CN100375621C - Vinorelbine liposome micro ball injection and its prepn - Google Patents
Vinorelbine liposome micro ball injection and its prepn Download PDFInfo
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Abstract
The present invention relates to a vinorelbine lipid microsphere injection and a preparation method thereof. 90% to 98% of vinorelbine is coated in an oil phase of lipid microspheres and an oil-water interface film, and thereby, the toxicity and the stimulation of the vinorelbine used in clinics are greatly reduced, and the antitumor treatment effect is enhanced. The medicine of the present invention is used as an antitumor medicine, is taken in an injection mode and has the advantages of low stimulation, low toxicity and high efficiency.
Description
Technical field
The present invention relates to medical technical field, relate to a kind of Lipid micropellet parenteral solution of auspicious bank of Changchun and its preparation method in particular.
Background technology
Along with the development and the progress of medicine and pharmacology technology, the mankind have controlled the infectious disease that in the past mainly threatens human health basically, then become the archenemy of human health gradually such as noninfectiouss such as tumor, cardiovascular and cerebrovascular diseases.According to 1997 years of World Health Organization (WHO), because of cancer mortality 6,300,000 people are arranged approximately in the whole world 5,800,000,000 populations in 1996, account for 12% of total death toll, wherein nearly 60% dies from pulmonary carcinoma, gastric cancer, breast carcinoma, colorectal carcinoma, oral cancer, hepatocarcinoma, cervical cancer and the esophageal carcinoma, is the second largest cause of the death that is only second to cardiovascular disease.The annual tumor patient of newly making a definite diagnosis in the whole world is all more than 1,030 ten thousand people since 1996, to the end of the year 1999 whole world tumor patient sum exceeded 4,000 ten thousand people.World Health Organization's calendar year 2001 report, world's cancer morbidity and mortality rate have risen 22% than the nineteen ninety, also will rise about 50% in 20 years from now on.The epidemiological study prompting, China not only tumor mortality rate is obvious ascendant trend, and the characteristics that have developing country and developed country spectrum occurred frequently concurrently and deposit, and China increases tumor patient 160-170 ten thousand people newly every year in recent years, and Estimate of Total Number is about 4,500,000 people.Therefore, the exploitation of antitumor drug is the most important thing of many pharmacy worker's researchs.In addition, because most antitumor drug untoward reaction are serious, body and mind to the patient in therapeutic process causes very major injury, therefore how when improving curative effect of medication, improve patient's life quality and become new direction and the emphasis of present antitumor drug research gradually thereby reduce the zest of medicine and toxicity.
Vinorelbine is a kind of semisynthetic vinca anti-cancer agent, the active anticancer height, and antitumor spectra is wide, and through external clinical research, single medicine or drug combination treatment nonsmall-cell lung cancer, breast carcinoma, ovarian cancer, malignant lymphoma etc. have shown outstanding curative effect.But the injection of this medicine has bigger zest when clinical use, such as the vinorelbine tartrate injection of the present clinical use commodity Navelbine by name of company (French Pierre Fabre) is hypertonicity solution, and it is acid that its aqueous solution is, too high or medicinal liquid exosmoses and can produce bigger toxicity to transfusion vein and stimulate as local concentration, and can cause phlebitic generation.Its phlebitis incidence rate 47.2% of research is arranged.Toxicity mainly is that leukocyte count descends overall reaction rate 72%.Therefore the injection that uses clinically at present all requires and must be diluted to 50mL with normal saline earlier, in the short time (6-10 minute), import through vein, use 250-500 mL normal saline flushing vein then, and must confirm that injection needle can start injection at intravenous, in case medicine liquid leakage should stop injection immediately, surplus medicine changes vein in addition and injects.This brings a lot of miseries to the patient undoubtedly, brings a lot of inconvenience on using, and has limited vinorelbine generally popularization and application clinically.
Therefore in view of above-mentioned characteristic, bring into play clinical efficacy better for making vinorelbine, the research and development novel form, cover the zest of medicine with the advantage of novel form, the toxicity that reduces medicine is to give full play to the vinorelbine anti-tumor activity, and this undoubtedly will be significant to further promotion and the application of popularization vinorelbine in clinical.
Lipomul is applied to clinical nearly half a century as the important supply mode of the outer energy of intestinal.Between 1920～nineteen thirty, Japanese scholar was that raw material, lecithin are emulsifying agent with Oleum Ricini once, and at first the synthetic lipomul is tried out in animal; The U.S. has released Lipomul based on cotton seed oil the fifties and has been applied to patient but all fails to promote because of serious toxicity.1964, the U.S. stopped to produce and using lipomul.But in Europe, with Wretling be a collection of scholar of representative to study untiringly and use based on soybean oil, with the lecithin be emulsifying agent, be the lipomul Introlipid of isotonic agent with glycerol.1962, Introlipid was used for clinical in Sweden by official approval.1967, article " lipomul the is applied to complete intravenous nutrition " comprehensive summing up of delivering by Hallberg etc. experiment and the clinical research of Introlipid, prove that it is applied to clinical is safe and reliable, and proposed the criterion of Introlipid clinical practice." obtaining growth, growth and positive nitrogen balance under the long-term complete parenteral nutrition " literary composition that this literary composition and nineteen sixty-eight Dudrick etc. deliver is acknowledged as parenteral nutrition is developed into two pieces of classical works that routine clinical is used significant impact.After this more than 20 year, Introlipid obtained extensive use all over the world, and developed countries such as moral, method, Japan and the United States have developed national lipomul in succession.1976, U.S. appropriate authorities have ratified lipomul again can be in routine clinical application.At present, kind of a lipomul appeared on the market surplus the whole world had 20 at least.China is also joint the end of the eighties and Sweden Kabi company, and mass production Introlipid is for clinical practice.1973, that Solassol etc. have at first introduced is three-in-one, and (All-in-one, the AIO) notion of solution proved that lipomul and all other nutritional solutions can be mixed in the bottle or in the bag, can keep stable and nutritional support effect at certain condition with in the time.After this promoted AIO transfusion plastic bag, the preparation and the infusion of parenteral nutrition liquid simplified in this simple but relevant improvement greatly, for the wide clinical application of lipomul has been widened road.Up to the present, it is oil-in-water type (oil in water, the o/w) submicronized emulsion of emulsifying agent as decentralized photo with the Ovum Gallus domesticus Flavus lecithin that common lipomul is meant with fatty glyceride.Because the Chylomicron that exists behind the composition of lipomul emulsion droplet and particle diameter and the oral fat group food is very similar, therefore it has been generally acknowledged that the emulsion droplet of lipomul is also similar with Chylomicron in the intravital behavior of people in blood.Along with the further investigation to lipomul, it is also just bringing into play more and more important effect at pharmaceutical field.
The special physicochemical property and the hypotoxicity of lipomul have determined it to can be used as fat-soluble medicine, particularly the good carrier of cancer therapy drug, anaesthetic and anti-inflammatory drug.The normal method that adopts is the lipid core part that pharmaceutical pack is wrapped in lipomul because this structure also is similar to microsphere, so lipid microsphere (LipidMicrosphere, title LM) is also arisen at the historic moment.It is generally acknowledged that lipid microsphere is by medicine is dissolved in the fatty oil, and after phospholipid emulsifying is scattered in water, make, be a kind of be soft substrate and the microparticulate system sealed by immobilized artificial membrane with fatty oil, mean diameter is about 200nm.The structural representation of LM is seen accompanying drawing 1.
