CN101862329A - Amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation - Google Patents
Amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation Download PDFInfo
- Publication number
- CN101862329A CN101862329A CN 201010211282 CN201010211282A CN101862329A CN 101862329 A CN101862329 A CN 101862329A CN 201010211282 CN201010211282 CN 201010211282 CN 201010211282 A CN201010211282 A CN 201010211282A CN 101862329 A CN101862329 A CN 101862329A
- Authority
- CN
- China
- Prior art keywords
- atorvastatin calcium
- preparation
- amlodipine besylate
- amlodipine
- atorvastatin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation which is prepared from amlodipine besylate and atorvastatin calcium medicine compound liposome and other solid preparation auxiliary materials; and the amlodipine besylate and atorvastatin calcium medicine compound liposome is prepared from benzene sulfonic acid amlodipine, atorvastatin calcium, soybean phosphatidyl glycerin, kennedy acute-inflammation sodium and cholesterol. Compared with traditional preparation, the preparation greatly improves the stability and the bioavailability, and has the advantages of stable medicine delivery, small side effect and more significant curative effect.
Description
Technical field
The present invention relates to a kind of medical solid preparation, be specifically related to a kind of amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation and method for making thereof, belonged to medical technical field.
Background technology
Development along with society, the people's living standard is more and more higher, the people who suffers from hypertension is then more and more, yet hypertension itself is not fearful, diagnoses and treatment all is easy to, fearful is hypertensive various complication: the hyperpietic causes the whole body arteriolosclerosis because the arterial pressure persistence raises, thereby influences the blood supply of histoorgan, cause various serious consequences, become the complication of hypertension.
Antihypertensive drugs in the market is a lot, but cuts both ways, and mostly is single medicine greatly, can not control the essential hypertension of light moderate fully.The therapeutic alliance of amlodipine and Atorvastatin calcium can solve the problem that present single medicine cann't be solved, and treats light moderate hypertension disease preferably.The amlodipine angiotensin I forms Angiotensin II (AGII) under Angiotensin-Converting (ACE) effect, AGII is the important activity composition of renin angiotensin aldosterone system (RAAS), bring into play physiological action widely with the special receptors bind on each cell membranes in tissue, comprise direct or indirect participation blood pressure regulating.Angiotensin II is a kind of strong vaso-excitor material, can bring into play direct pressor effect, also can promote the heavily absorption of sodium, stimulates the aldosterone secretion.Amlodipine is a kind of orally active specific angiotensin (AT) II receptor antagonist, and it optionally acts on the AT1 receptor subtype, and is strong 20000 times with the affinity of AT2 receptor with the affinity ratio of AT1 receptor.The physiological reaction of AT1 receptor subtype mediation Angiotensin II, AT2 receptor subtype and cardiovascular effect are irrelevant, and amlodipine does not have the activity of partial agonist to the AT1 receptor.Amlodipine does not suppress ACE (having another name called kininase II), and this enzyme makes angiotensin I be converted into Angiotensin II and degraded Kallidin I.Amlodipine does not have inhibitory action to ACE, does not cause the retention of Kallidin I and P material, so be difficult for causing cough.Relatively the clinical trial of amlodipine and ACE inhibitor confirms that the incidence rate (2.6%) of amlodipine group dry cough significantly is lower than ACE inhibitor group (7.9%) (P＜0.05).Find that a clinical trial that the patient who once accepted ACE inhibitor treatment back generation dry cough symptom is carried out amlodipine group, diuretic group, ACEI group have 19.5%, 19.0%, 68.5% patient cough (P＜0.05) to occur respectively.In contrast clinical trial, the incidence rate that the patient who treats with amlodipine and Atorvastatin calcium coughs is 2.9%.Amlodipine does not have influence to other known hormone receptor or ion channels that play an important role in cardiovascular is regulated.Amlodipine does not influence heart rate reducing elevated blood pressure.To Most patients, single agent produces antihypertensive effect in oral 2 hours, reaches the effect peak in 4～6 hours, antihypertensive effect be maintained until take medicine back more than 24 hours.In long-term treatment, reach the maximum reducing curative effect after 2～4 weeks of treatment, and be maintained.Strengthen the hypotensive effect of amlodipine significantly with the Atorvastatin calcium use in conjunction.Stop the amlodipine treatment, do not cause hypertension " knock-on " or other side effect suddenly.Amlodipine does not influence hyperpietic's empty stomach T-CHOL, triglyceride, blood glucose or uric acid level.The main site of action of Atorvastatin calcium thiazide diuretic is the Distal convoluted tubule near-end.Studies show that exist the receptor of high-affinity at renal cortex, it is the main binding site and the site of action of thiazide diuretic, suppress the sodium chloride transhipment of Distal convoluted tubule near-end.The thiazide model of action is for suppressing cotransporting of sodium and chloride ion, and competition chloride ion service portion potential energy influences electrolytical heavy absorption, and this will directly increase the drainage of sodium and chlorine, and reduce the blood plasma volume indirectly, then increase plasma renin activity, aldosterone secretion and potassium are drained, and serum potassium is reduced.Because it is dependent that feritin-aldosterone system is an Angiotensin II, unite and use angiotensin ii receptor antagonist can reduce the potassium loss relevant with thiazide diuretic.
