CN103040777B - Olmesartan ester liposome solid preparation - Google Patents
Olmesartan ester liposome solid preparation Download PDFInfo
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- CN103040777B CN103040777B CN201210548880.7A CN201210548880A CN103040777B CN 103040777 B CN103040777 B CN 103040777B CN 201210548880 A CN201210548880 A CN 201210548880A CN 103040777 B CN103040777 B CN 103040777B
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Abstract
The invention discloses an olmesartan ester liposome solid preparation and a preparation method thereof. Active ingredient-olmesartan ester, particularly-combined phosphatidyl inositol, di-stearoyl phosphatidyl glycerol, cholesterol succinate and tween 80 are prepared into liposome, the stability, the dissolution rate and the bioavailability of the preparation is greatly increased, the action is stable and lasting, and the curative effect is significant. The product quality of the preparation is increased, and the toxic and side effects are reduced.
Description
Technical field
The present invention relates to a kind of novel formulation of olmesartan medoxomil, be specifically related to Olmesartan ester liposome and solid preparation thereof and method for making, belong to medical technical field.
Background technology
Hypertension is current one of the most common clinical, most important cardiovascular disease.According to International Society of Hypertension, report demonstration, hypertension or the higher crowd of blood pressure are suffered from the whole world nearly 1,000,000,000 at present, are equivalent to adult population's 26.4% a few days ago.Along with improving constantly of people's living standard, the hypertensive prevalence of China is also soaring year by year.According to hypertension statistics, China's hypertensive prevalence of growing up has 5.1% of nineteen fifty-nine to rise to current 11.68%.Hypertension can be the caused a kind of clinical manifestation of different reasons and disease on the one hand, and it can be used as again the infringement that reason causes the important organs such as the heart, brain, kidney on the other hand.The target organ damages such as the Secondary cases heart being caused by hypertension, brain, kidney have a strong impact on the disease that life-span of patient and quality of life have become serious threat human health and life.
Olmesartan medoxomil (Olmesartan medoxomi), faint yellow to off-white powder, 175～180 ℃ of fusing points, insoluble in water; Slightly molten in methanol, be dissolved in glacial acetic acid, chemical name is: 2,3-dihydroxy-crotyl-4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[p-(o-1H-tetrazolium-5-phenyl) benzyl] and imidazoles-5-hydroxy acid, ring 2,3-carbonic ester; Molecular formula: C
30h
30n
6o
6, molecular weight: 556.67, structural formula is as follows:
Olmesartan medoxomil (Olmesartan MedoxomiI) is by Japanese Sankyo (San Gong company) and U.S. ForestLaboratories exploitation, go on the market in the U.S. with trade name Benicar in May, 2002, and August in the same year is granted and listing at the beginning of 10 months in Germany.Olmesartan medoxomil is that in August, 2006 is at a kind of new Angiotensin Ⅱ receptor antagonist (ARB) medicine of Discussion on Chinese Listed.Olmesartan medoxomil is the up-to-date member of Angiotensin Ⅱ receptor antagonist (ARB) class medicine, is a kind of prodrug, and entering after gastrointestinal tract can be rapidly, complete hydrolysis is activated metabolite Olmesartan, and its absorption is not affected by material object.Because olmesartan medoxomil is not by the metabolism of cytochrome P 450 enzymes metabolic system, also do not affect P450 enzymatic activity, so the interaction of this medicine is few.Olmesartan medoxomil, through the excretion of the Liver and kidney dual pathways, is affected by liver function little.
Olmesartan medoxomil is a kind of comparatively ideal antihypertensive drug, and all types of high pressure are all had to good therapeutic effect, and its outstanding feature is that the half-life is longer, can in one day, effectively control blood pressure, therefore takes more for convenience.Compare with other Angiotensin Ⅱ receptor antagonist class medicine simultaneously.There is the obvious advantages such as dosage is little, rapid-action, hypotensive effect incidence rate stronger and lasting, untoward reaction is low.Clinical research shows; Olmesartan medoxomil can also be taken to reach with other depressor simultaneously more desirable therapeutic effect.In addition, olmesartan medoxomil all has good effect to arteriosclerosis, myocardial hypertrophy, heart failure, diabetes, nephropathy etc.
In listing medicine, there is the common compressed tablet of olmesartan medoxomil both at home and abroad at present, yet but there is following problem in this dosage form: due to reasons such as technologies of preparing, the oral formulations of most drug is taken and is all existed that the time of leaching is long, dissolution is low, it is poor to absorb, medicining times is many, release is uncontrollable afterwards, the problems such as bioavailability is lower, thereby affect the performance of drug effect, also directly affect therapeutic effect, so its bioavailability is lower.
