CN102626387A - Clopidogrel bisulfate liposome solid preparation - Google Patents
Clopidogrel bisulfate liposome solid preparation Download PDFInfo
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Abstract
The invention discloses a clopidogrel bisulfate liposome solid preparation and a preparation method thereof. The method is to prepare liposome from an active ingredient clopidogrel bisulfate, and soybean lecithin, dioleoyl phosphatidylglycerole, cholesterol and tween 80 in a specific combination. The prepared liposome greatly improves stability, dissolution rate and bioavailability of a drug, and has stable and lasting action and notable curative effect. The preparation provided by the invention improves product quality of a preparation and reduces toxic and side effects.
Description
Technical field
The present invention relates to a kind of new solid preparation of minodronic acid, be specifically related to minodronic acid lipidosome solid preparation and method for making thereof, belong to medical technical field.
Background technology
Minodronic acid (Clopidogrel Bisulfate), by the development of Japanese Yamanouchi drugmaker, 2002 in Japan's exploitation listing, and the little wild drugmaker of Japan is given in the market development mandate.The former minodronic acid tablet (trade name Bonoteo/Recalbon) that grinds of in January, 2009 Astellas and little wild company, granted in Japan first, be used to treat osteoporotic the 3rd generation azepine aromatic double phosphonate derivatives.The chemical name of minodronic acid is: and 1-hydroxyl-2-[imidazo (1,2-a) pyridin-3-yl] ethylidene) two phosphonic acids monohydrates, molecular formula: C
9H
12N
2O
7P
2H
2O, molecular weight: 340.16, structural formula is following:
The WHO statistics shows; Osteoporosis in the present world wide (Osteoporosis, OP) patient's sum surpasses 200,000,000 people, and wherein only just there are more than 7,500 ten thousand people in the U.S., West Europe and Japan; Annual flower in treatment and the expense on being in hospital up to 25,000,000,000 dollars, its average annual growth rate surpasses 10%.Osteoporosis is acknowledged as the second largest healthy killer who is only second to cardiovascular disease.The main hazard result of osteoporosis is prone to cause fracture; Image height blood pressure diseases control is bad, and to be prone to cause apoplexy the same; Osteoporosis incidence rate in the women of west development country is high, in the U.S. 2,500 ten thousand patients is arranged approximately, and the concurrent fracture of 1,500,000 patients is arranged every year approximately; About 20% fracture patient is in 1 year concurrent pulmonary infarction of endogenous cause of ill, pneumonia and death; The mortality rate that causes at women's osteoporotic fracture surpasses the summation of mastocarcinoma, cervical cancer and carcinoma of uterine body, and the survivor of half Hip Fracture loses the ability of living on one's own life, and about 20% patient can only live in the nursing home.Osteoporosis significantly exists race and regional difference with the fracture incidence rate, and African women's bone amount is lower than American-European pink toes, but the fracture incidence rate is lower than white man.Along with social population's aging, the osteoporotic sickness rate in countries in the world also can increase, estimate to the year two thousand fifty the whole world will have 50% to occur in Asian countries.
According to statistics, China more than 60 years old the old man have more than 200,000,000, got into aging society.Wherein 60～70 years old old man has 1/3 to suffer from osteoporosis, and the women more than 80 years old suffers from the more of this disease, accounts for 2/3.At present, China's patients with osteoporosis is about 9,000 ten thousand, accounts for 7% of total population, and wherein 3/4 is the women.This is because of normal person after the bone amount reaches peak value (30～40 years old), and the speed that old sclerotin is got rid of is faster than the speed that new sclerotin forms, and sclerotin begins nature and runs off; And for the women, because after the menopause, human body no longer produces the estrogen that helps skeleton strong, so sclerotin loss meeting is faster, osteoporosis takes place very easily.Chinese five six administrative areas of the People's Republic of China 5593 examples in 2002 mid-aged population osteoporosis investigation demonstration more than 40 years old, total prevalence rate is 16.1%, and wherein the male 11.5%, and the women 19.9%.Though the osteoporotic incidence rate China old people does not have definite report, show that from the survey result in Shanghai City the male is 13.4%, the women is more than 40.1%, 60 years old among the old man, and the male is 14.6%, and the women is 61.8%, and the women is considerably beyond the male.In the old people, the epidemiology of fracture shows that city old women incidence rate up to 19.6%, secondly is city male 12.4%, rural area women 8.8%, rural area male 3.4%.
