CN1634058A - Vinorelbine emulsion and its preparing method - Google Patents
Vinorelbine emulsion and its preparing method Download PDFInfo
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- CN1634058A CN1634058A CN 200410065105 CN200410065105A CN1634058A CN 1634058 A CN1634058 A CN 1634058A CN 200410065105 CN200410065105 CN 200410065105 CN 200410065105 A CN200410065105 A CN 200410065105A CN 1634058 A CN1634058 A CN 1634058A
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Abstract
The invention relates to a vinorelbine emulsion which comprises (by weight ratio) vinorelbine 0.001-10%, emulsifying agent 0.1-20%, triglyceride compounds 0.1-30%, osmoregulation agent 0.1-10%, stabilizing agent 0.05-5%, anti-oxidant 0.01-5%, and balancing water for injection. The invention has the advantages of increased medicament stability and improved curative effect.
Description
One, technical field
The present invention relates to a kind of anti-tumor medicinal preparation and preparation method thereof, exactly is a kind of vinorelbine emulsion and preparation method thereof.
Two, background technology
Vinorelbine is a kind of semisynthetic vinca antitumor drug, the active anticancer height, antitumor spectra is wide, its mechanism of action and vincaleucoblastine (VLB) and vincristine (VCR) are basic identical, belong to vinca and suppress fissional antitumor drug, directly act on the dynamic equilibrium of tubulin/microtubule, can suppress the polymerization of tubulin, and make division stage microtubule disintegrate, only under high concentration, influence the aixs cylinder microtubule, effect to the tubulin spiralization is lower than vincristine, by the mitosis of blocking-up G2 and M phase cell, cause entering interval or the anaphase of cell division cell death; Pharmacokinetics is three-compartment model behind the intravenously administrable, and the last phase average half-life is 40hr eventually, and plasma clearance is higher, is about 800ml/kg body weight/hr, organizes uptake rate high and lasting, because of biliary tract elimination factor height, so mainly through defecate.Plasma protein in conjunction with level up to 50-80%.
Clinical research shows that single medicine of this product or drug combination can be treated nonsmall-cell lung cancer, metastatic breast cancer and intractable lymphoma, ovarian cancer, tumor of head and neck.Single therapy, recommended dose is 25-30mg/m2 weekly; Platinum medicine drug combinations such as normal and cisplatin.
The dosage form that vinorelbine is commonly used clinically is injection and freeze-dried powder, dosage is that 5-50mg/ props up, because it contacts with alkaline matter and is easy to generate precipitation, and be adsorbed easily after transfusion device contacts, therefore must dilute with normal saline earlier in use, 250-500ml normal saline flushing vein is used in input then in the short time (6-10min).Vinorelbine has stronger zest to blood vessel, patient's poor compliance simultaneously.Have a strong impact on its clinical use and clinical safety and clinical efficacy.
Three, summary of the invention
Vinorelbine emulsion provided by the invention, be intended to improve the stability of vinorelbine, clinical use convenience, improve the patient compliance, reduce its zest to blood vessel, better bring into play clinical efficacy.Described vinorelbine emulsion both can be oral, but intravenous injection again.To used for intravenous injection Emulsion can be liquid preparation, also can be with the lyophilized preparation after the Emulsion lyophilization.
The present invention also comprises the preparation method of vinorelbine industrializing implementation.
Vinorelbine emulsion of the present invention is grouped into (percentage by weight, down together) by following one-tenth:
Vinorelbine 0.001-10% emulsifying agent 0.1-20%
Triglyceride compounds 0.1-30% osmotic pressure regulator 0.1-10%
Stabilizing agent 0.05-5% surplus is a water.
Be used for intravenous lyophilized preparation, also contain 0.5～10% excipient.
Preferred proportioning is:
Vinorelbine 0.05～5% emulsifying agent 0.5～10%
Triglyceride compounds 0.2～15% osmotic pressure regulator 0.5～5%
Stabilizing agent 0.1～3% surplus is a water.
Be used for intravenous freeze-dried emulsion, also contain 1～5% excipient.