Liposome (Liposome) is a kind of novel targeting microgranule drug administration carrier; the main mechanism of action is drug microparticles or solution are wrapped in interior aqueous phase that the liposome bilayer lipid membrane sealed or embed in the liposome phospholipid bilayer film with certain proportion, and this microgranule has the class cellularity.Conventional liposome enters the autoimmune function that is mainly activated body in the human body by reticuloendothelial system phagocytic, and the interior distribution of the body that changes encapsulated medicine, drug main will be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of the therapeutic dose and the reduction medicine of medicine.In recent years, continuous progress along with biotechnology, liposome preparation technology is progressively perfect, the liposome mechanism of action is further illustrated, liposome is fit to vivo degradation, avirulence and non-immunogenicity in addition, particularly great number tested data proof liposome can improve the Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces advantage such as drug dose.
Summary of the invention
The object of the present invention is to provide a kind of amlodipine besylate and atorvastatin calcium medicine compound solid preparation, earlier make liposome by active component Amlodipine Besylate Tablet, Atorvastatin calcium and specific combination soybean phospholipid acyl glycerol, NaGC, cholesterol, be mixed and made into solid preparation with other pharmaceutic adjuvants again, good stability, drug release rate is steady, the bioavailability height, side effect is little, more remarkable treatment effect.
Technical solution of the present invention is as follows:
A kind of amlodipine besylate and atorvastatin calcium medicine compound liposome is characterized in that it being to be made by Amlodipine Besylate Tablet, Atorvastatin calcium, soybean phospholipid acyl glycerol, NaGC and cholesterol.
Above-mentioned described amlodipine besylate and atorvastatin calcium medicine compound liposome, wherein calculate by weight, 1 part of Amlodipine Besylate Tablet (in amlodipine), 1～16 part of Atorvastatin calcium (in atorvastatin), 3～30 parts of soybean phospholipid acyl glycerol, 0.6～15 part of NaGC, 1.2～12 parts in cholesterol.
A kind of amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation is made up of Amlodipine Besylate Tablet, Atorvastatin calcium, soybean phospholipid acyl glycerol, NaGC, cholesterol and other pharmaceutic adjuvants, and each composition weight umber is:
1 part of Amlodipine Besylate Tablet (in amlodipine)
1～16 part of Atorvastatin calcium (in atorvastatin)
3～30 parts of soybean phospholipid acyl glycerol
0.6～15 part of NaGC
1.2～12 parts in cholesterol
5～80 parts of other pharmaceutic adjuvants.
As the present invention's one preferred embodiment, each composition weight umber of described amlodipine besylate and atorvastatin calcium lipidosome solid preparation is:
1 part of Amlodipine Besylate Tablet (in amlodipine)
1～16 part of Atorvastatin calcium (in atorvastatin)
4～24 parts of soybean phospholipid acyl glycerol
0.8～6 part of NaGC
1.6～8 parts in cholesterol
11～36 parts of other pharmaceutic adjuvants.
Wherein, as preferably, the specification of preparation is that per unit preparation Amlodipine Besylate Tablet/Atorvastatin calcium (respectively in amlodipine and atorvastatin) is respectively 5mg/40mg, perhaps 5mg/20mg, perhaps 5mg/10mg, perhaps 5mg/80mg, perhaps 10mg/10mg, perhaps 10mg/40mg, perhaps 10mg/80mg, preferred specification is 5mg/40mg, perhaps 5mg/20mg, perhaps 5mg/10mg.
In the preferred embodiments of the invention, wherein the Amlodipine Besylate Tablet chemical name is: 3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate, molecular formula: C
20H
25N
2O
5ClC
6H
6O
3S, molecular weight: 567.1, structural formula is:
The consumption of Amlodipine Besylate Tablet is counted 1-30mg with amlodipine, is preferably 5-10mg.
In the preferred embodiments of the invention, wherein the Atorvastatin calcium chemistry is called [R-(R, R)]-and 2-(4-fluorophenyl)-b, d-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(anilino-) carbonyl]-1 hydrogen-pyrroles-1-Calcium salt enanthate trihydrate, molecular formula is (C
33H
34FN
2O
5) 2Ca3H
2O, molecular weight are 1209.42, and structural formula is:
The consumption of Atorvastatin calcium is counted 5-160mg with atorvastatin, is preferably 10-80mg.
