CN102342937A - Amlodipine and candesartan pharmaceutical composition and preparation method thereof - Google Patents
Amlodipine and candesartan pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN102342937A CN102342937A CN2011102045272A CN201110204527A CN102342937A CN 102342937 A CN102342937 A CN 102342937A CN 2011102045272 A CN2011102045272 A CN 2011102045272A CN 201110204527 A CN201110204527 A CN 201110204527A CN 102342937 A CN102342937 A CN 102342937A
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- amlodipine
- hydrate crystal
- amlodipine maleate
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- 239000002053 C09CA06 - Candesartan Substances 0.000 title claims abstract description 13
- 229960000932 candesartan Drugs 0.000 title claims abstract description 13
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- TZNOWAJJWCGILX-BTJKTKAUSA-N (z)-but-2-enedioic acid;3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical group OC(=O)\C=C/C(O)=O.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl TZNOWAJJWCGILX-BTJKTKAUSA-N 0.000 claims abstract description 50
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Abstract
The invention relates to an amlodipine and candesartan pharmaceutical composition. The pharmaceutical composition comprises the following components in parts by weight: 2.5-5 parts of amlodipine hydrate crystal, 4-16 parts of candesartan, 5-50 parts of compressible starch, 10-60 parts of microcrystalline cellulose, 15-40 parts of low-substituted hydroxypropyl cellulose, 10-45 parts of cross-linked polyvinyl pyrrolidone and 1-3 parts of magnesium stearate, wherein the amlodipine is amlodipine maleate hydrate crystal with a molecular formula of C24H29ClN2O9.1.5H2O. The pharmaceutical composition has the advantages that: amlodipine maleate has rapid and stable action, and can be stably released within 24 hours; and the pharmaceutical composition has strong synergism, accumulation and complementation effects, and has high bioavailability.
Description
Technical field
The invention belongs to medical technical field, be specifically related to Pharmaceutical composition of a kind of amlodipine and candesartan Cilexetil and preparation method thereof.
Background technology
Candesartan Cilexetil; The Chinese another name: (±)-1-[[(hexamethylene oxo) carbonyl] oxo] ethyl-2-ethyoxyl-1-[[2 '-(1H-tetrazole base-5)-[1; 1 '-xenyl]-the 4-yl] methyl]-the 1H-benzimidazole-7-carboxylate, English name: Candesartan cilexetil, molecular formula: C33H34N6O6; Molecular weight: 610.67, structural formula is following:
Candesartan Cilexetil is hydrolyzed into the active metabolite Candesartan in vivo rapidly; Candesartan is selectivity angiotensin-ii receptor (AT1) antagonist; Through the vasoconstriction effect of the nervous plain II of antagonizing vessel with vascular smooth muscle AT1 receptors bind, thereby reduce peripheral vascular resistance.Other has and thinks: Candesartan can be brought into play certain hypotensive effect through suppressing the acth secretion aldosterone.Candesartan does not suppress kininase II, does not influence the Kallidin I degraded.The experiment of carrying out the hyperpietic shows: raise but the patient repeatedly takes these article hyperamization slurry RA, hypertensin 1 concentration and Angiotensin II concentration; Take continuously for 1 time these article 2-8mg every day, systolic pressure, diastolic pressure are descended, left ventricular mass, peripheral vascular resistance reduce, and CO, ejection fraction, renal vascular resistance, renal blood flow, glomerular filtration rate are not had obvious influence; To the former generation property hyperpietic of cerebrovascular disorders is arranged, cerebral blood flow there is not influence.
Amlodipine, Chinese another name: 6-methyl-2-(2-amino ethoxy) methyl-4-(2-chlorphenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid methyl ethyl ester, English name: Amlodipine, molecular formula: C20H25ClN2O5, molecular weight: 408.88.Amlodipine is dihydropyridine type calcium antagonists (calcium ion antagonist or a slow channel blocking agent); Can block the outer Ca2+ of cardiac muscle and VSMC and cause cardiac muscle and vascular smooth muscle relaxation through cell membrane calcium channel entering cell, main site of action is in periphery vascular tissue.The generation of hypotensive effect causes the systemic vascular resistance reduction relevant with the peripheral blood vessel expansion.
