CN102204922B - Solid preparation of sodium fosinopril and hydrochlorothiazide medicinal composition - Google Patents
Solid preparation of sodium fosinopril and hydrochlorothiazide medicinal composition Download PDFInfo
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- CN102204922B CN102204922B CN201110065273A CN201110065273A CN102204922B CN 102204922 B CN102204922 B CN 102204922B CN 201110065273 A CN201110065273 A CN 201110065273A CN 201110065273 A CN201110065273 A CN 201110065273A CN 102204922 B CN102204922 B CN 102204922B
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Abstract
The invention discloses a liposome preparation of sodium fosinopril and hydrochlorothiazide. The liposome is mainly prepared from the following components in part by weight: 10 to 20 parts of sodium fosinopril, 12.5 parts of hydrochlorothiazide, 50 to 200 parts of soybean phosphatidylcholine, 20 to 100 parts of cholesterol and 5 to 60 parts of sodium deoxycholate. The invention also discloses a solid preparation of a sodium fosinopril and hydrochlorothiazide medicinal composition, which is prepared from the liposome preparation of sodium fosinopril and hydrochlorothiazide, and other excipients usually used pharmaceutically. The quality of the preparation is improved and the toxic and side effects are reduced.
Description
Technical field
The present invention relates to a kind of fosinopril sodium hydrochlorothiazide compound preparation, be specifically related to a kind of fosinopril sodium hydrochlorothiazide pharmaceutical composition solid preparation, belong to medical technical field.
Background technology
Fosinopril sodium, its chemical name are 4-cyclohexyl-1-[(2-methyl isophthalic acid-(propionyloxy) propoxyl group) (4-phenyl butyl) phosphono acetyl group]-L-Sodium proline, and molecular formula is C
30H
45NNaO
7P, molecular weight are 585.65, and structural formula is:
Fosinopril sodium is an antihypertensive, is angiotensin converting enzyme inhibitor.Be transformed into the fosinoprilat with pharmacologically active in vivo, the latter can suppress Angiotensin-Converting, reduces the concentration of Angiotensin II and aldosterone, makes the peripheral blood vessel expansion, and vascular resistance reduces, and produces pressure reduction effect.During treatment hypertension, can use separately, or unite use with other antihypertensive drug as the initial therapy medicine.During the treatment heart failure, can share with diuretic.
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 promptly common alleged " water urine ball " mainly suppresses the heavily absorption of medullary loop ascending branch cortex portion to Na+ and Cl-, and kidney is increased and the generation diuresis the drainage of sodium chloride, is a kind of middle diuretic of imitating.Over nearly more than 30 years, be that main thiazide diuretic is one of main force of antihypertensive drugs always with the hydrochlorothiazide, and though this medicine single with or with other antihypertensive drugs logotypes, clear and definite curative effect is all 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 like low potassium, and 25mg or 12.5mg hydrochlorothiazide can reduce untoward reaction and still keep curative effect every day.
Share through the two in the fosinopril sodium hydrochlorothiazide, can alleviate the reverse regulating action of hydrochlorothiazide, thereby strengthen the antihypertensive effect of diuretic RAS; Selective exclusion AT1 subtype acceptor and strengthen hypotensive effect simultaneously.Fosinopril sodium and hydrochlorothiazide share, and except strengthening curative effect, also can offset the ill effect of the latter to blood potassium and blood uric acid.This is to use the unify activation of RAS of the caused sympathetic nervous system of diuretic because fosinopril sodium can be offset, and these can resist the hypotensive effect of these medicines by the compensatory mechanism that diuretic brought out, and reduce the blood potassium level; Simultaneously, fosinopril sodium has the effect that promotes that uric acid is discharged, and can reduce hypertensive patients metabolic arthritis patient the dangerous incidence rate of cardiovascular event takes place.
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, fosinopril sodium hydrochlorothiazide liposome tablet provided by the invention will become a new lover of compound hypertension medicine.
The inventor through creationary research; The fosinopril sodium hydrochlorothiazide liposome that discovery selects for use the excipient of certain content and composition to process; Its drug content and envelop rate are far superior to the product of prior art, and process 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 fosinopril sodium 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; Bioavailability is high, and 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 these three kinds of materials of soybean lecithin, cholesterol and NaTDC, finds the combination of soybean lecithin, cholesterol and three kinds of materials of NaTDC unexpectedly, has solved the stability and the not good technical problem of envelop rate of liposome; Obtained beyond thought preparation effect, thereby superior in quality liposome is provided.Though do not want to receive one theory, effect of the present invention possibly be the common and/or synergistic result of soybean lecithin, cholesterol and three kinds of materials of NaTDC.