In the preferred embodiments of the invention, wherein said solid preparation can be tablet, dispersible tablet and capsule, other pharmaceutic adjuvants are selected from filler, disintegrating agent, binding agent, lubricant, fluidizer and their combination thereof, and its consumption is selected according to the general consumption of each adjuvant in solid preparation.As preferably, above-mentioned described amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation, wherein calculate by weight, described other solid preparation adjuvants are filler 6-27 part, disintegrating agent 1.2-5 part, binding agent 0.5-1.5 part, fluidizer and/or lubricant 0.3-4 part.
In the above-mentioned preferred embodiment of the present invention, further, as preferably, filler can be selected from one or more the combination in starch, mannitol, lactose, xylitol, sorbitol, dextrin, glucose, the sucrose, is preferably starch and lactose.
In the above-mentioned preferred embodiment of the present invention, further, as preferably, disintegrating agent can be selected from one or more the combination in carboxymethylstach sodium, pregelatinized Starch, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, the cross-linking sodium carboxymethyl cellulose, is preferably polyvinylpolypyrrolidone.
In the above-mentioned preferred embodiment of the present invention, further, as preferably, binding agent can be selected from one or more the combination in hypromellose, sodium carboxymethyl cellulose, xanthan gum, 30 POVIDONE K 30 BP/USP 30, arabic gum, methylcellulose, the ethyl cellulose, is preferably 30 POVIDONE K 30 BP/USP 30.
In the above-mentioned preferred embodiment of the present invention, further, as preferably, fluidizer or lubricant can be selected from one or more the combination in Pulvis Talci, micropowder silica gel, zinc stearate, magnesium stearate, the stearic acid, are preferably magnesium stearate.
The present invention also provides a kind of method for preparing the amlodipine besylate and atorvastatin calcium lipidosome solid preparation, comprises preparation liposome and two steps of preparation solid preparation:
(1) preparation liposome: Amlodipine Besylate Tablet, Atorvastatin calcium and soybean phospholipid acyl glycerol, NaGC and cholesterol are mixed and made into lipidosome solid;
(2) preparation solid preparation: lipidosome solid and filler, disintegrating agent, binding agent, lubricant, fluidizer are mixed with the amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation.
As the present invention's one preferred embodiment, the concrete steps of its preparation liposome comprise:
(1) soybean phospholipid acyl glycerol, NaGC and cholesterol are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotation film evaporimeter, makes immobilized artificial membrane;
(2) add buffer salt solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) Amlodipine Besylate Tablet and Atorvastatin calcium is water-soluble, regulate pH value to 7.0～8.0 with the pH regulator agent, filtering with microporous membrane, filtrate adds in the blank liposome suspension, is incubated 55 ℃ and stirs 30-60 minute, and spray drying makes lipidosome solid.
As the present invention's one preferred embodiment, the concrete steps of its preparation solid preparation comprise:
(1) lipidosome solid and filler, the disintegrating agent with Amlodipine Besylate Tablet and Atorvastatin calcium mixes, and the mix homogeneously that sieves adds binder solution and prepares soft material, the granulation of sieving, drying;
(2) dried granule and fluidizer or mix lubricant is even, the granulate that sieves, tabletting or filled capsules make the amlodipine besylate and atorvastatin calcium lipidosome solid preparation.
Further, as preferably, the present invention prepares the method for amlodipine besylate and atorvastatin calcium lipidosome solid preparation, comprises the steps:
(1) soybean phospholipid acyl glycerol, NaGC and cholesterol are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotation film evaporimeter, makes immobilized artificial membrane;
(2) add buffer salt solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) Amlodipine Besylate Tablet and Atorvastatin calcium is water-soluble, regulate pH value to 7.0～8.0 with the pH regulator agent, filtering with microporous membrane, filtrate adds in the blank liposome suspension, is incubated 55 ℃ and stirs 30-60 minute, and spray drying makes lipidosome solid;
(4) lipidosome solid and filler, the disintegrating agent with Amlodipine Besylate Tablet and Atorvastatin calcium mixes, and the mix homogeneously that sieves adds binder solution and prepares soft material, the granulation of sieving, drying;
(5) dried granule and fluidizer or mix lubricant is even, granulate sieves;
(6) tabletting or filled capsules make the amlodipine besylate and atorvastatin calcium lipidosome solid preparation.
The preparation method of above-mentioned described amlodipine besylate and atorvastatin calcium lipidosome solid preparation also can comprise tablet bag film-coat process, and with the plain sheet bag of gained gastric solubleness film-coat, weightening finish 2-4% makes Film coated tablets.Wherein the used gastric solubleness coating materials of gastric solubleness film-coat for example can be reined in easy GAI type coating materials, Ka Lekang Opadry gastric solubleness coating materials etc. for auspicious safe GS-H type coating materials, love.
Further, as preferably, wherein said buffer salt solution is selected from a kind of in phosphate buffer salt, carbonate buffer solution, the citrate buffer, is preferably the phosphoric acid-disodium hydrogen phosphate buffer solution of pH value 6.0;
Further, as preferably, wherein said pH value regulator is selected from a kind of in sodium hydroxide, sodium bicarbonate, sodium citrate, the sodium hydrogen phosphate, is preferably sodium hydrogen phosphate.