European hypertension guide, U.S.'s hypertension guide and Chinese hypertension prevention and control guide all proposed in 2007, and the hypertension more than 2 grades needs therapeutic alliance.Recently research is thought, in order at utmost to obtain the hypertensive curative effect of treatment, require to bring high blood pressure down greatly, and single therapy usually can not reach this purpose, and the dosage increase is prone to untoward reaction.Extensive clinical trial shows the depressor Combined application, and the depressor of promptly uniting two or more can strengthen antihypertensive effect, and the synergism and the complementary action of performance medicine, can reduce dosage, can offset untoward reaction again.In this case, many scholars propose to treat hypertension with the drug combination mode again, and think that there is clear superiority in drug combination when treatment hypertension: (1) mechanism of action different drug hypotensive effect possibly add up, work in coordination with or be complementary; The ill effect that dosage caused more greatly when (2) low dose of associating can reduce single drug; (3) but and medicament passivation counter regulation, limit mutually that another is drug-induced bad compensatory; (4) help taking into account multiple risk factor that the patient exists with and deposit disease; (5) improve patient's compliance and quality of life; Find that simultaneously therapeutic alliance has good toleration, therefore, reasonably the Combined application antihypertensive drug is of crucial importance in hypertensive treatment.
Li Dongyan " candesartan Cilexetil and Levamlodipine share the influence to the essential hypertension Microalbuminuria " (contemporary Chinese medicinal application volume o. 11th June the 4th in 2010); Reach a conclusion: as strong calcium antagonist and angiotensin-ii receptor blocker; Candesartan Cilexetil and Levamlodipine are except that having effective hypotensive effect; Both all can reduce the effect of urine trace albumin; Both have share and have better more obviously reduced the urine trace albumin, thereby better kidney protection effect is arranged, and it is the preferential selection of the early stage renal damage treatment of hypertension that candesartan Cilexetil and Levamlodipine share.
People such as Xing Xiangjun " candesartan Cilexetil associating Amlodipine Besylate Tablet is treated diabetes complicated hypertension 45 examples " (medical Leader the 28th the 1st phase of volume of January in 2009); Reach a conclusion: candesartan Cilexetil (ARB) is superior to single drug with Amlodipine Besylate Tablet (calcium channel antagonistic) Combined application; Can make blood pressure reach desirable controlled target value, target organ damage alleviates, non-evident effect; Better toleration is arranged, be worth clinical expansion.
Candesartan Cilexetil amlodipine sheet associating angiotensin ii receptor antagonist and calcium antagonist are united different blood pressure lowering mechanism, act on different action sites simultaneously, under the prerequisite that does not improve drug dose, reach the purpose of control patient blood pressure.Simultaneously, drug combination is controlling blood pressure more effectively not only, because the dosage that uses is merely the lowest dose level of two kinds of medicines, also can more fully protect blood vessel and target organ, reduces side effect, improves the compliance of patient to treatment.
In the prior art; Amlodipine and Amlodipine (like amlodipine maleate, Amlodipine Besylate Tablet, Amlodipine mesylate etc.) are almost insoluble in water, in human body, absorb slowly, and 6～12h reaches the blood drug level peak value after the medication; The blood drug level aggregate level is low; Particularly the blood drug level at initial stage is very low after the administration, and this medicine onset is very slow, and effect slowly; And 3～4h reaches the blood concentration peak concentration behind the candesartan Cilexetil medicine, and this medicine is rapid-action, and the time phase difference when two kinds of medicines reach the blood drug level peak value after the administration at the same time separately is far away, works in coordination with, adds up, complementary action is very limited.A kind of Pharmaceutical composition that contains Amlodipine Besylate Tablet and candesartan Cilexetil is disclosed like Chinese patent CN101371834A; The weight ratio of Amlodipine Besylate Tablet and candesartan Cilexetil is 1: 1-6; Has certain synergism aspect blood pressure lowering, the expansion blood vessel in this Pharmaceutical composition; But the Amlodipine Besylate Tablet onset is slow, and the Pharmaceutical composition synergism of Amlodipine Besylate Tablet and candesartan Cilexetil is limited.
In addition, in order to improve the bioavailability of Amlodipine, prior art adopts the Amlodipine with raceme to be split as levo-amlodipine salt; After the levo-amlodipine salt administration; Though bioavailability increases, its time that reaches the blood drug level peak value remains 6～12h, and onset is slow; Blood drug level by the initial stage after the administration of normal human's required dosage is very low, the working in coordination with of itself and candesartan Cilexetil, add up, complementary action is very limited.Chinese patent CN102106853A discloses the hypertensive Pharmaceutical composition of a kind of treatment; Its active component is left-handed Amlodipine Besylate Tablet and candesartan Cilexetil; Said composition treatment hypertension, low than the folk prescription consumption, have synergism; But left-handed Amlodipine Besylate Tablet onset is slow, and the synergism of the two is very limited.And, Amlodipine is split as levo-amlodipine salt, increased production process, and in the process that splits, the loss of R salt and the introducing of impurity have been arranged, this has greatly increased the cost of medicine.
In view of this, the special present technique scheme that proposes.
