CN101810580A - Valsartan liposome, preparation method thereof and medicinal composition containing same - Google Patents

Abstract

The invention relates to valsartan liposome, a preparation method thereof and a medicinal composition containing the same. Active components of the medicinal composition are valsartan and/or amlodipine. The valsartan liposome consists of the valsartan or pharmaceutically acceptable salt thereof and phospholipid, wherein the weight of the phospholipid is 1 to 10 times that of the valsartan or the pharmaceutically acceptable salt thereof; and the medicinal composition prepared by the valsartan liposome not only meets the requirement of Chinese Pharmacopoeia, but also has the advantages of quicker dissolution, quicker drug effect exertion, obviously improved biological utilization compared with conventional valsartan medicinal composition.

Description

A kind of valsartan liposome, its preparation method and comprise its pharmaceutical composition

Technical field

The pharmaceutical composition that the present invention relates to a kind of valsartan liposome, its preparation method and contain it, the advantage that described valsartan liposome has is rapider than common valsatan medicinal composition stripping, the drug effect performance is faster, the bioavailability significance improves belongs to medical technical field.

Background technology

Because the change of The development in society and economy and people life style, population of China hypertension prevalence is sustainable growth trend.Hypertension is a kind of commonly encountered diseases frequently-occurring disease, also is the most important risk factor of cardiovascular and cerebrovascular disease.Blood pressure level and cardiovascular diseases's sickness rate are continuous positive correlation.Hypertensive important complication apoplexy, heart disease and nephropathy serious harm China people ' s health, the disability rate height that causes death brings white elephant (with reference to non-patent literature 1) for individual, family and society.

In recent years, hypertension prevention and control guide both domestic and external shows (with reference to non-patent literature 1,2), strengthen the blood pressure lowering dynamics, make hyperpietic's blood pressure reduce to 140/90 millimetres of mercury following (it is following that the best should be reduced to 130/80 millimetres of mercury) actively, enduringly, effectively the target organ damages such as heart and brain kidney that cause of alleviating hypertension.In addition, the administering drug combinations of hypertension drug, can treat all kinds hypertension, angina pectoris, atherosclerosis effectively, and prevention or cardiovascular and cerebrovascular diseases such as treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma, reduce incident rate, mortality rate and the disability rate of cardiovascular and cerebrovascular disease, improve patients ' life quality, prolong patient's life-span.

Valsartan of the present invention (with reference to patent documentation 1) is a kind of orally active specificity angiotensin (AT) II receptor antagonist, because of its specificity and selectivity that has increased blood circulation and organized the nervous plain II acceptor levels blocking-up of medium vessels, have than the more superior characteristics of angiotensin converting enzyme (ACE) inhibitor, do not increase Kallidin I effect due to the ACE enzyme, thereby can not cause the side effect of cough.The chemical name of valsartan is: (S)-N-valeryl-N-{[2 '-(1H-tetrazole-5-yl) [1,1 '-phenylbenzene]-the 4-yl] methyl }-the L-valine, English name is: valsartan.

The absolute oral administration biaavailability of valsartan only has an appointment 25%, and the scope of broad is 10～35%; Valsartan also has the dissolubility that depends on pH, its scope solvable in from the slightly soluble sour environment to the gastrointestinal neutral environment; In addition, development makes things convenient for the challenge of the valsartan peroral dosage form that the patient uses to be its bulk density very low (with reference to patent documentation 2).Therefore, need urgent valsartan dissolubility under one's belt and the bulk density problem in the peroral dosage form of solving, promote its absorption under one's belt.

Valsartan mainly is with oral form administration in the prior art, the listing dosage form has tablet, capsule, dispersible tablet and chewable tablet, described dosage form all is to adopt the simple valsartan raw materials of compound medicine that does not add any modification to make, the dissolubility and the bioavailability of gained preparation are relatively poor, can not effectively bring into play the pharmacological activity of valsartan.

From people such as late 1960s Rahman at first use liposome as pharmaceutical carrier since, continuous progress along with science and technology, liposome preparation technology is progressively perfect, and the liposome mechanism of action is further illustrated, and liposome becomes the hot technology field of current research.Verified, liposome is fit to vivo degradation, avirulence and non-immunogenicity, the what is more important liposome can improve Drug therapy exponential sum bioavailability, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, has reduced drug dose thus.The applicant imagines with the liposome valsartan thus to obtain the pharmacological activity of expectation.

Phospholipid is the main component that constitutes the liposome bimolecular film, and it is inside that the hydrophilic and hydrophobic two kinds of groups in the phospholipid align into hydrophobic layer, the bilayer that hydrophilic layer is outside.The hydrophobic small molecules chemical compound can embed or be wrapped in the hydrophobic layer of phospholipid bilayer center.Valsartan or its pharmaceutically acceptable salt be wrapped in form liposome in the phospholipid, form valsatan medicinal composition with pharmaceutically acceptable carrier again; Perhaps form the valsartan amlodipine medicament composition with amlodipine or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier again; Can improve Drug therapy exponential sum bioavailability, the reduction drug toxicity of valsartan and reduce drug side effect.

The inventor by creationary research, the valsartan liposome that discovery selects for use the excipient of certain content and composition to make, not only drug content is higher, its envelop rate is far superior to the product of prior art, and make after the pharmaceutically acceptable dosage form, promote that medicine absorbs under one's belt, prolong drug is at the circulation time of blood, thereby also significance raising of bioavailability.

Amlodipine of the present invention (with reference to patent documentation 3) is a calcium channel blocker, and the retardance calcium ion is striden film and entered cardiac muscle and vascular smooth muscle cell.The mechanism of amlodipine antihypertensive function is direct loose vascular smooth muscle.Allevating angina pectoris cutter system really is also not sure fully, but it can reduce total peripheral vascular resistance by expansion periphery small artery and coronary artery, remove coronary vasospasm, reduce the afterload of heart, reduce the heart energy expenditure and the demand of oxygen, thus allevating angina pectoris.The amlodipine oral absorption is good, and is not subjected to the influence of dietary intake.6～12 hours blood drug level reaches to the peak after the administration, and absolute bioavailability is about 64～80%, and apparent volume of distribution is about 21L/kg, and eventually the end is eliminated the half-life and is about 35～50 hours, once a day, successive administration after 7～8 days blood drug level reach to stable state.