In prior art, also have some reports about olmesartan medoxomil preparation technique.For example, patent documentation CN101478966A discloses a kind of pharmaceutical preparation that contains olmesartan medoxomil and method for making thereof with the elution property of improvement, wherein except containing olmesartan medoxomil, also contain suitable excipient and adjuvant thereof, described excipient and adjuvant are selected from disintegrating agent, diluent, lubricant, binding agent, emulsifying agent, flavoring agent, flavoring agent and applicable activating agent.The method adopts the power consumption method of high pressure compressed, this conventional solid preparation of producing, and bioavailability is low, and stability is bad.Patent documentation CN101842096A discloses a kind of olmesartan medoxomil film-coated preparation and preparation method thereof, reduces the abnormal flavour of medicine by film coating, and transformation of the way agent adopts conventional production process, also contains polyvinyl alcohol or vinyl alcohol-based copolymer in film-coat.Although improved medicine stability, routine fashion makes its bioavailability low.Patent documentation CN102119930A discloses a kind of olmesartan medoxomil tablet and preparation method thereof, adjuvant comprises lactose, microcrystalline Cellulose, PVPK30, low-substituted hydroxypropyl cellulose, magnesium stearate and appropriate ethanol water, in this preparation method, need medicine and lactose to grind, make complex process, and bioavailability is low.Patent documentation CN102327265A discloses a kind of amlodipine olmesartan medoxomil Pharmaceutical composition and preparation method thereof, by weight, described Pharmaceutical composition comprises amlodipine 2.5-10 part, olmesartan medoxomil 20-40 part, amylum pregelatinisatum 5-50 part, microcrystalline Cellulose 10-60 part, low-substituted hydroxypropyl cellulose 15-40 part, polyvinylpolypyrrolidone 10-45 part, essence 1-5 part, magnesium stearate 1-3 part.Although Pharmaceutical composition is rapid-action and steady, can complementary action strong, the bioavailability of conventional formulation be lower.
Yet Olmesartan ester formulation prepared by said method, is prepared although screened specific adjuvant, having must advantage; But dissolution and the bioavailability of medicine still have much room for improvement, and the long-time stability of medicine are undesirable, are unfavorable for long-term storage.
Liposome refers to the middle made spherical targeted drug carrier formulation of superminiature of the thin film that drug encapsulation is formed in lipoids bimolecular, belongs to a kind of novel form of targeting drug delivery system.Liposome, as pharmaceutical carrier, has plurality of advantages: as liposome, can seal fat-soluble medicine, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce release rate in body; Can effectively protect and be wrapped medicine, improve bioavailability; Change medicine distribution in vivo, and can targeting release, the toxic and side effects of medicine can be reduced; Be applicable to multipath administration etc.
Liposome Main Function mechanism is that drug powder or solution are wrapped in the water that liposome bilayer lipid membrane seals or are embedded in liposome bilayer lipid membrane, this microgranule has class cellularity, enter principal agent in human body and by reticuloendothelial system phagocytic, activated the autoimmune function of body, and the interior distribution of the body that changes encapsulated medicine, drug main will be put aside in the histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of therapeutic dose and the reduction medicine of medicine.
But, the challenge of preparing liposome is to select suitable liposome constituent and method for making.Because the character of liposome is as directly closely related with the composition of liposome in stability, envelop rate, onset time, circulation time, bioavailability and toxic and side effects etc. in vivo, and the composition of liposome is directly closely related with the pharmaceutical properties that will seal, therefore the Olmesartan ester liposome of, selecting which type of composition formation to have better quality is problem urgently to be resolved hurrily.
In prior art, there is no open Olmesartan ester liposome and the solid preparation thereof designing for oral application.Therefore, exist and further need, to provide stability better to use Olmesartan ester formulation more easily.The inventor is through long-term conscientious research, unexpectedly found a kind of novel form liposome technology of targeting drug delivery system to be applied in olmesartan medoxomil solid preparation, the lipidosome solid preparation that adopts particular excipient and olmesartan medoxomil to make has effectively overcome the problem of principal agent poor stability, improved the dissolution of medicine simultaneously, delay to discharge, increase medicine retention time in vivo, eliminated bad smell, thereby completed the present invention.
Summary of the invention
In order to form colory olmesartan medoxomil lipidosome solid preparation, thereby importantly find, can it well be sealed and non-leakage filmogen with the olmesartan medoxomil compatibility is good, to form colory Olmesartan ester liposome, make the stripping property of this liposome excellent, release time is suitable and bioavailability is high, and screening can form with Olmesartan ester liposome the suitable pharmaceutic adjuvant of excellent solid preparation.
As the phospholipid that is used to form liposome, can use natural phospholipid and synthetic phospholipid.Described phospholipid comprises PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Phosphatidylserine, phosphatidylinositols, phosphatidylcholine, Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, EPG, egg yolk lecithin acyl serine, PI, soybean lecithin, hydrogenated soy phosphatidyl choline, hydrolecithin, EPG, lecithin acyl serine, lecithin acyl inositol, DOPC, DSPC, dipalmitoyl phosphatidyl choline, DSPG, DLPC, DOPG, DMPC, DPPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, PE, DOPE (DOPE), DSPE (DSPE), DMPEA (DMPE), DPPE (DPPE) and polyglycol derivatization phospholipid be PEG-DSPE 2000 for example, two soft ester acyl gallbladder phospholipid-Macrogol 2000s, HSPC-Macrogol 2000, DOPC-Macrogol 2000 etc.Additives are generally selected cholesterol, vitamin E, 18-amine., DCP.
