CN102429879A - Ambroxol hydrochloride liposome injection - Google Patents
Ambroxol hydrochloride liposome injection Download PDFInfo
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- CN102429879A CN102429879A CN2011103886379A CN201110388637A CN102429879A CN 102429879 A CN102429879 A CN 102429879A CN 2011103886379 A CN2011103886379 A CN 2011103886379A CN 201110388637 A CN201110388637 A CN 201110388637A CN 102429879 A CN102429879 A CN 102429879A
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Abstract
The invention discloses an ambroxol hydrochloride liposome injection and a preparation method thereof. The liposome injection is prepared from ambroxol hydrochloride, cholesterol, soybean phosphatidylserine, sojasterol, Tween 80, trehalose and PVP (Polyvinylpyrolidone) in a specific weight ratio. The liposome injection has high preparation stability, and a liposome does not crack due to fusion, ice crystals and the like and keeps high entrapment rate simultaneously after being stored for a long time; the solubility of the ambroxol hydrochloride is increased, the quality of a preparation product is enhanced, the toxic and side effects are reduced, the retention time of a medicament in systemic circulation is increased, the bioavailability of the medicament is enhanced, and the curative effect is enhanced remarkably; and moreover, a preparation method is simple, and is suitable for industrial mass production.
Description
Technical field
The present invention relates to a kind of ambroxol hydrochloride injection, be specifically related to a kind of ambroxol hydrochloride lipidosome injection and method for making thereof, belong to technical field of medicine.
Background technology
Ambroxol hydrochloride, its chemical name are trans-4-[(the amino 3.5-dibromo-benzyl of 2-) amino] cyclohexanol hydrochloridumi, molecular formula: C
13H
18Br
2N
2OHCl, molecular weight: 414.57, its structural formula is following:
Ambroxol hydrochloride has the characteristic that promotes mucus to get rid of and dissolve secretions, can promote the eliminating of the inner thick secretions of respiratory tract and reduce mucous delay, thereby significantly promote expectoration, improves breath state.When using the ambroxol hydrochloride treatment, the mucous secretion of patient can return to normal condition, and cough and amount of expectoration significantly reduce usually, the surfactant on the respiratory mucosa thereby can bring into play its normal defencive function.
Ambroxol hydrochloride is slightly soluble in water, and this medicine mouthfeel is acute bitter, numb, and this bitterness and picotement are lasting, and it can not be sheltered through adding sweetener and correctives routinely, causes patient's drug compliance poor, especially is unfavorable for child's administration.So the ambroxol hydrochloride preparation formulation is main with capsule, tablet and oral liquid at present; These dosage forms are taken inconvenience concerning the child, be satisfied with, meet taking of drug standard and granule easy to carry, that be easy to absorb, be fit to children taking but can't process other people at present.
A main difficult problem for preparing the granule existence with ambroxol hydrochloride is to be difficult to filter out effective correctives to cover its extremely strong bitterness; Though it is more to can be used for preparing the correctives of granule at present; But when rectifying flavor through the consumption that significantly improves correctives (the usually sucrose consumption will can be covered its bitterness for 700 times of ambroxol hydrochloride) such as sucrose; Again can be too high and make granule be easy to the moisture absorption, caking, drug effect to reduce because of containing sugar; And make it very easily rotten, can not preserve, lose actual application value.
Patent documentation CN1954808A high dose Ambroxol hydrochloride freeze-dried preparation and preparation method thereof.Ambroxol hydrochloride is except that as the expectorant; When heavy dose is used, also having the pulmonary surfactant of increasing generates; Suppress the effect that superoxides and peroxide generate; Be widely used in hyaline membrane disease of newborn and adult respiratory distress syndrome clinically, and the treatment of acute lung injury.In order to adapt to clinical needs, the one of the main divisions of the male role in traditional opera produces the ambroxol hydrochloride injection of high dose specification.Because the aqueous solution of ambroxol hydrochloride is stable inadequately, particularly meets light and be prone to degraded, on the other hand; The dissolubility of ambroxol hydrochloride in water is big inadequately; At room temperature, 1 ml water only can dissolve about 15 milligrams ambroxol hydrochloride, therefore; Prepare the ambroxol hydrochloride injection of high dose specification by conventional method, particularly stable high lyophilized formulations is difficulty very
The liposome of a patent ZL200910017862.4 loratadine-ambroxol pharmaceutical composite is characterized in that comprising the component of weight portion meter: 1 part of loratadine, 5 parts of ambroxol hydrochlorides, Ovum Gallus domesticus Flavus lecithin 3-30 part, cholesterol 1-14 part, NaTDC 1.2-10 part and poloxamer 188 3-18 parts.
