CN104825449A - Compound composition containing atorvastatin calcium and amlodipine and preparation method of same - Google Patents
Compound composition containing atorvastatin calcium and amlodipine and preparation method of same Download PDFInfo
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- CN104825449A CN104825449A CN201410048572.7A CN201410048572A CN104825449A CN 104825449 A CN104825449 A CN 104825449A CN 201410048572 A CN201410048572 A CN 201410048572A CN 104825449 A CN104825449 A CN 104825449A
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Abstract
The invention provides a compound composition containing atorvastatin calcium and amlodipine and a preparation method of the same, wherein the compound composition is a double-layer tablet which contains the atorvastatin calcium and the amlodipine and is suitable for being prepared through a dry-method granulation tabletting process. The preparation method solves a problem of compatibility between the atorvastatin calcium and the amlodipine and ensures the dissolution rate and the dissolution stability of the atorvastatin calcium and the amlodipine. The preparation method is good in operability and repeatability, is simplified in processes maximally and is reduced in process period.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field.Particularly, the present invention relates to high compound containing Atorvastatin calcium and amlodipine of a kind of steady quality, dissolution and preparation method thereof.
Background technology
Along with the change of Chinese society development, the change of circumstances, population structure and people life style, make the generation of some diseases, new trend appears in development.Cardiovascular system M & M is in continuous rising, and in city, occupy the first, and high-cholesterol disease and abnormalities of sugar/lipid metabolism are the principal elements causing cardiovascular disease, it seriously threatens the life and health of the mankind.
China's adult hypertension prevalence reaches 20%, wherein has the hyperpietic of 35% ~ 50% to be accompanied with hyperlipidemia, illly easily causes atherosclerosis for a long time, and coronary heart disease is one of topmost cause of the death of world today's population.Namely unique effectively preventing method is adopt decompression treatment in conjunction with lipid-lowering therapy simultaneously at present, and the critical point of the high-risk disease of cardiovascular is moved forward.Find according to ASCOT-CCA research, on amlodipine blood pressure lowering basis, after giving Lipid modulating, significantly reduce blood pressure and blood fat while, reduce cardiac load, alleviate cardiac pressure, can reduce and prevent the generation of cardiovascular and cerebrovascular disease and the remarkable generation reducing non-lethal myocardial infarction and lethal coronary heart disease.
Amlodipine blood pressure lowering onset is rapid, and its hypotensive effect is not subject to the impact of other drug, food, and high sodium is taken in and the use of nonsteroidal anti-inflammatory agent does not all affect its hypotensive effect, can be used for the patient of complication with diabetes, coronary heart disease, peripheral blood vessel.
Atorvastatin calcium is brand-new third generation statins antilipemic medicine, represents the top level of world's lipid lowering agent.After Atorvastatin calcium goes on the market abroad, the market share in blood lipid-lowering medicine rises and has become as the fastest product of world today's growth rate very soon, and occupy the first in the Statins medicine gone on the market at present.
Atorvastatin calcium Clinical practice determined curative effect, Be very effective, blood plasma total plasma cholesterol (TC) LDL-C and the apolipoprotein B of homozygote and heterozygote familial hypercholesterolemia and non-familial hypercholesterolemia and mixed lipids dysbolismus patient can be reduced, the level of C-VLDL (VLDL-C) and apolipoprotein can also be reduced.
Atorvastatin calcium presses biological classification system classification, belong to BSC II class medicine, for poorly water soluble drugs, dissolubility in sour water is extremely low, therefore the quality problems that general atorvastatin calcium preparation occurs usually are exactly because the bad Dissolution of Tablet caused of water solublity is on the low side, and along with the prolongation of standing time or the aggravation of stability conditions, preparation stripping there will be situation about reducing gradually, and simultaneously Atorvastatin calcium all exists sensitivity in various degree to light, humidity, heating condition.Therefore related substance is also the key point that the quality of the pharmaceutical preparations controls, and ensure that catabolite is few as much as possible, need to study and optimized choice its preparation production technique, while guarantee product quality, simplify production technology as much as possible.
