CN102335172B - Amlodipine and losartan potassium medicinal composition and preparation method thereof - Google Patents
Amlodipine and losartan potassium medicinal composition and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an amlodipine and losartan potassium medicinal composition, which comprises the following components calculated according to weight part: 2.5-10 parts of amlodipine, 20-100 parts of losartan potassium, 5-20 parts of pregelatinized starch, 20-60 parts of microcrystalline cellulose, 15-40 parts of low substitution hydroxypropyl cellulose, 1-8 parts of carboxymethyl starch sodium and 1-3 parts of magnesium stearate. The amlodipine is an amlodipine maleate hydrate crystal with a molecular formula of C24H29ClN2O9.1.5H2O. The amlodipine maleate in the medicinal composition can be used for stably releasing the medicinal effect within 24 hours and stably and quickly taking effect. The medicinal composition has strong synergism, accumulation and complementary action and high bioavailability.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of amlodipine and with Losartan Potassium Pharmaceutical composition and preparation method thereof.
Background technology
Losartan Potassium; The Chinese another name: 2-butyl-4-chloro-5-(methylol)-[[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] imidazoles potassium, English name: Losartan potassium, molecular formula: C22H22CIKN6OK; Molecular weight: 461.01, structural formula is following:
Losartan Potassium is a kind of novel non-peptide class angiotensin-ii receptor (AT1) antagonist, can bring high blood pressure down, and can improve heart failure, prevents and treats concurrent vessel wall thickening of hypertension and myocardial hypertrophy.Have kidney maintenance effect, renal blood flow increasing, glomerular filtration rate increase the discharge of urine and urine sodium, uric acid, can reduce adrenal gland's aldosterone and adrenergic secretion.
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, structural formula is following:
Amlodipine is dihydropyridine type calcium antagonists (calcium ion antagonist or a slow channel blocking agent), can block the outer Ca of cardiac muscle and VSMC
2+Get into cell through the cell membrane calcium channel and cause cardiac muscle and vascular smooth muscle relaxation, 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.
People such as Chen Xin " Losartan Potassium and the hypertensive clinical observation of amlodipine therapeutic alliance companion's hyperuricemia " (University Of Nanhua's journal medicine the 35th the 6th phase of volume of November in 2007); Reach a conclusion: the author thinks; Hyperuricemia complicated hypertension patient; Select antihypertensive effectively to bring high blood pressure down, again can releasing uric acid, and can dwindle pulse pressure difference.Through this laboratory observation, Losartan Potassium and amlodipine use and can not only effectively bring high blood pressure down, and can reduce serum uric acid level, improve renal function, and dwindle pressure reduction.
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 the blood drug level of losartan and active metabolite thereof reached the blood concentration peak concentration respectively at 1 hour and 3-4 hour; Drug effect is rapid-action; 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, accumulation, complementary action are very limited.A kind of compositions that is used to prevent or treat cardiovascular disorder is disclosed like Chinese patent CN101472587A; Said composition comprises amlodipine or its pharmaceutically acceptable salt and losartan or its pharmaceutically acceptable salt; This invention has improved the dissolution rate and the stability of amlodipine and Losartan Potassium; Onset is slow but amlodipine remains unchanged, and the synergism of the two is very 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 Losartan Potassium, add up, complementary action is very limited.A kind of Pharmaceutical composition of treating hypertension and cardiovascular disease is disclosed like Chinese patent CN1883478; Comprise Levamlodipine and losartan; And disclose this Pharmaceutical composition and can be made into tablet, granule, capsule, injection, slow releasing agent, this invention has improved the chemical stability and the dissolubility of medicine, but initial stage blood drug level is low after the Amlodipine administration; Onset is slow, and it is very limited with the synergism of losartan.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 a kind of amlodipine and Losartan Potassium Pharmaceutical composition; 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 a kind of amlodipine and Losartan Potassium Pharmaceutical composition, the amlodipine that adopts the preparation of this method for preparing and Losartan Potassium 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 Losartan Potassium; In weight portion, said Pharmaceutical composition comprises 2.5～10 parts of amlodipines, 20～100 parts of Losartan Potassiums, 5～20 parts of pregelatinized Starch, 20～60 parts of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose 15～40,1～8 part of carboxymethyl starch sodium, 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.
Preferably, in weight portion, the consumption of amlodipine and Losartan Potassium is in the said Pharmaceutical composition:
25 parts of 2.5 parts/Losartan Potassiums of amlodipine,
50 parts of 5 parts/Losartan Potassiums of amlodipine,
Or 100 parts of 10 parts/Losartan Potassiums of amlodipine.