Summary of the invention
First purpose of the present invention is to provide the Pharmaceutical composition of a kind of amlodipine and candesartan Cilexetil; The amlodipine onset is very fast and steady in this Pharmaceutical composition; And can in 24 hours, steadily discharge drug effect; The working in coordination with of this Pharmaceutical composition, add up, complementary action is strong, its bioavailability is high.
Second purpose of the present invention is to provide the method for preparing of the Pharmaceutical composition of a kind of amlodipine and candesartan Cilexetil, a kind of amlodipine that adopts this method for preparing preparation and candesartan Cilexetil Pharmaceutical composition have the purity height, safe and effective, outward appearance good, stable better advantage.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
The Pharmaceutical composition of a kind of amlodipine and candesartan Cilexetil; In weight portion, said Pharmaceutical composition comprises 2.5～5 parts of amlodipines, candesartan Cilexetil 4-16 part, 5～50 parts of amylum pregelatinisatums, 10～60 parts of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose 15～40,10～45 parts of crospolyvinylpyrrolidone, 1～3 part of magnesium stearate; Said amlodipine is the amlodipine maleate hydrate crystal.
The molecular formula of said amlodipine maleate hydrate crystal is C
24H
29ClN
2O
91.5H
2O.
In the X-ray powder diffraction pattern of said amlodipine maleate hydrate crystal at 5.4 °, 6.1 °, 7.5 °, 11.6 °, 14.6 °; 15.8 °, 17.7 °, 18.9 °, 20.4 °, 21.6 °; 24.9 °, 26.1 °, 26.9 °, 29.4 °, 31.4 °; 34.1 °, 36.5 °, 42.2 °, there is characteristic peak at 44.2 ° of angle of diffraction places.
The particle diameter of said amlodipine maleate hydrate crystal is 75～150 μ m.
The method for preparing of said amlodipine maleate hydrate crystal is: in agitated reactor, add amlodipine maleate, ethanol, dimethyl sulfoxine, deionized water, regulate pH to 6～6.5 with triethylamine or acetic acid, stir 30min, sealing; In 125-130 ℃ of baking oven, placed 3 days, take out agitated reactor, place the 40KHz ultrasound field to lower the temperature naturally agitated reactor; The question response still slowly is cooled to 70-75 ℃, opens agitated reactor, drips 70-75 ℃ of deionized water; The adularescent crystalline powder is separated out, and is cooled to room temperature and closes ultrasound wave, filters; With dichloromethane, washing with alcohol, vacuum drying 2-3h obtains the amlodipine maleate hydrate crystal.
In weight portion, preferred, said Pharmaceutical composition comprises: 2.5 parts of amlodipines, 8 parts of candesartan Cilexetils, 35 parts of amylum pregelatinisatums, 50 parts of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose 35,42 parts of crospolyvinylpyrrolidone, 1 part of magnesium stearate.
In weight portion, preferred, said Pharmaceutical composition comprises: 5 parts of amlodipines, 8 parts of candesartan Cilexetils, 35 parts of amylum pregelatinisatums, 50 parts of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose 35,42 parts of crospolyvinylpyrrolidone, 1 part of magnesium stearate.
For realizing second purpose of the present invention, the invention provides the method for preparing of the Pharmaceutical composition of a kind of amlodipine and candesartan Cilexetil, said method for preparing comprises the steps:
(1) the pharmaceutic adjuvant pulverize separately is crossed 80 mesh sieves, with the microcrystalline Cellulose and the amlodipine maleate hydrate crystal mix homogeneously of recipe quantity;
(2) add candesartan Cilexetil, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose and the crospolyvinylpyrrolidone of recipe quantity again, mix homogeneously;
(3) magnesium stearate that adds at last recipe quantity is again mixed 5min, intermediate after the assay was approved, direct compression promptly gets this Pharmaceutical composition chip;
(4) film coating.
In the above-mentioned method for preparing, film coating is specially in the step (4):
A, preparation film-coat layer are stirred well to and are even emulsus.
B, get the Pharmaceutical composition chip of preparation in the step (3), place in the coating pan, coating pan slowly rotates, and heating waits chip temperature to be increased to 45 ℃ simultaneously.
C, the coating solution of atomizing slowly evenly is sprayed at the sheet wicking surface of rolling with spray gun, along with coating pan and label continue to be heated, solvent evaporation, coating material forms the film coating layer at the sheet wicking surface, until the film-coat of formation uniform drying.