Although existing correlational study, all can not solve the problems such as the compatibility of Atorvastatin calcium and amlodipine compound, dissolution and stripping stability at present.Such as, Chinese patent application 201110204228.9 discloses a kind of technique of the compound recipe of preparation in a wet process Atorvastatin calcium amlodipine, through the compound preparation that experimental study shows to use the technique of this wet granulation to prepare, there is obvious problem in compatibility aspect, first Atorvastatin calcium and amlodipine directly contact the situation that there will be related substance and increase, and the adjuvant used in addition also exists obvious incompatibility with Atorvastatin calcium and amlodipine; In Compound Tablet prepared by wet processing, Atorvastatin calcium easily occurs in suitability for industrialized production, be not easy the problem that dissolution reduces to control, and do not add alkaline stabiliser in prescription, and atorvastatin calcium preparation long-term stability can not be effectively guaranteed.
Chinese patent application 201110180761.6 discloses the preparation method of the Orally-administered solid composition of a kind of Atorvastatin calcium and Amlodipine Besylate Tablet, wherein adopt Atorvastatin calcium first use wet granulation, after drying again with Amlodipine Besylate Tablet, other adjuvant mix homogeneously after tabletting.Through verification experimental verification, adopt atorvastatin agent prepared by wet granulation technology, its stripping stability is bad, after placing certain condition, particularly after super-humid conditions, there will be the situation that dissolution declines.
Chinese patent application 201310000141.9 disclose a kind of can the atorvastatin agent and preparation method thereof of Fast Stripping, by celphere coating medicine carrying, after mixing with proper auxiliary materials, direct compression.In preparation process, due to the control not easily good reproduction of celphere drug loading, need calculate the adjuvant amount that should add again after measuring drug loading, can produce directly impact to the powder fluidity of its vertical compression technique, technique repeatability is difficult to be guaranteed at every turn.
Summary of the invention
Therefore, for the above-mentioned defect existed in prior art, an object of the present invention is to provide a kind of stay-in-grade compound containing Atorvastatin calcium and amlodipine, another object of the present invention is to provide a kind of preparation method of this compound.
Above-mentioned purpose of the present invention is achieved by the following technical solution:
On the one hand, the invention provides a kind of compound containing Atorvastatin calcium and amlodipine, it is the biplate layer compound containing atorvastatin layer and amlodipine lamella, by weight percentage:
Described atorvastatin layer comprises 10 ~ 20%(preferably 12%) atorvastatin calcium, 30 ~ 70%(preferably 44%) filler, 10 ~ 20%(preferably 16%) alkaline stabiliser, 3 ~ 12%(preferably 9%) disintegrating agent, 0.3 ~ 3%(preferably 0.5%) cosolvent, 0.3 ~ 3%(preferably 0.5%) lubricant and 0.3 ~ 3%(preferably 0.5%) fluidizer;
Described amlodipine lamella comprises 10 ~ 20%(preferably 15%) amlodipine, 60 ~ 80%(preferably 75%) filler, 3 ~ 10%(preferably 5%) disintegrating agent, 0.3 ~ 3%(preferably 0.5%) lubricant and 0.3 ~ 3%(preferably 0.5%) fluidizer.
According to compound of the present invention, in described atorvastatin layer, described filler be selected from microcrystalline Cellulose, pregelatinized Starch, mannitol, starch and lactose one or several, be preferably microcrystalline Cellulose and/or pregelatinized Starch; Preferably, described alkaline stabiliser is selected from calcium carbonate and/or magnesium oxide, is preferably calcium carbonate; More preferably, described disintegrating agent is polyvinylpolypyrrolidone; Further preferably, described cosolvent is selected from sodium lauryl sulphate and/or Tween 80, is preferably sodium lauryl sulphate; Still more preferably, described lubricant is Pulvis Talci; Again further preferably, described fluidizer is magnesium stearate.
According to compound of the present invention, in amlodipine lamella, described filler is selected from microcrystalline Cellulose and/or calcium hydrogen phosphate; Preferably, described disintegrating agent is crosslinked carboxymethyl fecula sodium; More preferably, described lubricant is Pulvis Talci; Further preferably, described fluidizer is magnesium stearate.
According to compound of the present invention, in described atorvastatin layer or amlodipine lamella, also comprise pigment such as light blue.
Preferably, in described atorvastatin layer or amlodipine lamella containing accounting for the pigment that its weight ratio is about 0.1%.
According to compound of the present invention, described amlodipine is Amlodipine Besylate Tablet or maleic acid levo amido chloro diping.
