CN102247324A - Flumazenil liposome injection - Google Patents
Flumazenil liposome injection Download PDFInfo
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- CN102247324A CN102247324A CN 201110196556 CN201110196556A CN102247324A CN 102247324 A CN102247324 A CN 102247324A CN 201110196556 CN201110196556 CN 201110196556 CN 201110196556 A CN201110196556 A CN 201110196556A CN 102247324 A CN102247324 A CN 102247324A
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Abstract
The invention discloses a flumazenil liposome injection and a preparation method thereof. The liposome injection is prepared from flumazenil, cholesterol, phosphatidyl ethanolamine, soyasterol, tween 80, trehalose and polyvinylpyrrolidone in specific proportions by weight. The liposome injection disclosed by the invention has favorable preparation stability, the liposome can not be ruptured due to fusion, ice crystal and the like in the freezing process, and the liposome keeps the same favorable entrapment rate after long-term storage. The flumazenil liposome injection disclosed by the invention improves the solubility of flumazenil, improves the quality of the preparation product, reduces the toxic side effect, increases the retention time of the medicament in systemic circulation, improves the bioavailability of the medicament, obviously improves the curative effect, has a simple preparation method and is suitable for industrialized big production.
Description
Technical field
The present invention relates to a kind of lipidosome injection and method for making thereof, be specifically related to a kind of flumazenil lipidosome injection and method for making thereof, belong to medical technical field.
Background technology
The flumazenil chemical name is a 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a] [1,4] Benzodiazepine-3-Ethyl formate, molecular formula C
15H
14FN
3O
3, molecular weight 303.29, structural formula is as follows:
Flumazenil is white or off-white color crystalline powder, and is almost insoluble in water.
Flumazenil is 1, and 4-imidazoles Benzodiazepine derivant is Benzodiazepine (BZD) receptor antagonist, can act on brain BDZ receptor, reverses the maincenter sedation of BDZ class, retardance BDZ receptor and the effect that do not produce the BDZ medicine.Flumazenil can reverse the BDZ class and to the effect of the non-BDZ class medicine of central nervous system BDZ receptor tool affinity (as helping a clone, Triazolopyridazine), anticonvulsant action that also can part antagonism sodium valproate.
Clinically, flumazenil is used to reverse the maincenter sedation of BDZ class: (1) is used for anesthesia back: the inpatient induce with the BDZ class and keep general anesthesia after available this product stop its effect; (2) be used for first aid:, or get rid of BDZ and poison as the diagnostic medicine of BDZ class poisoning.
The flumazenil dosage form of listing is mainly injection at present, the flumazenil injection that common process is prepared, physics and chemical property poor stability, the long-term storage drug quality can descend but also can generate some impurity, bring toxic and side effects, stayed hidden danger for clinical use.
Patent CN101322688B discloses a kind of for the oil in water emulsion of vein with flumazenil, is made up of flumazenil, oil for injection, emulsifying agent, Palmic acid, di-tert-butyl toluene, Osmolyte regulator etc.Yet the preparation of Emulsion need add a large amount of organic cosurfactants, increases manufacturing cost; And the automatic dispersing uniformity in dilution back is poor when using, and influences result of use.
In the pharmaceutical carrier induction system, the research of submicrons such as microemulsion, microsphere, nanoparticle, liposome, pharmacosomes has become field very active in the novel pharmaceutical formulation research.Drug encapsulation can be changed medicine distribution in vivo in these submicrons, increase the abundance of medicine, thereby improve curative effect, alleviate toxic and side effects at target organ.
In targeting drug delivery system, the research of liposome is comparatively extensive, and liposome has good targeting and biocompatibility in vivo.
As a kind of new medicinal preparation, Liposomal formulation has the following advantages:
(1) have slow releasing function: active component slowly discharges, and delays renal excretion and metabolism, thereby prolongs action time, and effect improves the quality;
(2) reduce drug toxicity;
(3) dissolubility of increase medicine improves the quality of the pharmaceutical preparations;
(4) have targeting: the contained medicine of liposome is kept high concentration in liver, spleen reticuloendothelial system internal organs part, thereby plays the effect of medicine organ targeting;
(5) has protective effect to active pharmaceutical ingredient.