LM has many physical chemistry and advantage biologically:
1. be the good carrier of fat-soluble medicine.Clinical many medicine poorly water-solubles must rely on the effect of organic solvent competence exertion, and organic solvent not only itself have certain toxicity, also may the interference medicament effect.
2. can effectively increase stability of drug.In the pastille lipid microsphere, quite a few drug distribution is arranged in oil phase or oil-water interfacial film, avoided directly contacting with water.Change responsive medicine for facile hydrolysis or to pH, this " isolation " played the effect that increases stability.
3.LM Chinese medicine partly is wrapped in oil phase or the interfacial film, avoided with body fluid until contacting, thereby reduced issuable part of medicine self and blood vessel irritation.In addition, medicine is by slowly discharge the untoward reaction that can avoid medicine to cause owing to the initial stage excessive concentration in the oil phase when injection in vivo.
4. the small particle of particle diameter about 200 nm can be engulfed by the phagocyte of the reticular tissue system of body and be trapped in the reticular tissue system (as liver, lung etc.), have targeting, this characteristics for antitumor drug improve drug effect, to reduce toxic and side effects particularly important.
We are decided to be encapsulation ratio with the medicine total amount of oil phase and emulsifying agent layer, and assay method is as follows:
(1) the accurate vinorelbine liposome micro ball 100 μ L that draw of the mensuration of medicine total amount add 2mL chromatographically pure ether in the 10mL measuring bottle, add chromatographically pure methanol to scale, mixing, ultrasonic 10min, 0.22 μ m filtering with microporous membrane, get subsequent filtrate, measure, record peak area A with the HPLC method
T
(2) mensuration of aqueous phase medicament contg is got vinorelbine liposome micro ball 4mL, put in the supercentrifuge with 46 000rpm (=approx.10,7000g) centrifugal 4h, temperature 10C, take off layer settled solution 100 μ L in the 10mL measuring bottle, be diluted to scale with methanol, mixing, 0.22 μ m filtering with microporous membrane, get subsequent filtrate, measure, record peak area A with the HPLC method
w
(3) encapsulation ratio=preparation of Chinese medicine total amount-aqueous phase medication amount
Computing formula is as follows:
Vinorelbine O-I=1-vinorelbine W
Vinorelbine W=(1-W oil) * Cw/CT=(1-W oil) * Aw/AT
Wherein: vinorelbine O-I is the distribution sum of medicine at oil phase and emulsifying agent layer;
Vinorelbine W is the distribution of medicine at aqueous phase;
Cw is the aqueous phase drug level;
CT is the preparation of Chinese medicine total concentration;
W oil is the percentage by weight of oil phase in the preparation.
So, encapsulation ratio=[1-(1-W oil) * Cw/CT] * 100%=[1-(1-W oil) * Aw/AT] and * 100%
The patent of application number 200410065105.1 and application number 200510038178.6 provides a kind of prescription and preparation method for preparing injection for intravenous with vinorelbine emulsion, but the vinorelbine medicine in these patents is not wrapped in oil phase or the interfacial film effectively, thus can't reach reduction to the zest of blood vessel, improve purpose such as curative effect; In addition, because the easy oxidative degradation of vinorelbine, the unstability of vinorelbine medicine also is the major issue that present vinorelbine medicine is deposited in actual applications, more than two patents effective solution is not provided yet.
Summary of the invention
Purpose of the present invention is exactly to overcome the defective that existing vinorelbine dosage form exists, and a kind of vinorelbine liposome micro ball injection of injection for intravenous is provided, and its preparation method also is provided simultaneously.This vinorelbine liposome micro ball injection provided by the invention, wherein vinorelbine can be wrapped in oil phase and the oil-water interfacial film well, and therefore, this lipide microsphere injection has reduced zest and the toxic and side effects of vinorelbine to blood vessel, good stability, evident in efficacy.
The present invention relates to a kind of Lipid micropellet parenteral solution of auspicious bank of Changchun and its preparation method.
Lipide microsphere injection provided by the invention is made up of vinorelbine, oil-soluble medium, surfactant, oil phase solubilizing agent, osmotic pressure regulator, antioxidant, metal-chelator and water for injection; The percentage by weight of its composition is:
Vinorelbine 0.001%～10%
Oil-soluble medium 2%～50%
Surfactant 0.2%～10%
Osmotic pressure regulator 0.1%～10%
Oil phase solubilizing agent 0.1%～5%
Antioxidant 0.001%～2%
Metal-chelator 0.001%～2%
All the other are water for injection.
Vinorelbine among the present invention is vinorelbine alkali or the various salt that obtained by vinorelbine alkali and available acid reaction pharmaceutically; The oil-soluble medium is a kind of or its mixture in mineral oil, vegetable oil, animal oil, quintessence oil or the artificial oil; Described surfactant is a phospholipid, polyoxyethylene sorbitan fatty acid ester tween Tween, pluronic poloxamer, enuatrol, oleic acid, cholic acid, deoxycholic acid or its mixture; Osmotic pressure regulator is a glycerol, sorbitol, mannitol, glucose or its mixture; The oil phase solubilizing agent is 10-hydroxyl-2-decylenic acid, fatty acid esters of sorbitan Span or its mixture; Antioxidant is water solublity antioxidant: sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, L-cysteine; Oil-soluble antioxidant: vitamin E or its mixture; The metal chelating is disodium EDTA EDTA, calcium disodium salt of EDTA or its mixture.
Preferred version of the present invention is: vinorelbine is tartrate, maleate, lactate, malate, hydrochlorate, sulfate, the phosphate of vinorelbine; Vegetable oil in the described oil-soluble medium is a safflower oil, soybean oil, Semen Maydis oil, Semen Coicis oil, Oleum Fructus Bruceae, Oleum Ricini, Oleum Gossypii semen, Oleum Cocois, Petiolus Trachycarpi oil, MCT Oil MCT or its mixture; Animal oil is sebum, Adeps Sus domestica, fish oil, sperm oil and composition thereof; Phospholipid in the described surfactant is lecithin, fabaceous lecithin or its mixture; Tween in the described surfactant is a polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85, or its mixture; The pluronic of described surfactant is pluronic F68; Fatty acid esters of sorbitan Span in the described oil phase solubilizing agent is Span20,40,60,80, and perhaps its mixture.
The vinorelbine of 90%-98% is wrapped in oil phase or the oil-water interfacial film in the lipide microsphere injection of vinorelbine of the present invention.
To better implement the present invention, the composition of injection can be:
Vinorelbine 0.01%～5%
Oil-soluble medium 5%～30%
Surfactant 0.5%～5%
Osmotic pressure regulator 0.5%～5%
Oil phase solubilizing agent 0.2%～3%
Antioxidant 0.01%～1%
Metal-chelator 0.01%～1%
All the other are water for injection.