One of the object of the invention is to provide a kind of fosinopril sodium hydrochlorothiazide pharmaceutical composition solid preparation, and this solid preparation is a tablet, and its specification is 10mg/12.5mg and 20mg/12.5mg.
One of the object of the invention is to provide a kind of fosinopril sodium hydrochlorothiazide Liposomal formulation, mainly is to be processed by fosinopril sodium, hydrochlorothiazide, soybean lecithin, cholesterol and NaTDC; Further preferably, its content proportioning is counted fosinopril sodium 10-20 part based on weight, 12.5 parts of hydrochlorothiazide, soybean lecithin 50-200 part, cholesterol 20-100 part, NaTDC 5-60 part; Most preferably, its content proportioning is counted fosinopril sodium 10-20 part based on weight, 12.5 parts of hydrochlorothiazide, soybean lecithin 60-150 part, cholesterol 30-70 part, NaTDC 8-40 part.
As the present invention's one preferred embodiment, described fosinopril sodium hydrochlorothiazide Liposomal formulation, the ratio of weight and number of each component of the liposome of its preparation UD is:
As the present invention's one preferred embodiment, described fosinopril sodium hydrochlorothiazide Liposomal formulation, the ratio of weight and number of each component of the liposome of its preparation UD is:
As the present invention's one preferred embodiment, described fosinopril sodium hydrochlorothiazide Liposomal formulation, the ratio of weight and number of each component of the liposome of its preparation UD is:
As the present invention's one preferred embodiment, described fosinopril sodium hydrochlorothiazide Liposomal formulation, the ratio of weight and number of each component of the liposome of its preparation UD is:
In the preferred embodiments of the invention, wherein the fosinopril sodium chemical name is 4-cyclohexyl-1-[(2-methyl isophthalic acid-(propionyloxy) propoxyl group) (4-phenyl butyl) phosphono acetyl group]-L-Sodium proline, and molecular formula is C
30H
45NNaO
7P, molecular weight are 585.65, and structural formula is:
The consumption of fosinopril sodium is 5-50mg, is preferably 10mg and 20mg.
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 consumption of hydrochlorothiazide is 2.5-30mg, is preferably 5-20mg, more preferably 12.5mg.
Another object of the present invention is to provide a kind of fosinopril sodium hydrochlorothiazide liposome tablet; Mainly count fosinopril sodium 10-20 part based on weight by the content proportioning; 12.5 parts of hydrochlorothiazide, soybean lecithin 50-200 part, cholesterol 20-100 part; The fosinopril sodium hydrochlorothiazide liposome that NaTDC 5-60 part is processed is added other excipient pharmaceutically commonly used and is processed fosinopril sodium hydrochlorothiazide liposome tablet of the present invention.
Liposome tablet of the present invention, other excipient wherein pharmaceutically commonly used comprise filler, disintegrating agent, binding agent, lubricant.Its amount ranges is the conventional amount used scope of general solid preparation, does not have specific (special) requirements and regulation.
As preferably, filler can be selected from one or more in starch, lactose, mannitol, sorbitol, microcrystalline Cellulose, pregelatinized Starch, the dextrin, is preferably pregelatinized Starch and 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 magnesium stearate and micropowder silica gel.
The present invention also provides a kind of method for preparing fosinopril sodium hydrochlorothiazide liposome tablet; Its first fosinopril sodium, hydrochlorothiazide, soybean lecithin, cholesterol and NaTDC are processed liposome; Other mixed with excipients again and pharmaceutically commonly used are processed tablet, and concrete preparation process comprises:
(1) soybean lecithin, cholesterol and NaTDC being dissolved in an amount of volume ratio is in 2: 3 the mixed solvent of acetonitrile and dichloromethane, a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed the pyriform bottle, in 45-55 ℃ of water bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) fosinopril sodium 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, promptly get liposome turbid liquor;
(4) place Ultrasound Instrument ultrasonic above-mentioned suspension to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m; Filtrating 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 fosinopril sodium hydrochlorothiazide;
(6) the lipidosome freeze-dried powder of fosinopril sodium hydrochlorothiazide of above-mentioned preparation and other adjuvants pharmaceutically commonly used are comprised that filler, disintegrating agent mix, the mix homogeneously that sieves adds binding agent and prepares soft material, the granulation of sieving, drying, granulate;
(7) dried granule adds lubricant, mix homogeneously;
(8) tabletting makes fosinopril sodium hydrochlorothiazide liposome tablet.
