-package tablet by combining the amlodipine layer granules by using a core-in-package tablet press. The problem that the mixing uniformity of total mixed particles (and the content uniformity of plain tablets) is poor due to the large difference of two particles when the conventional wet granulation process is adopted for trial production of the conventional tablets is effectively solved, and the content uniformity of the product is improved;

(3) Compared with a double-layer tablet, the amlodipine atorvastatin calcium tablet is designed and manufactured into a coated tablet, so that the complete isolation of two APIs is realized, the content uniformity of the APIs in the double-layer tablet (especially the second layer) is further improved, and meanwhile, the yield of a tablet is greatly improved (the yield is equivalent to that of a common tablet test);

(4) According to the amlodipine atorvastatin calcium tablet, sodium laurylsulfate and meglumine are added into the prescription, so that the dissolution rate of a medicine (atorvastatin calcium) is further improved, and the product quality is further improved and ensured.

All of the features disclosed in this specification, or all of the steps in a method or process disclosed, may be combined in any combination, except for mutually exclusive features or steps.

In view of the shortcomings in the prior art, the inventor of the present invention has long studied and practiced in a large number of ways to propose the technical scheme of the present invention. The technical scheme, the implementation process, the principle and the like are further explained as follows.

The invention is further described below with reference to examples. The present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions which are not noted are conventional conditions in the industry. The technical features of the various embodiments of the present invention may be combined with each other as long as they do not collide with each other.

The experimental methods in the following examples are all conventional methods unless otherwise specified; the experimental materials used, if not specified, can be obtained from biochemical reagent manufacturers with corresponding products for sale, and the reagents only need to meet the medicinal standard.

Example 1 (prescription 1): trial batch 10000 tablets (chip)

The preparation method comprises the following steps:

adding 4g of polysorbate 80 into 500g of purified water with the temperature of 50-60 ℃ under stirring, continuously stirring and dissolving until the mixture is clarified, slowly adding 20g of meglumine under stirring and dissolving until the mixture is clarified, slowly adding 25.5g of hydroxypropyl cellulose under stirring, continuously stirring and dissolving until the mixture is clarified, and cooling to below 40 ℃ for standby.

Sequentially adding the microcrystalline cellulose 101, calcium carbonate, pregelatinized starch, atorvastatin calcium and croscarmellose sodium with the prescribed amount into a wet granulator, and mixing for 5min at the stirring rotation speed of 80rpm and the granulating knife rotation speed of 300 rpm; adding the prepared adhesive solution while stirring at the stirring rotation speed of 120rpm and the granulating blade rotation speed of 300rpm, wherein the liquid adding time is 2-3 min; after the liquid adding is finished, granulating for 1.5min at the stirring rotation speed of 120rpm and the granulating knife rotation speed of 1000rpm, adopting a square stainless steel screen with the diameter of 4 multiplied by 4mm, finishing the granulating at the rotation speed of 900rpm, and discharging. And (3) placing the wet particles in a fluidized bed, drying at 60-75 ℃ until the moisture of the particles is less than or equal to 3.0%, and discharging to obtain the dry particles.

And (3) placing the dried granules, the sodium lauryl sulfate with the prescription amount and the magnesium stearate into a mixer, mixing for 10min at the rotating speed of 6rpm, and discharging to obtain granules 1.

The sodium carboxymethyl starch and amlodipine besylate with the prescribed amounts are placed in a mixer to be mixed for 15min at the rotating speed of 6rpm, and then about 1/2 amount of microcrystalline cellulose 101 and about 1/2 amount of anhydrous calcium hydrophosphate are continuously added to be mixed for 10min, and the mixture is screened by a 1.0mm screen of a granulator for one time. The addition of about 1/2 of microcrystalline cellulose 101 and about 1/2 of anhydrous dibasic calcium phosphate was continued and mixed for an additional 20 minutes. Continuously adding the magnesium stearate with the prescription amount, mixing for 10 minutes at the mixing speed of 6rpm, and discharging to obtain mixed powder 2.

