CN103040746B - Palonosetron hydrochloride lipidosome injection - Google Patents
Palonosetron hydrochloride lipidosome injection Download PDFInfo
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Abstract
The invention discloses a palonosetron hydrochloride lipidosome injection and a preparation method thereof. The lipidosome injection is prepared by using palonosetron hydrochloride, soybean phosphatidylserine, phosphatidyl glycerol, soyasterol, Tween 80 and trehalose according to a specific weight ratio. The hydrochloride thiamphenicol glycinate lipidosome injection disclosed by the invention has the advantage of good preparation stability and a lipidosome cannot be cracked due to melting, ice crystals and the like in the refrigerating process; after the hydrochloride thiamphenicol glycinate lipidosome injection is stored for a long time, the lipidosome is also kept with good encapsulation efficiency; the quality of a preparation product is improved, the retention time of a drug in systemic circulation is prolonged, the biological availability of the drug is increased, toxic and side effects are reduced and a curative effect is obviously improved; and moreover, the palonosetron hydrochloride lipidosome injection disclosed by the invention has the advantage of simple preparation method and is suitable for large-scale industrial 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 PalonosetronHydrochloride lipidosome injection and method for making thereof, belong to technical field of medicine.
Background technology
PalonosetronHydrochloride, chemical name: 2-[(S)-1-azabicyclo [2.2.2] octane-3-yl]-2,3,3a (S), 4,5,6-, six hydrogen-1H-benzisoquinoline-1-keto hydrochloride, molecular formula: C
19h
24n
2oHCl, molecular weight: 332.87, its structural formula is as follows:
Acid palonosetron is white or off-white color crystalline powder, odorless tasteless; In water, dissolve, be insoluble in ethanol.It is a kind of 5-HT3 receptor antagonist of efficient, high selectivity, what be that the 4th of FDA approval is used for the treatment of that chemotherapeutics causes acutely feels sick and the 5-HT3 receptor antagonist of vomiting, is that first approval can be used for moderate and causes the drug-induced retardance of vomitting and feel sick and the medicine of vomiting.This medicine is succeeded in developing by Switzerland Helsinn Healthcare, is approved listing by U.S. FDA in July, 2003.
National patent CN 1965829A discloses a kind of injection of palonosetron, and the officinal salt that contains palonosetron and pharmaceutic adjuvant add water for injection to make simultaneously.Described pharmaceutic adjuvant is sodium chloride.In this injection, the concentration of palonosetron is 0.01-20mg/ml, preferably 0.05mg/ml.The PH scope of injection is that 6.00-8.00. preparation method is by PalonosetronHydrochloride and adjuvant sodium chloride, adds a certain amount of water for injection simultaneously, obtains finished product through ultrafiltration, except thermal source, membrane filtration, embedding, sterilizing.
National patent CN 101057827A discloses a kind of injection of palonosetron and preparation method thereof.The chief component of this injection is: PalonosetronHydrochloride 0.01-0.05mg/ml, glucose 45-55mg/ml, glycine 0.2-10mg/ml.The preparation method of described injection comprises the steps: that (1) glycine is dissolved in appropriate water for injection, regulates pH value, injects water to aequum; (2) gained solution is filtered with microporous filter membrane; (3) solution after aseptic filtration is carried out to subpackage, be filled with noble gas or carbon dioxide, tamponade, adds a cover.
Can be found out by patent, prescription all studies intensively and screens with technique, but does not still escape the problem that normal injection preparation stability is low.
The present invention has developed a kind of PalonosetronHydrochloride lipidosome injection, can not only improve its stability, can also improve its bioavailability, reduces toxic and side effects.
Liposome is drug encapsulation to be changed in phospholipid submicron to medicine distribution in vivo, increases the abundance of medicine at target organ, thereby improves curative effect, alleviates toxic and side effects.
