CN105106138A - Atorvastatin calcium composition granules for treating hypercholesteremia - Google Patents
Atorvastatin calcium composition granules for treating hypercholesteremia Download PDFInfo
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- CN105106138A CN105106138A CN201510629572.0A CN201510629572A CN105106138A CN 105106138 A CN105106138 A CN 105106138A CN 201510629572 A CN201510629572 A CN 201510629572A CN 105106138 A CN105106138 A CN 105106138A
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Abstract
The invention relates to atorvastatin calcium composition granules for treating hypercholesteremia and belongs to the technical field of medicine. The atorvastatin calcium composition granules comprise atorvastatin calcium, sorbitol, fumaric acid, di-tert-butyl p-cresol, purified water and orange essence. The atorvastatin calcium is a new crystal compound, the X-ray powder diffraction diagram, obtained by using Cu-K alpha rays for measuring, of the atorvastatin calcium is shown in figure 1, and the atorvastatin calcium is different from atorvastatin calcium reported in the prior art. Experiments show that the new crystal compound evidently improves moisture absorption performance, increases solubility of medicine in acid media and water, is low in moisture and impurity content and good in stability, is prevented from being destroyed in a gastric acid environment and lowers the occurrence rate of the side effect of myalgia, and the granules prepared by the atorvastatin calcium are good in stability and high in bioavailability.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine Atorvastatin calcium composition granule for the treatment of hypercholesterolemia.
Background technology
Atorvastatin calcium (AtorvastatinCalcium) belongs to hydroxyl first glutaryl CoA (HMG-CoA) reductase inhibitor, by suppressing the biosynthesis of HMG-COA reductase and cholesterol in liver thus reducing cholesterol and serum lipoprotein concentration in blood plasma, and by the low density lipoprotein receptor in rat liver that increases cell surface to strengthen picked-up and the metabolism of low density lipoprotein, LDL.Atorvastatin calcium effectively can reduce homozygote and heterozygote familial hypercholesterolemia, non-familial hypercholesterolemia and mixed type disorder of lipid metabolism patients blood plasma T-CHOL, low-density lipoprotein cholesterol, apolipoprotein and triglyceride levels, simultaneously high density lipoprotein increasing cholesterol and ApoA l level to some extent.Atorvastatin calcium has the plurality of specifications such as 10mg, 20mg, 40mg and 80mg, and dosage form has tablet, dispersible tablet, capsule etc.
Atorvastatin calcium has highly lipophilic, poorly water-soluble, and has stronger bitterness, all responsive to humidity, light, heat and low pH etc., can be degraded to lactone especially in low pH situation.Atorvastatin calcium dissolubility in sour environment is poor, in under sour environment, all Atorvastatin calciums mixed in pharmaceutical formulation all can not dissolve, because the dissolubility of Atorvastatin calcium is low, make to prepare the preparation that biological activity is stablized, effect is consistent.After testing, commercially available product (lipitor, Pfizer) in pH1.2 hydrochloric acid medium 10min dissolution probably about 36%.How to improve preparation stability and medicine dissolution in acid medium annoyings pharmaceutics personnel always.
In acid condition, concretely, be can be degraded to its lactone form under gastric acid condition, the molecule of this lactone form does not have Lipid-lowering activities to Atorvastatin calcium, but can cause the side effect of the myalgia of well-known statins.
As everyone knows, health adult's gastric juice becomes acid, roughly suitable with 0.1M hydrochloric acid, and the normal medicine gastric emptying time is approximately 2 hours, after the solid preparation oral administration of Atorvastatin calcium, is detained 2 hours, inevitably can degrades in gastric juice.
For the substance characteristics of Atorvastatin calcium instability, bibliographical information was once had to attempt to solve this difficult problem by optimizing atorvastatin pharmaceutical formulation technique.Such as, alkalescence or buffer agent (W000/35425, W094/16603) is added in the formula prepared at tablet.
Chinese patent CN1630510A discloses the Atorvastatin calcium of medicament forms, its compositions and comprises the pharmaceutical preparation of Atorvastatin calcium, adopt wet granulation technique, calcium carbonate is added as stabilizing agent in prescription, to ensure that medicine is in alkaline environment, avoid drug degradation and improve drug dissolution.
