CN101564536B - Sustained and controlled release preparation for pharmaceutical composition for curing hypertension - Google Patents
Sustained and controlled release preparation for pharmaceutical composition for curing hypertension Download PDFInfo
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- CN101564536B CN101564536B CN2008100156989A CN200810015698A CN101564536B CN 101564536 B CN101564536 B CN 101564536B CN 2008100156989 A CN2008100156989 A CN 2008100156989A CN 200810015698 A CN200810015698 A CN 200810015698A CN 101564536 B CN101564536 B CN 101564536B
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Abstract
The invention provides a sustained and controlled release preparation for a pharmaceutical composition for curing hypertension. The sustained and controlled release preparation composition includes a specific proportion of levamlodipine and angiotensin II receptor blocking pharmacon, wherein the levamlodipine is taken as the sustained and controlled release part and the angiotensin II receptor blocking pharmacon is taken as the common release part. The provided sustained and controlled release preparation enhances the therapeutic effect and reduces the treatment risk of the patients.
Description
Technical field:
The invention belongs to field of medicine preparations, relate to the hypertensive sustained-release preparation of the treatment that contains two kinds of active constituents of medicine, wherein a kind of medicine is a Levamlodipine, and another kind of medicine is an angiotensin-ii receptor blockers.
Background technology
Hypertension is modal cardiovascular disease, has become the great public health problem in the global range.Show that according to national hygiene department statistics to the end of the year 2006, China patients with hypertension crowd has reached 1.6 hundred million people, and annual newly-increased patient is more than 3,000,000.
Hypertension is a cause of disease and the very complicated syndrome of pathogenesis, once making a definite diagnosis, promptly needs lifelong medication.At present, domestic and international medical circle is generally tended to the antihypertensive use in conjunction with two kinds of different mechanism of action.According to U.S.'s prevention, the 6th report of the detection assessment and the treatment hypertension National Committee, the fixed compound preparation of these antihypertensive low doses not only can be used as the two wires medicine, also can be used as a line medicine and be used for hypertensive treatment, more should be like this when especially the patient has other complication or complication to exist simultaneously.Chinese hypertension prevention and control guides in 2004 of China's revision in 2004 (originally practical) are thought, adopt the fixed mixing ratio compound recipe, and its advantage is convenient, helps improving patient's compliance.
Chinese patent CN1312715, CN1733307 disclose a kind of treatment or prevent diabetes, hypertension is followed diabetes, diabetic nephropathy drugs compositions, comprise valsartan and calcium channel blocker, yet this invention is only mentioned with prior art this pharmaceutical composition is made tablet, capsule, suppository.
Chinese patent CN1883478 discloses a kind of pharmaceutical composition for the treatment of hypertension and cardiovascular disease, comprise a kind of in Levamlodipine and losartan, irbesartan, valsartan, Eprosartan, Candesartan or the Tasosartan, and disclose this pharmaceutical composition and can make tablet, granule, capsule, injection, slow releasing agent, yet slow releasing agent only is simple one to carry, and does not provide concrete technical scheme.
Summary of the invention
The objective of the invention is to prescription design, a kind of sustained-release preparation for the treatment of hypertensive pharmaceutical composition is provided, thereby reaches antihypertensive effect more stably by a series of science.
This sustained-release preparation compositions contains the Levamlodipine and the angiotensin-ii receptor blockers of special ratios, and wherein angiotensin-ii receptor blockers comprises losartan, valsartan, telmisartan, Candesartan, Tasosartan, Eprosartan, irbesartan, Olmesartan or its officinal salt.Levamlodipine comprises its benzene sulfonate, maleate, tartrate, aspat, hydrochlorate, sulfate, formates, acetate, hydrobromate.The weight ratio of Levamlodipine and angiotensin-ii receptor blockers is 1: 10～1: 600.
The pharmaceutical composition that the present invention relates to is to be prepared into sustained-release preparation by following technical solution.
1) Levamlodipine is as slow-released part, and angiotensin-ii receptor blockers is as common release portion.Particularly:
Levamlodipine is designed sustained-release tablet recipe; Angiotensin-ii receptor blockers design ordinary tablet prescription is developed double-layer tablet, promptly then.
Or Levamlodipine is designed the slow releasing capsule micropill write out a prescription; Angiotensin-ii receptor blockers design ordinary tablet prescription is made slow-release micro-pill respectively and is closed common pellets, with filling capsule shell behind the micropill mix homogeneously, promptly.
