CN102138899A - Olmesartan liposome solid preparation - Google Patents
Olmesartan liposome solid preparation Download PDFInfo
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- CN102138899A CN102138899A CN2011100652533A CN201110065253A CN102138899A CN 102138899 A CN102138899 A CN 102138899A CN 2011100652533 A CN2011100652533 A CN 2011100652533A CN 201110065253 A CN201110065253 A CN 201110065253A CN 102138899 A CN102138899 A CN 102138899A
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Abstract
The invention discloses an olmesartan liposome solid preparation prepared by the following raw and supplementary material components in parts by weight: 1 part of olmesartan, 2.5-14 parts of dioleoyl-phosphatidylcholine, 0.5-6 parts of cholesterol, 0.8-10 parts of sodium glycyl-cholate, 0.2-5 parts of soy sterol and 2-20 parts of pharmaceutically acceptable carriers or excipients. The liposome solid preparation provided by the invention has high entrapment rate, even grain size, long medicament retention time in blood circulation, simple equipment, easiness in operation, improved product quality of the preparation and lessened toxic and side effects and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of lipidosome solid preparation, be specifically related to a kind of A Qishatan ester liposome solid preparation and preparation method thereof, belong to medical technical field.
Background technology
The A Qishatan ester, be that form with potassium salt exists in pharmaceutical preparation, chemistry (5-methyl-2-oxo-1 by name, the 3-Dioxol-4-yl) methyl-2-ethyoxyl-1-{[2 '-(5-oxo-4,5 dihydros-1,2,4-oxadiazoles-3 base) biphenyl-4-yl] methyl }-1H-benzimidazole-7-carboxylic acid monopotassium salt, molecular formula C
30H
23KN
4O
8, molecular weight 606.62, structural formula is:
On February 25th, 2011, Japanese military field drugmaker announces that FDA (Food and Drug Adminstration) (FDA) has ratified angiotensin-ii receptor blocker Edarbi (A Qishatan ester) and has been used for the treatment of adult's hypertension.This medicine is an oral medication, takes medicine every day 1 time, both can singly use, also can with other depressor couplings.Edarbi can block the vasoconstriction that Angiotensin II causes, thereby makes blood pressure drops.
The CEO Shinji Honda of Tap Pharmaceutical Products (US) represents to tickle to death to this medicine is granted, and he says that " by discovery, exploitation and the commercialization of this new drug, military field is devoted to new drugs such as Edarbi are introduced to the market.Edarbi is that an important new treatment is selected to the hyperpietic and for it provides the medical personnel of treatment.”
Edarbi belongs to angiotensin II acceptor inhibitor, reaches the effect that brings high blood pressure down by the activity of blocking angiotensin II receptor.This pharmaceutical quantities is divided into 80 milligrams and 40 milligrams two kinds, and recommended dose is 80 milligrams of every days, and 40 milligrams are applicable to that then those use the high dose diuretic to reduce the patient of salt in the body.
The clinical experiment result shows, compares with Benicar with other the two kinds hypertension therapeutic medicine Diovan that ratified by FDA, and the blood pressure lowering effect of Edarbi within 24 hours is even better.
Liposome (liposomes) is to be proposed by biomembranous models of conduct research such as Britain Banghan nineteen sixty-five the earliest.Discoveries such as Banghan form multilamellar vesicle when phospholipid is dispersed in the water, and each layer is lipid bilayer, are separated by water between each layer.Be made up of the lipid bimolecular this afterwards, inside is called liposome for the closed vesicle of water.
People are by discovering, liposome can be controlled the release of medicine as the carrier of medicine, improves drug targeting, reduces drug toxicity and side effect, improves curative effect of medication.
If the A Qishatan ester can be made liposome, then be expected to overcome a series of problems that existing A Qishatan ester formulation exists, improve stability of drug, prolong drug retention time in vivo, permanent performance drug effect improves bioavailability, reduces toxic and side effects, reduce incidence rate of adverse reaction, improve treatment speed and therapeutic effect.
