CN103169702A - Compound antihypertensive drug composition - Google Patents
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- CN103169702A CN103169702A CN2013101244583A CN201310124458A CN103169702A CN 103169702 A CN103169702 A CN 103169702A CN 2013101244583 A CN2013101244583 A CN 2013101244583A CN 201310124458 A CN201310124458 A CN 201310124458A CN 103169702 A CN103169702 A CN 103169702A
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Abstract
The invention belongs to the technical field of medicines, and relates to a compound antihypertensive drug composition. The composition is a compound bilayer tablet containing atenolol and amlodipine, wherein the first layer of tablet contains effective dosage (12.5mg) of atenolol; and the second layer of tablet contains effective dosage (2.5mg) of amlodipine. The preparation can be evenly and effectively dissolved, is good in stability, and has good clinical effect and low adverse effect rate.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of compound hypertension medicine compositions, said composition is the compound double-layer tablet that contains atenolol and amlodipine, and said preparation has good clinical effectiveness and lower adverse reaction rate.
Background technology
Hypertension is a kind of common clinical, and frequently-occurring disease is the important risk factor of multiple cardiovascular disease, and affects the internal organs physiological functions such as the heart, kidney, finally causes its nonfunction.For the not agnate and hypertension colony age, the reduction of its blood pressure all can effectively reduce the generation of cardiovascular disease.According to statistics, China hypertensive patient has 1.6 hundred million, the hypertensive awareness of population of China was 30.2% in 2002, treatment rate is 24.7%, and control rate is 6.1%, and the U.S.'s hypertensive awareness of crowd in 2000 is 70%, the rate of taking medicine is 59%, control rate is 34%, compares with the U.S. also that there is a big difference, and the task of preventing and treating of China's hypertension is still one of significant problem that medical worker faces in present stage.
Pathogenesis and the pathological change in the course of disease thereof of hypertension are very complicated.Clinically, reducing blood pressure and prevent the generation of its complication, is the final goal of Hypertension.For a long time, people are exploring the antihypertensive drug that dosage is little and toxic and side effects is low always.Though the folk prescription antihypertensive drug can effectively reduce blood pressure, often because Hypotensive Mechanism is single, can not well take into account the disease that other pathogenesis for the treatment of is brought out, there is certain drawback.From world wide, the Novel blood pressure-reducing medicine does not also have infusive noval chemical compound to occur, and from the angle of medicine innovation, new compound medicine innovation has equal importance with the novel compound innovation.From the pathomechanism of hypertension, that hypertension has is multifactor, the pathogenic characteristic of many target spots, even single drug generally only can be controlled 40%～60% patient's blood pressure still less.U.S.'s Treatment Guidelines for Hypertension the 7th edition and " European Treatment Guidelines for Hypertension " 2007 editions all explicitly point out in order to reach the target blood pressure, and most of needs of patients uses more than one treated with combined medication.Drug combination acts on a plurality of target spots and produces Synergistic Hypotensive Effects by using the different antihypertensive drugs of two or more mechanism of action, and the performance organ protection, reduce the appearance of cardiovascular complication when more effectively controlling blood pressure.Compound antihypertensive drug adopts different Hypotensive Mechanisms, passes through each component rational proportion, can effectively reduce blood pressure and reduce the damage of Functional tissue when reducing dosage.The low dose of compound hypertension medicine of fixed mixing ratio is one of important channel of hypertension therapeutic, can improve China's hypertension treatment rate, situation that control rate is lower, and adverse reaction rate is descended, and clinical practice is efficient, compliance good, and cost performance is good.
The compound amlodipine sheet is the compound hypertension medicine that dihydropyridine calcium ion antagonist amlodipine and beta-blocker atenolol form.Atenolol is long-acting, selectivity β
1Adrenoreceptor blocker is to the β of blood vessel and bronchial smooth muscle
2A little less than receptor suppresses.Active without the endogenous sympathomimetic, without membrane stability, the also effect of unrestraint myocardial contraction.Amlodipine enters cell by retardance cardiac muscle and the outer calcium ion of vascular smooth muscle cell through the calcium channel (slow channel) of cell membrane, direct vasodilator smooth muscle, expansion periphery small artery, Peripheral resistance (afterload) is reduced, coronary artery dilator is particularly evident, has resisting hypertension and alleviates anginal effect.