As a kind of new medicinal preparation, Liposomal formulation has the following advantages:
(1) there is slow releasing function: active component slowly discharges, delay renal excretion and metabolism, thereby extend action time, improve mass effect;
(2) dissolubility of increase medicine, improves the quality of the pharmaceutical preparations;
(3) there is targeting: the contained medicine of liposome maintains high concentration in liver, spleen reticuloendothelial system internal organs part, thereby plays the effect of medicine organ targeting;
(4) there is the protective effect to active pharmaceutical ingredient;
(5) reduced drug toxicity.
Liposome (Liposome) is dispersed in water discovery while carrying out electron microscopic observation by British scholar Bangham and Standlish by phospholipid at first.Phospholipid is dispersed in water self-assembling formation multilamellar vesicle, and every layer is all equal bilayers of lipid not; Vesicle central authorities and being separated by water between each layer, bilayer thickness is about 4nm.Afterwards, this bimolecular folliculus with similar biofilm structure was called to 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 20-50 nanometer; Large unilamellar vesicle is of a size of micron number magnitude.
The people such as Britain Lai Men in 1971 start liposome for pharmaceutical carrier, Main Function mechanism is that drug powder or solution are wrapped in the water that liposome bilayer lipid membrane seals or are embedded in liposome bilayer lipid membrane, this microgranule has class cellularity, enter the interior principal agent of human body is activated body autoimmune function by reticuloendothelial system phagocytic, and the interior distribution of the body that changes encapsulated medicine, make the drug main will be liver, spleen, in the histoorgan such as lung and bone marrow, put aside, thereby improve the therapeutic index of medicine, reduce the toxicity of therapeutic dose and the reduction medicine of medicine.
In recent years, along with the continuous progress of biotechnology, liposome preparation technology gradual perfection, liposome mechanism of action is further illustrated, in addition liposome is applicable to vivo degradation, avirulence and non-immunogenicity, particularly great number tested data proves that liposome can improve Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces the advantages such as drug dose.
Due to many deficiencies of current common palonosetron hydrochloride for injection, so exist demand for PalonosetronHydrochloride lipidosome injection.
Summary of the invention
In order to form colory PalonosetronHydrochloride lipidosome injection, can good compatible with PalonosetronHydrochloride it well be sealed and non-leakage filmogen thereby importantly find, and find the excipient composition that can make liposome form stable injectable agent.
To achieve these goals, large quantity research and realization that the inventor carries out, find the PalonosetronHydrochloride of specified weight proportioning, soy phosphatidylserine, phosphatidyl glycerol, soyasterol, Tween 80 and trehalose can be made PalonosetronHydrochloride lipidosome injection, wherein, envelop rate as the PalonosetronHydrochloride of active constituents of medicine is high, liposome particle diameter is little and be evenly distributed, compared with PalonosetronHydrochloride of the prior art, the retention time significant prolongation of the active constituents of medicine of preparation of the present invention in body circulation, the biocompatibility of medicine is high, bioavailability obviously improves, curative effect obviously improves.
The object of the present invention is to provide a kind of PalonosetronHydrochloride lipidosome injection, its composition by following weight proportion is made:
Wherein, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of soyasterol are 2: 1-3: 1,
The weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of Tween 80 are 5: 1-7: 1.
The preparation method that another object of the present invention is to provide above-mentioned PalonosetronHydrochloride lipidosome injection, the method comprises the following steps:
(1) cholesterol, soy phosphatidylserine, phosphatidyl glycerol, soyasterol and Tween 80 are dissolved in buffer salt solution, make blank liposome;
(2) by the blank liposome of above-mentioned preparation through flowing steam sterilization processing, then supersound process twice, each 20 minutes;
(3) under aseptic condition, in the liposome of molten condition, add PalonosetronHydrochloride, under constantly stirring, add trehalose;
(4) quick freezing, then returns to room temperature, and standardize solution stirs, 0.22 μ m filtering with microporous membrane, and fill, obtains PalonosetronHydrochloride lipidosome injection.