Preferred version of the present invention is:
Vinorelbine 0.05%～1%
Oil-soluble medium 8%～20%
Surfactant 1%～3%
Osmotic pressure regulator 1%～5%
Oil phase solubilizing agent 0.4%～2%
Antioxidant 0.05%～0.5%
Metal-chelator 0.02%～0.5%
All the other are water for injection.
A preferred version more of the present invention is:
The composition of this injection is by weight percentage:
Vinorelbine 0.1%
Oil-soluble medium (oil phase) (soybean oil/MCT Oil=2/8) 10%
Surfactant is lecithin 1.2%Tween-80 0.2% enuatrol 0.1%
Osmotic pressure regulator is a glycerol 2.5%
The oil phase solubilizing agent is 10-hydroxyl-2-decylenic acid 0.5%Span80 0.1%
Antioxidant is L-cysteine 0.2% vitamin E 0.05%
Metal-chelator is EDTA 0.05%
All the other are water for injection.
The present invention also provides the preparation method of vinorelbine liposome micro ball injection, comprise following steps: mix surfactant, osmotic pressure regulator, water solublity antioxidant, the metal chelating of recipe quantity (1) with the water for injection that is preheated to 70-80 ℃, change in the tissue mashing machine, stir, until each composition dissolving, get water; With in the oil-soluble antioxidant of recipe quantity, the oil-soluble medium that the oil phase solubilizing agent adds to recipe quantity, be heated to 70-80 ℃ simultaneously, dissolving, oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stir,, get colostrum until the oil phase homodisperse; (3) the recipe quantity vinorelbine is added to above-mentioned Ruzhong just, use sodium hydroxide, hydrochloric acid is regulated pH value 7-9, and adding is preheated to 70-80 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 1-10 time, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Its preferred version is: mix surfactant, osmotic pressure regulator, water solublity antioxidant, the metal chelating of recipe quantity (1) with the water for injection that is preheated to 70 ℃, changes in the tissue mashing machine, stirs, and until each composition dissolving, gets water; With in the oil-soluble antioxidant of recipe quantity, the oil-soluble medium that the oil phase solubilizing agent adds to recipe quantity, be heated to 70 ℃ simultaneously, dissolving, oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stir,, get colostrum until the oil phase homodisperse; (3) the recipe quantity vinorelbine is added to above-mentioned Ruzhong just, use sodium hydroxide, hydrochloric acid is regulated pH value 8.5, and adding is preheated to 70 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Using the acceptable material of term " oil " indication one big class physiology among the present invention, can be mineral oil, vegetable oil, animal oil, quintessence oil, artificial oil, or its mixture.Therefore, use term " oil " in order to refer to the very material of different chemical character that has of a wide region herein.With type or functional classification oil the time, as mineral oil source from oil and comprise fat or cerul hydrocarbon, aromatic hydrocarbon or blended fat and aromatic radical hydrocarbon.The oil such as the refined paraffin wax wet goods that in the mineral oil classification, also comprise petroleum derivation.In the vegetable oil classification, oil is mainly derived from seed or nut, and comprises drying oil such as Semen Lini and Oleum Verniciae fordii; Semi-drying oil such as safflower oil and soybean oil; Non-drying oil such as Oleum Ricini, Oleum Gossypii semen, Oleum Cocois and Petiolus Trachycarpi oil.In the animal oil classification, oil is usually from sebum, Adeps Sus domestica.Aqueous animal oil comprises fish oil, the spermaceti wet goods.Be preferably long-chain fat acid glyceride, medium chain length fatty acid triglyceride, and composition thereof.
Used surfactant can be various nonionic surfactant, anionic surfactant or amphoteric ionic surfactant, is generally phospholipid, tween (Tween), pluronic (poloxamer), enuatrol, oleic acid, cholic acid, deoxycholic acid and composition thereof.Described phospholipid is selected from lecithin, fabaceous lecithin, and composition thereof.Described tween is selected from polysorbas20, polysorbate40, and polysorbate60, Tween 80, polysorbate85, and composition thereof.Be preferably lecithin, fabaceous lecithin, enuatrol, oleic acid, Tween 80, pluronic F68, and composition thereof.
The oil phase solubilizing agent is fatty acid esters of sorbitan (Span) class nonionic surfactant, 10-hydroxyl-2-decylenic acid, and composition thereof.
Antioxidant is water solublity antioxidant: sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, L-cysteine; Oil-soluble antioxidant: vitamin E, and composition thereof.
The metal chelating is disodium edetate (disodium EDTA), sodium calcium edetate (calcium disodium salt of EDTA), and composition thereof.
Vinorelbine is an alkaloid, and adding fat-soluble sour 10-hydroxyl-2-decylenic acid and its reaction in the prescription can increase that it is fat-soluble; Add less surfactant fatty acid esters of sorbitan (Span) class of hydrophile-lipophile balance value (HLB value) in the prescription and also can increase the fat-soluble of medicine.Adopt high pressure homogenize on the preparation technology, high speed airflow bump forms a kind of supersonic speed and stirs, and makes medicine dissolving and be penetrated in the oil-water interfacial film with molecular forms rapidly.
After the present invention makes lipide microsphere injection to the medicine vinorelbine, because the pharmaceutical pack more than 90% is wrapped in oil phase or the oil-water interfacial film, can avoid contacting, thereby reduce medicine at zest that the injection site produced and the general toxicity that causes therefrom with the direct of blood vessel or body fluid.The acute toxicity tests shows: compare vinorelbine liposome micro ball injection toxicity with commercially available vinorelbine liquid drugs injection injection and reduce greatly.
According to the literature, particle diameter can concentrate in reticuloendothelial system abundant liver and pulmonary with blood circulation after injection enters human body at the microgranule about 200nm, therefore particle diameter has the guiding distribution performance of relative targeting to the reticular tissue cell system at the medicine carrying lipid microsphere of this scope, this for the curative effect that improves cancer therapy drug, reduce that it is highly beneficial to Normocellular infringement, thereby the untoward reaction that can lower general, increase the useful effect of medicine.
The antitumor drug vinorelbine liposome micro ball injection that the present invention is prepared has the characteristics of low irritant, hypotoxicity, high efficiency.
In addition, the most inappetence of patient after the chemotherapy, digestive function is low, should in time supplement the nutrients and energy.Lipide microsphere injection mainly is made up of oil phase, emulsifying agent and isoosmotic adjusting agent etc., it can provide essential fatty acid and energy for body, keep the constant of cellularity and body fat tissue, this obviously is comparatively ideal selection concerning supply with the fatty patient who is difficult to tolerate through gastrointestinal.
The investigation of vinorelbine dilution stability
For satisfying the needs of different dosing regimes, when using clinically, injectable drug often needs dilution back administration, and diluent media commonly used comprises sodium chloride injection (0.9%) and glucose injection (5.4%).Because lipid microsphere is different from common solution type injection agent, it all belongs to Unstable Systems on thermodynamics and kinetics, diluent media and dilution time can produce material impact to its stability, and bibliographical information is arranged, if the vinorelbine injection dilutes with glucose, can precipitate, so this preparation dilutes and the time that can use safely after definite the dilution with normal saline.