The chemical name of Amlodipine Besylate Tablet is: 3-ethyl-5-methyl-2-(the amino ethoxymethyl of 2-)-4-(2-chlorphenyl)-1, and 4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate, English name is: amlodipine Besylate.

Chinese patent CN101391098A discloses a kind of melittin Liposomal formulation, it is characterized in that being made up of for 10～140 parts 1 part of melittin, phosphatidase 15～40 part, 1.3～10 parts in cholesterol, poloxamer.Prepared liposome adjuvant content is higher, and drug content is less; The overall dimensions of the pharmaceutical composition made of liposome is too big thus, is not suitable for the higher kind of drug content.

Chinese patent CN101229157A discloses a kind of pharmaceutical composition that comprises the Candesartan ester liposome, it is characterized in that being made up of the phospholipid of candesartan Cilexetil and 0.5～10 times, and prepared candesartan Cilexetil liposome encapsulation is higher.The decomposition that said composition can suppress candesartan Cilexetil keeps its long-term stability, thereby prolongs the effect duration of Candesartan ester formulation.

Chinese patent CN100336507A discloses a kind of preparation method of Nimodipime nanometer liposome, it is characterized in that being made up of nimodipine 10mg, hydrogenation egg yolk lecithin 150mg, cholesterol 20mg, poloxamer 200mg, sodium deoxycholate 10mg.Prepared liposome also is that adjuvant content is higher, and drug content is less; The overall dimensions of the pharmaceutical composition made of liposome is too big thus, also is not suitable for the higher kind of drug content.

Pharmaceutical composition of the present invention, 1 administration every day, the patient takes medicine very conveniently like this, can prevent from effectively the acute variation of blood pressure to make blood pressure be in more equilibrated state, has improved the compliance that the patient takes medicine simultaneously, improves patient's quality of life.

Non-patent literature 1: Chinese hypertension prevention and control guide revised edition in 2005,4-5,9,31-32

Non-patent literature 2:2007 Europe hypertension association and ESC's hypertension guide new highlight. Chinese hypertension magazine, the 15th the 9th phase of volume of JIUYUE in 2007,708-710

Patent documentation 1: U.S. Pat 5399578

Patent documentation 2: Chinese patent CN101237859A

Patent documentation 3: U.S. Pat 4572909

Patent documentation 4: Chinese patent CN101391098A

Patent documentation 5: Chinese patent CN101229157A

Patent documentation 6: Chinese patent CN100336507A

Summary of the invention

Problem to be solved by this invention is that the defective that overcomes prior art provides a kind of valsartan liposome, its preparation method and contains its pharmaceutical composition, and purpose is to solve valsartan dissolution problem under one's belt, improves the bioavailability of valsartan.

Another object of the present invention also is to provide a kind of pharmaceutical composition that contains valsartan liposome and preparation method thereof, described pharmaceutical composition can be pharmaceutically acceptable various dosage forms, includes but not limited to tablet, capsule, chewable tablet, oral cavity disintegration tablet, drop pill, granule or dispersible tablet.

The technical scheme that the present invention solves is as follows:

A kind of valsartan liposome is characterized in that, described valsartan liposome is made up of valsartan or its pharmaceutically acceptable salt and phospholipid, and wherein the weight of phospholipid is valsartan or its pharmaceutically acceptable salt 1～10 times.

Described valsartan or its pharmaceutically acceptable salt be selected from valsartan, valsartan calcium, valsartan magnesium, valsartan one potassium salt, valsartan di-potassium, valsartan one sodium salt, valsartan disodium salt, valsartan calcium/magnesium salt-mixture, the two diethyl ammonium salts of valsartan, the two dipropyl ammonium salts of valsartan, the two dibutyl ammonium salts of valsartan, valsartan one-L-arginine salt, valsartan two-L-arginine salt, valsartan one-L-lysinate or valsartan two-L-lysinate.Valsartan or its pharmaceutically acceptable salt can crystallizations, especially hydrate and polycrystalline form exist for partially crystallizable or amorphous forms, solvate; Its crystal formation can be selected from I type～XIII type or H type.

As a preferred embodiment of the present invention, described valsartan or its pharmaceutically acceptable salt are preferably valsartan.

Wherein, described phospholipid is selected from one or more in hydrogenated soy phosphatidyl choline, soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, two stearic acid lecithin, two palmitic acid lecithin, two myristic acid lecithin, EPG, egg yolk lecithin acyl serine, the egg yolk lecithin acyl inositol; Be preferably hydrogenated soy phosphatidyl choline, soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrogenated yolk lecithin; Most preferably be hydrogenated soy phosphatidyl choline.

The present invention also provides a kind of method for preparing valsartan liposome, comprises the steps:

(1) phospholipid of valsartan or its pharmaceutically acceptable salt and 1～10 times is dissolved in 1～20 times the organic solvent, mix homogeneously, recording volume filters, and evaporation is removed organic solvent and is made immobilized artificial membrane, drying;

(2) the adding pH value is 3.0～7.5 buffer, soaked 1～2 hour, and high-speed stirred, after 5～20 minutes,, concentration dissolved with same buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.5～1.0mg/ml ₃₀Solution, and supply buffer to original volume;

(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get valsartan liposome.

Above-mentioned valsartan liposome is at the buffer that preparation process added, and is selected from phosphate buffer, structure rafter phthalate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer one or more; Be preferably acetate buffer or phosphate buffer.Described buffer pH value is 3.0～7.5, is preferably pH value 3.0～4.5.

In the above-mentioned preparation method, organic solvent is selected from one or more in dehydrated alcohol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane; Be preferably dehydrated alcohol, isopropyl alcohol or the tert-butyl alcohol; Most preferably be dehydrated alcohol.The amount of used organic solvent is 1～20 times of valsartan; Be preferably 3～10 times.

The present invention also provides a kind of pharmaceutical composition, it is characterized in that, is made up of valsartan liposome of the present invention and pharmaceutically acceptable carrier.The dosage of wherein said valsartan or its pharmaceutically acceptable salt is counted 20.00mg～640.00mg with valsartan.