According to PalonosetronHydrochloride lipidosome injection provided by the invention by selecting suitable material composition and adopting suitable preparation method to obtain, wherein liposome particle diameter is little, and particle size distribution is even, and envelop rate is high, stability is high, gained PalonosetronHydrochloride lipidosome injection best in quality.
Accompanying drawing explanation
Fig. 1 illustrates the blood drug level-time graph of PalonosetronHydrochloride lipidosome injection.
Wherein:
The specific embodiment
Below describe the present invention, the features and advantages of the invention can become more clear along with these descriptions.
According to an aspect of the present invention, provide a kind of PalonosetronHydrochloride lipidosome injection, its composition by following weight proportion is made:
Wherein, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of soyasterol are 2: 1-3: 1,
The weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of Tween 80 are 5: 1-7: 1.
Preferably, provide a kind of PalonosetronHydrochloride lipidosome injection, its composition by following weight proportion is made:
Wherein, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of soyasterol are 2: 1-3: 1,
The weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of Tween 80 are 5: 1-7: 1.
More preferably, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of soyasterol are 2: 1-5: 2,
The weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of Tween 80 are 6: 1-7: 1.
In the present invention, according to the feature of active ingredient hydrochloric acid palonosetron, the inventor finds by research, the combination of fabaceous lecithin acyl serine, phosphatidyl glycerol is particularly suitable for as basic phospholipid filmogen, by they are combined with soyasterol and Tween 80 simultaneously, can obtain the lipidosome injection that envelop rate is high, stability is high.In the time using other phospholipid, be difficult to form colory liposome, the character such as envelop rate, stability and the percolation ratio of liposome are deteriorated.
In PalonosetronHydrochloride lipidosome injection of the present invention, for the PalonosetronHydrochloride of 1 weight portion, the consumption of soy phosphatidylserine is 10-50 weight portion.If the consumption of soy phosphatidylserine, lower than 10 weight portions, cannot form stable liposome; Otherwise if the consumption of soy phosphatidylserine, higher than 50 weight portions, declines as the envelop rate of the PalonosetronHydrochloride of active constituents of medicine, the quality of injection and curative effect reduce.
In PalonosetronHydrochloride lipidosome injection of the present invention, for the PalonosetronHydrochloride of 1 weight portion, the consumption of phosphatidyl glycerol is 10-20 weight portion.If the consumption of phosphatidyl glycerol, lower than 10 weight portions, cannot form stable liposome; Otherwise if the consumption of phosphatidyl glycerol, higher than 20 weight portions, declines as the envelop rate of the PalonosetronHydrochloride of active constituents of medicine, the quality of injection and curative effect reduce.
In PalonosetronHydrochloride lipidosome injection of the present invention, soyasterol and Tween 80 are for regulating the membrane stability of liposome.
Soyasterol (soybean sterol, SS) is the hydrolyzate that soyasterol glucoside removes glucose residue, and described soyasterol glucoside is the mixture of the sterol glucoside from separating through the Soybeanresidue of refinement Oleum Glycines.As a kind of natural product, soyasterol source is abundant, low price.
In PalonosetronHydrochloride lipidosome injection of the present invention, for the PalonosetronHydrochloride of 1 weight portion, the consumption of soyasterol is 5-20 weight portion.If the consumption of soyasterol is lower than 5 weight portions, the stability of gained liposome obviously reduces; If the consumption of soyasterol is higher than 5 weight portions, the envelop rate of active constituents of medicine PalonosetronHydrochloride also can decline thereupon, and the quality of injection and curative effect reduce.
In PalonosetronHydrochloride lipidosome injection of the present invention, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of soyasterol are 3: 1-2: 1, within the scope of this, can form stable PalonosetronHydrochloride liposome.If the weight ratio of the weight sum of soy phosphatidylserine and phosphatidyl glycerol and soyasterol was lower than 2: 1, membrane stability reduces, and PalonosetronHydrochloride is easy to seepage; If the weight ratio of the weight sum of soy phosphatidylserine and phosphatidyl glycerol and soyasterol was higher than 3: 1, liposome membrane mobility is too high, and the PalonosetronHydrochloride being wrapped in liposome is easy to discharge.
