CN102429879B - Ambroxol hydrochloride liposome injection - Google Patents
Ambroxol hydrochloride liposome injection Download PDFInfo
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- CN102429879B CN102429879B CN 201110388637 CN201110388637A CN102429879B CN 102429879 B CN102429879 B CN 102429879B CN 201110388637 CN201110388637 CN 201110388637 CN 201110388637 A CN201110388637 A CN 201110388637A CN 102429879 B CN102429879 B CN 102429879B
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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 liposome injection and method for making thereof, belong to technical field of medicine.
Background technology
Ambroxol hydrochloride, its chemical name are the amino 3.5-dibromo-benzyl of trans-4-[(2-) amino] cyclohexanol hydrochloridumi, molecular formula: C
13H
18Br
2N
2OHCl, molecular weight: 414.57, its structural formula is as follows:
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 the delay of minimizing mucus, thereby significantly promote expectoration, improves breath state.When using ambroxol hydrochloride therapy, the secretion of patient's mucus 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 by adding routinely sweetener and correctives, causes patient's drug compliance poor, especially is unfavorable for child's administration.So the ambroxol hydrochloride preparation formulation is take capsule, tablet and oral liquid as main 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 make at present other people.
The main bugbear for preparing the granule existence with ambroxol hydrochloride is to be difficult to filter out effective correctives to cover its extremely strong bitterness, although it is more to can be used at present preparing the correctives of granule, but when coming taste masking by the consumption that significantly improves the correctivess (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 as the expectorant, also having the pulmonary surfactant of increasing when heavy dose is used generates, suppress the effect that superoxides and peroxide generate, be widely used in clinically hyaline membrane disease of newborn and adult respiratory distress syndrome, 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 in Auxiliary of high dose specification.Because the aqueous solution of ambroxol hydrochloride is stable not, particularly meeting light easily degrades, on the other hand, the dissolubility of ambroxol hydrochloride in water is large not, at room temperature, 1 ml water only can dissolve about 15 milligrams ambroxol hydrochloride, therefore, the Ambroxol Hydrochloride in Auxiliary for preparing according to a conventional method the high dose specification, particularly stable high lyophilized formulations is very difficult
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 PLURONICS F87 3-18 part.
Patent documentation CN1628645A has disclosed the preparation method of Orally disintegrating tablet of ambroxol hydrochloride.Oral cavity disintegration tablet is that the oral cavity does not need water or only have under a small amount of water existence to place on the tongue, after the rapid dissolving of chance saliva or the disintegrate, borrows swallowing act to enter the stomach onset.By the fast disintegrate of Orally disintegrating tablet of ambroxol hydrochloride of adding conventional correctives and effervescent, also can instantaneously cover bitterness and the picotement of oral administration, but fully after the disintegrate, still can leave over bitterness, the picotement of lower ambroxol hydrochloride in the oral cavity, that is to say that this conventional preparation method 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 by adding correctives (such as sucrose, stevioside, Fen Meiyi) and essence, but this medicine is slightly soluble in water, cause fraction to be dissolved in medicine in the water, still have stronger bitterness and picotement.
Patent documentation CN101416956A discloses a kind of for the vein ambroxol hydrochloride injection, it by active ingredient hydrochloric acid ambroxol and pharmaceutically acceptable carrier such as the stable type pharmaceutical composition that water-soluble filler, PH regulator, stabilizing agent, water for injection, osmotic pressure regulator etc. form.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.
Although above preparation prescription is through meticulous screening, its product is not still escaped, and common method for making prepares injection, and the physics and chemistry stable in properties is poor; The long-term storage drug quality can descend but also can generate some impurity, brings the stupid points such as toxic and side effects, can bring hidden danger for clinical use.
In the pharmaceutical carrier induction system, the research of the 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 medicine in the abundance of target organ, thereby improve curative effect, alleviate toxic and side effects.
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, improves mass effect;
(2) dissolubility of increase medicine improves the quality of the pharmaceutical preparations;
(3) 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;
(4) has protective effect to active pharmaceutical ingredient.
(5) reduced drug toxicity;
Liposome (Liposome) is dispersed in water phospholipid by British scholar Bangham and Standlish at first and finds when carrying out electron microscopic observation.Phospholipid is dispersed in water the self-assembling formation multilamellar vesicle, 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 again small unilamellar vesicle and large unilamellar vesicle.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.