The present invention has carried out complete pharmacy, clinical further investigation to specification and the prescription of amlodipine and atenolol double-layer tablet.a clinical multicenter that is carrying out, at random, double blinding, placebo, parallel group, in 4 * 3 Factorial Design clinical trials, amlodipine and the clinical using dosage of atenolol have been carried out further screening, find atenolol and amlodipine content than having good clinical therapeutic efficacy and low adverse reaction rate for the compound tablet of 12.5mg:2.5mg, simultaneously, the inventor is optimized processing to atenolol and amlodipine double-layer tablet preparation prescription, effectively guaranteed the even of atenolol and 2 kinds of compositions of amlodipine, effective stripping and preparation stability.
Summary of the invention
A first aspect of the present invention provides a kind of compound double-layer tablet, and it comprises:
The first lamella wherein contains atenolol 12.5mg, and pharmaceutically acceptable excipient or adjuvant, and
The second lamella wherein contains amlodipine or its pharmaceutical salts 2.5mg(in the base amlodipine), and pharmaceutically acceptable excipient or adjuvant.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, wherein, described amlodipine pharmaceutical salts is Amlodipine Besylate Tablet, amlodipine maleate or other pharmaceutically useful Amlodipines, is preferably Amlodipine Besylate Tablet.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, wherein, in the first lamella, described pharmaceutically acceptable excipient or adjuvant are to be selected from one or more in calcium hydrogen phosphate, microcrystalline Cellulose, PVP K-30, carboxymethyl starch sodium, magnesium stearate; Wherein, described calcium hydrogen phosphate can be calcium phosphate dibasic anhydrous or dicalcium phosphate dehydrate.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, wherein, in the first lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0～165mg, microcrystalline Cellulose 20～165mg, PVP K-30 0～3mg, carboxymethyl starch sodium 4～12mg, magnesium stearate 0.5～1.5mg.
Preferably, in the first lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0～120mg, microcrystalline Cellulose 30～120mg, PVP K-30 0.5～3mg, carboxymethyl starch sodium 5～10mg, magnesium stearate 0.5～1.5mg.
More preferably, in the first lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 60mg, 0mg, 120mg or 50mg, microcrystalline Cellulose 116.7mg, 102mg, 60mg, 30mg, 50mg, 120mg, PVP K-30 1mg, carboxymethyl starch sodium 10mg, 5mg, 8.3mg, magnesium stearate 1mg.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, wherein, in the second lamella, described pharmaceutically acceptable excipient or adjuvant are to be selected from one or more in calcium hydrogen phosphate, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate.Preferably, described calcium hydrogen phosphate is calcium phosphate dibasic anhydrous or dicalcium phosphate dehydrate.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, wherein, in the second lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0～50mg, microcrystalline Cellulose 30～90mg, carboxymethyl starch sodium 1～3mg, magnesium stearate 0.5～1.5mg.
Preferably, in the second lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0～30mg, microcrystalline Cellulose 50～90mg, carboxymethyl starch sodium 1～3mg, magnesium stearate 0.5～1.5mg.
More preferably, in the second lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0mg or 30mg, microcrystalline Cellulose 50mg, 60 or 90mg, carboxymethyl starch sodium 2mg, magnesium stearate 1mg.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, described the first lamella and/or the second lamella are fast-release tablet or slow-release tablet.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, wherein said tablet is plain sheet or thin membrane coated tablet;
Preferably, described tablet is the film coated tablet;
More preferably, described coating material is selected from one or more in hydroxypropyl emthylcellulose, tween 80, Pulvis Talci, titanium dioxide.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, wherein atenolol and/or amlodipine are in the dissolution medium of 0.01mol/L hydrochloric acid, adopt the second method (slurry method) mensuration in Chinese Pharmacopoeia (version in 2010) appendix, dissolution (30min)〉60, dissolution (45min)〉75.
In a specific embodiment of the present invention, the described compound double-layer tablet of first aspect present invention, also contain the other types antihypertensive drug in described the first lamella and/or the second lamella, other types antihypertensive drug such as telmisartan, hydrochlorothiazide, enalapril, benazepril.
A second aspect of the present invention provides the preparation method of the described compound double-layer tablet of first aspect present invention any one, wherein, the preparation method of the first lamella was for to pulverize 60 orders or 80 mesh sieves with atenolol, preferred 80 mesh sieves of crossing, after adjuvant mixes, granulate with wet granulation technology, the preparation method of the second lamella is direct powder compression.