As preferably, the concentration of the solution of binding agent is the 50%-80% ethanol water in the above-mentioned described method for preparing.
As preferably, cross 80 mesh sieve mix homogeneously after supplementary material mixes in the above-mentioned described method for preparing, cross 20-30 mesh sieve system wet granular behind the system soft material, 50-60 ℃ of drying, 18 mesh sieve granulate.
Beneficial effect of the present invention:
(1) liposome tablet provided by the invention is fosinopril sodium and hydrochlorothiazide drug combination, and effect is better, has avoided a lot of deficiencies of single medicine;
(2) the liposome preparation process is simple, and envelop rate is high, 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.
The specific embodiment
Below further specify the present invention through embodiment, but should not be construed as limitation of the present invention.
The preparation of embodiment 1 fosinopril sodium hydrochlorothiazide liposome tablet
Prescription (1000)
Preparation technology
(1) 60g soybean lecithin, 30g cholesterol and 8g NaTDC being dissolved in the 2000ml volume ratio is in 2: 3 the mixed solvent of acetonitrile and dichloromethane, a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed the pyriform bottle, in 55 ℃ of waters bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) 10g fosinopril sodium and 12.5g 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, promptly get liposome turbid liquor;
(4) place Ultrasound Instrument ultrasonic above-mentioned suspension to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m; Filtrating 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 fosinopril sodium hydrochlorothiazide;
(6) the lipidosome freeze-dried powder of fosinopril sodium hydrochlorothiazide and 30g pregelatinized Starch, 50g microcrystalline Cellulose, the 10g carboxymethylstach sodium with above-mentioned preparation mixes; Cross 80 mesh sieve mix homogeneously; Add 2% hydroxypropyl cellulose, 50% 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 2g magnesium stearate and 2g micropowder silica gel, mix homogeneously;
(8) tabletting makes fosinopril sodium hydrochlorothiazide liposome tablet.
The preparation of embodiment 2 fosinopril sodium hydrochlorothiazide liposome tablets
Prescription (1000)
Preparation technology
(1) 150g soybean lecithin, 70g cholesterol and 40g NaTDC being dissolved in the 5000ml volume ratio is in 2: 3 the mixed solvent of acetonitrile and dichloromethane, a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed the pyriform bottle, in 45 ℃ of waters bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) 10g fosinopril sodium and 12.5g 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, promptly get liposome turbid liquor;
(4) place Ultrasound Instrument ultrasonic above-mentioned suspension to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m; Filtrating 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 fosinopril sodium hydrochlorothiazide;
(6) the lipidosome freeze-dried powder of fosinopril sodium hydrochlorothiazide and 60g pregelatinized Starch, 40g microcrystalline Cellulose, the 20g carboxymethylstach sodium with above-mentioned preparation mixes; Cross 80 mesh sieve mix homogeneously; Add 2% hydroxypropyl cellulose, 80% alcoholic solution and prepare soft material; The wet grain of the 30 mesh sieve systems of crossing, 60 ℃ of dryings, 18 mesh sieve granulate;
(7) dried granule adds 4g magnesium stearate and 4g micropowder silica gel, mix homogeneously;
(8) tabletting makes fosinopril sodium hydrochlorothiazide liposome tablet.
The preparation of embodiment 3 fosinopril sodium hydrochlorothiazide liposome tablets
Prescription (1000)
Preparation technology
(1) 100g soybean lecithin, 50g cholesterol and 25g NaTDC being dissolved in the 4000ml volume ratio is in 2: 3 the mixed solvent of acetonitrile and dichloromethane, a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed the pyriform bottle, in 50 ℃ of waters bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) 20g fosinopril sodium 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, promptly get liposome turbid liquor;
(4) place Ultrasound Instrument ultrasonic above-mentioned suspension to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m; Filtrating 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 fosinopril sodium hydrochlorothiazide;
(6) the lipidosome freeze-dried powder of fosinopril sodium hydrochlorothiazide and 40g pregelatinized Starch, 70g microcrystalline Cellulose, the 20g carboxymethylstach sodium with above-mentioned preparation mixes; Cross 80 mesh sieve mix homogeneously; Add 2% hydroxypropyl cellulose, 60% alcoholic solution and prepare soft material; The wet grain of the 24 mesh sieve systems of crossing, 55 ℃ of dryings, 18 mesh sieve granulate;
(7) dried granule adds 3g magnesium stearate and 3g micropowder silica gel, mix homogeneously;
(8) tabletting makes fosinopril sodium hydrochlorothiazide liposome tablet.