2) Levamlodipine is as the controlled release part, and angiotensin-ii receptor blockers is as common release portion.Particularly:
Levamlodipine is designed controlled release capsule micropill prescription; Angiotensin-ii receptor blockers design ordinary tablet prescription is made slow-release micro-pill respectively and is closed common pellets, with filling capsule shell behind the micropill mix homogeneously.
Main prescription is formed
The controlled release part
Ball core prescription
Celphere
Levamlodipine
Diluent
Lubricant
Adhesive
The coating prescription
The pastille micropill
The coating adjuvant
The common pellets part
Angiotensin-ii receptor blockers
Diluent
Adhesive
Levamlodipine and adjuvant are pulverized about 150 μ m, and the adding mix lubricant is even, crosses 150 μ m sieve.Celphere is added in the coating machine, regulates machine parameters such as wind speed, rotating speed and temperature, make it to be in appropriate state, after adhesive is slowly evenly sprayed into, treat the moistening of ball core after, will mix powder and evenly add on the distribution celphere.Sieve after drying then, promptly get micropill.
Micropill with gained joins in the coating machine then, regulates machine parameters such as wind speed, rotating speed and temperature, makes it to be in appropriate state, and the coating adjuvant is evenly added, and drying promptly gets controlled release micro pill.
Common pellets adopts to be extruded round as a ball comminutor and prepares slow-release micro-pill, then with two kinds of micropill mix homogeneously of recipe quantity, and the filling capsule shell, promptly.
The advantage of the present composition is embodied in following several aspect:
(1) at first, in therapeutic process, merge the different depressor of application mechanism of action and often can strengthen therapeutic effect, look after the different links in the hypertension incidence mechanism simultaneously, make multiple risk factor or and deposit disease and obtain Optimal Control, more help the protection of hypertension target organ 26S Proteasome Structure and Function, further reduce the incidence rate of cardiovascular event;
(2) secondly, because when forming immobilised compound, the dosage of each single medicine all has minimizing, thereby the incidence rate of drug side effect reduces; About medical expense, reduce when using separately owing to used drug dose ratio, and production and packing cost reduction, therefore, medical expense not only can not increase, and has decline on the contrary, and the benefit/expense ratio of feasible treatment is significantly improved.Therefore patient's treatment compliance increases greatly, and quality of life also just obviously improves.
(3) the 3rd, take once every day.With drug prepared compositions sustained-release preparation of the present invention, take 1 time after only needing to wake up early morning every day, can prevent the blood pressure acute variation after wake up early morning effectively, make blood pressure be in state very stably.For the patient, overcome traditional every day of the defective of taking medicine repeatedly, under the situation of administration once a day, just reached ten minutes antihypertensive effect stably, both made things convenient for patient's use, reached a unapproachable antihypertensive effect of ordinary preparation again.
(4) the 4th, overcome the prejudice of prior art.Chinese patent CN1883478 emphasizes in its description, in various dosage forms (comprising slow releasing agent), and the conventional tablet and the capsular best results of the husky smooth class compound recipe of Levamlodipine.Yet the inventor finds by a series of pharmacodynamics tests, and sustained-release preparation is than conventional tablet and capsule better effects if, and significant difference is arranged.
(5) the 5th, because sustained-release preparation provided by the invention can guarantee that the patient has a stable blood concentration, thereby guarantee blood pressure held stationary in 24h of patient, reduce the mortality rate that apoplexy causes, see embodiment 13 for details.
This compound preparation if can be applied to clinical, can increase hypertensive patient's the medication range of choice, simplifies Therapeutic Method, increases patient's treatment compliance, improves China hypertensive patient's controlling of blood pressure rate, also reduces the mortality rate that apoplexy causes when reducing hypertension.
Specific embodiment
The preparation of embodiment 1 slow releasing tablet
Slow-released part
Levamlodipine besylate 5g
Hydroxypropyl emthylcellulose 8g
Lactose 12g
80% alcoholic solution is an amount of
Common part
Candesartan Cilexetil 2.5g
Microcrystalline Cellulose 15g
Dextrin 3g
70% the alcoholic solution of 3%PVPk30 is an amount of
Magnesium stearate 0.6g
Preparation technology:
Earlier Levamlodipine besylate, candesartan Cilexetil are crossed 100 mesh sieves; Hydroxypropyl emthylcellulose, microcrystalline Cellulose, lactose, dextrin are crossed 80 mesh sieves.