But, the challenge of preparation liposome is to select suitable liposome constituent and method for making.Because character such as envelop rate, stability, onset time, circulation time in vivo, bioavailability and the toxic and side effects etc. of liposome are directly closely related with the composition of liposome, and the composition of liposome is directly closely related with the pharmaceutical properties that will seal, therefore, selecting which type of composition to form the A Qishatan ester liposome with better quality is the problem that needs to be resolved hurrily.
Summary of the invention
The inventor is through research in earnest for a long time, discovery can be prepared into liposome according to specific ratio with A Qishatan ester, dioleoyl phospholipid phatidylcholine, cholesterol, NaGC and soyasterol, again liposome and pharmaceutically acceptable carrier or excipient are made tablet, thereby finished the present invention.
A Qishatan ester liposome envelop rate height provided by the invention, good stability, the bioavailability height can solve the stability and the not good technical problem of envelop rate of liposome, has obtained beyond thought effect, thereby has improved the product quality of preparation.
The object of the present invention is to provide a kind of A Qishatan ester liposome solid preparation and preparation method thereof, by active component A Qishatan ester, dioleoyl phospholipid phatidylcholine, cholesterol, NaGC and soyasterol are prepared into liposome, make solid preparation with pharmaceutically acceptable carrier or excipient again.
As one of purpose of the present invention, A Qishatan ester liposome preparation comprises that the supplementary material of the component of following weight proportion makes:
As the present invention's one preferred embodiment, above-mentioned described A Qishatan ester liposome preparation comprises that the supplementary material of the component of following weight proportion makes:
More preferably, described supplementary material comprises the component of following weight proportion:
In A Qishatan ester liposome of the present invention, the phospholipid material that uses is the dioleoyl phospholipid phatidylcholine.
The phospholipid material commonly used that is used to form is of a great variety, comprises soybean lecithin, lecithin, Ovum Gallus domesticus Flavus lecithin, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine, soybean phospholipid acyl inositol, two Laurel phosphatidyl cholines, two myristoyl phosphatidyl phatidylcholines, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, the myristoyl phosphatidylcholine, palmityl myristoyl phosphatidylcholine, palmityl stearoyl phosphatidylcholine, the stearoyl palmitoylphosphatidyl choline, the dioleoyl phospholipid phatidylcholine, two lauroyl phosphatidyl glycerols, two myristoyl phosphatidyl acyl glycerol, two palmityl phosphatidyl glycerols, the distearyl phosphatidyl glycerol, DOPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, DOPG, two myristoyl phosphatidic acid, two palmityl phosphatidic acid, two palmityl PHOSPHATIDYL ETHANOLAMINE, two palmityl PHOSPHATIDYL ETHANOLAMINE, two myristoyl Phosphatidylserine, with two palmityl Phosphatidylserine etc.
The inventor is through discovering with keen determination, in common phospholipid material, the dioleoyl phospholipid phatidylcholine as natural phospholipid of appropriate amount can be used to form colory A Qishatan ester liposome, can form the suitably high liposome of envelop rate of size, appropriate configuration composition by the method that provides among the present invention, and these compositions, especially the A Qishatan ester is non-leakage in formed liposome.
In the A Qishatan ester liposome of the present invention, based on 1 weight portion A Qishatan ester, if the amount of dioleoyl phospholipid phatidylcholine is lower than 2.5 weight portions, then can't form stabilized liposomes, if the amount of dioleoyl phospholipid phatidylcholine is higher than 14 weight portions, then the envelop rate of A Qishatan ester reduces, and the stability of liposome descends to some extent.
In the A Qishatan ester liposome of the present invention, the membrane structure of cholesterol regulation liposome is regulated the flowability and the permeability of membrane structure.Based on 1 weight portion A Qishatan ester, the cholesterol of 0.5-6 weight portion can form the liposome that has good stability.
