CN104774230A - Method for improving stability of tylosin phosphate - Google Patents
Method for improving stability of tylosin phosphate Download PDFInfo
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- CN104774230A CN104774230A CN201410015201.9A CN201410015201A CN104774230A CN 104774230 A CN104774230 A CN 104774230A CN 201410015201 A CN201410015201 A CN 201410015201A CN 104774230 A CN104774230 A CN 104774230A
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Abstract
The invention belongs to the antibiotic drug preparation field, and particularly relates to a method for improving stability of tylosin phosphate; the method includes that in a tylosin phosphate production process, an alkali or strong-alkali weak-acid salt having the content of 1.0-10.0% according to the tylosin phosphate mass is added into an aqueous solution before a spray drying process, so as to improve the pH value of tylosin phosphate. The pH value of the tylosin phosphate product is improved by a way of adding a small amount of the alkali or strong-alkali weak-acid salt, so that the stability is improved, and the problem in the prior art that previous stability is difficult to guarantee because a tylosin phosphate product is processed into a pre-mixing agent is effectively solved.
Description
Technical field
The invention belongs to antibiotic medicine preparation field, be specifically related to a kind of method that effectively can improve Webel Tylan Premix stability.
Background technology
Tylosin is a kind of fowl, raises special macrolide antibiotic, it is the mixture of A, B, C, D tetra-components obtained from the nutrient solution of streptomyces fradiae, wherein: component A is tylosin (Tylosin), B component is decarburization sugar tylosin ((Desmycosin), component C is Tylosin C (Macrosin), and D component is thunder Lip river rhzomorph (Relomycin) and analog clarke booth rhzomorph.In above four components, except the rhzomorph of thunder Lip river, other component all has anti-microbial activity in vitro, and Tylosin A component has confirmed greater activity in vivo.Tylosin and derivative thereof have very high fungicidal activity, are the choice drugs of universally acknowledged treatment and prevention livestock and poultry mycoplasma infection.
At present, the general extraction process of domestic tylosin is: obtain ferment filtrate through Plate Filtration after tylosin broth pre-treatment, extract be rich in the organic phase of tylosin with butylacetate to ferment filtrate, strip with sour water again, through neutralization, decolouring, concentrate and obtain Webel Tylan Premix fine work after spraying dry.
Webel Tylan Premix generally adds in the middle of animal-feed with the form of pre-mixture, prevents Animal diseases.But, after Webel Tylan Premix products production, sale be experienced, transport, be processed into pre-mixture, sail again and sell transport, then just can be used by raiser through a shelf lives quite grown.So the stability of Webel Tylan Premix is extremely important.In addition, Webel Tylan Premix is added in the middle of the process of feed, and due to the impact (such as moist, heating) of manufacturing procedure environment, quality product also can be subjected to sizable destruction.
In fact, Webel Tylan Premix is a kind of extremely unstable microbiotic.Experimental study shows, under the condition of 40 DEG C, the component A of Webel Tylan Premix and biological value can decline 7 ~ 10% in one month; At normal temperatures, the component A of Webel Tylan Premix and biological value will not reach standards of pharmacopoeia after 8 ~ 10 months, this means that the stationary phase of Webel Tylan Premix only has 8 ~ 10 months.This is an acid test for the application of Webel Tylan Premix in aquaculture.
So be necessary very much to adopt some method to improve the stability of Webel Tylan Premix.Publication number is that the United States Patent (USP) of US4048268A to report with soyflour, Semen Maydis powder, sorghum flour, wheat-flour etc. as carrier, is mixed by Webel Tylan Premix with carrier; Carry out dressing using starch, gelatin etc. as tackiness agent again, make the stability that pre-mixture can improve Webel Tylan Premix.But the effect that the method improves Webel Tylan Premix stability is not fine.And for example publication number be the United States Patent (USP) of US5468735 report improve Webel Tylan Premix pre-mixture pH value method to improve the stability of pre-mixture.These two patents are all solve Webel Tylan Premix stability problem by the production of pre-mixture, but as was noted, after Webel Tylan Premix products production, also can experience a period quite grown and just can be made into pre-mixture, so the method that still needs is to guarantee the stability of Webel Tylan Premix product itself.