Chinese patent CN102920675A discloses a kind of atorvastatin agent and preparation method thereof, adopts wet granule compression tablet.This patent is added with the calcium carbonate of 22.01 parts as filler, and is surrounded by film-coat, and be added with polyoxyethylene sorbitan monoleate as stripping promoter, calcium carbonate wherein can play Stabilization simultaneously, but still can not solve the problem that in storage process, related substance raises completely.
Chinese patent CN103705484A discloses a kind of stable atorvastatin and preparation method thereof, comprise label and film-coat layer, label is made up of the complex stabilizer of Atorvastatin calcium and filler, disintegrating agent, lubricant and suitable consumption, and film-coat layer contains the stabilizing agents such as calcium carbonate, magnesium oxide, sodium bicarbonate.
Above patent, all by adding the alkaline matters such as calcium carbonate, makes Atorvastatin calcium stablize in the basic conditions, decreases the generation of impurity.But a large amount of calcium carbonate can react with gastric acid, cause the untoward reaction such as constipation, flatulence, dyspepsia.
Chinese patent CN1911209A discloses a kind of quickly disintegrated atorvastatin and preparation method thereof, adopts wet granulation to prepare atorvastatin, adds a large amount of disintegrating agent in formula.But the problem that a large amount of disintegrating agent brings is the easy moisture absorption, thus causes the degraded of Atorvastatin calcium.Moreover, add a certain amount of sodium lauryl sulphate in formula, improve dissolution in vitro, but the membership that adds of surfactant brings GI irritation.
Chinese patent CN102309462A provides a kind of atorvastatin agent, and adopt dry method secondary granulation technique, technique is comparatively complicated, less stable, and can not stripping completely in acid.
Chinese patent CN102138910A adopts direct compression technology, by Atorvastatin calcium, cross-linking sodium carboxymethyl cellulose, lactose, magnesium stearate mixing, and tabletting and get final product.But 30min only stripping 60% in acid, fails complete Fast Stripping.Meanwhile, lactose is slant acidity material, can cause the degraded of Atorvastatin calcium.
Chinese patent CN103006602A discloses atorvastatin of a kind of Fast Stripping and preparation method thereof, Atorvastatin calcium is dissolved in methanol, add disintegrating agent to be uniformly dispersed, porphyrize, control the granularity D90 < 20 microns of suspension, this suspension is sprayed in fluid bed coating on medicinal piller and obtains drug-loaded pellets, drug-loaded pellets and pharmaceutic adjuvant direct compression are prepared from.This invention adopts the lactose of slant acidity and the polyvinylpolypyrrolidone of very easily moisture absorption, can cause the degraded of Atorvastatin calcium.
Chinese patent CN101791297B discloses a kind of atorvastatin calcium oral disintegrating tablet and preparation method thereof, prepares the tasteless microcapsule of Atorvastatin calcium, but complex process, and stripping is unhappy.
Chinese patent CN102309467A discloses a kind of atorvastatin calcium capsule preparation method, amorphous atorvastatin calcium is mixed homogeneously with water-soluble solid dispersible carrier, heating makes the melting of solid dispersal carrier, after making amorphous atorvastatin calcium be dispersed in the dispersible carrier of melting, cooling curing; After the mixture cold drying of acquisition, obtain the granule of mixture; After being mixed with other pharmaceutic adjuvant by the granule obtained again, insert capsule.The carrier materials such as the PEG4000 that this invention is used and capsule shells, all containing higher moisture, easily cause Atorvastatin calcium fast degradation.
Chinese patent CN102139115B discloses the cyclodextrin clathrate of Atorvastatin calcium and the preparation method of oral solid formulation thereof, and Sulfobutyl ether β _ cyclodextrin moisture used is high, easily causes Atorvastatin calcium to be degraded.Meanwhile, containing sodium lauryl sulphate in prescription, there is comparatively strong and stimulating.