According to compound of the present invention, it also comprises coatings, preferably, the material of described coatings be selected from Opardy II, Opardy I, Opardy amb and Opardy XY one or more, more preferably, the material of described coatings is Opardy II, more preferably, described coatings weightening finish is 3 ~ 4%.
It is known to those skilled in the art that also not all prescription all can adopt dry method to be prepared in the art, should be appreciated that using the prescription being applicable to wet-layer preparation instead dry process may be difficult to carry out or produce less desirable problem.That is, there is not the relation of mutually replacing between wet-layer preparation and dry process.The present inventor is by being surprised to find that after great many of experiments, and compound of the present invention can be good at being applicable to dry process.
Other method, the present invention also provides a kind of preparation method containing Atorvastatin calcium and amlodipine compound, and the method comprises the following steps:
A) atorvastatin layer composition is prepared:
(1) Atorvastatin calcium is crossed 100 mesh sieves, 60 mesh sieves crossed by fluidizer, and other adjuvant such as filler, alkaline stabiliser, disintegrating agent, cosolvent and lubricant waited 80 mesh sieves;
(2) in Atorvastatin calcium, add adjuvant such as alkaline stabiliser, cosolvent and fluidizer, mix homogeneously, then add filler, obtain the mixture of mix homogeneously;
(3) adopt dry method to granulate, obtain Atorvastatin calcium granule, then add disintegrating agent and lubricant, mix homogeneously;
B) amlodipine layer composition is prepared
(1) amlodipine is crossed 100 mesh sieves, 60 mesh sieves crossed by fluidizer, and other adjuvant such as filler, disintegrating agent and lubricant waited 80 mesh sieves;
(2) in amlodipine, add adjuvant such as filler and disintegrating agent, then it is even to add mix lubricant;
C) step a) and b) obtained atorvastatin layer composition and amlodipine layer composition are pressed into double-layer tablet, obtain described compound.
According to preparation method of the present invention, also comprise and coating is carried out to the double-layer tablet made in step c).
The material of described coatings be selected from Opardy II, Opardy I, Opardy amb and Opardy XY one or more, preferably, the material of described coating is Opardy II, and more preferably, described coating weight gain is 3 ~ 4%.
According to preparation method of the present invention, it is characterized in that, the hardness of described compound is 5 ~ 7Kg/mm
2.
The present invention, not by the restriction of dry-forming method, should be appreciated that in this area, the conventional dry method adopted all can be used for the present invention.Such as, the model that Hua Quan Machinery Co., Ltd. of Ningbo City can be adopted to produce is that LGJ-80PLC type dry granulating machine is granulated, and technological parameter is: extrusion speed 10 ~ 20rpm, feeding speed 8 ~ 15rpm, squeeze pressure 1.1 ~ 2.5Kg.
The present invention is not also by the restriction of double-layer tablet drawing method, and the bi-layer tablet press of different principle can be used to suppress, can be pressed into inside and outside two-layer double-layer tablet, also can be bilevel double-layer tablet.Being applicable to bi-layer tablet press of the present invention can be the ZPW23 type 23 stamping machine that Shanghai Tianxiang Jian Tai Machinery Co., Ltd. produces, during tabletting, respectively the atorvastatin layer granule of preparation and amlodipine are mixed powder to be loaded in two-layer feedstuff device and to carry out tabletting, tabletting 3 ~ 7kg.
The present inventor finds through large quantifier elimination, and in compound preparation, its principal agent Atorvastatin calcium and Amlodipine Besylate Tablet exist consistency problem, together prescription after tabletting, and the related substance of Atorvastatin calcium increases obviously.And adopt dry method to prepare atorvastatin layer, and itself and amlodipine lamination are made double-layer tablet, find the quality stability that not only ensure that Atorvastatin calcium and amlodipine so better unexpectedly, also well solve dissolution and the stripping stability problem of Atorvastatin calcium.
In the present invention, described " coatings weightening finish " or " coating weight gain " refer to the ratio of the weight of coatings and compound weight.