In PalonosetronHydrochloride lipidosome injection of the present invention, for the PalonosetronHydrochloride of 1 weight portion, the consumption of Tween 80 is 4-10 weight portion.If the consumption of Tween 80, lower than 4 weight portions, cannot form stable liposome; If the consumption of Tween 80 is higher than 10 weight portions, liposome be easy to seepage.
In PalonosetronHydrochloride lipidosome injection of the present invention, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of Tween 80 are 5: 1-7: 1.If weighing less than 5: 1 of the weight sum of soy phosphatidylserine and phosphatidyl glycerol and Tween 80, membrane stability is too low, and PalonosetronHydrochloride is easy to seepage; If the weight of the weight sum of soy phosphatidylserine and phosphatidyl glycerol and Tween 80 was higher than 7: 1, liposome membrane mobility is too high, and the PalonosetronHydrochloride being wrapped in liposome is easy to discharge.
Especially, when the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of soyasterol are 2: 1-5: 2, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of Tween 80 are 6: 1-7: 1 o'clock, the membrane stability of liposome was the strongest, and toxicity is minimum.
In PalonosetronHydrochloride lipidosome injection of the present invention, use trehalose as excipient, be used to form stable injection.In PalonosetronHydrochloride lipidosome injection of the present invention, trehalose can effectively be protected form and the stability of liposome particles, further improves the stability of lipidosome injection.
In the present invention, in the time using the PalonosetronHydrochloride, soy phosphatidylserine, phosphatidyl glycerol, soyasterol, Tween 80 of above-mentioned specified quantitative and trehalose, can obtain colory PalonosetronHydrochloride lipidosome injection, its envelop rate and stability are all very high, uniform particle diameter, toxicity is low, and bioavailability is high.
Research shows, the stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of PalonosetronHydrochloride lipidosome injection of the present invention is high, is to cause one of factor that drug bioavailability is high.
PalonosetronHydrochloride lipidosome injection of the present invention, the specification of its PalonosetronHydrochloride is: 5ml: 0.25mg(injection volume: PalonosetronHydrochloride weight).
According to a further aspect in the invention, provide the preparation method of above-mentioned PalonosetronHydrochloride lipidosome injection, the method comprises the following steps:
(1) cholesterol, soy phosphatidylserine, phosphatidyl glycerol, soyasterol and Tween 80 are dissolved in buffer salt solution, make blank liposome;
(2) by the blank liposome of above-mentioned preparation through flowing steam sterilization processing, then supersound process twice, each 20 minutes;
(3) under aseptic condition, in the liposome of molten condition, add PalonosetronHydrochloride, under constantly stirring, add trehalose;
(4) quick freezing, then returns to room temperature, and standardize solution stirs, 0.22 μ m filtering with microporous membrane, and fill, obtains PalonosetronHydrochloride lipidosome injection.
In the method according to the invention, in step (1), described buffer salt solution is selected from the one in phosphate buffered solution, citrate buffer solution, carbonate buffer solution, borate buffer solution, is preferably pH and is sodium hydrogen phosphate-sodium dihydrogen phosphate buffer of 7.0.
In the method according to the invention, in step (3), the temperature of described molten condition liposome is 60 ℃.
In the method according to the invention, in step (4), the temperature of described quick freezing is-40 ℃.
The inventor, by selecting suitable material composition, adopting suitable preparation technology, has obtained colory PalonosetronHydrochloride lipidosome injection, and 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.The PalonosetronHydrochloride liposome particles of preparing by the inventive method is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
embodiment
Further describe the present invention by exemplary instantiation below.But, these illustrative examples are only illustrative, scope of the present invention are not construed as limiting.
