CN101711762A - Medicine composition for treating hypertension - Google Patents
Medicine composition for treating hypertension Download PDFInfo
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- CN101711762A CN101711762A CN200910127578A CN200910127578A CN101711762A CN 101711762 A CN101711762 A CN 101711762A CN 200910127578 A CN200910127578 A CN 200910127578A CN 200910127578 A CN200910127578 A CN 200910127578A CN 101711762 A CN101711762 A CN 101711762A
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Abstract
The invention belongs to the field of medicine preparations, which relates to a medicine composition containing the active components of levorotatory amlodipine/amlodipine and losartan. Concretely, the medicine composition is an osmotic pump preparation. The osmotic pump preparation contains main medicines, high molecular substances, a surfactant, an osmotic pressure promoter, an osmosis promotion polymer and auxiliary materials of other conventional preparation tablets and a coating. The medicine composition represents an obvious advantage in the indexes of the pressure relief, the sugar tolerance, the urine content of urine trace albumin, blood leucocyte after stress and the like.
Description
Technical field
The invention belongs to field of medicine preparations, relate to the hypertensive pharmaceutical composition of the treatment that contains two kinds of active constituents of medicine, particularly a kind ofly contain the pharmaceutical composition that active component is Levamlodipine/amlodipine and losartan.
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." the Chinese hypertension prevention and control guide (originally practical) in 2004 " of China's revision in 2004 thinks that adopt the fixed mixing ratio compound recipe, 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 the preparation of slow releasing agent does not provide concrete technical scheme.
Summary of the invention
Angiotensin receptor antagonist pressure reduction effects such as losartan are slow, the length of holding time, and the half-life of amlodipine and Levamlodipine is very long, all is administration once a day now.However, the inventor still looks for another way, and has carried out following investigative test: with losartan property and divide every day three times (the slow controlled releases of simulation) to give SHR rat once a day, antihypertensive effect strengthens after the administration of losartan gradation as a result; And Levamlodipine divides three fluctuations of blood pressure after the administration to reduce significantly, and the steady antihypertensive effect of this significance is that the inventor is beyond thought.In addition; finding through after the long term administration; divide three better whiles of administration antihypertensive effect; at carbohydrate tolerance, microdose urine protein urine content, stress the back blood leucocyte etc. show clear superiority aspect the index; this just points out the inventor that losartan, Levamlodipine are prepared into controlled release preparation; especially adopt advanced osmotic pump controlled-releasing technology to be prepared into controlled release preparation; must hyperpietic's heart and kidney protection more be had superiority, more have superiority reducing concurrent diabetes of hyperpietic and risk of cardiovascular diseases.Therefore, the objective of the invention is to prescription design, a kind of osmotic pump preparation for the treatment of hypertensive pharmaceutical composition is provided, thereby reaches antihypertensive effect more stably by a series of science.
This osmotic pump preparation composition contains Levamlodipine/amlodipine and losartan or its officinal salt of special ratios.Levamlodipine comprises its benzene sulfonate, maleate, tartrate, aspat, hydrochlorate, sulfate, formates, acetate, hydrobromate.The weight ratio of Levamlodipine/amlodipine and losartan is 1: 0.5～600.
Described osmotic pump tablet preparation is to contain the preparation that following weight proportion raw material and adjuvant are prepared from:
Raw material and ratio of adjuvant are divided into label and coating solution prescription two parts, wherein:
The label prescription
Levamlodipine/amlodipine 0.1～10%
Losartan 5～60%
Polymer substance 0～20%
Surfactant 0～10%
Osmotic pressure promoter 10～60%
Short osmopolymer 0～40%
The adjuvant 10～80% of other conventional preparation tablets
Coating fluid prescription
Macromolecule filming material 10～50g
Plasticizer 1～25g
Porogen 0.1～25g
Coating solvent 1000ml
Coating weightening finish 2～15%
Wherein polymer substance is one or more in polyoxyethylene (PEO), hydroxypropyl methylcellulose (K4M, K15M, K100M), carbomer (934P, 947P), microcrystalline Cellulose and the sodium alginate; Surfactant is sodium lauryl sulphate, in dodecylbenzene sodium sulfonate, octyl sodium sulfonate, octyl sodium sulfate, poloxamer, Tween 80, Myrj 45 and the polyoxyethylene hydrogenated Oleum Ricini one or more; Penetration enhancer is wherein one or more of sodium chloride, potassium chloride, lactose, mannitol, PEG4000, PEG6000, glucose, sucrose; Described short osmopolymer is one or more in polyoxyethylene, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer, cross-linking sodium carboxymethyl cellulose and the polyvinylpyrrolidone.