Liposome (Liposome) is dispersed in phospholipid by Britain scholar Bangham and Standlish at first and finds when carrying out electron microscopic observation in the water.Phospholipid is dispersed in the water and forms multilamellar vesicle naturally, every layer of equal bilayer of lipid not; Separated by water between vesicle central authorities and each layer, bilayer thickness is about 4nm.Afterwards, this bimolecular folliculus with similar biofilm structure was called liposome.Liposome can be divided into multilamelar liposome and courage and insight liposome.Unilamelar liposome is divided into small unilamellar vesicle and large unilamellar vesicle again.Small unilamellar vesicle is spherical, and size is generally the 20-50 nanometer; Large unilamellar vesicle is of a size of the micron number magnitude.
People such as Britain Lai Men began liposome is used for pharmaceutical carrier in 1971, the main mechanism of action is 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 has the class cellularity, enter the interior principal agent of human body is activated body by reticuloendothelial system phagocytic autoimmune function, and the interior distribution of the body that changes encapsulated medicine, make the drug main will be liver, spleen, put aside in the histoorgan such as lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of the therapeutic dose and the reduction medicine of medicine.
In recent years, continuous progress along with biotechnology, liposome preparation technology is progressively perfect, the liposome mechanism of action is further illustrated, liposome is fit to vivo degradation, avirulence and non-immunogenicity in addition, particularly great number tested data proof liposome can improve the Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces advantage such as drug dose.
Because there is demand in the deficiency of flumazenil injection for the flumazenil lipidosome injection at present.
Summary of the invention
The inventor is through discovering with keen determination, by flumazenil, cholesterol, PHOSPHATIDYL ETHANOLAMINE, soyasterol, Tween 80, trehalose and the polyvinylpyrrolidone (PVP) of selecting the specified weight proportioning for use, can form the flumazenil lipidosome injection of excellent quality, thereby finish the present invention.
The purpose of this invention is to provide a kind of flumazenil lipidosome injection, it is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1-1: 2.
Preferably, flumazenil lipidosome injection according to the present invention is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1-3: 4.
Further preferably, flumazenil lipidosome injection according to the present invention is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1.
Another object of the present invention provides the preparation method of above-mentioned flumazenil lipidosome injection, and this method may further comprise the steps:
(1) cholesterol, PHOSPHATIDYL ETHANOLAMINE, soyasterol, Tween 80 are dissolved in an amount of buffer salt solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 15 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add flumazenil, constantly stir adding trehalose and PVP down;
(4) 0.45um filtering with microporous membrane, quick freezing returns to room temperature then, and fill promptly gets the flumazenil lipidosome injection.
Lipidosome injection of the present invention has reduced toxic and side effects, improved the formulation products quality, had good preparation stability, liposome can not break because of dehydration, fusion, ice crystal etc. in the refrigerating process, after the long term storage, liposome keeps good envelop rate equally.
By the flumazenil lipidosome injection that the inventive method makes, improved the dissolubility of flumazenil, improved the quality of formulation products, reduced toxic and side effects, increased the retention time of medicine in the body circulation, improved bioavailability of medicament, curative effect obviously improves; And preparation method is simple, is suitable for industrialized great production.
Description of drawings
Fig. 1 is the blood drug level-time graph of flumazenil lipidosome injection.
The specific embodiment
Below further specify by specific embodiment the present invention, characteristics of the present invention and advantage will become more clear along with these explanations.
In order to form colory flumazenil lipidosome injection, can good compatible with flumazenil it well be sealed and non-leakage filmogen thereby importantly seek, and seek the excipient composition that can make liposome form stable injectable liquid.