Compared with prior art, the present invention at least has following beneficial effect:
(1) atorvastatin layer has stripping feature rapidly;
(2) atorvastatin layer dissolution and stripping have good stability, and after placement influence factor condition, dissolution is without obvious downward trend;
(3) technique is simple, with short production cycle, reduces production cost, energy-saving and cost-reducing;
(4) without heating process, also without the direct introducing of moisture, preparation degrades impurity reduces, and is conducive to ensureing the quality of the pharmaceutical preparations.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 is that a preferred embodiment of the present invention was at 0 day and the stripping curve of placement influence factor's 92.5%RH super-humid conditions after 10 days;
Fig. 2 is the stripping curve of comparative example 1 and 20 day time;
Fig. 3 is that comparative example 1 was at 0 day and the stripping curve of placement influence factor's 92.5%RH super-humid conditions after 10 days;
Fig. 4 is that Pfizer's product reaches one at 0 day and the stripping curve of placement influence factor's 92.5%RH super-humid conditions after 10 days.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further described in detail, the embodiment provided only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
embodiment 1 supplementary material compatibility experiments
Table 1 supplementary material proportioning
| Sample number into spectrum | Sample | Ratio (weight) |
| 1 | AT raw material | ----- |
| 2 | AL：AT | 1:2 |
| 3 | AT: pregelatinized Starch | 1:4 |
| 4 | AT: microcrystalline Cellulose | 1:2 |
| 5 | AT: calcium hydrogen phosphate | 1:2 |
| 6 | AT: polyvinylpolypyrrolidone | 2:1 |
| 7 | AT: cross-linking sodium carboxymethyl cellulose | 2:1 |
| 8 | AT: polyvidone | 20:1 |
| 9 | AT: hydroxypropyl emthylcellulose | 20:1 |
| 10 | AT: calcium carbonate | 2:1 |
| 11 | AT: meglumine | 2:1 |
| 12 | AT: magnesium oxide | 2:1 |
*aT: Atorvastatin calcium AL: Amlodipine Besylate Tablet
Prepare sample by the weight ratio of each sample in table 1, and carry out compatibility test under different affecting factors condition, test result is as shown in the table:
Compatibility test result after influence factor's condition placed by table 2
According to above experimental result: 1. Atorvastatin calcium and amlodipine exist consistency problem to a certain degree, after Atorvastatin calcium raw material and amlodipine raw material are mixed place with certain proportions, within 10 days, related substance result has obvious increase than 0 day related substance, and the related substance situation of 10 days also has obvious increase compared with independent atorvastatin calcium raw material drug; Conform to the incompatibility problem mentioned in Chinese patent application 201110204228.9; 2. find that normally used disintegrating agent cross-linking sodium carboxymethyl cellulose and Atorvastatin calcium exist obvious consistency problem in the prescription of existing commercialized product Atorvastatin calcium, in placement 92.5% super-humid conditions after 10 days, rising appreciably appears in Atorvastatin calcium and cross-linking sodium carboxymethyl cellulose related substance; Also there is obvious consistency problem in the major auxiliary burden calcium hydrogen phosphate 3. used in amlodipine prescription and atorvastatin, after placement 60 DEG C of hot conditionss, Atorvastatin calcium compares with the related substance of calcium hydrogen phosphate mixture has obvious growth in 0 day.Atorvastatin calcium and amlodipine are prepared into double-layer tablet by the Double layer pellet technique that therefore the present invention uses, more directly effectively the incompatibility probability of compound preparation is down to minimum, wherein in the technical process of dry method direct compression that adopts of atorvastatin layer without the introducing of heating process and moisture, the catabolite that production process produces is less, can ensure the quality of double-layer tablet preparation better.