The people such as Britain Lai Men in 1971 begin liposome is used for pharmaceutical carrier, Main Function mechanism is drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane seals 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 therapeutic dose and the reduction medicine of medicine.
In recent years, continuous progress along with biotechnology, liposome preparation technology gradual perfection, 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 the advantage such as drug dose.The present invention has overcome the deficiency of common ambroxol hydrochloride injection, proposes Ambroxol hydrochloride liposome injection.
Summary of the invention
In order to form colory Ambroxol hydrochloride liposome 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, large quantity research and realization that the inventor carries out, find the ambroxol hydrochloride of specified weight proportioning, cholesterol, soy phosphatidylserine, soyasterol, Tween 80, trehalose and PVP can make Ambroxol hydrochloride liposome injection, wherein, envelop rate as the ambroxol hydrochloride of active constituents of medicine is high, the liposome particle diameter is little and be evenly distributed, compare 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, bioavailability obviously improves, and curative effect obviously improves.
The purpose of this invention is to provide a kind of Ambroxol hydrochloride liposome injection, it is mainly made by the composition of following weight proportion:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the soy phosphatidylserine are 1: 1-1: 2.
As one of the specific embodiment of the present invention, Ambroxol hydrochloride liposome injection of the present invention, mainly made by the composition of following weight proportion:
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, PI, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, PHOSPHATIDYL ETHANOLAMINE and soybean phospholipid acyl inositol etc.Synthetic phospholipid is cholesterol, DOPC, DSPC, dipalmitoyl phosphatidyl choline, DMPC, DLPC, DOPG, DSPG, DPPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, PE etc.
In the present invention, as the ambroxol hydrochloride of active constituents of medicine, its poorly water-soluble is fat-soluble good.For the characteristics of ambroxol hydrochloride, the inventor finds that by research soy phosphatidylserine is particularly suitable for as basic phospholipid filmogen.
Soy phosphatidylserine (phosphatidyl ethanolamine, PE) is as a kind of natural phospholipid, and its content is very high, obtains easily, and is cheap.The phase transition temperature of soy phosphatidylserine is higher, is easy to form stable liposome membrane.
When using other phospholipid, be difficult to form colory liposome, the 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 liposome 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 stable liposome; 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 liposome injection of the present invention, cholesterol and soyasterol and Tween 80 are used for regulating 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 the liposome bi-layer membrane solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
Soyasterol (soybean sterol, SS) is the hydrolyzate that the soyasterol glucoside removes glucose residue, and described soyasterol glucoside is the mixture from the sterol glucoside of separating through the Soybeanresidue 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 soy phosphatidylserine film, and its regulating action effect to stability is better than cholesterol.
The inventor finds through research, 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, and the ambroxol hydrochloride that is wrapped in the liposome is easy to discharge.In addition, research finds, when the weight sum of cholesterol and soyasterol and soy phosphatidylserine weight ratio were 1: 1, formed liposome toxicity was minimum.
Studies show that the stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of Ambroxol hydrochloride liposome injection of the present invention is high, is to cause one of high factor of drug bioavailability.
On the other hand, the inventor studies discovery, in Ambroxol hydrochloride liposome 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 liposome injection is high.
In Ambroxol hydrochloride liposome injection of the present invention, further improve the stability of liposome membrane with Tween 80.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 liposome injection.
In Ambroxol hydrochloride liposome 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 liposome injection inadequate owing to its consumption is excessively low, 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.
Research is found, 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 consists of; self property is highly stable, and its most obvious character is that the biomembranous ability of protection is arranged under anhydrous condition, even make liposome also keep complete form in the situation of dehydration.
In Ambroxol hydrochloride liposome injection of the present invention, trehalose can effectively be protected form and the stability of liposome particles, further improves the stability of lipidosome injection.
PVP is macromolecular compound, fusing point is high, 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 moisture film in the middle of the liposome and make water soluble drug have higher envelop rate, and can make medicine stable in storage.