Take by weighing Levamlodipine besylate, hydroxypropyl emthylcellulose and lactose by recipe quantity, with its mixing, add 80% alcoholic solution system soft material, cross 18 mesh sieves and granulate, wet granular is 50～60 ℃ of dryings, and dried granule adds magnesium stearate, mixing through 16 mesh sieve granulate.
Take by weighing candesartan Cilexetil, microcrystalline Cellulose and dextrin by recipe quantity,, add 70% the alcoholic solution system soft material of 3%PVPk30, cross 18 mesh sieves and granulate its mixing, wet granular is 50～60 ℃ of dryings, and dried granule adds magnesium stearate through 16 mesh sieve granulate, mixing, the bi-layer tablet press tabletting, promptly.
The preparation of embodiment 2 slow releasing tablet
Slow-released part
Levamlodipine besylate 2.5g
Hydroxypropyl emthylcellulose 8g
Lactose 12g
80% alcoholic solution is an amount of
Common part
Candesartan Cilexetil 4g
Microcrystalline Cellulose 15g
Starch 3g
70% the alcoholic solution of 3%PVPk30 is an amount of
Magnesium stearate 0.5g
Preparation technology:
Earlier Levamlodipine besylate, candesartan Cilexetil are crossed 100 mesh sieves; Hydroxypropyl emthylcellulose, microcrystalline Cellulose, lactose, starch are crossed 80 mesh sieves.
Take by weighing Levamlodipine besylate, hydroxypropyl emthylcellulose and lactose by recipe quantity, with its mixing, add 80% alcoholic solution system soft material, cross 18 mesh sieves and granulate, wet granular is 50～60 ℃ of dryings, and dried granule adds magnesium stearate, mixing through 16 mesh sieve granulate.
Take by weighing candesartan Cilexetil, microcrystalline Cellulose and starch by recipe quantity,, add 70% the alcoholic solution system soft material of 3%PVPk30, cross 18 mesh sieves and granulate its mixing, wet granular is 50～60 ℃ of dryings, and dried granule adds magnesium stearate through 16 mesh sieve granulate, mixing, the bi-layer tablet press tabletting, promptly.
The preparation of embodiment 3 slow releasing tablet
Slow-released part
Levamlodipine besylate 5g
Hydroxypropyl emthylcellulose 750g
Lactose 120g
80% alcoholic solution is an amount of
Common part
Methanesulfonic acid Eprosartan 600g
Microcrystalline Cellulose 450g
Starch 300g
70% the alcoholic solution of 3%PVPk30 is an amount of
Magnesium stearate 5g
Preparation technology:
Earlier Levamlodipine besylate, methanesulfonic acid Eprosartan are crossed 100 mesh sieves; Hydroxypropyl emthylcellulose, microcrystalline Cellulose, lactose, starch are crossed 80 mesh sieves.
Take by weighing Levamlodipine besylate, hydroxypropyl emthylcellulose and lactose by recipe quantity, the principal agent Levamlodipine besylate is adopted equivalent incremental method and auxiliary materials and mixing, add 80% alcoholic solution system soft material, crossing 18 mesh sieves granulates, wet granular is 50～60 ℃ of dryings, dried granule adds magnesium stearate, mixing through 16 mesh sieve granulate.
Take by weighing methanesulfonic acid Eprosartan, microcrystalline Cellulose and starch by recipe quantity, with its mixing, 70% the alcoholic solution system soft material that adds 3%PVPk30, cross 18 mesh sieves and granulate, wet granular is 50～60 ℃ of dryings, and dried granule is through 16 mesh sieve granulate, add magnesium stearate, mixing, the bi-layer tablet press tabletting, promptly.
The preparation of embodiment 4 slow releasing tablet
Slow-released part
(S)-(-)-Amlodipine hydrochloride 5g
Hydroxypropyl emthylcellulose 35g
Lactose 12g
80% alcoholic solution is an amount of
Common part
Losartan Potassium 50g
Microcrystalline Cellulose 45g
Starch 9g
70% the alcoholic solution of 3%PVPk30 is an amount of
Magnesium stearate 1g
Preparation technology:
Earlier (S)-(-)-Amlodipine hydrochloride, Losartan Potassium are crossed 100 mesh sieves; Hydroxypropyl emthylcellulose, microcrystalline Cellulose, lactose, starch are crossed 80 mesh sieves.