Patent documentation CN1628645A has disclosed the method for preparing of Orally disintegrating tablet of ambroxol hydrochloride.Oral cavity disintegration tablet is that the oral cavity does not need water or only have under the low amounts of water existence to place on the tongue, after rapid dissolving of chance saliva or the disintegrate, borrows swallowing act to go into the stomach onset.Through the Orally disintegrating tablet of ambroxol hydrochloride disintegrate fast of adding conventional correctives and effervescent; Also can instantaneously cover the bitterness and the picotement of oral administration; But fully after the disintegrate; Still can leave over down bitterness, the picotement of ambroxol hydrochloride in the oral cavity, that is to say that this conventional method for preparing can not cover the bad mouthfeel of ambroxol hydrochloride fully.
Patent documentation CN1628647A has disclosed a kind of ambroxol hydrochloride granula; This invention is covered the extremely strong bitterness of medicine through adding correctives (like sucrose, stevioside, Fen Meiyi) and essence; But this medicine is slightly soluble in water; Cause fraction to be dissolved in the medicine in the water, still have stronger bitterness and picotement.
Patent documentation CN101416956A discloses a kind of confession vein and has used the ambroxol hydrochloride injection, it by active ingredient hydrochloric acid ambroxol and pharmaceutically acceptable carrier like the stable type pharmaceutical composition that water-soluble filler, PH regulator, stabilizing agent, water for injection, osmotic pressure regulator etc. are formed.Patent documentation CN101647777A discloses ambroxol hydrochloride injection with small volume and method for making thereof.Patent documentation CN101224196A discloses ambroxol hydrochloride freeze-dried powder injection and method for making thereof.
Though above preparation prescription is through meticulous screening, its product is not still escaped, and common method for making prepares injection, physics and chemical property poor stability; The long-term storage drug quality can descend but also can generate some impurity, brings stupid points such as toxic and side effects, can bring hidden danger for clinical 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 property 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) dissolubility of increase medicine improves the quality of the pharmaceutical preparations;
(3) have targeting property: 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 property;
(4) has protective effect to active pharmaceutical ingredient.
(5) reduced drug toxicity;
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, and every layer all is equal bilayers 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 unilamelar 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 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 that principal agent is activated the autoimmune function of body in the human body by reticuloendothelial system phagocytic, and change and distributed in the body of entrapped drug, drug main will 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.
In recent years; Continuous progress along with biotechnology; Liposome preparation technology is progressively perfect, and the liposome mechanism of action is further illustrated, and 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.The present invention has overcome the deficiency of common ambroxol hydrochloride injection, proposes the ambroxol hydrochloride lipidosome injection.
Summary of the invention
In order to form colory ambroxol hydrochloride lipidosome injection, can good compatible with ambroxol hydrochloride 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 that ambroxol hydrochloride, cholesterol, soy phosphatidylserine, soyasterol, Tween 80, trehalose and the PVP of specified weight proportioning can process the ambroxol hydrochloride lipidosome injection; Wherein, Envelop rate as the ambroxol hydrochloride of active constituents of medicine is high, and the liposome particle diameter is little and be evenly distributed, and compares with ambroxol hydrochloride 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 of medicine is high, and bioavailability obviously improves, and curative effect obviously improves.
The purpose of this invention is to provide a kind of ambroxol hydrochloride lipidosome injection, it is mainly processed by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the soy phosphatidylserine are 1: 1-1: 2.
As one of specific embodiment of the present invention, ambroxol hydrochloride lipidosome injection of the present invention, mainly process by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the soy phosphatidylserine are 1: 1.
As the phospholipid that is used to form liposome, can use natural phospholipid and synthetic phospholipid.Natural phospholipid comprises soy phosphatidylserine, 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, PHOSPHATIDYL ETHANOLAMINE and soybean phospholipid acyl inositol etc.Synthetic phospholipid is cholesterol, 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 ambroxol hydrochloride of active constituents of medicine, its poorly water-soluble is fat-soluble good.To the characteristics of ambroxol hydrochloride, the inventor is particularly suitable for as basic phospholipid filmogen through discovering soy phosphatidylserine.
(phosphatidyl ethanolamine, PE) as a kind of natural phospholipid, its content is very high, obtains easily, and is cheap for soy phosphatidylserine.The phase transition temperature of soy phosphatidylserine 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 soy phosphatidylserine is more than 98%, and is preferred more than 99%.