Macromolecule filming material is one or more in ethyl cellulose (EC), cellulose acetate (CA), crylic acid resin, cellulose acetate acetate, hydroxypropyl methylcellulose acetate, the polyvinyl alcohol, preferred EC or CA.
The selection of plasticizer is because during low temperature, the easy embrittlement of coating membrane is so need adding; Porogen is used to control the hydration rate of drug release rate or control adjuvant; Wherein plasticizer is a PEG class (1500,4000,6000), one or more in hypromellose class (K4M, K15M, K100M), adjacent benzene two tetracid dibutyl esters (DBP), diethyl phthalate (DEP), triethyl citrate (TEC), glycerol, the propylene glycol; Porogen is a class or the multiclass in PEG class, PVP, the sucrose; The coating solvent is one or more in acetone, isopropyl alcohol, ethanol, chloroform methyl acetate, the water.In addition, the weight ratio of macromolecule filming material and plasticizer is 1: 0.1～0.5, and the weight ratio of described macromolecule filming material and porogen is 1: 0.01～0.5.
The adjuvant of other conventional preparation tablets comprises that filler is one or more in lactose, microcrystalline cellulose, calcium hydrogen phosphate, the Powderd cellulose; The stick agent is one or more water and/or the alcoholic solution in 30 POVIDONE K 30 BP/USP 30, HPMC, starch, sodium carboxymethyl cellulose, methylcellulose, the ethyl cellulose.Lubricant is one or more in magnesium stearate, Pulvis Talci, stearic acid, Polyethylene Glycol (6000), sodium lauryl sulphate, the stearic acid fumaric acid, and coloring agent is a kind of in iron oxide red, the iron oxide yellow.
Osmotic pump preparation wherein of the present invention is: micro-porous osmotic pump tablet, single chamber mono-layer osmotic pump sheet and single chamber double-layer osmotic pump tablet.
Wherein the thickness of the coating membrane of controlled release preparation of the present invention is 2～15%, and wherein coating membrane thickness is represented with the coating membrane rate of body weight gain, and the thickness of coating membrane is preferred 4～10%, most preferably 6～8%.
Particularly, micro-porous osmotic pump tablet of the present invention is to be prepared from by following weight proportion raw material and adjuvant:
The label prescription
Levamlodipine/amlodipine 0.1～10%
Losartan 5～60%
Polymer substance 1～10%
Surfactant 0～10%
Osmotic pressure promoter 10～50%
Short osmopolymer 1～20%
The adjuvant 10～80% of other conventional preparation tablets
Coating solution prescription
Macromolecule filming material 10～40g
Plasticizer 1～20g
Porogen 0.1～20g
Coating solvent 1000ml
Coating weightening finish 2～15%
Particularly, single chamber mono-layer osmotic pump sheet of the present invention is to be prepared from by following weight proportion raw material and adjuvant:
The label prescription
Levamlodipine/amlodipine 0.1～10%
Losartan 5～60%
Polymer substance 0～10%
Surfactant 0～10%
Osmotic pressure promoter 10～50%
Short osmopolymer 5～20%
The adjuvant 10～80% of other conventional preparation tablets
Coating fluid prescription
Macromolecule filming material 10～40g
Plasticizer 1～20g
Porogen 0.1～20g
Coating solvent 1000ml
Coating weightening finish 2～15%
Particularly, single chamber double-layer osmotic pump tablet of the present invention is to be prepared from by following weight proportion raw material and adjuvant:
The label prescription
Medicated layer
Levamlodipine/amlodipine 0.1～10%
Losartan 5～60%
Polymer substance 0～20%
Surfactant 0～10%
The boosting layer
Osmotic pressure promoter 10～50%
Short osmopolymer 5～20%
The adjuvant 10～80% of other conventional preparation tablets
Coating fluid prescription
Macromolecule filming material 10～40g
Plasticizer 1～20g
Porogen 0.1～20g
Coating solvent 1000ml
Coating weightening finish 2～15%
Experiment according to us is found, use general osmotic pumps prescription to be difficult to reach the controlled release purpose of principal agent, the principal agent losartan is soluble in water in the osmotic pump tablet of the present invention, adopts common single chamber mono-layer osmotic pump sheet or micro-porous osmotic pump tablet, and " prominent releasing " phenomenon takes place losartan easily; Levamlodipine/amlodipine is according to salifiable kind difference, dissolubility in water has bigger difference, when Levamlodipine/when the amlodipine pharmaceutical salts is slightly soluble in water, its can be after the label aquation crystallize precipitation and cause discharging not exclusively or discharge inhomogeneous.Add suitable macromolecular material in the osmotic pump tablet in the present invention as carrier, promptly reached the dispersibility that the release that slows down losartan has improved Levamlodipine/amlodipine again.The present invention also by adding the apparent solubility of the little Levamlodipine/amlodipine pharmaceutical salts of surfactant raising dissolubility, adds short osmopolymer, improves the release completeness of Levamlodipine/amlodipine by the expansion of polymer.