Abroad in the main medicine of clinical practice; The ratio of diphosphonate in market is about 35%; Estrogen and receptor modulators thereof are more than half rivers and mountains that 52%, two big series products has occupied Forteo, and calcitonin and vitamin D active metabolite have then occupied 11% share.
The medicine of treatment and Prevention and Treatment of Osteoporosis mainly contains calcium preparation, diphosphonates, estrogen, androgen, vitamin D class, calcitonin and Hormone Replacement Therapy etc., Market competition at present.The HRT (hormone replacement therapy) that is considered to important preventive means in the past is because it increases risk and the no longer recommended life-time service of breast carcinoma and other diseases.And anti-absorption medicine diphosphate has become the golden standard of osteoporosis therapy, especially to the people of height risk of bone fracture is arranged.Research shows, bisphosphonates be in the osteoporosis therapy medicine research the most comprehensively, curative effect the most definite, the widest kind of application surface.It can not only significantly reduce too high bone turnover rate, obviously carries high bone mass, improves bone mass, can also effectively reduce the fracture that comprises spinal vertebral, hip and extremity and the incidence rate of refracture.Because it can reduce the bone resorption that a variety of causes causes; Therefore be used to prevention and treatment primary osteoporosis (aged with menopause after), brake the osteoporosis that causes, bone tumor, osteogenesis imperfecta, fibrous dysplasia, inflammatory bone disease etc., also can be used for the secondary osteoporosis that glucocorticoid, thyroxine and heparin etc. cause.In addition, diphosphonate still is the first-line treatment medicine of the hypercalcemia that causes of malignant tumor and paget's disease of bone.
Minodronic acid is a kind of new type heterocycle bis-phosphonic acids compounds; The bone dissolving that is used to treat osteoporosis and causes by osteoporosis and malignant tumor; Through suppressing farnesyl pyrophosphate (EPP) synthase activity in the osteoclast, suppress the bone resorption of osteoclast, reduce the bone conversion; Play the effect of control osteoporosis, its inhibition bone resorption activity is respectively alendronic Acid and pamidronic acid 10 times and 100 times.Because characteristic is good especially before it clinical, it is chosen as osteoporosis therapy medicine and mammary gland and lung cancer with osseous metabolism curative and multiple myeloma (multiple myeloma) curative and further develops.
Also have some reports in the prior art about the minodronic acid preparation technique.For example; Patent documentation CN102144982A openly comes a kind of minodronic acid tablet and method for making thereof; It prepares solid preparation through changing method of granulating and tabletting method; It is made as dispersible tablet, but does not solve the low problem of bioavailability, and the Polyethylene Glycol of using in the preparation there is certain influence to human body; Patent documentation CN102078323A discloses a kind of preparation technology who contains minodronic acid drug regimen tablet; Its by the alkaline auxiliary solvent combinations of one type of minodronic acid and sodium carbonate together to improve stripping property; But the minodronic acid tablets of traditional method preparation is inconvenient; Very strong side effect is arranged, and bioavailability is low; Patent documentation CN102020676A discloses a kind of preparation minodronic acid method, and the synthetic use extremely toxic substance of having avoided of multistep is arranged.
Also have some documents to disclose the method for preparing of minodronic acid crude drug; US5480875A discloses the crystal formation problem that improves the minodronic acid of yield; EP0354806A is than the method for preparing minodronic acid that discloses of morning.WO9400462A1 openly produces the crystal formation with minodronic acid.
Yet the minodronic acid preparation of method for preparing prepares though screened specific adjuvant, has certain advantage; But the dissolution of medicine and bioavailability still remain to be improved, and the long-time stability of medicine are undesirable, are unfavorable for long preservation.
Therefore, be necessary to seek a kind of can overcome minodronic acid in the preparation in the process of taking, be difficult to swallow and bigger method and the preparation thereof of side effect, and this method will be fit to large-scale production.
Liposome is meant drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms, and belongs to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine like liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can protect the medicine that is wrapped effectively, improve bioavailability; Change medicine distribution in vivo, and can the release of targeting property, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.