The preparation of embodiment 4 fosinopril sodium hydrochlorothiazide liposome tablets
Prescription (1000)
Preparation technology
(1) 150g soybean lecithin, 30g cholesterol and 40g NaTDC being dissolved in the 6000ml volume ratio is in 2: 3 the mixed solvent of acetonitrile and dichloromethane, a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed the pyriform bottle, in 55 ℃ of waters bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) 20g fosinopril sodium 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, promptly get liposome turbid liquor;
(4) place Ultrasound Instrument ultrasonic above-mentioned suspension to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m; Filtrating 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 fosinopril sodium hydrochlorothiazide;
(6) the lipidosome freeze-dried powder of fosinopril sodium hydrochlorothiazide and 40g pregelatinized Starch, 80g microcrystalline Cellulose, the 20g 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 4g magnesium stearate and 4g micropowder silica gel, mix homogeneously;
(8) tabletting makes fosinopril sodium hydrochlorothiazide liposome tablet.
Embodiment 5
The preparation of the fosinopril sodium hydrochlorothiazide Liposomal formulation of Comparative Examples 1-4
Above-mentioned Comparative Examples 1-4 accomplishes according to preparation technology (1)-(5) step of fosinopril sodium hydrochlorothiazide liposome among the embodiment 1-4 respectively by the set of dispense ratio.
The preparation of embodiment 6 liposome tablet Comparative Examples 5-8
With the fosinopril sodium hydrochlorothiazide liposome of Comparative Examples 1-4 preparation be active component, accomplish according to (6)-(8) step of embodiment 1-4 respectively.
The mensuration of embodiment 7 envelop rates
Get the fosinopril sodium hydrochlorothiazide liposome of embodiment 1-4 and Comparative Examples 1-4 preparation, the total content that HPLC detects fosinopril sodium 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, and in the chromatographic column of packing into (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; Process the solution that contains fosinopril sodium 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 collection add rupture of membranes agent (ethanol: 50ml benzyl alcohol=8: 1); Mixing, HPLC detects the content M1 of fosinopril sodium.
Envelop rate %=M1/M * 100%.
Investigate 0,3,6,12 month respectively, result such as following table:
Can find out by above result, the liposome of embodiment of the invention preparation, envelop rate is high, and does not almost 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.
The mensuration of embodiment 8 bioavailability
Adopt open, at random, single center EXPERIMENTAL DESIGN of dual crossing, two cycles, single oral dose.20 health volunteers are divided into A, B2 group at random, and the fosinopril sodium hydrochlorothiazide liposome tablet of embodiment 1, Comparative Examples 5-8 preparation is 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 fosinopril sodium 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 0.5,1.0,2.0,3.0,4.0,5.0,6.0,8.0,10,12,16 and 24h respectively get veins of upper extremity blood 5ml, and anticoagulant heparin is placed the centrifugal blood plasma of obtaining behind the 30min ,-20 ℃ of preservations, and room temperature is thawed during mensuration.Adopt high-efficient liquid phase technique that the fosinopril sodium in the blood plasma is measured, data are following:
Relevant pharmacokinetic parameters
Can be found out that by above experimental data the fosinopril sodium hydrochlorothiazide liposome tablet of the embodiment of the invention 1 preparation is compared with Comparative Examples 5-8, bioavailability improves greatly.Proved absolutely the present invention because the liposome of processing of particular excipient and active component has synergism, the tablet that is prepared from improves bioavailability widely, has obtained unexpected technical effect.
Obviously, the above embodiment of the present invention only be for clearly the present invention is described and is done for example, and be not to be qualification to embodiment of the present invention.For the those of ordinary skill in affiliated field, on the basis of above-mentioned explanation, can also make other multi-form variation or change.Here need not also can't give exhaustive to all embodiments.And these belong to conspicuous variation or the change that spirit of the present invention extended out and still are among protection scope of the present invention.