The preparation of embodiment 1 PalonosetronHydrochloride lipidosome injection
Raw materials used as follows:
Preparation process is as follows:
(1) soy phosphatidylserine 6.5g, phosphatidyl glycerol 2.5g, soyasterol 3.25g and 1.5g Tween 80 are dissolved in to 500ml pH and, in sodium hydrogen phosphate-sodium dihydrogen phosphate buffer of 7.0, make blank liposome;
(2) by the blank liposome of above-mentioned preparation through flowing steam sterilization processing, then supersound process twice, each 20 minutes;
(3) under aseptic condition, in the liposome of molten condition, add PalonosetronHydrochloride 0.25g, under constantly stirring, add 3.25g trehalose;
(4)-40 ℃ of quick freezing, then return to room temperature, and inject water standardize solution and stir to 5000ml, 0.22 μ m filtering with microporous membrane, fill (5ml/ bottle), obtains 1000 bottles of PalonosetronHydrochloride lipidosome injections.
The preparation of embodiment 2 PalonosetronHydrochloride lipidosome injections
Raw materials used as follows:
Preparation process is as follows:
(1) soy phosphatidylserine 5g, phosphatidyl glycerol 2.5g, soyasterol 2.5g and 1.25g Tween 80 are dissolved in to 500ml pH and, in sodium hydrogen phosphate-sodium dihydrogen phosphate buffer of 7.0, make blank liposome;
(2) by the blank liposome of above-mentioned preparation through flowing steam sterilization processing, then supersound process twice, each 20 minutes;
(3) under aseptic condition, in the liposome of molten condition, add PalonosetronHydrochloride 0.25g, under constantly stirring, add 2.5g trehalose;
(4)-40 ℃ of quick freezing, then return to room temperature, and inject water standardize solution and stir to 5000ml, 0.22 μ m filtering with microporous membrane, fill (5ml/ bottle), obtains 1000 bottles of PalonosetronHydrochloride lipidosome injections.
The preparation of embodiment 3 PalonosetronHydrochloride lipidosome injections
Raw materials used as follows:
Preparation process is as follows:
(1) soy phosphatidylserine 10g, phosphatidyl glycerol 5g, soyasterol 5g and 2.5g Tween 80 are dissolved in to 500ml pH and, in sodium hydrogen phosphate-sodium dihydrogen phosphate buffer of 7.0, make blank liposome;
(2) by the blank liposome of above-mentioned preparation through flowing steam sterilization processing, then supersound process twice, each 20 minutes;
(3) under aseptic condition, in the liposome of molten condition, add PalonosetronHydrochloride 0.25g, under constantly stirring, add 3.75g trehalose;
(4)-40 ℃ of quick freezing, then return to room temperature, and inject water standardize solution and stir to 5000ml, 0.22 μ m filtering with microporous membrane, fill (5ml/ bottle), obtains 1000 bottles of PalonosetronHydrochloride lipidosome injections.
Comparative example 1-3
Adopt respectively and production technology identical in embodiment 1-3, the composition in comparative example 1-3 as shown in Table 1 below made respectively to PalonosetronHydrochloride lipidosome injection:
Composition used in table 1 comparative example 1-3
| Composition | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| PalonosetronHydrochloride | 0.25g | 0.25g | 0.25g |
| Cholesterol | 3.25g | 2.5g | / |
| Soy phosphatidylserine | 6.5g | / | 20g |
| Phosphatidyl glycerol | 3.5g | 2.5g | 5g |
| Soyasterol | 3.25g | / | 6g |
| Ovum Gallus domesticus Flavus lecithin | / | 5g | / |
| Tween 80 | 2g | 1.25g | 3g |
| Trehalose | 3.25g | 2.5g | 6g |
Wherein, "/" represents not use.
the mensuration of test example 1 liposome particle diameter
Under room temperature condition, get the PalonosetronHydrochloride lipidosome injection in embodiment 1-3 and comparative example 1-3, be placed in 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 following table 2.