The main mechanism of action of conventional liposome is that drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane sealed or embed in the liposome bilayer lipid membrane; This microgranule type of having cellularity; Get into the interior principal agent of human body is activated body by reticuloendothelial system phagocytic autoimmune function; And change is distributed in the body of entrapped drug; Drug main to be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the therapeutic dose and the toxicity that reduces medicine of medicine.
If can minodronic acid be processed liposome, then be expected to overcome a series of problems that existing minodronic acid preparation exists, thereby improve the dissolubility and the stability of medicine; Prolong drug retention time in vivo; Improve bioavailability, reduce toxic and side effects, improve treatment speed and therapeutic effect.
But, the challenge of preparation liposome is to select suitable liposome constituent and method for making.Because the character of liposome is directly closely related with the composition of liposome like stability, envelop rate, onset time, in vivo circulation time, bioavailability and toxic and side effects etc.; And the composition of liposome with the pharmaceutical properties that will seal directly closely related; Therefore, selecting which type of composition to form the minodronic acid liposome with better quality is the problem that needs to be resolved hurrily.
In sum; In view of minodronic acid in the prior art and the problem that fixedly exists in the pharmacodynamics aspect of the physico-chemical property that exists of preparation and bioavailability thereof; The inventor is through research chronically, and after paying creative work, the lipidosome solid preparation of selecting for use particular excipient and minodronic acid to process has been protected active constituents of medicine effectively; And overcome the problem of its degraded and principal agent poor stability; Improved the dissolution of medicine simultaneously, increased medicine retention time in vivo, obtained to have minodronic acid Liposomal formulation and solid preparation thereof far above the biological sharp degree of prior art.
Summary of the invention
In order to form colory minodronic acid lipidosome solid preparation; Can good compatible with minodronic acid it well be sealed and non-leakage filmogen thereby importantly seek; So that form colory minodronic acid liposome; Make the molten different of this liposome and bioavailability is high, and seek the pharmaceutic adjuvant that can form solid preparation with the minodronic acid liposome.
To achieve these goals, big quantity research and realization that the inventor carries out find that minodronic acid, soybean lecithin, DOPG, cholesterol and the Tween 80 of specified weight proportioning can be processed the minodronic acid liposome; Wherein, Minodronic acid envelop rate as active constituents of medicine is high, and stripping property is good, the retention time significant prolongation of the active constituents of medicine in the gained solid preparation in the body circulation; Bioavailability obviously improves, and curative effect obviously improves.
The inventor is through discover with keen determination; Through minodronic acid, soybean lecithin, DOPG, cholesterol and the Tween 80 of selecting the specified weight proportioning for use; Can form after the minodronic acid liposome of excellent quality; Again liposome is processed solid preparation with general formulation method, thereby accomplish the present invention.
The purpose of this invention is to provide a kind of minodronic acid liposome, it is mainly processed by the composition of following weight proportion:
Preferably, the weight ratio of soybean lecithin and DOPG is 4: 1, the weight of soybean lecithin and DOPG and with the weight ratio of cholesterol be 1: 1-2: 1.
Preferably, minodronic acid liposome provided by the invention, mainly process by following components by weight ratio:
Part preferably, the weight ratio of soybean lecithin and DOPG is 4: 1, the weight of soybean lecithin and DOPG and with the weight ratio of cholesterol be 1: 1-1.5: 1.
In a most preferred embodiment of minodronic acid liposome provided by the invention, the weight of soybean lecithin and DOPG and with the weight ratio of cholesterol be 1: 1.
In minodronic acid liposome of the present invention, with 4: 1 compositions of weight ratio, wherein soybean lecithin is that natural phospholipid and DOPG are synthetic phospholipid to the phospholipid material that uses as soybean lecithin and DOPG.
As the phospholipid that is used to form liposome, it is of a great variety, and commonly used have natural phospholipid and a synthetic phospholipid.The inventor is through long-term conscientious research; Through a large amount of screening tests; Find to adopt general phospholipid and additives for the minodronic acid liposome of film material preparation under the accelerated test of 40 ℃ of high temperature, relative humidity 75% ± 5%, stable and envelop rate is not good.
