CN101744799B - Veterinary valnemulin, novel liposome formulation of the salt thereof and preparation method thereof - Google Patents
Veterinary valnemulin, novel liposome formulation of the salt thereof and preparation method thereof Download PDFInfo
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- CN101744799B CN101744799B CN2008102395217A CN200810239521A CN101744799B CN 101744799 B CN101744799 B CN 101744799B CN 2008102395217 A CN2008102395217 A CN 2008102395217A CN 200810239521 A CN200810239521 A CN 200810239521A CN 101744799 B CN101744799 B CN 101744799B
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Abstract
The invention relates to veterinary valnemulin, a novel liposome formulation of the salt thereof and a preparation method thereof, which belongs to the field of veterinary antibiotic preparations. In the preparation, valnemulin and the salt thereof serve as the main components, phospholipid and cholesterol serve as membranes, and the common liposomes, the lung targeting liposomes or the long circulating liposomes of valnemulin or valnemulin salt can be prepared. The valnemulin and the liposomes of the salt thereof have better tissue selectivity compared with the common preparation, are effective to the bacterial and mycoplasma infection in cells, and can reduce the toxic and side effect. The lung targeting liposomes targets the medicine to the lung, and has significant effect to the mycoplasma infection of the lung, bacterial infection and the like, and reduces the toxic and side effect. The long circulating liposomes significantly improves the circulation time of the liposomes in thebody, so that the medicines displays the efficacy for a longer time more effectively, so s to reduce the delivery times and the dosage.
Description
Technical field
The invention belongs to antibiotic formulations for animals field, relate to novel liposome formulation of valnemulin and salt thereof and preparation method thereof.
Background technology
Valnemulin (valnemulin) and salt thereof are new one bag of pleuromulins semisynthetic antibiotics; Belong to two terpenes; Belonging to same type of medicine with taimulin, is the animal specific antibiotic, is mainly used in mycoplasma and the gram positive bacteria infection of control pig, cattle, sheep and poultry.Be used to prevent and treat swine dysentery that is caused by the short spirochaete infection of swine dysentery and the porcine enzootic pneumonia that is caused by mycoplasma pneumoniae infection by European Community approval in 1999, it is the veterinary drug pre-mixing agent of first all Europe approval, is classified as prescription drugs for animals.
The ordinary preparation of valnemulin; As: pre-mixing agent, injection etc., medicine uniform distribution in blood and tissue does not have targeting property after the medication; And after medicine gets into blood circulation; Want and protein binding, stand metabolism and the drainage of plurality of enzymes, tissue, organ etc., have only small amount of drug can reach target site.If improve the drug level of target area, just must increase dosage, this not only increases cost, causes the waste of medicine, and in animal body residual of the toxic and side effects that has also increased medicine and medicine increased the chemical sproof probability of generation.
Liposome (liposomes) is a new drug carrier, is the miniature vesicle that is formed by lipid bilayer.Liposome more and more comes into one's own as the research of pharmaceutical carrier in recent years, and progress is very fast, and the research field of liposome is enlarged gradually and deepens continuously.But; The correlational study of veterinary liposome preparation is less both at home and abroad; And the research of veterinary liposome preparation is main with parasiticide, trace element, nutrient drug mainly, and kind is quantitatively on the low side, especially lacks the research of antibiotics and digestive system medicine lisposome preparation.
Summary of the invention
The object of the present invention is to provide the liposome of a kind of veterinary valnemulin (valnemulin) and salt thereof; Valnemulin and salt thereof are processed liposome; Improved the tissue selectivity of medicine, improved the curative effect of medicine, antibacterial and mycoplasma infection are also effective in the pair cell; The lung target liposomes makes drug targeting in pulmonary, for the pulmonary infection more remarkable effect; Long circulating liposomes has significantly improved liposome circulation time in vivo, makes the more long-term more effective performance drug effect of medicine.