Above-mentioned vinorelbine is meant the various salt that vinorelbine alkali or itself and the acid reaction that pharmaceutically allows obtain, as: liquor epinephrinae bitartratis ophthalmicus, maleic acid, lactic acid, hydrochloric acid, sulphuric acid, phosphoric acid, malic acid etc.; Emulsifying agent is one or more blended emulsifiers in nonionic surfactant, fabaceous lecithin, the lecithin; The triglyceride compounds is meant one or more mixed triglycerides of long chain triglyceride and/or medium chain triglyceride, and commonly used have soybean oil, Oleum Arachidis hypogaeae semen, Semen Maydis oil, Oleum Cocois, Oleum Ricini, a Flos Carthami wet goods; Osmotic pressure regulator is the salt that glycerol, ethylene glycol, isopropyl alcohol and sodium chloride etc. pharmaceutically allow.Stabilizing agent is vitamin E, poloxamer, oleic acid, enuatrol and/or cholesterol etc.The excipient that uses during the preparation lyophilized formulations mainly contains lactose, mannose, mannitol, sorbitol, dextran, glucose etc.
The preparation method of vinorelbine emulsion of the present invention comprises the preparation of oil phase and water and mixing and emulsifying thereof, packing, sterilization, and it is characterized in that: described emulsifying is ultrasonic emulsification or homogenizer emulsifying, transfers pH 4～9 simultaneously.
Above-mentioned Emulsion can be directly oral after sterilization.For making the emulsion particle diameter more homogeneous that distributes, can select the aperture for use is that the microporous filter membrane of 0.45 μ m filters, and then the packing sterilization.
Above-mentioned Emulsion is if being used for intravenous injection must be through filtering with microporous membrane with degerming.Preferably selecting the aperture for use is the microporous filter membrane of 0.22 μ m.
The concrete operations step is as follows:
(1) with the even oil phase A that gets of vinorelbine, emulsifying agent, stabilizing agent and triglyceride compound;
(2) water soluble ingredient glycerol etc. is dissolved in the water aqueous phase B;
(3) oil phase A is joined in the aqueous phase B,, regulate pH value, obtain Emulsion C in the 4-9 scope through ultrasound wave or homogenizer emulsifying.Perhaps oil phase A is joined in the aqueous phase B, be emulsified into colostrum, regulate pH value, through ultrasound wave or homogenizer emulsifying, obtain Emulsion C again in the 4-9 scope.
Above Emulsion C can filtering with microporous membrane through 0.45 μ m after, packing, the packing volume is 0.5-100ml.Use as medicinal preparation for oral administration the sterilization back.
Perhaps, after the microporous filter membrane aseptic filtration of above Emulsion C through 0.22 μ m, packing, the packing volume is 0.5-100ml.Use as injection medicament the sterilization back.
The preparation of used for intravenous injection lyophilized preparation is with in 0.5～10% the excipient adding aqueous phase B, then oil phase A is added aqueous phase B and mixes, and is emulsified into colostrum, regulates pH value in the 4-9 scope, through ultrasound wave or homogenizer emulsifying, obtains Emulsion D again.After the microporous filter membrane aseptic filtration of Emulsion D through 0.22 μ m, packing, the packing volume is 0.5-5ml, lyophilization is used as the lyophilizing injection medicament.
Four, the specific embodiment
Be non-limiting examples below, be described below:
Example 1:
Get vinorelbine 2g, soybean phospholipid 20g, soybean oil 4g, cholesterol 6g, vitamin E 1g, mix homogeneously gets oil phase A solution; Get glycerol 20g, poloxamer 6g is dissolved in water, and to the 800ml aqueous phase B.Described water is water for injection (down together).
Oil phase A is joined in the aqueous phase B, grind and be emulsified into colostrum, regulating pH value with 1M NaOH is 8, and adding water to volume is 1000ml, through homogenizer emulsifying, prepares Emulsion again.Packing, packing volume 100ml becomes Orally taken emulsion after the rotation sterilization.Perhaps packing behind the microporous filter membrane of 0.45 μ m, sterilization.
After the microporous filter membrane aseptic filtration of above-mentioned Emulsion through 0.22 μ m, packing, the packing volume is 5ml, rotation steriliser sterilization back becomes injectable emulsion.
Example 2:
Get vinorelbine 2g, lecithin 25g, Oleum Ricini 4g, cholesterol 6g, vitamin E 1g, mix homogeneously gets oil phase A solution; Get glycerol 20g, poloxamer 6g is dissolved in water, and to the 800ml aqueous phase B.
Oil phase A is joined in the aqueous phase B, grind and be emulsified into colostrum, regulating pH value with 1M NaOH is 8, and adding water to volume is 1000ml, through homogenizer emulsifying, prepares Emulsion again.
After the microporous filter membrane aseptic filtration through 0.22 μ m, packing, the packing volume is 5ml, rotation steriliser sterilization back becomes injectable emulsion.