In A Qishatan ester liposome of the present invention, NaGC further strengthens the stability of liposome.Based on 1 weight portion A Qishatan ester, the NaGC of 0.8-10 weight portion can form the liposome that has good stability.
In A Qishatan ester liposome of the present invention, soyasterol further strengthens the stability of liposome.Based on 1 weight portion A Qishatan ester, the soyasterol of 0.2-5 weight portion can form the liposome that has good stability.
Described soyasterol is the hydrolyzate that the soyasterol glucoside removes glucose residue, and the soyasterol glucoside is the mixture from the sterol glucoside of separating through the Semen sojae atricolor residue of refinement Oleum Glycines, is the product of natural origin, and is safe, be easy to obtain, and low price.
In A Qishatan ester liposome of the present invention, the collaborative adjusting facilitation to membrane structure of cholesterol, NaGC and soyasterol by an amount of proportioning can form envelop rate height, A Qishatan ester liposome that stability is high.
As two of purpose of the present invention, a kind of preparation method of A Qishatan ester liposome preparation also is provided, step is as follows:
(a) A Qishatan ester, dioleoyl phospholipid phatidylcholine, cholesterol, NaGC and soyasterol are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) add buffer solution and make the complete aquation of immobilized artificial membrane,, filter, make liposome turbid liquor by microporous filter membrane with the even at a high speed matter emulsifying of tissue mashing machine;
(c), make A Qishatan ester liposome powder with above-mentioned liposome turbid liquor spray drying.
Preferably, in the above-mentioned preparation method step (a), described organic solvent is selected from one or more in ethanol, methanol, acetone, isopropyl alcohol, acetonitrile, n-butyl alcohol, the tert-butyl alcohol, benzyl alcohol, normal hexane and the dichloromethane, and preferred volume ratio is 1: 2 the ethanol and the mixed solvent of normal hexane;
Preferably, in listing preparation method step (b), described buffer solution is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer and the carbonate buffer solution, is preferably pH and is citric acid-sodium citrate buffer solution of 6.0;
Preferably, in the listing preparation method step (b), being used for filtering microporous filter membrane aperture is 0.45 μ m.
Preferably, in the listing preparation method step (b), concrete steps are as follows:
Add buffer solution, jolting was stirred 30 minutes, rotating speed was 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 10-15 minute, rotating speed 5000-10000r/min is 0.45 μ m filtering with microporous membrane with the aperture, makes liposome turbid liquor.
A Qishatan ester liposome powder diameter by method preparation provided by the invention is little, and particle size distribution is even, the envelop rate height, and stability is high.
Three of purpose of the present invention also provides a kind of A Qishatan ester liposome solid preparation, and by A Qishatan ester liposome and pharmaceutically acceptable carrier or excipient 2-20 weight portion, preferred 3-12 weight portion is based on 1 weight portion A Qishatan ester;
Preferably, A Qishatan ester liposome solid preparation is made by the supplementary material of following weight proportion:
Above-mentioned described A Qishatan ester liposome solid preparation is a tablet, and specification is 40mg and 80mg.
Above-mentioned described A Qishatan ester liposome solid preparation is characterized in that described pharmaceutically acceptable carrier or excipient are selected from diluent, disintegrating agent, binding agent, lubricant and combination thereof.The consumption of various pharmaceutic adjuvants can be selected according to the general consumption of each adjuvant in solid preparation by those skilled in the art, and this is in those skilled in the art's limit of power.
Further, as preferably, diluent can be selected from one or more in starch, Icing Sugar, lactose, amylum pregelatinisatum, microcrystalline Cellulose, dextrin, the mannitol, is preferably mannitol and microcrystalline Cellulose.Its consumption can be preferably 30%-40% (w/w) for the 20%-50% (w/w) of described tablet total weight amount.