Described pharmaceutically acceptable carrier can be selected from diluent, disintegrating agent, binding agent, fluidizer, lubricant, dissolubility promoter and their combination.The amount of pharmaceutically acceptable every kind of carrier in pharmaceutical composition can change in the normal ranges of this area.

Suitable diluent can be selected from microcrystalline Cellulose, optimize microcrystalline Cellulose, Powderd cellulose, saccharide, sugar derivatives, calsium supplement and their combination; Calsium supplement is selected from calcium carbonate, calcium phosphate, calcium hydrogen phosphate, Malic acid citric acid calcium, Citric acid calcium, calcium malate, calcium lactate or calcium acetate;

Suitable disintegrants can be selected from carboxymethylstach sodium, polyvinylpolypyrrolidone, primojel, L-hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, dried starch and their combination;

Suitable bonding can be selected from polyvidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, pre-paying starch, starch and their combination; Polyvidone is preferably 30 POVIDONE K 30 BP/USP 30;

Suitable fluidizer can be selected from micropowder silica gel, magnesium trisilicate, cellulose powder, starch, Talcum and their combination;

Examples of suitable lubricants can be selected from magnesium stearate, calcium stearate, stearic acid, calcium silicates, Talcum and their combination;

Suitable dissolubility promoter can be selected from polyvinylpolypyrrolidone, polyvidone and their combination.

The present invention also provides a kind of pharmaceutical composition, it is characterized in that, is made up of valsartan liposome of the present invention and amlodipine or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.The dosage of wherein said valsartan or its pharmaceutically acceptable salt is counted 20.00mg～640.00mg with valsartan; The dosage of described amlodipine or its pharmaceutically acceptable salt is counted 0.625mg～40.00mg with amlodipine.Described pharmaceutically acceptable carrier can also be selected from above-mentioned diluent, disintegrating agent, binding agent, fluidizer, lubricant, dissolubility promoter and their combination.

As a preferred embodiment of the present invention, described amlodipine or its pharmaceutically acceptable salt are preferably Amlodipine Besylate Tablet.

The pharmaceutical composition that comprises valsartan liposome of the present invention can be selected from tablet, capsule, chewable tablet, oral cavity disintegration tablet, drop pill, granule or dispersible tablet.The method of pharmaceutical compositions of the present invention is the routine techniques of pharmaceutical preparation production field, can adopt wet granulation, dry granulation or direct powder compression; The tablet that comprises the valsartan amlodipine can the monolayer tabletting, also can double-deck tabletting, if double-deck tabletting, can adopt amlodipine is ground floor and valsartan liposome is the second layer; Tablet can randomly carry out film coating, can be the gastric solubleness coating, also can be enteric coating.

The present invention also provides a kind of preparation to comprise the method for the pharmaceutical composition of above-mentioned valsartan liposome, comprises the steps:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) various pharmaceutically acceptable carriers are carried out drying respectively, cross 80～100 mesh sieves and pulverize;

(C) valsartan liposome that will sieve and the various pharmaceutically acceptable carrier that sieved in blender by the equivalent method mix homogeneously that progressively increases;

(D) the mixed powder compacting that above-mentioned mixing is obtained forms compacting material;

(E) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(F) mixing of materials of will milling forms the valsartan liposome granule;

(G) use tablet machine that the valsartan liposome granule is pressed into tablet or dispersible tablet, perhaps use the capsule subpackage machine that the valsartan liposome granule is distributed into capsule.

The present invention also provides a kind of preparation to comprise the method for the pharmaceutical composition of valsartan liposome, comprises the steps:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) amlodipine or its pharmaceutically acceptable salt are carried out drying, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) various pharmaceutically acceptable carriers are carried out drying respectively, cross 80～100 mesh sieves and pulverize, then mix homogeneously;

(D) will be the various pharmaceutically acceptable carrier of valsartan liposome, amlodipine or its pharmaceutically acceptable salt and mix homogeneously of mix homogeneously in blender by the equivalent method mix homogeneously that progressively increases;

(E) the mixed powder compacting that above-mentioned mixing is obtained forms compacting material;

(F) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(G) mixing of materials of will milling forms valsartan amlodipine granule;

(H) use tablet machine that valsartan amlodipine granule is pressed into tablet or dispersible tablet, perhaps use the capsule subpackage machine that valsartan amlodipine granule is distributed into capsule.

Tablet and the capsule that comprises valsartan liposome of the present invention carried out the dissolution test, dissolution all reaches more than 90%, illustrate that the pharmaceutical composition that comprises valsartan liposome of the present invention not only satisfies the Chinese Pharmacopoeia requirement, and having rapidlyer than common valsartan liposome pharmaceutical composition stripping, drug effect is brought into play advantage faster.Owing to valsartan of the present invention is adopted the form of liposome, and to preparation technology's research control, realized the targeted delivery of medicine, can make medicine arrive gastrointestinal tract mucous cell quickly and accurately, thereby performance curative effect, improved bioavailability, brought convenience to clinical application.

Compare with prior art, valsartan liposome pharmaceutical composition provided by the invention has following unforeseeable technique effect:

(1) valsartan liposome of the present invention do not comprise emulsifying agents such as cholesterol and poloxamer, thereby drug content is higher, and its envelop rate still surpasses 90%;

(2) pharmaceutical composition that contains valsartan liposome of the present invention, not only dissolution and bioavailability are higher than prior art products far away, and bring great convenience to clinical application;

(3) pharmaceutical composition that contains valsartan liposome of the present invention has been avoided the peak valley phenomenon in the drug release process, has the permanent effect of slow release, can bring into play drug action more fully, and toxic and side effects is little;

(4) valsartan liposome of the present invention inside is added with 30 POVIDONE K 30 BP/USP ₃₀, the outside also is added with 30 POVIDONE K 30 BP/USP ₃₀Or polyvinylpolypyrrolidone, bioavailability is further enhanced;

(5) adopt conventional process equipment, but commercial scale, high efficiency production, and constant product quality is a kind of uniqueness and blanket, low-cost industrial preparation method.