For realizing second purpose of the present invention, the method for preparing of a kind of amlodipine and Losartan Potassium Pharmaceutical composition is provided, said method for preparing may further comprise 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 Losartan Potassium, pregelatinized Starch, low-substituted hydroxypropyl cellulose and the carboxymethyl starch sodium 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.
Described film coating is:
A, preparation film-coat layer are stirred well to and are even emulsus.
B, get the Pharmaceutical composition chip of preparation in the above-mentioned steps (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 done further detailed description:
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 maleate; Thereby change speed and the degree of amlodipine maleate 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 the novel crystal forms of drug effect.
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.Losartan Potassium reached the blood drug level peak in 1-2 hour after administration; With amlodipine maleate hydrate crystal and Losartan Potassium is that the Pharmaceutical composition of active component is 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 Losartan Potassium.
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 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.Pregelatinized Starch and microcrystalline Cellulose had both increased the flowability of material in prescription, make material that compressibility is preferably arranged simultaneously, increased the hardness of tablet and did not influence its disintegrate, also helped to improve the dissolution of compositions; Carboxymethyl starch sodium has lubrication, can reduce the strength that tablet ejects from nib; Good disintegration and dry adhesion are arranged, can increase the hardness of tablet, reduce friability.The use of low-substituted hydroxypropyl cellulose 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, and compressibility is good, and generally speaking, consumption can increase the hardness of tablet at 5% o'clock.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.Pregelatinized Starch is good fluidity, and compressibility is good; Lubrication is arranged, can reduce the strength that tablet ejects from nib; Good disintegration and dry adhesion are arranged, can increase the hardness of tablet, reduce friability.These article are the ideal multi-functional auxiliary materials of direct powder compression; The carboxymethyl starch sodium good fluidity, compressibility is good; Lubrication is arranged, can reduce the strength that tablet ejects from nib; Good disintegration and dry adhesion are arranged, can increase the hardness of tablet, reduce friability.These article are the ideal multi-functional auxiliary materials of direct powder compression.
Relative with prior art, the beneficial effect of amlodipine maleate provided by the invention and Losartan Potassium Pharmaceutical composition and preparation method thereof is:
(1) prescription is reasonable, and used adjuvant is safe and reliable, has improved patient's drug safety greatly;
(2) obtained label outward appearance is good, has better dissolving out capability simultaneously;
(3) steady quality is difficult for decomposing and goes bad, and also can not jolt because of transportation produces destruction to tablet;
(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 and Losartan Potassium, 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 the average blood drug level-time graphs of two kinds of amlodipines at healthy human body
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 2400II of Perkin-Elmer company 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, does not decompose as yet, in the time of 59～78 ℃, loses 0.5 H2O molecule; In the time of 91～127 ℃, lose 1 H2O molecule, begin 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 2400II of Perkin-Elmer company 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, TG-time graph that obtains and embodiment's 1 is consistent.
The X-ray powder diffraction figure that use Cu-K alpha ray measures is consistent with embodiment's 1.
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 Losartan Potassium, pregelatinized Starch and low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium mix homogeneously; Mix 5min with magnesium stearate again, the intermediate check, direct compression promptly gets the said composition chip; Film coating promptly gets.
Experimental example 1
The selection of pharmaceutic adjuvant
(1) selection of filler: select for use microcrystalline Cellulose, pregelatinized Starch, microcrystalline Cellulose and pregelatinized Starch 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) |
| Pregelatinized Starch | Rough surface, lackluster | 5N |
| Microcrystalline Cellulose | Rough surface, lackluster | 15N |
| Pregelatinized Starch+microcrystalline Cellulose | Smooth surface, glossy | 40N |
Therefore, the filler of confirming at last is pregelatinized Starch+microcrystalline Cellulose.
(2) selection of disintegrating agent: experiment selected low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose+carboxymethyl starch sodium 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 Losartan Potassium 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+carboxymethyl starch sodium as disintegrating agent, the tablet stripping percentage rate of amlodipine maleate hydrate crystal and Losartan Potassium 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 active component in the prepared Pharmaceutical composition of the embodiment of the invention 3, and its result sees table 5:
The content of table 5 active component and the assay of related substance
Experimental example 4
This experimental example has compared behind two kinds of amlodipines of 30 routine men's health volunteer orals/Losartan Potassium tablet 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 B iosystem Company products; 1100 HPLC infusion pump comprise automatic sampler, U.S. Agilent Company products.