Below the present invention is made further detailed description:
Extensive clinical trial shows the depressor Combined application, and the depressor of promptly uniting two or more can strengthen antihypertensive effect, and the synergism and the complementary action of performance medicine, can reduce dosage, can offset untoward reaction again.Candesartan Cilexetil amlodipine associating angiotensin ii receptor antagonist and calcium antagonist are united different blood pressure lowering mechanism, act on different action sites simultaneously, under the prerequisite that does not improve drug dose, reach the purpose of control patient blood pressure.Simultaneously, drug combination is controlling blood pressure more effectively not only, because the dosage that uses is merely the lowest dose level of two kinds of medicines, also can more fully protect blood vessel and target organ, reduces side effect, improves the compliance of patient to treatment.Therefore, reasonably the Combined application antihypertensive drug is of crucial importance in hypertensive treatment.
With a kind of crude drug; Different crystal formations causes inner solid-state structure different; Different crystal formations causes its lattice energy different, thereby causes its physical property also different, so can have different apparent solubilities and rate of dissolution; This directly has influence on the speed and the degree of drug absorption, and then influences its drug effect and bioavailability.Certificate is in this; The inventor attempts through changing the crystal structure of amlodipine; Thereby change speed and the degree of amlodipine in the intravital absorption of people, in the hope of obtain a kind of absorb fast, onset is very fast and steadily and in 24 hours, steadily discharge drug effect, novel crystal forms that bioavailability is high.
Inventor of the present invention is raw material through repeatedly experiment with the amlodipine maleate, has prepared a kind of novel amlodipine maleate hydrate crystal; Compare with the amlodipine maleate of prior art; Increased hydrophilic group in the amlodipine maleate hydrate molecule, the dissolubility in water increases to some extent, and the change of its crystal structure has also produced influence to its physical property in addition; The amlodipine maleate hydrate of this crystal formation is easier to absorbed by human body; The blood drug level at initial stage is higher than the Amlodipine of prior art after the administration, and 4-5 reached blood medicine peak in individual hour after administration, and the drug effect onset is very fast and steady; Blood concentration fluctuation is little in 24 hours, can steadily discharge drug effect.Candesartan Cilexetil reached the blood drug level peak in 1-2 hour after administration; With amlodipine maleate hydrate crystal and candesartan Cilexetil as the Pharmaceutical composition of active component after administration; Time ratio between the blood drug level peak value of the two is more approaching; This Pharmaceutical composition onset is very fast and steady; And because the blood drug level of initial stage amlodipine maleate obviously improves after the administration, adding up between its two, work in coordination with, complementary action significantly strengthens, thereby strengthened this Pharmaceutical composition in the intravital bioavailability of people.
In order to obtain the less crystal grain of particle diameter, the present invention introduces ultrasound wave in the preparation process of amlodipine maleate hydrate crystal, and under the hyperacoustic interference of 40KHz, having formed particle diameter is the C of 75～150 μ m
24H
29ClN
2O
91.5H
2The O crystallite.The particle diameter of this crystallite is very little, and specific surface area obviously increases, and therefore crystalline dissolution rate obviously speeds, and has accelerated the intravital absorption the people, also helps improving it in the intravital bioavailability of people.Prepared microcrystalline powder can be crossed 80 purposes sieve fully; Do not need to grind; Can directly be used for preparation; In the prepared tablet, the amlodipine maleate hydrate crystal still keeps its perfect crystal structure, thereby has guaranteed that the physical property of amlodipine maleate hydrate crystal in the preparation process remains unchanged.
The present invention adopts is safe and reliable pharmaceutic adjuvant, plays extraordinary assosting effect for the Pharmaceutical composition of amlodipine maleate hydrate crystal and candesartan Cilexetil.
Direct powder compression means the powder of medicine with after suitable adjuvant mixes, the method for direct compression without making granule.If powder itself can satisfy the flowability and the requirement of compression forming property of tabletting, just can use direct powder compression.The adjuvant of direct powder compression removes and meets flowability, compression forming property, also needs bigger medicine saturation and lubricity, and this just becomes the key of pressed powder.Generation for fear of film and magnesium hydrophobic effect; In practical operation, earlier that unclassified stores is mixed, mix with essence and magnesium stearate more at last; And the control incorporation time, and lubricant can not mix with the direct compression mixture of powders in the high speed shear blender simultaneously.
Therefore the present invention adopts direct powder compression to prepare, prepared compositions in water rapidly disintegrate become uniform viscosity suspension, have taking convenience, absorb characteristics such as fast, bioavailability height.
Adopt direct powder compression, according to raw material properties, the screening of adjuvant is very important.Amylum pregelatinisatum and microcrystalline Cellulose had both increased the flowability of material in prescription; Make material that compressibility is preferably arranged simultaneously; Also help to improve the dissolution of compositions; The use of low-substituted hydroxypropyl cellulose and crospolyvinylpyrrolidone has guaranteed the disintegration and the dispersing uniformity of compositions, and magnesium stearate makes powder have lubricity preferably.