embodiment 2-6 preparation contains the compound of Atorvastatin calcium and amlodipine
Adopt following method to prepare the compound containing Atorvastatin calcium and amlodipine in embodiment 2 to 6, wherein, in embodiment 2 to 6, the kind of each raw material and consumption (weight portion) are in table 3 and 4.Described method is:
A) atorvastatin layer composition is prepared:
(1) Atorvastatin calcium is crossed 100 mesh sieves, 60 mesh sieves crossed by fluidizer, and other adjuvant such as filler, alkaline stabiliser, disintegrating agent, cosolvent and lubricant waited 80 mesh sieves;
(2) in Atorvastatin calcium, add adjuvant such as alkaline stabiliser, cosolvent and fluidizer, mix homogeneously, then add filler, obtain the mixture of mix homogeneously;
(3) dry granulating machine (model that Hua Quan Machinery Co., Ltd. of Ningbo City produces is LGJ-80PLC type) is used, at technological parameter be: granulate under extrusion speed 10 ~ 20m/s, feeding speed 8 ~ 15m/s and squeeze pressure 1.1 ~ 2.5MPa, obtain Atorvastatin calcium granule, then disintegrating agent and lubricant is added, mix homogeneously;
B) amlodipine layer composition is prepared
(1) amlodipine is crossed 100 mesh sieves, 60 mesh sieves crossed by fluidizer, and other adjuvant such as filler, disintegrating agent and lubricant and optionally pigment waited 80 mesh sieves;
(2) in amlodipine, add adjuvant such as filler and disintegrating agent, then it is even to add mix lubricant;
C) step a) and b) obtained atorvastatin layer composition and amlodipine layer composition are pressed into double-layer tablet, obtain described compound;
D) optionally, the double-layer tablet made in step c) is carried out coating, coating weight gain is 3 ~ 4%.
Table 3 atorvastatin layer prescription and consumption (weight portion)
| Component | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 |
| Atorvastatin calcium | 10.8 | 10 | 20 | 12 | 15 |
| Microcrystalline Cellulose | 40 | 30 | 30 | 55 | |
| Pregelatinized Starch | 15 | 15 | 10 | 44 | |
| Mannitol | 10.5 | 10 | |||
| Starch | 10 | ||||
| Lactose | 10 | ||||
| Calcium carbonate | 15 | 10 | 8 | 20 | |
| Magnesium oxide | 20 | 8 | |||
| Polyvinylpolypyrrolidone | 8 | 3 | 9 | 12 | 12 |
| Sodium lauryl sulphate | 0.42 | 3 | |||
| Tween 80 | 0.5 | 0.3 | 3 | ||
| Pulvis Talci | 0.42 | 0.5 | 0.3 | 3 | 3 |
| Magnesium stearate | 0.42 | 0.5 | 0.4 | 3 | 3 |
Table 4 amlodipine lamella prescription and consumption (weight portion)
| Component | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 |
| Amlodipine Besylate Tablet | 6.9 | 5 | 5 | 7.5 | |
| Maleic acid levo amido chloro diping | 10 | ||||
| Microcrystalline Cellulose | 20 | 37.5 | 20 | 20 | |
| Calcium hydrogen phosphate | 16 | 37.5 | 20 | 17.5 | |
| Crosslinked carboxymethyl fecula sodium | 2.3 | 5 | 1.5 | 3.35 | 2.5 |
| Pulvis Talci | 0.23 | 1 | 0.15 | 1.5 | 1.2 |
| Magnesium stearate | 0.23 | 1.5 | 0.85 | 0.15 | 1.25 |
| Light blue | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 |
Atorvastatin layer obtained for embodiment 2 to 6 and amlodipine lamella are pressed into by bi-layer tablet press (the ZPW23 type 23 stamping machine that Shanghai Tianxiang Jian Tai Machinery Co., Ltd. produces) double-layer tablet that weight is 136mg/ sheet, wherein atorvastatin layer about 90mg/ sheet, amlodipine lamella is about 46mg/ sheet.Then use Opadry II coating, weightening finish controls at 3-4%.
comparative example 1
According to formula preparation Atorvastatin calcium and the amlodipine biplate layer compound of embodiment 2; unlike; this comparative example adopts wet-layer preparation, is specially: the Atorvastatin calcium of mixing homogeneously with adjuvant is placed in high speed wet granulator and granulates, after 60 degree of dryings; granulate; be pressed into double-layer tablet with the amlodipine layer composition prepared again, obtain Atorvastatin calcium and amlodipine biplate layer compound, use Opadry II; coating, weightening finish control 3-4%.
comparative example 2
According to formula preparation Atorvastatin calcium and the amlodipine monolithic layer compound of embodiment 2; unlike; this comparative example adopts wet granulation; be specially: the Atorvastatin calcium of mixing homogeneously with adjuvant is placed in high speed wet granulator and granulates; after 60 degree of dryings; granulate; add amlodipine principal agent, additional disintegrating agent and lubricant; mix homogeneously; re-use tablet machine to suppress, obtain Atorvastatin calcium and amlodipine monolithic layer compound, use Opadry II; coating, weightening finish control 3-4%.