Other factor complexity that influence osmotic pump preparation rate of releasing drug and time are various, and cross action is arranged, and can not know by inference by general theoretical logic research.And the consumption of raw material of the present invention, adjuvant is selected and the report of the selection of preparation technology parameter by existing controlled release preparation can't come in direct derivation, and being needs through a large amount of experiment sieving combining with theoretical analysis and next.
The factor that influences the osmotic pump tablet coating is more, mainly contain roundness of the kind of rotating speed, coating material of coating pan and concentration and consumption, coating temperature, plain sheet etc., therefore the uniformity of coating membrane is difficult to control, the present invention is by the selection of the prescription of coating solution, and to the screening of coating preparation technology parameter, well solved the uppity defective of osmotic pumps technology controlled release coat film uniformity, The selection result is as follows: the coating kettle temperature is that 30～45 ℃, coating solution concentration 1～7%, coating solution flow velocity 2～4ml/min, atomizing pressure are 0.4～0.8kg/cm
2, coating pan rotating speed 10～30r/min, coating pan inclination angle 45 degree.
The advantage of the present composition is embodied in following several aspect:
(1) 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) 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) 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 the comparison poised state.For the patient, solved traditional every day of 3 times the defective of taking medicine, made things convenient for patient's use.
(4) 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/amlodipine.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) because sustained-release preparation provided by the invention can guarantee that the patient has a stable blood concentration, thereby the blood pressure that guarantees the patient keeps more steady in 24h, reduce the mortality rate that apoplexy causes, and sees embodiment 13 for details.
The resisting hypertension compound controlled release preparation and the existing antihypertensive drugs of the present invention's research and development compare, and blood pressure lowering more stably can better improve patient's insulin resistant, to realize better organ protection.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
In following each embodiment, Levamlodipine is in free alkali, and losartan is in free acid.
The preparation of embodiment 1 compound microporous osmotic pump tablet
1, label prescription:
Levamlodipine 5g
Losartan 2.5g
Sodium alginate 15g
Poloxamer 10g
Sodium chloride 30g
HPMC 10g
Lactose 160g
Stearic acid 2g
3% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of
Be prepared into 1000
2, coating solution prescription:
Cellulose acetate 25g
Macrogol 4000 15g
Diethyl phthalate 12ml
97% aqueous acetone solution 1000ml
Coating weightening finish 7%
3, preparation technology:
The raw material and the adjuvant of recipe quantity in the label are crossed 100 mesh sieves respectively, and mix homogeneously adds 3% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution and makes soft material in right amount, crosses 20 mesh sieves and granulates, 40 ℃ of dryings 8～12 hours are crossed 20 mesh sieve granulate, add the lubricant mixing, tabletting makes label, and hardness is 4～6kg/mm
2
Label is placed in the coating pan, kettle temperature is set: 40～45 ℃, atomizing pressure is 0.8kg/cm
2, coating pan rotating speed 20r/min, coating pan inclination angle 45 degree, be that 2～4ml/min sprays into coating solution with flow velocity, make label weightening finish 7%; Place 40～50 ℃ of baking ovens to solidify 8～16 hours promptly.