Take by weighing (S)-(-)-Amlodipine hydrochloride, hydroxypropyl emthylcellulose and lactose by recipe quantity, with its mixing, add 80% alcoholic solution system soft material, cross 18 mesh sieves and granulate, wet granular is 50～60 ℃ of dryings, and dried granule adds magnesium stearate, mixing through 16 mesh sieve granulate.
Claim Losartan Potassium, microcrystalline Cellulose and starch by recipe quantity,, add 70% the alcoholic solution system soft material of 3%PVPk30, cross 18 mesh sieves and granulate its mixing, wet granular is 50～60 ℃ of dryings, and dried granule adds magnesium stearate through 16 mesh sieve granulate, mixing, the bi-layer tablet press tabletting, promptly.
The preparation of embodiment 5 slow releasing capsule
Slow-released part
Tartaric acid Levamlodipine 5g
Microcrystalline Cellulose 16g
Ethyl cellulose 15g
Hypromellose 13g
60% ethanol is an amount of
Common part
Irbesartan 150g
Microcrystalline Cellulose 95g
Lactose 60g
25% ethanol is an amount of
Preparation technology:
Employing is extruded round as a ball comminutor and is prepared slow-release micro-pill.Earlier tartaric acid Levamlodipine and adjuvant are pulverized, crossed 100 mesh sieves.Take by weighing recipe quantity tartaric acid Levamlodipine and ethyl cellulose, hypromellose, mix homogeneously, add 60% ethanol and make soft material in right amount, be extruded into the suitable fine strip shape of diameter through extruding sieve plate (aperture 0.8mm), make then strip-shaped materials advance spheronizator round as a ball after, take out micropill, in about 50～60 ℃ of oven dry 3h, make moisture be controlled at 1%～3%.
Same employing is extruded round as a ball comminutor and is prepared common pellets.Earlier irbesartan and microcrystalline Cellulose, lactose are pulverized, crossed 100 mesh sieves.Take by weighing recipe quantity irbesartan and microcrystalline Cellulose, lactose, mix homogeneously, add 25% ethanol and make soft material in right amount, be extruded into the suitable fine strip shape of diameter through extruding sieve plate (aperture 0.8mm), make then strip-shaped materials advance spheronizator round as a ball after, take out micropill, in about 50～60 ℃ of oven dry 3h, make moisture be controlled at 1%～3%.
Get 18～24 purpose slow-release micro-pill and common pellets mix homogeneously then, determine capsular loading amount, carry out capsule charge with filling machine, promptly.
The preparation of embodiment 6 slow releasing capsule
Slow-released part
Sulphuric acid Levamlodipine 5g
Microcrystalline Cellulose 20g
Ethyl cellulose 18g
Hypromellose 14g
60% ethanol is an amount of
Common part
Valsartan 80g
Microcrystalline Cellulose 105g
Lactose 50g
25% ethanol is an amount of
Preparation technology:
Employing is extruded round as a ball comminutor and is prepared slow-release micro-pill.Earlier sulphuric acid Levamlodipine and adjuvant are pulverized, crossed 100 mesh sieves.Take by weighing recipe quantity sulphuric acid Levamlodipine and ethyl cellulose, hypromellose, mix homogeneously, add 60% ethanol and make soft material in right amount, be extruded into the suitable fine strip shape of diameter through extruding sieve plate (aperture 0.8mm), make then strip-shaped materials advance spheronizator round as a ball after, take out micropill, in about 50～60 ℃ of oven dry 3h, make moisture be controlled at 1%～3%.
Same employing is extruded round as a ball comminutor and is prepared common pellets.Earlier valsartan and microcrystalline Cellulose, lactose are pulverized, crossed 100 mesh sieves.Take by weighing recipe quantity valsartan and microcrystalline Cellulose, lactose, mix homogeneously, add 25% ethanol and make soft material in right amount, be extruded into the suitable fine strip shape of diameter through extruding sieve plate (aperture 0.8mm), make then strip-shaped materials advance spheronizator round as a ball after, take out micropill, in about 50～60 ℃ of oven dry 3h, make moisture be controlled at 1%～3%.
Get 18～24 purpose slow-release micro-pill and common pellets mix homogeneously then, determine capsular loading amount, carry out capsule charge with filling machine, promptly.