Claims (10)
1. a fosinopril sodium hydrochlorothiazide Liposomal formulation is characterized in that being processed by fosinopril sodium, hydrochlorothiazide, soybean lecithin, cholesterol and NaTDC; The content proportioning is counted fosinopril sodium 10-20 part based on weight, 12.5 parts of hydrochlorothiazide, soybean lecithin 50-200 part, cholesterol 20-100 part, NaTDC 5-60 part.
2. fosinopril sodium hydrochlorothiazide Liposomal formulation according to claim 1; It is characterized in that the content proportioning counts fosinopril sodium 10-20 part based on weight, 12.5 parts of hydrochlorothiazide, soybean lecithin 60-150 part; Cholesterol 30-70 part, NaTDC 8-40 part.
3. fosinopril sodium hydrochlorothiazide Liposomal formulation according to claim 2, the ratio of weight and number of each component that it is characterized in that preparing the liposome of UD is:
4. fosinopril sodium hydrochlorothiazide Liposomal formulation according to claim 2, the ratio of weight and number of each component that it is characterized in that preparing the liposome of UD is:
5. fosinopril sodium hydrochlorothiazide Liposomal formulation according to claim 2, the ratio of weight and number of each component that it is characterized in that preparing the liposome of UD is:
6. fosinopril sodium hydrochlorothiazide Liposomal formulation according to claim 2, the ratio of weight and number of each component that it is characterized in that preparing the liposome of UD is:
7. a fosinopril sodium hydrochlorothiazide pharmaceutical composition solid preparation is characterized in that each described Liposomal formulation by claim 1-6, adds that other pharmaceutically commonly used excipient process, and this solid preparation is a tablet.
8. fosinopril sodium hydrochlorothiazide liposome tablet according to claim 7 is characterized in that other excipient pharmaceutically commonly used are selected from filler, disintegrating agent, binding agent, lubricant.
9. fosinopril sodium hydrochlorothiazide liposome tablet according to claim 8 is characterized in that filler is pregelatinized Starch and microcrystalline Cellulose; Disintegrating agent is a carboxymethylstach sodium; Binding agent is a hydroxypropyl cellulose; Lubricant is magnesium stearate and micropowder silica gel.
10. method for preparing the described fosinopril sodium hydrochlorothiazide of claim 8 liposome tablet; It is characterized in that processing liposome by fosinopril sodium, hydrochlorothiazide, soybean lecithin, cholesterol and NaTDC in the claim 1; Other mixed with excipients pharmaceutically commonly used are processed tablet, and concrete preparation process is following:
(1) soybean lecithin, cholesterol and NaTDC being dissolved in an amount of volume ratio is in 2: 3 the mixed solvent of acetonitrile and dichloromethane, a type lipoprotein solution;
(2) above-mentioned type of lipoprotein solution placed the pyriform bottle, in 45-55 ℃ of water bath with thermostatic control, rotary evaporation is removed mixed solvent, forms even lipid membrane;
(3) fosinopril sodium 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, promptly get liposome turbid liquor;
(4) place Ultrasound Instrument ultrasonic above-mentioned suspension to translucent colloid solution;
(5) with the filtering with microporous membrane of above-mentioned suspension with 0.45 μ m, filtrating 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, obtain fosinopril sodium hydrochlorothiazide lipid freeze-dried powder to dry;
(6) the lipidosome freeze-dried powder of fosinopril sodium hydrochlorothiazide and filler, the disintegrating agent with above-mentioned preparation mixes, and the mix homogeneously that sieves adds binding agent and prepares soft material, the granulation of sieving, drying, granulate;
(7) dried granule adds lubricant, mix homogeneously;
(8) tabletting makes fosinopril sodium hydrochlorothiazide liposome tablet.
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| CN102579348B (en) * | 2012-03-02 | 2014-01-15 | 海南美兰史克制药有限公司 | Fosinopril sodium liposome solid preparation |
| CN102579346B (en) * | 2012-03-02 | 2013-09-25 | 海南美兰史克制药有限公司 | Liposome solid preparation of benazepril/hydrochlorothiazide medicine combination |
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| Title |
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| 蒋维等.蒙诺联合氢氯噻嗪治疗原发性高血压疗效观察.《现代医药卫生》.2009,第25卷(第20期),第3050-3051页. * |
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