CN102342937B - 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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- CN102342937B CN102342937B CN 201110204527 CN201110204527A CN102342937B CN 102342937 B CN102342937 B CN 102342937B CN 201110204527 CN201110204527 CN 201110204527 CN 201110204527 A CN201110204527 A CN 201110204527A CN 102342937 B CN102342937 B CN 102342937B
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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, 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 as follows:
Candesartan Cilexetil is hydrolyzed into rapidly the active metabolite Candesartan in vivo, Candesartan is selectivity angiotensin-ii receptor (AT1) antagonist, by the vasoconstrictor effects of antagonizing vessel Angiotensin Converting Enzyme II 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 by suppressing the acth secretion aldosterone.Candesartan does not suppress kininase II, does not affect the Kallidin I degraded.The experiment of carrying out the hyperpietic shows: raise but the patient repeatedly takes this product hyperamization slurry renin activity, hypertensin 1 concentration and Angiotensin II concentration; Take continuously for 1 time this product 2-8mg every day, systolic pressure, diastolic pressure are descended, left ventricular mass, peripheral vascular resistance reduce, and heart output, ejection fraction, renal vascular resistance, renal blood flow, glomerular filtration rate are had no significant effect; To the former generation hyperpietic of cerebrovascular disorders is arranged, on cerebral blood flow without impact.
Amlodipine, Chinese another name: 6-methyl-2-(2-amino ethoxy) methyl-4-(2-chlorphenyl)-Isosorbide-5-Nitrae-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 slow channel blocking agent), energy retardance cardiac muscle and the outer Ca2+ of vascular smooth muscle cell enter cell through the cell membrane calcium channel and cause cardiac muscle and vascular smooth muscle relaxation, and the Main Function position 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 Guideline, U.S.'s Hypertension Guideline 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 for the treatment of, require to reduce blood pressure greatly, and single therapy usually can not reach this purpose, and the dosage increase is prone to untoward reaction.Clinical trial shows the depressor use in conjunction, and the depressor of namely uniting two or more can strengthen antihypertensive effect, and 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 in the drug combination mode again, and think that there is clear superiority in drug combination when treatment hypertension: the different medicine hypotensive effect of (1) mechanism of action may 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 with medicine passivation counter regulation, limit mutually that another is drug-induced bad compensatory; (4) be conducive to take into account Other Risk Factors that the patient exists with and deposit disease; (5) improve patient compliance and quality of life; Find that simultaneously therapeutic alliance has good toleration, therefore, reasonably the use in conjunction antihypertensive drug is of crucial importance in hypertensive treatment.
Li Dongyan " candesartan Cilexetil and Levamlodipine share the impact on 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 having effective hypotensive effect; both all can reduce the effect of urine trace albumin; both have share better more obvious minimizing urine trace albumin; thereby better Renoprotective Effect is arranged, and it is the preferential selection of hypertension Renal Injury treatment that candesartan Cilexetil and Levamlodipine share.
The people such as Xing Xiangjun " candesartan Cilexetil associating Amlodipine Besylate Tablet is treated diabetes complicated hypertension 45 examples " (medical Leader the 1st phase of the 28th volume January in 2009), reach a conclusion: candesartan Cilexetil (ARB) is better than single drug with Amlodipine Besylate Tablet (calcium channel antagonistic) use in conjunction, can make blood pressure reach desirable control desired value, target organ damage alleviates, non-evident effect, better toleration is arranged, and clinic is promoted.
Candesartan Cilexetil amlodipine associating angiotensin ii receptor antagonist and calcium antagonist are united different Hypotensive Mechanisms, act on simultaneously different action sites, under the prerequisite that does not improve drug dose, reach the purpose of control patient blood pressure.Simultaneously, drug combination not only can more effectively be controlled blood pressure, because the dosage that uses only is the lowest dose level of two kinds of medicines, also can more fully protect blood vessel and target organ, reduces side effect, improves the patient to the compliance for the treatment of.
In the prior art, amlodipine and Amlodipine (such as amlodipine maleate, Amlodipine Besylate Tablet, Amlodipine mesylate etc.) are almost insoluble in water, in human body, absorb slow, 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, collaborative, cumulative, complementary action is very limited.A kind of Pharmaceutical composition that contains Amlodipine Besylate Tablet and candesartan Cilexetil is disclosed such as 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, although 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, itself and candesartan Cilexetil collaborative, cumulative, complementary action is very limited.Chinese patent CN102106853A discloses a kind of hypertensive Pharmaceutical composition for the treatment of, its active component is left-handed Amlodipine Besylate Tablet and candesartan Cilexetil, said composition treatment hypertension, low than the folk prescription consumption, has 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（+）-AMLODIPINE salt and the introducing of impurity have been arranged, this has greatly increased the cost of medicine.
