CN101972263A - Valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation - Google Patents
Valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation Download PDFInfo
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Abstract
The invention relates to a valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation as well as a preparation method and application thereof to preparing a medicament for treating mild and moderate primary hypertension which can not be fully controlled by a single medicament. The valsartan hydrochlorothiazide pharmaceutical composition liposome mainly comprises valsartan, hydrochlorothiazide, soyabean phosphatidylserine, glycocholatesodium and tween 80. The solid preparation of the invention improves the stability and dissolution rate of medicaments and has less side effect and more obvious curative effect; and the preparation method has the advantages of simple equipment and easy operation and is beneficial to industrialized mass production. The solid preparation of the invention has obvious curative effect on treating the mild and moderate primary hypertension which can not be fully controlled by a single medicament.
Description
Technical field
The present invention relates to a kind of valsartan and Hydrochlorothiade medicine compound liposome solid preparation and method for making thereof, also relate to this solid preparation the treatment single medicine fully controlling blood pressure gently, application in the moderate essential hypertension, belong 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 valsartan and hydrochlorothiazide can solve the problem that present single medicine cann't be solved, and treats light moderate hypertension disease preferably.
Valsartan: 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.Valsartan 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 valsartan does not have the activity of partial agonist to the AT1 receptor.Valsartan 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.Valsartan does not have inhibitory action to ACE, does not cause the retention of Kallidin I and P material, so be difficult for causing cough.The relatively clinical trial confirmation of valsartan and ACE inhibitor, the incidence rate (2.6%) of valsartan group dry cough significantly be lower than ACE inhibitor group (7.9%) (P＜; 0.05).Find once accepting the clinical trial that the dry cough symptom takes place in ACE inhibitor treatment back patient carries out at one, valsartan group, diuretic group, ACEI group have respectively 19.5%, 19.0%, 68.5% patient occur cough (P＜; 0.05).Valsartan does not have influence to other known hormone receptor or ion channels that play an important role in cardiovascular is regulated.Valsartan 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.
Hydrochlorothiazide: the main site of action of 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.
Valsartan and hydrochlorothiazide use in conjunction strengthen the hypotensive effect of valsartan significantly.Even stop the valsartan treatment suddenly, can not cause hypertension " knock-on or other side effect yet.Valsartan does not influence hyperpietic's empty stomach T-CHOL, triglyceride, blood glucose or uric acid level.
Chinese patent 200610050161.7 discloses a kind of valsartan and Hydrochlorothiade pills and preparation technology thereof, is made up of valsartan, hydrochlorothiazide and drop pill substrate, and valsartan and hydrochlorothiazide weight ratio are 8: 1.25.Chinese patent 200710046393.6 discloses a kind of solid orally ingestible that contains valsartan and preparation method thereof, with valsartan and pharmaceutically acceptable salt thereof and (or) hydrochlorothiazide is active component, by active constituents of medicine is obtained compact with the roll-in method compacting; Compact sieved or grind obtain granulate; Mix with pharmaceutic adjuvant again, mixture is changed into solid orally ingestible.Chinese patent 200780024142.x discloses solid preparation of a kind of valsartan, amlodipine and hydrochlorothiazide and preparation method thereof.Above-mentioned patent is valsartan and hydrochlorothiazide drug combination, but the product bioavailability that makes is relatively poor, because main component valsartan poorly water-soluble, the preparation dissolution that makes is very low, and stability of formulation is poor, places for a long time to occur the defective phenomenon of content in 12 months.
Summary of the invention
The inventor is through research in earnest for a long time, find to adopt the combination of soy phosphatidylserine, natrii tauroglycocholas, these three kinds of materials of Tween 80 according to special ratios, itself and valsartan, hydrochlorothiazide are prepared into liposome by a certain percentage, again this liposome preparation is become solid preparation, the stability and the not good technical problem of envelop rate of liposome can have been solved, obtained beyond thought preparation effect, thereby superior in quality lipidosome solid preparation is provided.Though the mechanism of the advantageous property of this liposome also is not clear and definite especially, the inventor expects that the effect of preparation of the present invention may be the common and/or synergistic result of soy phosphatidylserine, natrii tauroglycocholas, three kinds of materials of Tween 80.And for this area membrane material phospholipid and cholesterol commonly used, for example natural phospholipid and synthetic phospholipid, such as Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soy phosphatidyl choline, soybean phospholipid acyl glycerol, soy phosphatidylserine, soybean phospholipid acyl inositol, the 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, two lauroyl phosphatidyl glycerols etc., adopt wherein any one or two kinds of, according to this area routine techniques, all can there be less stable in the valsartan and Hydrochlorothiade liposome for preparing, problems such as envelop rate is low, especially 40 ℃ of high temperature, under relative humidity 75% ± 5% accelerated test, these shortcomings are more obvious, both be unfavorable for storing, also be unfavorable for clinical practice.