To achieve these goals, big quantity research and realization that the inventor carries out, find the flumazenil of specified weight proportioning, cholesterol, PHOSPHATIDYL ETHANOLAMINE, soyasterol, Tween 80, trehalose and PVP can make the flumazenil lipidosome injection, wherein, envelop rate height as the flumazenil of active constituents of medicine, the liposome particle diameter is little and be evenly distributed, compare with flumazenil injection of the prior art, the retention time significant prolongation of the active constituents of medicine of preparation of the present invention in the body circulation, the biocompatibility height of medicine, bioavailability obviously improves, and curative effect obviously improves.
On the one hand, the invention provides a kind of flumazenil lipidosome injection, it is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1-1: 2.
Preferably, flumazenil lipidosome injection according to the present invention is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1-3: 4.
Further preferably, flumazenil lipidosome injection according to the present invention is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1.
As the phospholipid that is used to form liposome, can use natural phospholipid and synthetic phospholipid.Natural phospholipid comprises PHOSPHATIDYL ETHANOLAMINE, Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine and soybean phospholipid acyl inositol etc.Synthetic phospholipid is dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, two myristoyl phosphatidylcholines, two Laurel phosphatidyl cholines, DOPG, distearyl phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two lauroyl phosphatidyl glycerols etc.
In the present invention, as the flumazenil of active constituents of medicine, its poorly water-soluble is fat-soluble good.At the characteristics of flumazenil, the inventor is particularly suitable for as basic phospholipid filmogen by discovering PHOSPHATIDYL ETHANOLAMINE.
(phosphatidyl ethanolamine, PE) as a kind of natural phospholipid, its content is very high, obtains easily, and is cheap for PHOSPHATIDYL ETHANOLAMINE.The phase transition temperature of PHOSPHATIDYL ETHANOLAMINE is higher, is easy to form the stabilized liposomes film.
When using other phospholipid, be difficult to form colory liposome, character such as the envelop rate of liposome, stability and percolation ratio are poor.
In order to improve the stability of liposome, the purity of used PHOSPHATIDYL ETHANOLAMINE is more than 98%, and is preferred more than 99%.
In flumazenil lipidosome injection of the present invention, for the flumazenil of 1 weight portion, the consumption of PHOSPHATIDYL ETHANOLAMINE is the 50-200 weight portion.If the consumption of PHOSPHATIDYL ETHANOLAMINE is lower than 50 weight portions, then can't form stabilized liposomes; Otherwise if the consumption of the consumption of PHOSPHATIDYL ETHANOLAMINE is higher than 200 weight portions, then the envelop rate as the flumazenil of active constituents of medicine descends, and the quality of injection and curative effect reduce.
In flumazenil lipidosome injection of the present invention, cholesterol and soyasterol and tween 80 are used to regulate the membrane stability of liposome.
Cholesterol is a kind of amphiphilic, combines with PHOSPHATIDYL ETHANOLAMINE, stops it to be condensed into crystal structure.Cholesterol mixes the PHOSPHATIDYL ETHANOLAMINE bilayer, is similar to " buffer agent " and equally plays the effect of regulating membrane structure " flowability ".When being lower than phase transition temperature, cholesterol can make film reduce ordered arrangement, increases mobile; When being higher than phase transition temperature, cholesterol can increase the ordered arrangement of film, thereby reduces the flowability of film.Cholesterol can make liposome bimolecular tunic solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
(soybean sterol SS) is the hydrolyzate that the soyasterol glucoside removes glucose residue to soyasterol, and described soyasterol glucoside is the mixture from the sterol glucoside of separating through the Semen sojae atricolor residue of refinement Oleum Glycines.As a kind of natural product, the soyasterol source is abundant, low price.
With cholesterol seemingly, soyasterol also can be regulated the stability of PHOSPHATIDYL ETHANOLAMINE film, and its regulating action effect to stability is better than cholesterol.
The inventor is through discovering, when the weight sum and the PHOSPHATIDYL ETHANOLAMINE weight ratio of cholesterol and soyasterol is 1: 1-1: in the time of 2, can form stable flumazenil liposome.When the weight sum of cholesterol and soyasterol and PHOSPHATIDYL ETHANOLAMINE weight ratio were higher than 1: 1, membrane stability reduced, and flumazenil is easy to seepage; When the weight sum of cholesterol and soyasterol and PHOSPHATIDYL ETHANOLAMINE weight ratio were lower than 1: 2, flumazenil liposome membrane flowability was too high, is wrapped in the intravital flumazenil of lipid and is easy to discharge.In addition, discover that when the weight sum and the PHOSPHATIDYL ETHANOLAMINE weight ratio of cholesterol and soyasterol is 1: 1-1: in the time of 2, formed liposome toxicity is low.