In view of this, the special the technical program 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, this Pharmaceutical composition collaborative, cumulative, complementary action is strong, its bioavailability is high.
The second purpose of the present invention is to provide the preparation method of the Pharmaceutical composition of a kind of amlodipine and candesartan Cilexetil, a kind of amlodipine that adopts this preparation method preparation and candesartan Cilexetil Pharmaceutical composition have the purity height, safe and effective, outward appearance good, stable better advantage.
For realizing the 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, described 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; Described amlodipine is the amlodipine maleate hydrate crystal.
The molecular formula of described amlodipine maleate hydrate crystal is C
24H
29ClN
2O
91.5H
2O.
In the X-ray powder diffraction pattern of described 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 described amlodipine maleate hydrate crystal is 75～150 μ m.
The preparation method of described amlodipine maleate hydrate crystal is: add amlodipine maleate in reactor, ethanol, dimethyl sulfoxine, deionized water, with triethylamine or second acid for adjusting pH to 6～6.5, stir 30min, sealing, in 125-130 ℃ of baking oven, placed 3 days, take out reactor, place the 40KHz ultrasound field naturally to lower the temperature reactor, question response still slow cooling is to 70-75 ℃, open reactor, drip 70-75 ℃ of deionized water, the adularescent crystalline powder is separated out, and is cooled to room temperature and closes ultrasound wave, filter, use dichloromethane, washing with alcohol, vacuum drying 2-3h obtains the amlodipine maleate hydrate crystal.
In weight portion, preferred, described 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, described 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 the second purpose of the present invention, the invention provides the preparation method of the Pharmaceutical composition of a kind of amlodipine and candesartan Cilexetil, described preparation method comprises the steps:
(1) pharmaceutic adjuvant was pulverized respectively 80 mesh sieves, with microcrystalline Cellulose and the amlodipine maleate hydrate crystal mix homogeneously of recipe quantity;
(2) add again candesartan Cilexetil, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose and the crospolyvinylpyrrolidone of recipe quantity, mix homogeneously;
(3) magnesium stearate that adds again at last recipe quantity is mixed 5min, intermediate after the assay was approved, direct compression namely gets this Pharmaceutical composition chip;
(4) film coating.
In the above-mentioned preparation method, 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, with spray gun the coating solution of atomizing slowly evenly is sprayed at the sheet wicking surface of rolling, 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 form the film-coat of uniform drying.
Hereinafter, the present invention is described in further detail:
Clinical trial shows the depressor use in conjunction, and the depressor of namely uniting two or more can strengthen antihypertensive effect, and 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 Hypotensive Mechanisms, act on simultaneously different action sites, under the prerequisite that does not improve drug dose, reach the purpose of control patient blood pressure.Simultaneously, drug combination not only can more effectively be controlled blood pressure, because the dosage that uses only is the lowest dose level of two kinds of medicines, also can more fully protect blood vessel and target organ, reduces side effect, improves the patient to the compliance for the treatment of.Therefore, reasonably the use in conjunction antihypertensive drug is of crucial importance in hypertensive treatment.
The same crude drug, different crystal formations causes inner solid-state structure different, cause its lattice energy different, thereby cause its physical property also different, so different crystal formations can have different apparent solubilities and rate of dissolution, this directly has influence on speed and the degree of drug absorption, and then affects its drug effect and bioavailability.According in this, the inventor attempts by changing the crystal structure of amlodipine, thereby change speed and the degree of the absorption of amlodipine in human body, in the hope of obtain a kind of absorb fast, onset is very fast and steadily and steadily discharged drug effect, novel crystal forms that bioavailability is high in 24 hours.
The present inventor is through repeatedly experiment, take amlodipine maleate as raw material, 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, dissolubility in water increases to some extent, the change of its crystal structure has also produced impact to its physical property in addition, the amlodipine maleate hydrate of this crystal formation is easier to be 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, 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 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, cumulative, collaborative, complementary action between its two significantly strengthen, thereby have strengthened the bioavailability of this Pharmaceutical composition in human body.