Document " Study of the stability of tylosin A in aqueous solutions " and the research of " Isolation of decomposition products of tylosin using liquid chromatography " show, the stability of Webel Tylan Premix depends on pH value and the temperature of product very much, the present inventor's experimental study shows, the stability of Webel Tylan Premix finished product also depends on the weight loss on drying of product very much.The major cause of Webel Tylan Premix instability is: in the environmental system residing for whole Webel Tylan Premix, under trace or the hydrionic effect of denier, Webel Tylan Premix component A can be sloughed a mycaminose and be formed de-mycaminose Webel Tylan Premix (Tylosin B component).In this system, the pH value of product determines the height of hydrogen ion content in whole system, has conclusive impact to the degradation speed of Webel Tylan Premix; It is medium that Webel Tylan Premix DeR needs with water, and the water content of whole system depends on the weight loss on drying degree of product, so the stability of Webel Tylan Premix product also depends on the weight loss on drying of product very much; The DeR rate against temperature of Webel Tylan Premix is very responsive, and the higher then DeR of temperature is faster.
In three influence factors above, temperature mainly refers to the envrionment temperature of Webel Tylan Premix product storing, residing for transportation to the impact of stability.Temperature stability that is higher, then Webel Tylan Premix is poorer, and contriver studies discovery, and the component A of Webel Tylan Premix is basicly stable at 5 DEG C, at 25 DEG C, degrade about 1% after 1 month, a then just degraded about 8% in month at 40 DEG C.But keep the cost of low-temperature storage transport too high, scientific research personnel cannot utilize Webel Tylan Premix to stablize this characteristic at low temperatures substantially.In addition, the weight loss on drying of Webel Tylan Premix product is less, then the water ratio of product is lower, and stability is higher.But this index of weight loss on drying depends on the spray-dired temperature of Webel Tylan Premix product, the weight loss on drying of the higher then product of spray drying temperature is lower, Unfortunately, because Webel Tylan Premix product is to the susceptibility of temperature, spray drying temperature rises and quality product will be made to be subject to larger destruction.So, improve the more feasible approach of its stability one by the pH value improving Webel Tylan Premix.
Summary of the invention
For the characteristic of above-mentioned existing Webel Tylan Premix product in preparation, storage, transport and the process such as application and deficiency, contriver aims to provide a kind of method improving Webel Tylan Premix stability, intend the pH value by improving Webel Tylan Premix, thus greatly improve the stability of Webel Tylan Premix.
The object of the invention is to be implemented by the following technical programs:
A kind of method improving Webel Tylan Premix stability, be included in Webel Tylan Premix production process, add in the aqueous solution before spray drying process in the alkali of 1.0 ~ 10.0% of Webel Tylan Premix quality or strong base-weak acid salt, to improve the pH value of Webel Tylan Premix.The add-on of alkali or salt very little then the pH value that improves of Webel Tylan Premix product very little, DeGrain is improved to product stability; If the amount added is too many, then the pH value of Webel Tylan Premix product is too high, and according to " Study of the stability of tylosin A in aqueous solutions " research, too high pH value is equally unfavorable for the stability of product; In addition, too high pH value can make the pH of product not meet the requirement of pharmacopeia.
Preferably, according to a kind of method improving Webel Tylan Premix stability of the present invention, wherein, the alkali added is sodium hydroxide or potassium hydroxide; Strong base-weak acid salt comprises Tripotassium phosphate, dipotassium hydrogen phosphate, salt of wormwood, sodium carbonate.These alkali or the side effect of salt pair animal very little, cheap, compare the ancillary additions being suitable as auxiliary Webel Tylan Premix product.
Preferably, according to a kind of method improving Webel Tylan Premix stability of the present invention, wherein, add in the alkali of 2.0 ~ 5.0% of Webel Tylan Premix quality or strong base-weak acid salt.Webel Tylan Premix product can be made like this to be in a pH value range the most stable.