Adding the granules 1 into a tablet press, and according to the standard tablet weight of 1=10 (mg)/total mixed granule content of 1 (atorvastatin), the tablet pressing speed is 3-6 ten thousand tablets/hour, the feeding frequency is 25-40 Hz, and the main pressure is 5-8 kN; the weight difference in the tabletting process is controlled to be +/-5.0%, the average hardness range of 10 tablets is 60+/-15N, the disintegration time limit is less than or equal to 5min, the friability is less than or equal to 0.8% of the weight loss, and the tablets are pressed into plain tablets.

The plain tablets are placed in a coating machine, the rotating speed of a pan body is set to be 2-6 rpm, the atomization pressure is set to be 0.5-0.5 MPa, the rotating speed of a liquid spraying peristaltic pump is set to be 10-20 rpm, coating is started, and liquid sprayed on the surfaces of the tablets is dried to form a protective film. The temperature of the tablet bed is maintained at 38-48 ℃ in the coating process, the weight is increased by 2.5-4.0% according to the coating, and the tablet core of the coated tablet is obtained after coating.

Respectively adding mixed powder 2 and a chip-coated tablet core into a hopper corresponding to a chip-coated tablet press, wherein the tablet pressing speed is 2-4 ten thousand tablets/hour according to the standard tablet weight 2 (chip-coated) =average tablet weight (chip-coated tablet core) +5 (mg)/total mixed particle content 1 (amlodipine), the feeding frequency of the inner-layer tablet core is 25-40 Hz, the feeding frequency of the mixed powder is 25-40 Hz, and the main pressure is 8-12 kN; the weight difference in the pressing process is controlled to be +/-5.0%, the average hardness range of 10 tablets is 120+/-15N, the disintegration time is less than or equal to 6min, the friability is less than or equal to 0.8% of the weight loss, and the tablet is obtained by pressing into a package chip.

Example 2 (prescription 2): trial batch 10000 tablets (chip)

Example 2 is essentially the same as example 1, except for the formulation, the formulation of example 2 is as follows.

Comparative example 1 (prescription 3): trial batch 10000 tablets (common tablet)

The preparation method comprises the following steps:

adding 4g of polysorbate 80 into 500g of purified water with the temperature of 50-60 ℃ under stirring, continuously stirring and dissolving until the mixture is clear, slowly adding 15g of hydroxypropyl cellulose under stirring, continuously stirring and dissolving until the mixture is clear, and cooling to below 40 ℃ for standby.

Sequentially adding microcrystalline cellulose 101 (internal addition), calcium carbonate, pregelatinized starch, atorvastatin calcium and croscarmellose sodium (internal addition) into a wet granulator, stirring at a speed of 80rpm, and mixing at a speed of 300rpm for 5min; adding the prepared adhesive while stirring at the stirring rotation speed of 120rpm and the granulating blade rotation speed of 300rpm, and controlling the liquid adding time to be 2-3 min; after the liquid adding is finished, granulating for 1.5min at the stirring rotation speed of 120rpm and the granulating knife rotation speed of 1000rpm, and discharging after wet granulation. And (3) placing the wet particles in a fluidized bed, drying at 60-75 ℃ until the moisture of the particles is less than or equal to 3.0%, and discharging to obtain particles 1.

Microcrystalline cellulose 101 (added), amlodipine besylate, croscarmellose sodium (added) and colloidal silicon dioxide with the prescribed amount are placed in a mixer to be mixed for 30 minutes at the speed of 6rpm, and the mixture is filtered through a 1.0mm screen of a granulator for one time, and then the mixture is discharged to obtain mixed powder 2.

Placing the granules 1 and the mixed powder 2 in a mixer for continuous mixing for 20min, sieving the granules with a 1.0mm screen of the granulator for one time, continuously mixing for 20min at a rotating speed of 6rpm, continuously adding the magnesium stearate with the prescription amount, mixing for 10min at a mixing rotating speed of 6rpm, and discharging to obtain the total mixed granules.