Further, as preferably, disintegrating agent can be selected from one or more the combination in carboxymethylstach sodium, dried starch, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, the polyvinylpolypyrrolidone, is preferably cross-linking sodium carboxymethyl cellulose.Its consumption can be preferably 3%-5% (w/w) for the 2%-7% (w/w) of described solid preparation gross weight.
Further, as preferably, binding agent can be selected from a kind of in hypromellose, 30 POVIDONE K 30 BP/USP 30, sodium carboxymethyl cellulose, xanthan gum, arabic gum, methylcellulose, ethyl cellulose, the hydroxypropyl cellulose, is preferably hydroxypropyl cellulose.Its consumption can be preferably 0.5%-0.8% (w/w) for the 0.3%-2% (w/w) of described solid preparation gross weight.
Further, as preferably, lubricant can be selected from one or more the combination in Pulvis Talci, micropowder silica gel, magnesium stearate, zinc stearate, Macrogol 4000, the stearic acid, is preferably magnesium stearate.Its consumption can be preferably 0.7%-1% (w/w) for the 0.3%-2% (w/w) of described solid preparation gross weight.
Four of the object of the invention also provides a kind of preparation method of A Qishatan ester liposome tablet, may further comprise the steps:
(1) preparation of A Qishatan ester liposome: A Qishatan ester, dioleoyl phospholipid phatidylcholine, cholesterol, NaGC, soyasterol are made the liposome powder together;
(2) preparation of A Qishatan ester liposome tablet: with gained A Qishatan ester liposome in the step (1) and pharmaceutically acceptable carrier or mixed with excipients, preparation A Qishatan ester liposome tablet.
As preferably, in the above-mentioned described method, step (2) comprises the steps:
(d) A Qishatan ester liposome powder and diluent, disintegrating agent are mixed, cross 60 mesh sieve mix homogeneously, add binder solution and prepare soft material, cross the 20-30 mesh sieve and granulate drying;
(e) dried granule and mix lubricant is even, cross 18 mesh sieve granulate;
(f) tabletting, coating makes A Qishatan ester liposome tablet.
In the method for the invention, can also sterilize to liposome and/or liposome tablet 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.
The present invention becomes liposome by the specific combined preparation of active component A Qishatan ester, dioleoyl phospholipid phatidylcholine, cholesterol, NaGC, soyasterol earlier, makes tablet with pharmaceutically acceptable carrier or mixed with excipients again.The particle diameter of gained Liposomal formulation is little, is evenly distributed, and the envelop rate height, good stability, the dissolubility in water is big, and medicine retention time in blood circulation is long, and is evident in efficacy; Used adjuvant cheap and simple, the availability height, pollute little, the economic worth height; The preparation method of A Qishatan ester liposome tablet provided by the invention has improved product quality, has reduced toxic and side effects, and the equipment of preparation method is simple, easy operating, and industrialized great production is highly advantageous to.
In this article, if not explanation especially, content or consumption are all in weight portion, the device that is adopted, instrument, raw material, material, consumption, method, time, appropriateness and other conditions all be well-known in the art, or those skilled in the art can obtain in conjunction with prior art according to the description of application.
Fig. 1 is the average blood drug level and the time relation curve of the A Qishatan ester liposome tablet of the A Qishatan ester liposome tablet of embodiment 1 and Comparative Examples 1.
The specific embodiment
Further specify the present invention by the following examples, but 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.
The preparation of embodiment 1 A Qishatan ester liposome tablet
Prescription:
Preparation technology
(a) 40g A Qishatan ester, 200g dioleoyl phospholipid phatidylcholine, 96g cholesterol, 80g NaGC and 52g soyasterol are dissolved among the mixed solvent 1200ml that volume ratio is 1: 2 ethanol and normal hexane, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) adding pH is citric acid-sodium citrate buffer solution of 6.0, and jolting was stirred 30 minutes, rotating speed was 500r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 10 minutes, rotating speed 5000r/min is 0.45 μ m filtering with microporous membrane with the aperture, makes liposome turbid liquor.