Therefore, the object of the present invention is to provide a kind of valsartan and Hydrochlorothiade medicine compound liposome solid preparation, combined preparation by active component valsartan, hydrochlorothiazide and soy phosphatidylserine, natrii tauroglycocholas, Tween 80 becomes liposome earlier, make solid preparation with other pharmaceutically acceptable mixed with excipients again, greatly improved its dissolubility in water, help the stripping of pharmaceutical preparation, improved bioavailability and stability of formulation.
Valsartan and Hydrochlorothiade medicine compound liposome solid preparation provided by the invention, comprise valsartan, hydrochlorothiazide, soy phosphatidylserine, natrii tauroglycocholas, Tween 80 and be suitable for preparing other pharmaceutically acceptable excipient of solid preparation, the part by weight of described component is:
80 parts of valsartan
12.5 parts of hydrochlorothiazide
Soy phosphatidylserine 140-680 part
Natrii tauroglycocholas 65-330 part
Tween 80 50-280 part
Other pharmaceutically acceptable excipient 400-600 part.
In a preferred embodiment of the invention, each composition weight ratio of described valsartan and Hydrochlorothiade medicine compound liposome solid preparation is:
80 parts of valsartan
12.5 parts of hydrochlorothiazide
Soy phosphatidylserine 180-420 part
Natrii tauroglycocholas 80-170 part
Tween 80 66-130 part
Other pharmaceutically acceptable excipient 450-550 part.
In a preferred embodiment of the invention, described valsartan and Hydrochlorothiade medicine compound liposome solid preparation is made up of the above-mentioned component of listing.
In one embodiment of the invention, described valsartan and Hydrochlorothiade medicine compound liposome solid preparation comprises 80 parts of valsartan, 12.5 parts of hydrochlorothiazide, 180 parts of soy phosphatidylserines, 80 parts of natrii tauroglycocholass, 66 parts of Tween 80s and other pharmaceutically acceptable excipient 450-550 part.
In a preferred embodiment of the invention, described pharmaceutical composition solid preparation comprises tablet, dispersible tablet or capsule.
In the present invention, described other pharmaceutically acceptable excipient is selected from diluent, disintegrating agent, binding agent, fluidizer, lubricant and their combination thereof, and its consumption can be selected according to the general consumption of each excipient in solid preparation by those skilled in the art.
Further, as preferably, diluent can be selected from one or more the combination in starch, microcrystalline Cellulose, lactose, mannitol, sorbitol, dextrin, glucose, the sucrose, is preferably lactose and sorbitol.Its consumption can be preferably 20%-60% (w/w) for the 10%-80% (w/w) of described solid preparation gross weight.
Further, as preferably, disintegrating agent can be selected from one or more the combination in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the pregelatinized Starch, is preferably carboxymethylstach sodium or polyvinylpolypyrrolidone.Its consumption can be preferably 3%-6% (w/w) for the 1%-10% (w/w) of described solid preparation gross weight.
Further, as preferably, binding agent can be selected from a kind of in hypromellose, 30 POVIDONE K 30 BP/USP 30, sodium carboxymethyl cellulose, xanthan gum, arabic gum, methylcellulose, the ethyl cellulose, is preferably 30 POVIDONE K 30 BP/USP 30.Its consumption can be preferably 0.02%-0.5% (w/w) for the 0.01%-2% (w/w) of described solid preparation gross weight.
