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CN101143846B - Metal salt of quinaprilat - Google Patents

Metal salt of quinaprilat Download PDF

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Publication number
CN101143846B
CN101143846B CN2006101675245A CN200610167524A CN101143846B CN 101143846 B CN101143846 B CN 101143846B CN 2006101675245 A CN2006101675245 A CN 2006101675245A CN 200610167524 A CN200610167524 A CN 200610167524A CN 101143846 B CN101143846 B CN 101143846B
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quinaprilat
salt
metal
sodium
metal salt
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CN101143846A (en
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晁阳
高建兴
梁静
黄振华
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NANJING YOKO PHARMACEUTICAL CO Ltd
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XINGANG MEDICINE
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Abstract

The invention belonging to the field of medical technique relates to a metal salt of S-2-[S-N-[(S)-1-carboxyl-3-phenpropyl]-L-alanyl]-1, 2, 3, 4-tetrahydro-3-isoquinoline acid (quinaprilat) and a hydrate of the metal salt, a preparation method and applications in preparing medicines of curing high blood pressure. As proved by experiments, compared with the quinaprilat, the water solubility and stability of the metal salt of quinaprilat of the invention including salt and hydrate synthesized by the the metal salt of quinaprilat and one or two of ions of lithium, natrium, kalium, barium, calcium, magnesium and zinc, particularly the sodium salt, kalium salt, sodium potassium salt of the metal salt and the hydrate of the metal salt, is notably increased, and various clinically acceptable dosage forms can be easily produced.

Description

The metal-salt of quinaprilat
1, technical field
The invention belongs to medical technical field, be specifically related to S-2-[S-N-[(S)-1-carboxyl-3-hydrocinnamyl]-the L-alanyl]-1,2,3,4-tetrahydrochysene-3-isoquinoline acid is the metal-salt and the hydrate thereof of quinaprilat, and preparation method thereof and the purposes in the hypertensive medicine of preparation treatment.
2, background technology
Essential hypertension is a kind of serious harm human health, influences the disease of quality of life.Clinical manifestation has headache, dizziness, and alliteration, neck is pulled sense, tinnitus, dim eyesight, forgetful, insomnia, unhappiness, weak, numbness of the limbs, palpitaition etc.Also be to cause quadriplegia, heart failure, cerebral infarction, hematencephalon, the major reason of renal failure, of common occurrence because of the essential hypertension lethal case that disables clinically, be called as " stealthy killer ".China's hypertension morbidity is about 12%, and existing patient surpasses 100,000,000 people, and increases 3,000,000 people's speed increment newly with every year.Essential hypertension just increases fast with bigger amplification, the trend that becoming younger appears in sicken age, and hypertensive control is becoming the great task of China's health industry.
Quinaprilat is by the exploitation of U.S. Pfizer company, and nineteen ninety-five at first in Germany's listing, after this goes on the market in Switzerland again.Quinaprilat can suppress ACE, and the prevention angiotensin i-converting is an Angiotensin II, thereby the vasoconstriction effect that Angiotensin II is mediated obviously weakens, and reduces the vascular resistance of artery; Also suppressing the synthetic of aldosterone simultaneously, reduce water and sodium retention that aldosterone produced, blood pressure is further descended, is a kind of safe, antihypertensive drugs efficiently.But, bring great inconvenience for production, storage, circulation and clinical application because water-soluble and stable bad not ideal enough.
3, summary of the invention
The purpose of this invention is to provide the better metal-salt derivative of quinaprilat of a kind of solvability and stability, and its preparation method is provided and has been used for the treatment of application in the hypertensive medicine in preparation.
In order to solve the problem of the water-soluble and poor stability of quinaprilat, the inventor is through a large amount of screening operations, find that the metal-salt of quinaprilat and hydrate thereof can improve greatly that it is water-soluble and stable, comprise its with lithium, sodium, potassium, barium, calcium, magnesium, zine ion in a kind of or any two kinds combine salt and hydrate thereof, especially its sodium salt, sylvite, natrium potassium salt and the hydrates thereof that form.
Technical scheme of the present invention is as follows:
The invention provides a kind of S-2-[S-N-[(S)-1-carboxyl-3-hydrocinnamyl]-the L-alanyl]-1,2,3,4-tetrahydrochysene-3-isoquinoline acid is the metal-salt and the hydrate thereof of quinaprilat, and metal ion wherein is a kind of in lithium, sodium, potassium, barium, calcium, magnesium, the zinc or any two kinds.Be preferably sodium salt, sylvite, natrium potassium salt, optimum is a sodium salt.