The preparation of embodiment 7 slow releasing tablet
Slow-released part
Aspartic acid Levamlodipine 5g
Hydroxypropyl emthylcellulose 8g
Lactose 12g
80% alcoholic solution is an amount of
Common part
Telmisartan 40g
Microcrystalline Cellulose 20g
Starch 35g
70% the alcoholic solution of 3%PVPk30 is an amount of
Magnesium stearate 1g
Preparation technology:
Earlier aspartic acid Levamlodipine, telmisartan are crossed 100 mesh sieves; Hydroxypropyl emthylcellulose, microcrystalline Cellulose, lactose, starch are crossed 80 mesh sieves.
Take by weighing aspartic acid Levamlodipine, hydroxypropyl emthylcellulose and lactose by recipe quantity, with its mixing, add 80% alcoholic solution system soft material, cross 18 mesh sieves and granulate, wet granular is 50～60 ℃ of dryings, and dried granule adds magnesium stearate, mixing through 16 mesh sieve granulate.
Take by weighing telmisartan, microcrystalline Cellulose and starch by recipe quantity,, add 70% the alcoholic solution system soft material of 3%PVPk30, cross 18 mesh sieves and granulate its mixing, wet granular is 50～60 ℃ of dryings, and dried granule adds magnesium stearate through 16 mesh sieve granulate, mixing, the bi-layer tablet press tabletting, promptly.
The preparation of embodiment 8 slow releasing capsule
Slow-released part
Formic acid Levamlodipine 5g
Microcrystalline Cellulose 20g
Ethyl cellulose 18g
Hypromellose 14g
60% ethanol is an amount of
Common part
Olmesartan medoxomil 20g
Microcrystalline Cellulose 35g
Lactose 20g
25% ethanol is an amount of
Preparation technology:
Employing is extruded round as a ball comminutor and is prepared slow-release micro-pill.Earlier formic acid Levamlodipine and adjuvant are pulverized, crossed 100 mesh sieves.Take by weighing recipe quantity formic acid Levamlodipine and ethyl cellulose, hypromellose, mix homogeneously, add 60% ethanol and make soft material in right amount, be extruded into the suitable fine strip shape of diameter through extruding sieve plate (aperture 0.8mm), make then strip-shaped materials advance spheronizator round as a ball after, take out micropill, in about 50～60 ℃ of oven dry 3h, make moisture be controlled at 1%～3%.
Same employing is extruded round as a ball comminutor and is prepared common pellets.Earlier olmesartan medoxomil and microcrystalline Cellulose, lactose are pulverized, crossed 100 mesh sieves.Take by weighing recipe quantity olmesartan medoxomil and microcrystalline Cellulose, lactose, mix homogeneously, add 25% ethanol and make soft material in right amount, be extruded into the suitable fine strip shape of diameter through extruding sieve plate (aperture 0.8mm), make then strip-shaped materials advance spheronizator round as a ball after, take out micropill, in about 50～60 ℃ of oven dry 3h, make moisture be controlled at 1%～3%.
Get 18～24 purpose slow-release micro-pill and common pellets mix homogeneously then, determine capsular loading amount, carry out capsule charge with filling machine, promptly.
The preparation of embodiment 9 slow releasing capsule
Slow-released part
Hydrobromic acid Levamlodipine 5g
Microcrystalline Cellulose 20g
Ethyl cellulose 18g
Hypromellose 14g
60% ethanol is an amount of
Common part
Tasosartan 100g
Microcrystalline Cellulose 110g
Lactose 55g
25% ethanol is an amount of
Preparation technology:
Employing is extruded round as a ball comminutor and is prepared slow-release micro-pill.Earlier hydrobromic acid Levamlodipine and adjuvant are pulverized, crossed 100 mesh sieves.Take by weighing recipe quantity hydrobromic acid Levamlodipine and ethyl cellulose, hypromellose, mix homogeneously, add 60% ethanol and make soft material in right amount, be extruded into the suitable fine strip shape of diameter through extruding sieve plate (aperture 0.8mm), make then strip-shaped materials advance spheronizator round as a ball after, take out micropill, in about 50～60 ℃ of oven dry 3h, make moisture be controlled at 1%～3%.
Same employing is extruded round as a ball comminutor and is prepared common pellets.Tasosartan and microcrystalline Cellulose, lactose are pulverized, crossed 100 mesh sieves.Take by weighing recipe quantity Tasosartan and microcrystalline Cellulose, lactose, mix homogeneously, add 25% ethanol and make soft material in right amount, be extruded into the suitable fine strip shape of diameter through extruding sieve plate (aperture 0.8mm), make then strip-shaped materials advance spheronizator round as a ball after, take out micropill, in about 50～60 ℃ of oven dry 3h, make moisture be controlled at 1%～3%.