Valsartan liposome pharmaceutical composition provided by the invention is carried out stability test to be investigated: placed respectively 10 days under high temperature is 60 ℃, high humility (relative humidity 90% ± 5%), illumination 4500LX condition, every detection index has no significant change; Carried out accelerated test 6 months under temperature is 40 ℃, relative humidity 75% ± 5% condition, every detection index does not all have significant change; In temperature is that 25 ℃, relative humidity are to carry out long term test 24 months under 60% ± 10% condition, and every detection index does not all have significant change.

Valsartan liposome pharmaceutical composition provided by the invention carries out acute toxicity test and abnormal toxicity test inspection, and the result is all up to specification, and safety obtains proof.

The specific embodiment

Describe the present invention in detail below in conjunction with embodiment.

Embodiment 1: the preparation of valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan magnesium	??20.00	??40.00	??80.00	??160.00
Hydrogenated yolk lecithin	??20.00	??40.00	??80.00	??160.00
					Amount to	??40.00	??80.00	??160.00	??320.00

Preparation method:

(1) hydrogenated yolk lecithin of valsartan magnesium and 1 times is dissolved in 1 times the tert-butyl alcohol, mix homogeneously, recording volume filters, and evaporation is removed the tert-butyl alcohol and is made immobilized artificial membrane, vacuum drying;

(2) the adding pH value is 3.0 structure rafter phthalate buffer, soaked 1 hour, and high-speed stirred, after 5 minutes,, concentration dissolved with same structure rafter phthalate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.5mg/ml ₃₀Solution, and supply buffer to original volume;

(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get valsartan liposome.

Embodiment 2: the preparation of valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan calcium	??20.00	??40.00	??80.00	??160.00
Soybean lecithin	??60.00	??120.00	??240.00	??480.00
					Amount to	??80.00	??160.00	??320.00	??640.00

Preparation method:

(1) soybean lecithin of valsartan calcium and 3 times is dissolved in 10 times the n-butyl alcohol, mix homogeneously, recording volume filters, and evaporation is removed n-butyl alcohol and is made immobilized artificial membrane, vacuum drying;

(2) the adding pH value is 3.5 phosphate buffer, soaked 1.5 hours, and high-speed stirred, after 10 minutes,, concentration dissolved with same phosphate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.75mg/ml ₃₀Solution, and supply buffer to original volume;

(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get valsartan liposome.

Embodiment 3: the preparation of valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan	??20.00	??40.00	??80.00	??160.00
Soybean lecithin	??100.00	??200.00	??400.00	??800.00
					Amount to	??120.00	??240.00	??480.00	??960.00

Preparation method:

(1) soybean lecithin of valsartan and 5 times is dissolved in 10 times the dehydrated alcohol, mix homogeneously, recording volume filters, and evaporation is removed dehydrated alcohol and is made immobilized artificial membrane, vacuum drying;

(2) the adding pH value is 4.0 acetate buffer, soaked 1 hour, and high-speed stirred, after 15 minutes,, concentration dissolved with same acetate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.75mg/ml ₃₀Solution, and supply buffer to original volume;

(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get valsartan liposome.

Embodiment 4: the preparation of valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan	??20.00	??40.00	??80.00	??160.00
Hydrogenated soy phosphatidyl choline	??140.00	??280.00	??560.00	??1120.00
					Amount to	??160.00	??3200.00	??640.00	??1280.00

Preparation method:

(1) hydrogenated soy phosphatidyl choline of valsartan and 7 times is dissolved in 15 times the dehydrated alcohol, mix homogeneously, recording volume filters, and evaporation is removed dehydrated alcohol and is made immobilized artificial membrane, vacuum drying;

(2) the adding pH value is 4.5 acetate buffer, soaked 1.5 hours, and high-speed stirred, after 15 minutes,, concentration dissolved with same acetate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.85mg/ml ₃₀Solution, and supply buffer to original volume;

(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get valsartan liposome.

Embodiment 5: the preparation of valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan	??20.00	??40.00	??80.00	??160.00
Hydrogenated soy phosphatidyl choline	??200.00	??400.00	??800.00	??1600.00
					Amount to	??220.00	??440.00	??880.00	??1760.00

Preparation method:

(1) hydrogenated soy phosphatidyl choline of valsartan and 10 times is dissolved in 20 times the dehydrated alcohol, mix homogeneously, recording volume filters, and evaporation is removed dehydrated alcohol and is made immobilized artificial membrane, vacuum drying;

(2) the adding pH value is 7.5 acetate buffer, soaked 2 hours, and high-speed stirred, after 20 minutes,, concentration dissolved with same acetate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 1.0mg/ml ₃₀Solution, and supply buffer to original volume;

(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get valsartan liposome.

Embodiment 6: the tablet that comprises valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome *	??20.00	??40.00	??80.00	??160.00
Calcium carbonate	??13.04	??26.08	??52.15	??104.30
					30 POVIDONE K 30 BP/USP 30	??5.00	??10.00	??20.00	??40.00
Carboxymethylstach sodium	??1.65	??3.30	??6.60	??13.20
					Micropowder silica gel	??0.41	??0.82	??1.65	??3.30
Magnesium stearate	??1.15	??2.30	??4.60	??9.20
					Sheet is heavy	??41.25	??82.50	??165.00	??330.00

*--the dosage of-valsartan liposome calculates with valsartan, and is as follows.

Preparation method:

(A) by prescription valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) by prescription with calcium carbonate, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize, then mix homogeneously;

(C) calcium carbonate of the valsartan liposome that will sieve and mix homogeneously, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel, magnesium stearate in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(E) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(F) mixing of materials of will milling forms the valsartan liposome granule;

(G) use rotary tablet machine that the valsartan liposome granule is pressed into tablet, make 10000, get final product.