Further, as preferably, fluidizer or lubricant can be selected from one or more the combination in Pulvis Talci, micropowder silica gel, magnesium stearate, zinc stearate, Macrogol 4000, the stearic acid, are preferably Pulvis Talci and magnesium stearate.Its consumption can be preferably 1%-3% (w/w) for the 0.5%-5% (w/w) of described solid preparation gross weight.
In the preferred embodiments of the invention, wherein the valsartan chemistry is by name: N-1-valeryl-N-[4-[2-1H-tetrazole-5-base phenyl] benzyl]-the L-valine, molecular formula is: C
24H
29N
5O
3, molecular weight: 435.52, structural formula is:
The specification dosage of valsartan is 40-120mg, is preferably 80mg.
In the preferred embodiments of the invention, wherein the hydrochlorothiazide chemistry is called 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, molecular formula C
7H
8ClN
3O
4S
2, molecular weight is 297.74, structural formula is:
The specification dosage of hydrochlorothiazide is 5-50mg, is preferably 12.5mg.
The present invention also provides a kind of preparation method of valsartan and Hydrochlorothiade medicine compound liposome solid preparation, and step comprises:
(1) preparation of liposome: valsartan, hydrochlorothiazide and soy phosphatidylserine, natrii tauroglycocholas, Tween 80 are prepared into lipidosome solid together;
(2) preparation of solid preparation: lipidosome solid and other pharmaceutically acceptable mixed with excipients that step (1) is obtained prepare the valsartan and Hydrochlorothiade solid preparation, and wherein said other pharmaceutically acceptable excipient is selected from diluent, disintegrating agent, binding agent, fluidizer, lubricant and combination thereof.
In preparation method of the present invention, the preparation of step (1) liposome comprises following concrete steps:
(a) soy phosphatidylserine, natrii tauroglycocholas, Tween 80 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) add buffer solution, transferring pH with the pH regulator agent is 5.0-6.0, and jolting is stirred, and makes the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) valsartan and hydrochlorothiazide are scattered in the water, add in the blank liposome suspension again, be incubated 50-70 ℃ and stirred 60-90 minute, spray drying makes lipidosome solid.
In preparation method of the present invention, the preparation of step (2) solid preparation comprises the steps:
(d) valsartan and hydrochlorothiazide lipidosome solid and diluent, disintegrating agent are mixed, the mix homogeneously that sieves adds binder solution and prepares soft material, the granulation of sieving, 60 ℃ of dryings;
(e) dried granule and fluidizer or mix lubricant is even, granulate sieves;
(f) tabletting or filled capsules make the valsartan and Hydrochlorothiade lipidosome solid preparation.
Wherein, can be with 0.45 μ m filtering with microporous membrane in the step (b); The mixing of sieving in the step (d) is preferably crossed the 60-80 mesh sieve and is mixed; The granulate that sieves in sieving granulation and the step (e) in the step (d) is preferably crossed 20 mesh sieves; What the binder solution in the step (d) referred to is certain density ethanol water, and concentration of ethanol is also inequality according to the different amounts of binding agent, and this can be determined that the general concentration of alcohol that adopts is 20%-95% by those skilled in the art.
Wherein, jolting in the step (b), the degree of stirring gets final product for making the complete aquation of immobilized artificial membrane, and high-speed tissue mashing machine is adopted at a high speed even matter emulsifying, and rotating speed is 2000-5000r/min, and such as 3000r/min, even matter emulsifying number of times can be 5 times, each 3-5min.
Buffer solution described in the preparation method of the present invention is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer, borate buffer solution and the carbonate buffer solution, preferred pH value is a kind of in 5.4 phosphate buffer, citrate buffer, acetate buffer, borate buffer solution and the carbonate buffer solution, preferably citric acid-citric acid is received towards solution, and more preferably pH value is that citric acid-sodium citrate of 5.4 is towards solution.
PH value regulator described in the preparation method of the present invention is selected from one or both in potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, hydrochloric acid, citric acid, the phosphoric acid, is preferably citric acid and sodium citrate.
Organic solvent described in the preparation method of the present invention is selected from one or more in chloroform, dichloromethane, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, acetonitrile, benzyl alcohol, the normal hexane, and mixed solvent, chloroform and the acetone volume ratio that is preferably dichloromethane and acetonitrile volume ratio and is 1: 2 is that 1: 5 mixed solvent, ethanol and isopropyl alcohol volume ratio is 1: 3 mixed solvent.Wherein the consumption of organic solvent does not have specific requirement, and can dissolve soy phosphatidylserine, natrii tauroglycocholas, Tween 80 fully for being advisable, those skilled in the art can determine suitable consumption according to routine techniques and instruction of the present invention.