Get 18～24 purpose slow-release micro-pill and common pellets mix homogeneously then, determine capsular loading amount, carry out capsule charge with filling machine, promptly.
The preparation of embodiment 10 controlled release capsules
The controlled release part
Ball core prescription
Celphere 15g
Levamlodipine besylate 2.5g
Starch 3g
Lactose 2.5g
25% syrup is an amount of
The coating prescription
Pastille micropill 25g
Acrylic resin 0.6g
Polyethylene Glycol 0.2g
80% alcoholic solution 20g
Pulvis Talci 0.3g
The common pellets part
Losartan Potassium 50g
Microcrystalline Cellulose 50g
Lactose 10g
25% alcoholic solution is an amount of
Preparation technology:
Levamlodipine besylate, starch, lactose are pulverized about 150 μ m, and mix homogeneously is crossed 150 μ m sieve.Celphere is added in the coating machine, regulates machine parameters such as wind speed, rotating speed and temperature, make it to be in appropriate state, after 25% syrup is slowly evenly sprayed into, treat the moistening of ball core after, will mix powder and evenly add on the distribution celphere.Sieve after drying then, promptly get micropill.
Then with acrylic resin, Polyethylene Glycol 80% dissolve with ethanol solution, the micropill of gained is joined in the coating machine, regulate machine parameters such as wind speed, rotating speed and temperature, make it to be in appropriate state, coating liquid is evenly added, and drying promptly gets controlled release micro pill.
Common pellets adopts to be extruded round as a ball comminutor and prepares slow-release micro-pill, then with two kinds of micropill mix homogeneously of recipe quantity, and the filling capsule shell, promptly.
The preparation of embodiment 11 controlled release capsules
The controlled release part
Ball core prescription
Celphere 15g
Levamlodipine besylate 2.5g
Microcrystalline Cellulose 3g
Lactose 2.5g
2.5%PVP is an amount of
The coating prescription
Pastille micropill 25g
Acrylic resin 0.3g
Hydroxypropyl emthylcellulose 0.3g
Polyethylene Glycol 0.2g
80% alcoholic solution 20g
Pulvis Talci 0.3g
The common pellets part
Valsartan 80g
Microcrystalline Cellulose 100g
Lactose 15g
25% alcoholic solution is an amount of
Preparation technology:
Levamlodipine besylate, microcrystalline Cellulose, lactose are pulverized about 150 μ m, and mix homogeneously is crossed 150 μ m sieve.Celphere is added in the coating machine, regulates machine parameters such as wind speed, rotating speed and temperature, make it to be in appropriate state, after 25% syrup is slowly evenly sprayed into, treat the moistening of ball core after, will mix powder and evenly add on the distribution celphere.Sieve after drying then, promptly get micropill.
Then with acrylic resin, hydroxypropyl emthylcellulose, Polyethylene Glycol 80% dissolve with ethanol solution, the micropill of gained is joined in the coating machine, regulate machine parameters such as wind speed, rotating speed and temperature, make it to be in appropriate state, coating liquid is evenly added, drying promptly gets controlled release micro pill.
Common pellets adopts to be extruded round as a ball comminutor and prepares slow-release micro-pill, then with two kinds of micropill mix homogeneously of recipe quantity, and the filling capsule shell, promptly.
The preparation of embodiment 12 controlled release agent
The controlled release part
Ball core prescription
Celphere 15g
Levamlodipine besylate 2.5g
Microcrystalline Cellulose 3g
Lactose 2.5g
2.5%PVP is an amount of
The coating prescription
Pastille micropill 25g
Acrylic resin 0.3g
Hydroxypropyl emthylcellulose 0.3g
Polyethylene Glycol 0.2g
80% alcoholic solution 20g
Pulvis Talci 0.3g
The common pellets part
Telmisartan 40g
Microcrystalline Cellulose 60g
Lactose 10g
25% alcoholic solution is an amount of
Preparation technology:
Levamlodipine besylate, microcrystalline Cellulose, lactose are pulverized about 150 μ m, and mix homogeneously is crossed 150 μ m sieve.Celphere is added in the coating machine, regulates machine parameters such as wind speed, rotating speed and temperature, make it to be in appropriate state, after 25% syrup is slowly evenly sprayed into, treat the moistening of ball core after, will mix powder and evenly add on the distribution celphere.Sieve after drying then, promptly get micropill.