Embodiment 7: the dispersible tablet that comprises valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Mannitol	??12.54	??25.08	??50.15	??100.30
					Polyvinylpolypyrrolidone	??5.00	??10.00	??20.00	??40.00
Carboxymethylstach sodium	??1.65	??3.30	??6.60	??13.20
					Micropowder silica gel	??0.41	??0.82	??1.65	??3.30
Magnesium stearate	??0.40	??0.80	??1.60	??3.20
					Sheet is heavy	??40.00	??80.00	??160.00	??320.00

Preparation method:

(A) by prescription valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) by prescription with mannitol, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃～80 ℃ dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(C) mannitol of the valsartan liposome that will sieve and mix homogeneously, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel, magnesium stearate in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(E) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(F) mixing of materials of will milling forms the valsartan liposome granule;

(G) use rotary tablet machine that the valsartan liposome granule is pressed into dispersible tablet, make 10000.

Embodiment 8: the capsule that comprises valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Calcium carbonate	??13.04	??26.08	??52.15	??104.30
					30 POVIDONE K 30 BP/USP 30	??3.00	??6.00	??12.00	??24.00

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Polyvinylpolypyrrolidone	??2.00	??4.00	??8.00	??16.00
Carboxymethylstach sodium	??1.65	??3.30	??6.60	??13.20
					Micropowder silica gel	??0.41	??0.82	??1.65	??3.30
Magnesium stearate	??1.15	??2.30	??4.60	??9.20
					Capsule is heavy	??41.25	??82.50	??165.00	??330.00

Preparation method:

(A) by prescription valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) by prescription with calcium carbonate, 30 POVIDONE K 30 BP/USP 30, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(C) calcium carbonate of the valsartan liposome that will sieve and mix homogeneously, 30 POVIDONE K 30 BP/USP 30, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel, magnesium stearate in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(E) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(F) mixing of materials of will milling forms the valsartan liposome granule;

(G) use the capsule subpackage machine that the valsartan liposome granule is distributed into capsule, make 10000.

Embodiment 9: the tablet that comprises valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Microcrystalline Cellulose	??10.21	??20.42	??40.85	??81.70
					30 POVIDONE K 30 BP/USP 30	??5.00	??10.00	??20.00	??40.00
Carboxymethylstach sodium	??1.50	??3.00	??6.00	??12.00
					Micropowder silica gel	??0.41	??0.82	??1.65	??3.30
Magnesium stearate	??0.38	??0.75	??1.50	??3.00
					Sheet is heavy	??37.50	??75.00	??150.00	??300.00

Preparation method:

(A) by prescription valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) by prescription with microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃～80 ℃ dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(C) valsartan liposome that will sieve and the microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel, magnesium stearate of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) measure drug content, it is heavy to calculate sheet, connects with diameter 8mm punch die straightening and makes tablet, makes 10000, and the control tablet hardness is 4.0～6.0kg;

(E) stir with Opadry II and an amount of purified water and make coating solution, the above-mentioned tablet of suppressing is carried out film coating.

Embodiment 10: the granule that comprises valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Mannitol	??18.72	??37.45	??74.90	??149.80
					30 POVIDONE K 30 BP/USP 30	??5.00	??10.00	??20.00	??40.00
Sucralose	??1.25	??2.50	??5.00	??10.00
					Strawberry essence	??0.02	??0.05	??0.10	??0.20
Grain is heavy	??45.00	??90.00	??180.00	??360.00

Preparation method:

(A) by prescription valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) by prescription with mannitol, sucralose respectively at 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize, then mix homogeneously;

(C) valsartan liposome that will sieve and the mannitol, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;

(E) with the various supplementary materials of above-mentioned mix homogeneously and the strawberry essence of recipe quantity, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make the valsartan liposome granule;

(F) use the granule racking machine to be distributed into granule exsiccant valsartan liposome granule, make 10000 bags, promptly.

Embodiment 11: the oral cavity disintegration tablet that comprises valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Microcrystalline Cellulose	??15.00	??30.00	??60.00	??120.00
Mannitol	??8.28	??16.55	??33.10	??66.20
					30 POVIDONE K 30 BP/USP 30	??5.00	??10.00	??20.00	??40.00
Sodium bicarbonate	??0.48	??0.95	??1.90	??3.80
					Sucralose	??1.25	??2.50	??5.00	??10.00
Sheet is heavy	??50.00	??100.00	??200.00	??400.00

Preparation method:

(A) by prescription valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) by prescription with microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(C) valsartan liposome that will sieve and the microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;

(E) with the various supplementary materials of above-mentioned mix homogeneously, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make the valsartan liposome granule;

(F) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into oral cavity disintegration tablet with ф 8mm drift, makes 10000, promptly.

Embodiment 12: the drop pill that comprises valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??2.00	??4.00	??8.00	??16.00
??PEG6000	??6.20	??12.40	??24.80	??49.60
					Polyoxyethylene sorbitan monoleate	??0.05	??0.10	??0.20	??0.40
Ball is heavy	??8.25	??16.50	??33.00	??66.00

Preparation method:

(A) by prescription valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) PEG6000 of recipe quantity and polyoxyethylene sorbitan monoleate mixing post-heating to 55 ℃～60 ℃ are made fusion;

(C) valsartan liposome is added in the fused solution stir, move in the funnel 55 ℃～60 ℃ insulations, adjusting dropping funnel size, dimethicone with-20～-5 or liquid paraffin are the cooling phase, the system of dripping, make 10000 balls, filter, wash, select ball, get final product.

Embodiment 13: the chewable tablet that comprises valsartan liposome

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Magnesium stearate	??0.50	??1.00	??2.00	??4.00
					30 POVIDONE K 30 BP/USP 30	??4.50	??9.00	??18.00	??36.00
Microcrystalline Cellulose	??13.50	??27.00	??54.00	??108.00
					0.5% cochineal solution	??0.40	??0.80	??1.60	??3.20
0.25% lemon yellow solution	??0.40	??0.80	??1.60	??3.20
					Sucralose	??0.50	??1.00	??2.00	??4.00
Mannitol	??10.0	??20.00	??40.00	??80.00
					Strawberry essence	??0.20	??0.40	??0.80	??1.60
Sheet is heavy	??50.00	??100.00	??200.00	??400.00

Preparation method:

(A) by prescription valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) by prescription with magnesium stearate, sucralose, mannitol and microcrystalline Cellulose respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(C) valsartan liposome that will sieve and the microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;

(E) with the various supplementary materials of above-mentioned mix homogeneously and 0.5% cochineal solution, 0.25% lemon yellow solution, the strawberry essence of recipe quantity, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate 55 ℃ of oven dry, 16 order granulate make the valsartan liposome granule;

(F) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into chewable tablet with ф 8mm drift, makes 10000, promptly.