The method of valsartan and Hydrochlorothiade medicine compound liposome solid preparation of the present invention also can comprise tablet bag film-coat step, after obtaining plain sheet, with the plain sheet bag gastric solubleness film-coat (can be any coating materials known in the art) of gained, weightening finish 1-5% makes Film coated tablets.
The present invention also provide described valsartan and Hydrochlorothiade medicine compound liposome solid preparation the treatment single medicine fully controlling blood pressure gently, application in the moderate essential hypertension.By with the valsartan and Hydrochlorothiade sheet clinical case observation of curative effect contrast of listing, fully shown valsartan and Hydrochlorothiade lipidosome solid preparation of the present invention the treatment single medicine fully controlling blood pressure gently, compare the remarkable superiority of similar medicine in the moderate essential hypertension.
The present invention becomes liposome by the specific combined preparation of active component valsartan, hydrochlorothiazide and soy phosphatidylserine, natrii tauroglycocholas, Tween 80 earlier, make solid preparation with other pharmaceutically acceptable mixed with excipients again, its stability and dissolution have greatly been improved, side effect is littler, more remarkable treatment effect; Used adjuvant cheap and simple, the availability height, pollute little, economic worth height, and the equipment of preparation method is simple, easy operating is very advantageous in industrialized great production.
In this article, if not explanation especially, content or consumption are all in weight portion; If not explanation especially, the device that is adopted, instrument, raw material, material, consumption, method, time, temperature and other condition etc. all are well-known in the art, or those skilled in the art can obtain in conjunction with prior art according to the application's description.
The specific embodiment
The preparation of embodiment 1 valsartan and Hydrochlorothiade sheet
Prescription: (1000)
Amounts of components
Valsartan 80g
Hydrochlorothiazide 12.5g
Soy phosphatidylserine 180g
Natrii tauroglycocholas 80g
Tween 80 66g
Lactose 240g
Sorbitol 100g
Carboxymethylstach sodium 50g
30 POVIDONE K 30 BP/USP 30 20g
Pulvis Talci 30g
Magnesium stearate 10g
Preparation technology:
(a) 180g soy phosphatidylserine, 80g natrii tauroglycocholas, 66g Tween 80 being dissolved in 1500ml dichloromethane and acetonitrile volume ratio is in 1: 2 the mixed solvent, mix homogeneously, and mixed solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) add pH value 5.4 citric acid-sodium citrate buffer solution 800ml, transferring pH with 5% citric acid soln is 5.0, jolting, stir, make the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5 times, each 5min, rotating speed 2000r/min, 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(c) 80g valsartan and 12.5g hydrochlorothiazide are dissolved in 1000ml water, 0.45 μ m filtering with microporous membrane, filtrate adds in the blank liposome suspension, is incubated 50 ℃ and stirs 90 minutes, and spray drying makes lipidosome solid;
(d) with above-mentionedly obtain lipidosome solid and 240g lactose, 100g sorbitol, the 50g carboxymethylstach sodium mixes, and crosses 80 mesh sieve mix homogeneously, 50% alcoholic solution that adds 5% 30 POVIDONE K 30 BP/USP 30 prepares soft material, crosses 20 mesh sieves and granulates 60 ℃ of dryings;
(e), cross 20 mesh sieve granulate with dried granule and 30g Pulvis Talci, 10g magnesium stearate mix homogeneously;
(f) tabletting makes valsartan and Hydrochlorothiade liposome sheet, is the off-white color sheet.