The microcrystalline Cellulose compressibility is good, has effects such as bonding, fluidizer concurrently, is applicable to direct compression process.Microcrystalline Cellulose can effectively improve the flowability of powder, has spongy porous tubular structure, very easily distortion; Compressibility is good, and generally speaking, consumption was at 5% o'clock; Can increase the hardness of tablet; If the hardness that in producing mainly is tablet has problem, its consumption can be up to 65%, and the tablet that contains microcrystalline Cellulose has the characteristic that disintegrate is fast, hardness is big and fragility is low.Low-substituted hydroxypropyl cellulose has very big surface area and porosity, so he has absorption speed and the water absorption that has very much, its expansion rate of water absorption is 500%～700%, and the granule after the disintegrate is also more tiny, so help the stripping of medicine.Crospolyvinylpyrrolidone (PVPP) has efficient capillary effect and significant hydration, and disintegrate is effective.Amylum pregelatinisatum is claimed pregelatinized Starch again, is white or off-white powder; Be slightly soluble in cold water (20 ℃), be insoluble to organic solvent, good compressibility, flowability and self-lubricity are arranged; The tablet hardness of processing, disintegrative are all better, are suitable for direct powder compression especially.
Relative with prior art, provided by the inventionly a kind ofly by amlodipine and candesartan Cilexetil as the beneficial effect of Pharmaceutical composition of active ingredient and preparation method thereof be:
(1) relative substance is few, steady quality;
(2) disintegrating property of Pharmaceutical composition and dissolution are good;
(3) favorable reproducibility;
(4) cost is low, and is profitable;
(5) onset is very fast and steadily after the Pharmaceutical composition administration, steadily discharges drug effect in 24 hours, and user's fluctuation of blood pressure is little, the working in coordination with of amlodipine maleate and candesartan Cilexetil, add up, complementary action is strong, external stripping is good, its bioavailability height.
Description of drawings
Fig. 1 is the X-ray powder diffraction spectrogram of the amlodipine maleate hydrate crystal of the embodiment of the invention 1 preparation
Fig. 2 is the thermogravimetric analysis figure of the amlodipine maleate hydrate crystal of the embodiment of the invention 1 preparation
Fig. 3 is that two kinds of amlodipines are at the intravital average blood drug level-time graph of healthy subjects
The specific embodiment
Following embodiment will do to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
Embodiment 1
In the 100ml agitated reactor, add amlodipine maleate 9g, ethanol 21ml, dimethyl sulfoxine 42ml, deionized water 7ml, regulate pH to 6, stir 30min, sealing with triethylamine or acetic acid; In 125 ℃ of baking ovens, placed 3 days, take out agitated reactor, place the 40KHz ultrasound field to lower the temperature naturally agitated reactor; The question response still slowly is cooled to 70 ℃, opens agitated reactor, drips 70 ℃ of deionized waters; The adularescent crystalline powder is separated out, and is cooled to room temperature and closes ultrasound wave, filters; With dichloromethane, washing with alcohol, vacuum drying 2h obtains the amlodipine maleate hydrate crystal.This crystalline particle size range is 75～150 μ m, mp:178～180 ℃.
Adopt the U.S. PE of Perkin-Elmer company 2400 II elemental analyser, elementary analysis (%) value of calculation is: C (52.22), H (5.84), Cl (6.42), N (5.08), O (30.44); Elementary analysis (%) measured value: C (52.25), H (5.88), Cl (6.39), N (5.06), O (30.42).
Adopt the U.S. PE Pyris Diamond TG of Perkin-Elmer company thermal analyzer; The thermogravimetric analysis experiment shows (see figure 2): the amlodipine maleate hydrate crystal of present embodiment 1 preparation is a platform at the curve of temperature between 25～59 ℃; Explanation amlodipine maleate hydrate crystal in this temperature range is very stable; Do not decompose as yet, in the time of 59～78 ℃, lose 0.5 H
2The O molecule loses 1 H in the time of 91～127 ℃
2The O molecule begins to decompose at 180 ℃.
Characteristic peak is 5.4 ° at 2 θ in the X-ray powder diffraction spectrogram (see figure 1) that use Cu-K alpha ray measures, 6.1 °, and 7.5 °, 11.6 °, 14.6 °; 15.8 °, 17.7 °, 18.9 °, 20.4 °, 21.6 °; 24.9 °, 26.1 °, 26.9 °, 29.4 °, 31.4 °; 34.1 °, 36.5 °, 42.2 °, 44.2 ° of demonstrations.