In a specific embodiment of the present invention, the described preparation method of second aspect present invention comprises the steps:
1, the first lamella (atenolol layer) is granulated, and adopts wet granulation technology:
Make solvent with 50% ethanol, PVP K-30 is made into the PVP K-30 solution of 1.4-1.6% concentration, as binding agent, stand-by;
The atenolol of recipe quantity shattered 80 mesh sieves, then mixed in wet granulator with adjuvant (such as microcrystalline Cellulose, calcium hydrogen phosphate, carboxymethyl starch sodium etc.), and added binding agent and granulate.With the granule that makes after 50 ℃ of aeration-drying, add partly measure carboxymethyl starch sodium in addition, magnesium stearate is evenly mixed, obtains the first lamella granule;
2, the second lamella (Amlodipine Besylate Tablet layer) adopts direct compression technique:
Except magnesium stearate, amlodipine or its pharmaceutical salts are mixed with blender with other adjuvants (for example: calcium hydrogen phosphate, microcrystalline Cellulose, carboxymethyl starch sodium etc.).Add magnesium stearate before tabletting and mix, obtain the second lamella raw material, stand-by;
3, tabletting: the first lamella granule of above-mentioned preparation is placed in the ground floor loading hopper of bi-layer tablet press, in the second layer loading hopper of the second lamella raw material as for bi-layer tablet press, the compacting double-layer tablet obtains the double-layer tablet label;
4, coating selectively: with coating solution use the high-efficiency coating pot by spray gun spraying being on the above-mentioned double-layer tablet label for preparing of fluidized state, form outer tunicle, with insulation blocking.
A third aspect of the present invention provides the purposes of the described compound double-layer tablet of first aspect present invention any one in the medicine of the target organ relevant disease that causes for the preparation for the treatment of hypertension or hypertension; Preferably, described hypertension is 1 grade of hypertension or 2 grades of hypertension.
A fourth aspect of the present invention provides the compound double-layer tablet that is prepared by the described preparation method of second aspect present invention.
Detailed Description Of The Invention
Compound double-layer tablet provided by the invention, described the first lamella pastille atenolol 12.5mg of effective dose, particularly, contain atenolol 12.5mg, calcium hydrogen phosphate 0～165mg, microcrystalline Cellulose 20～165mg, PVP K-30 0～3mg, carboxymethyl starch sodium 2～12mg, magnesium stearate 0.5～1.5mg; Preferably phosphoric acid hydrogen calcium 0～120mg, 30～140mg, 40～130mg or 50～120mg, microcrystalline Cellulose 30～120mg, 30～110mg, 40～150mg, 50～130mg or 40～120mg, PVP K-30 0.5～3mg, 0.8～2.5mg, 0.8～2mg or 0.8～1.5mg, carboxymethyl starch sodium 2～10mg, 3～8mg, 4～9mg or 5～10mg, magnesium stearate 0.5～1.5mg, 0.6～1.4mg, 0.8～1.3mg or 0.9～1.2mg; More preferably calcium hydrogen phosphate 60mg, 0mg, 120mg or 50mg, microcrystalline Cellulose 116.7mg, 102mg, 60mg, 30mg, 50mg, 120mg, PVP K-30 1mg, carboxymethyl starch sodium 10mg, 5mg, 8.3mg, magnesium stearate 1mg
Described the second synusia pastille particularly, contains amlodipine 5mg, calcium hydrogen phosphate 0～50mg, microcrystalline Cellulose 30～90mg, carboxymethyl starch sodium 1～3mg, magnesium stearate 0.5～1.5mg with the amlodipine 5mg of effective dose; Preferably phosphoric acid hydrogen calcium 0～30mg, microcrystalline Cellulose 50～90mg, carboxymethyl starch sodium 1.5～2.5mg, magnesium stearate 0.8～1.2mg; More preferably calcium hydrogen phosphate 0mg, 30mg, microcrystalline Cellulose 50mg, 60mg or 90mg, carboxymethyl starch sodium 2mg, magnesium stearate 1mg.
Compound double-layer tablet provided by the invention, the first synusia atenolol preparation method is wet granulation technology, particularly, makes solvent with 50% ethanol, is made into the PVP K-30 solution of 1.4-1.6% concentration; Atenolol with microcrystalline Cellulose, calcium hydrogen phosphate, partly measure carboxymethyl starch sodium and mix in wet granulator, add binding agent and granulate.50 ℃ of aeration-dryings.The second synusia amlodipine preparation method is direct powder compression, all supplementary materials except magnesium stearate, Amlodipine Besylate Tablet and adjuvant, blender mixes.Adding magnesium stearate before tabletting mixes.
The compound double-layer tablet that the present invention relates to, wherein said calcium hydrogen phosphate can be calcium phosphate dibasic anhydrous, dicalcium phosphate dehydrate, preferred calcium phosphate dibasic anhydrous.