Further, as preferably, wherein said organic solvent is selected from one or more in methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, chloroform, dichloromethane, ether, benzyl alcohol, the normal hexane, and being preferably volume ratio is 1: 5 the dichloromethane and the mixed solvent of ether.
Preparation liposome membrane material commonly used is phospholipid and cholesterol, wherein phospholipid can be selected natural phospholipid and synthetic phospholipid for use usually, and described natural phospholipid is one or more in Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine, the soybean phospholipid acyl inositol; Described synthetic phospholipid is one or more in dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, dimyristoyl phosphatidyl choline, two Laurel phosphatidyl cholines, DOPG, distearyl acid phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, the two lauroyl phosphatidyl glycerols.The inventor is through research in earnest for a long time, through a large amount of screening experiment, find to adopt general phospholipid and cholesterol be the liposome of membrane material preparation under 40 ℃ of high temperature, relative humidity 75% ± 5% accelerated test, stability and envelop rate are not good.Inventor's finishing screen is chosen the combination of soybean phospholipid acyl glycerol, NaGC, cholesterol, the stability and the not good technical problem of envelop rate of amlodipine besylate and atorvastatin calcium medicine compound liposome have been solved, obtained beyond thought preparation effect, thereby superior in quality liposome is provided.Though do not want to be bound by theory, effect of the present invention may be soybean phospholipid acyl glycerol, NaGC, cholesterol is common and/or synergistic result.
Product of the present invention is compared with existing listing preparation, thereby active component is protected because Amlodipine Besylate Tablet and Atorvastatin calcium are wrapped in the liposome, improve dissolubility, and fundamentally guaranteed the stability of Amlodipine Besylate Tablet and Atorvastatin calcium; Used soybean phospholipid acyl glycerol, NaGC and cholesterol degradation in vivo, avirulence and non-immunogenicity, and can improve therapeutic index, the reduction drug toxicity of medicine and reduce drug side effect.Product effect of the present invention is steadily lasting, and stability is better, and dissolution and bioavailability are higher.
Description of drawings
Fig. 1: amlodipine release profiles
Curve A is the amlodipine release profiles of prepared sample among the embodiment 1
Curve B is the amlodipine release profiles of prepared sample in the Comparative Examples 1
Curve C is the amlodipine release profiles of prepared sample in the Comparative Examples 2
Curve D is the amlodipine release profiles of prepared sample in the Comparative Examples 3
Curve E is the amlodipine release profiles of prepared sample in the Comparative Examples 4
Fig. 2: atorvastatin release profiles
Curve 1 is the atorvastatin release profiles of prepared sample among the embodiment 1
Curve 3 is the atorvastatin release profiles of prepared sample in the Comparative Examples 2
Curve 5 is the atorvastatin release profiles of prepared sample in the Comparative Examples 4
The specific embodiment
Below will further explain to the present invention by several routine embodiment and Comparative Examples, test example; but not that conduct is to further restriction of the present invention; data that occur during all are enumerated and raw and auxiliary material all are the sub-fractions in the preferred version of the present invention; those skilled in the art all can make change easily and modify, and these are all within protection domain of the present invention.
The preparation prescription (1000) of embodiment 1 amlodipine besylate and atorvastatin calcium liposome sheet:
Amlodipine Besylate Tablet (in amlodipine) 5g
Atorvastatin calcium (in atorvastatin) 10g
Soybean phospholipid acyl glycerol 20g
NaGC 4g
Cholesterol 8g
Starch 38g
Lactose 30g
Polyvinylpolypyrrolidone 6g
30 POVIDONE K 30 BP/USP 30 5g
Magnesium stearate 1.5g
Preparation process:
(1) 20g soybean phospholipid acyl glycerol, 4g NaGC and 8g cholesterol are dissolved in the mixed solvent that the 400ml volume ratio is 1: 5 dichloromethane and ether, mix homogeneously, mixed solvent is removed in decompression on rotation film evaporimeter, makes immobilized artificial membrane;
(2) phosphoric acid-disodium hydrogen phosphate buffer solution of adding pH value 6.0, jolting is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(3) 5g Amlodipine Besylate Tablet and 10g Atorvastatin calcium are dissolved in 300ml water, regulate pH value to 7.0, reuse 0.45 μ m filtering with microporous membrane with 6% sodium hydrogen phosphate, filtrate adds in the blank liposome suspension, be incubated 55 ℃ and stirred 60 minutes, spray drying makes lipidosome solid;
(4) lipidosome solid and 38g starch, 30g lactose, the 6g polyvinylpolypyrrolidone with Amlodipine Besylate Tablet and Atorvastatin calcium mixes, cross 60 mesh sieve mix homogeneously, 60% alcoholic solution that adds 5% 30 POVIDONE K 30 BP/USP 30 prepares soft material, crosses 20 mesh sieves and granulates 60 ℃ of dryings;
(5), cross 20 mesh sieve granulate with dried granule and 1.5g magnesium stearate mix homogeneously;
(6) tabletting makes the amlodipine besylate and atorvastatin calcium liposome tablet.