Then with acrylic resin, hydroxypropyl emthylcellulose, Polyethylene Glycol 80% dissolve with ethanol solution, the micropill of gained is joined in the coating machine, regulate machine parameters such as wind speed, rotating speed and temperature, make it to be in appropriate state, coating liquid is evenly added, drying promptly gets controlled release micro pill.
Common pellets adopts to be extruded round as a ball comminutor and prepares slow-release micro-pill, then with two kinds of micropill mix homogeneously of recipe quantity, and the filling capsule shell, promptly.
The husky smooth class slow releasing agent compound recipe of embodiment 13 Levamlodipine besylates is to the influence of SHRsp rat blood pressure
1. grouping
10 week essential hypertension apoplectic type rat in age (SHRsp) totally 135, be divided into model group at random, Levamlodipine Candesartan ordinary preparation group (ammonia Kemp group), Levamlodipine Eprosartan ordinary preparation group (ammonia is according to general group), Levamlodipine losartan ordinary preparation group (general group of ammonia chlorine), Levamlodipine Tasosartan ordinary preparation group (ammonia he general group), Levamlodipine Candesartan slow releasing preparation group (the slow group of ammonia bank), Levamlodipine Eprosartan slow releasing preparation group (ammonia is according to slow group), Levamlodipine losartan slow releasing preparation group (the slow group of ammonia chlorine), Levamlodipine Tasosartan slow releasing preparation group (he delays group ammonia), every group 15 respectively, female 7, male 8.
2. medication
With Levamlodipine with an amount of purified water wiring solution-forming, or make sustained-release micro-spheres by prior art, the ordinary preparation group gives Levamlodipine solution, the slow releasing preparation group gives the Levamlodipine sustained-release micro-spheres, husky smooth class is with an amount of purified water wiring solution-forming, each organizes the equal gastric infusion of rat, continues for 18 weeks, and dosage is as follows respectively:
Model group: with volume 0.9% normal saline;
Ammonia Kemp group: 0.58mg/ (kg.d) Levamlodipine+0.47mg/ (kg.d) Candesartan
Ammonia is according to general group: 0.58mg/ (kg.d) Levamlodipine+70mg/ (kg.d) Eprosartan
General group of ammonia chlorine: 0.58mg/ (kg.d) Levamlodipine+5.8mg/ (kg.d) losartan
Ammonia he general group: 0.58mg/ (kg.d) Levamlodipine+17.5mg/ (kg.d) Tasosartan
The slow group of ammonia bank: 0.58mg/ (kg.d) Levamlodipine+0.47mg/ (kg.d) Candesartan
Ammonia is organized according to slow: 0.58mg/ (kg.d) Levamlodipine+70mg/ (kg.d) Eprosartan
The slow group of ammonia chlorine: 0.58mg/ (kg.d) Levamlodipine+5.8mg/ (kg.d) losartan
He delays group ammonia: 0.58mg/ (kg.d) Levamlodipine+17.5mg/ (kg.d) Tasosartan
3. detection index
3.1 the hypertension compound recipe is to the influence of SHRsp rat blood pressure
The 1st weekend, 5 weekends, 12 weekends were carried out 24 hours monitoring of blood pressure respectively after administration began, and promptly 2h, 5h, 10h, 22h carry out arteria caudalis systolic pressure mensuration one time after that morning 9:00 administration.Experimental data is carried out statistical analysis with the Excel system.
After table 1 administration the 1st weekend compound recipe to the influence (mmHg) of SHRsp rat blood pressure 24h
Compare with model group,
#P＜0.05,
##P＜0.01
Compare with the ordinary preparation group,
*P＜0.05
In addition, after we also replace with irbesartan, Olmesartan, valsartan respectively with above-mentioned losartan, Candesartan, Tasosartan, compare with the ordinary preparation of drug combination, slow releasing preparation has been obtained better the steadily effect of blood pressure lowering equally to Hypertensive Rats.
After table 2 administration the 5th weekend compound recipe to the influence (mmHg) of SHRsp rat blood pressure 24h
Compare ##p＜0.01 with model group
Compare * p＜0.05 with the ordinary preparation group
In addition, we also replace with irbesartan, Olmesartan, valsartan respectively with above-mentioned losartan, Candesartan, Tasosartan, compare with the ordinary preparation of drug combination, slow releasing preparation has been obtained better the steadily effect of blood pressure lowering equally to Hypertensive Rats.