To achieve these goals, the inventor is through long-term conscientious research, through a large amount of screening tests, find to adopt general phospholipid and or the Olmesartan ester liposome prepared of the film material of additives combination under the accelerated test of 40 ℃ of high temperature, relative humidity 75% ± 5%, stability and envelop rate are not good, thus film material and the olmesartan medoxomil compatibility very important.
The inventor is in the large quantity research carrying out and experiment, be surprised to find that olmesartan medoxomil, phosphatidylinositols, DSPG, cholesterol succinate and the Tween 80 of specified weight proportioning can make the Olmesartan ester liposome of good quality, wherein, olmesartan medoxomil good stability, envelop rate as active constituents of medicine are high, stripping property good, release is complete, the retention time significant prolongation of active constituents of medicine in solid preparation in body circulation, bioavailability obviously improves, and curative effect obviously improves.
One of object of the present invention is to provide a kind of Olmesartan ester liposome, and it is mainly made by the composition of following weight proportion:
Preferably, the weight ratio of phosphatidylinositols and DSPG is 2:1, the weight of phosphatidylinositols and DSPG and with the weight ratio of cholesterol succinate be 1:1-3:1.One of the specific embodiment of the present invention, preferably the weight of phosphatidylinositols and DSPG and with the weight ratio of cholesterol succinate be 2:1.
One of the specific embodiment of the present invention, Olmesartan ester liposome provided by the invention, mainly by the composition of following weight proportion, made:
Preferably, the weight ratio of phosphatidylinositols and DSPG is 2:1, the weight of phosphatidylinositols and DSPG and with the weight ratio of cholesterol succinate be 2:1.
In Olmesartan ester liposome of the present invention, the phospholipid material using is phosphatidylinositols and the DSPG compositions with weight ratio 2:1, wherein phosphatidylinositols is a kind of natural phospholipid of hydrogenation, and DSPG is a kind of synthetic phospholipid.
The inventor is through research discovery with keen determination, in common phospholipid material, the phosphatidylinositols as natural phospholipid of appropriate amount and can be used to form colory Olmesartan ester liposome with the combination phospholipid of weight ratio 2:1 as the DSPG of synthetic phospholipid.By the method providing in the present invention, can form the suitably high liposome of envelop rate of size, appropriate configuration composition, and these compositions, especially olmesartan medoxomil are non-leakage in formed liposome, and in liposome, the stripping property of olmesartan medoxomil is excellent.If using amount ratio is phosphatidylinositols and the DSPG combination phospholipid except 2:1, or select other phospholipid material as Ovum Gallus domesticus Flavus lecithin etc., the poor stability of formed liposome, envelop rate is low, stripping property is poor, can not realize object of the present invention.
In Olmesartan ester liposome of the present invention, for the olmesartan medoxomil of 1 weight portion, the consumption of phosphatidylinositols is 10-100 weight portion, and the consumption of DSPG is 5-50 weight portion, and the weight ratio of phosphatidylinositols and DSPG is 2:1.If the consumption of phosphatidylinositols and DSPG, respectively lower than 10 weight portions and 5 weight portions, has, a large amount of free olmesartan medoxomils are not encapsulated, and the drug loading of liposome is low, and stability also can decline, and stripping property also can affect adversely; Otherwise the consumption of phosphatidylinositols and DSPG is respectively higher than 100 weight portions and 50 weight portions, the envelop rate as the olmesartan medoxomil of active constituents of medicine declines.
In Olmesartan ester liposome of the present invention, cholesterol succinate and Tween 80 are for regulating membrane stability and the permeability of liposome.Cholesterol succinate (cholesterol hemisuccinate, CHS) is the succinum ester derivant of cholesterol, has another name called Cholesteryl hemisuccinate, and cholesterol hemisuccinate is a kind of crude drug of arteriosclerosis.Cholesterol succinate, except bear electric charge, also has good liposome membrane Stabilization.The succinic acid derivative of this cholesterol, biodegradable in body, there is not security risks, can safety as elecrtonegativity materials'use.
Cholesterol succinate combines with phosphatidylinositols and DSPG, stops it to be condensed into crystal structure.Cholesterol succinate mixes in the duplicature of phosphatidylinositols and DSPG formation, is similar to " buffer agent " and equally plays the effect that regulates membrane structure " mobility ".When lower than phase transition temperature, cholesterol succinate can make film reduce ordered arrangement, increases mobility; When higher than phase transition temperature, cholesterol succinate can increase the ordered arrangement of film, thereby reduces the mobility of film.Cholesterol succinate can make liposome bi-layer membrane solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
The inventor finds through research, while being 1:1-3:1 when the weight of phosphatidylinositols and DSPG with the weight ratio of cholesterol succinate, can form stable Olmesartan ester liposome.When the weight of phosphatidylinositols and DSPG with the weight ratio of cholesterol succinate during higher than 3:1, membrane stability reduces; When the weight of phosphatidylinositols and DSPG with the weight ratio of cholesterol succinate during lower than 1:1, liposome membrane mobility is too high, and the olmesartan medoxomil being wrapped in liposome is easy to discharge.In Olmesartan ester liposome of the present invention, for the olmesartan medoxomil of 1 weight portion, the consumption of cholesterol succinate is 5-150 weight portion, is preferably 15-65 weight portion.In contrast experiment, the cholesterol succinate in Olmesartan ester liposome of the present invention is significantly better than cholesterol.