Embodiment 2
In the 100ml agitated reactor, add amlodipine maleate 9g, ethanol 21ml, dimethyl sulfoxine 42ml, deionized water 7ml, regulate pH to 6.5, stir 30min, sealing with triethylamine or acetic acid; In 130 ℃ of baking ovens, placed 3 days, take out agitated reactor, place the 40KHz ultrasound field to lower the temperature naturally agitated reactor; The question response still slowly is cooled to 75 ℃, opens agitated reactor, drips 75 ℃ of deionized waters; The adularescent crystalline powder is separated out, and is cooled to room temperature and closes ultrasound wave, filters; With dichloromethane, washing with alcohol, vacuum drying 3h obtains the amlodipine maleate hydrate crystal.This crystalline particle size range is 75～150 μ m, mp:178～180 ℃.
Adopt the U.S. PE of Perkin-Elmer company 2400 II elemental analyser, elementary analysis (%) value of calculation is: C (52.22), H (5.84), Cl (6.42), N (5.08), O (30.44); Elementary analysis (%) measured value: C (52.26), H (5.83), Cl (6.39), N (5.06), O (30.46).
Adopt the U.S. PE Pyris Diamond TG of Perkin-Elmer company thermal analyzer, the TG-time graph that obtains is consistent with embodiment's 1.
The X-ray powder diffraction figure that use Cu-K alpha ray measures is consistent with embodiment's 1.
Embodiment 3
Prepare burden by following prescription:
All process 1000
Method for preparing:
The supplementary material pulverize separately is crossed 80 mesh sieves; With microcrystalline Cellulose and amlodipine maleate hydrate crystal mixing; Again with candesartan Cilexetil, amylum pregelatinisatum and low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone mix homogeneously; Mix 5min with magnesium stearate again, the intermediate check, direct compression promptly gets the said composition chip.
The last magnesium stearate that adds recipe quantity again, mix homogeneously, intermediate after the assay was approved, direct compression promptly gets this Pharmaceutical composition chip; Film coating promptly gets.
Experimental example 1
The selection of pharmaceutic adjuvant
(1) selection of filler: select for use microcrystalline Cellulose, amylum pregelatinisatum, microcrystalline Cellulose and amylum pregelatinisatum as filler respectively, the tablet situation that different filleies extrude is seen table 1.
The tablet situation that the different filleies of table 1 extrude
| Filler | The tablet appearance shape | Hardness (power that can bear) |
| Amylum pregelatinisatum | Rough surface, lackluster | 5N |
| Microcrystalline Cellulose | Rough surface, lackluster | 15N |
| Amylum pregelatinisatum+microcrystalline Cellulose | Smooth surface, glossy | 40N |
Therefore, the filler of confirming at last is amylum pregelatinisatum+microcrystalline Cellulose.
(2) selection of disintegrating agent: experiment selected low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose+crospolyvinylpyrrolidone are as disintegrating agent, and test data is seen table 2, table 3.
The amlodipine maleate hydrate crystal tablet of the different disintegrating agents of table 2 is at the dissolution rate (%) of different time
The candesartan Cilexetil tablet of the different disintegrating agents of table 3 is at the dissolution rate (%) of different time
Learn that by table 2,3 select low-substituted hydroxypropyl cellulose+crospolyvinylpyrrolidone as disintegrating agent, the tablet stripping percentage rate of amlodipine maleate hydrate crystal and candesartan Cilexetil is high.
Experimental example 2
Measure angle of repose
Adopt fixedly conical bottom method.The chassis is the culture dish of diameter 7cm, and two glass funnels are overlapping up and down, is fixed on the iron stand, and following hopper outlet and chassis distance are 3.5～6.0cm.According to technology preparation, it is some to get powder to be measured, under certain frequency of vibration, powder is slowly added from upper funnel, through the funnel smooth outflow, till obtaining the highest cone.Measure cone inclined-plane and planar angle, triplicate is got its meansigma methods.The high H that promptly gets, every kind of sample measured three times, averages, and is calculated as follows angle of repose: θ=arctg (H/R) wherein, θ is angle of repose, R is the chassis radius.
Table 4 is measured the result angle of repose
Angle of repose is more little, explains that frictional force is more little, and flowability is good more, and good fluidity when it is generally acknowledged θ≤30 ° can satisfy demand mobile in the production process during θ≤40 °.
Test Example 3
This Test Example detects the content and the related substance of amlodipine maleate hydrate crystal and candesartan Cilexetil in the prepared Pharmaceutical composition of the embodiment of the invention 3, and its result sees table 5:
The content of table 5 amlodipine maleate hydrate crystal and candesartan Cilexetil and related substance assay
Experimental example 4
This experimental example has compared behind two kinds of candesartan Cilexetils of 30 routine men's health volunteer orals/amlodipine sheet average blood drug level in the body.