Three batches of lipide microsphere injection samples with the dilution of 4 times of amount normal saline, are surveyed its particle diameter respectively at sampling in 0,2,4,6,8,12 hour, and average result is seen accompanying drawing 2.Measured its encapsulation ratio in 0,2,6,12 hour respectively at placing, average result is respectively 94.2%, 93.5%, 86.4% and 80.6%.
Conclusion: determine that by above experimental result during with 4 times of sodium chloride injection (0.9%) dilutions, it is safe and rational using to vinorelbine liposome micro ball injection when clinical use in 2 hours.
The vinorelbine liposome micro ball injection irritation test
(1) blood vessel irritation experiment
Two kinds of different dosage forms of vinorelbine injection are carried out body surface area by clinical application amount (30mg/ time) to convert and draws experimental rabbit with dosage (1.4mg/kg).The dosage of pressing 2ml/kg before the test is with the fresh preparation of aseptic normal saline solution.Select 6 of the healthy new zealand white rabbits of body weight 2.5-3.0kg for use, male and female have concurrently.After iodine tincture and ethanol disinfection were used in the injection site, 3 white rabbits were in auris dextra auricular vein injection vinorelbine liquid drugs injection injection (Cs), and left ear is injected the aseptic normal saline solution of same dose in contrast; 3 white rabbits are in auris dextra auricular vein injection vinorelbine liposome micro ball injection (Cz) in addition, and left ear is injected the aseptic normal saline solution of same dose in contrast, and injection speed is 2.8ml/min (being equivalent to people's clinical injection speed).Once a day, continuous three days, the last administration was after 24 hours, inject air by auricular vein and put to death white rabbit, the response situation of perusal injection site, and dissect rabbit ear blood vessel and surrounding tissue is done paraffin section (entad holding 1cm and 5cm place under the injection site), HE dyeing, light microscopy checking.The result of perusal injection site reaction situation is shown in table-1, and pathological section is checked by disease prevention and control center, Liaoning Province, and presented audit report.
The result: shown in table-1, two kinds of dosage form blood vessel irritation tests of vinorelbine injection perusal.The result shows: the blood vessel irritation of Cz is weaker than Cs; Microscopy report shows: the Cs group has to a certain degree blood vessel irritation to New Zealand white rabbit ear blood vessel, and the Cz group is not seen obvious irritation to New Zealand white rabbit ear blood vessel.
Table-1 blood vessel irritation test perusal
(2) muscle irritation experiment
The dosage of vinorelbine injection converts, the selection of medicine preparation, New Zealand white rabbit the same (totally 4, every kind dosage form 2).Cut off the rabbit hair at quadriceps femoris position, white rabbit both sides, behind iodine tincture and ethanol disinfection, respectively at right lateral thigh musculus quadriceps injection vinorelbine liquid drugs injection injection (Cs) and vinorelbine liposome micro ball injection (Cz) injection 1ml, the physiological saline solution injection of left side quadriceps femoris injection equivalent is injected after 48 hours in contrast, goes into air by auricular vein and puts to death white rabbit, dissect and take out quadriceps femoris, vertically cut, observe the response situation of injection site muscular tissue, determine the order of reaction.
0 grade: no change.
1 grade: mild hyperaemia, its scope is below 0.5cm * l.0cm.
2 grades: moderate hyperemia, its scope is more than 0.5cm * 1.0cm.
3 grades: severe hyperemia, with myodegeneration.
4 grades: necrosis occurs, the brown degeneration is arranged.
5 grades: the popularity necrosis occurs.
Calculate 4 quadriceps femoris order of reaction summations then, test again if the difference of the peak of the quadriceps femoris order of reaction and minimum, then should be got 2 healthy rabbits in addition greater than 2.After obtaining the result, if 4 quadriceps femoris order of reaction summations, think then that the local irritation test of test sample is up to specification less than 10.
The result: the muscle irritation result of the test of two kinds of dosage form injection of vinorelbine is shown in table-2.
The result shows: the muscle irritation of Cz is weaker than Cs.
Table-2 muscle irritation result of the tests
The hemolytic experiment
Get blood 20ml from the common carotid artery of New Zealand white rabbit, place in the flask, stir gently with Glass rod, after several minutes, remove and defibrinate, take out blood, add the equivalent normal saline solution, centrifugal (1500r/min 10min), removes supernatant; Sedimentary erythrocyte adds normal saline solution again and cleans, and is centrifugal.Transparent until supernatant so repeatedly, be made into 2% suspension with normal saline by erythrocytic capacity.
Get 7 of clean tube, numbering adds each liquid in the following table successively respectively, the 6th pipe does not add test liquid as the blank pipe, and the 7th effective distilled water replaces normal saline, shakes up, whether place 37 ℃ of water-baths, observing respectively at 0.5 hour, 1 hour, 2 hours, 3 hours has haemolysis to take place.
The result: the hemolytic experimental result of two kinds of dosage form injection of vinorelbine sees Table-3, shows-4.
Table-3 vinorelbine liquid drugs injection dregs penetrate drips (Cs) hemolytic experimental result
| The test tube numbering | Cs (ml) | Normal saline (ml) | 2% cell suspension (ml) | 0.5 hour | 1 |
2 hours | 3 hours |
| 1 2 3 4 5 6 7 | 0.1 0.3 0.4 0.5 O distilled water 2.5 O.2 | 2.4 2.3 2.2 2.1 2.0 2.5 0 | 2.5 2.5 2.5 2.5 2.5 2.5 2.5 | ------+ | ------+ | ------+ | ------+ |
-, do not see haemolysis; +, haemolysis.
Table-4 vinorelbine liposome micro ball injections (Cz) hemolytic experimental result
| The test tube numbering | Cs (ml) | Normal saline (ml) | 2% cell suspension (ml) | 0.5 hour | 1 |
2 hours | 3 hours |
| 1 2 3 4 5 6 7 | 0.1 0.2 0.3 0.4 0.5 0 distilled water 2.5 | 2.4 2.3 2.2 2.1 2.0 2.5 0 | 2.5 2.5 2.5 2.5 2.5 2.5 2.5 | - - - - - - + | - - - - - - + | - - - - - - + | - - - - - - + |
One, do not see haemolysis; Ten, haemolysis.
The result shows: Cs, Cz do not see that haemolysis takes place, all qualified anaphylaxis experiment of the hemolytic experiment of two kinds of dosage forms
Get 8 of healthy guinea pigs, body weight 250-280g, male and female half and half, vinorelbine liquid drugs injection injection (Cs), two kinds of dosage forms of vinorelbine liposome micro ball injection (Cz) each 4 (male and female half and half), prepare by clinical practice dosage (30mg/ time) the conversion Cavia porcellus consumption (O.46mg/200g) of vinorelbine injection and with normal saline solution, the corresponding test liquid 0.5ml of every Cavia porcellus ip (lumbar injection), the next day once, totally three times.The the 14th, the 21 day corresponding reagent liquid 1ml (the dosage conversion is the same) that supplies of lateral vein injection outside the hind paw of every Cavia porcellus after injection first attacks.Each intravenously administrable was observed 2 hours, as two or more person who occurs grabbing in nose, perpendicular hair, cough, the dyspnea is judged to the positive; Be judged to the positive if any one of spasm, gatism, collapse, shock, phenomena of mortality person.The negative of above-mentioned symptom do not appear.