The preparation prescription (1000) of embodiment 2 amlodipine besylate and atorvastatin calcium liposome sheets:
Amlodipine Besylate Tablet (in amlodipine) 5g
Atorvastatin calcium (in atorvastatin) 80g
Soybean phospholipid acyl glycerol 120g
NaGC 30g
Cholesterol 40g
Microcrystalline Cellulose 55g
Lactose 76g
Low-substituted hydroxypropyl cellulose 25g
Hypromellose 4g
Magnesium stearate 5g
Pulvis Talci 15g
Preparation process:
(1) 120g soybean phospholipid acyl glycerol, 30g NaGC and 40g cholesterol are dissolved in the mixed solvent that the 700ml volume ratio is 1: 5 dichloromethane and ether, mix homogeneously, mixed solvent is removed in decompression on rotation film evaporimeter, makes immobilized artificial membrane;
(2) phosphoric acid-disodium hydrogen phosphate buffer solution of adding pH value 6.0, jolting is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(3) 5g Amlodipine Besylate Tablet and 80g Atorvastatin calcium are dissolved in 500ml water, regulate pH value to 8.0, reuse 0.45 μ m filtering with microporous membrane with 5% sodium hydrogen phosphate, filtrate adds in the blank liposome suspension, be incubated 55 ℃ and stirred 30 minutes, spray drying makes lipidosome solid;
(4) lipidosome solid and 55g microcrystalline Cellulose, 76g lactose, the 25g low-substituted hydroxypropyl cellulose with Amlodipine Besylate Tablet and Atorvastatin calcium mixes, cross 60 mesh sieve mix homogeneously, add 2% hypromellose, 30% alcoholic solution and prepare soft material, cross 20 mesh sieves and granulate 60 ℃ of dryings;
(5), cross 20 mesh sieve granulate with dried granule and 5g magnesium stearate, 15g Pulvis Talci mix homogeneously;
(6) tabletting;
(7) the bag film-coat is made into the concentration of solid content 5% with auspicious safe GS-H type coating materials, and solvent is 80% alcoholic solution, spraying bag film-coat continuously, and weightening finish 3.2%, drying makes the amlodipine besylate and atorvastatin calcium Film coated tablets.
The preparation prescription of embodiment 3 amlodipine besylate and atorvastatin calcium liposome methods (1000):
Amlodipine Besylate Tablet (in amlodipine) 10g
Atorvastatin calcium (in atorvastatin) 10g
Soybean phospholipid acyl glycerol 150g
NaGC 30g
Cholesterol 50g
Starch 90g
Carboxymethylstach sodium 15g
30 POVIDONE K 30 BP/USP 30 10g
Magnesium stearate 5g
Preparation process:
(1) 150g soybean phospholipid acyl glycerol, 30g NaGC and 50g cholesterol are dissolved in the mixed solvent that the 800ml volume ratio is 1: 5 dichloromethane and ether, mix homogeneously, mixed solvent is removed in decompression on rotation film evaporimeter, makes immobilized artificial membrane;
(2) citric acid-sodium citrate buffer solution of adding pH value 6.0, jolting is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(3) 10g Amlodipine Besylate Tablet and 10g Atorvastatin calcium are dissolved in 400ml water, regulate pH value to 7.5, reuse 0.45 μ m filtering with microporous membrane with 10% sodium citrate, filtrate adds in the blank liposome suspension, be incubated 55 ℃ and stirred 40 minutes, spray drying makes lipidosome solid;
(4) lipidosome solid and 90g starch, the 15g carboxymethylstach sodium with Amlodipine Besylate Tablet and Atorvastatin calcium mixes, and crosses 60 mesh sieve mix homogeneously, and the 80% alcoholic solution 200ml that adds 5% 30 POVIDONE K 30 BP/USP 30 prepares soft material, crosses 20 mesh sieves and granulates 60 ℃ of dryings;
(5), cross 20 mesh sieve granulate with dried granule and 5g magnesium stearate mix homogeneously;
(6) filled capsules makes the amlodipine besylate and atorvastatin calcium lipidosome capsule.
The preparation prescription (1000) of embodiment 4 amlodipine besylate and atorvastatin calcium liposome dispersible tablets:
Amlodipine Besylate Tablet (in amlodipine) 10g
Atorvastatin calcium (in atorvastatin) 80g
Soybean phospholipid acyl glycerol 240g
NaGC 8g
Cholesterol 80g
Microcrystalline Cellulose 40g
Starch 24g
Polyvinylpolypyrrolidone 25g
Carboxymethylstach sodium 20g
30 POVIDONE K 30 BP/USP 30 15g
Magnesium stearate 6g
Pulvis Talci 20g
Preparation process makes amlodipine besylate and atorvastatin calcium liposome dispersible tablet with embodiment 1.