Table 2 liposome particle diameter testing result
| Numbering | Mean diameter | Outward appearance |
| Embodiment 1 | 242.8nm | Spherical, evenly |
| Comparative example 1 | 445.6nm | Inhomogeneous, mixed and disorderly |
| Embodiment 2 | 222.7nm | Spherical, evenly |
| Comparative example 2 | 426.4nm | Inhomogeneous, mixed and disorderly |
| Embodiment 3 | 207.5nm | Spherical, evenly |
| Comparative example 3 | 452.3nm | Inhomogeneous, mixed and disorderly |
As known from Table 2, the liposome particle diameter that embodiment 1-3 makes is even, aobvious spherical, big or small homogeneous; The liposome particle diameter that comparative example 1-3 makes is inhomogeneous, and shape is indefinite, not of uniform size.
Particularly, even in the time adopting same production technology, in embodiment 1-3, the particle appearance of gained PalonosetronHydrochloride liposome and mean diameter thereof are obviously better than the PalonosetronHydrochloride liposome of gained in comparative example 1-3.When composition beyond using the present invention's composition used is described, or in the time that composition consumption is outside the composition amount ranges of the present invention's restriction, the outward appearance of gained PalonosetronHydrochloride liposome is inferior to the present invention, and mean diameter goes out greatly a lot.
the mensuration of test example 2 envelop rates
Rotating speed high speed centrifugation by the PalonosetronHydrochloride lipidosome injection of preparing in embodiment 1-3 and comparative example 1-3 with 5000r/min, centrifugal 20 minutes, gets supernatant, dissolve with acetonitrile solution, HPLC method is surveyed PalonosetronHydrochloride content, and computational envelope rate, the results are shown in following table 3.
Table 3 entrapment efficiency determination result
| Numbering | Embodiment 1 | Comparative example 1 | Embodiment 2 | Comparative example 2 | Embodiment 3 | Comparative example 3 |
| Envelop rate | 83.3% | 51.4% | 86.5% | 50.9% | 85.7% | 51.6% |
The envelop rate of the Liposomal formulation that as shown in Table 3, prepared by embodiment 1-3 is significantly higher than the envelop rate of the Liposomal formulation of comparative example 1-3.When composition beyond using the present invention's composition used is described, or in the time that composition consumption is outside the composition amount ranges of the present invention's restriction, the liposome encapsulation of gained liposome is lower than the present invention.
test example 3 study on the stability
Sample prepared by embodiment of the present invention 1-3 and listing palonosetron hydrochloride for injection (lot number: 20101103, Shandong pharmacy (Hainan) company limited, production address: the high and new technology industrial development zone No. 273-A in main road, the South Sea of Haikou City country) be placed in respectively lower 6 months of the condition of 40 ℃ of high temperature, relative humidity 75%, carry out accelerated test investigation, the results are shown in following table 4.
Table 4 accelerated test result
As shown in Table 4, while accelerating June, the content of listing preparation and comparative example 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 4 percolation ratio tests
Get sample prepared by test example 1-3 and comparative example 1-3, 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 comparison of sealing for 0 day, calculate percolation ratio, the results are shown in following table 5.
Table 5 percolation ratio result of the test
As shown in Table 5, when long term storage, the PalonosetronHydrochloride lipidosome injection percolation ratio of preparing in embodiment of the present invention 1-3 changes little, and the injection percolation ratio of preparing in comparative example 1-3 increases gradually, liposome seepage is serious, and PalonosetronHydrochloride lipidosome injection prepared by this explanation the present invention has higher stability.
the mensuration of test example 5 blood drug level
42 rats are divided into 7 groups at random, every group of injection of preparing in drug administration by injection embodiment 1-3 and comparative example 1-3 respectively, and commercially available palonosetron hydrochloride for injection (lot number: 20101103, Shandong pharmacy (Hainan) company limited, production address: the high and new technology industrial development zone No. 273-A in main road, the South Sea of Haikou City country), specification is 5ml:0.25mg palonosetron hydrochloride for injection.After administration, respectively at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h, take a blood sample, blood sample after treatment, is measured blood drug level with HPLC-MS method.Draw PalonosetronHydrochloride lipidosome injection and the blood drug level of commercially available palonosetron hydrochloride for injection and the relation curve of time in the PalonosetronHydrochloride lipidosome injection prepared in embodiment 1-3, comparative example 1-3, prepared, be shown in accompanying drawing 1.