Another object of the present invention is to provide the method for preparing of the liposome of valnemulin and salt thereof.
The objective of the invention is to realize through following technical scheme:
The present invention provides the liposome of a kind of veterinary valnemulin and salt thereof, it is characterized in that with valnemulin or valnemulin salt be crude drug, is the film material with phospholipid and cholesterol.
The liposome of valnemulin of the present invention and salt thereof can be prepared into conventional liposome, lung target liposomes or the long circulating liposomes of valnemulin or valnemulin salt, can carry out finishing with adjuvant as required in the preparation process.
Wherein, hydrochlorate, phosphate or tartrate that valnemulin salt of the present invention is valnemulin, described phospholipid are the mixture of natural phospholipid, synthetic phospholipid or said two devices.
In the liposome of valnemulin of the present invention and salt thereof, the weight ratio of valnemulin or valnemulin salt and phospholipid is 2: 1～1: 110.
Further, the weight ratio preferable range of valnemulin or valnemulin salt and phospholipid is 1: 5～1: 50.
Wherein, the particle size range of the lung target liposomes of valnemulin or valnemulin salt is 7-30 μ m, and the adjuvant that is used for carrying out finishing is any of N-acetylamino mannose, epichitosamine alcohol, amino deoxy mannitol; The adjuvant that is used for finishing in the long circulating liposomes of valnemulin and salt thereof comprises any of Polyethylene Glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, chitosan.
Be used to carry out the adjuvant of finishing in the lung target liposomes of the present invention and the weight ratio of phospholipid is 1: 5～1: 200; Be used to carry out the adjuvant of finishing in the long circulating liposomes and the weight ratio of phospholipid is: 1: 5～1: 200.
The present invention also provides the method for preparing of the liposome of this veterinary valnemulin and salt thereof, and its step is following:
1) phospholipid, cholesterol and/or the adjuvant that is used for finishing are dissolved in chloroform, place round-bottomed flask, rotary evaporation is dried to and is dry thin layer;
2) valnemulin or its salt are dissolved in the PBS solution;
3) the PBS solution with valnemulin or its salt is added in the flask, and the aquation of vibrating promptly gets the liposome of valnemulin or its salt.
The method for preparing of the liposome of veterinary valnemulin of the present invention and salt thereof, its preparation also can be advanced down as follows:
1) phospholipid, cholesterol and/or the adjuvant that is used for finishing are dissolved in chloroform or ether, place round-bottomed flask;
2) valnemulin or its salt are dissolved in the PBS solution;
3) the PBS solution with valnemulin or its salt is added in the flask, carries out ultrasonic emulsification, carries out reduction vaporization then, reach colloidal state after, drip PBS solution, continue reduction vaporization, promptly get the liposome of valnemulin or its salt.
The method for preparing of the liposome of veterinary valnemulin of the present invention and salt thereof, its preparation also can be advanced down as follows:
1) phospholipid, cholesterol and/or the adjuvant that is used for finishing are dissolved in ether, place beaker;
2) valnemulin or its salt are dissolved in the PBS solution;
3) under 60 ℃ of heated and stirred, be injected into the PBS solution of valnemulin or its salt, continue to be stirred to and wave most ether, promptly get the liposome of valnemulin or its salt.
As, can be prepared into the lipidosome injection of valnemulin and salt thereof further with liposome process cobalt 60 ray sterilizings that make; Or liposome carried out lyophilization, promptly get the liposome freeze-drying powder injection of valnemulin and salt thereof.
The liposome of valnemulin of the present invention and salt thereof can reduce the toxic and side effects of common valnemulin injection, improves drug effect; The lung target liposomes can messenger drug is more effective concentrates in pulmonary, significantly improve the effect of valnemulin treatment pulmonary infection, and toxic and side effects is lower; Long circulating liposomes can prolong valnemulin circulation time in vivo, obviously the action time of prolong drug, reduces administration number of times.