comparative example 3
The prescription that table 5 comparative example 3 adopts
The compound of biplate layer containing Atorvastatin calcium and amlodipine is prepared by dry method according to the prescription of table 5, be specially: Atorvastatin calcium and Amlodipine Besylate Tablet are crossed 100 mesh sieves, other adjuvants except magnesium stearate are crossed 80 mesh sieves, and magnesium stearate crosses 60 mesh sieves; In Atorvastatin calcium, add polyoxyethylene sorbitan monoleate, then add calcium carbonate mix homogeneously and obtain mixture 1; By mixture 1, add starch, microcrystalline Cellulose, lactose and the agent of Nei Jia partial disintegration, mix homogeneously obtains mixture 2; Granulating adding in dry granulating machine in mixture 2, because material fluidity is not good, can not obtain dry granule continuously, and pinch roller adhesion happening occasionally, technique is unfavorable for amplifying, producing.
As can be seen here, the prescription of table 5 is not also suitable for dry method, and lactose and amlodipine exist obvious consistency problem, should not be designed to main adjuvant.
comparative example 4
The prescription that table 6 comparative example 4 adopts
The compound of biplate layer containing Atorvastatin calcium and amlodipine is prepared by dry method according to the prescription of table 6, be specially: Atorvastatin calcium and Amlodipine Besylate Tablet are crossed 100 mesh sieves, other adjuvants except magnesium stearate are crossed 80 mesh sieves, and magnesium stearate crosses 60 mesh sieves; In Atorvastatin calcium, add other adjuvants and the agent of Nei Jia partial disintegration, mix homogeneously obtains mixture 1; In mixture 1, add microcrystalline Cellulose and lactose, mix homogeneously obtains mixture 2; Granulating adding in dry granulating machine in mixture 2, because material fluidity is not good, can not obtain dry granule continuously, and pinch roller adhesion happening occasionally, technique is unfavorable for amplifying, producing.
As can be seen here, the prescription of table 6 is not also suitable for dry method, and prescription does not comprise cosolvent and stabilizing agent, and therefore the dissolution of prescription gained sample is undesirable.Also there is some problems in preparation long-time stability.
dissolution test method
Measure according to dissolution method (Chinese Pharmacopoeia 2010 editions two annex XC second methods); get tablet prepared by the embodiment of the present invention 2 dry granulation tabletting and tablet prepared by comparative example 1 and 2 wet granule compression tablet; with the phosphate buffer 900ml of pH6.8 for solvent; rotating speed 75 revs/min; operate in accordance with the law, respectively at 5,10,15,20,30 minutes sampling and measuring; It is appropriate that another precision measures Atorvastatin calcium reference substance, adds acetonitrile: water (1:1) is ultrasonic makes dissolving, be mixed with the solution that concentration is 11 μ g/ml concentration, product solution in contrast.It is appropriate that another precision measures Amlodipine Besylate Tablet reference substance, adds acetonitrile: water (1:1) is ultrasonic makes dissolving, be mixed with the solution that concentration is 7.6 μ g/ml concentration, product solution in contrast.
According to high performance liquid chromatography, take octadecylsilane chemically bonded silica as filler, with ammonium acetate buffer salt (ph5.2)-methanol (37:63) for mobile phase; Flow velocity is 1ml/min; Column temperature 30 DEG C, determined wavelength 240nm, extracting sample solution and contrast solution sample introduction measure, and by external standard method with calculated by peak area, calculate the dissolution of Atorvastatin calcium in each point slice, and draw stripping curve.
dissolution test result
Tablet prepared by the tablet prepare embodiment 2 dry granulation tabletting and comparative example 1 and 2 wet granule compression tablet, measures dissolution according to the method described above and draws stripping curve, seeing Fig. 1 and 2.
Tablet prepared by the tablet prepare embodiment 2 dry granulation tabletting and comparative example 1 and 2 wet granule compression tablet, to place after influence factor 92.5%RH super-humid conditions 10 days, measures dissolution according to the method described above and draw stripping curve, seeing Fig. 1 and 3.
Pfizer's product to reach after a placement influence factor 92.5%RH super-humid conditions 10 days, measures dissolution according to the method described above and draws stripping curve, seeing Fig. 4.