The anaphylaxis experimental result of two kinds of dosage form injection of vinorelbine is shown in table-5.
In the experimentation, Cs dosage group may be because the gastrointestinal irritation of medicine is excessive, causes the Cavia porcellus anorexia to detest water, diet initiatively not, respectively at different number of days death after the administration.(experiment triplicate)
Table-5 anaphylaxis experimental results
" feminine gender " expression is not irritated.
The result shows: two kinds of dosage forms of Cs, Cz all meet the anaphylaxis experimental standard.
Description of drawings
Fig. 1 LM structural representation
1 medicine, 2 lipid cores, 3 immobilized artificial membranes
Vinorelbine liposome micro ball injection change of granularity figure after Fig. 2 dilution
The specific embodiment
The prescription of vinorelbine preparation and preparation technology
Comparative Examples 1
Prescription 1:
Oil phase (soybean oil/MCT Oil=2/8) 10%
Vinorelbine 0.1%
Lecithin 1.2%
Glycerol 2.5%
Tween-80 0.2％
Enuatrol 0.1%
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.1％
Water for injection adds to 100ml
Preparation method 1:
(1) with lecithin, glycerol, Tween-80, the enuatrol of recipe quantity and be preheated to 70-80 ℃ an amount of water for injection and mix, change in the tissue mashing machine, stirred for several minute, 5 times, disperse until each uniform ingredients, water; (2) 10-hydroxyl-2-decylenic acid, the Span80 of recipe quantity added to 70-80 ℃ of mixing of heating in the mixing oil phase of injection soybean oil and injection MCT Oil, get oil phase: (3) add aqueous phase with oil phase, change in the tissue mashing machine, stirred for several minute, 1-5 time, until the oil phase homodisperse, get colostrum; (4) the vinorelbine drug powder is added this Ruzhong just, stirred 10 minutes, regulate about pH value to 8.5; (5) get above-mentioned colostrum add be preheated to 70-80 ℃ water for injection to full dose, be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (6) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Comparative Examples 2
Prescription 2:
Injection soybean oil 10%
Vinorelbine 0.1
Fabaceous lecithin 1.2%
Glycerol 2.5%
Tween-80 0.2％
Enuatrol 0.1%
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.1％
Water for injection adds to 100ml
Preparation method 2:
(1) Tween-80 of recipe quantity, enuatrol, fabaceous lecithin, glycerol are mixed with preheating 70-80 ℃ an amount of water for injection, change in the tissue mashing machine, stirred for several minute, 5 times, disperse until each uniform ingredients, water; Simultaneously 10-hydroxyl-2-decylenic acid, Span80 are added to 70-80 ℃ of heating mixing in the recipe quantity soybean oil, get oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stirred 10 minutes, 3 times,, get colostrum until the oil phase homodisperse; (3) the vinorelbine drug powder is added this Ruzhong just, stirred 10 minutes, regulate about pH value to 8.5, the water for injection that adds 70-80 ℃ of preheating is to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Comparative Examples 3
Prescription 3:
Oil phase (soybean oil/MCT Oil=2/8) 10%
Vinorelbine 0.1%
Lecithin 1.2%
Glycerol 2.5%
lween-80 0.2％
Enuatrol 0.1%
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.1％
Vitamin E 0.05%
Ascorbic acid 0.1%
Water for injection adds to 100ml
Preparation method 3:
(1) with lecithin, glycerol, Tween-80, enuatrol, the ascorbic acid of recipe quantity and be preheated to 70-80 ℃ an amount of water for injection and mix, change in the tissue mashing machine, stirred for several minute, 5 times, disperse until each uniform ingredients, water; Simultaneously vitamin E, 10-hydroxyl-2-decylenic acid, Span80 are added to 70-80 ℃ of heating mixing in the recipe quantity oil phase, get oil phase; (2) oil phase is added to aqueous phase, changes in the tissue mashing machine, stirred 10 minutes,, get colostrum until the oil phase homodisperse; (3) vinorelbine is added to above-mentioned Ruzhong just, stir, regulate about pH value to 8.5; The water for injection that adds preheating 70-80 ℃ is transferred in the high pressure homogenizer to full dose, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (4) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Embodiment 1
Prescription 4:
Oil phase (soybean oil/MCT Oil=2/8) 10%
Vinorelbine 0.1%
Lecithin 1.2%
Glycerol 2.5%
Enuatrol 0.1%
Tween-80 0.2％
L0-hydroxyl-2-decylenic acid 0.5%
Span80 0.1％
Ascorbic acid 0.1%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100mL
Preparation method 4:
(1) recipe quantity lecithin, Tween-80, glycerol, enuatrol, ascorbic acid, the EDTA an amount of water for injection with preheating 70-80 ℃ is mixed, changes in the tissue mashing machine, stirred for several minute, 5 times, disperse until each uniform ingredients, water; Simultaneously recipe quantity vitamin E, 10-hydroxyl-2-decylenic acid, Span80 are added in the mixing oil phase of being made up of injection MCT Oil, injection soybean oil, are stirred to complete mixing under heating 70-80 ℃, oil phase.(2) oil phase is added to aqueous phase, places high-speed tissue mashing machine's stirred for several minute, 3 times, colostrum.(3) vinorelbine is added so far in the colostrum, stirring and evenly mixing is regulated about pH value to 8.5, and the water for injection that adds preheating 70-80 ℃ is transferred to the high pressure homogenizer homogenizing 10 times to full dose.The sampling microscopy, to particle diameter below 0.3 micron; (4) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Prescription 5:
Injection soybean oil 10%
Vinorelbine tartrate 0.1%
Fabaceous lecithin 1.2%
Glycerol 2.5%
Tween-80 0.2％
Enuatrol 0.1%
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.1％
Sodium sulfite 0.2%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100ml
Preparation method 5:
(1) fabaceous lecithin of recipe quantity, Tween-80, enuatrol, glycerol, sodium sulfite, the EDTA an amount of water for injection with preheating 70-80 ℃ is mixed, changes in the tissue mashing machine, stirred for several minute, 5 times, disperse until each uniform ingredients, water; Vitamin E, 10-hydroxyl-2-decylenic acid, Span80 with recipe quantity adds to 70-80 ℃ of heating for dissolving in the recipe quantity injection soybean oil simultaneously, gets oil phase; (2) oil phase is added aqueous phase, changes in the tissue mashing machine, stirred for several minute, 5 times, until the oil phase homodisperse, colostrum; (3) the recipe quantity vinorelbine tartrate is added to above-mentioned Ruzhong just, regulate pH value about 8.5, adding is preheated to 70-80 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Embodiment 3
Prescription 6:
Oil phase (soybean oil/MCT Oil=2/8) 10%