Example 3:
Get vinorelbine 5g, soybean phospholipid 30g, soybean oil 5g, cholesterol 1g, vitamin E 0.5g, mix homogeneously gets oil phase A solution; Get glycerol 10g, mannitol 3g is dissolved in water, and to the 800ml aqueous phase B.
Oil phase A is joined in the aqueous phase B, grind and be emulsified into colostrum, regulating pH value with 1M NaOH is 8, and adding water to volume is 1000ml, through homogenizer emulsifying, prepares Emulsion again.
After the microporous filter membrane aseptic filtration through 0.22 μ m, packing, the packing volume is 2ml, lyophilization gelation dry injection Emulsion.
Example 4:
Get vinorelbine 5g, lecithin 20g, Oleum Ricini 4g, cholesterol 1g, vitamin E 1g, mix homogeneously gets oil phase A solution; Get glycerol 10g, mannitol 4g is dissolved in water, and to the 800ml aqueous phase B.
Oil phase A is joined in the aqueous phase B, grind and be emulsified into colostrum, regulating pH value with 1M NaOH is 8, and adding water to volume is 1000ml, through homogenizer emulsifying, prepares Emulsion again.
After the microporous filter membrane aseptic filtration through 0.22 μ m, packing, the packing volume is 2ml, lyophilization gelation dry injection Emulsion.
Example 5:
(1) hemolytic
Get rabbit, in the dried and clean small beaker, stir except that defibrinating with glass rod from the about 2ml of heart extracting blood, add 5%GS to 10ml, shake up the centrifugal 5min of 2000rpm, remove supernatant, add 5%GS (glucose injection) again, mixing, the same operation, 2-3 time repeatedly, colourless to supernatant, remove supernatant, measure blood cell 1ml, add 5%GS to 50ml, be made into 2% red blood cell suspension, standby.
Get 7 in test tube, numbering is arranged on the test tube rack, adds each solution by subordinate list, and No. 6 pipe be for blank, manages positive contrast, after each pipe shakes up gently, puts and be incubated observed result after 0.5,1,2,3 hour in 37 ℃ of water-baths for No. 7.See Table 1.
Table 1 hemolytic experimental result
Examination
The pipe number
Liquid 1234567
ml
Need testing solution 0.1 0.2 0.3 0.4 0.5 //
5%GS 2.4 2.3 2.2 2.1 2.0 2.5 aquae destillatas 2.5
2% erythrocyte liquid 2.5 2.5 2.5 2.5 2.5 2.5 2.5
0.5h????-????-????-????-????-????-????+
1h????-????-????-????-????-????-????+
2h????-????-????-????-????-????-????+
3h????-????-????-????-????-????-????+
4h????-????-????-????-????-????-????+
Annotate: "+" full haemolysis; "-" no haemolysis or do not have coagulation; " ± " part haemolysis
The result shows that example 1,2,3,4 each Guan Jun of sample are haemolysis not.
(2) zest
Get rabbit, be divided into three groups at random, be i.e. normal saline group, vinorelbine injectable emulsion (2mg/ml) group and low dosage (1mg/ml) group.Rabbit is fixed in the rabbit hutch, respectively from auricular vein instillation investigational agent or contrast solvent, once a day, and continuous 5 days, the variation of perusal every day blood vessel and surrounding tissue.Last injection is after 1 hour, remove dead animal, get auricular vein and surrounding tissue, draw materials being 0 point to snack made with traditional Chinese medicines, every interval 1cm draws materials once by centripetal direction, get altogether 3 times, i.e. 0,1,2 points are respectively with 10% formaldehyde fixed, specimens paraffin embedding slices, HE dyes, and optical microscope is observed down and had or not thrombosis, endothelial injury and other pathological change, marks, compares by following standard.The result shows that example 1,2,3,4 samples all do not have vein irritating.
Example 6:
With the sample of above each examples preparation, under 40 ℃ of conditions, quicken to investigate stability separately.The investigation index comprises: character, content, related substance, particle diameter, assay method is with reference to the countries concerned's standard of Chinese Pharmacopoeia version related content in 2000 or vinorelbine.This product 1,3, the stability in June are investigated in 4 ℃ of placements simultaneously.