The preparation of embodiment 2 compound microporous osmotic pump tablets
1, label prescription:
Levamlodipine 0.5g
Losartan 300g
Sodium alginate 15g
Poloxamer 5g
Polyoxyethylene 10g
Lactose 75g
Stearic acid 3g
3% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution are an amount of
Be prepared into 1000
2, coating solution prescription:
Ethyl cellulose 30g
Macrogol 4000 20g
Hypromellose K4M 10g
Acetone/water (14/5/1) 1000ml
Coating weightening finish 7%
3, preparation technology is with embodiment 1
The preparation of embodiment 3 compound recipe single chamber mono-layer osmotic pump sheets
1, label prescription:
Levamlodipine 5g
Losartan 10g
Carbomer 934 P 30g
Sodium lauryl sulphate 10g
Potassium chloride 20g
Sucrose 150g
Magnesium stearate 3g
5% hydroxypropyl methylcellulose aqueous solution is an amount of
Be prepared into 1000
2, coating solution prescription:
Ethyl cellulose 30g
PEG?4000 5g
Glycerol 10ml
97% aqueous acetone solution 1000ml
Coating weightening finish 8%
3, preparation technology:
The raw material and the adjuvant of recipe quantity in the label are crossed 100 mesh sieves respectively, and mix homogeneously adds 5% hydroxypropyl methylcellulose aqueous solution and makes soft material in right amount, crosses 20 mesh sieves and granulates, 40 ℃ of dryings 8～12 hours are crossed 20 mesh sieve granulate, add the lubricant mixing, tabletting makes label, and hardness is 4～6kg/mm
2
Label is placed in the coating pan, kettle temperature is set: 40～45 ℃, atomizing pressure is 0.8kg/cm
2, coating pan rotating speed 20r/min, coating pan inclination angle 45 degree, be that 2～4ml/min sprays into coating solution with flow velocity, make label weightening finish 8%; Place 40～50 ℃ of baking ovens to make coating membrane solidify 8～16 hours promptly.
Prepare the small delivery aperture of a 0.5mm in coated tablet one side with laser or Mechanical Method then, promptly get single chamber mono-layer osmotic pump sheet.
The preparation of embodiment 4 compound recipe single chamber mono-layer osmotic pump sheets
1, label prescription:
Levamlodipine 5g
Losartan 50g
Hydroxypropyl methylcellulose K15M 20g
Poloxamer 10g
Sodium chloride 20g
Lactose 120g
Magnesium stearate 3g
5% hydroxypropyl methylcellulose aqueous solution is an amount of
Be prepared into 1000
2, coating solution prescription:
Cellulose acetate 32g
PEG6000 8g
Triethyl citrate 10ml
Acetone 800ml
Isopropyl alcohol 200ml
Coating weightening finish 7%
3, preparation technology: with embodiment 3
The preparation of embodiment 5 compound recipe single chamber mono-layer osmotic pump sheets
1, label prescription:
Amlodipine 10g
Losartan 10g
Polyoxyethylene 30g
Tween 15g
Lactose 170g
Sodium lauryl sulphate 5g
10% polyvinylpyrrolidone aqueous solution is an amount of
Be prepared into 1000
2, coating solution prescription:
Cellulose acetate 30g
PEG6000 5g
Triethyl citrate 10ml
Ethanol 1000ml
Coating weightening finish 7%
3, preparation technology: with embodiment 3
The preparation of embodiment 6 compound recipe single chamber double-layer osmotic pump tablets
1, label prescription:
The medicated layer prescription:
Levamlodipine 0.5g
Losartan 100g
Carbomer 934 P 50g
Poloxamer 10g
Magnesium stearate 3g
10% hydroxypropyl methylcellulose aqueous solution is an amount of
Boosting layer prescription:
Polyoxyethylene 50g
Sodium chloride 20g
Magnesium stearate 3g
Iron oxide red 3g
10% hydroxypropyl methylcellulose aqueous solution is an amount of
Be prepared into 1000
2, coating solution prescription:
Cellulose acetate 25g
PEG6000 8g
Triethyl citrate 10ml
Acetone 800ml
Isopropyl alcohol 200ml
Coating weightening finish 7%
3, preparation technology:
The raw material and the adjuvant of recipe quantity in the label are crossed 100 mesh sieves respectively, and mix homogeneously adds 5% hydroxypropyl methylcellulose aqueous solution and makes soft material in right amount, crosses 20 mesh sieves and granulates, 40 ℃ of dryings 8～12 hours are crossed 20 sieve granulate, add the lubricant mixing, tabletting makes label, and hardness is 4～6kg/mm
2
Label is placed in the coating pan, kettle temperature is set: 40～45 ℃, atomizing pressure is 0.8kg/cm
2, coating pan rotating speed 20r/min, coating pan inclination angle 45 degree, be that 2～4ml/min sprays into coating solution with flow velocity, make label weightening finish 8%; Place 40～50 ℃ of baking ovens that coating membrane was solidified 8～16 hours.