(c), make A Qishatan ester liposome powder with above-mentioned liposome turbid liquor spray drying.
(d) A Qishatan ester liposome powder and 90g mannitol, 220g microcrystalline Cellulose and 30g cross-linking sodium carboxymethyl cellulose are mixed, cross 60 mesh sieve mix homogeneously, add 2% hydroxypropyl cellulose, 70% alcoholic solution and prepare soft material, cross 20 mesh sieves and granulate 50 ℃ of dryings;
(e), cross 18 mesh sieve granulate with dried granule and 8g magnesium stearate mix homogeneously;
(f) tabletting, coating makes A Qishatan ester liposome tablet.
The preparation of Comparative Examples 1 A Qishatan ester liposome tablet
Prescription:
Adopt different liposome components, preparation technology makes A Qishatan ester liposome tablet with embodiment 1.
The preparation of embodiment 2 A Qishatan ester liposome tablets
Prescription:
Preparation technology
(a) 80g A Qishatan ester, 240g dioleoyl phospholipid phatidylcholine, 64g cholesterol, 80g NaGC and 40g soyasterol are dissolved among the mixed solvent 1300ml that volume ratio is 1: 2 ethanol and normal hexane, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) adding pH is citric acid-sodium citrate buffer solution of 6.0, jolting, stirred 30 minutes, rotating speed is 1000r/min, make the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 15 minutes, rotating speed 10000r/min, with the aperture is 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor.
(c), make A Qishatan ester liposome powder with above-mentioned liposome turbid liquor spray drying.
(d) A Qishatan ester liposome powder and 60g mannitol, 180g microcrystalline Cellulose and 32g cross-linking sodium carboxymethyl cellulose are mixed, cross 60 mesh sieve mix homogeneously, add 2% hydroxypropyl cellulose, 50% alcoholic solution and prepare soft material, cross 30 mesh sieves and granulate 60 ℃ of dryings;
(e), cross 18 mesh sieve granulate with dried granule and 6g magnesium stearate mix homogeneously;
(f) tabletting, coating makes A Qishatan ester liposome tablet.
The preparation of Comparative Examples 2 A Qishatan ester liposome tablets
Prescription:
The liposome component adopts outside the limits of the present invention, and preparation technology makes A Qishatan ester liposome tablet with embodiment 2.
The preparation of embodiment 3 A Qishatan ester liposome tablets
Prescription:
Preparation technology
(a) 40g A Qishatan ester, 320g dioleoyl phospholipid phatidylcholine, 160g cholesterol, 120g NaGC and 80g soyasterol are dissolved among the mixed solvent 3000ml that volume ratio is 1: 2 ethanol and normal hexane, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) adding pH is citric acid-sodium citrate buffer solution of 6.0, and jolting was stirred 30 minutes, rotating speed was 700r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 12 minutes, rotating speed 8000r/min is 0.45 μ m filtering with microporous membrane with the aperture, makes liposome turbid liquor.
(c), make A Qishatan ester liposome powder with above-mentioned liposome turbid liquor spray drying.
(d) A Qishatan ester liposome powder and 130g mannitol, 240g microcrystalline Cellulose and 50g cross-linking sodium carboxymethyl cellulose are mixed, cross 60 mesh sieve mix homogeneously, add 2% hydroxypropyl cellulose, 80% alcoholic solution and prepare soft material, cross 24 mesh sieves and granulate 55 ℃ of dryings;
(e), cross 18 mesh sieve granulate with dried granule and 10g magnesium stearate mix homogeneously;
(f) tabletting, coating makes A Qishatan ester liposome tablet.