The preparation of embodiment 2 valsartan and Hydrochlorothiade sheets
Prescription: (1000)
Constituent content
Valsartan 80g
Hydrochlorothiazide 12.5g
Soy phosphatidylserine 420g
Natrii tauroglycocholas 170g
Tween 80 130g
Microcrystalline Cellulose 225g
Starch 132g
Polyvinylpolypyrrolidone 70g
Low-substituted hydroxypropyl cellulose 40g
Hypromellose 18g
Micropowder silica gel 50g
Magnesium stearate 15g
Preparation technology:
(a) 420g soy phosphatidylserine, 170g natrii tauroglycocholas, 130g Tween 80 being dissolved in 5000ml dichloromethane and acetonitrile volume ratio is in 1: 2 the mixed solvent, mix homogeneously, and mixed solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) add pH value 5.4 citric acid-sodium citrate buffer solution 3000ml, transferring pH with 10% liquor sodii citratis is 6.0, jolting, stir, make the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5 times, each 3min, rotating speed 5000r/min, 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(c) 80g valsartan and 12.5g hydrochlorothiazide are dissolved in 1000ml water, 0.45 μ m filtering with microporous membrane, filtrate adds in the blank liposome suspension, is incubated 70 ℃ and stirs 60 minutes, and spray drying makes lipidosome solid;
(d) with above-mentionedly obtain lipidosome solid and 225g microcrystalline Cellulose, 132g starch, 70g polyvinylpolypyrrolidone, the 40g low-substituted hydroxypropyl cellulose mixes, cross 60 mesh sieve mix homogeneously, 20% alcoholic solution that adds 2% hypromellose prepares soft material, crosses 20 mesh sieves and granulates 60 ℃ of dryings;
(e), cross 20 mesh sieve granulate with dried granule and 50g micropowder silica gel, 15g magnesium stearate mix homogeneously;
(f) tabletting makes valsartan and Hydrochlorothiade liposome sheet, is the off-white color sheet;
(g) the bag film-coat is pressed plain sheet bag gastric solubleness film-coat with institute, coating weightening finish 2.5%, and drying makes the valsartan and Hydrochlorothiade Film coated tablets.
The preparation of embodiment 3 valsartan and Hydrochlorothiade dispersible tablets
Prescription: (1000)
Amounts of components
Valsartan 80g
Hydrochlorothiazide 12.5g
Soy phosphatidylserine 680g
Natrii tauroglycocholas 330g
Tween 80 280g
Lactose 80g
Microcrystalline Cellulose 240g
Carboxymethylstach sodium 110g
Cross-linking sodium carboxymethyl cellulose 60g
30 POVIDONE K 30 BP/USP 30 30g
Pulvis Talci 60g
Magnesium stearate 20g
Preparation technology:
(a) with in 680g soy phosphatidylserine, the 330g taurine, to be dissolved in 8000ml chloroform and acetone volume ratio be in 1: 5 the mixed solvent to the 280g Tween 80, mix homogeneously, mixed solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) add pH value 5.4 sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution 4000ml, transferring pH with the 0.1M hydrochloric acid solution is 5.2, jolting, stir, make the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5 times, each 5min, rotating speed 4000r/min, 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(c) 80g valsartan and 12.5g hydrochlorothiazide are scattered in the 1000ml water, add in the blank liposome suspension again, be incubated 60 ℃ and stirred 70 minutes, spray drying makes lipidosome solid;
(d) with above-mentionedly obtain lipidosome solid and 240g microcrystalline Cellulose, 80g lactose, 110g carboxymethylstach sodium, the 60g cross-linking sodium carboxymethyl cellulose mixes, cross 80 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;
(e), cross 20 mesh sieve granulate with dried granule and 60g Pulvis Talci, 20g magnesium stearate mix homogeneously;
(f) tabletting makes valsartan and Hydrochlorothiade liposome dispersible tablet, is the off-white color sheet.