The inventor is through discover with keen determination; In common phospholipid material, appropriate amount can be used to form colory minodronic acid liposome as the soybean lecithin of natural phospholipid with as the DOPG of synthetic phospholipid with 4: 1 combination phospholipid of weight ratio.Can form the suitably high liposome of envelop rate of size, appropriate configuration composition through the method that provides among the present invention, and these compositions, especially minodronic acid are non-leakage in formed liposome, and the stripping property of minodronic acid is excellent in the liposome.If using amount ratio is soybean lecithin and DOPG combination phospholipid except 4: 1; Perhaps select other phospholipid material such as lecithin etc. for use; Then the poor stability of formed liposome, envelop rate is low, stripping property is poor, can not realize the object of the invention.
In minodronic acid liposome of the present invention; For the minodronic acid of 1 weight portion; The consumption of soybean lecithin is the 10-80 weight portion, and the consumption of DOPG is the 2.5-20 weight portion, and the weight ratio of soybean lecithin and DOPG is 4: 1.If the consumption of soybean lecithin and DOPG is lower than 10 weight portions and 2.5 weight portions respectively, have a large amount of free minodronic acids and do not sealed, the drug loading of liposome is low, and stability also can descend, and stripping property also can affect adversely; Otherwise the consumption of soybean lecithin and DOPG is higher than 80 weight portions and 20 weight portions respectively, and then the envelop rate as the minodronic acid of active constituents of medicine descends.
In minodronic acid liposome of the present invention, cholesterol and Tween 80 are used to regulate the membrane stability and the permeability of liposome.
The inventor is through discovering, when the weight of soybean lecithin and DOPG and with the weight ratio of cholesterol be 1: 1-2: in the time of 1, can form stable minodronic acid liposome.When being higher than 2: 1 when the weight of soybean lecithin and DOPG with the weight ratio of cholesterol, membrane stability reduces; When being lower than 1: 1 when the weight of soybean lecithin and DOPG with the weight ratio of cholesterol, the liposome membrane flowability is too high, is wrapped in the intravital minodronic acid of lipid and is easy to discharge.
In addition, discover, when the weight of soybean lecithin and DOPG and with the weight ratio of cholesterol be 1: 1-2: in the time of 1, formed liposome stripping property is excellent.
Research shows that the stability of liposome and stripping property and bioavailability have close corresponding relation.Stability is high more, and stripping property is good more, and bioavailability is high more.Therefore, the stability of minodronic acid liposome of the present invention is high, stripping property is excellent, is to cause one of high factor of drug bioavailability.
In addition; The inventor discovers, in minodronic acid liposome of the present invention, for the minodronic acid of 1 weight portion; The consumption of soybean lecithin is the 10-80 weight portion; The consumption of DOPG is the 2.5-20 weight portion, and the weight ratio of soybean lecithin and DOPG is 4: 1, and the envelop rate of formed minodronic acid liposome is high.
In minodronic acid liposome of the present invention, use Tween 80 further to improve the stability and the envelop rate of liposome membrane.Tween 80 is a kind of non-ionic surface active agent, when being used for the duplicature of soybean lecithin and DOPG combination phospholipid formation, can not only further improving the dissolubility of minodronic acid, 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 minodronic acid liposome.
In minodronic acid liposome of the present invention, for the minodronic acid of 1 weight portion, the consumption of Tween 80 is the 6-50 weight portion.If the consumption of Tween 80 is lower than 6 weight portions; Then cause improving not enough to the stability and the envelop rate of liposome owing to its consumption is low excessively; Otherwise if the consumption of Tween 80 is higher than 50 weight portions, it is too high and cause liposome membrane to be easy to destroy and reveal active component then to be used for its consumption.
In minodronic acid liposome of the present invention; The collaborative adjusting facilitation to soybean lecithin and DOPG combination immobilized artificial membrane structure of cholesterol through an amount of proportioning and Tween 80; Can form envelop rate height, stable high minodronic acid liposome; Its stripping property is excellent, had good sustained release effect, and bioavailability is high.
On the other hand, the present invention provides a kind of method for preparing of minodronic acid liposome, and this method may further comprise the steps:
(a) minodronic acid, soybean lecithin, DOPG, cholesterol, Tween 80 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 45 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 45 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes minodronic acid liposome powder.
In an embodiment preferred of minodronic acid method for preparing lipidosome of the present invention; Organic solvent described in the step (a) is selected from one or more in ethanol, chloroform, dichloromethane, methanol, oxolane, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, acetonitrile, the normal hexane, and preferred volume ratio is 2: 1 the mixed solvent for the oxolane and the tert-butyl alcohol.