From experimental result: in the compound tablet using wet granule compression tablet technology to prepare, 0 day stripping situation of Atorvastatin calcium is unstable, the how many Dissolution of Tablet impact on producing of amount adding binding agent is comparatively large, is not easy to control in technical process; The tablet prepared by wet processing placed influence factor's super-humid conditions after 10 days, and dissolution significantly reduces, preparation dissolution poor stability; And the formulation disintegrates using dry granulation pressed-disc technique to prepare is rapid, stripping is fast, and through influence factor's experimental verification, place super-humid conditions after 10 days, the significant change of stripping curve thing, preparation stripping has good stability.
Pfizer's product reaches one, the sample measuring placement 10 days influence factor's super-humid conditions is carried out according to same dissolution determination method, all there is obvious reduction in the stripping data that the stripping curve of its two main constituents Atorvastatin calcium and amlodipine compares 0 day, by comparison comparatively, the Atorvastatin calcium amlodipine compound preparation dissolution stability that described in the present invention prepared by method is adopted to be greatly increased.
Claims (10)
1. contain a compound for Atorvastatin calcium and amlodipine, it is the biplate layer compound containing atorvastatin layer and amlodipine lamella, by weight percentage:
Described atorvastatin layer comprise 10 ~ 20% atorvastatin calcium, 50 ~ 70% filler, 10 ~ 20% alkaline stabiliser, 3 ~ 12% disintegrating agent, the cosolvent of 0.3 ~ 3%, the lubricant of 0.3 ~ 3% and 0.3 ~ 3% fluidizer;
Described amlodipine lamella comprise 10 ~ 20% amlodipine, 60 ~ 80% filler, the disintegrating agent of 3 ~ 10%, the lubricant of 0.3 ~ 3% and 0.3 ~ 3% fluidizer.
2. compound according to claim 1, it is characterized in that, in described atorvastatin layer, described filler be selected from microcrystalline Cellulose, pregelatinized Starch, mannitol, starch and lactose one or several, be preferably microcrystalline Cellulose and/or pregelatinized Starch; Preferably, described alkaline stabiliser is selected from calcium carbonate and/or magnesium oxide, is preferably calcium carbonate; More preferably, described disintegrating agent is polyvinylpolypyrrolidone; Further preferably, described cosolvent is selected from sodium lauryl sulphate and/or Tween 80, is preferably sodium lauryl sulphate; Still more preferably, described lubricant is Pulvis Talci; Again further preferably, described fluidizer is magnesium stearate.
3. compound according to claim 1 and 2, is characterized in that, in amlodipine lamella, described filler is selected from microcrystalline Cellulose and/or calcium hydrogen phosphate; Preferably, described disintegrating agent is crosslinked carboxymethyl fecula sodium; More preferably, described lubricant is Pulvis Talci; Further preferably, described fluidizer is magnesium stearate.
4. compound according to any one of claim 1 to 3, is characterized in that, in described atorvastatin layer or amlodipine lamella, also comprises pigment such as light blue.
5. compound according to any one of claim 1 to 4, is characterized in that, described amlodipine is Amlodipine Besylate Tablet or maleic acid levo amido chloro diping.
6. compound according to any one of claim 1 to 5, it is characterized in that, described compound also comprises coatings, preferably, the material of described coatings be selected from Opardy II, Opardy I, Opardy amb and Opardy XY one or more, more preferably, the material of described coatings is Opardy II, again preferably, described coatings weightening finish is 3 ~ 4%.
7. the preparation method of compound according to any one of claim 1 to 6, the method comprises the following steps:
A) atorvastatin layer composition is prepared:
(1) Atorvastatin calcium is crossed 100 mesh sieves, 60 mesh sieves crossed by fluidizer, and other adjuvant such as filler, alkaline stabiliser, disintegrating agent, cosolvent and lubricant waited 80 mesh sieves;
(2) in Atorvastatin calcium, add adjuvant such as alkaline stabiliser, cosolvent and fluidizer, mix homogeneously, then add filler, obtain the mixture of mix homogeneously;
(3) adopt dry method to granulate, obtain Atorvastatin calcium granule, then add disintegrating agent and lubricant, mix homogeneously;
B) amlodipine layer composition is prepared
(1) amlodipine is crossed 100 mesh sieves, 60 mesh sieves crossed by fluidizer, and other adjuvant such as filler, disintegrating agent and lubricant waited 80 mesh sieves;
(2) in amlodipine, add adjuvant such as filler and disintegrating agent, then it is even to add mix lubricant;
C) step a) and b) obtained atorvastatin layer composition and amlodipine layer composition are pressed into double-layer tablet, obtain described compound.