The capsular preparation of embodiment 4 valsartan and Hydrochlorothiades
Prescription: (1000)
Amounts of components
Valsartan 80g
Hydrochlorothiazide 12.5g
Soy phosphatidylserine 140g
Natrii tauroglycocholas 65g
Tween 80 50g
Microcrystalline Cellulose 315g
Pregelatinized Starch 50g
30 POVIDONE K 30 BP/USP 30 15g
Pulvis Talci 20g
Preparation technology:
(a) 140g soy phosphatidylserine, 65g natrii tauroglycocholas, 50g Tween 80 being dissolved in 4000ml ethanol and isopropyl alcohol volume ratio is in 1: 3 the mixed solvent, mix homogeneously, and mixed solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) add pH value 5.4 acetic acid-sodium acetate buffer solution 2000ml, transferring pH with 5% sodium carbonate liquor is 5.8, jolting, stir, make the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5 times, each 4min, rotating speed 3000r/min, 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(c) 80g valsartan and 12.5g hydrochlorothiazide are scattered in the 1000ml water, add in the blank liposome suspension again, be incubated 60 ℃ and stirred 90 minutes, spray drying makes lipidosome solid;
(d) with above-mentionedly obtain lipidosome solid and 315g microcrystalline Cellulose, the 50g pregelatinized Starch mixes, and crosses 80 mesh sieve mix homogeneously, 80% alcoholic solution that adds 5% 30 POVIDONE K 30 BP/USP 30 prepares soft material, crosses 20 mesh sieves and granulates 60 ℃ of dryings;
(e), cross 20 mesh sieve granulate with dried granule and 20g Pulvis Talci mix homogeneously;
(f) filled capsules with the granule branch of the gained capsule of packing into, makes the valsartan and Hydrochlorothiade capsule.
The investigation of test example 1 liposome
Sample prepared among the embodiment 1-4 is carried out quality investigation, mainly carry out liposome morphologic observation, particle size determination and liposome encapsulation and measure.
Wherein liposome form and particle size determination adopt optical microscopy and the computing of statistica5.0 statistical software to observe about 2000 to average.Entrapment efficiency determination adopts column chromatography for separation in conjunction with spectrophotometry, this method operating procedure is: use column chromatography the liposome in the drug solution is separated, utilize surfactant to destroy the liposome bilayer, after being discharged, medicine calculates envelop rate with HPLC method and standard control again, by formula Q
Ooze%=(W
Bag-W
Storage)/W
Bag* 100% calculates percolation ratio.
Every result adds up as following table 1:
The investigation of table 1 liposome
| The liposome form | Mean diameter (nm) | Envelop rate (%) | Percolation ratio (%) | |
| Embodiment 1 | Spherical or oval entity | 320 | 85.6 | 0.58 |
| Embodiment 2 | Spherical or oval entity | 360 | 84.7 | 0.66 |
| Embodiment 3 | Spherical or oval entity | 280 | 85.9 | 0.81 |
| Embodiment 4 | Spherical or oval entity | 310 | 84.3 | 0.72 |
Above result has proved absolutely that the liposome effect of embodiment of the invention 1-4 preparation is fine, the form rule, and the size homogeneous, envelop rate is higher, and percolation ratio is very low, has proved practical feasibility of the present invention.
Test example 2 stability and dissolution are investigated
With the sample of above embodiment 1-4 preparation and (the special medicine company limited production of Shandong southern Shandong shellfish of the valsartan and Hydrochlorothiade sheet of listing, lot number 20091103) under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 month, carry out accelerated test and investigate, the results are shown in Table 2.
Table 2 accelerated test result
Be found that by above the valsartan and Hydrochlorothiade sheet dissolution of listing is low, content reduces obviously when quickening June, and related substance raises; And the sample dissolution height of embodiment of the invention preparation quickens 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 3 efficacy of antihypertensive treatment clinical trials of test example relatively
1, object of study is selected
Selecting light, moderate hyperpietic's 56 examples is object of study, its age 30-65 year, average 57.1 ± 6.2 years old.SBP (systolic pressure) 〉=140mmHg (1mmHg=0.133kPa), DBP (diastolic pressure) 〉=95mmHg.
Patient's 56 examples be will be selected in and valsartan of the present invention/hydrochlorothiazide group and listing valsartan/hydrochlorothiazide group, every group 28 example will be divided at random.
2, research method
Valsartan of the present invention/hydrochlorothiazide group: the valsartan and Hydrochlorothiade sheet of the administration embodiment of the invention 1 preparation, 1 slice/day, took medicine continuously for 8 weeks;
Listing valsartan/hydrochlorothiazide group: administration valsartan/hydrochlorothiazide tablet (the special medicine company limited of Shandong southern Shandong shellfish is produced lot number 20091103), 1 slice/day, took medicine continuously for 8 weeks;
3, efficacy assessment standard
The evaluation of blood pressure is judged according to relevant medicine for cardiovascular system clinical trial evaluation criterion in the Ministry of Public Health " Clinical Researches of New Drugs guideline ".