Adding the total mixed particles into a tablet press, pressing the total mixed particles into a tablet according to the standard tablet weight= (10 (mg)/total mixed particle content 1 (atorvastatin) +5 (mg)/total mixed particle content 2 (amlodipine))/2, and the hardness of 65+/-15N, placing the tablet into a coating machine, and coating according to the coating weight gain of 2.5% -4.0%, thus obtaining the tablet.

Comparative example 2: amlodipine atorvastatin calcium tablet sold in original ground and market

The amlodipine atorvastatin calcium tablet (caplet) of the present invention was mixed with amlodipine atorvastatin calcium tablet (specification: 5mg/10mg; trade name: lot number: w14152; the manufacturer: pfizer Manufacturing Deutschland GmbH (Betriebsstatte Freiburg) for quality comparison studies.

Comparative example 3 (prescription 4): trial batch 10000 tablets (chip)

Comparative example 3 is substantially the same as example 1, except for the formulation, and the formulation of comparative example 3 is shown in the following table.

Comparative example 4 (recipe 4): trial batch 10000 tablets (double-layer tablet)

The preparation method comprises the following steps:

Adding 4g of polysorbate 80 into 500g of purified water with the temperature of 50-60 ℃ under stirring, continuously stirring and dissolving until the mixture is clear, slowly adding 25.5g of hydroxypropyl cellulose under stirring at last, continuously stirring and dissolving until the mixture is clear, and cooling to the temperature of below 40 ℃ for standby.

Sequentially adding the microcrystalline cellulose 101, calcium carbonate, pregelatinized starch, atorvastatin calcium and croscarmellose sodium with the prescription amount into a wet granulator, stirring at a speed of 80rpm, and mixing for 5min at a speed of 300 rpm; adding the prepared adhesive while stirring at the stirring rotation speed of 120rpm and the granulating blade rotation speed of 300rpm, and controlling the liquid adding time to be 2-3 min; after the liquid adding is finished, granulating for 1.5min at the stirring rotation speed of 120rpm and the granulating knife rotation speed of 1000rpm, and discharging after wet granulation. And (3) placing the wet particles in a fluidized bed, drying at 60-75 ℃ until the moisture of the particles is less than or equal to 3.0%, and discharging to obtain the dry particles.

And (3) placing the dried granules and the prescribed amount of magnesium stearate into a mixer, mixing for 10min at the rotating speed of 6rpm, and discharging to obtain granules 1.

The sodium carboxymethyl starch and amlodipine besylate with the prescribed amounts are placed in a mixer to be mixed for 15min at the rotating speed of 6rpm, and then about 1/2 amount of microcrystalline cellulose 101 and about 1/2 amount of anhydrous calcium hydrophosphate are continuously added to be mixed for 10min, and the mixture is screened by a 1.0mm screen of a granulator for one time. The addition of about 1/2 of microcrystalline cellulose 101 and about 1/2 of anhydrous dibasic calcium phosphate was continued and mixed for an additional 20 minutes. Continuously adding the magnesium stearate with the prescription amount, mixing for 10 minutes at the mixing speed of 6rpm, and discharging to obtain mixed powder 2.

The granules 1 and the mixed powder 2 are respectively added into a corresponding charging hopper of a double-layer tablet press, and pressed into tablets according to the standard tablet weight (mg) =10 (mg)/total mixed granule content 1 (atorvastatin) +5 (mg)/total mixed granule content 2 (amlodipine)), and the hardness is 120+/-15N. And (3) placing the double-layer tablets into a coating machine, and coating according to the weight gain of 2.5% -4.0% of the coating, thereby obtaining the tablet.

Comparative example 5 (prescription 5): trial batch 10000 tablets (chip)

Comparative example 5 is substantially the same as example 1, except for the formulation, and the formulation of comparative example 5 is shown in the following table.

Comparative example 6 (prescription 6): trial batch 10000 tablets (chip)

Comparative example 6 is substantially the same as example 1, except for the formulation, and the formulation of comparative example 6 is shown in the following table.