Embodiment 14: the tablet that comprises valsartan liposome and Amlodipine Besylate Tablet

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Amlodipine Besylate Tablet	??1.74	??3.47	??6.94	??13.88
					Calcium carbonate	??11.30	??22.60	??45.21	??90.42
30 POVIDONE K 30 BP/USP 30	??5.00	??10.00	??20.00	??40.00
					Carboxymethylstach sodium	??1.65	??3.30	??6.60	??13.20
Micropowder silica gel	??0.41	??0.82	??1.65	??3.30
					Magnesium stearate	??1.15	??2.30	??4.60	??9.20
Sheet is heavy	??41.25	??82.50	??165.00	??330.00

Preparation method:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) with calcium carbonate, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize, then mix homogeneously;

(D) will be mix homogeneously valsartan liposome, Amlodipine Besylate Tablet and the calcium carbonate, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel, magnesium stearate of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(E) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(F) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(G) mixing of materials of will milling forms valsartan amlodipine granule;

(H) use rotary tablet machine that valsartan amlodipine granule is pressed into tablet, make 10000, this tablet can randomly carry out the film coating.

Embodiment 15: the dispersible tablet that comprises valsartan liposome and Amlodipine Besylate Tablet

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Amlodipine Besylate Tablet	??1.74	??3.47	??6.94	??13.88
Mannitol	??10.82	??21.63	??43.26	??86.52
					Polyvinylpolypyrrolidone	??5.00	??10.00	??20.00	??40.00
Carboxymethylstach sodium	??1.65	??3.30	??6.60	??13.20
					Micropowder silica gel	??0.41	??0.82	??1.65	??3.30
Magnesium stearate	??0.40	??0.80	??1.60	??3.20
					Sheet is heavy	??40.00	??80.00	??160.00	??320.00

Preparation method:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) with mannitol, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃～80 ℃ dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(D) will be mix homogeneously valsartan liposome, Amlodipine Besylate Tablet and the mannitol, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel, magnesium stearate of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(E) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(F) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(G) mixing of materials of will milling forms valsartan amlodipine granule;

(H) use rotary tablet machine that valsartan amlodipine granule is pressed into dispersible tablet, make 10000, get final product.

Embodiment 16: the capsule that comprises valsartan liposome and Amlodipine Besylate Tablet

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Amlodipine Besylate Tablet	??1.74	??3.47	??6.94	??13.88
					Calcium carbonate
30 POVIDONE K 30 BP/USP 30	??3.00	??6.00	??12.00	??24.00
					Polyvinylpolypyrrolidone	??2.00	??4.00	??8.00	??16.00

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Carboxymethylstach sodium	??1.65	??3.30	??6.60	??13.20
Micropowder silica gel	??0.41	??0.82	??1.65	??3.30
					Magnesium stearate	??1.15	??2.30	??4.60	??9.20
Capsule is heavy	??41.25	??82.50	??165.00	??330.00

Preparation method:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) with calcium carbonate, 30 POVIDONE K 30 BP/USP 30, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(D) will be mix homogeneously valsartan liposome, Amlodipine Besylate Tablet and the calcium carbonate, 30 POVIDONE K 30 BP/USP 30, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel, magnesium stearate of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(E) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(F) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(G) mixing of materials of will milling forms valsartan amlodipine granule;

(H) use the capsule subpackage machine that valsartan amlodipine granule is distributed into capsule, make 10000, get final product.

Embodiment 17: the tablet that comprises valsartan liposome and Amlodipine Besylate Tablet

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Amlodipine Besylate Tablet	??0.87	??1.74	??3.47	??6.94
					Microcrystalline Cellulose	??9.34	??18.69	??37.38	??74.76
30 POVIDONE K 30 BP/USP 30	??5.00	??10.00	??20.00	??40.00
					Carboxymethylstach sodium	??1.50	??3.00	??6.00	??12.00
Micropowder silica gel	??0.41	??0.82	??1.65	??3.30
					Magnesium stearate	??0.38	??0.75	??1.50	??3.00
Sheet is heavy	??37.50	??75.00	??150.00	??300.00

Preparation method:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) with microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃～80 ℃ dryings 6 hours, cross 100 mesh sieves and pulverize mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer then;

(D) will be mix homogeneously valsartan liposome, Amlodipine Besylate Tablet and the microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel, magnesium stearate of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(E) measure drug content, it is heavy to calculate sheet, directly makes tablet with rotary tablet machine, makes 10000, and the control tablet hardness is 4.0～10.0kg;

(F) stir with Opadry II and an amount of purified water and make coating solution, the above-mentioned tablet of suppressing is carried out film coating.

Embodiment 18: the granule that comprises valsartan liposome and Amlodipine Besylate Tablet

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Amlodipine Besylate Tablet	??0.87	??1.74	??3.47	??6.94
					Mannitol	??17.86	??35.71	??71.42	??142.84
30 POVIDONE K 30 BP/USP 30	??5.00	??10.00	??20.00	??40.00
					Sucralose	??1.25	??2.50	??5.00	??10.00
Strawberry essence	??0.02	??0.05	??0.10	??0.20
					Grain is heavy	??45.00	??90.00	??180.00	??360.00

Preparation method:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) with mannitol, sucralose respectively at 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize, then mix homogeneously;

(D) will be mix homogeneously valsartan liposome, Amlodipine Besylate Tablet and the mannitol, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(E) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;

(F) with the various supplementary materials of above-mentioned mix homogeneously and the strawberry essence of recipe quantity, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make valsartan amlodipine granule;

(G) use the granule racking machine to be distributed into granule exsiccant valsartan amlodipine granule, make 10000 bags, promptly.