Studies show that the stability of liposome and bioavailability have close corresponding relation.Stability is high more, and bioavailability is high more.Therefore, the stability of flumazenil lipidosome injection of the present invention is high, is to cause one of high factor of drug bioavailability.
On the other hand, the inventor discovers, in flumazenil lipidosome injection of the present invention, for the flumazenil of 1 weight portion, the consumption of PHOSPHATIDYL ETHANOLAMINE is the 50-200 weight portion, and cholesterol is the 50-200 weight portion, and soyasterol is the 10-50 weight portion, and the weight sum of cholesterol and soyasterol and PHOSPHATIDYL ETHANOLAMINE weight ratio are 1: 1-1: 2 o'clock, and the envelop rate height of formed flumazenil lipidosome injection.
In flumazenil lipidosome injection of the present invention, use tween 80 further to improve the stability of liposome membrane.Tween 80 (polysorbate-80) is a kind of non-ionic surface active agent, when being used for the PHOSPHATIDYL ETHANOLAMINE duplicature, can improve the chemical energy between this duplicature, thereby improve the chemical stability of liposome in waterborne liquid, and then improve the stability of flumazenil lipidosome injection.
In flumazenil lipidosome injection of the present invention, for the flumazenil of 1 weight portion, the consumption of tween 80 is the 1-60 weight portion.If the consumption of tween 80 is lower than 1 weight portion, then cause the stability improvement of flumazenil lipidosome injection not enough owing to its consumption is low excessively, otherwise if the consumption of tween 80 is higher than 60 weight portions, it is too high and cause liposome membrane to be easy to reveal then to be used for its consumption.
Discover that when the flumazenil that uses above-mentioned specified quantitative, PHOSPHATIDYL ETHANOLAMINE, cholesterol, soyasterol and tween 80, can obtain colory flumazenil liposome, its envelop rate and stability are all very high, toxicity is low, the bioavailability height.
In flumazenil lipidosome injection of the present invention, use trehalose and polyvinylpyrrolidone as excipient, be used to form stable injection.
Trehalose be trehalose be by two glucose molecules with α, α, 1; the nonreducing sugar that the 1-glycosidic bond constitutes; self property is highly stable, and its most tangible character is that the biomembranous ability of protection is arranged under anhydrous condition, even make liposome also keep complete form under the situation of dehydration.
In flumazenil lipidosome injection of the present invention, trehalose can effectively be protected the form and the stability of liposome particles, further improves the stability of lipidosome injection.
Polyvinylpyrrolidone (PVP) is a macromolecular compound, the fusing point height, dissolubility in water and organic solvent is all good, toxicity is low, physiological compatibility is good, has the effect of dispersion medicine, because its existence can make the water viscosity increase, be encapsulated in the intermediary moisture film of liposome and make water soluble drug have higher entrapment, and can make medicine stable in storage.
Flumazenil lipidosome injection of the present invention, the specification of its flumazenil can be 2ml: 0.2mg, 5ml: 0.5mg and 10ml: 1mg (injection volume: flumazenil weight).
On the other hand, the present invention also provides a kind of preparation method of flumazenil lipidosome injection, specifically comprises being prepared as follows step:
(1) cholesterol, PHOSPHATIDYL ETHANOLAMINE, soyasterol, Tween 80 are dissolved in an amount of buffer salt solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 15 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add flumazenil, constantly stir adding trehalose and PVP down;
(4) 0.45um filtering with microporous membrane, quick freezing returns to room temperature then, and fill promptly gets the flumazenil lipidosome injection.
Above-mentioned described preparation method, wherein said buffer salt solution are selected from a kind of in phosphate buffered solution, citrate buffer solution, carbonate buffer solution, the borate buffer solution, are preferably pH and are 7.2 phosphate buffered solution.