The present invention is the hydrate of the metal-salt of claimed above-mentioned quinaprilat further, comprises semihydrate, monohydrate, sesqui hydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate etc.The hydrate of the further claimed quinaprilat sodium of the present invention; comprise semihydrate, monohydrate, sesqui hydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate etc.; especially semihydrate, monohydrate, sesqui hydrate, dihydrate are because of it shows better stability.
The method of quinaprilat metal-salt of the present invention can be carried out with reference to pharmaceutically conventional method, can prepare by following method as the quinaprilat sodium salt:
Get 5.0g purified quinapril hydrochloride, be dissolved in the mixed solvent of dioxane and water, stir, transfer pH value of solution with NaOH, 60 ℃ of reactions.Add NaOH again and transfer pH value of solution, continue to be stirred to reaction and finish (can put the plate monitoring).Add gac, filtered while hot, filtrate is oily matter after revolving steaming, adds to be preheated to the acetone that boils, the shake of exerting oneself, the oily matter dissolving, insolubles is NaCl, filtered while hot.Filtrate is put in 0～5 ℃ of environment, a large amount of white solids occur, filter, solid is in vacuum-drying, get the quinaprilat sodium salt, its chemical name is S-2-[S-N-[(S)-1-carboxyl-3-hydrocinnamyl]-the L-alanyl]-1,2,3,4-tetrahydrochysene-3-isoquinoline acid disodium salt, reaction formula:
Figure DEST_PATH_G200610167524501D00011
Quinaprilat sylvite can prepare by following method:
Quinapril hydrochloride is dissolved in 1, and in the mixing solutions of 4-dioxane and water, heating in water bath stirs.Treat the solid dissolving back slow KOH of dropping solution accent pH, continue to stir,, get solid the solution decompression evaporate to dryness.Add the small amount of acetone dissolving, remove by filter insolubles, the filtrate decompression evaporate to dryness, vacuum-drying gets white solid, quinaprilat sylvite, its chemical name are S-2-[S-N-[(S)-1-carboxyl-3-hydrocinnamyl]-the L-alanyl]-1,2,3,4-tetrahydrochysene-3-isoquinoline acid di-potassium, reaction formula:
Figure S061G7524520070111D000031
The sodium salt of the metal-salt of the further claimed quinaprilat of the present invention and hydrate thereof, especially quinaprilat, sylvite and hydrate thereof are used for the treatment of application in the hypertensive medicine in preparation.
The present invention is the claimed metal-salt of quinaprilat and the pharmaceutical composition of hydrate and other depressor thereof of comprising further, is used for the hypertensive medicine of preparation treatment.These depressor comprise the diuretic antihypertensive medicine, calcium antagonists, the beta receptor blocking agent, angiotensin converting enzyme inhibitor and angiotensin-ii receptor blocking agent, as Zestoretic, navidrex, chlorthalidone, torasemide, indapamide, bumetanide, eplerenone, verapamil, nisoldipine, Odizem, amlodipine, nifedipine, felodipine, metoprolol, Proprasylyte, timolol, bisoprolol, sotalol, esmolol, captopril, benazepril, fosinopril, enalapril, lisinopril, telmisartan, irbesartan, Candesartan, valsartan, losartan etc.
The present invention is further claimed to comprise the pharmaceutical composition that the metal-salt of quinaprilat or its hydrate and acceptable accessories are made, and the unitary dose of the effective constituent that it comprises is counted 0.5mg～100mg (with C with quinaprilat 23H 26N 2O 5Meter).Said composition is pharmaceutically arbitrary or acceptable forms clinically, can be applied to the patient who needs this treatment in the mode of parenteral or oral administration, is preferably injection.Containing the metal-salt of quinaprilat of the present invention and the unitary dose of hydrate thereof in the aforementioned pharmaceutical compositions is that 0.5mg～100mg is (with C 23H 26N 2O 5Meter), for example: 0.5mg, 1mg, 2mg, 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, preferred dose is 2.5mg, 5mg, 10mg, 20mg.
The preparation of aforementioned pharmaceutical compositions can adopt the ordinary method production in the existing pharmacy field, can add various pharmaceutically acceptable carriers when needing.Described carrier comprises vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Quinaprilat sodium salt of the present invention and the solubility property of quinaprilat sylvite in water are far superior to quinaprilat, requirement with reference to two ones of Chinese Pharmacopoeia versions in 2005 is tested, to quinaprilat sodium salt of the present invention and quinaprilat sylvite 25 ℃ more water-soluble with the quinaprilat raw material ratio, the results are shown in Table 1.