In an embodiment preferred of minodronic acid method for preparing lipidosome of the present invention; Buffer salt solution described in the step (c) is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer, borate buffer solution and the carbonate buffer solution, and preferred pH value is 7.0 PBS.
Through said method, can prepare the little and uniform minodronic acid 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.
Discover that the size of liposome is to influence the liposome principal element with the time of staying that distributes in vivo, the particle diameter of liposome is more little, and the time of staying is long more in the body.Minodronic acid liposome particles through the inventive method preparation is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
A purpose more of the present invention provides a kind of minodronic acid lipidosome solid preparation, and it is mainly processed by minodronic acid liposome and pharmaceutically acceptable excipient.
Minodronic acid lipidosome solid preparation of the present invention is preferably from solid preparations such as granule, tablet, capsule, dry suspension.
The minodronic acid lipidosome solid preparation that the present invention preferably provides is a tablet.
In this article; Used term " pharmaceutically acceptable excipient " is meant the medicinal material except the minodronic acid liposome that uses in order to prepare the minodronic acid lipidosome solid preparation, comprises diluent, disintegrating agent, binding agent, wetting 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.
Minodronic acid lipidosome solid preparation of the present invention is mainly processed by minodronic acid liposome of the present invention, diluent, disintegrating agent, binding agent, wetting agent and lubricant; Weight meter based on the used minodronic acid of preparation minodronic acid liposome; When adopting 1 part of minodronic acid, prepare minodronic acid lipidosome solid preparation of the present invention and need add diluent 50-300 part, disintegrating agent 1-20 part, binding agent 1-30 part, wetting agent 1-60 part and lubricant 0.5-10 part.
In an embodiment preferred of minodronic acid lipidosome solid preparation of the present invention, said diluent is selected from one or more in starch, lactose, Icing Sugar, amylum pregelatinisatum, sorbitol, microcrystalline Cellulose, the dextrin, is preferably microcrystalline Cellulose.
In an embodiment preferred of minodronic acid lipidosome solid preparation of the present invention; Said disintegrating agent is selected from one or more in low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, the dried starch, preferred carboxymethyl starch sodium.
In an embodiment preferred of minodronic acid lipidosome solid preparation of the present invention; Said binding agent is selected from a kind of in 30 POVIDONE K 30 BP/USP 30, starch slurry, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, arabic gum, the xanthan gum, is preferably 30 POVIDONE K 30 BP/USP 30.
In an embodiment preferred of minodronic acid lipidosome solid preparation of the present invention, said wetting agent is the alcoholic solution of 10-80%, preferred 40% alcoholic solution.
In an embodiment preferred of minodronic acid lipidosome solid preparation of the present invention; Said lubricant is selected from one or more in magnesium stearate, zinc stearate, sodium laurylsulfate, Pulvis Talci, micropowder silica gel, Macrogol 4000, the stearic acid, is preferably micropowder silica gel.
Minodronic acid lipidosome solid preparation of the present invention; Weight meter based on the used minodronic acid of preparation minodronic acid liposome; When adopting 1 part of minodronic acid, needing adding diluents microcrystalline cellulose 50-300 part, disintegrating agent carboxymethyl base Starch Sodium 1-20 part, binding agent 30 POVIDONE K 30 BP/USP 30 is that 40% ethanol water is 1-60 part and lubricant micropowder silica gel 0.5-10 part for 1-30 part, wetting agent.
Minodronic acid lipidosome solid preparation provided by the invention is an oral formulations, is tablet.
In practice, consider the effective dose of medicine and the convenience of medication, in the preferred embodiment of minodronic acid lipidosome solid preparation of the present invention, the specification of preparation is that per unit preparation minodronic acid is 1mg.
On the one hand, the present invention provides the method for preparing of above-mentioned minodronic acid lipidosome solid preparation again, and this method may further comprise the steps:
(1) preparation of minodronic acid liposome: minodronic acid, soybean lecithin, DOPG, cholesterol and Tween 80 are prepared into the liposome powder together;
(2) preparation of minodronic acid lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with the minodronic acid lipidosome solid preparation.
Wherein, said pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, wetting agent, lubricant and combination thereof.