The compound double-layer tablet that the present invention relates to, the second synusia amlodipine is amlodipine or its addition salts of medicinal effective dose, particularly the amlodipine addition salts is Amlodipine Besylate Tablet, amlodipine maleate and other pharmaceutically acceptable Amlodipines, preferred Amlodipine Besylate Tablet.
Compound double-layer tablet provided by the invention, the first synusia atenolol can be atenolol single preparations of ephedrine, compound preparation, particularly, single preparations of ephedrine is that atenolol is as unique active ingredient, compound preparation is that active ingredient contains atenolol and other active ingredient drug combinations, other compositions can be the antihypertensive drug of other types, include but not limited to diuretic, renin-angiotensin system depressant, calcium channel blocade.More specifically, include but not limited to telmisartan, hydrochlorothiazide, enalapril, benazepril.
Compound double-layer tablet provided by the invention, the second synusia amlodipine can be single preparations of ephedrine, compound preparation.Single preparations of ephedrine is that amlodipine is as unique active ingredient, compound preparation is that active ingredient contains amlodipine and other active ingredient drug combinations, other compositions can be the antihypertensive drug of other types, include but not limited to diuretic, renin-angiotensin system depressant, calcium channel blocade.More specifically, include but not limited to telmisartan, hydrochlorothiazide, enalapril, benazepril.
The compound double-layer tablet that the present invention relates to, the first synusia atenolol and/or the second synusia amlodipine can be fast-release tablet, slow-release tablet.
The compound double-layer tablet that the present invention relates to can plain sheet, thin membrane coated tablet, the preferred film coated tablet.
The content of the amlodipine described in the present invention or its pharmaceutical salts is all in the base amlodipine, for example in the formula in embodiment 1, the active component of the second lamella is that its content of amlodipine pharmaceutical salts Amlodipine Besylate Tablet is 6.96g, and its weight of amounting to into base is 5g.
Term in the present invention " FAS crowd " refers to qualified case and the case data set that comes off, but does not comprise the rejecting case.
Term in the present invention " SS crowd " refers to the data of safety collection.
Beneficial effect of the present invention
The new specification 12.5mg:2.5mg of compound atenolol amlodipine bilayer tablet provided by the invention; compare with atenolol (12.5mg), amlodipine (2.5mg); produce Synergistic Hypotensive Effects by a plurality of target spots; the performance organ protection, reduce the appearance of cardiovascular complication when more effectively controlling blood pressure.by clinical multicenter, at random, double blinding, placebo, parallel group, 4 * 3 Factorial Design experimental studies show, compound atenolol amlodipine bilayer tablet (12.5mg:2.5mg) is than alone atenolol (12.5mg), alone amlodipine (2.5mg), compound atenolol amlodipine bilayer tablet (12.5mg:1.25mg), compound atenolol amlodipine bilayer tablet (25mg:1.25mg) has better resisting hypertension effect, with alone atenolol (12.5mg), alone amlodipine (2.5mg), compound atenolol amlodipine bilayer tablet (12.5mg:1.25mg), compound atenolol amlodipine bilayer tablet (25mg:1.25mg) is compared, has higher safety.
Simultaneously, the inventor is optimized processing to atenolol and amlodipine double-layer tablet preparation prescription and preparation technology thereof, increased the atenolol particle size distribution has been investigated the impact of preparation stripping, the evidence atenolol was pulverized 80 mesh sieves and was compared without pulverizing and sieving, cross 60 sieves before wet granulation, result of extraction and stability be can improve, thereby even, effective stripping and the preparation stability of atenolol and 2 kinds of compositions of amlodipine effectively guaranteed.If atenolol was pulverized greater than 80 mesh sieves, as 100 sieves, after adjuvant mixed, wet granule compression tablet can affect greatly the mouldability of slice, thin piece, was prone to sliver, fell lid.
Compound double-layer tablet provided by the invention, the atenolol of medicinal effective dose and the amlodipine of medicinal effective dose are in dissolution medium at 0.01mol/L hydrochloric acid, adopt the second method (slurry method) mensuration in Chinese Pharmacopoeia (version in 2010) appendix, rotating speed 75 turns/min, dissolution (30min)〉60, dissolution (45min)〉75.