Preferably, according to a kind of method improving Webel Tylan Premix stability of the present invention, wherein, when adding alkali or strong base-weak acid salt, the temperature of the Webel Tylan Premix aqueous solution should control between 5 ~ 20 DEG C.Prevent from adjusting in pH process because of the too high crystallization of temperature at Webel Tylan Premix solution.
Preferably, according to a kind of method improving Webel Tylan Premix stability of the present invention, wherein, the aqueous solution before Webel Tylan Premix spray drying process is obtained by following approach: tylosin ferment filtrate organic solvent extraction, again with phosphate aqueous solution strip obtain Aqueous extracts, Aqueous extracts to 5.5 ~ 6.5 with calcium hydroxide adjust pH, then filters through activated carbon decolorizing, blows solvent, the concentrated or concentrated aqueous solution formed before spray drying process.
The present invention compared with prior art, has the following advantages:
The Webel Tylan Premix product stability produced both at home and abroad is at present poor, the method solving product stability all needs realized by the production of Webel Tylan Premix pre-mixture substantially, and the stability like this before Webel Tylan Premix product is processed to pre-mixture is difficult to be guaranteed.The present invention improves the pH value of Webel Tylan Premix product by the mode of adding a small amount of alkali or strong base-weak acid salt, thus improves its stability.
Embodiment
Below in conjunction with embodiment, further illustrate content of the present invention.Should be appreciated that enforcement of the present invention is not limited to the following examples, any pro forma accommodation make the present invention and/or change all will fall into scope.
In the present invention, if not refer in particular to, in the present invention, if not refer in particular to, all parts, per-cent are weight unit, and all equipment and raw material etc. all can be buied from market or the industry is conventional.Method in following embodiment, if no special instructions, is the ordinary method of this area.
The Webel Tylan Premix aqueous solution in embodiment, derive from the large production of Zhejiang Kang Yu Biology Pharmacy Co., Ltd, its preparation process is: tylosin broth after pretreatment filter press collects filtrate, with n-butyl acetate extraction, Aqueous extracts is obtained again through the phosphoric acid solution reextraction of 1.0% ~ 3.0%, Aqueous extracts with calcium hydroxide adjust pH to 5.5 ~ 6.5, filter through activated carbon decolorizing, blow solvent, concentrated (or not concentrating) form the aqueous solution before spray drying process, the content of the Webel Tylan Premix wherein in the aqueous solution controls at 10% ~ 30%(W/V).
Tylosin ferment filtrate, derive from the ferment filtrate that tank is put in the large production of Zhejiang Kang Yu Biology Pharmacy Co., Ltd, its preparation process is: 120 tons of fermentor tank preparation substratum, sterilizing, inoculation.At pH6.0-7.0, temperature 28 DEG C-37 DEG C, air flow quantity 800-1600m
3cultivate 150-200 hour under the condition of/min, mixing speed 200rpm-300rpm, put tank.With filter press after fermentation liquor acidifying, the pre-treatment of polyaluminium aluminum flocculation, obtain tylosin ferment filtrate.
comparative example 1webel Tylan Premix is produced by existing ordinary process
Webel Tylan Premix aqueous solution 200ml, pH value is 6.3, and measuring Webel Tylan Premix content by liquid phase is 18.8%(W/V).Carry out spraying dry with laboratory room small-sized spray-drier, obtain Webel Tylan Premix product 38.8g.Product stability investigates data in table 1.
embodiment 1webel Tylan Premix stability is improved with sodium hydroxide
Adopt with the Webel Tylan Premix aqueous solution 200ml in comparative example 1, control temperature is 5 DEG C, slowly adds 10%(W/V while stirring) sodium hydroxide solution 18ml.Mix rear laboratory room small-sized spray-drier and carry out spraying dry, obtain Webel Tylan Premix product 40.7g.Product stability investigates data in table 1.