Vinorelbine tartrate 0.1%
Lecithin 1.2%
Glycerol 2.5%
Tween-80 0.2％
Enuatrol 0.1%
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.1％
L-cysteine 0.2%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100ml
Preparation method 6:
(1) lecithin of recipe quantity, Tween-80, enuatrol, glycerol, L-cysteine, the EDTA an amount of water for injection with preheating 70-80 ℃ is mixed, changes in the tissue mashing machine, stirred for several minute, 5 times, disperse until each uniform ingredients, water; Simultaneously vitamin E, 10-hydroxyl-2-decylenic acid, the Span80 of recipe quantity added to 70-80 ℃ of heating for dissolving in the mixing oil phase of recipe quantity injection soybean oil and injection MCT Oil, oil phase; (2) oil phase is added aqueous phase, changes in the tissue mashing machine, stirred for several minute, 5 times, until the oil phase homodisperse, colostrum; (3) the recipe quantity vinorelbine tartrate is added to above-mentioned Ruzhong just, regulate pH value about 8.5, the water for injection that adds 70-80 ℃ of preheating is to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
| Sample | Outward appearance | PH value | Mean diameter | Zeta potential | Content (mg/ml) | Encapsulation ratio |
| Prescription 1 | Even emulsion | 8.45 | 175nm | -25.76 | 0.962 | 96.5 |
| Prescription | ||||||
| 2 | Even emulsion | 8.40 | 256nm | -27.85 | 0.973 | 92.3％ |
| Prescription 3 | Even emulsion | 7.36 | 212nm | -30.58 | 0.954 | 94.5％ |
| |
Even emulsion | 7.40 | 182nm | -32.56 | 0.925 | 96.3％ |
| Prescription 5 | Even emulsion | 8.36 | 259nm | -35.64 | 0.942 | 94.5 |
| Prescription | ||||||
| 6 | Even emulsion | 8.31 | 198nm | -26.15 | 0.978 | 98.8％ |
The sample room temperature of above-mentioned 6 prescription preparations was placed one month for 25 ℃, and every index is investigated as follows:
| Sample | Outward appearance | PH value | Mean diameter | Zeta potential | Content (mg/ml) | Encapsulation ratio |
| Prescription 1 | Even emulsion | 8.43 | 183nm | -25.50 | 0.764 | 95.0 |
| Prescription | ||||||
| 2 | Even emulsion | 8.37 | 270nm | -27.90 | 0.770 | 91.2％ |
| Prescription 3 | Even emulsion | 7.26 | 220nm | -29.58 | 0.845 | 93.8 |
| Prescription | ||||||
| 4 | Even emulsion | 7.24 | 185nm | -31.26 | 0.924 | 96.0％ |
| Prescription 5 | Even emulsion | 8.38 | 265nm | -34.48 | 0.941 | 94.0 |
| Prescription | ||||||
| 6 | Even emulsion | 8.28 | 199nm | -25.35 | 0.967 | 98.3％ |
| Sample | Outward appearance | PH value | Mean diameter | Zeta potential | Content (mg/ml) | |
| Prescription | ||||||
| 4 | Even emulsion | 7.20 | 188nm | -30.22 | 0.920 | 96.2％ |
| Prescription 5 | Even emulsion | 8.40 | 268nm | -35.48 | 0.940 | 93.8 |
| Prescription | ||||||
| 6 | Even emulsion | 8.23 | 212nm | -24.24 | 0.962 | 98.0％ |
| Sample | Outward appearance | PH value | Mean diameter | Zeta potential | Content (mg/ml) | |
| Prescription | ||||||
| 4 | Even emulsion | 7.16 | 193nm | -31.26 | 0.921 | 95.5％ |
| Prescription 5 | Even emulsion | 8.45 | 271nm | -35.20 | 0.937 | 93.0 |
| Prescription | ||||||
| 6 | Even emulsion | 8.22 | 215nm | -23.75 | 0.960 | 97.6％ |
Result: do not add sample (Comparative Examples 1 and the Comparative Examples 2) room temperature that the prescription of antioxidant and metal ion chelation agent makes and placed drug degradation about 20% one month for 25 ℃; Add antioxidant and do not add the sample room temperature that the prescription (Comparative Examples 3) of metal ion chelation agent makes and placed one month drug degradation about 10% for 25 ℃; Not only added antioxidant but also added the sample room temperature that the prescription (embodiment 1-embodiment 3) of metal ion chelation agent makes and placed one month for 25 ℃, medicine is degraded not.
Not only added antioxidant but add sample that the prescription (embodiment 1-embodiment 3) of metal ion chelation agent makes through 6 months every quality index of accelerated test all within acceptability limit; Keep sample 12 months result of the tests of room temperature show that every quality index is stable, all within acceptability limit, can fix tentatively 1 year its storage period.
Prescription 7:
Safflower oil 10%
Vinorelbine 0.05%
Lecithin 1.2%
Mannitol 3%
Cholic acid 0.1%
Poloxamer F68 0.2％
10-hydroxyl-2-decylenic acid 1%
Sodium pyrosulfite 0.1%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100mL
Preparation method 7:
(1) with recipe quantity lecithin, Poloxamer F68, mannitol, cholic acid, sodium pyrosulfite, EDTA and be preheated to 70-80 ℃ an amount of water for injection and mix, change in the tissue mashing machine stirred for several minute, 5 times over to, disperse until each uniform ingredients, get water; (2) recipe quantity vitamin E, 10-hydroxyl-2-decylenic acid are added in the safflower oil, are stirred to complete mixing under heating 70-80 ℃, oil phase.(3) oil phase is added to aqueous phase, places high-speed tissue mashing machine's stirred for several minute, 5 times, colostrum.(4) vinorelbine is added so far in the colostrum, stirring and evenly mixing is regulated pH value to 8.5, and the water for injection dilution is settled to recipe quantity, is transferred to the high pressure homogenizer homogenizing 10 times.The sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Embodiment 5
Prescription 8:
Oil phase (Semen Coicis oil/Oleum Fructus Bruceae) 10%
Vinorelbine tartrate 0.1%
Lecithin 1.5%
Glycerol 2.5%
Tween-80 0.2％
Cholic acid 0.2%
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.2％
L-cysteine 0.2%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100ml
Preparation method 8:
(1) with lecithin, L-cysteine, cholic acid, glycerol, EDTA, the Tween-80 of recipe quantity and be preheated to 70-80 ℃ an amount of water for injection and mix, change in the tissue mashing machine, stirred for several minute, 1-5 time, disperse until each uniform ingredients, water; Simultaneously vitamin E, 10-hydroxyl-2-decylenic acid, the Span80 of recipe quantity added to 70-80 ℃ of heating for dissolving in the mixing oil phase of recipe quantity Semen Coicis oil, Oleum Fructus Bruceae, oil phase; (2) oil phase is added aqueous phase, changes in the tissue mashing machine, stirred for several minute, 5 times, until the oil phase homodisperse, colostrum; (3) the recipe quantity vinorelbine tartrate is added to above-mentioned Ruzhong just, regulate pH value 8.5, adding is preheated to 70-80 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Prescription 9:
Oil phase (soybean oil/MCT Oil=4/6) 10%
Vinorelbine 0.2%
Lecithin 1.2%
Glucose 5%
Enuatrol 0.01%
Poloxamer F68 0.2％
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.5％
Sodium sulfite 0.1%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100mL
Preparation method 9:
(1) with recipe quantity lecithin, Poloxamer F68, glucose, enuatrol, sodium sulfite, EDTA and be preheated to 70-80 ℃ an amount of water for injection and mix, change in the tissue mashing machine stirred for several minute, 1-5 time over to, disperse until each uniform ingredients, get water; (2) recipe quantity vitamin E, 10-hydroxyl-2-decylenic acid, Span80 are added in the mixing oil phase of being made up of injection MCT Oil, injection soybean oil, are stirred to complete mixing under heating 70-80 ℃, oil phase.(3) oil phase is added to aqueous phase, places high-speed tissue mashing machine's stirred for several minute, 3 times, colostrum.(4) vinorelbine is added so far in the colostrum, stirring and evenly mixing is regulated pH value to 8.5, and the water for injection dilution is settled to recipe quantity, is transferred to the high pressure homogenizer homogenizing 10 times.The sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Embodiment 7
Prescription 10:
Oil phase (soybean oil/MCT Oil=2/8) 20%
Vinorelbine 1.0%
Fabaceous lecithin 1.2%
Glycerol 2.5%
Enuatrol 0.1%
Poloxamer F68 0.2％
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.5％
Sodium sulfite 0.1%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100mL
Preparation method 10:
(1) with recipe quantity fabaceous lecithin, PoloxamerF68, glycerol, enuatrol, sodium sulfite, EDTA and be preheated to 70-80 ℃ an amount of water for injection and mix, change in the tissue mashing machine stirred for several minute, 5 times over to, disperse until each uniform ingredients, get water; (2) recipe quantity vitamin E, 10-hydroxyl-2-decylenic acid, Span80 are added in the mixing oil phase of being made up of injection MCT Oil, injection soybean oil, are stirred to complete mixing under heating 70-80 ℃, oil phase.(3) oil phase is added to aqueous phase, places high-speed tissue mashing machine's stirred for several minute, 5 times, colostrum.(4) vinorelbine is added so far in the colostrum, stirring and evenly mixing is regulated pH value to 8.5, and the water for injection dilution is settled to recipe quantity, is transferred to the high pressure homogenizer homogenizing 10 times.The sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Prescription 11:
Oil phase (Semen Coicis oil/Oleum Fructus Bruceae) 15%
Vinorelbine 0.5%
Fabaceous lecithin 1.5%
Glycerol 2.5%
Tween-80 0.2％
Cholic acid 0.2%
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.1％
L-cysteine 0.2%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100ml
Preparation method 11:
(1) with fabaceous lecithin, Tween-80, glycerol, L-cysteine, cholic acid, the EDTA of recipe quantity and be preheated to 70-80 ℃ an amount of water for injection and mix, change in the tissue mashing machine, stirred for several minute, 5 times, disperse until each uniform ingredients, water; Simultaneously vitamin E, 10-hydroxyl-2-decylenic acid, the Span80 of recipe quantity added to 70-80 ℃ of heating for dissolving in the mixing oil phase of recipe quantity Semen Coicis oil, Oleum Fructus Bruceae, oil phase; (2) oil phase is added aqueous phase, changes in the tissue mashing machine, stirred for several minute, 5 times, until the oil phase homodisperse, colostrum; (3) the recipe quantity vinorelbine is added to above-mentioned Ruzhong just, regulate pH value 8.5, adding is preheated to 70-80 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
Claims (10)
1. lipide microsphere injection that contains vinorelbine is characterized in that the composition of injection is by weight percentage:
Vinorelbine 0.001%～10%
Oil-soluble medium 2%～50%
Surfactant 0.2%～10%
Osmotic pressure regulator 0.1%～10%
Oil phase solubilizing agent 0.1%～5%
Antioxidant 0.001%～2%
Metal-chelator 0.001%～2%
All the other are water for injection.
Wherein, vinorelbine is tartrate, maleate, lactate, malate, hydrochlorate, sulfate, the phosphate of vinorelbine;
Vegetable oil in the oil-soluble medium is a safflower oil, soybean oil, Semen Maydis oil, Semen Coicis oil, Oleum Fructus Bruceae, Oleum Ricini, Oleum Gossypii semen, Oleum Cocois, Petiolus Trachycarpi oil, MCT Oil MCT or its mixture; Animal oil is sebum, Adeps Sus domestica, fish oil, sperm oil and composition thereof;
Surfactant is that the phospholipid in the described surfactant is lecithin, fabaceous lecithin or its mixture;
Osmotic pressure regulator is a glycerol, sorbitol, mannitol, glucose or its mixture;
The oil phase solubilizing agent is 10-hydroxyl-2-decylenic acid, fatty acid esters of sorbitan Span or its mixture;
Antioxidant is water solublity antioxidant: sodium sulfite, sodium pyrosulfite, sodium sulfite, ascorbic acid, L-cysteine; Oil-soluble antioxidant: vitamin E or its mixture;
Metal-chelator is disodium EDTA EDTA, calcium disodium salt of EDTA or its mixture.
2. a kind of lipide microsphere injection that contains vinorelbine according to claim 1 is characterized in that; Phospholipid in the described surfactant is lecithin, fabaceous lecithin or its mixture; Tween in the described surfactant is a polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85, or its mixture; The pluronic of described surfactant is pluronic F68; Fatty acid esters of sorbitan Span in the described oil phase solubilizing agent is Span20,40,60,80, and perhaps its mixture.
3. a kind of lipide microsphere injection that contains vinorelbine according to claim 1 and 2 is characterized in that the vinorelbine of 90%-98% is wrapped in oil phase or the oil-water interfacial film in the injection.
4. a kind of lipide microsphere injection that contains vinorelbine according to claim 3 is characterized in that consisting of of this injection:
Vinorelbine 0.01%～5%
Oil-soluble medium 5%～30%
Surfactant 0.5%～5%
Osmotic pressure regulator 0.5%～5%
Oil phase solubilizing agent 0.2%～3%
Antioxidant 0.01%～1%
Metal-chelator 0.01%～1%
All the other are water for injection.
5. a kind of lipide microsphere injection that contains vinorelbine according to claim 4 is characterized in that consisting of of this injection:
Vinorelbine 0.05%～1%
Oil-soluble medium 8%～20%
Surfactant 1%～3%
Osmotic pressure regulator 1%～5%
Oil phase solubilizing agent 0.4%～2%
Antioxidant 0.05%～0.5%
Metal-chelator 0.02%～0.5%
All the other are water for injection.
6. a kind of lipide microsphere injection that contains vinorelbine according to claim 5 is characterized in that the composition of this injection is by weight percentage:
Vinorelbine 0.1%
The oil-soluble medium is soybean oil 2% MCT Oil 8%
Surfactant is lecithin 1.2%Tween-80 0.2% enuatrol 0.1%
Osmotic pressure regulator is a glycerol 2.5%
The oil phase solubilizing agent is 10-hydroxyl-2-decylenic acid 0.5%Span80 0.1%
Antioxidant is L-cysteine 0.2% vitamin E 0.05%
Metal-chelator is EDTA 0.05%
All the other are water for injection.