(1) instrument, medicine and reagent
Instrument: API4000 type triple quadrupole bar liquid chromatography-tandem mass spectrometry appearance, be furnished with electro-spray ionization source and Analyst 1.3 data processing softwares, U.S. Applied Biosystem Company products; 1100 HPLC infusion pump comprise automatic sampler, U.S. Agilent Company products.
Receive test preparation: adopt the amlodipine and the candesartan cilexetil of first group of preparation in the FORMULATION EXAMPLE 3 of the present invention, specification: contain amlodipine maleate hydrate crystal 5mg; Reference substance 1: candesartan Cilexetil amlodipine sheet, originate from Japanese military field drugmaker, specification: contain amlodipine 5mg (being Amlodipine Besylate Tablet 6.93mg).
Reagent: methanol, ethyl acetate and formic acid (U.S. Merck company, chromatographically pure); Sodium hydroxide (analytical pure) is available from China Medicine (Group) Shanghai Chemical Reagent Co.;
(2) amlodipine maleate is at the average blood drug level-time graph of healthy human body
The healthy volunteer is divided into two groups at random, and one group for receiving the test preparation group, and one group is 1 group of reference substance, every group 15 people.Behind healthy volunteer's overnight fasting; In morning the 7:00 single oral dose receive test preparation (containing amlodipine maleate hydrate crystal 5mg) and reference substance 1 (containing Amlodipine Besylate Tablet 6.53mg); Use the 200mL warm water delivery service, can drink water behind the 2h that takes medicine, the unified low fat diet of feed behind the 4h.Got ulnar vein blood 3mL in 0.5,1,2,3,4,5,6,7,8,10,12,18,24,36 hour before administration and after the administration; Anticoagulant heparin behind the centrifugal 10rain of 3500r/rain (centrifugal radius 7cm), is obtained blood plasma; Preserve to be measured in one 20 ℃ of refrigerators; Note lucifuge in blood sampling and the centrifugal process, measure amlodipine concentration in the blood plasma, see Fig. 3.
Can be known that by Fig. 3 the Amlodipine Besylate Tablet in the reference substance 1 reached the blood drug level peak value in 6～12 hours after administration, the drug effect onset is slow; Receive test preparation amlodipine maleate hydrate crystal after administration to reach the blood drug level peak value in 4-5 hour; The blood drug level at initial stage is higher than Amlodipine Besylate Tablet in the reference substance 1 after the administration; The drug effect onset is very fast and steadily, the blood concentration fluctuation after the administration in 36 hours is little, and drug effect is steadily lasting; Bioavailability is high, the working in coordination with of amlodipine maleate hydrate crystal and candesartan Cilexetil, add up, complementary action is strong.
In addition; The present invention has also measured the prepared amlodipine maleate of other group among the embodiment 3 and the candesartan cilexetil average blood drug level-time graph at healthy human body, and the amlodipine and the candesartan cilexetils of 3 first groups of preparations of the result of acquisition and the foregoing description are similar.
Claims (8)
1. the Pharmaceutical composition of amlodipine and candesartan Cilexetil; It is characterized in that; In weight portion, said Pharmaceutical composition comprises 2.5～5 parts of amlodipines, candesartan Cilexetil 4-16 part, 5～50 parts of amylum pregelatinisatums, 10～60 parts of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose 15～40,10～45 parts of crospolyvinylpyrrolidone, 1～3 part of magnesium stearate; Said amlodipine is the amlodipine maleate hydrate crystal.
2. Pharmaceutical composition according to claim 1 is characterized in that, the molecular formula of said amlodipine maleate hydrate crystal is C
24H
29ClN
2O
91.5H
2O.
3. Pharmaceutical composition according to claim 1 and 2 is characterized in that, in the X-ray powder diffraction pattern of said amlodipine maleate hydrate crystal at 5.4 °, 6.1 °, 7.5 °, 11.6 °; 14.6 °, 15.8 °, 17.7 °, 18.9 °, 20.4 °; 21.6 °, 24.9 °, 26.1 °, 26.9 °, 29.4 °; 31.4 °, 34.1 °, 36.5 °, 42.2 °, there is characteristic peak at 44.2 ° of angle of diffraction places.
4. Pharmaceutical composition according to claim 3 is characterized in that, the particle diameter of said amlodipine maleate hydrate crystal is 75～150 μ m.