embodiment 2webel Tylan Premix stability is improved with potassium hydroxide
Adopt with the Webel Tylan Premix aqueous solution 200ml in comparative example 1.Control temperature 15 DEG C, slowly adds 10%(W/V while stirring) potassium hydroxide solution 10ml.Mix rear laboratory room small-sized spray-drier and carry out spraying dry, obtain Webel Tylan Premix product 40g.Product stability investigates data in table 1.
embodiment 3webel Tylan Premix stability is improved with dipotassium hydrogen phosphate
Adopt with the Webel Tylan Premix aqueous solution 200ml in comparative example 1.Control temperature 10 DEG C, slowly adds 30%(W/V while stirring) dipotassium hydrogen phosphate solution 10ml.Mix rear laboratory room small-sized spray-drier and carry out spraying dry, obtain Webel Tylan Premix product 41.8g.Product stability investigates data in table 1.
embodiment 4webel Tylan Premix stability is improved with sodium carbonate
Adopt with the Webel Tylan Premix aqueous solution 200ml in comparative example 1.Control temperature 20 DEG C, slowly adds 10%(W/V while stirring) sodium hydroxide solution 10ml.Mix rear laboratory room small-sized spray-drier and carry out spraying dry, obtain Webel Tylan Premix product 39.6g.Product stability investigates data in table 1.
comparative example 2webel Tylan Premix is produced by existing ordinary process
Webel Tylan Premix aqueous solution 200ml, pH value is 6.4, and measuring Webel Tylan Premix content by liquid phase is 15.8%(W/V).Carry out spraying dry with laboratory room small-sized spray-drier, obtain Webel Tylan Premix product 32.6g.Product stability investigates data in table 2.
embodiment 5webel Tylan Premix stability is improved with sodium hydroxide
Adopt with the Webel Tylan Premix aqueous solution 200ml in comparative example 2, control temperature is 5 DEG C, slowly adds 15%(W/V while stirring) Tripotassium phosphate solution 8ml.Mix rear laboratory room small-sized spray-drier and carry out spraying dry, obtain Webel Tylan Premix product 34.1g.Product stability investigates data in table 2.
embodiment 6webel Tylan Premix stability is improved with potassium hydroxide
Adopt with the Webel Tylan Premix aqueous solution 200ml in comparative example 2.Control temperature 10 DEG C, slowly adds 15%(W/V while stirring) solution of potassium carbonate 10ml.Mix rear laboratory room small-sized spray-drier and carry out spraying dry, obtain Webel Tylan Premix product 34.3g.Product stability investigates data in table 2.
Under temperature 40 DEG C, relative humidity 75% condition, stability test is carried out to the sample in above-mentioned front 5 examples, in three months, measures the component A of each sample every other month.Measurement result is as table 1.Under 60 DEG C of conditions, carry out stability test to the sample of rear 3 examples, measured the component A of each sample every 5 days, measurement result is in table 2.
the steadiness of each example sample under table 1 40 DEG C of conditions
the steadiness of each example sample under table 2 60 DEG C of conditions
From table 1 and table 2, compared with the sample of comparative example 1,2, the degraded situation of the component A in embodiment 1 ~ 6 sample after the inventive method process obviously reduces, and the stability of Webel Tylan Premix product improves greatly.
Above preferred embodiment, just for instruction and explanation of content of the present invention, does not form the restriction to content of the present invention.Although contriver enumerates in more detail to invention has been, but, the content that those skilled in the art discloses according to summary of the invention part and embodiment, various amendment can be made or/and it is obvious for supplementing or adopting similar mode to substitute to described specific embodiment, and technique effect of the present invention can be realized, therefore, repeat no longer one by one herein.The term occurred in the present invention, for the elaboration of technical solution of the present invention and understanding, is not construed as limiting the invention.
Claims (5)
1. one kind is improved the method for Webel Tylan Premix stability, it is characterized in that being included in Webel Tylan Premix production process, add in the aqueous solution before spray drying process in the alkali of 1.0 ~ 10.0% of Webel Tylan Premix quality or strong base-weak acid salt, to improve the pH value of Webel Tylan Premix.