Through the following example the present invention will be described more specifically, and it should be understood that said embodiment only is for the present invention is described, rather than limit scope of the present invention by any way.
The specific embodiment
The preparation of embodiment 1 valnemulin hydrochloride liposome
1) lecithin 1000mg, cholesterol 100mg are dissolved in the 20ml chloroform, place round-bottomed flask,
On rotary evaporator, vacuum evaporation is dried to and is dry thin layer;
2) the 150mg valnemulin hydrochloride is dissolved among the 25ml PBS;
3) valnemulin hydrochloride PBS solution is added in the flask, the aquation of vibrating promptly gets the valnemulin hydrochloride liposome.
The preparation of embodiment 2 valnemulin liposomees
1) with lecithin 2000mg, cholesterol 100mg be dissolved in 20ml chloroform-ether (1: 1, V/V), place round-bottomed flask;
2) the 40mg valnemulin is dissolved in the 20ml PBS solution;
3) the PBS solution of valnemulin is added in the flask, carries out ultrasonic emulsification 3min, carry out reduction vaporization then, reach colloidal state after, Dropwise 5 ml PBS solution continues reduction vaporization, promptly gets the valnemulin liposome.
The preparation of embodiment 3 phosphoric acid valnemulin liposomees
1) soybean phospholipid 1000mg, cholesterol 150mg are dissolved in the 30ml ether, place beaker;
2) 2000mg phosphoric acid valnemulin is dissolved in the 25mlPBS solution;
3) under 60 ℃ of heated and stirred, be injected into the PBS solution of phosphoric acid valnemulin, continue to be stirred to and wave most ether, promptly get phosphoric acid valnemulin liposome.
The preparation of embodiment 4 tartaric acid valnemulin liposomees
1) soybean lecithin 1100mg, cholesterol 100mg are dissolved in the 20ml chloroform, place round-bottomed flask, on rotary evaporator, vacuum evaporation is dried to and is dry thin layer;
2) tartaric acid valnemulin 10mg is dissolved among the 25ml PBS;
3) valnemulin PBS solution is added in the flask, the aquation of vibrating promptly gets tartaric acid valnemulin liposome.
The preparation of embodiment 5 valnemulin hydrochloride lung target liposomes
1) with soybean phospholipid 1000mg, cholesterol 100mg, N-acetylamino mannose 100mg be dissolved in 20ml chloroform-ether (1: 1, V/V), place round-bottomed flask;
2) the 150mg valnemulin hydrochloride is dissolved in the 20ml PBS solution;
3) the PBS solution of valnemulin hydrochloride is added in the flask, carries out ultrasonic emulsification 3min, carry out reduction vaporization then, reach colloidal state after, Dropwise 5 ml PBS solution continues reduction vaporization, promptly gets valnemulin hydrochloride lung target liposomes.
The preparation of embodiment 6 valnemulin hydrochloride long circulating liposomess
1) soybean phospholipid 750mg, cholesterol 100mg, Polyethylene Glycol-2000 120mg are dissolved in ether, place beaker;
2) the 150mg valnemulin hydrochloride is dissolved in the 25mlPBS solution;
3) under 60 ℃ of heated and stirred, be injected into the PBS solution of valnemulin hydrochloride, continue to be stirred to and wave most ether, promptly get the valnemulin hydrochloride long circulating liposomes.
The preparation of embodiment 7 phosphoric acid valnemulin long circulating liposomess
1) soybean phospholipid 1500mg, cholesterol 100mg, Polyethylene Glycol-4000 300mg are dissolved in ether, place beaker;
2) 50mg phosphoric acid valnemulin is dissolved in the 25mlPBS solution;
3) under 60 ℃ of heated and stirred, be injected into the PBS solution of phosphoric acid valnemulin, continue to be stirred to and wave most ether, promptly get phosphoric acid valnemulin long circulating liposomes.