Above-mentioned described preparation method, wherein the temperature of the molten condition liposome described in the step (3) is 60 ℃.
Above-mentioned described preparation method, wherein the temperature of the quick freezing described in the step (4) is-80 ℃.
The challenge of preparation liposome is how to make liposome membrane to form the high vesicle of envelop rate of suitable size, appropriate configuration material.And these materials do not spill at the formation liposome.
The inventor has obtained colory flumazenil lipidosome injection by selecting suitable material composition, adopting suitable preparation technology, and the liposome particle diameter is little, and particle size distribution is even, the envelop rate height, and stability is high.
Discover that the size of liposome is to influence that liposome distributes in vivo and the principal element of the time of staying, the particle diameter of liposome is more little, and the time of staying is long more in the body.Flumazenil liposome particles by the inventive method preparation is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
Embodiment
Below by concrete preferred embodiment the present invention is further specified.These embodiment only are illustrative, and should not be construed as limitation of the present invention.
The preparation of embodiment 1 flumazenil lipidosome injection
Raw materials used composition and weight thereof are as follows:
Adopt preparation technology to prepare the flumazenil lipidosome injection:
(1) 120g cholesterol, 150g PHOSPHATIDYL ETHANOLAMINE, 30g soyasterol and 10g Tween 80 are dissolved in 3000mlpH and in 7.2 the phosphate buffered saline, make blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 1g flumazenil, constantly stir adding 100g trehalose and 150g PVP down;
(4) 0.45um filtering with microporous membrane ,-80 ℃ of quick freezing return to room temperature then, and fill promptly gets the flumazenil lipidosome injection.
The preparation of embodiment 2 flumazenil lipidosome injections
Raw materials used composition and weight thereof are as follows:
Adopt preparation technology to prepare the flumazenil lipidosome injection:
(1) pH that 75g cholesterol, 100g PHOSPHATIDYL ETHANOLAMINE, 25g soyasterol and 20g Tween 80 is dissolved in 3000ml in 7.2 the phosphate buffered saline, makes blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 0.5g flumazenil, constantly stir adding 30g trehalose and 40g PVP down;
(4) 0.45um filtering with microporous membrane ,-80 ℃ of quick freezing return to room temperature then, and fill promptly gets the flumazenil lipidosome injection.
The preparation of embodiment 3 flumazenil lipidosome injections
Raw materials used composition and weight thereof are as follows:
Adopt preparation technology to prepare the flumazenil lipidosome injection:
(1) pH that 30g cholesterol, 40g PHOSPHATIDYL ETHANOLAMINE, 10g soyasterol and 10g Tween 80 is dissolved in 3000ml in 7.2 the phosphate buffered saline, makes blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 0.2g flumazenil, constantly stir adding 10g trehalose and 30g PVP down;
(4) 0.45um filtering with microporous membrane ,-80 ℃ of quick freezing return to room temperature then, and fill promptly gets the flumazenil lipidosome injection.
The preparation of Comparative Examples 1-3 flumazenil lipidosome injection
Adopt with respectively with embodiment 1-3 in identical production technology, the material composition in will the Comparative Examples 1-3 as shown in following table 1 is made the flumazenil lipidosome injection respectively:
Raw materials used composition among the table 1 Comparative Examples 1-3
Wherein, "/" expression is not used.
The mensuration of test example 1 liposome particle diameter
Under the room temperature condition, get the flumazenil lipidosome injection among embodiment 1-3 and the Comparative Examples 1-3, place the sample cell of Submicron Particle Sizer Model 370 particle diameter detectors, measure particle size distribution and mean diameter; Observe particle shape with projection electron microscope.The results are shown in the following table 2.
Table 2 liposome particle diameter testing result
As known from Table 2, the solid lipid nanoparticle particle diameter that embodiment 1-3 makes is even, shows spherical, big or small homogeneous; The solid lipid nanoparticle particle diameter that Comparative Examples 1-3 makes is inhomogeneous, and shape is indefinite, and is not of uniform size.