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, so the dissolution rate of crystal obviously speeds, and has accelerated the absorption in human body, also is conducive to improve its bioavailability in human body.Prepared microcrystalline powder can be crossed 80 purposes sieve fully, do not need to grind, can be directly used in 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 granule processed.If powder itself can satisfy flowability and the compact property requirement of tabletting, just can use direct powder compression.The adjuvant of direct powder compression is except meeting flowability, compact property, and also needing has larger 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, first 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 be prepared, and prepared compositions can rapid disintegrate become uniform viscosity suspension in water, have taking convenience, absorb fast, bioavailability high.
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 simultaneously material that preferably compressibility is arranged, also help to improve the dissolution of compositions, the use of low-substituted hydroxypropyl cellulose and crospolyvinylpyrrolidone, guaranteed disintegration and the dispersing uniformity of compositions, magnesium stearate makes powder have preferably lubricity.
The microcrystalline Cellulose compressibility is good, has the effects such as bonding, fluidizer concurrently, is applicable to direct compression process.Microcrystalline Cellulose can effectively improve the flowability of powder, tubular structure with spongy porous, very easily distortion, compressibility is good, and generally speaking, consumption is 5% the time, 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 large and fragility is low.Low-substituted hydroxypropyl cellulose has very large 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 be conducive to the stripping of medicine.Crospolyvinylpyrrolidone (PVPP) has efficient capillary effect and significant hydration, and disintegrate is effective.Amylum pregelatinisatum claims again pregelatinized Starch, 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 making, disintegrative are all better, especially are suitable for direct powder compression.
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, amlodipine maleate and candesartan Cilexetil collaborative, cumulative, complementary action is strong, In Vitro Dissolution is good, its bioavailability is high.
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 the average blood drug level-time graphs of two kinds of amlodipines in healthy human body
The specific embodiment
The following examples will be done 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 reactor, add amlodipine maleate 9g, ethanol 21ml, dimethyl sulfoxine 42ml, deionized water 7ml, with triethylamine or second acid for adjusting pH to 6, stir 30min, sealing, in 125 ℃ of baking ovens, placed 3 days, take out reactor, place the 40KHz ultrasound field naturally to lower the temperature reactor, question response still slow cooling to 70 ℃, open reactor, drip 70 ℃ of deionized waters, the adularescent crystalline powder is separated out, and is cooled to room temperature and closes ultrasound wave, filter, use dichloromethane, washing with alcohol, vacuum drying 2h obtains the amlodipine maleate hydrate crystal.The particle size range of this crystal 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 (seeing Fig. 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, not yet decompose, 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 ℃.
The middle characteristic peak of the X-ray powder diffraction spectrogram (seeing Fig. 1) that uses the Cu-K alpha ray to measure is 5.4 ° at 2 θ, 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 reactor, add amlodipine maleate 9g, ethanol 21ml, dimethyl sulfoxine 42ml, deionized water 7ml, with triethylamine or second acid for adjusting pH to 6.5, stir 30min, sealing, in 130 ℃ of baking ovens, placed 3 days, take out reactor, place the 40KHz ultrasound field naturally to lower the temperature reactor, question response still slow cooling to 75 ℃, open reactor, drip 75 ℃ of deionized waters, the adularescent crystalline powder is separated out, and is cooled to room temperature and closes ultrasound wave, filter, use dichloromethane, washing with alcohol, vacuum drying 3h obtains the amlodipine maleate hydrate crystal.The particle size range of this crystal 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 make 1000
Preparation method:
Supplementary material was pulverized respectively 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 namely gets the said composition chip.
The last magnesium stearate that adds again recipe quantity, mix homogeneously, intermediate after the assay was approved, direct compression namely gets this Pharmaceutical composition chip; Film coating and get final product.
Experimental example 1
The selection of pharmaceutic adjuvant
(1) selection of filler: select respectively microcrystalline Cellulose, amylum pregelatinisatum, microcrystalline Cellulose and amylum pregelatinisatum as filler, the tablet situation that different filleies extrude sees 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 determining at last is amylum pregelatinisatum+microcrystalline Cellulose.