After table 3 administration the 12nd weekend compound recipe to the influence (mmHg) of SHRsp rat blood pressure 24h
Compare ##p＜0.01 with model group
Compare * p＜0.05 with the ordinary preparation group
In addition, we also replace with irbesartan, Olmesartan, valsartan respectively with above-mentioned losartan, Candesartan, Tasosartan, compare with the ordinary preparation of drug combination, slow releasing preparation has been obtained better the steadily effect of blood pressure lowering equally to Hypertensive Rats.
3.2 the hypertension compound recipe is to the influence of SHRsp body weight and survival condition
The result shows that SHRsp is along with the outbreak of apoplexy, and during 28 ages in week, dead 8 of model group, compound recipe ordinary preparation group have dead 5-7 only, and the dead 1-2 of compound slow release preparation group only.This has shown that fully the compound slow release preparation group has a very significant reduction effect for the apoplexy mortality rate of SHRsp rat.
Table 4 hypertension compound recipe is to the influence (n=15) of SHRsp survival of rats rate situation
Claims (3)
1. treat hypertensive pharmaceutical composition for one kind, active component is made up of Levamlodipine or its officinal salt and angiotensin-ii receptor blockers, it is characterized in that it is a sustained-release preparation, form by slow controlled release part and common release portion, Levamlodipine or its officinal salt are the active component of slow controlled release part, angiotensin-ii receptor blockers is the active component of common release portion, the weight ratio of Levamlodipine or its officinal salt and angiotensin-ii receptor blockers is 1: 10～1: 120, and angiotensin-ii receptor blockers is a losartan, valsartan, telmisartan, Candesartan, WAY-ANA 756, Eprosartan, irbesartan, Olmesartan or its officinal salt.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the officinal salt of described Levamlodipine is its benzene sulfonate, maleate, tartrate, aspat, hydrochlorate, sulfate, formates, acetate, hydrobromate.
3. pharmaceutical composition as claimed in claim 1 is characterized in that, it is slow releasing tablet, slow releasing capsule or controlled release capsule.
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| CN101780079B (en) * | 2010-03-03 | 2011-10-05 | 施慧达药业集团(吉林)有限公司 | Levamlodipine compound drug composition |
| CN102028670A (en) * | 2010-09-06 | 2011-04-27 | 邓俐丽 | Composite capsule containing telmisartan and calcium ion channel antagonist |
| TW201304775A (en) * | 2010-09-30 | 2013-02-01 | Tsh Biopharm Corp Ltd | Compositions and methods for treating hypertension using eprosartan and amlodipine |
| CN102342937B (en) * | 2011-07-20 | 2013-01-09 | 海南锦瑞制药股份有限公司 | Amlodipine and candesartan pharmaceutical composition and preparation method thereof |
| CN107320462B (en) * | 2016-10-14 | 2018-11-13 | 杨彦玲 | A kind of sustained release preparation and preparation method thereof of levamlodipine or its salt |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1023800C (en) * | 1986-04-04 | 1994-02-16 | 菲泽有限公司 | Improvements in pharmaceutically acceptable salts |
| CN1652777A (en) * | 2002-05-17 | 2005-08-10 | 诺瓦提斯公司 | Combination of organic compounds |
| CN1765362A (en) * | 2004-09-30 | 2006-05-03 | 江苏恒瑞医药股份有限公司 | Composition containing amlodipine and angiotensin II receptor inhibitor |
| WO2007001066A1 (en) * | 2005-06-27 | 2007-01-04 | Daiichi Sankyo Company, Limited | Pharmaceutical preparation containing an angiotensin ii receptor antagonist and a calcium channel blocker |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1023800C (en) * | 1986-04-04 | 1994-02-16 | 菲泽有限公司 | Improvements in pharmaceutically acceptable salts |
| CN1652777A (en) * | 2002-05-17 | 2005-08-10 | 诺瓦提斯公司 | Combination of organic compounds |
| CN1765362A (en) * | 2004-09-30 | 2006-05-03 | 江苏恒瑞医药股份有限公司 | Composition containing amlodipine and angiotensin II receptor inhibitor |
| WO2007001066A1 (en) * | 2005-06-27 | 2007-01-04 | Daiichi Sankyo Company, Limited | Pharmaceutical preparation containing an angiotensin ii receptor antagonist and a calcium channel blocker |
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