Particularly, even when adopting same production technology, the particle appearance of gained flumazenil liposome and mean diameter thereof obviously are better than the flumazenil liposome of gained among the Comparative Examples 1-3 among the embodiment 1-3.When the composition beyond using the used composition of the present invention was described, perhaps when the composition consumption was outside the composition amount ranges that the present invention limits, the outward appearance of gained flumazenil liposome was inferior to the present invention, and mean diameter obviously goes out greatly a lot.
The mensuration of test example 2 envelop rates
With the flumazenil lipidosome injection for preparing among embodiment 1-3 and the Comparative Examples 1-3 rotating speed high speed centrifugation with 5000r/min, centrifugal 20 minutes, get supernatant, use dissolve with methanol, the HPLC method is surveyed flumazenil content, and the computational envelope rate the results are shown in the following table 3.
Table 3 entrapment efficiency determination result
As shown in Table 3, the envelop rate of the Liposomal formulation of embodiment 1-3 preparation is higher than the envelop rate of the Liposomal formulation of Comparative Examples 1-3 significantly.When the composition beyond using the used composition of the present invention was described, perhaps when the composition consumption was outside the composition amount ranges that the present invention limits, the liposome encapsulation of gained liposome was lower than the present invention.
Test example 3 study on the stability
Sample and listing flumazenil injection (lot number: H20093464 with embodiment of the invention 1-3 preparation, Zhengqing Pharmaceutical Group Corp., Ltd., Hunan Prov.) places following 6 months of the condition of 40 ℃ of high temperature, relative humidity 75% respectively, carry out accelerated test and investigate, experimental result is shown in the following table 4.
Table 4 accelerated test result
As shown in Table 4, when quickening June, the listing formulation content reduces, and related substance raises; And sample character of the present invention, content and related substance variation are all not obvious, illustrate that product stability of the present invention is good.
The test of test example 4 percolation ratios
Get the sample of test routine 1-3 and Comparative Examples 1-3 preparation, at ambient temperature,, make regular check on, measure envelop rate respectively at 0 day, 30 days, 60 days, 90 days and 180 days, with the dose of sealing in 0 day relatively, calculate percolation ratio, the results are shown in the following table 5.
Table 5 percolation ratio result of the test
As shown in Table 5, during long term storage, the flumazenil lipidosome injection percolation ratio for preparing among the embodiment of the invention 1-3 changes little, and the injection percolation ratio for preparing among the Comparative Examples 1-3 increases gradually, the liposome seepage is serious, and the flumazenil lipidosome injection of this explanation the present invention preparation has higher stability.
The mensuration of test example 5 blood drug level
28 rats are divided into 4 groups at random, every group of injection for preparing among drug administration by injection embodiment 1-3 and the Comparative Examples 1-3 respectively, and commercially available flumazenil injection (lot number: H20093464, Zhengqing Pharmaceutical Group Corp., Ltd., Hunan Prov.), injection volume is the 0.2mg flumazenil.Respectively at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h, take a blood sample after the administration, blood sample is measured blood drug level with the HPLC-MS method after treatment.The flumazenil lipidosome injection for preparing among the flumazenil lipidosome injection for preparing among the drafting embodiment 1-3, the Comparative Examples 1-3 and the blood drug level and the time relation curve of commercially available flumazenil injection are shown in the accompanying drawing 1.
As shown in Figure 1, compare with commercially available flumazenil lipidosome injection with the flumazenil lipidosome injection for preparing among the Comparative Examples 1-3, the flumazenil lipidosome injection for preparing among the embodiment of the invention 1-3 has the following advantages: elimination speed is in vivo slowed down, distribution time prolongs in the body circulation, reached improved slow release effect, bioavailability increases.
Industrial applicibility
By the result of the foregoing description and experimental example as can be known, flumazenil liposome of the present invention has good surface appearance, and granule is little, and particle diameter is even, the envelop rate height, stability is high, and percolation ratio is low, the time of staying in vivo is long, and the bioavailability height has the favorable industrial using value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; but should understand; these explanations do not constitute any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; can carry out multiple modification, improvement and replacement to technical solutions and their implementation methods of the present invention, these are all because of falling within the scope of protection of the present invention.