In the above examples and comparative examples, key quality inspection index conditions of intermediate and finished parts of amlodipine atorvastatin calcium tablets prepared by different prescription processes are shown in table 2. Visual inspection is adopted for appearance characteristics, HPLC is adopted for dissolution detection, HPLC is adopted for total impurity detection (see Table 1 for details). As can be seen from comparative example 1 (or example 2) and comparative example 1 (or comparative example 2), the total mixed particle mixing uniformity, content uniformity and impurity level of the amlodipine atorvastatin calcium tablet prepared by the chip-in-chip process are obviously improved compared with those of the common tablet; as can be seen from comparative examples 1 (or example 2) and 3,5 and 6, the dissolution rate of atorvastatin calcium is not significantly improved after adding meglumine or sodium lauryl sulfate as a cosolvent alone in the formulation, but the dissolution rate of atorvastatin calcium is significantly improved when meglumine and sodium lauryl sulfate as a cosolvent are added simultaneously; as can be seen from comparative example 1 (or example 2) and comparative example 4, the uniformity of the atorvastatin calcium layer content and the product yield of the amlodipine atorvastatin calcium tablet prepared by the chip-packing process are significantly improved compared with the dual-layer tablet.

TABLE 1

TABLE 2

In each of the above examples and comparative examples, the acceleration test (40.+ -. 2 ℃ C./relative humidity 75%.+ -. 5% RH) was examined for 6 months, and samples were examined on days 0, months 3 and months 6, respectively, and the test items such as properties, substances and contents were examined, respectively, according to the key quality index. The detailed results are shown in Table 3.

TABLE 3 Table 3

Among them, comparing examples 1 and 2 and comparative examples 1 and 2 in table 2, it can be seen that the test of the samples using the chip-in-package process contributes to some extent to the improvement of the product stability. Comparing examples 1, 2 and 4 in table 2, it can be seen that the test-fabricated samples using the chip-in-package process can be more advantageous for improving the product stability than the double-layer chip process.

From the above results, it can be seen that in the embodiment 1 or 2 of the present invention, the amlodipine atorvastatin calcium tablet is manufactured by adopting the core-spun chip manufacturing process, so that the mixing uniformity of the intermediate and the content uniformity of the finished product in the product manufacturing process are effectively improved, and meanwhile, the stability and the yield of the product are further ensured; in addition, the dissolution rate of the product is further improved by further adding the combination of sodium lauryl sulfate and meglumine in the prescription, and the accelerated stability test result proves that the properties, the content and the dissolution rate of the product in the embodiment 1 or 2 are not obviously changed, and the stability of the product is obviously better than that of a commercially available sample under the accelerated condition. Therefore, the amlodipine atorvastatin calcium tablet prepared by the method has good stability and quality and improved safety.

The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes according to the spirit of the invention should be covered by the protection scope of the invention.

Claims (10)

1. An amlodipine atorvastatin calcium tablet which is characterized in that: the amlodipine atorvastatin calcium tablet is a core-in-package tablet and comprises an inner tablet core containing atorvastatin calcium and an outer tablet layer containing amlodipine besylate, wherein the inner tablet core also comprises meglumine and sodium lauryl sulfate.

2. The amlodipine atorvastatin calcium tablet of claim 1 wherein: the mass ratio of the meglumine to the sodium lauryl sulfate is 0.5-5: 1.

3. The amlodipine atorvastatin calcium tablet of claim 1 or 2 wherein: the mass of the meglumine accounts for 1-3% of the total mass of the inner layer tablet core.

4. The amlodipine atorvastatin calcium tablet of claim 1 wherein: the composition of the inner layer tablet core also comprises 35-45% of filler, 30-38% of stabilizer, 2-8% of disintegrating agent, 1-5% of adhesive, 0.1-1% of surfactant, 0.5-2% of lubricant and 2-5% of coating material;

the composition of the outer layer sheet layer comprises 80-92% of filler, 2-12% of disintegrating agent and 0.5-2.5% of lubricant.