Embodiment 19: the oral cavity disintegration tablet that comprises valsartan liposome and Amlodipine Besylate Tablet

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Amlodipine Besylate Tablet	??1.74	??3.47	??6.94	??13.88
					Microcrystalline Cellulose	??15.00	??30.00	??60.00	??120.00
Mannitol	??6.54	??13.08	??26.16	??52.32
					30 POVIDONE K 30 BP/USP 30	??5.00	??10.00	??20.00	??40.00
Sodium bicarbonate	??0.48	??0.95	??1.90	??3.80
					Sucralose	??1.25	??2.50	??5.00	??10.00
Sheet is heavy	??50.00	??100.00	??200.00	??400.00

Preparation method:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) with amlodipine or its pharmaceutically acceptable salt in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) with microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(D) will be mix homogeneously valsartan liposome, Amlodipine Besylate Tablet and the microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(E) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;

(F) with the various supplementary materials of above-mentioned mix homogeneously, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make valsartan amlodipine granule;

(G) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into oral cavity disintegration tablet with rotary tablet machine, makes 10000, promptly.

Embodiment 20: the drop pill that comprises valsartan liposome and Amlodipine Besylate Tablet

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??2.000	??4.000	??8.000	??16.000
Amlodipine Besylate Tablet	??0.174	??0.347	??0.694	??1.388
					??PEG6000	??6.026	??12.053	??24.106	??48.212
Polyoxyethylene sorbitan monoleate	??0.050	??0.100	??0.200	??0.400
					Ball is heavy	??8.250	??16.500	??33.000	??66.000

Preparation method:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) PEG6000 and polyoxyethylene sorbitan monoleate mixing post-heating to 55 ℃～60 ℃ are made fusion;

(D) will be the valsartan liposome of mix homogeneously and Amlodipine Besylate Tablet add to and stir in the fused solution, move in the funnel, 55 ℃～60 ℃ insulations, adjusting dropping funnel size, dimethicone with-20～-5 or liquid paraffin are the cooling phase, and the system of dripping is made 10000 balls, filter, wash, select ball, get final product.

Embodiment 21: the chewable tablet that comprises valsartan liposome and Amlodipine Besylate Tablet

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Valsartan liposome	??20.00	??40.00	??80.00	??160.00
Amlodipine Besylate Tablet	??1.74	??3.47	??6.94	??13.88
					Magnesium stearate	??0.50	??1.00	??2.00	??4.00
30 POVIDONE K 30 BP/USP 30	??4.50	??9.00	??18.00	??36.00
					Microcrystalline Cellulose	??11.76	??23.53	??47.06	??94.12
0.5% cochineal solution	??0.40	??0.80	??1.60	??3.20
					0.25% lemon yellow solution	??0.40	??0.80	??1.60	??3.20
Sucralose	??0.50	??1.00	??2.00	??4.00
					Mannitol	??10.0	??20.00	??40.00	??80.00

The supplementary material title	Dosage 1 (mg)	Dosage 2 (mg)	Dosage 3 (mg)	Dosage 4 (mg)
					Strawberry essence	??0.20	??0.40	??0.80	??1.60
Sheet is heavy	??50.00	??100.00	??200.00	??400.00

Preparation method:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) with magnesium stearate, sucralose, mannitol and microcrystalline Cellulose respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(D) will be mix homogeneously valsartan liposome, Amlodipine Besylate Tablet and the microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(E) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;

(F) with the various supplementary materials of above-mentioned mix homogeneously and 0.5% cochineal solution, 0.25% lemon yellow solution, the strawberry essence of recipe quantity, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, crossing 18 mesh sieves granulates, 55 ℃ of oven dry, 16 order granulate make valsartan amlodipine granule;

(G) measure intermediate content, it is heavy to calculate sheet according to assay, uses rotary tablet machine that valsartan amlodipine granule is pressed into chewable tablet, makes 10000, promptly.

Embodiment 22: the monolayer tablet that comprises valsartan liposome and Amlodipine Besylate Tablet

Preparation method:

(I) the particulate granulation of valsartan liposome:

(A) valsartan liposome being crossed 80 mesh sieves pulverizes;

(B) with 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(C) valsartan liposome that will sieve and 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate and the carboxymethylstach sodium of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(E) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(F) mixing of materials of will milling forms the valsartan liposome granule, and is standby;

(II) the particulate granulation of amlodipine:

(G) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize;

(H) with 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(I) Amlodipine Besylate Tablet that will sieve and 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate and the carboxymethylstach sodium of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(J) 30 POVIDONE K 30 BP/USP 30 usefulness 50% ethanol of recipe quantity is made 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, make adhesive and use;

(K) with the various supplementary materials of above-mentioned mix homogeneously, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make the amlodipine granule, and are standby;

(III) be pressed into the monolayer tablet:

(L) with the above-mentioned valsartan liposome granule that makes and amlodipine granule in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(M) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into the monolayer tablet with rotary tablet machine, makes 10000, promptly.

Embodiment 23: the monolayer tablet that comprises valsartan liposome and amlodipine maleate

Preparation method:

(I) the particulate granulation of valsartan liposome:

(A) with valsartan liposome in 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize;

(B) with 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(C) valsartan liposome that will sieve and 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate and the carboxymethylstach sodium of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) 30 POVIDONE K 30 BP/USP 30 usefulness 50% ethanol of recipe quantity is made 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, make adhesive and use;

(E) with the various supplementary materials of above-mentioned mix homogeneously, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make the valsartan liposome granule, and are standby;

(II) the particulate granulation of amlodipine maleate:

(F) with amlodipine maleate in 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize;

(G) with 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(H) amlodipine maleate that will sieve and 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate and the carboxymethylstach sodium of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(I) 30 POVIDONE K 30 BP/USP 30 usefulness 50% ethanol is made 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, make adhesive and use;

(J) with the various supplementary materials of above-mentioned mix homogeneously, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make the amlodipine maleate granule, and are standby;

(III) compressed single tablet:

(K) with the above-mentioned valsartan liposome granule that makes and amlodipine maleate granule in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(L) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into the monolayer tablet with rotary tablet machine, makes 10000, promptly.