In addition, research finds, while being 1:1-3:1 when the weight of phosphatidylinositols and DSPG with the weight ratio of cholesterol succinate, formed liposome stripping property is excellent.As the concrete preferred implementation of the present invention, the weight of phosphatidylinositols and DSPG and with the weight ratio of cholesterol succinate be 2:1.
Research shows, the stability of liposome and stripping property and bioavailability have close corresponding relation.Stability is higher, and stripping property is better, and bioavailability is higher.Therefore, the stability of Olmesartan ester liposome of the present invention is high, stripping property is excellent, is to cause one of factor that drug bioavailability is high.
In addition, the inventor studies discovery, in Olmesartan ester liposome of the present invention, for the olmesartan medoxomil of 1 weight portion, the consumption of phosphatidylinositols is 10-100 weight portion, the consumption of DSPG is 5-50 weight portion, and the weight ratio of phosphatidylinositols and DSPG is 2:1, and the envelop rate of formed Olmesartan ester liposome is high.
In Olmesartan ester liposome of the present invention, with Tween 80, further improve stability and the envelop rate of liposome membrane.Tween 80 is a kind of non-ionic surface active agent, when for phosphatidylinositols and DSPG combination phospholipid, form duplicature time, can not only further improve the dissolubility of olmesartan medoxomil, thereby improve envelop rate; And can improve the chemical energy between this duplicature, thus the chemical stability of liposome in waterborne liquid improved, and then improve the stability of Olmesartan ester liposome.
In Olmesartan ester liposome of the present invention, for the olmesartan medoxomil of 1 weight portion, the consumption of Tween 80 is 1-10 weight portion.If the consumption of Tween 80 is lower than 1 weight portion, because its consumption is too low, cause the stability of liposome and envelop rate to be improved not, otherwise, if the consumption of Tween 80 is higher than 10 weight portions, too high for its consumption and cause liposome membrane to be easy to destroy and reveal active component.In contrast experiment, the Tween 80 in Olmesartan ester liposome of the present invention is significantly better than other non-ionic surface active agent, is also significantly better than other spans surfactant.
In Olmesartan ester liposome of the present invention, by cholesterol succinate and the collaborative adjusting facilitation of Tween 80 to phosphatidylinositols and DSPG combination immobilized artificial membrane structure of appropriate proportioning, can form the Olmesartan ester liposome that envelop rate is high, stability is high, its stripping property is excellent, had good sustained release effect, bioavailability is high.
Another object of the present invention, the invention provides a kind of preparation method of Olmesartan ester liposome, and the method comprises the following steps:
(a) olmesartan medoxomil, phosphatidylinositols, DSPG, cholesterol succinate, Tween 80 are dissolved in organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed in to eggplant-shape bottle, organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue, 45 ℃ of water-bath normal pressure rotations, to make films swell hydration;
(d) by 0.45 μ m filtering with microporous membrane for above-mentioned solution, filtrate is placed in to-20 ℃ of refrigerator and cooled and freezes and spend the night, then take out and melt, multigelation three times, the dry Olmesartan ester liposome powder that makes of spraying.
In a preferred embodiment of olmesartan medoxomil method for preparing lipidosome of the present invention, organic solvent described in step (a) is selected from one or more in ethanol, chloroform, dichloromethane, methanol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, acetonitrile, normal hexane, the mixed solvent for methanol and acetone that preferred volume ratio is 2:1.
In a preferred embodiment of olmesartan medoxomil method for preparing lipidosome of the present invention, buffer salt solution described in step (c) is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer, borate buffer solution and carbonate buffer solution, the acetate buffer solution that preferably pH value is 6.0.
By said method, can prepare the little and uniform Olmesartan ester liposome of particle size distribution of granule, its envelop rate is high, and stability is high, and stripping property is good, and bioavailability is high.
Research finds, the size of liposome is affect that liposome distributes in vivo and the principal element of the time of staying, and the particle diameter of liposome is less, and the interior time of staying of body is longer.The olmesartan medoxomil liposome particles of preparing by the inventive method 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.
Another object of the present invention, provides a kind of olmesartan medoxomil lipidosome solid preparation, and it is mainly made by Olmesartan ester liposome and other pharmaceutic adjuvants,
In this article, the meaning of term used " other pharmaceutic adjuvants " or " pharmaceutic adjuvant " is equivalent in meaning with " excipient " or " pharmaceutically acceptable excipient ", refer to the medicinal material except Olmesartan ester liposome using in order to prepare olmesartan medoxomil lipidosome solid preparation, comprise diluent, disintegrating agent, binding agent, wetting agent, lubricant and combination thereof.