8. preparation method according to claim 7, it is characterized in that, described preparation method also comprises carries out coating to the double-layer tablet made in step c), preferably, the material of described coatings be selected from Opardy II, Opardy I, Opardy amb and Opardy XY one or more, more preferably, the material of described coating is Opardy II.
9. preparation method according to claim 8, is characterized in that, described coating weight gain is 3 ~ 4%.
10. according to preparation method of the present invention, it is characterized in that, the hardness of described compound is 5 ~ 7Kg/mm
2.
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| CN201410048572.7A Pending CN104825449A (en) | 2014-02-12 | 2014-02-12 | Compound composition containing atorvastatin calcium and amlodipine and preparation method of same |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110063944A (en) * | 2018-01-24 | 2019-07-30 | 北京红太阳药业有限公司 | A kind of Levamlodipine besylate atorvastatin and preparation method thereof |
| CN113230223A (en) * | 2021-05-13 | 2021-08-10 | 宜昌人福药业有限责任公司 | Preparation method of atorvastatin calcium film coated tablet |
| CN114674944A (en) * | 2022-03-04 | 2022-06-28 | 苏州东瑞制药有限公司 | Method for detecting related substances of amlodipine besylate and atorvastatin calcium compound preparation |
| CN114903862A (en) * | 2022-06-15 | 2022-08-16 | 湖北中古生物制药有限公司 | Policosanol atorvastatin calcium compound preparation and preparation method thereof |
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| CN1805732A (en) * | 2003-06-12 | 2006-07-19 | 沃纳-兰伯特公司 | Pharmaceutical compositions of atorvastatin |
| WO2008146178A2 (en) * | 2007-05-30 | 2008-12-04 | Wockhardt Research Centre | A novel tablet dosage form |
| CN102000075A (en) * | 2010-12-11 | 2011-04-06 | 林飞 | Novel pharmaceutical composite containing amlodipine and atorvastatin calcium anhydride |
| CN102038682A (en) * | 2010-12-09 | 2011-05-04 | 林飞 | Pharmaceutical composition containing amlodipine and atorvastatin calcium solvate |
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| CN1805732A (en) * | 2003-06-12 | 2006-07-19 | 沃纳-兰伯特公司 | Pharmaceutical compositions of atorvastatin |
| WO2008146178A2 (en) * | 2007-05-30 | 2008-12-04 | Wockhardt Research Centre | A novel tablet dosage form |
| CN102038682A (en) * | 2010-12-09 | 2011-05-04 | 林飞 | Pharmaceutical composition containing amlodipine and atorvastatin calcium solvate |
| CN102000075A (en) * | 2010-12-11 | 2011-04-06 | 林飞 | Novel pharmaceutical composite containing amlodipine and atorvastatin calcium anhydride |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110063944A (en) * | 2018-01-24 | 2019-07-30 | 北京红太阳药业有限公司 | A kind of Levamlodipine besylate atorvastatin and preparation method thereof |
| CN110063944B (en) * | 2018-01-24 | 2021-07-16 | 北京红太阳药业有限公司 | Levamlodipine besylate atorvastatin calcium tablet and preparation method thereof |
| CN113230223A (en) * | 2021-05-13 | 2021-08-10 | 宜昌人福药业有限责任公司 | Preparation method of atorvastatin calcium film coated tablet |
| CN114674944A (en) * | 2022-03-04 | 2022-06-28 | 苏州东瑞制药有限公司 | Method for detecting related substances of amlodipine besylate and atorvastatin calcium compound preparation |
| CN114903862A (en) * | 2022-06-15 | 2022-08-16 | 湖北中古生物制药有限公司 | Policosanol atorvastatin calcium compound preparation and preparation method thereof |
| CN114903862B (en) * | 2022-06-15 | 2023-08-22 | 湖北中古生物制药有限公司 | Polypolicosanol atorvastatin calcium compound preparation and preparation method thereof |
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