Receive test preparation: adopt the amlodipine maleate hydrate crystal/Losartan Potassium sheet of the 7th group of preparation in the FORMULATION EXAMPLE 3 of the present invention, specification: contain amlodipine maleate hydrate crystal 5mg; Reference substance 1: amlodipine d-camphorsulfonic acid salt/Losartan Potassium sheet, adopt the method preparation of patent CN200780022975.2 embodiment 1, specification: contain amlodipine d-camphorsulfonic acid salt 7.84mg (promptly containing amlodipine 5mg).
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 5mg); 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 amlodipine d-camphorsulfonic acid salt reached the blood drug level peak value in 6～12 hours in the reference substance 1 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 d-camphorsulfonic acid salt in the reference substance 1 after the administration; The drug effect onset is very fast and steadily, after the administration in 36 hours the blood concentration fluctuation of amlodipine maleate hydrate crystal little, drug effect is steadily lasting; Bioavailability is high, the working in coordination with of amlodipine maleate hydrate crystal and Losartan Potassium, 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 Losartan Potassium sheet average blood drug level-time graph at healthy human body, and the amlodipine and the Losartan Potassium sheet of the 7th group of preparation of the result of acquisition and the foregoing description 3 are similar.
Claims (5)
1. the Pharmaceutical composition of amlodipine and Losartan Potassium; It is characterized in that; In weight portion, said Pharmaceutical composition comprises 2.5～10 parts of amlodipines, 20～100 parts of Losartan Potassiums, 5～20 parts of pregelatinized Starch, 20～60 parts of microcrystalline Cellulose, low-substituted hydroxypropyl cellulose 15～40,1～8 part of carboxymethyl starch sodium, 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; Said amlodipine maleate hydrate crystal has X-ray powder diffraction characteristic peak as shown in Figure 1.
2. Pharmaceutical composition according to claim 1 is characterized in that, the particle diameter of said amlodipine maleate hydrate crystal is 75 ~ 150 μ m.
3. Pharmaceutical composition according to claim 1 is characterized in that, in weight portion, the consumption of amlodipine and Losartan Potassium is in the said Pharmaceutical composition:
25 parts of 2.5 parts/Losartan Potassiums of amlodipine,
50 parts of 5 parts/Losartan Potassiums of amlodipine,
Or 100 parts of 10 parts/Losartan Potassiums of amlodipine.
4. Pharmaceutical composition according to claim 1 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.
5. the method for preparing of the described Pharmaceutical composition of claim 1 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 Losartan Potassium, pregelatinized Starch, low-substituted hydroxypropyl cellulose and the carboxymethyl starch sodium 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110204755 CN102335172B (en) | 2011-07-20 | 2011-07-20 | Amlodipine and losartan potassium medicinal composition and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110204755 CN102335172B (en) | 2011-07-20 | 2011-07-20 | Amlodipine and losartan potassium medicinal composition and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN102335172A CN102335172A (en) | 2012-02-01 |
| CN102335172B true CN102335172B (en) | 2012-12-12 |
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| KR101506148B1 (en) * | 2013-09-24 | 2015-03-26 | 대봉엘에스 주식회사 | Direct-compressible pharmaceutical composition comprising amlodipine and losartan, and tablet using the same |
| CN110215455A (en) * | 2019-03-26 | 2019-09-10 | 山东省药学科学院 | A kind of pharmaceutical formulation for blood pressure lowering |
| CN112274490B (en) * | 2020-11-19 | 2022-11-22 | 四川尚锐生物医药有限公司 | Preparation method of amlodipine and losartan potassium compound composition |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472587A (en) * | 2006-12-08 | 2009-07-01 | 韩美药品株式会社 | Pharmaceutical composition comprising amlodipine and losartan |
| CN101468002A (en) * | 2007-12-29 | 2009-07-01 | 北京瑞康医药技术有限公司 | Therapeutic composition containing amlodipine salt and losartan medicine |
| CN101849942A (en) * | 2009-04-02 | 2010-10-06 | 鲁南制药集团股份有限公司 | Medicinal composition for treating hypertension |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472587A (en) * | 2006-12-08 | 2009-07-01 | 韩美药品株式会社 | Pharmaceutical composition comprising amlodipine and losartan |
| CN101468002A (en) * | 2007-12-29 | 2009-07-01 | 北京瑞康医药技术有限公司 | Therapeutic composition containing amlodipine salt and losartan medicine |
| CN101849942A (en) * | 2009-04-02 | 2010-10-06 | 鲁南制药集团股份有限公司 | Medicinal composition for treating hypertension |
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Address after: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee after: Hainan Jinrui Pharmaceutical Co., Ltd. Address before: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee before: Hainan Jinrui Pharmaceutical Co., Ltd. |