In this article, term used " amounts of other pharmaceutic adjuvants " refers to the weight sum of above-mentioned pharmaceutic adjuvant, i.e. the olmesartan medoxomil based on 1 weight portion, and the total amount of other pharmaceutic adjuvants is 10-100 part.
The consumption of various pharmaceutic adjuvants can by those skilled in the art according to each adjuvant the general consumption in solid preparation select, this is in those skilled in the art's limit of power.
In a preferred embodiment of olmesartan medoxomil lipidosome solid preparation of the present invention, described diluent is selected from one or more in starch, lactose, Icing Sugar, amylum pregelatinisatum, sorbitol, microcrystalline Cellulose, dextrin, is preferably microcrystalline Cellulose.
In a preferred embodiment of olmesartan medoxomil lipidosome solid preparation of the present invention, described disintegrating agent is selected from one or more in low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, dried starch, preferably polyvinylpolypyrrolidone.
In a preferred embodiment of olmesartan medoxomil lipidosome solid preparation of the present invention, described binding agent is selected from a kind of in PVP K30, starch slurry, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, arabic gum, xanthan gum, is preferably PVP K30.
In a preferred embodiment of olmesartan medoxomil lipidosome solid preparation of the present invention, the alcoholic solution that described wetting agent is 10-80%, preferably 50% alcoholic solution.
In a preferred embodiment of olmesartan medoxomil lipidosome solid preparation of the present invention, described lubricant is selected from one or more in magnesium stearate, zinc stearate, sodium laurylsulfate, Pulvis Talci, micropowder silica gel, Macrogol 4000, stearic acid, is preferably micropowder silica gel.
As one of concrete embodiment, olmesartan medoxomil lipidosome solid preparation of the present invention, mainly by following component by weight, made:
Based on 1 weight portion olmesartan medoxomil, comprise that the alcoholic solution of microcrystalline Cellulose 1-50 part, polyvinylpolypyrrolidone 0.1-2 part, 0.1-5 part PVP K30, micropowder silica gel 0.05-1 part and 50% is appropriate.
As the specific embodiment of the invention, olmesartan medoxomil lipidosome solid preparation provided by the invention is oral formulations, is tablet.
In the specific embodiment of the present invention, consider the effective dose of medicine and the convenience of medication, in the preferred embodiment of olmesartan medoxomil lipidosome solid preparation of the present invention, the specification of preparation is that per unit preparation olmesartan medoxomil is 20mg and 40mg.
One of another object of the present invention, the invention provides the preparation method of above-mentioned olmesartan medoxomil lipidosome solid preparation, and the method comprises the following steps:
(e) Olmesartan ester liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves, adds wetting agent to prepare soft material, and the granulation of sieving is dry;
(f) dry granule and mix lubricant is even, granulate sieves;
(g) tabletting, makes olmesartan medoxomil lipidosome solid preparation.
In the method for the invention, can also to liposome and/or lipidosome solid preparation, carry out sterilizing as required.Sterilizing methods does not have specific (special) requirements, can use liposome sterilizing methods conventional in pharmaceutical field, as heat sterilization, filtration sterilization, radiation sterilization or sterile working etc.
Advantage of the present invention:
The present invention first combination of the specified weight by active component olmesartan medoxomil and phosphatidylinositols, DSPG, cholesterol succinate, Tween 80 is prepared into liposome, then is mixed and made into solid preparation with other pharmaceutic adjuvant.Solid preparation product quality is high, and particle diameter is even, and stability is high, and envelop rate is high, and stripping property is good, and medicine retention time in blood circulation is long, evident in efficacy, has reduced toxic and side effects.
The preparation method of olmesartan medoxomil lipidosome solid preparation provided by the invention has improved product quality, and equipment is simple, easy operating, and method is simple, is suitable for industrialized great production.The particle size range of the application's Olmesartan ester liposome is 120～230nm, is preferably 150～200nm.
In this article, if not explanation especially, content or consumption are all by weight.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is the release in vitro curve of the Olmesartan ester liposome powder of embodiment 1-3, comparative example 1-4.
Wherein:
The specific embodiment
By concrete preferred embodiment and comparative example, the present invention is further described below.These embodiment and comparative example are only illustrative, and should not be construed as limitation of the present invention.