Table 1 quinaprilat of the present invention and sodium salt thereof, the sylvite solubleness in water relatively
Annotate: easily dissolving means that solute 1g (ml) can dissolve in solvent 1～less than 10ml;
The slightly molten solute 1g (ml) that means can dissolve in solvent 30～less than 100ml.
The above results shows the sodium salt of quinaprilat, the water-soluble quinaprilat that obviously is better than of sylvite.
The inventor is by further studying stability, and the result shows the stability of quinaprilat sodium salt of the present invention under high temperature and the strong illumination condition quinaprilat that surpasses far away.Below be that quinaprilat sodium and quinapril are pulled in the stability result of placing under 40 ℃ of the high temperature, 60 ℃, the condition of illumination 4500Lx 5 days, 10 days, investigating index is proterties and related substance, the results are shown in Table 2, table 3.
The stable comparative result of table 2 quinaprilat sodium and quinaprilat (5 days)
The stable comparative result of table 3 quinaprilat sodium and quinaprilat (10 days)
Figure S061G7524520070111D000053
Table 2, table 3 are respectively quinaprilat sodium and quinapril and are pulled in study on the stability result under high temperature, the strong illumination condition.By table 2 and table 3 as can be seen, after placing 5 days or 10 days under 40 ℃ of high temperature or the 60 ℃ of conditions, the related substance of quinaprilat extremely significantly raises, and the related substance of quinaprilat sodium does not have variation substantially; After placing 5 days or 10 days under the illumination 4500Lx condition, the related substance of quinaprilat raises to some extent, and the related substance of quinaprilat sodium does not have to change substantially.The above results shows quinaprilat to the high temperature instability, and the high-temperature stability of quinaprilat sodium improves greatly.
The present invention further investigates the high humidity stability of quinapril and quinaprilat sodium, and the result shows that the two after placing 5 days or 10 days under high humidity 75% or 92.5% condition, all has moisture absorption, but related substance does not have to change substantially.
The above results shows that quinaprilat sodium is compared with quinaprilat, and the stability under high temperature, strong illumination condition significantly improves, and especially the pyritous stability utmost point is significantly improved, and is more conducive to the storage of medicine, has improved clinical application safety.
The metal-salt of quinaprilat of the present invention is compared with existing quinaprilat, has following characteristics:
(1) the present invention provides the metal-salt of quinaprilat first, comprise its with lithium, sodium, potassium, barium, calcium, magnesium, zine ion in a kind of or any two kinds combine the salt that form, especially quinaprilat sodium and quinaprilat potassium, compare with commercially available quinaprilat, water-soluble raising greatly, be easy to make the above formulation of any pharmaceutics, especially be easy to make injection.Quinaprilat sodium is compared with quinaprilat, and the stability under high temperature, strong illumination condition significantly improves, and especially the pyritous stability utmost point is significantly improved, and is more conducive to the storage of medicine, has improved clinical application safety.
(2) preparation technology of the metal-salt of quinaprilat of the present invention is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
4, embodiment
Embodiment by the following examples is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
The preparation of embodiment 1 quinaprilat metal-salt
1) preparation of quinaprilat sodium:
Reaction formula:
Figure S061G7524520070111D000071
Get 5.0g purified quinapril hydrochloride, be dissolved in the 100ml dioxane: in the water (9:1), stir 5min, transfer pH value of solution to 12,60 ℃ of reactions with 1N NaOH.Behind the 20min, add 1N NaOH again and transfer pH value of solution to 12, continue to stir the 30min reaction and finish (can put the plate monitoring).Add the 1.0g gac, filtered while hot behind the 15min, filtrate is revolved in 50 ℃ and is oily matter after steaming 1h, and add 100ml and be preheated to the acetone that boils, shake firmly, the oily matter dissolving, insolubles is NaCl, filtered while hot.Filtrate is put about 3h in 0～5 ℃ of environment, a large amount of white solids occur, filter, solid is in 40 ℃ of vacuum-dryings 20 hours, about 4.0g that weighs, and yield 80%, purity is more than 99.5%.
Molecular formula: C 23H 24N 2Na 2O 5
Molecular weight: 454.43
Results of elemental analyses:
Measured value: C:60.73%; H:5.41%; N:6.13%; Na:10.08%
Theoretical value: C:60.79%; H:5.32%; N:6.16%; Na:10.12%
1H-NMR(300MHz，DMSO-d 6)δ(ppm)：7.08～7.23(m，9H)，4.83(d，1H)，4.34(d，2H)，3.70(d，1H)，3.27(d，2H)，2.94(t，2H)，2.59(m，2H)，1.64～1.76(m，2H)，0.96(d，3H)
2) preparation of quinaprilat potassium:
Reaction formula:
Figure S061G7524520070111D000081
(2.5g 5.26mmol) is dissolved in 1 of 60ml, the 4-dioxane: in the mixing solutions of water (9:1), 50 ℃ of heating in water bath stirred 10 minutes with quinapril hydrochloride.The KOH solution for the treatment of slowly to drip 1N after the solid dissolving continues to stir after 2.5 hours to pH12, and solution in 50 ℃ of evaporated under reduced pressure, is got solid.Add the small amount of acetone dissolving, remove by filter insolubles (being mainly KCl), 50 ℃ of evaporated under reduced pressure of filtrate, 50 ℃ of vacuum-dryings.Get white solid 2.1g, productive rate 84%.
Molecular formula: C 23H 24N 2K 2O 5
Molecular weight: 486.64
Results of elemental analyses:
Measured value: C:56.78%; H:4.96%; N:5.75%; K:16.05%
Theoretical value: C:56.77%; H:4.97%; N:5.76%; K:16.07%
The preparation of embodiment 2 aseptic powder of the present invention
1, prescription
Prescription 1:
Figure S061G7524520070111D000082
Prescription 2:
Figure S061G7524520070111D000083
Prescription 3
Figure S061G7524520070111D000084
2, preparation technology:
In aseptic weighing room, take by weighing aseptic The compounds of this invention by prescription, packing is sealed, promptly.
The preparation of embodiment 3 aqueous injections of the present invention
1, prescription
Prescription 1:
Figure S061G7524520070111D000091
Prescription 2:
Figure S061G7524520070111D000092
Prescription 3:
Figure S061G7524520070111D000093
2, preparation technology:
1) container of earlier dosing being used, ampoule, the plant-scale equipment, instrument etc. carry out pre-treatment.
2) take by weighing raw material and auxiliary material by recipe quantity.
3) raw material is added stirring and dissolving in the water for injection of dosing amount 80%, add 0.1% needle-use activated carbon temperature control and stirred filtering decarbonization 10 minutes for 50 ℃.
4) the pH value of survey solution adds water and is settled to cumulative volume.
5) with the filtering with microporous membrane of 0.45 μ m.
6) clarity of inspection solution.
7) inspection of semifinished product.
8) the qualified back of inspection of semifinished product sealing by fusing is in ampoule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.05% methylene blue solution hunts leak.
11) warehouse-in is examined, packed to finished product entirely.
The preparation of embodiment 4 powder pins of the present invention
1, prescription:
Prescription 1:
Figure S061G7524520070111D000094
Prescription 2:
Figure S061G7524520070111D000101
Prescription 3:
Figure S061G7524520070111D000102
2, preparation technology:
1) will produce used cillin bottle, plug and dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation;
2) take by weighing raw material and auxiliary material by prescription;
3) N.F,USP MANNITOL is added dosing amount 80% water for injection, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% then stirs 15min, filters, and takes off charcoal;
4) in solution, add raw material, stirring and dissolving;
5) the pH value of survey solution;
6) benefit adds to the full amount of water for injection constant volume;
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m;
8) inspection of semifinished product;
9) soup packing 2ml is in cillin bottle, half tamponade;
10) sample is put in the Freeze Drying Equipment, adopted following freeze-dry process freeze-drying :-40 ℃ of pre-freezes 4 hours ,-30～0 ℃ of low-temperature vacuum drying 18 hours, 0～30 ℃ heated up dry 2 hours, 30 ℃ of freeze-day with constant temperature 2 hours.
11) freeze-drying finishes tamponade, Zha Gai;
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 sodium chloride injections of the present invention
1, prescription
Prescription 1:
Figure S061G7524520070111D000103
Prescription 2:
Figure S061G7524520070111D000111
Prescription 3:
Figure S061G7524520070111D000112
2, preparation technology:
1) with dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation.
2) take by weighing raw material and auxiliary material by prescription.
3) get the water for injection that sodium-chlor adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal.
4) in solution, add raw material, stirring and dissolving.
5) the pH value of survey solution is used adjust pH in case of necessity.
6) benefit adds to the full amount of water for injection constant volume.
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m.
8) inspection of semifinished product.
9) soup is loaded in the infusion bottle 250ml/ bottle.
10) 115 ℃ of pressure sterilizing 30min;
11) leak detection, the lamp inspection.
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 glucose injections of the present invention
1, prescription
Prescription 1:
Prescription 2:
Figure S061G7524520070111D000114
Prescription 3:
Figure S061G7524520070111D000121
2, preparation technology:
1) with dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation.
2) take by weighing raw material and auxiliary material by prescription.
3) get the water for injection that glucose adds dosing amount 80%, stirring and dissolving, heated and boiled; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal.
4) in solution, add raw material, stirring and dissolving.
5) the pH value of survey solution is used adjust pH in case of necessity.
6) benefit adds to the full amount of water for injection constant volume.
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m.
8) inspection of semifinished product.
9) soup is loaded in the infusion bottle 250ml/ bottle.
10) 115 ℃ of pressure sterilizing 30min;
11) leak detection, the lamp inspection;
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 tablets of the present invention
1, prescription
Prescription 1:
Figure S061G7524520070111D000122
Prescription 2:
Figure S061G7524520070111D000123
2, preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, and all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) PVPk30 is soaked dissolving and make 10% 50% ethanolic soln, standby.
3) take by weighing raw material and auxiliary material according to recipe quantity.
4) raw material and Microcrystalline Cellulose, pregelatinized Starch are mixed, add the tackiness agent of getting ready, stir, make suitable softwood, cross 20 mesh sieve system particles.
5) dry under 50 ℃ the condition.
6) particle is crossed the whole grain of 18 mesh sieves, adds Magnesium Stearate and silicon-dioxide and mixes.
7) sampling, work in-process chemical examination, the content of The compounds of this invention in the mensuration particle.
8) compressing tablet.
9) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 capsules of the present invention
1, prescription
Prescription 1:
Figure S061G7524520070111D000131
Prescription 2:
Figure S061G7524520070111D000132
2, preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) hypromellose is dissolved in to make 2% the aqueous solution in the 50% ethanol water standby.
4) raw material, starch, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
5) cross 20 mesh sieve system particles.
6) particle is dried under 60 ℃ condition.
7) dry good particle adds Magnesium Stearate, crosses the whole grain of 18 mesh sieves, mixes.
8) sampling, the work in-process chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.

Claims (7)

1. the metal-salt of quinaprilat is characterized in that, the metal-salt of quinaprilat is S-2-[S-N-[(S)-1-carboxyl-3-hydrocinnamyl]-the L-alanyl]-1,2,3, the sodium salt of 4-tetrahydrochysene-3-isoquinoline acid.
2. the application of the metal-salt of the described quinaprilat of claim 1 in the hypertensive medicine of preparation treatment.
3. comprise the metal-salt of the described quinaprilat of claim 1 and the pharmaceutical composition of other depressor.
4. the described pharmaceutical composition of claim 3, depressor wherein comprises diuretic antihypertensive medicine, calcium antagonists, beta receptor blocking agent, angiotensin converting enzyme inhibitor and angiotensin-ii receptor blocking agent.
5. comprise the pharmaceutical composition of the described quinaprilat metal-salt of claim 1, it is characterized in that, the metal-salt of this quinaprilat and acceptable accessories are made pharmaceutically arbitrary or acceptable forms clinically.
6. pharmaceutical composition as claimed in claim 5 is characterized in that, the unitary dose that contains the metal-salt of the described quinaprilat of claim 1 is 0.5mg～100mg.
7. as claim 5 or 6 each described pharmaceutical compositions, it is an injection.
CN2006101675245A 2006-09-12 2006-12-25 Metal salt of quinaprilat Expired - Fee Related CN101143846B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4344949A (en) * 1980-10-03 1982-08-17 Warner-Lambert Company Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids
US5158959A (en) * 1980-08-30 1992-10-27 Hoechst Aktiengesellschaft Decahydroisoquinoline carboxylic acids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5158959A (en) * 1980-08-30 1992-10-27 Hoechst Aktiengesellschaft Decahydroisoquinoline carboxylic acids
US4344949A (en) * 1980-10-03 1982-08-17 Warner-Lambert Company Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JP昭58-21666A 1983.02.08
Sylvester Klutchko, et al..Synthesis of Novel Angiotensin Converting Enzyme InhibitorQuinapril and Related Compounds. A Divergence ofStructure-Activity Relationships for Non-Sulfhydryl andSulfhydryl Types.J.Med.Chem.29 10.1986,29(10),1953-1961.
Sylvester Klutchko, et al..Synthesis of Novel Angiotensin Converting Enzyme InhibitorQuinapril and Related Compounds. A Divergence ofStructure-Activity Relationships for Non-Sulfhydryl andSulfhydryl Types.J.Med.Chem.29 10.1986,29(10),1953-1961. *

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