The preparation of Comparative Examples 3 A Qishatan ester liposome tablets
Prescription is with embodiment 3, and preparation technology is different from the present invention, and is specific as follows:
(a) 40g A Qishatan ester, 320g dioleoyl phospholipid phatidylcholine, 160g cholesterol, 120g NaGC and 80g soyasterol are dissolved among the mixed solvent 3000ml that volume ratio is 1: 2 ethanol and normal hexane, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) adding pH is citric acid-sodium citrate buffer solution of 6.0, and jolting was stirred 30 minutes, placed ultrasonic instrument ultrasonic 15 minutes, was 0.45 μ m filtering with microporous membrane with the aperture, made liposome turbid liquor.
(c), make A Qishatan ester liposome powder with above-mentioned liposome turbid liquor spray drying.
(d) A Qishatan ester liposome powder and 130g mannitol, 240g microcrystalline Cellulose and 50g cross-linking sodium carboxymethyl cellulose are mixed, cross 60 mesh sieve mix homogeneously, add 2% hydroxypropyl cellulose, 80% alcoholic solution and prepare soft material, cross 24 mesh sieves and granulate 55 ℃ of dryings;
(e), cross 18 mesh sieve granulate with dried granule and 10g magnesium stearate mix homogeneously;
(f) tabletting, coating makes A Qishatan ester liposome tablet.
The mensuration of test example 1 liposome encapsulation
Adopt ultracentrifugal method to measure the envelop rate of A Qishatan ester liposome, the concrete operations step is as follows:
(1) preparation of centrifugal sample solution: precision is measured the A Qishatan ester liposome suspension 4ml that makes among embodiment 1-3 and the Comparative Examples 1-3 in step (b), place freezing ultra-lowing centrifuge, 13000r/min, 4 ℃ centrifugal 30 minutes, get supernatant, be used for the free content of medicines of liposome solutions and measure.
(2) the not preparation of centrifuged sample solution: precision is measured the A Qishatan ester liposome suspension 4ml that makes among embodiment 1-3 and the Comparative Examples 1-3 in step (b), place the brown volumetric flask of 10ml, the alcoholic solution 8ml breakdown of emulsion of the Triton X-100 of adding 5%, with distilled water diluting and be settled to scale, shake up, be used for the total content of medicines of liposome and measure.
(3) get the centrifugal sample solution of gained A Qishatan ester liposome in above-mentioned (1) and the not centrifugal sample solution of above-mentioned (2) middle gained A Qishatan ester liposome respectively, measure peak area by corresponding chromatographic condition, and calculate the centrifugal sample solution Chinese medicine concentration (C of A Qishatan ester liposome
Free) and the not centrifugal sample solution Chinese medicine concentration (C of A Qishatan ester liposome
Always), multiply by separately more respectively, extension rate promptly gets the not weight (W of entrapped drug
Free) and the gross weight (W of liposome Chinese medicine
Always), by following formula computational envelope rate, envelop rate=(W
Always-W
Free)/W
Always* 100%.
Respectively the liposome turbid liquor among embodiment 1-3 and the Comparative Examples 1-3 is measured envelop rate, the result is as shown in following table 1.
The envelop rate of table 1 liposome
As shown in Table 1, compare with the liposome in the comparative example, the envelop rate of A Qishatan ester liposome of the present invention will exceed a lot.
By comparing embodiment 1 and Comparative Examples 1 as can be known, when using different liposome components, envelop rate of the present invention is higher, illustrates that A Qishatan ester liposome envelop rate and liposome components selection are closely related.
By comparing embodiment 2 and weight proportion not within the scope of the present invention Comparative Examples 2 as can be known, liposome of the present invention has higher envelop rate.This shows that the envelop rate of A Qishatan ester liposome is not only relevant with the composition that is used to form liposome, and is also directly related with the consumption of each composition.
By comparing embodiment 3 and Comparative Examples 3 as can be known, when using same supplementary material, the envelop rate of the liposome that makes by the inventive method is higher.
The mensuration of test example 2 liposome particle diameters
With the particle diameter of the A Qishatan ester liposome that makes among electron microscope observation embodiment 1-3 and the Comparative Examples 1-3, the result is as shown in following table 2.