In the preferred embodiment of the invention, the preparation process at step (1) the minodronic acid plastid of the method for preparing of minodronic acid liposome solid preparation comprises above-mentioned (a) to (d) four steps:
In the preferred embodiment of the invention, minodronic acid lipidosome solid preparation method for preparing of the present invention the preparation process of step (2) minodronic acid liposome solid preparation, may further comprise the steps:
(e) minodronic acid liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the preparation that sieves, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting makes the minodronic acid lipidosome solid preparation.
In the method for the invention, can also sterilize to liposome and/or lipidosome solid preparation as required.Sterilizing methods does not have specific (special) requirements, can use liposome sterilizing methods commonly used in the pharmaceutical field, like heat sterilization, filtration sterilization, radiation sterilization or sterile working etc.
The present invention becomes liposome through the active component minodronic acid with the combined preparation of the specified weight of soybean lecithin, DOPG, cholesterol, Tween 80 earlier, is mixed and made into solid preparation with other pharmaceutic adjuvant again.Gained 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, and is evident in efficacy, reduced toxic and side effects.
The method for preparing of minodronic acid 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.
Another object of the present invention provides the method for preparing of above-mentioned minodronic acid liposome, and this method may further comprise the steps:
(a) minodronic acid, soybean lecithin, DOPG, cholesterol, Tween 80 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 45 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 45 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes minodronic acid liposome powder.
Another object of the present invention has provided a kind of method for preparing of minodronic acid liposome solid preparation, preferably includes following substep:
(e) minodronic acid liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the preparation that sieves, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting makes the minodronic acid lipidosome solid preparation.
Compare with existing preparation technique, minodronic acid lipidosome solid preparation provided by the invention has improved preparation stripping property, stability and bioavailability greatly; Reduce toxic and side effects, improved the formulation products quality, improved therapeutic effect.
Description of drawings
Below, specify embodiment of the present invention in conjunction with accompanying drawing, wherein:
Fig. 1 is the release profiles of minodronic acid solid preparation.
Wherein:
The specific embodiment
Following examples are to further specify of the present invention, but never limit the scope of the present invention.Further set forth the present invention in detail with reference to embodiment below, but it will be appreciated by those skilled in the art that the present invention is not limited to the method for preparing of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modification to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
Embodiment 1Minodronic acid liposome sheet
Adopt following production technology to prepare minodronic acid liposome sheet:
(1) accurately takes by weighing 1g minodronic acid, 80g soybean lecithin, 20g DOPG, 50g cholesterol, 50g Tween 80, be dissolved in the 1000ml volume ratio and be in 2: 1 the oxolane and tert-butyl alcohol mixed solvent, stir and make its dissolving;
(2) above-mentioned solution is placed eggplant-shape bottle, dichloromethane and isopropyl alcohol are removed in 45 ℃ of water-bath decompressions, on the bottle wall, form uniformly transparent film;
(3) in eggplant-shape bottle, adding the 800ml pH value is 7.0 PBS, continues to make the films swell hydration 45 ℃ of water-bath normal pressures rotations;
(4) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes minodronic acid liposome powder;
(5) minodronic acid lipidosome solid powder and 300g microcrystalline Cellulose, 40g carboxymethyl starch sodium and 20g 30 POVIDONE K 30 BP/USP 30 are mixed, the mix homogeneously that sieves, the ethanol water that adds 200ml 40% prepares soft material, the preparation that sieves, drying;
(6) with dried granule and 10g micropowder silica gel mix homogeneously, granulate sieves;
(7) tabletting makes 1000 minodronic acid liposome sheets.