Prepare the small delivery aperture of a 0.6mm in coated tablet medicated layer one side with laser or Mechanical Method then, promptly get the single chamber double-layer osmotic pump tablet.
The preparation of embodiment 7 compound recipe single chamber double-layer osmotic pump tablets
1, label prescription:
The medicated layer prescription:
Levamlodipine 10g
Losartan 5g
Carbomer 934 P 50g
Poloxamer 10g
Lactose 70
Sodium lauryl sulphate 3g
10% starch slurry is an amount of
Boosting layer prescription:
Carboxymethyl starch sodium 70g
Sodium chloride 20g
Sodium lauryl sulphate 3g
Iron oxide yellow 3g
10% starch slurry is an amount of
Be prepared into 1000
2, coating solution prescription:
Ethyl cellulose 35g
Macrogol 4000 10g
Hypromellose K4M 8g
Acetone/water (14/5/1) 1000ml
Coating weightening finish 8%
3, preparation technology is with embodiment 6
The preparation of embodiment 8 compound recipe single chamber double-layer osmotic pump tablets
1, label prescription:
The medicated layer prescription:
Levamlodipine 5g
Losartan 25g
Carbomer 934 P 50g
Mannitol 60g
Sodium lauryl sulphate 10g
5% polyvidone aqueous solution is an amount of
Boosting layer prescription:
Carbomer 947P 60
Sodium chloride 20g
Sodium lauryl sulphate 3g
Iron oxide red 3g
5% polyvidone aqueous solution is an amount of
Be prepared into 1000
2, coating solution prescription:
Cellulose acetate 30g
Macrogol 4000 10g
Glycerol 10ml
Chloroform methyl acetate 1000ml
Coating weightening finish 7%
3, preparation technology is with embodiment 6
Embodiment 9 Levamlodipine losartan compound recipes are to the influence of SHR rat
1. grouping
10 all essential hypertension rats in age (SHR) are divided into model group, Levamlodipine losartan common group of (general group of ammonia chlorine), Levamlodipine losartan slow release group (the slow group of ammonia chlorine) at random.
2 medications
Levamlodipine, losartan are distinguished wiring solution-forming with an amount of purified water, and each organizes the equal gastric infusion of rat (pressing the 5ml/kg gastric infusion), continues for 6 weeks, and dosage is as follows respectively:
Model group: with the volume purified water; 3 times/day;
The dosage of losartan slow release group: 5mg/ (kg.d) losartan divides three administrations, is used for simulating sustained-release administration;
General group of ammonia chlorine: 0.25mg/ (kg.d) Levamlodipine+5mg/ (kg.d) losartan, disposable administration in afternoon is given sooner or later with the volume purified water;
The slow group of ammonia chlorine: press the dosage of 0.25mg/ (kg.d) Levamlodipine+5mg/ (kg.d) losartan, divide three administrations, be used for simulating sustained-release administration;
Irritate stomach every day 3 times, the morning 6:00, afternoon 14:00,22:00 administration in evening, irritate the weight of stomach medicine and calculate as follows: Levamlodipine is in free alkali, and losartan is in free acid.
3 detect index
3.1 the hypertension compound recipe is to the influence of SHR rat blood pressure
The 1st weekend, 3 weekends, 6 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.