The results are shown in Table 2,3,4,5,6
The stability of table 2 vinorelbine injectable emulsion (0 day)
| ????No | Character | Content (%) | Related substance (%) | Mean diameter (nm) |
| Example 1 | Evenly, not layering | ??98.4 | ????1.3 | ????180 |
| Example 2 | Evenly, not layering | ??97.8 | ????1.2 | ????172 |
| Example 3 | Evenly, not layering | ??99.2 | ????1.2 | ????198 |
| Example 4 | Evenly, not layering | ??97.6 | ????1.4 | ????185 |
The stability of table 3 vinorelbine injectable emulsion (10 days)
| ????No | Character | Content (%) | Related substance (%) | Mean diameter (nm) |
| Example 1 | Evenly, not layering | ????97.6 | ????1.2 | ????188 |
| Example 2 | Evenly, not layering | ????97.2 | ????1.3 | ????175 |
| Example 3 | Evenly, not layering | ????98.7 | ????1.4 | ????192 |
| Example 4 | Evenly, not layering | ????98.1 | ????1.4 | ????180 |
The stability of table 4 vinorelbine injectable emulsion (4 ℃, 1 month)
| ????No | Character | Content (%) | Related substance (%) | Mean diameter (nm) |
| Example 1 | Evenly, not layering | ?????97.2 | ???????1.3 | ????180 |
| Example 2 | Evenly, not layering | ?????96.7 | ???????1.3 | ????181 |
| Example 3 | Evenly, not layering | ?????98.1 | ???????1.5 | ????183 |
| Example 4 | Evenly, not layering | ?????98.2 | ???????1.5 | ????172 |
The stability of table 5 vinorelbine injectable emulsion (4 ℃, 3 months)
| ????No | Character | Content (%) | Related substance (%) | Mean diameter (nm) |
| Example 1 | Evenly, not layering | ?????97.0 | ??????1.4 | ????175 |
| Example 2 | Evenly, not layering | ?????97.1 | ??????1.4 | ????180 |
| Example 3 | Evenly, not layering | ?????98.4 | ??????1.3 | ????179 |
| Example 4 | Evenly, not layering | ?????98.5 | ??????1.5 | ????176 |
The stability of table 6 vinorelbine injectable emulsion (4 ℃, 6 months)
| ????No | Character | Content (%) | Related substance (%) | Mean diameter (nm) |
| Example 1 | Evenly, not layering | ?????97.4 | ???????1.3 | ????172 |
| Example 2 | Evenly, not layering | ?????96.8 | ???????1.3 | ????179 |
| Example 3 | Evenly, not layering | ?????98.7 | ???????1.6 | ????184 |
| Example 4 | Evenly, not layering | ?????98.1 | ???????1.5 | ????176 |
Experiment showed, that more than the vinorelbine emulsion method that adopts this method to prepare is simple, can realize industrialization, preparation nature is stable.
Claims (8)
1. vinorelbine emulsion for oral use, it is characterized in that: each component has following percentage by weight:
Vinorelbine 0.001-10% emulsifying agent 0.1-20%
Triglyceride compounds 0.1-30% osmotic pressure regulator 0.1-10%
Stabilizing agent 0.05-5% surplus is a water;
Described emulsifying agent is selected from one or more blended emulsifiers in nonionic surfactant, fabaceous lecithin, the lecithin;
Described triglyceride compounds is selected from one or more mixed triglycerides in soybean oil, Oleum Arachidis hypogaeae semen, Semen Maydis oil, Oleum Cocois, Oleum Ricini, the safflower oil;
Described osmotic pressure regulator is selected from one or more mixing regulators in glycerol, ethylene glycol, isopropyl alcohol and the sodium chloride;
Described stabilizing agent is selected from one or more mixed stabilizers in vitamin E, poloxamer, oleic acid, enuatrol and/or the cholesterol.
2, a kind of used for intravenous injection vinorelbine emulsion, it is characterized in that: each component has following percentage by weight:
Vinorelbine 0.001-10% emulsifying agent 0.1-20%
Triglyceride compounds 0.1-30% osmotic pressure regulator 0.1-10%
Stabilizing agent 0.05-5%, excipient 0.5～10%
Surplus is a water;
Described emulsifying agent is selected from one or more blended emulsifiers in nonionic surfactant, fabaceous lecithin, the lecithin;
Described triglyceride compounds is selected from one or more mixed triglycerides in soybean oil, Oleum Arachidis hypogaeae semen, Semen Maydis oil, Oleum Cocois, Oleum Ricini, the safflower oil;
Described osmotic pressure regulator is selected from one or more mixing regulators in glycerol, ethylene glycol, isopropyl alcohol and the sodium chloride;
Described stabilizing agent is selected from one or more mixed stabilizers in vitamin E, poloxamer, oleic acid, enuatrol and/or the cholesterol.
Described excipient is selected from lactose, mannose, mannitol, sorbitol, dextran, glucose.