The preparation prescription (1000) of embodiment 5 amlodipine besylate and atorvastatin calcium liposome sheets:
Amlodipine Besylate Tablet (in amlodipine) 5g
Atorvastatin calcium (in atorvastatin) 40g
Soybean phospholipid acyl glycerol 20g
NaGC 30g
Cholesterol 8g
Microcrystalline Cellulose 50g
Mannitol 21g
Cross-linking sodium carboxymethyl cellulose 10g
Xanthan gum 3g
Magnesium stearate 2g
Micropowder silica gel 4g
Preparation process makes amlodipine besylate and atorvastatin calcium liposome sheet with embodiment 1.
The preparation prescription (1000) of embodiment 6 amlodipine besylate and atorvastatin calcium liposome sheets:
Amlodipine Besylate Tablet (in amlodipine) 5g
Atorvastatin calcium (in atorvastatin) 20g
Soybean phospholipid acyl glycerol 100g
NaGC 25g
Cholesterol 15g
Microcrystalline Cellulose 28g
Lactose 22g
Pregelatinized Starch 12.5g
Arabic gum 2.5g
Pulvis Talci 7g
Micropowder silica gel 8g
Preparation process makes amlodipine besylate and atorvastatin calcium liposome sheet with embodiment 1.
The test of embodiment 7 Comparative Examples
Select for use composition and the combination outside the component preferred content proportioning of the present invention outside the preferred ingredient of the present invention to carry out the Comparative Examples test respectively, preparation technology is with embodiment 1.Each Comparative Examples component such as following table 1.
The test of table 1 Comparative Examples
Prepare the amlodipine besylate and atorvastatin calcium liposome tablet by above prescription component, preparation method is with embodiment 1.
Test example 1 stability and dissolution are investigated
With the sample of above embodiment 1-6 preparation under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the results are shown in Table 2.
Table 2 accelerated test result
Found that by above, and the sample dissolution height of embodiment of the invention 1-6 preparation, quicken that content and related substance all do not have significant change after 6 months.Proved absolutely the superiority of the present invention aspect raising stability and dissolution.
The test of test example 2 releases is investigated
Prepared sample in embodiment 1 and Comparative Examples 1, Comparative Examples 2, Comparative Examples 3, the Comparative Examples 4 has been carried out the release inspection.This test is carried out according to first method in 2010 editions appendix XD of Chinese Pharmacopoeia drug release determination method, and each sample result of the test of statistics has been made release profiles.
Sampling time point is in this experiment: 1,2,4,6,8 hours.
Experimental result:
Amlodipine discharges data (%):
Curve A is that the amlodipine of prepared sample among the embodiment 1 discharges data.
Curve B is that the amlodipine of prepared sample in the Comparative Examples 1 discharges data.
Curve C is that the amlodipine of prepared sample in the Comparative Examples 2 discharges data.
Curve D is that the amlodipine of prepared sample in the Comparative Examples 3 discharges data.
Curve E is that the amlodipine of prepared sample in the Comparative Examples 4 discharges data.Specifically see accompanying drawing 1.
Atorvastatin discharges data (%):
Curve 1 is that the atorvastatin of prepared sample among the embodiment 1 discharges data.
Curve 3 is that the atorvastatin of prepared sample in the Comparative Examples 2 discharges data.
Curve 5 is that the atorvastatin of prepared sample in the Comparative Examples 4 discharges data.Specifically see accompanying drawing 2.
Data in the above experimental result and curve chart can be strong confirmation adopt the prepared sample drug release rate of the present invention steady.Also can draw the combination of not adopting soybean phospholipid acyl glycerol preferred for this invention, NaGC, cholesterol by Comparative Examples, or consumption is outside preferred range of the present invention, effect is nothing like the present invention.
Foregoing description of the present invention is intended to explaining, rather than restriction.Concerning the art technology people, can carry out multiple variation or modification in the embodiment described herein.Do not depart from the scope of the present invention or spirit in can obtain these variations.Each list of references that the application quoted is incorporated herein by reference in full at this.
Claims (10)
1. an amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation is characterized in that it being to be made by Amlodipine Besylate Tablet, Atorvastatin calcium, soybean phospholipid acyl glycerol, NaGC and cholesterol.
2. amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation according to claim 1, wherein calculate by weight, 1 part of Amlodipine Besylate Tablet (in amlodipine), 1～16 part of Atorvastatin calcium (in atorvastatin), 3～30 parts of soybean phospholipid acyl glycerol, 0.6～15 part of NaGC, 1.2～12 parts in cholesterol.
3. amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation, it is characterized in that it being to make with other pharmaceutic adjuvants by claim 1 or 2 described amlodipine besylate and atorvastatin calcium medicine compound liposomees, calculate by weight and be: 1 part of Amlodipine Besylate Tablet (in amlodipine), 1～16 part of Atorvastatin calcium (in atorvastatin), 3～30 parts of soybean phospholipid acyl glycerol, 0.6～15 part of NaGC, 1.2～12 parts in cholesterol, 5～80 parts of other pharmaceutic adjuvants; Be preferably: 1 part of Amlodipine Besylate Tablet (in amlodipine), 1～16 part of Atorvastatin calcium (in atorvastatin), 4～24 parts of soybean phospholipid acyl glycerol, 0.8～6 part of NaGC, 1.6～8 parts in cholesterol, 11～36 parts of other pharmaceutic adjuvants.
4. amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation according to claim 3, it is characterized in that described solid preparation can be tablet, dispersible tablet or capsule, described other pharmaceutic adjuvants are selected from filler, disintegrating agent, binding agent, lubricant, fluidizer or their combination.
5. according to each described amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation of claim 1-4, the specification that it is characterized in that preparation is that per unit preparation Amlodipine Besylate Tablet/Atorvastatin calcium (respectively in amlodipine and atorvastatin) is respectively 5mg/40mg, perhaps 5mg/20mg, perhaps 5mg/10mg, perhaps 5mg/80mg, perhaps 10mg/10mg, perhaps 10mg/40mg, perhaps 10mg/80mg, preferred specification is 5mg/40mg, perhaps 5mg/20mg, perhaps 5mg/10mg.
6. method for preparing each described amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation of claim 1-5 is characterized in that comprising preparation liposome and two steps of preparation solid preparation:
(1) preparation liposome: Amlodipine Besylate Tablet, Atorvastatin calcium and soybean phospholipid acyl glycerol, NaGC and cholesterol are mixed and made into lipidosome solid;
(2) preparation solid preparation: lipidosome solid and filler, disintegrating agent, binding agent, lubricant, fluidizer are mixed with the amlodipine besylate and atorvastatin calcium medicine compound lipidosome solid preparation.
7. preparation method according to claim 6 is characterized in that the step of described preparation liposome is:
(1) soybean phospholipid acyl glycerol, NaGC and cholesterol are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotation film evaporimeter, makes immobilized artificial membrane;
(2) add buffer salt solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) Amlodipine Besylate Tablet and Atorvastatin calcium is water-soluble, regulate pH value to 7.0～8.0 with the pH regulator agent, filtering with microporous membrane, filtrate adds in the blank liposome suspension, is incubated 55 ℃ and stirs 30-60 minute, and spray drying makes lipidosome solid.
8. preparation method according to claim 6 is characterized in that the step of described preparation solid preparation is:
(1) lipidosome solid and filler, the disintegrating agent with Amlodipine Besylate Tablet and Atorvastatin calcium mixes, and the mix homogeneously that sieves adds binder solution and prepares soft material, the granulation of sieving, drying;
(2) dried granule and fluidizer or mix lubricant is even, the granulate that sieves, tabletting or filled capsules make the amlodipine besylate and atorvastatin calcium lipidosome solid preparation.
9. according to the described preparation method of claim 6-8, it is characterized in that described step also can comprise tablet bag film-coat process, with the plain sheet bag of gained gastric solubleness film-coat, weightening finish 2-4% makes Film coated tablets.
10. according to the arbitrary described preparation method of claim 6～9, it is characterized in that described buffer salt solution is selected from a kind of in phosphate buffer salt, carbonate buffer solution, the citrate buffer, is preferably the phosphoric acid-disodium hydrogen phosphate buffer solution of pH value 6.0; Described pH value regulator is selected from a kind of in sodium hydroxide, sodium bicarbonate, sodium citrate, the sodium hydrogen phosphate, is preferably sodium hydrogen phosphate; Described organic solvent is selected from one or more in methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, chloroform, dichloromethane, ether, benzyl alcohol, the normal hexane, and being preferably volume ratio is 1: 5 the dichloromethane and the mixed solvent of ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102112821A CN101862329B (en) | 2010-06-29 | 2010-06-29 | Amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102112821A CN101862329B (en) | 2010-06-29 | 2010-06-29 | Amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101862329A true CN101862329A (en) | 2010-10-20 |
| CN101862329B CN101862329B (en) | 2012-02-22 |
Family
ID=42954390
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102112821A Expired - Fee Related CN101862329B (en) | 2010-06-29 | 2010-06-29 | Amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101862329B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008440A (en) * | 2010-12-02 | 2011-04-13 | 海南美大制药有限公司 | Solid preparation of atorvastatin calcium liposome |