Produce effects: DBP (diastolic pressure) decline 1.33kPa above and reduce to normal (＜11.33kPa) or decline＞2.67kPa;
Effectively: DBP (diastolic pressure) decline＜1.33kPa but reduce to normal or decline 1.33-2.67kPa;
Invalid: as not reach above-mentioned standard.
4, result of the test
(1) two group of base case is relatively: general biochemical indicator comparative results such as two groups of patient ages, height, blood pressure, body weight are as follows:
Table 3 base case relatively
(2) variation of SBP (systolic pressure) and DBP (diastolic pressure) is compared before and after the treatment
Table 4 blood pressure lowering changes relatively
By The above results as can be seen, two groups of SBP (systolic pressure) and DBP (diastolic pressure) all have significant reduction before and after the treatment, and valsartan and Hydrochlorothiade group efficacy of antihypertensive treatment is remarkable but valsartan and Hydrochlorothiade group of the present invention is gone on the market.
(3) variation of biochemical indicator is compared before and after the treatment
The comparison of table 5 biochemical indicator
By The above results as can be seen, two groups of blood potassium, sodium, creatinine, blood urea nitrogen, uric acid, glutamic oxaloacetic transaminase, GOT, glutamate pyruvate transaminase and creatine kinases have no significant change before and after the treatment.
(4) untoward reaction
Headache 1 example (3.57%), dizzy 0 example (0%), 1 example of coughing (3.57%) take place in valsartan and Hydrochlorothiade group of the present invention.
Headache 3 examples (10.7%) dizzy 2 examples (7.14%), 2 examples of coughing (7.14%), polyuria 2 examples (7.14%) take place in listing valsartan and Hydrochlorothiade group.
Conclusion: as can be known by the The above results data, almost there is not significant change before and after two groups of patients' base case, the biochemical indicator treatment, and SBP (systolic pressure) and DBP (diastolic pressure) all have remarkable reduction, and valsartan and Hydrochlorothiade group efficacy of antihypertensive treatment is more remarkable but valsartan and Hydrochlorothiade group of the present invention is gone on the market.Proved absolutely valsartan and Hydrochlorothiade chemical compound lipidosome solid preparation of the present invention aspect blood pressure lowering, in particular for the treatment single medicine fully controlling blood pressure gently, the superiority of moderate essential hypertension.
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. valsartan and Hydrochlorothiade medicine compound liposome solid preparation, it is characterized in that comprising valsartan, hydrochlorothiazide, soy phosphatidylserine, natrii tauroglycocholas, Tween 80 and be suitable for preparing other pharmaceutically acceptable excipient of solid preparation, each composition weight ratio is:
80 parts of valsartan
12.5 parts of hydrochlorothiazide
Soy phosphatidylserine 140-680 part
Natrii tauroglycocholas 65-330 part
Tween 80 50-280 part
Other pharmaceutically acceptable excipient 400-600 part.
2. medicine compound liposome solid preparation according to claim 1 is characterized in that each composition weight ratio is:
80 parts of valsartan
12.5 parts of hydrochlorothiazide
Soy phosphatidylserine 180-420 part
Natrii tauroglycocholas 80-170 part
Tween 80 66-130 part
Other pharmaceutically acceptable excipient 450-550 part.
3. medicine compound liposome solid preparation according to claim 1 and 2 is characterized in that described other pharmaceutically acceptable excipient is selected from diluent, disintegrating agent, binding agent, fluidizer, lubricant and combination thereof.
4. a method for preparing each described medicine compound liposome solid preparation among the claim 1-3 is characterized in that comprising the steps:
(1) preparation of liposome: valsartan, hydrochlorothiazide and soy phosphatidylserine, natrii tauroglycocholas, Tween 80 are prepared into lipidosome solid together;
(2) preparation of solid preparation: lipidosome solid and other pharmaceutically acceptable mixed with excipients are prepared the valsartan and Hydrochlorothiade solid preparation, and wherein said other pharmaceutically acceptable excipient is selected from diluent, disintegrating agent, binding agent, fluidizer, lubricant and combination thereof.