As shown in Figure 1, compare with commercially available PalonosetronHydrochloride lipidosome injection with the PalonosetronHydrochloride lipidosome injection of preparing in comparative example 1-3, the PalonosetronHydrochloride lipidosome injection of preparing in embodiment of the present invention 1-3 has the following advantages: release rate is in vivo slower, in body circulation, distribution time extends, reached slow release effect, bioavailability has improved.
industrial applicibility
PalonosetronHydrochloride lipidosome injection provided by the invention, has good outward appearance, and granule is little, and particle diameter is even, and envelop rate is high, and stability is high, and percolation ratio is low, and the time of staying is in vivo 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 form any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; can carry out multiple modification, improvement and replacement to technical solutions and their implementation methods of the present invention, because these all fall within the scope of protection of the present invention.
Each list of references of mentioning in the application or quoting, which is hereby incorporated by reference.
Claims (7)
1. a PalonosetronHydrochloride lipidosome injection, its composition by following weight proportion is made:
Wherein, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of soyasterol are 2:1-3:1,
The weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of Tween 80 are 5:1-7:1.
2. PalonosetronHydrochloride lipidosome injection according to claim 1, wherein, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of soyasterol are 2:1-5:2.
3. PalonosetronHydrochloride lipidosome injection according to claim 1 and 2, wherein, the weight sum of soy phosphatidylserine and phosphatidyl glycerol and the weight ratio of Tween 80 are 6:1-7:1.
4. according to a preparation method for the PalonosetronHydrochloride lipidosome injection described in any one in claims 1 to 3, the method comprises the following steps:
(1) cholesterol, soy phosphatidylserine, phosphatidyl glycerol, soyasterol and Tween 80 are dissolved in buffer salt solution, make blank liposome, described buffer salt solution is selected from the one in phosphate buffered solution, citrate buffer solution, carbonate buffer solution, borate buffer solution;
(2) by the blank liposome of above-mentioned preparation through flowing steam sterilization processing, then supersound process twice, each 20 minutes;
(3) under aseptic condition, in the liposome of molten condition, add PalonosetronHydrochloride, under constantly stirring, add trehalose;
(4) quick freezing, then returns to room temperature, and standardize solution stirs, 0.22 μ m filtering with microporous membrane, and fill, obtains PalonosetronHydrochloride lipidosome injection.
5. method according to claim 4, in step (1), described buffer salt solution is that pH is sodium hydrogen phosphate-sodium dihydrogen phosphate buffer of 7.0.
6. method according to claim 4, in step (3), the temperature of described molten condition liposome is 60 ℃.
7. method according to claim 4, in step (4), the temperature of described quick freezing is-40 ℃.
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| KR20160128573A (en) * | 2015-04-29 | 2016-11-08 | 주식회사 삼양바이오팜 | Pharmaceutical package |
| JP2019038758A (en) * | 2017-08-23 | 2019-03-14 | 武田テバファーマ株式会社 | Pharmaceutical composition containing palonosetron or pharmaceutically acceptable salt thereof |
| CN108703960A (en) * | 2018-07-25 | 2018-10-26 | 无锡鑫连鑫生物医药科技有限公司 | A kind of palonosetron sustained-release micro-spheres and preparation method thereof and application method |
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| EP2384744A1 (en) * | 2004-01-14 | 2011-11-09 | Gilead Sciences, Inc. | Lipid-based dispersions useful for drug delivery |
| CN102327237B (en) * | 2011-07-14 | 2012-09-26 | 海南灵康制药有限公司 | Azasetron hydrochloride lipidosome injection |
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