embodiment 1olmesartan ester liposome sheet
Supplementary material used is as follows:
Adopt following production technology to prepare Olmesartan ester liposome sheet:
(1) accurately take 20g olmesartan medoxomil, 200g phosphatidylinositols, 100g DSPG, 50g cholesterol succinate, 40g Tween 80, being dissolved in 1000ml volume ratio is in the methanol and acetone mixed solvent of 2:1, stirs and makes its dissolving;
(2) above-mentioned solution is placed in to eggplant-shape bottle, methanol and acetone are removed in 45 ℃ of water-bath decompressions, on bottle wall, form uniformly transparent film;
(3) to adding 1000ml pH value in eggplant-shape bottle, be 6.0 acetate buffer solution, continue, 45 ℃ of water-bath normal pressures rotations, to make films swell hydration;
(4) by 0.45 μ m filtering with microporous membrane for above-mentioned solution, filtrate is placed in to-20 ℃ of refrigerator and cooled and freezes and spend the night, then take out and melt, multigelation three times, the dry Olmesartan ester liposome powder that makes of spraying;
(5) olmesartan medoxomil lipidosome solid powder and 500g microcrystalline Cellulose, 15g polyvinylpolypyrrolidone and 30g PVP K30 are mixed, the mix homogeneously that sieves, adds the alcoholic solution of 80ml 50% to prepare soft material, and the granulation of sieving is dry;
(6) by dry granule and 5g micropowder silica gel mix homogeneously, granulate sieves;
(7) tabletting, makes 1000 Olmesartan ester liposome sheets.
embodiment 2olmesartan ester liposome sheet
Supplementary material used is as follows:
Adopt following production technology to prepare Olmesartan ester liposome sheet:
(1) accurately take 20g olmesartan medoxomil, 400g phosphatidylinositols, 200g DSPG, 300g cholesterol succinate, 40g Tween 80, being dissolved in 2000ml volume ratio is in the methanol and acetone mixed solvent of 2:1, stirs and makes its dissolving;
(2) above-mentioned solution is placed in to eggplant-shape bottle, methanol and acetone are removed in 45 ℃ of water-bath decompressions, on bottle wall, form uniformly transparent film;
(3) to adding 2000ml pH value in eggplant-shape bottle, be 6.0 acetate buffer solution, continue, 45 ℃ of water-bath normal pressures rotations, to make films swell hydration;
(4) by 0.45 μ m filtering with microporous membrane for above-mentioned solution, filtrate is placed in to-20 ℃ of refrigerator and cooled and freezes and spend the night, then take out and melt, multigelation three times, the dry Olmesartan ester liposome powder that makes of spraying;
(5) olmesartan medoxomil lipidosome solid powder and 500g microcrystalline Cellulose, 15g polyvinylpolypyrrolidone and 30g PVP K30 are mixed, the mix homogeneously that sieves, adds the alcoholic solution of 100ml 50% to prepare soft material, and the granulation of sieving is dry;
(6) by dry granule and 5g micropowder silica gel mix homogeneously, granulate sieves;
(7) tabletting, makes 1000 Olmesartan ester liposome sheets.
embodiment 3olmesartan ester liposome sheet
Supplementary material used is as follows:
Adopt following production technology to prepare olmesartan medoxomil liposome tablet:
(1) accurately take 40g olmesartan medoxomil, 800g phosphatidylinositols, 400g DSPG, 600g cholesterol succinate, 80g Tween 80 and be dissolved in the methanol and acetone mixed solvent that 3000ml volume ratio is 2:1, stir and make its dissolving;
(2) above-mentioned solution is placed in to eggplant-shape bottle, methanol and acetone are removed in 45 ℃ of water-bath decompressions, on bottle wall, form uniformly transparent film;
(3) to adding 3000ml pH value in eggplant-shape bottle, be 6.0 acetate buffer solution, continue, 45 ℃ of water-bath normal pressures rotations, to make films swell hydration;
(4) by 0.45 μ m filtering with microporous membrane for above-mentioned solution, filtrate is placed in to-20 ℃ of refrigerator and cooled and freezes and spend the night, then take out and melt, multigelation three times, the dry Olmesartan ester liposome powder that makes of spraying;
(5) olmesartan medoxomil lipidosome solid powder and 1000g microcrystalline Cellulose, 30g polyvinylpolypyrrolidone and 60g PVP K30 are mixed, the mix homogeneously that sieves, adds the alcoholic solution of 180ml 50% to prepare soft material, and the granulation of sieving is dry;
(6) by dry granule and 10g micropowder silica gel mix homogeneously, granulate sieves;
(7) tabletting, makes 1000 Olmesartan ester liposome sheets.
comparative example 1-4
Adopt with respectively with embodiment 1-3 in identical production technology, the supplementary material composition in comparative example 1-3 is as shown in Table 1 below made respectively to Olmesartan ester liposome sheet;
The difference of the preparation technology of comparative example 4 and embodiment 1 is, step (4) is: the filtering with microporous membrane by above-mentioned suspension with 0.45 μ m, filtrate is placed under-20 ℃ of conditions freezing 4 hours, with the speed of 2 ℃/h, be warming up to 25 ℃ again, be incubated 3 hours to dry, obtain lipidosome freeze-dried powder:
Supplementary material composition used in table 1 comparative example 1-3
Wherein, "/" represents not use.
comparative example 3:CN 102138899A(*)
test example 1the mensuration of envelop rate
The Olmesartan ester liposome powder 0.5g that measures gained in the step (4) in embodiment 1-3 and comparative example 1-4 is dissolved in 10ml water, obtain suspension, get suspension 0.5ml, be added on SephadexG-50 gel column top, with phosphate buffer eluting, flow velocity 1ml/min, collect 4～11mL eluent (containing liposome), with nitrogen, blow to the about 0.5ml of volume, add dehydrated alcohol breakdown of emulsion and be settled to 10ml, shake up.The accurate 10 μ l solution of drawing, sample introduction, measures peak area, the content of the olmesartan medoxomil that calculating lipid body weight is sealed; Another precision measures olmesartan medoxomil liposome turbid liquor 0.5ml, with dehydrated alcohol, is settled to 10ml, shakes up.The accurate 10 μ l solution of drawing, the total amount of olmesartan medoxomil in mensuration liposome turbid liquor.Computational envelope rate, the results are shown in following table 2:
The measurement result of table 2 envelop rate
As shown in Table 2, compare with the liposome in comparative example, the envelop rate of Olmesartan ester liposome of the present invention will exceed a lot.