In ambroxol hydrochloride lipidosome injection of the present invention, for the ambroxol hydrochloride of 1 weight portion, the consumption of soy phosphatidylserine is the 5-7 weight portion.If the consumption of soy phosphatidylserine is lower than 5 weight portions, then can't form stabilized liposomes; Otherwise if the consumption of the consumption of soy phosphatidylserine is higher than 7 weight portions, then the envelop rate as the ambroxol hydrochloride of active constituents of medicine descends, and the quality of injection and curative effect reduce.
In ambroxol hydrochloride 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 soy phosphatidylserine, stops it to be condensed into crystal structure.Cholesterol mixes the soy phosphatidylserine 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 said soyasterol glucoside is the mixture from the sterol glucoside of through the Semen sojae atricolor residue that refines Oleum Glycines, separating.As a kind of natural product, the soyasterol source is abundant, low price.
With cholesterol seemingly, soyasterol also can be regulated the stability of soy phosphatidylserine film, and its regulating action effect to stability is superior to cholesterol.
The inventor is through discovering, when the weight sum of cholesterol and soyasterol and soy phosphatidylserine weight ratio are 1: 1, can form stable ambroxol hydrochloride liposome.When the weight sum of cholesterol and soyasterol and soy phosphatidylserine weight ratio were higher than 1: 1, membrane stability reduced, and ambroxol hydrochloride is easy to seepage; When the weight sum of cholesterol and soyasterol and soy phosphatidylserine weight ratio were lower than 1: 1, ambroxol hydrochloride liposome membrane flowability was too high, is wrapped in the intravital ambroxol hydrochloride of lipid and is easy to discharge.In addition, discover that when the weight sum of cholesterol and soyasterol and soy phosphatidylserine weight ratio were 1: 1, formed liposome toxicity was minimum.
Research shows that the stability of liposome and bioavailability have close corresponding relation.Stability is high more, and bioavailability is high more.Therefore, the stability of ambroxol hydrochloride 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 ambroxol hydrochloride lipidosome injection of the present invention; For the ambroxol hydrochloride of 1 weight portion; The consumption of soy phosphatidylserine is the 5-7 weight portion, and cholesterol is the 3-4 weight portion, and soyasterol is the 2-3 weight portion; And the weight sum of cholesterol and soyasterol and soy phosphatidylserine weight ratio are 1: 1 o'clock, and the envelop rate of formed ambroxol hydrochloride lipidosome injection is high.
In ambroxol hydrochloride 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 soy phosphatidylserine 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 ambroxol hydrochloride lipidosome injection.
In ambroxol hydrochloride lipidosome injection of the present invention, for the ambroxol hydrochloride of 1 weight portion, the consumption of Tween 80 is the 1-2 weight portion.If the consumption of Tween 80 is lower than 1 weight portion; Then cause the stability improvement of ambroxol hydrochloride lipidosome injection not enough owing to its consumption is low excessively; Otherwise if the consumption of Tween 80 is higher than 2 weight portions, it is too high and cause liposome membrane to be easy to reveal then to be used for its consumption.
Discover; When the ambroxol hydrochloride that uses above-mentioned specified quantitative, soy phosphatidylserine, cholesterol, soyasterol and Tween 80, can obtain colory ambroxol hydrochloride liposome, its envelop rate and stability are all very high; Toxicity is low, and bioavailability is high.
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 under the situation of dehydration, also keep complete form.
In ambroxol hydrochloride 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.
PVP is a macromolecular compound, and fusing point is high, and the 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.
In ambroxol hydrochloride lipidosome injection of the present invention, use trehalose and PVP as excipient, be used to form stable injection, this is another key point of the present invention.
Ambroxol hydrochloride lipidosome injection of the present invention, the specification of its ambroxol hydrochloride can be 2ml:15mg and 4ml:30mg (injection volume: ambroxol hydrochloride weight).
One of the object of the invention provides a kind of method for preparing of ambroxol hydrochloride lipidosome injection, specifically comprises being prepared as follows step:
(1) cholesterol, soy phosphatidylserine, soyasterol and Tween 80 are dissolved in the buffer salt solution, process blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride, constantly stir adding trehalose and PVP down;
(4) 0.45 μ m filtering with microporous membranes, quick freezing returns to room temperature then, and fill promptly gets the ambroxol hydrochloride lipidosome injection.
Wherein, step (4) comprising:
(a) quick freezing returns to room temperature then, and fill promptly gets the ambroxol hydrochloride lipidosome injection.
(b) packing, directly lyophilization obtains the ambroxol hydrochloride injection lyophilized injectable powder.
Above-mentioned described method for preparing, wherein said buffer salt solution are selected from a kind of in PBS, citrate buffer solution, carbonate buffer solution, the borate buffer solution, are preferably pH and are 7.2 PBS.