Chinese patent CN103690513A discloses Atorvastatin calcium nano-lipid carrier and preparation method thereof; Chinese patent CN103690485A discloses the oral proliposome and preparation method thereof containing Atorvastatin calcium.Both preparation technologies are all comparatively complicated, and use a large amount of surfactants, increased the weight of gastrointestinal zest.
In sum, the atorvastatin calcium preparation that provides a kind of good stability, bioavailability high is all failed in prior art.
On the other hand, the purity of pharmaceutically active substance is considered to the key factor guaranteeing drug safety and quality always.In the synthesis production process of Atorvastatin calcium, the complicated synthesis step that multistep is different inevitably produces a large amount of structure and characteristics except target product and the similar impurity compound of atorvastatin calcium compound.In addition, because it is responsive on the impact of environment in the synthesis production process of Atorvastatin calcium, such as, oxygen in temperature, pH, humidity, light, air and carbon dioxide and in process or storage process surrounding medium etc., these factors all likely cause atorvastatin calcium compound to be degraded, thus its biological activity is reduced, impurity compound improves.Be possible simultaneously and patient is taken to the preparation prepared future bring less desirable side effect, thus make to have a negative impact to the safety of medicine.Therefore, the crude drug active constituents of medicine as preparation requires stable and purification to greatest extent.
In a word, in method prepared by the Atorvastatin calcium crystal-form compound of existing research report and patent literature, the various crystal formation of acquisition or non-crystalline forms Atorvastatin calcium still total impurities is higher, optical purity is lower, and bioavailability is little.
In view of the conventional crystal formation of Atorvastatin calcium to the sensitivity of the air ambient factor, bioactive unstability, formulation processing conditions harshness.The present inventor starts with from the research of Atorvastatin calcium solid chemical material existence, a kind of new Atorvastatin calcium crystalline compounds has been prepared through a large amount of tests, find through overtesting, the hygroscopicity that the compound tool of this novel crystal forms structure has clear improvement, improve the dissolubility of medicine in acid medium and water, moisture and impurity content is low, good stability, avoid Atorvastatin calcium destroyed in stomach acidity environment, reduce the incidence rate of its myalgia side effect, its obtained granule good stability, bioavailability are high.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine Atorvastatin calcium composition granule for the treatment of hypercholesterolemia.
In order to complete object of the present invention, the technical scheme of employing is:
A kind of medicine Atorvastatin calcium composition granule for the treatment of hypercholesterolemia of the present invention, described compositions is made up of Atorvastatin calcium, sorbitol, fumaric acid, toluene di-tert-butyl phenol, purified water, flavoring orange essence; Described Atorvastatin calcium is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
As preferably, with parts by weight: described composition granule is made up of the Atorvastatin calcium of 1 weight portion, the sorbitol of 27-28 weight portion, the fumaric acid of 0.7-0.9 weight portion, the toluene di-tert-butyl phenol of 0.5-0.6 weight portion, the purified water of 6-8 weight portion, the flavoring orange essence of 0.4-0.6 weight portion.
As preferably, with parts by weight: described composition granule is made up of the Atorvastatin calcium of 1 weight portion, the sorbitol of 27.55 weight portions, the fumaric acid of 0.8 weight portion, the toluene di-tert-butyl phenol of 0.55 weight portion, the purified water of 7 weight portions, the flavoring orange essence of 0.5 weight portion.
As preferably, the preparation method of described composition granule comprises the following steps:
(1) supplementary material process: sieve Atorvastatin calcium 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: Atorvastatin calcium, sorbitol, fumaric acid, toluene di-tert-butyl phenol are added in wet mixing pelletizer, are dry mixed 25 minutes; Flavoring orange essence is dissolved in purified water, joins wet mixing pelletizer wet mixing cutting, select 16 orders granulation soft material processed;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4.0-4.5 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
As preferably, the preparation method of the Atorvastatin calcium crystal in the present composition comprises the following steps:
(1) be dissolved in by Atorvastatin calcium in the mixed solvent of methyl acetone and methanol, the solvent load that needs of every gram of Atorvastatin calcium is 100 milliliters, and the volume ratio of methyl acetone and methanol is 4:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains Atorvastatin calcium crystal.