5. The amlodipine atorvastatin calcium tablet of claim 4 wherein: in the inner sheet core, the filler comprises one or more of microcrystalline cellulose, lactose, and pregelatinized starch; the stabilizer comprises one or more of calcium carbonate, magnesium carbonate and magnesium oxide; the disintegrating agent comprises one or more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch; the binder comprises hydroxypropyl cellulose and/or povidone K30; the surfactant comprises one or more of polysorbate 80, poloxamer and span 20; the lubricant comprises magnesium stearate and/or sodium hard fumarate; the coating material is a composition of titanium dioxide, talcum powder, polyethylene glycol and polyvinyl alcohol;

In the outer ply layer, the filler comprises one or more of microcrystalline cellulose, pregelatinized starch, anhydrous dibasic calcium phosphate, and corn starch; the disintegrating agent comprises one or more of carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium and corn starch; the lubricant comprises magnesium stearate and/or colloidal silica.

6. The amlodipine atorvastatin calcium tablet of claim 1 wherein: the mass of the atorvastatin calcium accounts for 9-11% of the total mass of the inner tablet core, and the mass of the amlodipine besylate accounts for 3-4% of the total mass of the outer tablet core.

7. A process for the preparation of amlodipine atorvastatin calcium tablet of any one of claims 1 to 6 wherein: the method comprises the following steps:

(1) Mixing and granulating the materials of the inner layer tablet cores, tabletting and coating to obtain the inner layer tablet cores;

(2) Mixing the materials of the outer layer sheet layer to obtain mixed powder;

(3) And pressing the mixed powder and the inner layer tablet core to obtain the core-spun tablet.

8. The preparation method of amlodipine atorvastatin calcium tablet of claim 7 wherein: in the step (1), parameters for controlling the tabletting are as follows: tabletting speed is 3-6 ten thousand tablets/hour, feeding frequency is 25-40 Hz, and main pressure is 5-8 kN; the weight difference in the tabletting process is controlled to be +/-5.0%, the average hardness range of 10 tablets is 60+/-15N, the disintegration time limit is less than or equal to 5min, and the friability is less than or equal to 0.8% of the weight loss.

9. The preparation method of amlodipine atorvastatin calcium tablet of claim 7 wherein: in the step (3), parameters for controlling the pressing are as follows: the tabletting speed is 2-4 ten thousand tablets/hour, the feeding frequency of the inner layer tablet core is 25-40 Hz, the feeding frequency of the outer layer mixed powder is 25-40 Hz, and the main pressure is 8-12 kN; the weight difference in the pressing process is controlled to be +/-5.0%, the average hardness range of 10 tablets is 120+/-15N, the disintegration time is less than or equal to 6min, and the friability is less than or equal to 0.8% of the weight loss.

10. Process for the preparation of amlodipine atorvastatin calcium tablet according to any one of claims 7 to 9 characterized in that: the specific steps of the step (1) comprise:

1.1, adding a surfactant, meglumine and an adhesive into water, stirring and dissolving;

1.2, adding a filler, a stabilizer, atorvastatin calcium and a disintegrating agent into a wet granulator for premixing;

1.3, starting a wet granulator, and adding the solution prepared in the step 1.1 to prepare wet granules;

1.4, carrying out wet granulation on the prepared wet granules, and discharging;

1.5, drying the wet granules after finishing in a fluidized bed;

1.6, placing the dried particles, sodium laurylsulfate and a lubricant into a column mixer, and mixing to obtain total mixed particles;

1.7, tabletting the total mixed particles by adopting a tablet press;

1.8, coating the tablet cores subjected to tabletting by adopting a coating machine to obtain inner-layer tablet cores;

The specific steps of the step (2) comprise

2.1, Firstly adding a disintegrating agent and amlodipine besylate into a mixer for premixing to obtain mixed powder I;

2.2, putting 1/2 prescription amount of filler and the mixed powder I into a mixer for premixing to obtain mixed powder II;

2.3, placing the rest filler and the mixed powder II into a mixer for premixing to obtain mixed powder III;

And 2.4, mixing the mixed powder III with a lubricant to obtain the mixed powder.