Embodiment 24: the bilayer tablet that comprises valsartan liposome and Levamlodipine besylate

Preparation method:

(I) the particulate granulation of Levamlodipine besylate:

(A) with Levamlodipine besylate in 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize;

(B) with 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(C) Levamlodipine besylate that will sieve and 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate and the carboxymethylstach sodium of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(D) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(E) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(F) mixing of materials of will milling forms the Levamlodipine besylate granule, and is standby;

(G) measure valsartan liposome granule intermediate content, calculate packing weight according to assay;

(II) the particulate granulation of valsartan liposome:

(H) valsartan liposome being crossed 80 mesh sieves pulverizes;

(I) with 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;

(J) valsartan liposome that will sieve and 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate and the carboxymethylstach sodium of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;

(K) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;

(L) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(M) mixing of materials of will milling forms the valsartan liposome granule, and is standby;

(N) measure valsartan liposome granule intermediate content, calculate packing weight according to assay;

(III) be pressed into bilayer tablet:

(0) last, use double-deck rotary tablet machine that the Levamlodipine besylate granule is pressed into ground floor, subsequently the valsartan liposome granule is pressed into the second layer, make 10000, this bilayer tablet can randomly carry out the film coating.

Embodiment 25: the mensuration of envelop rate

Get the valsartan liposome of embodiment 1～5 preparation, the total content that high performance liquid chromatography detects valsartan is M, selects for use column chromatography to separate liposome.

Get 1.5g sephadex G-50, soak swelling more than 12 hours with the pH6.8 phosphate buffer, pack in the chromatographic column (200mm * 10mm), with above-mentioned phosphate buffer flushing balance, get the valsartan liposome that embodiment 1～5 makes, add water and make dissolving, make the solution that every 1ml contains valsartan 10mg approximately, get solution 1.0ml respectively, add the chromatographic column top, with above-mentioned phosphate buffer 50ml eluting, flow velocity 1.2ml/min, the eluent of collecting adds rupture of membranes agent (ethanol: 50ml benzyl alcohol=8: 1), mixing, the content M1 of high performance liquid chromatography detection valsartan.

Envelop rate %=M1/M * 100%.

Investigate 0,3,6,24 month respectively, result such as following table:

Obviously, the above embodiment of the present invention only is for example of the present invention clearly is described, and is not to be qualification to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here need not also can't give exhaustive to all embodiments.And these belong to conspicuous variation or the change that spirit of the present invention extended out and still are among protection scope of the present invention.

Claims (10)

1. a valsartan liposome is characterized in that, described valsartan liposome is made up of valsartan or its pharmaceutically acceptable salt and phospholipid, and wherein the weight of phospholipid is valsartan or its pharmaceutically acceptable salt 1～10 times.

2. valsartan liposome as claimed in claim 1 is characterized in that, described valsartan or its pharmaceutically acceptable salt are preferably valsartan.

3. as claim 1,2 each described valsartan liposomes, it is characterized in that described phospholipid is selected from one or more in hydrogenated soy phosphatidyl choline, soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, two stearic acid lecithin, two palmitic acid lecithin, two myristic acid lecithin, EPG, egg yolk lecithin acyl serine, the egg yolk lecithin acyl inositol.

4. a method for preparing each described valsartan liposome of claim 1 to 3 is characterized in that, described preparation method comprises:

(1) phospholipid of valsartan or its pharmaceutically acceptable salt and 1～10 times is dissolved in 1～20 times the organic solvent, mix homogeneously, recording volume filters, and evaporation is removed organic solvent and is made immobilized artificial membrane, drying;

(2) the adding pH value is 3.0～7.5 buffer, soaked 1～2 hour, and high-speed stirred, after 5～20 minutes,, concentration dissolved with same buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.5～1.0mg/ml ₃₀Solution, and supply buffer to original volume;

(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get valsartan liposome.

5. a pharmaceutical composition is characterized in that, is made up of each described valsartan liposome of claim 1 to 4 and pharmaceutically acceptable carrier.

6. a pharmaceutical composition is characterized in that, is made up of each described valsartan liposome of claim 1 to 4 and amlodipine or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

7. pharmaceutical composition as claimed in claim 6 is characterized in that, described amlodipine or its pharmaceutically acceptable salt are preferably Amlodipine Besylate Tablet.

8. the tablet, capsule, chewable tablet, oral cavity disintegration tablet, drop pill, granule or the dispersible tablet that comprise each described valsartan liposome of claim 1 to 7.

9. method for preparing claim 5,8 each described pharmaceutical compositions is characterized in that described preparation method comprises:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) various pharmaceutically acceptable carriers are carried out drying respectively, cross 80～100 mesh sieves and pulverize, then mix homogeneously;

(C) valsartan liposome that will sieve and the various pharmaceutically acceptable carrier of mix homogeneously in blender by the equivalent method mix homogeneously that progressively increases;

(D) the mixed powder compacting that above-mentioned mixing is obtained forms compacting material;

(E) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(F) mixing of materials of will milling forms the valsartan liposome granule;

(G) use tablet machine that the valsartan liposome granule is pressed into tablet or dispersible tablet, perhaps use the capsule subpackage machine that the valsartan liposome granule is distributed into capsule.

10. a method for preparing each described pharmaceutical composition of claim 6 to 8 is characterized in that, described preparation method comprises:

(A) valsartan liposome is pulverized, crossed 80 mesh sieves;

(B) amlodipine or its pharmaceutically acceptable salt are carried out drying, cross 100 mesh sieves and pulverize, then with the valsartan liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;

(C) various pharmaceutically acceptable carriers are carried out drying respectively, cross 80～100 mesh sieves and pulverize, then mix homogeneously;

(D) will be the various pharmaceutically acceptable carrier of valsartan liposome, amlodipine or its pharmaceutically acceptable salt and mix homogeneously of mix homogeneously in blender by the equivalent method mix homogeneously that progressively increases;

(E) the mixed powder compacting that above-mentioned mixing is obtained forms compacting material;

(F) will be the compacting material cross 80 mesh sieves and mill and form the material of having milled;

(G) mixing of materials of will milling forms valsartan amlodipine granule;

(H) use tablet machine that valsartan amlodipine granule is pressed into tablet or dispersible tablet, perhaps use the capsule subpackage machine that valsartan amlodipine granule is distributed into capsule.