5. Pharmaceutical composition according to claim 4 is characterized in that, the method for preparing of said amlodipine maleate hydrate crystal is: in agitated reactor, add amlodipine maleate, ethanol, dimethyl sulfoxine, deionized water; Regulate pH to 6～6.5 with triethylamine or acetic acid, stir 30min, sealing; In 125-130 ℃ of baking oven, placed 3 days, take out agitated reactor, place the 40KHz ultrasound field to lower the temperature naturally agitated reactor; The question response still slowly is cooled to 70-75 ℃, opens agitated reactor, drips 70-75 ℃ of deionized water; The adularescent crystalline powder is separated out, and is cooled to room temperature and closes ultrasound wave, filters; With dichloromethane, washing with alcohol, vacuum drying 2-3h obtains the amlodipine maleate hydrate crystal.
6. Pharmaceutical composition according to claim 1; It is characterized in that; In weight portion, said Pharmaceutical composition comprises: 2.5 parts of amlodipines, 8 parts of candesartan Cilexetils, 35 parts of amylum pregelatinisatums, 50 parts of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose 35,42 parts of crospolyvinylpyrrolidone, 1 part of magnesium stearate.
7. Pharmaceutical composition according to claim 1; It is characterized in that; In weight portion, said Pharmaceutical composition comprises: 5 parts of amlodipines, 8 parts of candesartan Cilexetils, 35 parts of amylum pregelatinisatums, 50 parts of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose 35,42 parts of crospolyvinylpyrrolidone, 1 part of magnesium stearate.
8. the method for preparing of each described Pharmaceutical composition of claim 1-7 is characterized in that, said method for preparing comprises the steps:
(1) the pharmaceutic adjuvant pulverize separately is crossed 80 mesh sieves, with the microcrystalline Cellulose and the amlodipine maleate hydrate crystal mix homogeneously of recipe quantity;
(2) add candesartan Cilexetil, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose and the crospolyvinylpyrrolidone of recipe quantity again, mix homogeneously;
(3) magnesium stearate that adds at last recipe quantity is again mixed 5min, intermediate after the assay was approved, direct compression promptly gets this Pharmaceutical composition chip;
(4) film coating.
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| WO2021088672A1 (en) | 2019-11-08 | 2021-05-14 | 施慧达药业集团(吉林)有限公司 | Composition containing legoamodipine besylate hydrate and preparation method therefor |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101371834A (en) * | 2007-08-21 | 2009-02-25 | 浙江永宁药业股份有限公司 | Medicament composition containing amlodipine besylate and candesartan cilexetil and medicine box |
| CN101564536A (en) * | 2008-04-21 | 2009-10-28 | 鲁南制药集团股份有限公司 | Sustained and controlled release preparation for pharmaceutical composition for curing hypertension |
| CN101711747A (en) * | 2008-10-08 | 2010-05-26 | 鲁南制药集团股份有限公司 | Medicine application preparation for treating hypertension |
| CN101836963A (en) * | 2009-03-16 | 2010-09-22 | 鲁南制药集团股份有限公司 | Medicinal application preparation for curing hypertension |
| CN101966181A (en) * | 2010-07-08 | 2011-02-09 | 王丽燕 | Oral solid preparation containing candesartan and amlodipine and new application thereof |
| CN102038683A (en) * | 2010-12-19 | 2011-05-04 | 王定豪 | Tablet containing amlodipine ester and candesartan ester and application thereof |
| CN102106853A (en) * | 2009-12-23 | 2011-06-29 | 赤峰维康生化制药有限公司 | Chemical medicine composition for treating hypertension |
-
2011
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101371834A (en) * | 2007-08-21 | 2009-02-25 | 浙江永宁药业股份有限公司 | Medicament composition containing amlodipine besylate and candesartan cilexetil and medicine box |
| CN101564536A (en) * | 2008-04-21 | 2009-10-28 | 鲁南制药集团股份有限公司 | Sustained and controlled release preparation for pharmaceutical composition for curing hypertension |
| CN101711747A (en) * | 2008-10-08 | 2010-05-26 | 鲁南制药集团股份有限公司 | Medicine application preparation for treating hypertension |
| CN101836963A (en) * | 2009-03-16 | 2010-09-22 | 鲁南制药集团股份有限公司 | Medicinal application preparation for curing hypertension |
| CN102106853A (en) * | 2009-12-23 | 2011-06-29 | 赤峰维康生化制药有限公司 | Chemical medicine composition for treating hypertension |
| CN101966181A (en) * | 2010-07-08 | 2011-02-09 | 王丽燕 | Oral solid preparation containing candesartan and amlodipine and new application thereof |
| CN102038683A (en) * | 2010-12-19 | 2011-05-04 | 王定豪 | Tablet containing amlodipine ester and candesartan ester and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021088672A1 (en) | 2019-11-08 | 2021-05-14 | 施慧达药业集团(吉林)有限公司 | Composition containing legoamodipine besylate hydrate and preparation method therefor |
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| CN102342937B (en) | 2013-01-09 |
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