Each list of references of mentioning among the application or quoting is incorporated herein by reference in full at this.
Claims (9)
1. flumazenil lipidosome injection, it is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1-1: 2.
2. flumazenil lipidosome injection according to claim 1, it is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1-3: 4.
3. flumazenil lipidosome injection according to claim 1, it is made by medicine that comprises following weight proportion and excipient composition:
Condition is: the weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soyasterol are 1: 1.
4. according to each described flumazenil lipidosome injection among the claim 1-3, wherein the specification of flumazenil is 2ml: 0.2mg, 5ml: 0.5mg or 10ml: a 1mg (injection volume: flumazenil weight).
5. a method for preparing the flumazenil lipidosome injection is characterized in that comprising the steps:
(1) cholesterol, PHOSPHATIDYL ETHANOLAMINE, soyasterol and Tween 80 are dissolved in the buffer salt solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 15 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add flumazenil, constantly stir adding trehalose and PVP down;
(4) 0.45um filtering with microporous membrane, quick freezing returns to room temperature then, and fill promptly gets the flumazenil lipidosome injection.
6. method according to claim 5 is characterized in that, described buffer salt solution is to be selected from a kind of in phosphate buffered solution, citrate buffer solution, carbonate buffer solution, the borate buffer solution.
7. method according to claim 6 is characterized in that, described buffer salt solution is that pH is 7.2 phosphate buffered solution.
8. the preparation method of flumazenil lipidosome injection according to claim 5, the temperature that it is characterized in that the molten condition liposome described in the step (3) is 60 ℃.
9. the preparation method of flumazenil lipidosome injection according to claim 5 is characterized in that the temperature of the quick freezing described in the step (4) is-80 ℃.
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| CN 201110196556 Expired - Fee Related CN102247324B (en) | 2011-07-14 | 2011-07-14 | Flumazenil liposome injection |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102429879A (en) * | 2011-11-29 | 2012-05-02 | 海南灵康制药有限公司 | Ambroxol hydrochloride liposome injection |
| CN104840465A (en) * | 2015-04-27 | 2015-08-19 | 海口通用康力制药有限公司 | Flumazenil injection and preparation method thereof |
| CN104958255A (en) * | 2015-07-15 | 2015-10-07 | 海南通用康力制药有限公司 | Flumazenil injection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101322688A (en) * | 2008-07-30 | 2008-12-17 | 海南本创医药科技有限公司 | Flumazenil oil-in-water emulsion for vein and preparation thereof |
| WO2009068668A1 (en) * | 2007-11-30 | 2009-06-04 | Pharnext | New therapeutic approaches for treating cmt and related disorders |
-
2011
- 2011-07-14 CN CN 201110196556 patent/CN102247324B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009068668A1 (en) * | 2007-11-30 | 2009-06-04 | Pharnext | New therapeutic approaches for treating cmt and related disorders |
| CN101322688A (en) * | 2008-07-30 | 2008-12-17 | 海南本创医药科技有限公司 | Flumazenil oil-in-water emulsion for vein and preparation thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102429879A (en) * | 2011-11-29 | 2012-05-02 | 海南灵康制药有限公司 | Ambroxol hydrochloride liposome injection |
| CN102429879B (en) * | 2011-11-29 | 2013-05-29 | 海南灵康制药有限公司 | Ambroxol hydrochloride liposome injection |
| CN104840465A (en) * | 2015-04-27 | 2015-08-19 | 海口通用康力制药有限公司 | Flumazenil injection and preparation method thereof |
| CN104958255A (en) * | 2015-07-15 | 2015-10-07 | 海南通用康力制药有限公司 | Flumazenil injection and preparation method thereof |
| CN104958255B (en) * | 2015-07-15 | 2017-09-22 | 海南通用康力制药有限公司 | A kind of Flumazenil parenteral solution and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102247324B (en) | 2012-11-21 |
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