7. according to the preparation method of the described a kind of vinorelbine liposome micro ball injection of arbitrary claim among the claim 1-6, it is characterized in that comprising following steps: mix surfactant, osmotic pressure regulator, water solublity antioxidant, the metal-chelator of recipe quantity (1) with the water for injection that is preheated to 70-80 ℃, change in the tissue mashing machine, stir, until each composition dissolving, get water; With in the oil-soluble antioxidant of recipe quantity, the oil-soluble medium that the oil phase solubilizing agent adds to recipe quantity, be heated to 70-80 ℃ simultaneously, dissolving, oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stir,, get colostrum until the oil phase homodisperse; (3) the recipe quantity vinorelbine is added to above-mentioned Ruzhong just, use sodium hydroxide, hydrochloric acid is regulated pH value 7-9, and adding is preheated to 70-80 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 1-10 time, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
8. the preparation method of the described a kind of vinorelbine liposome micro ball injection of claim 7 is characterized in that comprising following steps:
(1) surfactant, osmotic pressure regulator, water solublity antioxidant, the metal-chelator with recipe quantity mixes with the water for injection that is preheated to 70-80 ℃, changes in the tissue mashing machine, stirs, and until each composition dissolving, gets water; With in the oil-soluble antioxidant of recipe quantity, the oil-soluble medium that the oil phase solubilizing agent adds to recipe quantity, be heated to 70-80 ℃ simultaneously, dissolving, oil phase;
(2) oil phase is added aqueous phase, change in the tissue mashing machine, stir,, get colostrum until the oil phase homodisperse; (3) the recipe quantity vinorelbine is added to above-mentioned Ruzhong just, use sodium hydroxide, hydrochloric acid is regulated pH value 7-9, and adding is preheated to 70-80 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 1-10 time, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
9. the preparation method of the described a kind of vinorelbine liposome micro ball injection of claim 8 is characterized in that comprising following steps:
(1) surfactant, osmotic pressure regulator, water solublity antioxidant, the metal-chelator with recipe quantity mixes with the water for injection that is preheated to 70 ℃, changes in the tissue mashing machine, stirs, and until each composition dissolving, gets water; With in the oil-soluble antioxidant of recipe quantity, the oil-soluble medium that the oil phase solubilizing agent adds to recipe quantity, be heated to 70 ℃ simultaneously, dissolving, oil phase; (2) oil phase is added aqueous phase, change in the tissue mashing machine, stir,, get colostrum until the oil phase homodisperse; (3) the recipe quantity vinorelbine is added to above-mentioned Ruzhong just, use sodium hydroxide, hydrochloric acid is regulated pH value 8.5, and adding is preheated to 70 ℃ water for injection to full dose; (4) be transferred in the high pressure homogenizer, high pressure homogenize 10 times, the sampling microscopy, to particle diameter below 0.3 micron; (5) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
10. the preparation method of the described a kind of vinorelbine liposome micro ball injection of claim 9 is characterized in that comprising following steps:
Prescription is:
Oil phase: soybean oil/MCT Oil=2/8 10%
Vinorelbine 0.1%
Lecithin 1.2%
Glycerol 2.5%
Enuatrol 0.1%
Tween-80 0.2％
10-hydroxyl-2-decylenic acid 0.5%
Span80 0.1％
Ascorbic acid 0.1%
Vitamin E 0.05%
EDTA 0.05％
Water for injection adds to 100mL
Preparation method:
(1) recipe quantity lecithin, Tween-80, glycerol, enuatrol, ascorbic acid, the EDTA an amount of water for injection with preheating 70-80 ℃ is mixed, changes in the tissue mashing machine, stirred for several minute, 5 times, disperse until each uniform ingredients, water; Simultaneously recipe quantity vitamin E, 10-hydroxyl-2-decylenic acid, Span80 are added in the mixing oil phase of being made up of injection MCT Oil, injection soybean oil, are stirred to complete mixing under heating 70-80 ℃, oil phase.(2) oil phase is added to aqueous phase, places high-speed tissue mashing machine's stirred for several minute, 3 times, colostrum.(3) vinorelbine is added so far in the colostrum, stirring and evenly mixing is regulated about pH value to 8.5, and the water for injection that adds preheating 70-80 ℃ is transferred to the high pressure homogenizer homogenizing 10 times to full dose.The sampling microscopy, to particle diameter below 0.3 micron; (4) embedding is filled nitrogen in infusion bottle, places the high-pressure rotary steriliser to sterilize.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101155566A CN100375621C (en) | 2005-11-04 | 2005-11-04 | Vinorelbine liposome micro ball injection and its prepn |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101155566A CN100375621C (en) | 2005-11-04 | 2005-11-04 | Vinorelbine liposome micro ball injection and its prepn |
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| Publication Number | Publication Date |
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| CN1771954A CN1771954A (en) | 2006-05-17 |
| CN100375621C true CN100375621C (en) | 2008-03-19 |
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| CNB2005101155566A Expired - Fee Related CN100375621C (en) | 2005-11-04 | 2005-11-04 | Vinorelbine liposome micro ball injection and its prepn |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101129375B (en) * | 2007-07-06 | 2010-12-22 | 浙江大学 | Vinorelbine solid lipid nano granule, freeze drying formulated product and method of preparing the same |
| CN101879138A (en) | 2009-05-06 | 2010-11-10 | 上海恒瑞医药有限公司 | Vinca alkaloid nano emulsion injection and preparation method thereof |
| CN101904814A (en) | 2009-06-04 | 2010-12-08 | 上海恒瑞医药有限公司 | Preparation method of drug loaded emulsion |
| CN103720653B (en) * | 2012-10-12 | 2016-01-20 | 天津药物研究院 | A kind of vinorelbine submicron emulsion injection and preparation method thereof |
| US10220095B2 (en) | 2013-03-15 | 2019-03-05 | Taiwan Liposome Company, Ltd | Controlled drug release liposome compositions and methods thereof |
| NZ711500A (en) | 2013-03-15 | 2020-05-29 | Taiwan Liposome Co Ltd | Engineering a control drug release profile via liposome compositions in both aqueous and non-aqueous compartments |
| CN104706585A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Vinorelbine bitartrate fat emulsion concentrated solution, preparation method and application thereof |
| CN116546973A (en) * | 2020-11-19 | 2023-08-04 | 日本化药株式会社 | Composition containing water-soluble drug for causing vascular disorder, solution for preparing drug solution containing water-soluble drug for causing vascular disorder, kit, vascular disorder inhibitor, and solution containing nonionic surfactant |
| CN115645358A (en) * | 2022-09-09 | 2023-01-31 | 江苏豪森药业集团有限公司 | Vinorelbine tartrate injection preparation and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1446079A (en) * | 2000-06-30 | 2003-10-01 | 英耐克斯药品股份有限公司 | Liposomal antineoplastic drugs and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1446079A (en) * | 2000-06-30 | 2003-10-01 | 英耐克斯药品股份有限公司 | Liposomal antineoplastic drugs and uses thereof |
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