Below technical scheme of the present invention is made further explanation:
The present invention is by the precise controlling to crystallization condition, and prepared a kind of Atorvastatin calcium novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this Atorvastatin calcium crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, the compound of this novel crystal forms structure has the hygroscopicity significantly improved, improve the dissolubility of medicine in acid medium and water, moisture and impurity content is low, good stability, avoid Atorvastatin calcium destroyed in stomach acidity environment, reduce the incidence rate of its myalgia side effect, its obtained granule good stability, bioavailability are high.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the Atorvastatin calcium crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of Atorvastatin calcium crystal
(1) be dissolved in by Atorvastatin calcium in the mixed solvent of methyl acetone and methanol, the solvent load that needs of every gram of Atorvastatin calcium is 100 milliliters, and the volume ratio of methyl acetone and methanol is 4:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains Atorvastatin calcium crystal.
The X-ray powder diffraction pattern that the Atorvastatin calcium crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of Atorvastatin calcium granule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: sieve Atorvastatin calcium 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: Atorvastatin calcium, sorbitol, fumaric acid, toluene di-tert-butyl phenol are added in wet mixing pelletizer, are dry mixed 25 minutes; Flavoring orange essence is dissolved in purified water, joins wet mixing pelletizer wet mixing cutting, select 16 orders granulation soft material processed;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4.0-4.5 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
embodiment 3:the preparation of Atorvastatin calcium granule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: sieve Atorvastatin calcium 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: Atorvastatin calcium, sorbitol, fumaric acid, toluene di-tert-butyl phenol are added in wet mixing pelletizer, are dry mixed 25 minutes; Flavoring orange essence is dissolved in purified water, joins wet mixing pelletizer wet mixing cutting, select 16 orders granulation soft material processed;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4.0-4.5 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
embodiment 4:the preparation of Atorvastatin calcium granule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: sieve Atorvastatin calcium 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: Atorvastatin calcium, sorbitol, fumaric acid, toluene di-tert-butyl phenol are added in wet mixing pelletizer, are dry mixed 25 minutes; Flavoring orange essence is dissolved in purified water, joins wet mixing pelletizer wet mixing cutting, select 16 orders granulation soft material processed;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4.0-4.5 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
test example 1:wettability test
This test example compares the hygroscopicity of atorvastatin calcium compound provided by the invention and import atorvastatin calcium raw material drug.
Test method: respectively under the condition of humidity 60% and 90%, room temperature, each sample thief 1g is placed on electronic balance, and time recording weight, to detect moisture absorption degree, the results are shown in Table 1.
Table 1 sample hygroscopicity measurement result
Wherein:
Sample 1-3: Atorvastatin calcium 3 batch sample that the embodiment of the present invention 1 is obtained;
Sample 4: imported raw material medicine product.
As can be seen from above-mentioned result of the test, compared with the Atorvastatin calcium of prior art, Atorvastatin calcium provided by the present invention has the hygroscopicity significantly improved.
test example 2:solubility property and lactone content determination test
Simulate Atorvastatin calcium crystalline compounds of the present invention (obtained 3 batch samples of embodiment 1) in vitro, the solubility property in acidic stomach environment and lactone content.Being about the simulated gastric fluid of 3 at pH, is carry out dissolubility test in the HCL aqueous solution of 900ml0.001M in particular, and the concentration of the Atorvastatin calcium of then interval measurement dissolving in 10 minutes and lactone content, the results are shown in Table 2.
Table 2 solubility property and lactone content determination test result
From above-mentioned result of the test, the dissolubility of Atorvastatin calcium crystalline compounds of the present invention in gastric acid environment improves greatly, and lactone content is low, change little, avoid Atorvastatin calcium destroyed in stomach acidity environment, enhance the stability of medicine, reduce the incidence rate of its myalgia side effect, the effect of better performance medicine, facilitates patient to take.
test example 3:water solublity is tested
Measure by the method for Chinese Pharmacopoeia, the dissolubility of Atorvastatin calcium crystalline compounds of the present invention in water is 0.75mg/ml, and the dissolubility of imported product is less than 0.24mg/ml.
test example 4:stability test
Study on influencing factors is carried out to the Atorvastatin calcium granule prepared by embodiment 3, carries out influence factor's stability test according to " Chinese Pharmacopoeia " two version relevant regulations in 2010, the results are shown in Table 3.