2. a kind of method improving Webel Tylan Premix stability according to claim 1, is characterized in that the alkali added is sodium hydroxide or potassium hydroxide; Strong base-weak acid salt comprises Tripotassium phosphate, dipotassium hydrogen phosphate, salt of wormwood, sodium carbonate.
3. a kind of method improving Webel Tylan Premix stability according to claim 1, is characterized in that adding in the alkali of 2.0 ~ 5.0% of Webel Tylan Premix quality or strong base-weak acid salt.
4. a kind of method improving Webel Tylan Premix stability according to claim 1, is characterized in that when adding alkali or strong base-weak acid salt, and the temperature of the Webel Tylan Premix aqueous solution should control between 5 ~ 20 DEG C.
5. a kind of method improving Webel Tylan Premix stability according to claim 1, it is characterized in that the aqueous solution before Webel Tylan Premix spray drying process is obtained by following approach: tylosin ferment filtrate organic solvent extraction, again with phosphate aqueous solution strip obtain Aqueous extracts, Aqueous extracts to 5.5 ~ 6.5 with calcium hydroxide adjust pH, then filters through activated carbon decolorizing, blows solvent, the concentrated or concentrated aqueous solution formed before spray drying process.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410015201.9A CN104774230B (en) | 2014-01-14 | 2014-01-14 | A kind of method for improving Tylosin phosphate stability |
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| CN201410015201.9A CN104774230B (en) | 2014-01-14 | 2014-01-14 | A kind of method for improving Tylosin phosphate stability |
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| CN104774230A true CN104774230A (en) | 2015-07-15 |
| CN104774230B CN104774230B (en) | 2018-02-23 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106173271A (en) * | 2016-08-22 | 2016-12-07 | 浦城正大生化有限公司 | A kind of tylosin phosphonate pre-mixing agent preparation method |
| CN106265711A (en) * | 2016-08-25 | 2017-01-04 | 浦城正大生化有限公司 | Tylosin phosphonate pre-mixing agent formula and preparation technology |
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|---|---|---|---|---|
| US4048268A (en) * | 1975-02-19 | 1977-09-13 | Eli Lilly And Company | Stabilization method |
| CN1089098A (en) * | 1992-12-21 | 1994-07-13 | 伊莱利利公司 | Tylosin animal feed premix |
| CN101565438A (en) * | 2008-04-21 | 2009-10-28 | 王玉万 | Purification method for Tylosin |
| CN102584921A (en) * | 2012-01-20 | 2012-07-18 | 宁夏泰瑞制药股份有限公司 | Tylosin extraction menstruum and extraction method |
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2014
- 2014-01-14 CN CN201410015201.9A patent/CN104774230B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4048268A (en) * | 1975-02-19 | 1977-09-13 | Eli Lilly And Company | Stabilization method |
| CN1089098A (en) * | 1992-12-21 | 1994-07-13 | 伊莱利利公司 | Tylosin animal feed premix |
| CN101565438A (en) * | 2008-04-21 | 2009-10-28 | 王玉万 | Purification method for Tylosin |
| CN102584921A (en) * | 2012-01-20 | 2012-07-18 | 宁夏泰瑞制药股份有限公司 | Tylosin extraction menstruum and extraction method |
Non-Patent Citations (3)
| Title |
|---|
| J. PAESEN，等: "Isolation of decomposition products of tylosin using liquid chromatography", 《JOURNAL OF CHROMATOGRAPHY A》 * |
| J. PAESEN，等: "Study of the stability of tylosin A in aqueous solutions", 《JOURNAL OF PHARMACEYTICAL AND BIOMEDICAL ANALYSIS》 * |
| 王文生，等: "磷酸泰乐菌素的稳定性研究", 《中国兽药杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106173271A (en) * | 2016-08-22 | 2016-12-07 | 浦城正大生化有限公司 | A kind of tylosin phosphonate pre-mixing agent preparation method |
| CN106265711A (en) * | 2016-08-25 | 2017-01-04 | 浦城正大生化有限公司 | Tylosin phosphonate pre-mixing agent formula and preparation technology |
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| CN104774230B (en) | 2018-02-23 |
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