The specific embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only is used for explanation the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment carries out according to the condition of normal condition or manufacturer's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Embodiment 1: the preparation of compound atenolol amlodipine double-layer tablet (12.5mg/2.5mg)
Core formulation:
The coating prescription:
Compound atenolol amlodipine double-layer tablet (12.5mg/2.5mg) preparation technology:
The first lamella (atenolol layer) is granulated, and adopts wet granulation technology:
Atenolol was pulverized 80 mesh sieves, and was standby;
Make solvent with 50% ethanol, PVP K-30 is made into the PVP K-30 solution of 1.4-1.6% concentration, as binding agent, stand-by;
With the atenolol (12.5g) of above-mentioned recipe quantity with microcrystalline Cellulose (116.7g), calcium hydrogen phosphate (60g), partly measure carboxymethyl starch sodium (4.15g) and mix in wet granulator, add binding agent and granulate.With the granule that makes after 50 ℃ of aeration-drying, add partly measure carboxymethyl starch sodium (4.15g) in addition, magnesium stearate (1g) is evenly mixed, obtains the first lamella granule.
The second lamella (Amlodipine Besylate Tablet layer) adopts technique of direct powder compression:
Except magnesium stearate, with Amlodipine Besylate Tablet (3.48g) and other adjuvants (calcium hydrogen phosphate 30g, microcrystalline Cellulose 60g, carboxymethyl starch sodium 2g) of above-mentioned recipe quantity, blender mixes.Add magnesium stearate (1g) before tabletting and mix, obtain the second lamella raw material, stand-by.
Tabletting: the first lamella granule of above-mentioned preparation is placed in the ground floor loading hopper of bi-layer tablet press, in the second layer loading hopper of the second lamella raw material as for bi-layer tablet press, the compacting double-layer tablet obtains 1000 of double-layer tablet labels.
Coating: coating solution use high-efficiency coating pot being on the above-mentioned double-layer tablet label for preparing of fluidized state, forms outer tunicle, with insulation blocking by spray gun spraying.Coating weightening finish 1-2%.
Comparative Examples 1: atenolol in the formula of embodiment 1 was pulverized 60 mesh sieves, and other steps prepare compound atenolol amlodipine bilayer tablet (12.5mg/5mg) with embodiment 1.
Embodiment 2: the preparation of compound atenolol amlodipine double-layer tablet (12.5mg/2.5mg)
Core formulation:
The coating prescription:
Above-mentioned formula is prepared 1000 of bilayer preparations according to the preparation method of embodiment 1.
Embodiment 3: the preparation of compound atenolol amlodipine double-layer tablet (12.5mg/2.5mg)
Core formulation:
The coating prescription:
Above-mentioned formula is prepared 1000 of bilayer preparations according to the preparation method of embodiment 1.
Embodiment 4: the preparation of compound atenolol amlodipine double-layer tablet (12.5mg/2.5mg)
Core formulation:
The coating prescription:
Above-mentioned formula is prepared 1000 of bilayer preparations according to the preparation method of embodiment 1.
Embodiment 5: the preparation of compound atenolol amlodipine double-layer tablet (12.5mg/2.5mg)
Core formulation:
The coating prescription:
Above-mentioned formula is prepared 1000 of bilayer preparations according to the preparation method of embodiment 1.
Embodiment 6: the preparation of compound atenolol amlodipine double-layer tablet (12.5mg/2.5mg)
Core formulation:
The coating prescription:
Above-mentioned formula is prepared 1000 of bilayer preparations according to the preparation method of embodiment 1.
Experimental example 1 dissolution experiment
The impact of atenolol particle size distribution on the preparation stripping that the present invention has passed through the dissolution the effects.Measured the dissolution of the compound atenolol amlodipine double-layer tablet of embodiment 1 and Comparative Examples 1 preparation.The mensuration of dissolution is in the dissolution medium of 0.01mol/L hydrochloric acid, temperature 37 degree, and 75 rev/mins of rotating speeds adopt the second method (slurry method) mensuration in Chinese Pharmacopoeia (version in 2010) appendix.Measurement result as shown in Table 1 and Table 2.
Result shows, atenolol was pulverized 80 mesh sieves and compared with crossing 60 sieves before wet granulation, can improve result of extraction, thus effectively guaranteed atenolol and 2 kinds of compositions of amlodipine more evenly, effectively stripping.The results are shown in Table 1 and table 2.
The compound atenolol amlodipine double-layer tablet stripping data (condition: 0.1M HCl is dissolution medium) of table 1 embodiment 1 preparation
The compound atenolol amlodipine double-layer tablet stripping data (condition: 0.1M HCl is dissolution medium) of table 2 Comparative Examples 1 preparation
Experimental example 2 stability experiments
The compound atenolol amlodipine double-layer tablet three batch sample quality inspection results of embodiment 1 preparation are as shown in table 3.