Known by comparing embodiment 1-3 and comparative example 1-4, liposome of the present invention has higher envelop rate.This shows, the envelop rate of Olmesartan ester liposome is directly related with the composition kind that is used to form liposome.Experiment in addition also shows, during proportioning beyond using the present invention's composition range used, the envelop rate of gained Olmesartan ester liposome is starkly lower than the present invention.This shows, the envelop rate of Olmesartan ester liposome is not only relevant with the composition that is used to form liposome, also directly related with the consumption of each composition.In the time of outside the composition amount ranges that composition consumption limits in the present invention, the envelop rate of gained Olmesartan ester liposome is starkly lower than the present invention.
test example 2the size of liposome particle diameter and particle size distribution
In order to understand Olmesartan ester liposome particle size parameters and particle size distribution accurately, be taken at the appropriate liposome powder of gained in the step (4) in embodiment 1-3 and comparative example 1-4, directly with laser particle size analyzer (Easysizer20, Europe Mec AS) observe its outer light, and measure particle diameter, with dynamic light scattering process software, process, the distribution of measuring its diameter and calculating particle diameter, the results are shown in following table 3:
Table 3 liposome particle diameter
As shown in Table 3, in embodiment of the present invention 1-3, the mean diameter of gained liposome is little more a lot of than the mean diameter of gained liposome in comparative example 1-4, and size homogeneous, and outward appearance is better.
Known by comparing embodiment 1-3 and comparative example 1-4, liposome of the present invention has less mean diameter, and particle size distribution is more even, and outward appearance is better.This shows, the particle diameter of Olmesartan ester liposome is directly related with the composition kind that is used to form liposome.During composition beyond using the present invention's composition used, the character such as mean diameter, particle size distribution and outward appearance of gained Olmesartan ester liposome are obviously inferior to the present invention.In addition with weight proportion not other comparative example within the scope of the present invention compare knownly, liposome of the present invention has less mean diameter, particle size distribution is more even, outward appearance is better.This shows, the particle diameter of Olmesartan ester liposome is not only relevant with the composition that is used to form liposome, also directly related with the consumption of each composition.In the time of outside the composition amount ranges that composition consumption limits in the present invention, the character such as mean diameter, particle size distribution and outward appearance of gained Olmesartan ester liposome are obviously inferior to the present invention.
Now there are some researches show, liposome particles size and the degree of being evenly distributed and its envelop rate and stability and the time of staying in human body are relevant, liposome particles is less, particle size distribution is more even, its envelop rate and stability are higher, time of staying in human recycle system longer (referring to novel pharmaceutical formulation, front page, the 18 chapter, 408-468 page, Zhu Shengshan chief editor, Chemical Industry Press).The document is incorporated herein by reference in full.
Therefore, Olmesartan ester liposome mean diameter of the present invention is little, particle size distribution is evenly a factor that further promotes the excellent performances such as its envelop rate, stability, retention time time length in vivo, bioavailability, the application's particle size range is 120～230nm, is preferably 150～200nm.
test example 3stability and dissolution are investigated
Sample prepared by above embodiment 1-3 and comparative example 1-4 and olmesartan medoxomil tablet (Yi Sangong pharmacy (Shanghai) Co., Ltd. of listing, lot number 110731) 40 ℃ of high temperature, lower 6 months of relative humidity 75% ± 5% condition, carries out accelerated test investigation, the results are shown in Table 4.
Table 4 stability and dissolution determination result
As shown in Table 4, the olmesartan medoxomil tablet dissolution of listing and comparative example 1-4 is low, and while accelerating June, content reduces obviously, and related substance raises; And the sample dissolution of preparing in embodiment of the present invention 1-3 is high, accelerate after 6 months content and related substance all without significant change.Absolutely proved the superiority of the present invention aspect raising stability and dissolution.
test example 4release in vitro research
Accurate each 100mg of liposome powder that draws embodiment 1-3, comparative example 1-4 is dissolved in 10ml water, getting each 5ml of suspension is placed in bag filter and tightens, release medium is phosphate buffered solution (polysorbas20 containing the 0.25%) 100ml of pH6.8, bath temperature is 37 ℃, speed of agitator is 300rpm, respectively at 0.5,1,2,4,6,8,12,18,24h samples 1ml, measures release rate, draw release profiles, result as shown in Figure 1.