In Ambroxol hydrochloride liposome 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 liposome 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 purpose of the present invention provides a kind of preparation method of Ambroxol hydrochloride liposome injection, specifically comprises being prepared as follows step:
(1) cholesterol, soy phosphatidylserine, soyasterol and Tween 80 are dissolved in the buffer salt solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride, constantly stir lower add trehalose and PVP;
(4) 0.45 μ m filtering with microporous membranes, then quick freezing returns to room temperature, and fill namely gets Ambroxol hydrochloride liposome injection.
Wherein, step (4) comprising:
(a) then quick freezing returns to room temperature, and fill namely gets Ambroxol hydrochloride liposome injection.
(b) packing, directly lyophilization obtains the ambroxol hydrochloride injection lyophilized injectable powder.
Preparation method described above, 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.
Preparation method described above, wherein the temperature of the molten condition liposome described in the step (3) is 60 ℃.
Preparation method described above, 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 liposome injection by 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.
Research finds, the size of liposome is affect that liposome distributes in vivo and the principal element of the time of staying, and the particle diameter of liposome is less, and the interior time of staying of body is longer.Ambroxol hydrochloride 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.
Description of drawings
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is the blood drug level-time graph of Ambroxol hydrochloride liposome injection.
The specific embodiment
Below by 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 liposome injection
Prescription: (1000 bottles)
Preparation process:
(1) cholesterol 50g, soy phosphatidylserine 80g, soyasterol 30g and 20g Tween 80 are dissolved in 2000mlpH and in 7.2 the phosphate buffered solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride 15g, constantly stir lower add 20g trehalose and 30gPVP;
(4) 0.45 μ m filtering with microporous membranes, then quick freezing returns to room temperature, and fill (2ml/ bottle) namely gets Ambroxol hydrochloride liposome injection.
Embodiment 2The preparation of Ambroxol hydrochloride liposome injection
Prescription: (1000 bottles)
Preparation process:
(1) cholesterol 100g, soy phosphatidylserine 160g, soyasterol 60g and 40g Tween 80 are dissolved in 4000mlpH and in 7.2 the phosphate buffered solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride 30g, constantly stir lower add 40g trehalose and 60gPVP;
(4) 0.45 μ m filtering with microporous membranes, then quick freezing returns to room temperature, and fill (4ml/ bottle) namely gets Ambroxol hydrochloride liposome injection.
Embodiment 3The preparation of Ambroxol hydrochloride liposome injection
Prescription: (1000 bottles)
Preparation process
(1) cholesterol 50g, soy phosphatidylserine 80g, soyasterol 30g and 20g Tween 80 are dissolved in 2000mlpH and in 7.2 the phosphate buffered solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride 15g, constantly stir lower add 20g trehalose and 30gPVP;
(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 liposome injection
Adopt with embodiment 1 in identical production technology, the supplementary material composition in will the Comparative Examples 1-3 as shown in following table 1 is made respectively Ambroxol hydrochloride liposome injection.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 liposome 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, and is aobvious 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 better than 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 Ambroxol hydrochloride liposome 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 ambroxol hydrochloride 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 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 respectively lower 6 months of the condition of 40 ℃ of high temperature, relative humidity 75%, 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 accelerating June, the formulation content of listing and Comparative Examples reduces, and related substance raises; And sample property of the present invention, content and related substance variation are all not obvious, illustrate 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, respectively at 0 day, 30 days, 60 days, 90 days and 180 days, make regular check on, measure envelop rate, 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 Ambroxol hydrochloride liposome 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 Ambroxol hydrochloride liposome 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 the 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 liposome injection and the blood drug level of commercially available ambroxol hydrochloride injection and the relation curve of time that prepare among the Ambroxol hydrochloride liposome injection for preparing among the drafting embodiment 1-3, the Comparative Examples 1-3 are shown in the accompanying drawing 1.
As shown in Figure 1, compare with commercially available Ambroxol hydrochloride liposome injection with the Ambroxol hydrochloride liposome injection for preparing among the Comparative Examples 1-3, the Ambroxol hydrochloride liposome injection for preparing among the embodiment of the invention 1-3 has the following advantages: release rate in vivo is slow, distribution time prolongs in the body circulation, reached slow release effect, bioavailability has improved.