In addition, the present invention has also investigated 6 months accelerated stabilities of compound atenolol amlodipine double-layer tablet three batch samples of embodiment 1 preparation, and 6 months long-time stability.Wherein, the accelerated stability experiment is that compound atenolol amlodipine double-layer tablet three batch samples that embodiment 1 prepares are placed in 40 ℃ ± 2 ℃, under relative humidity 75% ± 5% condition, investigates 6 months, and during respectively at the 0th, 1,2,3,6 month, sampling detects; The long-time stability experiment is that compound atenolol amlodipine double-layer tablet three batch samples that embodiment 1 prepares are placed in 25 ℃ ± 2 ℃, under relative humidity 60% ± 10% condition, investigates 6 months, and during respectively at the 0th, 3,6 month, sampling detects.Testing result is listed in table 4 and table 5.
The compound atenolol amlodipine double-layer tablet three batch sample quality inspection results of table 3 embodiment 1 preparation (measuring in 0 o'clock)
Compound atenolol amlodipine double-layer tablet three batch sample of table 4 embodiment 1 preparation was accelerated quality inspection result (40 ℃ ± 2 ℃, relative humidity 75% ± 5%) in 6 months
Annotate: AM refers to amlodipine, and AT refers to atenolol, and AM (photodissociation) refers to the amlodipine photolytic product.
6 months long-term quality inspection results (25 ℃ ± 2 ℃, relative humidity 60% ± 10%) of placing of compound atenolol amlodipine double-layer tablet three batch sample of table 5 embodiment 1 preparation
Annotate: AM refers to amlodipine, and AT refers to atenolol, and AM (photodissociation) refers to the amlodipine photolytic product.
Result shows, the compound atenolol amlodipine double-layer tablet of the present invention's preparation is through accelerating and the long-time stability investigation, steady quality.
Experimental example 3 clinical experiments
Multicenter, random, double blinding, placebo, parallel group, 4 * 3 Factorial Designs are adopted in clinical trial, and concrete dosage is as shown in table 6.When having selected Amlodipine Besylate Tablet treatment essential hypertension from 0 to 4 of conventional initial dose than low dosage level, and during atenolol treatment essential hypertension from 0 to 3 of conventional initial dose than low dosage level.
Table 6
the experimenter's random assortment that meets selected/exclusion standard requirement enters each treatment group, comprise Amlodipine Besylate Tablet 1.25mg/ atenolol 12.5mg treatment group, Amlodipine Besylate Tablet 1.25mg/ atenolol 25mg treatment group, Amlodipine Besylate Tablet 2.5mg/ atenolol 12.5mg treatment group, Amlodipine Besylate Tablet 2.5mg/ atenolol 25mg treatment group, Amlodipine Besylate Tablet 5mg/ atenolol 12.5mg treatment group, Amlodipine Besylate Tablet 5mg/ atenolol 25mg treatment group, Amlodipine Besylate Tablet 1.25mg treatment group, Amlodipine Besylate Tablet 2.5mg treatment group, Amlodipine Besylate Tablet 5mg treatment group, atenolol 12.5mg treatment group, atenolol 25mg treatment group, placebo group.The drug dose of above-mentioned each treatment group is the content of every, and wherein the tablet of Amlodipine Besylate Tablet 2.5mg/ atenolol 12.5mg treatment group is according to formula and the method preparation of the embodiment of the present invention 1, and the tablet of other each treatment groups prepares according to a conventional method.
These clinical trial MethodsThe cases enrolled 480 examples are divided into 12 groups, and every group of 40 examples are completed by 16 clinical trial units respectively.Tested case is accepted the Drug therapy of embodiment 1 preparation, 6 weeks of the course for the treatment of, 1 time on the one, one time 1, take early morning.The rear 6 hours Measure blood pressures of taking medicine every day.
Clinical test results shows:
(1) curative effect index: the fall of Mean sitting diastolic blood pressure (difference).Each group is taken medicine and was compared data when selected the 6th weekend, sees Table 7, table 8.
The SiDBP fall that each test group of table 7 was taken medicine for the 6th weekend (mmHg, mean+SD, FAS crowd)
The SiDBP fall that each test group of table 8 was taken medicine for the 6th weekend (mmHg, corrected mean ± standard error, FAS crowd)
Annotate: * compares (two groups of relatively t checks, p＜0.05) with placebo group
# compares (two groups of relatively t checks, p＜0.05) with the amlodipine besylate tablets list medicine group of same dose
§ compares (two groups of relatively t checks, p＜0.05) with the atenolol tablet list medicine group of same dose
! Compare (Dunnett method, p＜0.05) with placebo group
$ compares (Dunnett method, p＜0.05) with the amlodipine besylate tablets list medicine group of same dose
﹠amp; Compare (Dunnett method, p＜0.05) with the atenolol tablet list medicine group of same dose
Table 7 and table 8 data show, each compound hypertension medicine group all show the trend that is better than placebo group and Isodose list medicine group.