Result shows, in the embodiment of the present invention 1-3 release of gained Olmesartan ester liposome slow, has reached the effect of fine slow release, thereby there is higher bioavailability, and in comparative example 1-4, gained Olmesartan ester liposome slow release effect is poor.
Similarly, the lipidosome solid preparation of embodiment 1-3, comparative example 1-4 is carried out to extracorporeal releasing experiment, found that in similar result embodiment of the present invention 1-3, the release of gained olmesartan medoxomil lipidosome solid preparation is slow, 24 hours basic releases completely, reached the effect of fine slow release, thereby there is higher bioavailability, and in comparative example 1-4, gained olmesartan medoxomil lipidosome solid preparation discharged completely substantially at 10 hours, discharge comparatively fast, slow release effect is poor.
industrial applicibility
Result from above-described embodiment and experimental example, olmesartan medoxomil lipidosome solid preparation of the present invention has good outward appearance, granule is little, and particle diameter is even, and envelop rate is high, stability is high, stripping property is good, and percolation ratio is low, and the time of staying is in vivo long, bioavailability is high, has good industrial application 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 form 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 in the application or quoting, which is hereby incorporated by reference.
Claims (9)
1. an Olmesartan ester liposome, is characterized in that mainly by the composition of following weight proportion, being made:
The weight ratio of described phosphatidylinositols and DSPG is 2:1, the weight of phosphatidylinositols and DSPG and with the weight ratio of cholesterol succinate be 2:1.
2. Olmesartan ester liposome according to claim 1, is characterized in that mainly by the composition of following weight proportion, being made:
3. a preparation method for the Olmesartan ester liposome described in claim 1 or 2, is characterized in that the method comprises the following steps:
(a) olmesartan medoxomil, phosphatidylinositols, DSPG, cholesterol succinate, Tween 80 are dissolved in organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed in to eggplant-shape bottle, organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue, 45 ℃ of water-bath normal pressure rotations, to make films swell hydration;
(d) by 0.45 μ m filtering with microporous membrane for above-mentioned solution, filtrate is placed in to-20 ℃ of refrigerator and cooled and freezes and spend the night, then take out and melt, multigelation three times, the dry Olmesartan ester liposome powder that makes of spraying.
4. method according to claim 3, wherein, it is the methanol of 2:1 and the mixed solvent of acetone that the organic solvent described in step (a) is selected from volume ratio;
It is 6.0 acetate buffer solution that buffer salt solution described in step (c) is selected from pH value.
5. an olmesartan medoxomil lipidosome solid preparation, it is made by Olmesartan ester liposome according to claim 1 and 2 and other pharmaceutic adjuvants, the olmesartan medoxomil based on 1 weight portion wherein, the amount of other pharmaceutic adjuvants is 10-100 part.
6. olmesartan medoxomil lipidosome solid preparation according to claim 5, it is tablet.
7. a preparation method of preparing olmesartan medoxomil lipidosome solid preparation claimed in claim 5, is characterized in that said method comprising the steps of:
(1) preparation of Olmesartan ester liposome: olmesartan medoxomil, phosphatidylinositols, DSPG, cholesterol succinate are prepared into liposome powder together with Tween 80;
(2) preparation of olmesartan medoxomil lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with to olmesartan medoxomil lipidosome solid preparation, based on 1 weight portion olmesartan medoxomil, comprise that the alcoholic solution of microcrystalline Cellulose 1-50 part, polyvinylpolypyrrolidone 0.1-2 part, 0.1-5 part PVP K30, micropowder silica gel 0.05-1 part and 50% is appropriate.
8. method according to claim 7, wherein the preparation of step (1) Olmesartan ester liposome comprises following sub-step:
(a) olmesartan medoxomil, phosphatidylinositols, DSPG, cholesterol succinate, Tween 80 are dissolved in organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed in to eggplant-shape bottle, organic solvent is removed in 45 ℃ of water-bath decompressions, on bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue, 45 ℃ of water-bath normal pressure rotations, to make films swell hydration;
(d) by 0.45 μ m filtering with microporous membrane for above-mentioned solution, filtrate is placed in to-20 ℃ of refrigerator and cooled and freezes and spend the night, then take out and melt, multigelation three times, the dry Olmesartan ester liposome powder that makes of spraying;
Wherein, the organic solvent described in sub-step (a) is selected from the mixed solvent for methanol and acetone that volume ratio is 2:1; It is 6.0 acetate buffer solution that buffer salt solution described in sub-step (c) is selected from pH value.
9. method according to claim 7, wherein, the preparation of step (2) olmesartan medoxomil liposome solid preparation comprises following sub-step:
(e) Olmesartan ester liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves, adds wetting agent to prepare soft material, and the granulation of sieving is dry;
(f) dry granule and mix lubricant is even, granulate sieves;
(g) tabletting, makes olmesartan medoxomil lipidosome solid preparation.
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| CN102138899B (en) * | 2011-03-18 | 2013-08-21 | 海南本创医药科技有限公司 | Olmesartan liposome solid preparation |
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