The preparation of embodiment 8 valnemulin long circulating liposomess
1) soybean phospholipid 800mg, cholesterol 100mg, polyvinylpyrrolidone k30 160mg are dissolved in the 20ml chloroform, place round-bottomed flask, on rotary evaporator, vacuum evaporation is dried to and is dry thin layer;
2) valnemulin 100mg is dissolved among the 25ml PBS;
3) valnemulin PBS solution is added in the flask, the aquation of vibrating promptly gets the valnemulin long circulating liposomes.
The preparation of embodiment 9 valnemulin hydrochloride long circulating liposomess
1) soybean phospholipid 1000mg, DMPC (dimyristoyl phosphatidyl choline) 200mg, cholesterol 100mg, polyvinylpyrrolidone k17 100mg are dissolved in the 20ml chloroform, place round-bottomed flask, on rotary evaporator, vacuum evaporation is dried to and is dry thin layer;
2) valnemulin hydrochloride 100mg is dissolved among the 25ml PBS;
3) valnemulin hydrochloride PBS solution is added in the flask, the aquation of vibrating promptly gets the valnemulin hydrochloride long circulating liposomes.
The preparation of embodiment 10 valnemulin hydrochloride long circulating liposomess
1) with DPPC (synthetic dipalmitoyl phosphatidyl choline) 2000mg, cholesterol 200mg, polyvinyl alcohol 10mg be dissolved in 20ml chloroform-ether (1: 1, V/V), place round-bottomed flask;
2) the 300mg valnemulin hydrochloride is dissolved in the 20ml PBS solution;
3) the PBS solution of valnemulin hydrochloride is added in the flask, carries out ultrasonic emulsification 3min, carry out reduction vaporization then, reach colloidal state after, Dropwise 5 ml PBS solution continues reduction vaporization, promptly gets the valnemulin hydrochloride liposome.
The preparation of embodiment 11 phosphoric acid valnemulin long circulating liposomess
1) soybean phospholipid 1500mg, DPPC (synthetic dipalmitoyl phosphatidyl choline) 200mg, cholesterol 100mg, polyacrylamide 100mg are dissolved in the 30ml ether, place beaker;
2) 150mg phosphoric acid valnemulin is dissolved in the 25mlPBS solution;
3) under 60 ℃ of heated and stirred, be injected into the PBS solution of phosphoric acid valnemulin, continue to be stirred to and wave most ether, promptly get phosphoric acid valnemulin long circulating liposomes.
The preparation of the macrocyclic liposome of embodiment 12 tartaric acid valnemulins
1) soybean phospholipid 1500mg, cholesterol 100mg, chitosan 50mg are dissolved in ether, place beaker;
2) 150mg tartaric acid valnemulin is dissolved in the 25mlPBS solution;
3) under 60 ℃ of heated and stirred, be injected into the PBS solution of tartaric acid valnemulin, continue to be stirred to and wave most ether, promptly get the fertile wonderful long circulation woods liposome of Buddhist nun of tartaric acid.
The preparation of embodiment 13 phosphoric acid valnemulin lung target liposomes
1) with soybean phospholipid 1200mg, cholesterol 100mg, epichitosamine alcohol 240mg be dissolved in 20ml chloroform-ether (1: 1, V/V), place round-bottomed flask;
2) 150mg phosphoric acid valnemulin is dissolved in the 20mlPBS solution;
3) the PBS solution of phosphoric acid valnemulin is added in the flask, carries out ultrasonic emulsification 3min, carry out reduction vaporization then, reach colloidal state after, Dropwise 5 ml PBS solution continues reduction vaporization, promptly gets phosphoric acid valnemulin lung target liposomes.
The preparation of embodiment 14 tartaric acid valnemulin lung target liposomes
1) with soybean phospholipid 1600mg, cholesterol 150mg, amino deoxy mannitol 8mg be dissolved in 20ml chloroform-ether (1: 1, V/V), place round-bottomed flask;
2) the 150mg valnemulin hydrochloride is dissolved in the 20ml PBS solution;
3) the PBS solution of tartaric acid valnemulin is added in the flask, carries out ultrasonic emulsification 3min, carry out reduction vaporization then, reach colloidal state after, Dropwise 5 ml PBS solution continues reduction vaporization, promptly gets tartaric acid valnemulin lung target liposomes.