(2) secondary efficacy evaluation index: the fall (difference) of average seat systolic pressure, each group are taken medicine and were compared data when selected the 6th weekend, see Table 9, table 10.
The seat systolic pressure fall (mmHg, Mean ± SD, FAS crowd) that each test group of table 9 was taken medicine for the 6th weekend
The seat systolic pressure fall (mmHg, corrected mean ± standard error, FAS crowd) that each test group of table 10 was taken medicine for the 6th weekend
Annotate: * compares (two groups of relatively t checks, p＜0.05) with placebo group
# compares (two groups of relatively t checks, p＜0.05) with the amlodipine besylate tablets list medicine group of same dose
§ compares (two groups of relatively t checks, p＜0.05) with the atenolol tablet list medicine group of same dose
! Compare (Dunnett method, p＜0.05) with placebo group
$ compares (Dunnett method, p＜0.05) with the amlodipine besylate tablets list medicine group of same dose
﹠amp; Compare (Dunnett method, p＜0.05) with the atenolol tablet list medicine group of same dose
Table 9 and table 10 data show, each compound hypertension medicine group all show the trend that is better than placebo group and Isodose list medicine group.
(3) effective percentage of Treatment of Hypertension:
The effective percentage of Treatment of Hypertension is: after experimenter's oral administration antihypertensive drug therapy, and the case load of Blood pressure drop and the clinical ratio that enters to organize total case load.Report symposium's summary according to national cardiovascular epidemiology in 1979 and crowd prevention and treatment, the diastolic pressure 10～19mmHg that descends, or declines＜10mmHg, but reached normal for treatment effective.
Each test group is taken medicine and was compared when selected the 6th weekend, and the total effective rate of Treatment of Hypertension sees Table 11.
Each test group of table 11 take medicine the 6th weekend Treatment of Hypertension total effective rate (%, FAS crowd)
(4) compliance rate of Treatment of Hypertension
The compliance rate of Treatment of Hypertension is: after experimenter's oral administration antihypertensive drug therapy, Blood pressure drop is to case load and the clinical ratio that enters to organize total case load of human body blood pressure normal level.Report symposium's summary according to national cardiovascular epidemiology in 1979 and crowd prevention and treatment, diastolic pressure declines 〉=10mmHg, and be down to normal (＜90mm Hg) or above up to standard for treating of decline 20mmHg.
Each test group is taken medicine and was compared when selected the 6th weekend, and the compliance rate of Treatment of Hypertension sees Table 12.
Each test group of table 12 take medicine the 6th weekend Treatment of Hypertension compliance rate (%, FAS crowd)
(5) with drug-associated adverse events incidence rate
Drug-associated adverse events incidence rate is: the ratio of total medical events in any bad unexpected bad medical events that experimenter's oral administration antihypertensive drugs occurs later on and clinical trial.The temporary disease that adverse events can make any unhelpful or unexpected sign (anomaly that comprises laboratory), symptom or follow during drug use, as: dizziness, insomnia etc.The relevant adverse events incidence rate of the medicine of each test group sees Table 13.
Each test group drug-associated adverse events incidence rate (%, SS crowd) of table 13
In this test, compound recipe Amlodipine Besylate Tablet/atenolol 2.5mg/12.5mg, 2.5mg/25mg, 5mg/12.5mg, 5mg/25mg medication group is to the range of decrease of SiDBP and the systolic pressure single medicine group greater than placebo group and Isodose, even greater than single medicine group of maximum dose level, and present the trend that curative effect increases with dosage.
In this test, each is organized the experimenter and all can tolerate safely, 1.25mg/12.5mg, and 1.25mg/25mg, 2.5mg/12.5mg, the trial drug dependency adverse events incidence rate of 5mg/25mg drug combination group is low.
Claims (13)
1. compound double-layer tablet, it comprises:
The first lamella wherein contains approximately 12.5mg of atenolol, and pharmaceutically acceptable excipient or adjuvant, and
The second lamella, wherein contain amlodipine or its pharmaceutical salts approximately 2.5mg(in the base amlodipine), and pharmaceutically acceptable excipient or adjuvant.
2. the compound double-layer tablet of claim 1, wherein, described amlodipine pharmaceutical salts is Amlodipine Besylate Tablet, amlodipine maleate or other pharmaceutically useful Amlodipines, is preferably Amlodipine Besylate Tablet.