The result shows, by the 1st weekend after the administration, the 3rd weekend, the 6th weekend the 24h monitoring of blood pressure, the slow group of ammonia chlorine relatively has significantly or utmost point significant difference with model group, the compound sustained-released administering mode of this explanation losartan Levamlodipine has very strong antihypertensive effect.Compare for general group with ammonia chlorine, the antihypertensive effect of the slow group of ammonia chlorine strengthens, and the 24h fluctuation of blood pressure reduces significantly after the administration.
After table 1 administration the 1st weekend compound recipe to the influence (mmHg) of SHR rat blood pressure 24h
Compare with model group,
#P＜0.05,
##P＜0.01
Compare for general group with ammonia chlorine,
*P＜0.05
Compare with losartan slow release group,
﹠amp;P＜0.05
After table 2 administration the 3rd weekend compound recipe to the influence (mmHg) of SHR rat blood pressure 24h
Compare with model group,
#P＜0.05;
##P＜0.01
Compare for general group with ammonia chlorine,
*P＜0.05;
*P＜0.01
Compare with losartan slow release group,
﹠amp;P＜0.05;
﹠amp; ﹠amp;P＜0.01
After table 3 administration the 6th weekend compound recipe to the influence (mmHg) of SHR rat blood pressure 24h
Compare with model group,
#P＜0.05,
##P＜0.01
Compare for general group with ammonia chlorine,
*P＜0.05,
*P＜0.01
Compare with losartan slow release group,
﹠amp;P＜0.05,
﹠amp; ﹠amp;P＜0.01
3.2 the hypertension compound recipe is to the influence of SHR rat microdose urine protein
After 6 weeks of administration, rat is irritated stomach pure water 5ml for every in irritating stomach after one hour, connect urine after, after 2500rpm is centrifugal, gets 2ml and add the 1mlBPB developer, survey absorbance in 600nm place, the content of microalbumin in the mensuration urine.
As can be seen from Table 4, after 6 weeks of administration, the slow group of ammonia chlorine is compared for general group with model group, ammonia chlorine, has utmost point significant difference, this explanation, and the sustained-release administration of losartan Levamlodipine can reduce microdose urine protein, strengthens renal function.
Table 4 Levamlodipine losartan sustained-release administration is to the influence of SHR rat microdose urine protein
Compare with model group,
#P＜0.05,
##P＜0.01
Compare for general group with ammonia chlorine,
*P＜0.05,
*P＜0.01
3.3 the hypertension compound recipe is to the influence of SHR rat carbohydrate tolerance
After 6 weeks of administration, rat is irritated stomach after 1 hour the morning, irritates stomach by 10g/kg and gives glucose, and respectively at 1 hour, 1.5 hours, eye socket was got blood in 2 hours, used determination of glucose oxidase blood glucose.
As can be seen from Table 5, when 1h, the 1.5h after irritating the stomach glucose, 2h, model group shows as blood glucose and reduces very slow, ammonia chlorine shows as blood glucose for general group and reduces very fast, the slow group of ammonia chlorine shows as blood glucose and descends rapidly, and the rat of the compound sustained-released administration of this explanation losartan Levamlodipine is relatively more responsive to blood glucose.
Table 5 Levamlodipine losartan sustained-release administration is to the influence (absorbance, A value) of SHR rat blood sugar
Compare with model group,
#P＜0.05,
##P＜0.01
Compare for general group with ammonia chlorine,
*P＜0.05
Compare with losartan slow release group,
﹠amp;P＜0.05
Discussion of results: insulin resistant is one of important pathogeny of hypertension, and it is the main pathogenic factor of type ii diabetes that insulin resistant causes carbohydrate tolerance to reduce, and participates in hypertensive morbidity simultaneously; The concurrent hypertension of patient's (prediabetes) that carbohydrate tolerance reduces makes the probability that coronary heart disease and apoplexy take place increase greatly.The slow group of compound recipe ammonia chlorine can make blood glucose comparatively fast descend, and improves patient's carbohydrate tolerance greatly, is indicating that the sustained-release preparation of Levamlodipine losartan compound recipe uses the generation probability that can reduce cardiovascular and cerebrovascular disease significantly clinically.