The pharmacokinetic of experimental example 1 embodiment 1 and the valnemulin liposome of embodiment 6 preparations
Experimental technique: get 15 healthy rats, be divided into 3 groups at random, be i.e. valnemulin hydrochloride injection group, valnemulin hydrochloride conventional liposome group, valnemulin hydrochloride long circulating liposomes group.At one night of fasting before the experiment, vena femoralis injection is equivalent to valnemulin hydrochloride injection, valnemulin hydrochloride conventional liposome, the valnemulin hydrochloride long circulating liposomes of 10mg/kg valnemulin dosage respectively.After the administration 0.25,0.5,1,2,4,8,12,24,48h gets blood 0.5ml from the rat eye socket, centrifugal separation plasma is measured the content of valnemulin in the blood plasma.
The pharmacokinetics experiment of experimental result: the embodiment 1 and the valnemulin liposome of embodiment 6 preparations
The result sees table 1.
The pharmacokinetic of table 1 embodiment 1 and the valnemulin liposome of embodiment 6 preparations
The lung targeted characteristic research of the valnemulin liposome of experimental example 2 embodiment 5 preparations
Experimental technique: 1, get 96 of healthy mices, be divided into two groups at random, be i.e. valnemulin hydrochloride injection group and valnemulin hydrochloride lung target liposomes group.One night of fasting before the experiment; Intravenous injection is equivalent to the valnemulin hydrochloride injection and the valnemulin hydrochloride lung target liposomes of 10mg/kg valnemulin dosage respectively; In injection 0.5,1,2,4,8,12,24 hour; 6 mouse orbits of every group of picked at random are got blood 0.5ml, centrifugal separation plasma.The sacrificed by decapitation mice is cut open the belly, and takes out lung, with the residual blood of normal saline rinsing, and the filter paper suck dry moisture, precision weighing tissue weight is prepared into the lung tissue homogenate of 0.5g/ml, detects valnemulin content.
The lung targeting result of study of the valnemulin liposome of experimental result: embodiment 5 preparations is seen table 2.
The lung targeting result of study of the valnemulin liposome of table 2 embodiment 5 preparations
The clinical test of pesticide effectiveness of the valnemulin hydrochloride liposome of experimental example 3 embodiment 1 preparation
Experimental technique: 1, choose body weight 20-30kg, be diagnosed as 60 of the pigs of asthma, be divided into three groups at random, be respectively A, B, C group, 20 every group.The intravenous injection of A group is equivalent to the valnemulin hydrochloride injection of 10mg/kg valnemulin dosage, and inject once every day, logotype three days.The intravenous injection of B group is equivalent to the valnemulin liposome of 6mg/kg valnemulin dosage, injects once with the 3rd day every day in first day, injects altogether twice.C organizes the not administration of negative matched group.
2, curative effect is judged.Cure: after medication a couple of days, appetite, breathe and recover normal, the complete obiteration of coughing, breathe, recidivist not in 10 days is called healing after the drug withdrawal; Take a turn for the better: clinical symptoms alleviates to some extent, or clinical symptoms temporarily disappears, but recidivist again in 10 days after the drug withdrawal is called improvement.
The clinical test of pesticide effectiveness result of the valnemulin hydrochloride liposome of experimental result: embodiment 1 preparation sees table 3.