3. the compound double-layer tablet of claim 1, wherein, in the first lamella, described pharmaceutically acceptable excipient or adjuvant are to be selected from one or more in calcium hydrogen phosphate, microcrystalline Cellulose, PVP K-30, carboxymethyl starch sodium, magnesium stearate;
Preferably, described calcium hydrogen phosphate is calcium phosphate dibasic anhydrous or dicalcium phosphate dehydrate.
4. the compound double-layer tablet of claim 1, wherein, in the first lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0～165mg, microcrystalline Cellulose 20～165mg, PVP K-30 0～3mg, carboxymethyl starch sodium 4～12mg, magnesium stearate 0.5～1.5mg;
Preferably, in the first lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0～120mg, microcrystalline Cellulose 30～120mg, PVP K-30 0.5～3mg, carboxymethyl starch sodium 5～10mg, magnesium stearate 0.5～1.5mg;
More preferably, in the first lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 60mg, 0mg, 120mg or 50mg, microcrystalline Cellulose 116.7mg, 102mg, 60mg, 30mg, 50mg, 120mg, PVP K-30 1mg, carboxymethyl starch sodium 10mg, 5mg, 8.3mg, magnesium stearate 1mg.
5. the compound double-layer tablet of claim 1, wherein, in the second lamella, described pharmaceutically acceptable excipient or adjuvant are to be selected from one or more in calcium hydrogen phosphate, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate;
Preferably, described calcium hydrogen phosphate is calcium phosphate dibasic anhydrous or dicalcium phosphate dehydrate.
6. the compound double-layer tablet of claim 1, wherein, in the second lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0～50mg, microcrystalline Cellulose 30～90mg, carboxymethyl starch sodium 1～3mg, magnesium stearate 0.5～1.5mg;
Preferably, in the second lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0～30mg, microcrystalline Cellulose 50～90mg, carboxymethyl starch sodium 1～3mg, magnesium stearate 0.5～1.5mg;
More preferably, in the second lamella, the content of described pharmaceutically acceptable excipient or adjuvant is as follows: calcium hydrogen phosphate 0mg, 30mg, microcrystalline Cellulose 50mg, 60mg or 90mg, carboxymethyl starch sodium 2mg, magnesium stearate 1mg.
7. the compound double-layer tablet of claim 1, described the first lamella and/or the second lamella are fast-release tablet or slow-release tablet.
8. the compound double-layer tablet of claim 1-7 any one, wherein said tablet is plain sheet or thin membrane coated tablet;
Preferably, described tablet is the film coated tablet;
Preferably, described coating material is selected from one or more in hydroxypropyl emthylcellulose, tween 80, Pulvis Talci, titanium dioxide.
9. the compound double-layer tablet of claim 1-7 any one, wherein atenolol and/or amlodipine are in the dissolution medium of 0.01mol/L hydrochloric acid, adopt the second method (slurry method) mensuration in Chinese Pharmacopoeia (version in 2010) appendix, dissolution (30min)〉60, dissolution (45min)〉75.
10. the compound double-layer tablet of claim 1, also contain the other types antihypertensive drug in described the first lamella and/or the second lamella.
11. the preparation method of the compound double-layer tablet of claim 1 to 7 any one, wherein, the preparation method of the first lamella was for to pulverize 60 orders or 80 mesh sieves with atenolol, preferred 80 mesh sieves of crossing, granulate with wet granulation technology after mixing with adjuvant, the preparation method of the second lamella is direct powder compression again.
12. the purposes of the compound double-layer tablet of claim 1 to 7 any one in the medicine of the target organ relevant disease that causes for the preparation for the treatment of hypertension or hypertension; Preferably, described hypertension is 1 grade of hypertension or 2 grades of hypertension.
13. the compound double-layer tablet that is prepared by the preparation method of claim 11.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101244583A CN103169702A (en) | 2013-04-11 | 2013-04-11 | Compound antihypertensive drug composition |
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| CN2013101244583A CN103169702A (en) | 2013-04-11 | 2013-04-11 | Compound antihypertensive drug composition |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1785185A (en) * | 2004-12-08 | 2006-06-14 | 北京双鹤药业股份有限公司 | Compounding hypotensor contg. amlodipine and atenolol |
| CN102085201A (en) * | 2009-12-08 | 2011-06-08 | 北京双鹤药业股份有限公司 | Atenolol and amlodipine bilayer tablet |
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2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1785185A (en) * | 2004-12-08 | 2006-06-14 | 北京双鹤药业股份有限公司 | Compounding hypotensor contg. amlodipine and atenolol |
| CN102085201A (en) * | 2009-12-08 | 2011-06-08 | 北京双鹤药业股份有限公司 | Atenolol and amlodipine bilayer tablet |
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