5. preparation method according to claim 4 is characterized in that the preparation of step (1) liposome specifically comprises the steps:
(a) soy phosphatidylserine, natrii tauroglycocholas, Tween 80 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) add buffer solution, transferring pH with the pH regulator agent is 5.0-6.0, and jolting is stirred, and makes the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(c) valsartan and hydrochlorothiazide are scattered in the water, add in the blank liposome suspension again, be incubated 50-70 ℃ and stirred 60-90 minute, spray drying makes the valsartan and Hydrochlorothiade lipidosome solid.
6. preparation method according to claim 4 is characterized in that the preparation of step (2) solid preparation comprises the steps:
(d) valsartan and Hydrochlorothiade lipidosome solid and diluent, disintegrating agent are mixed, the mix homogeneously that sieves adds binder solution and prepares soft material, the granulation of sieving, drying;
(e) dried granule and fluidizer or mix lubricant is even, granulate sieves;
(f) tabletting or filled capsules make the valsartan and Hydrochlorothiade lipidosome solid preparation.
7. preparation method according to claim 5, it is characterized in that described buffer solution is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer, borate buffer solution and the carbonate buffer solution, preferred pH value is 5.4 above-mentioned buffer, and more preferably pH value is that citric acid-sodium citrate of 5.4 is towards solution.
8. preparation method according to claim 5 is characterized in that described pH value regulator is selected from one or both in potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, hydrochloric acid, citric acid, the phosphoric acid, is preferably citric acid and sodium citrate.
9. preparation method according to claim 5, it is characterized in that described organic solvent is selected from one or more in chloroform, dichloromethane, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, acetonitrile, benzyl alcohol, the normal hexane, mixed solvent, chloroform and the acetone volume ratio that is preferably dichloromethane and acetonitrile volume ratio and is 1: 2 is that 1: 5 mixed solvent and ethanol and isopropyl alcohol volume ratio are 1: 3 mixed solvent.
Each medicine compound liposome solid preparation described or that prepare according to each preparation method among the claim 4-9 of a claim 1-3 the treatment single medicine fully controlling blood pressure gently, application in the moderate essential hypertension.
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| CN102166208A (en) * | 2011-03-18 | 2011-08-31 | 海南美兰史克制药有限公司 | Lisinopril and hydrochlorothiazide pharmaceutical composition liposome solid preparation |
| CN102614186A (en) * | 2012-03-02 | 2012-08-01 | 海南美兰史克制药有限公司 | Solid preparation of bisoprolol / hydrochlorothiazide medicine composition liposome |
| CN102626391A (en) * | 2012-04-19 | 2012-08-08 | 海南美兰史克制药有限公司 | Aliskiren-hydrochlorothiazide drug combination liposome solid preparation |
| CN102631357A (en) * | 2012-04-13 | 2012-08-15 | 重庆康刻尔制药有限公司 | Composite tablet of valsartan and hydrochlorothiazide and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102166208A (en) * | 2011-03-18 | 2011-08-31 | 海南美兰史克制药有限公司 | Lisinopril and hydrochlorothiazide pharmaceutical composition liposome solid preparation |
| CN102166208B (en) * | 2011-03-18 | 2012-09-26 | 海南美兰史克制药有限公司 | Lisinopril and hydrochlorothiazide pharmaceutical composition liposome solid preparation |
| CN102614186A (en) * | 2012-03-02 | 2012-08-01 | 海南美兰史克制药有限公司 | Solid preparation of bisoprolol / hydrochlorothiazide medicine composition liposome |
| CN102614186B (en) * | 2012-03-02 | 2013-12-11 | 海南美兰史克制药有限公司 | Solid preparation of bisoprolol / hydrochlorothiazide medicine composition liposome |
| CN102631357A (en) * | 2012-04-13 | 2012-08-15 | 重庆康刻尔制药有限公司 | Composite tablet of valsartan and hydrochlorothiazide and preparation method thereof |
| CN102631357B (en) * | 2012-04-13 | 2013-04-17 | 重庆康刻尔制药有限公司 | Composite tablet of valsartan and hydrochlorothiazide and preparation method thereof |
| CN102626391A (en) * | 2012-04-19 | 2012-08-08 | 海南美兰史克制药有限公司 | Aliskiren-hydrochlorothiazide drug combination liposome solid preparation |
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