Table 3 is according to the clinical test of pesticide effectiveness result of the valnemulin hydrochloride liposome of embodiment 1 preparation
| Group | Cure number (head) | Cure rate (%) | Good revolution (head) | Improvement rate (%) | Invalid number (head) | Inefficiency (%) |
| The A group | 15 | 75 | 5 | 25 | 0 | 0 |
| The B group | 19 | 95 | 1 | 5 | 0 | 0 |
| The C group | 0 | 0 | 2 | 10 | 18 | 90 |
Claims (2)
1. the liposome of a veterinary valnemulin (valnemulin) or its salt; It is characterized in that with valnemulin or valnemulin salt be crude drug; With phospholipid and cholesterol is the film material; Be prepared into conventional liposome, lung target liposomes or the long circulating liposomes of valnemulin or valnemulin salt, carry out finishing with adjuvant in the preparation process; The weight ratio of valnemulin or valnemulin salt and phospholipid is 1: 5～1: 50; Hydrochlorate, phosphate or tartrate that described valnemulin salt is valnemulin, described phospholipid are the mixture of natural phospholipid, synthetic phospholipid or said two devices; The particle size range of the lung target liposomes of valnemulin or valnemulin salt is 7-30 μ m, and the adjuvant that is used for carrying out finishing is any of N-acetylamino mannose, epichitosamine alcohol, amino deoxy mannitol; The adjuvant that is used for finishing in the long circulating liposomes of valnemulin or valnemulin salt is any of Polyethylene Glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, chitosan.
2. the liposome of veterinary valnemulin according to claim 1 or its salt is characterized in that being used to carry out the adjuvant of finishing in the lung target liposomes and the weight ratio of phospholipid is 1: 5～1: 200; Be used to carry out the adjuvant of finishing in the long circulating liposomes and the weight ratio of phospholipid is 1: 5～1: 200.
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| CN102846548B (en) * | 2012-08-31 | 2014-06-11 | 郑州后羿制药有限公司 | Preparation method for valnemulin liposome |
| CN104173296B (en) * | 2014-09-16 | 2017-08-18 | 曹炜 | A kind of method and immediate-release tablet for preparing composite particles |
| CN105878176B (en) * | 2016-04-06 | 2019-01-08 | 山东胜利生物工程有限公司 | A kind of valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1409631A (en) * | 1999-12-09 | 2003-04-09 | 诺瓦提斯公司 | New formulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1409631A (en) * | 1999-12-09 | 2003-04-09 | 诺瓦提斯公司 | New formulation |
Non-Patent Citations (2)
| Title |
|---|
| 吴小宁.氟苯尼考脂质体的制备及药效研究.《中国优秀博硕士学位论文全文数据库 (硕士) 工程科技Ⅰ辑》.2006,(第 02 期),8-10，13，14. * |
| 吴广辉等.新兽药盐酸沃尼妙林研究进展及使用.《兽医导刊》.2007,(第11期),29-30. * |
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Assignee: Shaoshan Dabeinong Animal Medicine Co.,Ltd. Assignor: BEIJING DABEINONG TECHNOLOGY GROUP Co.,Ltd.|Beijing Dabeinong Animal Health Care Technology Co.,Ltd.|Shaoshan Dabeinong Animal Medicine Co.,Ltd. Contract record no.: 2012430000081 Denomination of invention: Veterinary valnemulin, novel liposome formulation of the salt thereof and preparation method thereof Granted publication date: 20120111 License type: Exclusive License Open date: 20100623 Record date: 20120511 |
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Effective date of registration: 20220729 Address after: 101407 Beijing city Huairou District Yanqi Economic Development Zone No. 10 North Street Patentee after: Beijing Dabeinong Animal Health Care Technology Co.,Ltd. Patentee after: Shaoshan Dabeinong Animal Medicine Co.,Ltd. Address before: 100083, Zhongguancun building, No. 27 Zhongguancun street, Beijing, Haidian District, China, 14 floor Patentee before: BEIJING DABEINONG TECHNOLOGY GROUP Co.,Ltd. Patentee before: Beijing Dabeinong Animal Health Care Technology Co.,Ltd. Patentee before: Shaoshan Dabeinong Animal Medicine Co.,Ltd. |
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