3.4 the hypertension compound recipe is to the influence of SHR rat leukocyte quantity
After 6 weeks of administration, rat is in irritating stomach after one hour, 5～8 ℃ of cold water swimming 5min, the eye socket vein is got blood, measures routine blood test, quantity of leucocyte.
As can be seen from Table 6, after 6 weeks of administration, the slow group of ammonia chlorine is compared with model group has utmost point significant difference, the husky level quantity of leucocyte that can significantly reduce in the blood of releasing of this explanation compound recipe Levamlodipine, suppressed leukocytic mobilization afterwards, this can better improve hypertension complication after indicating compound sustained-released administration, effectively collaborative blood pressure lowering.
The compound sustained-released administration of table 6 losartan Levamlodipine is to SHR rat leukocyte (10
9Individual/L) influence
Compare with model group,
#P＜0.05,
##P＜0.01
Compare for general group with ammonia chlorine,
*P＜0.05
Compare with losartan slow release group,
﹠amp;P＜0.05
Discussion of results: clinical research confirmation has been arranged, and the hyperpietic is through exercise stress, and after leukocyte was mobilized in the body, leucocyte level rose highly more, and the danger that various cardiovascular and cerebrovascular diseases take place the patient in the future is also just high more.We find through the experiment of SHR rat, after extraneous cold water motion stimulates, Hypertensive Rats leukocyte number are increased, so simulated the leukocyte mobilization in hypertensive rat model rapidly.
The intravital leukocyte of machine is not the effect that only has the external infection of opposing, under the situation that body does not infect, leukocytic mobilization can cause the inflammatory damage of body on the contrary, the regular inflammatory damage of hyperpietic is the pathologic basis of hypertension and various cardiovascular and cerebrovascular diseases, and secular chronic inflammatory disease can be brought out various cardiovascular and cerebrovascular diseases.The present invention confirms by zoopery, the slow group of compound sustained-released administration group, especially ammonia chlorine can suppress and stress mobilize rising by the back leukocyte, leukocyte count is fallen now, and this is indicating that Levamlodipine losartan compound slow release preparation can reduce the generation probability of cardiovascular and cerebrovascular disease significantly.
Claims (19)
1. the hypertensive pharmaceutical composition of treatment is characterized in that it is an osmotic pump preparation, and wherein the contained drug active component is made up of Levamlodipine/amlodipine and losartan.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the weight ratio of Levamlodipine/amlodipine and losartan is 1: 0.5～600.
3. pharmaceutical composition as claimed in claim 2 is characterized in that Levamlodipine/amlodipine comprises its benzene sulfonate, maleate, tartrate, aspat, hydrochlorate, sulfate, formates, acetate, hydrobromate.
4. as the arbitrary described pharmaceutical composition of claim 1-3, it is characterized in that it contains following component:
Levamlodipine 0.1～10%;
Losartan 5～60%;
Polymer substance 0～20%;
Surfactant 0～10%;
Osmotic pressure promoter 10～60%;
Short osmopolymer 0～40%;
The adjuvant 10～80% of other conventional preparation tablets;
Coating 2～15%.
5. pharmaceutical composition as claimed in claim 4 is characterized in that, described polymer substance is one or more in polyoxyethylene, hydroxypropyl methylcellulose, carbomer, microcrystalline Cellulose and the sodium alginate.
6. pharmaceutical composition as claimed in claim 4, it is characterized in that described surfactant is sodium lauryl sulphate, in dodecylbenzene sodium sulfonate, octyl sodium sulfonate, octyl sodium sulfate, poloxamer, Tween 80, Myrj 45 and the polyoxyethylene hydrogenated Oleum Ricini one or more.
7. pharmaceutical composition as claimed in claim 4 is characterized in that, described penetration enhancer is one or more of sodium chloride, potassium chloride, lactose, mannitol, Macrogol 4000, polyethylene glycol 6000, glucose, sucrose.
8. pharmaceutical composition as claimed in claim 4, it is characterized in that described short osmopolymer is one or more in polyoxyethylene, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl emthylcellulose, carbomer, cross-linking sodium carboxymethyl cellulose and the polyvinylpyrrolidone.
9. pharmaceutical composition as claimed in claim 4 is characterized in that, described coating is prepared from by following coating fluid prescription: macromolecule filming material, plasticizer, porogen and coating solvent.