| CN102133187A (en) * | 2011-03-18 | 2011-07-27 | 海南美大制药有限公司 | Pravastatin sodium liposome solid preparation |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1827104A (en) * | 2006-04-12 | 2006-09-06 | 钱雪 | Pharmaceutical compositions of levo-amlodipine and atorvastatin |
| CN1843357A (en) * | 2005-04-08 | 2006-10-11 | 石药集团中奇制药技术（石家庄）有限公司 | Pharmaceutical compositions of levoamlodipine and atorvastatin |
| CN1857726A (en) * | 2005-04-30 | 2006-11-08 | 石家庄制药集团欧意药业有限公司 | Medicine composition for treating hypertension complicated with hyperlipemia and cardiac and cerebral vascular diseases |
| CN101623259A (en) * | 2009-07-23 | 2010-01-13 | 海南美大制药有限公司 | Amoxicillin lipidosome solid preparation and new application thereof |
| CN101623258A (en) * | 2009-07-23 | 2010-01-13 | 海南美大制药有限公司 | Ranitidine hydrochloride lipidosome capsule and new application thereof |
-
2010
- 2010-06-29 CN CN2010102112821A patent/CN101862329B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1843357A (en) * | 2005-04-08 | 2006-10-11 | 石药集团中奇制药技术（石家庄）有限公司 | Pharmaceutical compositions of levoamlodipine and atorvastatin |
| CN1857726A (en) * | 2005-04-30 | 2006-11-08 | 石家庄制药集团欧意药业有限公司 | Medicine composition for treating hypertension complicated with hyperlipemia and cardiac and cerebral vascular diseases |
| CN1827104A (en) * | 2006-04-12 | 2006-09-06 | 钱雪 | Pharmaceutical compositions of levo-amlodipine and atorvastatin |
| CN101623259A (en) * | 2009-07-23 | 2010-01-13 | 海南美大制药有限公司 | Amoxicillin lipidosome solid preparation and new application thereof |
| CN101623258A (en) * | 2009-07-23 | 2010-01-13 | 海南美大制药有限公司 | Ranitidine hydrochloride lipidosome capsule and new application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《中国现代医学杂志》 20090731 张阳德，曹政科，张峰 苯磺酸氨氯地平柔性纳米脂质体冻干工艺研究 第2111-2113页 1-10 第19卷, 第14期 2 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008440A (en) * | 2010-12-02 | 2011-04-13 | 海南美大制药有限公司 | Solid preparation of atorvastatin calcium liposome |
| CN102133187A (en) * | 2011-03-18 | 2011-07-27 | 海南美大制药有限公司 | Pravastatin sodium liposome solid preparation |
| CN102133187B (en) * | 2011-03-18 | 2012-06-27 | 海南美大制药有限公司 | Pravastatin sodium liposome solid preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101862329B (en) | 2012-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101797230B (en) | Liposome solid preparation of losartan potassium hydrochlorothiazide pharmaceutical composition | |
| CN101804029A (en) | Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin | |
| JP2011507973A (en) | Pharmaceutical composition of amlodipine and valsartan | |
| CN101816640B (en) | Prasugrel liposome solid preparation | |
| CN102166208B (en) | Lisinopril and hydrochlorothiazide pharmaceutical composition liposome solid preparation | |
| CN101862329B (en) | Amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation | |
| CN101972263B (en) | Valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation | |
| CN101862336B (en) | Irbesartan-hydrochlorothiazide drug combination liposome solid preparation | |
| CN101810580A (en) | Valsartan liposome, preparation method thereof and medicinal composition containing same | |
| CN101862302B (en) | Amlodipine besylate liposome tablet | |
| CN101317842A (en) | Treating uses of imidazole-5-carboxylic acid derivant | |
| CN102138899B (en) | Olmesartan liposome solid preparation | |
| CN101829071B (en) | Aliskiren liposome tablet | |
| CN101972253B (en) | Candesartan ester amlodipine besylate pharmaceutical composition lipid microsphere tablet | |
| CN102302453B (en) | Paroxetine hydrochloride liposome solid preparation | |
| CN103040777B (en) | Olmesartan ester liposome solid preparation | |
| CN102138900B (en) | Solid preparation of oxapium iodide liposome | |
| CN102579345B (en) | Irbesartan liposome solid preparation | |
| KR20130074808A (en) | The pharmaceutical composition comprising losartan for treating or preventing statin-induced muscle toxicity | |
| CN102302452B (en) | Pitavastatin calcium lipid solid preparation | |
| CN102133189A (en) | Telmisartan liposome solid preparation | |
| RU2506947C2 (en) | Prolonged release tablet containing theobromin | |
| CN102579344B (en) | Losartan potassium liposome solid preparation | |
| CN102600173B (en) | Amlodipine/benazepril medicament composition liposome solid preparation | |
| CN102579348B (en) | Fosinopril sodium liposome solid preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: HAINAN MEILAN SHIKE PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: WANG MING Effective date: 20130724 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 570125 HAIKOU, HAINAN PROVINCE TO: 570216 HAIKOU, HAINAN PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20130724 Address after: 6, No. 570216, Haikou Free Trade Zone, 168 Nanhai Avenue, Hainan, Haikou Patentee after: Hainan Meilan Shike Pharmaceutical Co., Ltd. Address before: The new business building No. 48 570125 Hainan city of Haikou province China World Trade Center Road, room 2601 Patentee before: Wang Ming |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120222 Termination date: 20160629 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |