CN102579346B - Liposome solid preparation of benazepril/hydrochlorothiazide medicine combination - Google Patents
Liposome solid preparation of benazepril/hydrochlorothiazide medicine combination Download PDFInfo
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- CN102579346B CN102579346B CN 201210052500 CN201210052500A CN102579346B CN 102579346 B CN102579346 B CN 102579346B CN 201210052500 CN201210052500 CN 201210052500 CN 201210052500 A CN201210052500 A CN 201210052500A CN 102579346 B CN102579346 B CN 102579346B
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- Prior art keywords
- hydrochlorothiazide
- benazepril
- liposome
- preparation
- amine
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Abstract
The invention discloses a liposome solid preparation of benazepril/hydrochlorothiazide and a preparation method thereof. The liposome solid preparation is prepared mainly by the liposome made of 1 portion of hydrochloric acid benazepril, 1.25 portions of hydrochlorothiazide, 50-200 portions of soya bean lecithin, 20-100 portions of octadecylamine and 5-60 portions of cholesterol acetyl lipide measured based on weight, the benazepril/hydrochlorothiazide liposome, and the other excipients typically used in pharmacy. According to the invention, the product quality of the preparation is improved,the toxic and side effects are reduced, the stability, dissolution and bioavailability of the medicine are greatly improved, and a stable and enduring function and remarkable therapeutic effects are achieved.
Description
Technical field
The present invention relates to a kind of compound preparation of benazepril/hydrochlorothiazide, be specifically related to a kind of solid preparation and method for making thereof of pharmaceutical composition of benazepril/hydrochlorothiazide, belong to medical technical field.
Background technology
Cardiovascular and cerebrovascular disease is one of the highest disease of world today's M ﹠ M, it is dead first cause, be healthy No.1 killer, the sickness rate of China's cardiovascular system diseases is identical substantially with world wide substantially, be ascendant trend year by year, the 7th of the dead cause of disease by the sixties rises to the 1st, and annual because cardiovascular and cerebrovascular disease death has 3,000,000 people, 1,000 ten thousand people are disabled because of cardiovascular and cerebrovascular disease.Almost each cardiovascular and cerebrovascular vessel patient has the clinical symptoms of hypertension, need carry out the blood pressure lowering treatment, and Altace Ramipril market is huge.At present the clinical experiment evidence shows, effectively blood pressure lowering and the common drug that reduces cardiovascular complication have angiotensin converting enzyme inhibitor (ACEI), Angiotensin (ARB), beta-blocker (BB).Calcium-channel antagonists (CCB), thiazide diuretic and compound preparation.Big specification clinical research finds that the α receptor blocking agent can increase the morbidity of heart failure, has not recommended it as a line medication of depressor treatment at present, can be used as the two wires antihypertensive drugs.
Benazepril (Benazepril) is as the hypertension therapeutic medicine, is one long-acting, as not contain sulfydryl angiotensin-convertion enzyme inhibitor, is a prodrug, is hydrolyzed into active matter benazeprilat (Benazeprilate) in vivo and the performance drug effect.Angiotensin converting enzyme is had stronger selectivity suppress and produce hypotensive effect, effect and captopril, enalapril are similar, and normotensive's blood pressure lowering and heart rate almost do not influenced.This chemical compound is sold so that the form of hydrochlorate is commercial, and the consumption of benazepril hydrochloride is 10mg every day clinically, and every day, maximum recommended dosage was 40mg, once or be divided into twice and take.
Benazepril hydrochloride (Benazepril Hydrochloride) molecular formula C
24H
29ClN
2O
5Molecular weight 461.0, structural formula is:
Benazepril hydrochloride can suppress the Angiotensin-Converting activity, reduces the angiotensin level, diastole small artery blood vessel.Polytype hypertension is all had tangible hypotensive effect, and can improve the cardiac function of patients with congestive heart failure.Its pharmacological action is mainly reflected in two aspects, (1) blood pressure lowering: this product is hydrolyzed to benazeprilat in liver, become a kind of competitive angiotensin converting enzyme inhibitor, stop angiotensin to be converted into angiotensin, vascular resistance is reduced, the aldosterone secretion reduces, and plasma renin activity increases.Benazeprilat also suppresses the degraded of Kallidin I, and vascular resistance is reduced, and produces hypotensive effect.(2) lower cardiac load: this product expansion artery and vein, reduce peripheral vascular resistance or cardiac afterload, reduce pulmonary capillary embedding pressure or cardiac preload, also reduce pulmonary vascular resistance, thereby improve cardiac output, make exercise tolerance and time lengthening.
Hydrochlorothiazide, its chemical name are chemistry 6-chloro-3 by name, 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:
Hydrochlorothiazide is a kind of diuretic, and namely common alleged " water urine ball " mainly suppresses medullary loop ascending branch cortex portion to the heavily absorption of Na+ and Cl-, and kidney is increased and the generation diuresis the drainage of sodium chloride, is a kind of middle diuretic of imitating.Hydrochlorothiazide is diuretic and the antihypertensive drugs of using always, because can certain influence be arranged to water, electrolyte excretion.So diuresis is arranged.This product mechanism of action mainly suppresses distal tubule leading portion and proximal tubule (acting on lighter) to the heavily absorption of sodium chloride, thereby increases the Na+-K+ exchange of distal tubule and collecting tubule, K+ secretion increasing.Its mechanism of action is not clear fully as yet.And this product can both suppress the carbonic anhydrase activity to some extent, so can explain that it is to the effect of proximal tubule.This class medicine can also suppress phosphodiesterase activity, reduce renal tubules to picked-up and the mitochondrion oxygen consumption of fatty acid, thereby the active to Na+, Cl-absorbs heavily to renal tubules in inhibition.Also having hypotensive effect in addition, except the effect of diuresis row sodium, may also have the outer mechanism of action of kidney to participate in blood pressure lowering, may be to increase gastrointestinal tract to the drainage of Na+.This product is to the influence of renal hemodynamics and glomerular filtration function.Because renal tubules heavily absorbs minimizing to water, Na+, the renal tubules internal pressure raises, and the water of the Distal convoluted tubule of flowing through and Na+ increase, stimulate macula densa by the reflection of pipe-ball, feritin in the kidney, blood vessel are increased through opening plain secretion, cause the kidney vasoconstriction, renal blood flow descends, glomerule goal and efferent glomerular arteriole shrink, and the glomerule rate is filtered also and descended.Over nearly more than 30 years, be one of main force of antihypertensive drugs based on the thiazide diuretic of hydrochlorothiazide always, and though this medicine single with or be used in conjunction with other antihypertensive drugs, clear and definite curative effect is arranged.Uncomplicated hyperpietic all advises in the several hypertension treatment principle of America and Europe committee, is first-selected with the diuretic.Its risk of diuretic/benefit ratio is dose dependent, and its many side effect are more common in heavy dose as low potassium, and 25mg or 12.5mg hydrochlorothiazide can reduce untoward reaction and still keep curative effect every day.
Share by the two in benazepril/hydrochlorothiazide compound recipe, can alleviate hydrochlorothiazide to the reverse regulating action of renin-angiotensin system, thereby strengthen the antihypertensive effect of diuretic; Benazepril and hydrochlorothiazide share, and except strengthening curative effect, also can offset the latter to the ill effect of blood potassium and blood uric acid.This is to use the unify activation of renin-angiotensin system of the caused sympathetic nervous system of diuretic because benazepril can be offset, and these compensatory mechanism of being brought out by diuretic can be resisted the hypotensive effect of these medicines, and reduce the blood potassium level; Can reduce the incidence rate that cardiovascular event danger takes place hypertensive patients metabolic arthritis patient.
The compound hypertension medicine existing market that comprises hydrochlorothiazide is existing a lot, for example losastan potassium/hydrochlorothiazide tablets, valsartan and Hydrochlorothiade sheet, telmisartan hydrochlorothiazide tablet etc., these all are the compound preparations of sartans and hydrochlorothiazide, the compound preparation of forming about Puli's class medicine and hydrochlorothiazide now also seldom, benazepril provided by the invention/hydrochlorothiazide liposome tablet will become an invention direction of compound hypertension medicine.
The inventor by creationary research, benazepril/hydrochlorothiazide liposome that discovery selects for use the excipient of certain content and composition to make, its drug content and envelop rate are 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.
Summary of the invention
The object of the present invention is to provide a kind of benazepril/hydrochlorothiazide pharmaceutical composition solid preparation and preparation method thereof, it has overcome the defective that prior art exists as the compound hypertension medicine compositions, good stability, the bioavailability height, side effect is little, and curative effect is more remarkable.
The inventor is through research in earnest for a long time, through a large amount of screening experiment, finishing screen is chosen the combination of soybean lecithin, 18-amine. and these three kinds of materials of cholesterol acetyl fat, find the combination of these three kinds of materials unexpectedly, stability and the not good technical problem of envelop rate of liposome have been solved, obtained beyond thought preparation effect, thereby superior in quality liposome is provided.Though do not want to be bound by theory, effect of the present invention may be the common and/or synergistic result of these three kinds of materials.
One of purpose of the present invention is to provide a kind of benazepril/hydrochlorothiazide pharmaceutical composition solid preparation, this solid preparation is tablet, and its specification is 5mg (benazepril meter)/6.25mg (hydrochlorothiazide meter) and 10mg (benazepril meter)/12.5mg (hydrochlorothiazide meter).
In this article, used term " benazepril/hydrochlorothiazide liposome " or " " liposome of benazepril/hydrochlorothiazide " " refer to described in the present invention to be the made liposome of active component with " benazepril hydrochloride " and " hydrochlorothiazide ".
In this article, used term " benazepril/hydrochlorothiazide lipidosome solid preparation " or " liposome solid preparation of benazepril/hydrochlorothiazide fat " refer to described in the present invention to be the made lipidosome solid preparation of active component with " benazepril hydrochloride " and " hydrochlorothiazide ".
In order to form colory benazepril/hydrochlorothiazide lipidosome solid preparation, thereby importantly seek can with good compatible it well being sealed and non-leakage filmogen of benazepril hydrochloride, hydrochlorothiazide, in order to form colory benazepril/hydrochlorothiazide liposome, make stripping property excellence and the bioavailability height of this liposome, and seek the pharmaceutic adjuvant that can form solid preparation with benazepril/hydrochlorothiazide liposome.
To achieve these goals, big quantity research and realization that the inventor carries out, benazepril hydrochloride, hydrochlorothiazide, soybean phospholipid, 18-amine. and the cholesterol acetyl fat of discovery specified weight proportioning can be made benazepril/hydrochlorothiazide liposome, wherein, as the benazepril/hydrochlorothiazide envelop rate height of active constituents of medicine, stripping property is good, the retention time significant prolongation of the active constituents of medicine in the gained solid preparation in the body circulation, bioavailability obviously improves, and curative effect obviously improves.
One object of the present invention is to provide a kind of benazepril/hydrochlorothiazide liposome, is mainly made by following components by weight ratio:
Preferably: the weight ratio of soybean lecithin and 18-amine. is 1: 1-2.5: 1.
In an embodiment preferred of benazepril of the present invention/hydrochlorothiazide lipidosome solid preparation, benazepril/hydrochlorothiazide liposome is mainly made by following components by weight ratio:
Preferably: the weight ratio of soybean lecithin and 18-amine. is 1: 1-2: 1.
In a most preferred embodiment of benazepril provided by the invention/hydrochlorothiazide liposome, the weight ratio of soybean lecithin and 18-amine. is 1: 1-2: 1.
In benazepril of the present invention/hydrochlorothiazide liposome, the phospholipid material that uses is soybean lecithin, is a kind of natural phospholipid.As the phospholipid that is used to form liposome, it is of a great variety, and commonly used have natural phospholipid and a synthetic phospholipid.Natural phospholipid comprises PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, hydrogenated soya phosphatide, Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, stearmide, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine and soybean phospholipid acyl inositol etc.Synthetic phospholipid comprises dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, two myristoyl phosphatidylcholines, two Laurel phosphatidyl cholines, DOPG, distearyl phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two lauroyl phosphatidyl glycerols etc.
The inventor is through long-term conscientious research, through a large amount of screening tests, find to adopt general phospholipid and additives for the benazepril/hydrochlorothiazide liposome of film material preparation under the accelerated test of 40 ℃ of high temperature, relative humidity 75% ± 5%, stability and envelop rate are not good.
In the present invention, the consumption of soybean lecithin is 50-200 part, if the consumption of soybean lecithin is lower than 50 weight portions or is higher than 200 weight portions, it is not encapsulated to have a large amount of benazepril hydrochlorides and hydrochlorothiazide, the drug loading of liposome is low, stability also can reduce, and stripping property also can be adversely affected.
In benazepril of the present invention/hydrochlorothiazide liposome, 18-amine. and cholesterol acetyl fat are used for regulating membrane stability and the permeability of liposome.
18-amine. is a kind of amphiphilic, combines with soybean lecithin, stops it to be condensed into crystal structure.18-amine. mixes in the film of soybean lecithin formation, is similar to " buffer agent " and equally plays the effect of regulating membrane structure " flowability ".When being lower than phase transition temperature, 18-amine. can make film reduce ordered arrangement, increases mobile; When being higher than phase transition temperature, 18-amine. can increase the ordered arrangement of film, thereby reduces the flowability of film.18-amine. can make liposome bimolecular tunic solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
The present invention is through discovering, when the weight of soybean lecithin and the weight ratio of 18-amine. are 1: 1-2.5: in the time of 1, can form stable benazepril/hydrochlorothiazide liposome, when the weight ratio of soybean lecithin and 18-amine. is lower than 1: 1 or is higher than 2.5: 1, the liposome membrane flowability is too high, and the benazepril/hydrochlorothiazide that is wrapped in the liposome discharges easily.
In addition, discover, when the weight of soybean lecithin and the weight ratio of 18-amine. are 1: 1-2.5: in the time of 1, formed liposome stripping property excellence.
Studies show that the stability of liposome and stripping property and bioavailability have close corresponding relation.Stability is more high, and stripping property is more good, and bioavailability is more high.Therefore, the stability of hydrochlorothiazide hydrochlorothiazide liposome of the present invention is high, stripping property is excellent, is to cause one of high factor of drug bioavailability.
In benazepril of the present invention/hydrochlorothiazide liposome, use cholesterol acetyl fat further to improve stability and the envelop rate of liposome membrane.
In the present invention, the consumption of soybean lecithin is 50-200 part, and the consumption of cholesterol acetyl fat is 5-60 part.If the consumption of cholesterol acetyl fat is lower than 5 weight portions, then cause owing to its consumption is low excessively improving not enough to stability and the envelop rate of liposome, otherwise, if the consumption of cholesterol acetyl fat is higher than 60 weight portions, then causes liposome membrane to be easy to destroy owing to its consumption is too high and reveal active component.
In benazepril of the present invention/hydrochlorothiazide liposome, the collaborative adjusting facilitation to the soybean lecithin membrane structure of 18-amine. and cholesterol acetyl fat by an amount of proportioning, can form envelop rate height, stable high benazepril/hydrochlorothiazide liposome, its stripping property excellence, had good sustained release effect, the bioavailability height.
On the other hand, the invention provides the preparation method of benazepril/hydrochlorothiazide liposome, this method may further comprise the steps:
(1) with soybean lecithin, 18-amine. and the liposoluble of cholesterol acetyl in appropriate amount of organic, get the class lipoprotein solution;
(2) above-mentioned class lipoprotein solution is placed the pyriform bottle, in 45-55 ℃ of water bath with thermostatic control, rotary evaporation is removed organic solvent, forms even lipid membrane;
(3) benazepril hydrochloride and hydrochlorothiazide are scattered in the water, add jog in the pyriform bottle, make the lipid membrane eluting and be distributed to the hydration medium dissolving, namely get liposome turbid liquor;
(4) above-mentioned suspension is placed Ultrasound Instrument ultrasonic to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrate was placed under-50 ℃ of conditions freezing 4 hours, be warming up to-10 ℃ with 1.3 ℃/hour speed again, be incubated 3 hours, be warming up to 25 ℃ again, be incubated 3 hours to dry, obtain lipidosome freeze-dried powder of the present invention.
Wherein, organic solvent described in the step (1) is selected from one or more in ethanol, chloroform, dichloromethane, methanol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, acetonitrile, the normal hexane, and preferred volume ratio is 2: 3 acetonitrile and the mixed solvent of dichloromethane.
By said method, can prepare the little and uniform benazepril of the particle size distribution/hydrochlorothiazide liposome of granule, its envelop rate height, stability is high, and stripping property is good, the bioavailability height.
Discover that the size of liposome is to influence that liposome distributes in vivo and the principal element of the time of staying, the particle diameter of liposome is more little, and the time of staying is more long in the body.Benazepril/hydrochlorothiazide liposome particles by the inventive method preparation is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
On the one hand, the invention provides benazepril/hydrochlorothiazide lipidosome solid preparation again, it is made by benazepril of the present invention/hydrochlorothiazide liposome and other pharmaceutic adjuvants,
In this article, used term " other pharmaceutic adjuvants " and excipient is equivalent in meaning, refer to the medicinal material except benazepril/hydrochlorothiazide liposome that uses in order to prepare benazepril/hydrochlorothiazide solid preparation comprise filler, disintegrating agent, binding agent, lubricant and combination thereof.
As preferably, filler can be selected from one or more in starch, lactose, mannitol, sorbitol, microcrystalline Cellulose, pregelatinized Starch, the dextrin, is preferably microcrystalline Cellulose.
As preferably, disintegrating agent is selected from one or more in low-substituted hydroxypropyl cellulose, carboxymethylstach sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, the carboxymethylcellulose calcium, is preferably carboxymethylstach sodium.
As preferably, binding agent is selected from a kind of in 30 POVIDONE K 30 BP/USP 30, starch slurry, hypromellose, sodium carboxymethyl cellulose, the hydroxypropyl cellulose, is preferably hydroxypropyl cellulose.
As preferably, lubricant is selected from one or more among magnesium stearate, zinc stearate, Pulvis Talci, micropowder silica gel, the PEG6000, is preferably micropowder silica gel.
On the one hand, the present invention also provides a kind of method for preparing benazepril/hydrochlorothiazide liposome tablet again, and concrete preparation process comprises:
(a) earlier benazepril hydrochloride, hydrochlorothiazide, soybean lecithin, 18-amine. and cholesterol acetyl fat are made the liposome powder,
(b) the liposome powder that again step (a) is made and pharmaceutically commonly used other mixed with excipients make tablet.
Wherein, liposome preparation step (a) comprises following substep:
(1) with soybean lecithin, 18-amine. and the liposoluble of cholesterol acetyl in appropriate amount of organic, get the class lipoprotein solution;
(2) above-mentioned class lipoprotein solution is placed the pyriform bottle, in 45-55 ℃ of water bath with thermostatic control, rotary evaporation is removed organic solvent, forms even lipid membrane;
(3) benazepril hydrochloride and hydrochlorothiazide are scattered in the water, add jog in the pyriform bottle, make the lipid membrane eluting and be distributed to the hydration medium dissolving, namely get liposome turbid liquor;
(4) above-mentioned suspension is placed Ultrasound Instrument ultrasonic to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrate was placed under-50 ℃ of conditions freezing 4 hours, be warming up to-10 ℃ with 1.3 ℃/hour speed again, be incubated 3 hours, be warming up to 25 ℃ again, be incubated 3 hours to dry, obtain lipidosome freeze-dried powder.
Wherein, organic solvent described in the step (1) is selected from one or more in ethanol, chloroform, dichloromethane, methanol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, acetonitrile, the normal hexane, and preferred volume ratio is 2: 3 acetonitrile and the mixed solvent of dichloromethane.
Wherein, the concrete preparation of step (b) comprises following substep:
(1) the lipidosome freeze-dried powder that step (a) is made and pharmaceutically commonly used other adjuvants comprise that filler, disintegrating agent mix, the mix homogeneously that sieves adds binding agent and prepares soft material, the granulation of sieving, drying, granulate;
(2) dried granule adds lubricant, mix homogeneously;
(3) tabletting makes benazepril of the present invention/hydrochlorothiazide liposome tablet.
As preferably, the concentration of the solution of binding agent is the 50%-80% ethanol water in the preparation method described above.
As preferably, cross 80 mesh sieve mix homogeneously after supplementary material mixes in the preparation method described above, cross 20-30 mesh sieve wet granular processed, 50-60 ℃ of drying, 18 mesh sieve granulate behind the soft material processed.
As one of the preferred embodiments of the invention, the solid preparation of the liposome of benazepril/hydrochlorothiazide of the present invention, mainly made by following components by weight ratio:
Wherein, the weight ratio of soybean lecithin and 18-amine. is 1: 1-2.5: 1.
In the method for the invention, can also sterilize to liposome and/or lipidosome solid preparation as required.Sterilizing methods does not have specific (special) requirements, can use liposome sterilizing methods commonly used in the pharmaceutical field, as heat sterilization, filtration sterilization, radiation sterilization or sterile working etc.
Beneficial effect of the present invention
(1) liposome tablet provided by the invention is benazepril hydrochloride and hydrochlorothiazide drug combination, and effect is better, has avoided a lot of deficiencies of single medicine;
(2) the liposome preparation process is simple, the envelop rate height, and drug content and envelop rate are far superior to the product of prior art, are suitable for suitability for industrialized production;
(3) liposome tablet of the present invention preparation has promoted medicine to absorb under one's belt, and prolong drug is at the circulation time of blood, remarkable has improved bioavailability, and curative effect is more remarkable;
(4) improve the formulation products quality, reduced toxic and side effects.
Description of drawings
Below, describe embodiment of the present invention by reference to the accompanying drawings in detail, wherein:
Fig. 1 is the plasma concentration curve of benazepril hydrochloride;
Fig. 2 is the plasma concentration curve of hydrochlorothiazide.
The specific embodiment
Following examples are to further specify of the present invention, but never limit the scope of the present invention.Further elaborate the present invention below with reference to embodiment, but it will be appreciated by those skilled in the art that the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modification to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
Embodiment 1The preparation of benazepril/hydrochlorothiazide liposome tablet
Prescription (1000) used supplementary material is as follows:
Preparation technology
(1) is in the mixed solvent of 2: 3 acetonitrile and dichloromethane with 250g soybean lecithin, 100g 18-amine. and the liposoluble of 25g cholesterol acetyl in the 1000ml volume ratio, gets the class lipoprotein solution;
(2) above-mentioned class lipoprotein solution is placed the pyriform bottle, in 55 ℃ of waters bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) 5g benazepril hydrochloride and 6.25g hydrochlorothiazide are scattered in the 500ml water, add jog in the pyriform bottle, make the lipid membrane eluting and be distributed to the hydration medium dissolving, namely get liposome turbid liquor;
(4) above-mentioned suspension is placed Ultrasound Instrument ultrasonic to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrate was placed under-50 ℃ of conditions freezing 4 hours, be warming up to-10 ℃ with 1.3 ℃/hour speed again, be incubated 3 hours, be warming up to 25 ℃ again, be incubated 3 hours to dry, obtain lipidosome freeze-dried powder;
(6) lipidosome freeze-dried powder and 250g microcrystalline Cellulose, the 10g carboxymethylstach sodium with above-mentioned preparation mixes, and crosses 80 mesh sieve mix homogeneously, adds 2% hydroxypropyl cellulose, 50% alcoholic solution and prepares soft material, the wet grain of the 20 mesh sieve systems of crossing, 50 ℃ of dryings, 18 mesh sieve granulate;
(7) dried granule adds 5g micropowder silica gel, mix homogeneously;
(8) tabletting makes 1000 tablet.
Embodiment 2The preparation of benazepril/hydrochlorothiazide liposome tablet
Prescription (1000) used supplementary material is as follows:
Preparation technology
(1) is in the mixed solvent of 2: 3 acetonitrile and dichloromethane with 700g soybean lecithin, 350g 18-amine. and the liposoluble of 200g cholesterol acetyl in the 2000ml volume ratio, gets the class lipoprotein solution;
(2) above-mentioned class lipoprotein solution is placed the pyriform bottle, in 45 ℃ of waters bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) 5g benazepril hydrochloride and 6.25g hydrochlorothiazide are scattered in the 500ml water, add jog in the pyriform bottle, make the lipid membrane eluting and be distributed to the hydration medium dissolving, namely get liposome turbid liquor;
(4) above-mentioned suspension is placed Ultrasound Instrument ultrasonic to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrate was placed under-50 ℃ of conditions freezing 4 hours, be warming up to-10 ℃ with 1.3 ℃/hour speed again, be incubated 3 hours, be warming up to 25 ℃ again, be incubated 3 hours to dry, obtain lipidosome freeze-dried powder;
(6) lipidosome freeze-dried powder and 1000g microcrystalline Cellulose, the 50g carboxymethylstach sodium with above-mentioned preparation mixes, and crosses 80 mesh sieve mix homogeneously, adds 2% hydroxypropyl cellulose, 80% alcoholic solution and prepares soft material, the wet grain of the 30 mesh sieve systems of crossing, 60 ℃ of dryings, 18 mesh sieve granulate;
(7) dried granule adds 15g micropowder silica gel, mix homogeneously;
(8) tabletting makes 1000 tablet.
Embodiment 3The preparation of benazepril/hydrochlorothiazide liposome tablet
Prescription (1000) used supplementary material is as follows:
Preparation technology
(1) is in the mixed solvent of 2: 3 acetonitrile and dichloromethane with 600g soybean lecithin, 300g 18-amine. and the liposoluble of 80g cholesterol acetyl in the 1500ml volume ratio, gets the class lipoprotein solution;
(2) above-mentioned class lipoprotein solution is placed the pyriform bottle, in 50 ℃ of waters bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) 10g benazepril hydrochloride and 12.5g hydrochlorothiazide are scattered in the 600ml water, add jog in the pyriform bottle, make the lipid membrane eluting and be distributed to the hydration medium dissolving, namely get liposome turbid liquor;
(4) above-mentioned suspension is placed Ultrasound Instrument ultrasonic to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrate was placed under-50 ℃ of conditions freezing 4 hours, be warming up to-10 ℃ with 1.3 ℃/hour speed again, be incubated 3 hours, be warming up to 25 ℃ again, be incubated 3 hours to dry, the lipidosome freeze-dried powder that obtains;
(6) lipidosome freeze-dried powder and 500g microcrystalline Cellulose, the 20g carboxymethylstach sodium with above-mentioned preparation mixes, and crosses 80 mesh sieve mix homogeneously, adds 2% hydroxypropyl cellulose, 60% alcoholic solution and prepares soft material, the wet grain of the 24 mesh sieve systems of crossing, 55 ℃ of dryings, 18 mesh sieve granulate;
(7) dried granule adds 10g micropowder silica gel, mix homogeneously;
(8) tabletting makes 1000 tablet.
Embodiment 4The preparation of benazepril/hydrochlorothiazide liposome tablet
Prescription (1000) used supplementary material is as follows:
Preparation technology
(1) is in the mixed solvent of 2: 3 acetonitrile and dichloromethane with 1400g soybean lecithin, 700g 18-amine. and the liposoluble of 400g cholesterol acetyl in the 3000ml volume ratio, gets the class lipoprotein solution;
(2) above-mentioned class lipoprotein solution is placed the pyriform bottle, in 55 ℃ of waters bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) 10g benazepril hydrochloride and 12.5g hydrochlorothiazide are scattered in the 600ml water, add jog in the pyriform bottle, make the lipid membrane eluting and be distributed to the hydration medium dissolving, namely get liposome turbid liquor;
(4) above-mentioned suspension is placed Ultrasound Instrument ultrasonic to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrate was placed under-50 ℃ of conditions freezing 4 hours, be warming up to-10 ℃ with 1.3 ℃/hour speed again, be incubated 3 hours, be warming up to 25 ℃ again, be incubated 3 hours to dry, the lipidosome freeze-dried powder that obtains;
(6) lipidosome freeze-dried powder and 2000g microcrystalline Cellulose, the 100g carboxymethylstach sodium with above-mentioned preparation mixes, cross 80 mesh sieve mix homogeneously, add 2% hydroxypropyl cellulose, 70% alcoholic solution and prepare soft material, the wet grain of the 20 mesh sieve systems of crossing, 50 ℃ of dryings, 18 mesh sieve granulate;
(7) dried granule adds 30g micropowder silica gel, mix homogeneously;
(8) tabletting makes 1000 tablet.
Comparative Examples 1-4
Adopt with embodiment 1 in identical production technology, the composition in will the Comparative Examples 1-3 as shown in following table 1 is made liposome tablet.
The difference of the preparation technology of Comparative Examples 4 and embodiment 1 is, step (5) is: with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrate was placed under-40 ℃ of conditions freezing 4 hours, be warming up to 25 ℃ with 2 ℃/hour speed again, be incubated 3 hours to dry, obtain lipidosome freeze-dried powder;
Used supplementary material composition among the table 1 Comparative Examples 1-4
Wherein, "/" expression is not used
Test example 1The mensuration of envelop rate
Get the liposome of embodiment 1-4 and Comparative Examples 1-4 preparation, the total content that high performance liquid chromatography detects benazepril 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 liposome that embodiment 1-4 and Comparative Examples 1-4 make, add water and make dissolving, make the solution that contains benazepril hydrochloride 0.4mg among every 1ml approximately, get solution 1.0ml respectively, add the chromatographic column top, with above-mentioned phosphate buffer 50ml eluting, flow velocity 0.9ml/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 benazepril hydrochloride.
Envelop rate %=M1/M * 100%.
Table 2 entrapment efficiency determination
By above result as can be seen, the liposome of embodiment of the invention preparation, the envelop rate height, and almost do not have significant change, the good stability of liposome after long-time the placement; And the liposome encapsulation of Comparative Examples 1-4 preparation is low, places envelop rate for a long time and descends a lot, stable bad; Proved absolutely superiority of the present invention.
This shows that the envelop rate of liposome of the present invention is relevant with the composition kind, content, the preparation technology that are used to form liposome.
Test example 2The size of liposome particle diameter and particle size distribution
In order to measure liposome of the present invention particle size parameters and particle size distribution accurately, be taken at an amount of liposome powder of gained in the step (4) among embodiment 1-4 and the Comparative Examples 1-4, directly with laser particle size analyzer (Easysizer20, America and Europe's gram company) observes its outer light, and mensuration particle diameter, handle with the dynamic light scattering process software, the distribution of measuring its diameter and calculating particle diameter the results are shown in the following table 3:
Table 3 liposome particle diameter
As shown in Table 3, the mean diameter of gained liposome is little more a lot of than the mean diameter of gained liposome among the Comparative Examples 1-4 among the embodiment of the invention 1-4, and the size homogeneous, and outward appearance is better.
By comparing embodiment 1-4 and Comparative Examples 1-4 as can be known, liposome of the present invention has littler mean diameter, and particle size distribution is more even, and outward appearance is better.This shows that the particle diameter of liposome of the present invention is relevant with the composition kind and the preparation technology that are used to form liposome.When composition, consumption and preparation technology were not in the composition amount ranges that the present invention limits, character such as the mean diameter of gained liposome of the present invention, particle size distribution and outward appearance obviously were inferior to the present invention.
Test example 3Stability and dissolution are investigated
With above embodiment 1-4 and the sample of Comparative Examples 1-4 preparation and benazepril/hydrochlorothiazide tablet (Beijing Novartis limited company of listing, lot number H20100731) 40 ℃ of high temperature, following 6 months of relative humidity 75% ± 5% condition is carried out accelerated test and is investigated, and the results are shown in Table 4.
Table 4 stability and dissolution determination result
As shown in Table 4, the benazepril/hydrochlorothiazide tablet dissolution of listing and Comparative Examples is low, and content reduces obviously when accelerating June, and related substance raises; And the sample dissolution height for preparing among the embodiment of the invention 1-4 accelerates 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.
Test example 4The mensuration of bioavailability
Adopt open, at random, single center EXPERIMENTAL DESIGN of dual crossing, two cycles, single oral dose.36 health volunteers are divided into 2 groups of A, B at random, and benazepril/hydrochlorothiazide liposome tablet and the commercially available benazepril/hydrochlorothiazide tablet of listing preparation, embodiment 1, Comparative Examples 1,2,4 preparations taken in every group of each test of experimenter respectively.After the 1d dinner, water 12h is can't help in fasting to the experimenter before test, and morning next day is oral above-mentioned benazepril/hydrochlorothiazide liposome tablet on an empty stomach, with the 200mL warm water delivery service, and notes down.The breakfast of seeking unity of standard behind the 2h of taking medicine can freely be drunk water.Duration of test is guarded by medical personnel, avoids strenuous exercise during being tried.The experimenter takes medicine preceding and take medicine back 0.5h, 1.0h, 1.5h, 2.0h, 4.0h, 6.0h, 8.0h, 10h, 12h, 16h and 24h respectively get veins of upper extremity blood 5ml, anticoagulant heparin, and centrifugal branch is got blood plasma behind the placement 30min ,-20 ℃ of preservations, room temperature is thawed during mensuration.Adopt high-efficient liquid phase technique that the benazepril in the blood plasma is measured, be shown among attached Fig. 1 and 2.
By Fig. 1 and Fig. 2 as can be seen, the benazepril/hydrochlorothiazide liposome tablet of the embodiment of the invention 1 preparation and Comparative Examples 1,2,4 and the listing product compare, bioavailability improves greatly.Proved absolutely the present invention because the liposome of making of particular excipient and active component has synergism, the tablet that is prepared from improves bioavailability widely, has obtained good slow release effect.
Industrial applicibility
By the result of above-described embodiment and experimental example as can be known, benazepril of the present invention/hydrochlorothiazide lipidosome solid preparation has good surface appearance, granule is little, and particle diameter is even, the envelop rate height, stability is high, stripping property is good, and percolation ratio is low, and the time of staying in vivo is long, the bioavailability height has the favorable industrial using value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; but should understand; these explanations do not constitute any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; can carry out multiple modification, improvement and replacement to technical solutions and their implementation methods of the present invention, these are all because falling within the scope of protection of the present invention.
Each list of references of mentioning among the application or quoting is incorporated herein by reference in full at this.
Claims (3)
1. benazepril/hydrochlorothiazide Liposomal formulation is characterized in that being made by following components by weight ratio:
Wherein, the weight ratio of soybean lecithin and 18-amine. is 1:1-2:1;
The preparation method of described preparation may further comprise the steps:
(1) with soybean lecithin, 18-amine. and the liposoluble of cholesterol acetyl in appropriate amount of organic, get the class lipoprotein solution; It is the acetonitrile of 2:3 and the mixed solvent of dichloromethane that described organic solvent is selected from volume ratio;
(2) above-mentioned class lipoprotein solution is placed the pyriform bottle, in 45-55 ℃ of water bath with thermostatic control, rotary evaporation is removed organic solvent, forms even lipid membrane;
(3) benazepril hydrochloride and hydrochlorothiazide are scattered in the water, add jog in the pyriform bottle, make the lipid membrane eluting and be distributed to the hydration medium dissolving, namely get liposome turbid liquor;
(4) above-mentioned suspension is placed Ultrasound Instrument ultrasonic to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrate was placed under-50 ℃ of conditions freezing 4 hours, be warming up to-10 ℃ with 1.3 ℃/hour speed again, be incubated 3 hours, be warming up to 25 ℃ again, be incubated 3 hours to dry, obtain the lipidosome freeze-dried powder of benazepril/hydrochlorothiazide.
2. benazepril/hydrochlorothiazide lipidosome solid preparation is characterized in that mainly by the benazepril/hydrochlorothiazide liposome of claim 1, add that other excipient pharmaceutically commonly used make, and this solid preparation is tablet.
3. benazepril/hydrochlorothiazide liposome tablet is characterized in that being made by following components by weight ratio:
Wherein, the weight ratio of soybean lecithin and 18-amine. is 1:1-2.5:1.
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| CN114053226A (en) * | 2021-11-18 | 2022-02-18 | 上海欣峰制药有限公司 | Pharmaceutical preparation of cefminox sodium compound and preparation method thereof |
| CN114209651A (en) * | 2021-11-18 | 2022-03-22 | 上海欣峰制药有限公司 | Pharmaceutical preparation of cefotaxime sodium compound and preparation method thereof |
| CN117538461B (en) * | 2024-01-10 | 2024-03-26 | 地奥集团成都药业股份有限公司 | Detection method of related substances of benazepril hydrochloride tablets |
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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 |
| CN102204922A (en) * | 2011-03-18 | 2011-10-05 | 海南瑞基药物研究有限公司 | Solid preparation of sodium fosinopril and hydrochlorothiazide medicinal composition |
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