Table 3 influence factor result of the test
From above-mentioned result of the test, the embodiment of the present invention 3 product not only moisture, lactone and total assorted content is low, and substantially unchanged under high temperature, high humidity and intense light conditions, good stability.
Identical experiment is carried out to other embodiments, has obtained analog result.
From above-mentioned test, crystal compound of the present invention has the hygroscopicity significantly improved, improve the dissolubility of medicine in acid medium and water, moisture and impurity content is low, good stability, avoid Atorvastatin calcium destroyed in stomach acidity environment, reduce the incidence rate of its myalgia side effect, its obtained granule good stability, bioavailability are high.
Claims (5)
1. treat a medicine Atorvastatin calcium composition granule for hypercholesterolemia, it is characterized in that: described compositions is made up of Atorvastatin calcium, sorbitol, fumaric acid, toluene di-tert-butyl phenol, purified water, flavoring orange essence; Described Atorvastatin calcium is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the medicine Atorvastatin calcium composition granule for the treatment of hypercholesterolemia according to claim 1, it is characterized in that: with parts by weight, described compositions is made up of the Atorvastatin calcium of 1 weight portion, the sorbitol of 27-28 weight portion, the fumaric acid of 0.7-0.9 weight portion, the toluene di-tert-butyl phenol of 0.5-0.6 weight portion, the purified water of 6-8 weight portion, the flavoring orange essence of 0.4-0.6 weight portion.
3. the medicine Atorvastatin calcium composition granule for the treatment of hypercholesterolemia according to claim 2, it is characterized in that: with parts by weight, described compositions is made up of the Atorvastatin calcium of 1 weight portion, the sorbitol of 27.55 weight portions, the fumaric acid of 0.8 weight portion, the toluene di-tert-butyl phenol of 0.55 weight portion, the purified water of 7 weight portions, the flavoring orange essence of 0.5 weight portion.
4., according to the medicine Atorvastatin calcium composition granule of the arbitrary described treatment hypercholesterolemia of claim 1-3, it is characterized in that, the preparation method of described composition granule comprises the following steps:
(1) supplementary material process: sieve Atorvastatin calcium 100 orders;
(2) weigh: weigh according to prescription;
(3) granulate: Atorvastatin calcium, sorbitol, fumaric acid, toluene di-tert-butyl phenol are added in wet mixing pelletizer, are dry mixed 25 minutes; Flavoring orange essence is dissolved in purified water, joins wet mixing pelletizer wet mixing cutting, select 16 orders granulation soft material processed;
(4) drying and screening: the wet granular of granulation gained is evenly split on the drip pan of baking oven, set temperature 60-65 DEG C, dry total time is 4.0-4.5 hour, and sieve material after drying 16-30 order;
(5) mix: after sieving, granule drops into three-dimensional motion mixer, arranges premixing speed 15 revs/min, incorporation time 5 minutes;
(6) pack: carry out subpackage according to after the theoretical loading amount scope of total mixed gained material cubage.
5. the medicine Atorvastatin calcium composition granule for the treatment of hypercholesterolemia according to claim 1, it is characterized in that, the preparation method of the crystal of described Atorvastatin calcium comprises the following steps:
(1) be dissolved in by Atorvastatin calcium in the mixed solvent of methyl acetone and methanol, the solvent load that needs of every gram of Atorvastatin calcium is 100 milliliters, and the volume ratio of methyl acetone and methanol is 4:5;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-10 DEG C, filters, dry, collects crystal and namely obtains Atorvastatin calcium crystal.
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| CN201510629572.0A CN105106138A (en) | 2015-09-29 | 2015-09-29 | Atorvastatin calcium composition granules for treating hypercholesteremia |
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| CN201510629572.0A CN105106138A (en) | 2015-09-29 | 2015-09-29 | Atorvastatin calcium composition granules for treating hypercholesteremia |
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Application publication date: 20151202 |