Above-mentioned described method for preparing, wherein the temperature of the molten condition liposome described in the step (3) is 60 ℃.
Above-mentioned described method for preparing, wherein the temperature of the quick freezing described in the step (4) is-50 ℃.
The challenge of preparation liposome is the high vesicle of envelop rate that how to make liposome membrane form well-balanced, suitable big or small appropriate configuration material.And the plastid that these materials form does not spill.
The inventor has obtained colory ambroxol hydrochloride lipidosome injection through selecting suitable material composition, adopting suitable preparation technology, and the liposome particle diameter is little, and particle size distribution is even, and envelop rate is high, and stability 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.Ambroxol hydrochloride 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.
Description of drawings
Below, specify embodiment of the present invention in conjunction with accompanying drawing, wherein:
Fig. 1 is the blood drug level-time graph of ambroxol hydrochloride lipidosome injection.
The specific embodiment
Below through the specific embodiment the present invention is further specified, what characteristics of the present invention and advantage will be along with these explanation statements is more clear.
Embodiment 1The preparation of ambroxol hydrochloride lipidosome injection
Prescription: (1000 bottles)
The preparation process:
(1) cholesterol 50g, soy phosphatidylserine 80g, soyasterol 30g and 20g Tween 80 being dissolved in 2000mlpH is in 7.2 the PBS, processes blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride 15g, constantly stir adding 20g trehalose and 30gPVP down;
(4) 0.45 μ m filtering with microporous membranes, quick freezing returns to room temperature then, and fill (2ml/ bottle) promptly gets the ambroxol hydrochloride lipidosome injection.
Embodiment 2The preparation of ambroxol hydrochloride lipidosome injection
Prescription: (1000 bottles)
The preparation process:
(1) cholesterol 100g, soy phosphatidylserine 160g, soyasterol 60g and 40g Tween 80 being dissolved in 4000mlpH is in 7.2 the PBS, processes blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride 30g, constantly stir adding 40g trehalose and 60gPVP down;
(4) 0.45 μ m filtering with microporous membranes, quick freezing returns to room temperature then, and fill (4ml/ bottle) promptly gets the ambroxol hydrochloride lipidosome injection.
Embodiment 3The preparation of ambroxol hydrochloride lipidosome injection
Prescription: (1000 bottles)
The preparation process
(1) cholesterol 50g, soy phosphatidylserine 80g, soyasterol 30g and 20g Tween 80 being dissolved in 2000mlpH is in 7.2 the PBS, processes blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride 15g, constantly stir adding 20g trehalose and 30gPVP down;
(4) 0.45 μ m filtering with microporous membranes, fill (2ml/ bottle), directly lyophilization obtains the ambroxol hydrochloride injection lyophilized injectable powder.
Comparative Examples 1-3The preparation of ambroxol hydrochloride lipidosome injection
Adopt with embodiment 1 in identical production technology, the supplementary material composition in will the Comparative Examples 1-3 shown in following table 1 is processed the ambroxol hydrochloride lipidosome injection respectively.Wherein, the excipient composition of Comparative Examples 1 is from the embodiment 1 of CN101627998B, and the excipient composition of Comparative Examples 2 is from the embodiment 1 of CN101601656B, and the excipient composition of Comparative Examples 3 is from the embodiment 1 of CN101601654B,
Raw materials used composition among the table 1 Comparative Examples 1-3
Wherein, "/" expression is not used.
Test Example 1The mensuration of liposome particle diameter
Under the room temperature condition, get the ambroxol hydrochloride 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 result is shown in the following table 2.
Table 2 liposome particle diameter testing result
Can know that from table 2 the solid lipid nanoparticle particle diameter that embodiment 1-3 makes is even, show 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 ambroxol hydrochloride liposome and mean diameter thereof obviously are superior to the ambroxol hydrochloride 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 ambroxol hydrochloride liposome was inferior to the present invention, and mean diameter goes out greatly a lot.
Test Example 2The mensuration of envelop rate
With the rotating speed high speed centrifugation of the ambroxol hydrochloride lipidosome injection for preparing among embodiment 1-3 and the Comparative Examples 1-3, centrifugal 20 minutes, get supernatant with 5000r/min; Use dissolve with methanol; The HPLC method is surveyed ambroxol hydrochloride content, and computational envelope rate, result are shown in the following table 3.
Table 3 entrapment efficiency determination result
Can know that by table 3 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 3Study on the stability
Sample and listing ambroxol hydrochloride injection (lot number: 20101210 with the embodiment of the invention and Comparative Examples 1-3 preparation; Tianjin Medicine Research Academy Pharmaceutical Co., Ltd) 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
Can be known that by table 4 when quickening June, the formulation content of listing and Comparative Examples reduces, related substance raises; And sample character of the present invention, content and related substance variation are all not obvious, explain that product stability of the present invention is good.