Embodiment 2The minodronic acid liposome tablet
Adopt following production technology to prepare the minodronic acid liposome tablet:
(1) accurately takes by weighing 1g minodronic acid, 60g soybean lecithin, 15g DOPG, 50g cholesterol, 40g Tween 80, be dissolved in the 1000ml volume ratio and be in 2: 1 the oxolane and tert-butyl alcohol mixed solvent, stir and make its dissolving;
(2) above-mentioned solution is placed eggplant-shape bottle, dichloromethane and isopropyl alcohol are removed in 45 ℃ of water-bath decompressions, on the bottle wall, form uniformly transparent film;
(3) in eggplant-shape bottle, adding the 600ml pH value is 7.0 PBS, continues to make the films swell hydration 45 ℃ of water-bath normal pressures rotations;
(4) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes minodronic acid liposome powder;
(5) minodronic acid lipidosome solid powder and 200g microcrystalline Cellulose, 40g carboxymethyl starch sodium and 20g 30 POVIDONE K 30 BP/USP 30 are mixed, the mix homogeneously that sieves, the ethanol water that adds 100ml 40% prepares soft material, the preparation that sieves, drying;
(6) with dried granule and 10g micropowder silica gel mix homogeneously, granulate sieves;
(7) tabletting makes 1000 minodronic acid liposome sheets
Comparative Examples 1-2
Material composition in will the Comparative Examples 1-3 shown in following table 1 adopt respectively with embodiment 1 in identical production technology, process minodronic acid liposome sheet:
Comparative Examples 4 is to adopt the technology of embodiment 1 to process, and difference is, step (4) be with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out thawing then, direct spray drying makes the minodronic acid liposome.
Used supplementary material composition among the table 1 Comparative Examples 1-3
Wherein, "/" expression is not used.
Test Example 1The mensuration of envelop rate
The minodronic acid liposome powder 1 of measuring gained in the step (4) in embodiment 1-2 and Comparative Examples 1-4 is dissolved in the 10ml water, gets suspension, gets suspension 0.5ml; Be added on SephadexG-50 gel column top, with the phosphate buffer eluting, flow velocity 1ml/min; Collect 4～11ml eluent (containing liposome); Blow to the about 0.5ml of volume with nitrogen, add the dehydrated alcohol breakdown of emulsion and be settled to 10ml, shake up.The accurate 10 μ l solution of drawing, sample introduction is measured peak area, the content of the minodronic acid that calculating lipid body weight is sealed; Precision is measured minodronic acid liposome turbid liquor 0.5ml in addition, is settled to 10ml with dehydrated alcohol, shakes up.The accurate 10 μ l solution of drawing, the total amount of minodronic acid in the mensuration liposome turbid liquor.Computational envelope rate, result are shown in the following table 2:
The mensuration result of table 2 envelop rate
Can know that by table 2 compare with the liposome in the comparative example, the envelop rate of minodronic acid liposome of the present invention will exceed a lot.The envelop rate of minodronic acid liposome is directly related with the composition kind that is used to form liposome.When the composition beyond the used composition of use the present invention, the envelop rate of gained minodronic acid liposome is starkly lower than the present invention.
Can know that through comparing embodiment 1-2 and Comparative Examples 4 another innovative point of the present invention " multigelation three times " is for the effect that also is significantly improved of the envelop rate of minodronic acid liposome of the present invention.
Test Example 2The size of liposome particle diameter and particle size distribution
In order to understand minodronic acid liposome particle size parameters and particle size distribution accurately; Be taken at an amount of liposome powder of gained in the step (4) among embodiment 1-2 and the Comparative Examples 1-4, directly use laser particle size analyzer (Easysizer20, American-European gram company) to observe its outer light; And mensuration particle diameter; Handle with the dynamic light scattering process software, the distribution of measuring its diameter and calculating particle diameter, the result is shown in the following table 3:
Table 3 liposome particle diameter
Can be known that by table 3 mean diameter of gained liposome is little more a lot of than the mean diameter of gained liposome among the Comparative Examples 1-4 among the embodiment of the invention 1-2, and the size homogeneous, outward appearance is better.
Can know that through comparing embodiment 1-2 and Comparative Examples 4 another innovative point of the present invention " multigelation three times " has tangible raising effect for the character such as mean diameter, particle size distribution and outward appearance of minodronic acid liposome of the present invention.
Therefore, little, the particle size distribution of minodronic acid 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 3Stability and dissolution are investigated
40 ℃ of high temperature, following 6 months of relative humidity 75% ± 5% condition is carried out the accelerated test investigation with the sample of above embodiment 1-2, Comparative Examples 1-4 preparation and the minodronic acid sheet of listing (the little wild Pharmaceutical Co., Ltd of Japan, lot number 0854), and the result is following:
Table 4 stability and dissolution determination result
Can be known that by table 4 the minodronic acid sheet dissolution of listing and Comparative Examples 1-4 is low, content reduces obviously when quickening June, and related substance raises; And the sample dissolution for preparing among the embodiment of the invention 1-2 is high, quickens that content and related substance all do not have significant change after 6 months.Proved absolutely the superiority of the present invention aspect raising stability and dissolution.