Industrial applicibility
By the result of above-described embodiment and experimental example as can be known, ambroxol hydrochloride liposome of the present invention has good outward 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 good industrial application value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; but should understand; these explanations do not consist of 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, because these all fall within the scope of protection of the present invention.
Each list of references of mentioning among the application or quoting, which is hereby incorporated by reference.
Claims (3)
1. Ambroxol hydrochloride liposome injection is characterized in that being made by the composition of following weight proportion:
Wherein, described PVP is polyvinylpyrrolidone.
2. Ambroxol hydrochloride liposome injection according to claim 1, wherein the specification of ambroxol hydrochloride injection is 2ml injection volume: 15mg ambroxol hydrochloride weight or 4ml injection volume: 30mg ambroxol hydrochloride weight, lyophilized powder injection specification are 15mg and 30mg.
3. a method for preparing each described Ambroxol hydrochloride liposome injection of claim 1-2 is characterized in that comprising the steps:
(1) cholesterol, soy phosphatidylserine, soyasterol and Tween 80 are dissolved in the buffer salt solution, make blank liposome; Described buffer salt solution is that pH is 7.2 phosphate buffered solution;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 20 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add ambroxol hydrochloride, constantly stir lower add trehalose and PVP; The temperature of described molten condition liposome is 60 ℃;
(4) 0.45 μ m filtering with microporous membranes, then quick freezing returns to room temperature, and fill namely gets Ambroxol hydrochloride liposome injection; The temperature of described quick freezing is-50 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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| CN109134279A (en) * | 2017-08-15 | 2019-01-04 | 陶灵刚 | 1/10 water ambroxol compound of one kind and its pharmaceutical composition |
| CN114652677B (en) * | 2021-12-27 | 2023-05-05 | 海南全星制药有限公司 | Ambroxol hydrochloride injection and preparation method thereof |
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| CN1954808A (en) * | 2005-10-27 | 2007-05-02 | 常州市第四制药厂有限公司 | High dose Ambroxol hydrochloride freeze-dried preparation and preparation method |
| CN101366699A (en) * | 2007-08-17 | 2009-02-18 | 香港浸会大学 | Novel formulation of dehydrated lipid vesicles for controlled release of active pharmaceutical ingredient via inhalation |
| CN101416956A (en) * | 2007-10-22 | 2009-04-29 | 天津康鸿医药科技发展有限公司 | Ambroxol hydrochloride injection |
| CN101601656A (en) * | 2009-07-03 | 2009-12-16 | 王明 | Edaravone lipidosome injection and new application the thereof |
| CN101627998A (en) * | 2009-08-14 | 2010-01-20 | 海南永田药物研究院有限公司 | Loratadine-ambroxol pharmaceutical composite and liposome solid preparation thereof |
| CN102247324A (en) * | 2011-07-14 | 2011-11-23 | 海南美兰史克制药有限公司 | Flumazenil liposome injection |
-
2011
- 2011-11-29 CN CN 201110388637 patent/CN102429879B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1954808A (en) * | 2005-10-27 | 2007-05-02 | 常州市第四制药厂有限公司 | High dose Ambroxol hydrochloride freeze-dried preparation and preparation method |
| CN101366699A (en) * | 2007-08-17 | 2009-02-18 | 香港浸会大学 | Novel formulation of dehydrated lipid vesicles for controlled release of active pharmaceutical ingredient via inhalation |
| CN101416956A (en) * | 2007-10-22 | 2009-04-29 | 天津康鸿医药科技发展有限公司 | Ambroxol hydrochloride injection |
| CN101601656A (en) * | 2009-07-03 | 2009-12-16 | 王明 | Edaravone lipidosome injection and new application the thereof |
| CN101627998A (en) * | 2009-08-14 | 2010-01-20 | 海南永田药物研究院有限公司 | Loratadine-ambroxol pharmaceutical composite and liposome solid preparation thereof |
| CN102247324A (en) * | 2011-07-14 | 2011-11-23 | 海南美兰史克制药有限公司 | Flumazenil liposome injection |
Non-Patent Citations (1)
| Title |
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| 时明，等.氨溴索脂质体的制备及理化性质研究.《中国生化药物杂志》.2008,第29卷(第4期),248-252. * |
Cited By (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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| CN102429879A (en) | 2012-05-02 |
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