The particle diameter of table 2 liposome
As shown in Table 2, the mean diameter of gained liposome is little more a lot of than the mean diameter of gained liposome among the Comparative Examples 1-3 among the embodiment of the invention 1-3, and the size homogeneous.
Existing studies show that, liposome particles size and the degree of being evenly distributed and its envelop rate and stability and relevant in the intravital time of staying of people, liposome particles is more little, particle size distribution is even more, its envelop rate and stability are high more, the time of staying in the human recycle system long more (referring to novel pharmaceutical formulation, front page, the 18 chapter, the 408-468 page or leaf, Zhu Shengshan chief editor, Chemical Industry Press).The document is introduced herein as a reference in full.
Therefore, little, the particle size distribution of A Qishatan ester liposome mean diameter of the present invention evenly is a factor that further promotes excellent performances such as its envelop rate, stability, retention time time length in vivo, bioavailability.
Test example 3 is measured A Qishatan ester liposome tablet of the present invention at the intravital blood drug level of beasle dog
12 male beasle dogs (body weight 10-12kg is from Shandong University's Experimental Animal Center) are divided into 2 groups at random.In one group, every beasle dog is irritated the A Qishatan ester liposome sheet that stomach gives preparation among the embodiment 1 respectively, irritates stomach every day once therein, each 80mg; In other one group, irritate stomach in the same manner respectively and give the A Qishatan ester liposome sheet of every beasle dog with Comparative Examples 1.After the administration respectively at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h by every beasle dog lower limb venous blood collection 3ml, blood sample is measured blood drug level with the HPLC-MS method of setting up after treatment.The average blood drug level and the time relation curve of the A Qishatan ester liposome tablet of the making embodiment of the invention 1 and the A Qishatan ester liposome sheet of Comparative Examples 1, as shown in fig. 1.
As shown in Figure 1, compare with the A Qishatan ester liposome sheet of Comparative Examples 1, the A Qishatan ester liposome tablet of taking the embodiment of the invention 1 has following characteristics: drug absorption is rapid, peak time is fast, peak concentration is high.Show that preparation of the present invention has characteristics such as onset is rapid, bioavailability height.
The stability study of test example 4 liposomees
By accelerated test, investigate the stability of the A Qishatan ester liposome tablet among embodiment of the invention 1-3 and the Comparative Examples 1-3.Carry out accelerated test under 40 ℃ of high temperature, high humidity 75% condition, amount to 180 days, the result is as shown in table 3 below.
Table 3 accelerated test result
As shown in Table 3, the stability of the A Qishatan ester liposome tablet of embodiment of the invention 1-3 is higher than the A Qishatan ester liposome tablet of Comparative Examples 1-3.
Claims (10)
1. Yi Zhong A Qishatan ester liposome preparation is characterized in that being made by the supplementary material of the component that comprises following weight proportion:
2. A Qishatan ester liposome preparation according to claim 1 is characterized in that being made by the supplementary material of the component that comprises following weight proportion:
Described supplementary material preferably includes the component of following weight proportion:
3. the preparation method of a claim 1 or 2 each described A Qishatan ester liposome preparations may further comprise the steps:
(a) A Qishatan ester, dioleoyl phospholipid phatidylcholine, cholesterol, NaGC and soyasterol are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains immobilized artificial membrane;
(b) add buffer solution and make the complete aquation of immobilized artificial membrane,, filter, make liposome turbid liquor by microporous filter membrane with the even at a high speed matter emulsifying of tissue mashing machine;
(c), make A Qishatan ester liposome powder with above-mentioned liposome turbid liquor spray drying.
4. preparation method according to claim 3 is characterized in that:
In step (a), described organic solvent is 1: 2 the ethanol and the mixed solvent of normal hexane; And/or
In step (b), described buffer solution is that pH is citric acid-sodium citrate buffer solution of 6.0; And/or
In step (b), being used for filtering microporous filter membrane aperture is 0.45 μ m.