Test Example 4Release in vitro research
Each 1g of liposome powder (amount with minodronic acid is as the criterion) that precision takes by weighing minodronic acid embodiment 1-2 and Comparative Examples 1-4 is dissolved in the 10ml water, gets each 5ml of suspension and places bag filter to tighten, and release medium is PBS (containing 0.25% the polysorbas20) 100ml of pH7.0; Bath temperature is 37 ℃; Speed of agitator is 300rpm, respectively at 0.5,1,2,4,6,8,12,18, the 24h 1ml that takes a sample, measures release rate; Draw release profiles, shown in result such as the accompanying drawing 1.
The result shows that gained minodronic acid lipidosome solid preparation of the present invention release is slow, has reached the effect of slow release, and the not fine realization slow release of Comparative Examples 1-4.
Industrial applicibility
Result by the foregoing description and experimental example can know that minodronic acid lipidosome solid preparation of the present invention has good surface appearance, and granule is little; Particle diameter is even, and envelop rate is high, and stability is high; Stripping property is good, and percolation ratio is low, and the time of staying in vivo is long; Bioavailability is high, has the favorable industrial using value.
More than through the specific embodiment and embodiment the present invention is specified; But should understand; These explanations do not constitute any restriction to scope of the present invention; Under the situation that does not depart from spirit of the present invention and protection domain, can carry out multiple modification, improvement and replacement to technical scheme of the present invention and embodiment thereof, these are all because of falling in protection scope of the present invention.
Each list of references of mentioning among the application or quoting is incorporated herein by reference at this in full.
Claims (10)
1. minodronic acid liposome is characterized in that mainly being processed by following components by weight ratio:
Preferably, the weight ratio of soybean lecithin and DOPG is 4: 1, the weight of soybean lecithin and DOPG and with the weight ratio of cholesterol be 1: 1-2: 1.
2. minodronic acid liposome according to claim 1 is characterized in that mainly being processed by following components by weight ratio:
Preferably, the weight ratio of soybean lecithin and DOPG is 4: 1, the weight of soybean lecithin and DOPG and with the weight ratio of cholesterol be 1: 1-1.5: 1.
3. method for preparing the minodronic acid liposome is characterized in that may further comprise the steps:
(a) minodronic acid, soybean lecithin, DOPG, cholesterol, Tween 80 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 45 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 45 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes minodronic acid liposome powder.
4. method according to claim 3, wherein,
Organic solvent described in the step (a) is selected from one or more in ethanol, chloroform, dichloromethane, methanol, oxolane, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, acetonitrile, the normal hexane, and preferred volume ratio is 2: 1 the oxolane and the mixed solvent of the tert-butyl alcohol;
Buffer salt solution described in the step (c) is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer, borate buffer solution and the carbonate buffer solution, and preferred pH value is 7.0 PBS.
5. a minodronic acid lipidosome solid preparation is characterized in that comprising the described minodronic acid liposome of claim 1.
6. minodronic acid lipidosome solid preparation according to claim 5 is characterized in that mainly by mainly being processed by the described minodronic acid liposome of claim 1 and diluent, disintegrating agent, binding agent, wetting agent, lubricant.
7. minodronic acid lipidosome solid preparation according to claim 5 is characterized in that being tablet.
8. the method for preparing of a minodronic acid lipidosome solid preparation, this method may further comprise the steps:
(1) preparation of minodronic acid liposome: minodronic acid, soybean lecithin, DOPG, cholesterol and Tween 80 are prepared into the liposome powder together;
(2) preparation of minodronic acid lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with the minodronic acid lipidosome solid preparation.
9. method according to claim 8, wherein, the preparation of step (2) minodronic acid liposome solid preparation comprises following substep:
(e) minodronic acid liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the preparation that sieves, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting makes the minodronic acid lipidosome solid preparation.
10. described minodronic acid liposome of claim 1 and the described minodronic acid lipidosome solid preparation of claim 5 are used for treating the application of osteoporotic medicine in preparation.
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| CN101415686A (en) * | 2006-04-03 | 2009-04-22 | P.安杰莱蒂分子生物学研究所 | Amide substituted indazole and benzotriazole derivatives as poly(ADP-ribose)polymerase (PARP) inhibitors |
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