(2) selection of disintegrating agent: test selects low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose+crospolyvinylpyrrolidone as disintegrating agent, and test data sees 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
Learnt 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 lower 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, evenly flows out by funnel, until obtain till the highest cone.Measure the angle on cone inclined-plane and plane, triplicate is got its meansigma methods.The high H that namely 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 measurement result angle of repose
Angle of repose is less, illustrates that frictional force is less, and flowability is better, 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 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 it the results are shown in 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 Cilexetil/amlodipines of 30 routine men's health volunteer orals average blood drug level in the body.
(1) instrument, medicine and reagent
Instrument: API4000 type triple quadrupole bar liquid chromatography-tandem mass spectrometry instrument, be furnished with electro-spray ionization source and Analyst 1.3 data processing softwares, U.S. Applied Biosystem company product; 1100 high performance liquid chromatography infusion pump comprise automatic sampler, U.S. Agilent company product.
Be subjected to test preparation: adopt amlodipine and the candesartan cilexetil of first group of preparation in the example of formulations 3 of the present invention, specification: contain amlodipine maleate hydrate crystal 5mg; Reference substance 1: the candesartan Cilexetil amlodipine, 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 being subjected to the test preparation group, and one group is 1 group of reference substance, every group of 15 people.Behind healthy volunteer's overnight fasting, in morning the 7:00 single oral dose be subjected to 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), divide and get blood plasma, to be measured in one 20 ℃ of Refrigerator stores, note lucifuge in blood sampling and the centrifugal process, measure Determination of The Amlodipine in Plasma, see Fig. 3.
As shown in Figure 3, the Amlodipine Besylate Tablet in the reference substance 1 reached the blood drug level peak value in 6～12 hours after administration, and the drug effect onset is slow; Be subjected to 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 steady, blood concentration fluctuation after the administration in 36 hours is little, drug effect is steadily lasting, bioavailability is high, amlodipine maleate hydrate crystal and candesartan Cilexetil collaborative, 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 candesartan cilexetil at the average blood drug level-time graph of healthy human body, and amlodipine and the candesartan cilexetils of 3 first groups of preparations of the result of acquisition and above-described embodiment are similar.
Claims (5)
1. the Pharmaceutical composition of an amlodipine and candesartan Cilexetil, it is characterized in that, in weight portion, described 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; Described amlodipine is the amlodipine maleate hydrate crystal; The molecular formula of described amlodipine maleate hydrate crystal is C
24H
29ClN
2O
91.5H
2O; Described amlodipine maleate hydrate crystal has X-ray powder diffraction characteristic peak as shown in Figure 1; The particle diameter of described amlodipine maleate hydrate crystal is 75 ~ 150 μ m.
2. Pharmaceutical composition according to claim 1, it is characterized in that, in weight portion, described 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.
3. Pharmaceutical composition according to claim 1, it is characterized in that, in weight portion, described 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.
4. Pharmaceutical composition according to claim 1, it is characterized in that, the preparation method of described amlodipine maleate hydrate crystal is: add amlodipine maleate in reactor, ethanol, dimethyl sulfoxine, deionized water, with triethylamine or second acid for adjusting pH to 6 ~ 6.5, stir 30min, sealing, in 125-130 ℃ of baking oven, placed 3 days, take out reactor, place the 40KHz ultrasound field naturally to lower the temperature reactor, question response still slow cooling is to 70-75 ℃, open reactor, drip 70-75 ℃ of deionized water, the adularescent crystalline powder is separated out, and is cooled to room temperature and closes ultrasound wave, filter, use dichloromethane, washing with alcohol, vacuum drying 2-3h obtains the amlodipine maleate hydrate crystal.
5. the preparation method of each described Pharmaceutical composition of claim 1-4 is characterized in that, described preparation method comprises the steps:
(1) pharmaceutic adjuvant was pulverized respectively 80 mesh sieves, with microcrystalline Cellulose and the amlodipine maleate hydrate crystal mix homogeneously of recipe quantity;
(2) add again candesartan Cilexetil, amylum pregelatinisatum, low-substituted hydroxypropyl cellulose and the crospolyvinylpyrrolidone of recipe quantity, mix homogeneously;
(3) magnesium stearate that adds again at last recipe quantity is mixed 5min, intermediate after the assay was approved, direct compression namely gets this Pharmaceutical composition chip;
(4) film coating.
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| 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 |
| CN101836963B (en) * | 2009-03-16 | 2012-03-07 | 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 |
-
2011
- 2011-07-20 CN CN 201110204527 patent/CN102342937B/en not_active Expired - Fee Related
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| CN102342937A (en) | 2012-02-08 |
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