Test Example 4The percolation ratio test
Get the sample of Test Example 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 result is shown in the following table 5.
Table 5 percolation ratio result of the test
Can know by table 5; During long term storage; The ambroxol hydrochloride 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, and the liposome seepage is serious, and the ambroxol hydrochloride lipidosome injection of this explanation the present invention preparation has higher stability.
Test Example 5The mensuration of 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 (lot number: 20101210, Tianjin Medicine Research Academy Pharmaceutical Co., Ltd), specification is a 2ml:15mg ambroxol hydrochloride injection.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 ambroxol hydrochloride lipidosome injection for preparing among the ambroxol hydrochloride 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 ambroxol hydrochloride injection are shown in the accompanying drawing 1.
Can know by Fig. 1; Compare with commercially available ambroxol hydrochloride lipidosome injection with the ambroxol hydrochloride lipidosome injection for preparing among the Comparative Examples 1-3; The ambroxol hydrochloride lipidosome injection for preparing among the embodiment of the invention 1-3 has the following advantages: elimination speed in vivo is slow; Distribution time prolongs in the body circulation, has reached slow release effect, and bioavailability has improved.
Industrial applicibility
Result by the foregoing description and experimental example can know that ambroxol hydrochloride liposome of the present invention has good surface appearance, and granule is little, and particle diameter is even; Envelop rate is high, and stability is high, and percolation ratio is low; The time of staying in vivo is long, and 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, because of these all fall 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 (9)
1. ambroxol hydrochloride lipidosome injection is characterized in that mainly being processed by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the soy phosphatidylserine are 1: 1-1: 2.
2. ambroxol hydrochloride lipidosome injection according to claim 1, process by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the soy phosphatidylserine are 1: 1.
3. according to each described ambroxol hydrochloride lipidosome injection among the claim 1-2, wherein the specification of ambroxol hydrochloride injection is that (the injection volume: ambroxol hydrochloride weight), the lyophilized powder injection specification is 15mg and 30mg for 2ml:15mg or 4ml:30mg.
4. a method for preparing the ambroxol hydrochloride lipidosome injection is characterized in that comprising the steps:
(1) cholesterol, soy phosphatidylserine, soyasterol and Tween 80 are dissolved in the buffer salt solution, process blank liposome;
(2) blank liposome of above-mentioned preparation is handled through flowing steam sterilization, supersound process twice then, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride, constantly stir adding trehalose and PVP down;
(4) 0.45 μ m filtering with microporous membranes, quick freezing returns to room temperature then, and fill promptly gets the ambroxol hydrochloride lipidosome injection;
Wherein, step (4) comprising:
(a) quick freezing returns to room temperature then, and fill promptly gets the ambroxol hydrochloride lipidosome injection.
(b) packing, directly lyophilization obtains the ambroxol hydrochloride injection lyophilized injectable powder.
5. method according to claim 4 is characterized in that described buffer salt solution is to be selected from a kind of in PBS, citrate buffer solution, carbonate buffer solution, the borate buffer solution.
6. method according to claim 5 is characterized in that described buffer salt solution is that pH is 7.2 PBS.
7. the method for preparing of ambroxol hydrochloride lipidosome injection according to claim 4, the temperature that it is characterized in that the molten condition liposome described in the step (3) is 60 ℃.
8. the method for preparing of ambroxol hydrochloride lipidosome injection according to claim 4 is characterized in that the temperature of the quick freezing described in the step (4) is-50 ℃.
9. the described ambroxol hydrochloride lipidosome injection of claim 1 is in the purposes of preparation in the expelling phlegm drugs.
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| CN109134279A (en) * | 2017-08-15 | 2019-01-04 | 陶灵刚 | 1/10 water ambroxol compound of one kind and its pharmaceutical composition |
| CN114652677A (en) * | 2021-12-27 | 2022-06-24 | 海南全星制药有限公司 | Ambroxol hydrochloride injection and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105496992A (en) * | 2015-12-08 | 2016-04-20 | 青岛正大海尔制药有限公司 | Ambroxol salbutamol lipid solid dispersion |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134279A (en) * | 2017-08-15 | 2019-01-04 | 陶灵刚 | 1/10 water ambroxol compound of one kind and its pharmaceutical composition |
| CN114652677A (en) * | 2021-12-27 | 2022-06-24 | 海南全星制药有限公司 | Ambroxol hydrochloride injection and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102429879B (en) | 2013-05-29 |
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