3, Orally taken emulsion according to claim 1 is characterized in that:
Vinorelbine 0.05-5% emulsifying agent 0.5-10%
Triglyceride compounds 0.2-15% osmotic pressure regulator 0.5-5%
Stabilizing agent 0.1-3% surplus is a water.
4, used for intravenous injection Emulsion according to claim 2 is characterized in that:
Vinorelbine 0.05-5% emulsifying agent 0.5-10%
Triglyceride compounds 0.2-15% osmotic pressure regulator 0.5-5%
Stabilizing agent 0.1-3% excipient 1-3%
Surplus is a water.
5, by the lacteal preparation method of the described vinorelbine of claim 1, comprise the preparation of oil phase and water and mixing and emulsifying thereof, packing, sterilization, it is characterized in that: described emulsifying is ultrasonic emulsification or homogenizer emulsifying, transfers pH4～9 simultaneously.
6, by the lacteal preparation method of the described vinorelbine of claim 2, comprise the preparation of oil phase and water and mixing and emulsifying thereof, packing, sterilization, it is characterized in that: described emulsifying is ultrasonic emulsification or homogenizer emulsifying, transfers pH4～9 simultaneously, uses filtering with microporous membrane after the emulsifying.
7, preparation method according to claim 6 is characterized in that: using the aperture is 0.22 μ m filtering with microporous membrane.
8, according to claim 6 or 7 described preparation methoies, it is characterized in that: the Emulsion of the pH4 that emulsifying obtains～9 with 0.22 μ m filtering with microporous membrane after packing, obtain the injection freeze-dried emulsion through lyophilization.
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| CN100462076C (en) * | 2005-01-20 | 2009-02-18 | 江苏正大天晴药业股份有限公司 | Stabilized oil-in-water emulsion of vinca alkaloids for vein and production thereof |
| CN1875981B (en) * | 2006-04-27 | 2010-08-11 | 高春平 | Injection emulsion containing breviscapinum and preparation method thereof |
| WO2010127541A1 (en) | 2009-05-06 | 2010-11-11 | 江苏恒瑞医药股份有限公司 | A nano-emulsion injection of vinca alkaloids and the preparation method thereof |
| CN101926757A (en) * | 2010-09-01 | 2010-12-29 | 北京大学 | Liquid composition of indissolvable medicines and preparation method thereof |
| CN101683367B (en) * | 2006-08-22 | 2011-07-20 | 浙江九旭药业有限公司 | Method for preparing emulsified medicinal composition containing oleum fructus bruceae |
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- 2004-10-20 CN CN 200410065105 patent/CN1634058A/en active Pending
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| JP4643641B2 (en) * | 2004-07-12 | 2011-03-02 | エスディー ファーマシューティカルズ インコーポレイティッド | Compositions for delivering highly water soluble drugs |
| JP2008505972A (en) * | 2004-07-12 | 2008-02-28 | エスディー ファーマシューティカルズ インコーポレイティッド | Compositions for delivering highly water soluble drugs |
| CN100462076C (en) * | 2005-01-20 | 2009-02-18 | 江苏正大天晴药业股份有限公司 | Stabilized oil-in-water emulsion of vinca alkaloids for vein and production thereof |
| CN1875981B (en) * | 2006-04-27 | 2010-08-11 | 高春平 | Injection emulsion containing breviscapinum and preparation method thereof |
| CN101683367B (en) * | 2006-08-22 | 2011-07-20 | 浙江九旭药业有限公司 | Method for preparing emulsified medicinal composition containing oleum fructus bruceae |
| CN101524330B (en) * | 2009-04-20 | 2013-01-09 | 重庆莱美药业股份有限公司 | Micro emulsion drug carrying system and manufacturing method thereof |
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| CN101926757A (en) * | 2010-09-01 | 2010-12-29 | 北京大学 | Liquid composition of indissolvable medicines and preparation method thereof |
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| CN101926757B (en) * | 2010-09-01 | 2013-01-02 | 北京大学 | Liquid composition of indissolvable medicines and preparation method thereof |
| US9339553B2 (en) | 2010-09-01 | 2016-05-17 | Peking University | Liquid compositions of insoluble drugs and preparation methods thereof |
| CN103720653A (en) * | 2012-10-12 | 2014-04-16 | 天津药物研究院 | Vinorelbine submicron emulsion injection and preparation method thereof |
| 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 |
| 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 |
| CN109044975A (en) * | 2018-10-17 | 2018-12-21 | 湖州浦瑞生物医药技术有限公司 | A kind of novel vinorelbine nanometer formulation and preparation method thereof |
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