5. according to claim 3 or 4 each described preparation methoies, it is characterized in that step (b) is as follows:
Add buffer solution, jolting was stirred 30 minutes, rotating speed was 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 10-15 minute, rotating speed 5000-10000r/min is 0.45 μ m filtering with microporous membrane with the aperture, makes liposome turbid liquor.
6. Yi Zhong A Qishatan ester liposome solid preparation, it comprises according to each described A Qishatan ester liposome and pharmaceutically acceptable carrier or excipient 2-20 weight portion in claim 1 or 2, preferred 3-12 weight portion, based on 1 weight portion A Qishatan ester,
A Qishatan ester liposome solid preparation is preferably made by the supplementary material of following weight proportion:
1 part of A Qishatan ester, 5 parts of dioleoyl phospholipid phatidylcholines, 2.4 parts in cholesterol, 2 parts of NaGCs, 1.3 parts of soyasterols and other pharmaceutic adjuvant 3-12 part.
7. A Qishatan ester liposome solid preparation according to claim 6 is characterized in that this solid preparation is a tablet, specification 40mg and 80mg.
8. according to the described A Qishatan ester liposome of claim 6 solid preparation, it is characterized in that described pharmaceutically acceptable carrier or excipient are selected from diluent, disintegrating agent, binding agent, lubricant and combination thereof.
9. according to the preparation method of claim 6-8 A Qishatan ester liposome tablet described in each, may further comprise the steps:
(1) preparation of A Qishatan ester liposome: A Qishatan ester, dioleoyl phospholipid phatidylcholine, cholesterol, NaGC, soyasterol are made the liposome powder together;
(2) preparation of A Qishatan ester liposome tablet: with gained A Qishatan ester liposome in the step (1) and pharmaceutically acceptable carrier or mixed with excipients, preparation A Qishatan ester liposome tablet.
10. method according to claim 9 is characterized in that step (2) comprises the steps:
(d) A Qishatan ester liposome powder and diluent, disintegrating agent are mixed, cross 60 mesh sieve mix homogeneously, add binder solution and prepare soft material, cross the 20-30 mesh sieve and granulate drying;
(e) dried granule and mix lubricant is even, cross 18 mesh sieve granulate;
(f) tabletting, coating makes A Qishatan ester liposome tablet.
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| CN102488691A (en) * | 2011-12-29 | 2012-06-13 | 石药集团欧意药业有限公司 | Medicine preparation used for treating or preventing hypertension or diseases caused by hypertension |
| CN103040777A (en) * | 2012-12-17 | 2013-04-17 | 海南百思特医药科技有限公司 | Olmesartan ester liposome solid preparation |
| CN118121598A (en) * | 2024-03-01 | 2024-06-04 | 浙江大学 | Stable pharmaceutical composition of losartan potassium, and preparation method and application thereof |
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| CN101066260A (en) * | 2006-11-17 | 2007-11-07 | 姚瑶 | Coenzyme Q10 emulsion and its freeze dried prepn and their prepn process |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102488691A (en) * | 2011-12-29 | 2012-06-13 | 石药集团欧意药业有限公司 | Medicine preparation used for treating or preventing hypertension or diseases caused by hypertension |
| CN102488691B (en) * | 2011-12-29 | 2014-10-29 | 石药集团欧意药业有限公司 | Medicine preparation used for treating or preventing hypertension or diseases caused by hypertension |
| CN103040777A (en) * | 2012-12-17 | 2013-04-17 | 海南百思特医药科技有限公司 | Olmesartan ester liposome solid preparation |
| CN118121598A (en) * | 2024-03-01 | 2024-06-04 | 浙江大学 | Stable pharmaceutical composition of losartan potassium, and preparation method and application thereof |
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| CN102138899B (en) | 2013-08-21 |
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