10. pharmaceutical composition as claimed in claim 9, it is characterized in that described macromolecule filming material is one or more in ethyl cellulose, cellulose acetate, crylic acid resin, cellulose acetate acetate, hydroxypropyl methylcellulose acetate, the polyvinyl alcohol.
11. pharmaceutical composition as claimed in claim 10 is characterized in that, described macromolecule filming material is that ethyl cellulose is or/and cellulose acetate.
12. pharmaceutical composition as claimed in claim 9, it is characterized in that described plasticizer is one or more in polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, hypromellose, adjacent benzene two tetracid dibutyl esters, O-phthalic diethylester, triethyl citrate, glycerol, the propylene glycol.
13. pharmaceutical composition as claimed in claim 9 is characterized in that, described porogen is one or more in polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, PVP, the sucrose.
14. pharmaceutical composition as claimed in claim 9 is characterized in that, described coating solvent is one or more of acetone, isopropyl alcohol, ethanol, chloroform methyl acetate, water.
15., it is characterized in that the weight ratio of described macromolecule filming material and plasticizer is 1: 0.1～0.5 as the arbitrary described pharmaceutical composition of claim 9-14, the weight ratio of described macromolecule filming material and porogen is 1: 0.01～0.5.
16. pharmaceutical composition as claimed in claim 4 is characterized in that, it is micro-porous osmotic pump tablet, single chamber mono-layer osmotic pump sheet or single chamber double-layer osmotic pump tablet.
17. pharmaceutical composition as claimed in claim 16 is characterized in that, described micro-porous osmotic pump tablet is to be prepared from by following weight proportion raw material and adjuvant:
Levamlodipine 0.1～10%;
Losartan 5～60%;
Polymer substance 1～10%;
Surfactant 0～10%;
Osmotic pressure promoter 10～50%;
Short osmopolymer 1～20%;
The adjuvant 10～80% of other conventional preparation tablets;
Coating 2～15%.
18. pharmaceutical composition as claimed in claim 16 is characterized in that, described single chamber mono-layer osmotic pump sheet is to be prepared from by following weight proportion raw material and adjuvant:
Levamlodipine 0.1～10%;
Losartan 5～60%;
Polymer substance 0～10%;
Surfactant 0～10%;
Osmotic pressure promoter 10～50%;
Short osmopolymer 5～20%;
The adjuvant 10～80% of other conventional preparation tablets;
Coating 2～15%.
19. pharmaceutical composition as claimed in claim 16 is characterized in that, described single chamber double-layer osmotic pump tablet is to be prepared from by following weight proportion raw material and adjuvant:
Medicated layer:
Levamlodipine 0.1～10%;
Losartan 5～60%;
Polymer substance 0～20%;
Surfactant 0～10%;
The boosting layer:
Osmotic pressure promoter 10～50%;
Short osmopolymer 5～20%;
The adjuvant 10～80% of other conventional preparation tablets;
Coating 2～15%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910127578A CN101711762A (en) | 2008-10-08 | 2009-03-16 | Medicine composition for treating hypertension |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810167180.7 | 2008-10-08 | ||
| CN200910127578A CN101711762A (en) | 2008-10-08 | 2009-03-16 | Medicine composition for treating hypertension |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101711762A true CN101711762A (en) | 2010-05-26 |
Family
ID=42416011
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910127578A Pending CN101711762A (en) | 2008-10-08 | 2009-03-16 | Medicine composition for treating hypertension |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101711762A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012006965A1 (en) * | 2010-07-16 | 2012-01-19 | Zhong Shuguang | Tablet with improved comprehensive performance and preparation method therefor |
| CN112516097A (en) * | 2020-12-22 | 2021-03-19 | 迪沙药业集团有限公司 | Levamlodipine besylate composition |
-
2009
- 2009-03-16 CN CN200910127578A patent/CN101711762A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012006965A1 (en) * | 2010-07-16 | 2012-01-19 | Zhong Shuguang | Tablet with improved comprehensive performance and preparation method therefor |
| CN112516097A (en) * | 2020-12-22 | 2021-03-19 | 迪沙药业集团有限公司 | Levamlodipine besylate composition |
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