The method of selection of antibiotics

 

(57) Abstract:

Usage: medicine, pharmacology, methods of isolation of natural antibiotics. The essence of the invention: method of extraction of antibiotics by sorption in the culture fluid pre-add components, connecting alkaline earth metals and 0.05 - 0.1 %, surfactants, and then spend the sorption of antibiotics on the cation size of the granules of 0.3 - 1.6 mm separating the target product.

The invention relates to medicine and pharmacology, more precisely to a method of allocating natural antibiotics directly from the fermentation media, without prior separation of biomass and provide a filtered fermentation medium with the dissolved antibiotic so-called native solution.

Known methods for producing antibiotics, such as streptomycin /1 5/, directly from the fermentation medium or the culture fluid (QOL). The method consists of passing through a fixed bed of sorbent pre-treated in a special way in order to reduce the viscosity of the QOL of the so-called dynamic way.

The main drawback of the dynamic method is visokosnomu physico-chemical status) and as a result, the fly ash sorbent and product loss. Another significant disadvantage is the need of heat treatment QOL for lowering the viscosity and consequently the heat treatment, the appearance of undesirable impurities in the target product.

The prototype of the invention can serve as a waveguide.St. N 1271078 from 1988 [6] the Method according to the prototype is that pre-dispersed sorbent with a grain size of 1.0 to 1.6 mm (instead of 0.3 to 1.6 mm, commercially available) add in QOL, and sorption are in the "wandering of the colony" (simulated countercurrent dynamic method). The extraction of the antibiotic from the aliquots QOL carried out as follows. There is a system of tanks speed from 5 to 10, in which load aliquots of pre-sifted cation. An aliquot QOL divided into equal portions, the first portion of QOL is brought into contact with the aliquot of the cation in 1 capacity (steps) at a certain time (30 min) this is the 1st cycle (stage 1) at the 1st stage of sorption. To conduct the 2nd cycle 1st proven capacity in the 1st cycle QOL separated on the sieve and move it into the 2nd tank, and the sorbent in the 1st tank fill fresh portion of QOL and so on, moving continuously from tank QOL and the sorbent protiviti the second tank for a few cycles or stages (the prototype in example 2 for 13 cycles or stages, as in example 4 for 19 cycles to gentamicin and other antibiotics 35 /7/) it is inferred from the process; separated on the sieve, washed several times with water and transferred to the column for further washing with water and conducting the selection of antibiotic-known techniques. Place 1st tank takes 2nd in the tail of the system introduce a new capacity with a fresh portion of the sorbent, keeping the total number of stages of sorption. Disadvantages the specified operation is the following.

First, in the prototype the process of extraction of the product from QOL is assessed only on "sbresny concentration", i.e., the residual concentration of the antibiotic in the waste QOL (the mother liquor) after sorption. However, the process of extracting substances by adsorption is inextricably linked with the inverse process - desorption and obtain the desired product in the form of technical eluate. And with a high degree of sorption reverse process of desorption (elution) can occur with a very low output (incomplete return to the matter at lumii or, in other words, the irreversible sorption). In addition, in the "waste concentrations may be inactivation of the antibiotic and therefore to characterize the degree of extraction on sbresny concentrations is not enough, you will receive the CTE of QOL, including the process of adsorption and desorption can be quite low, despite the high degree of sorption that occurs in the prototype. When declared a high degree of absorption and a very low degree of desorption and the total output stages of sorption-desorption and obtain the target product in the form of technical eluate that it is a valid characterization of the degree of extraction, in the proposed prototype is quite low, and reaches 34%

In the proposed method, the yield of the target product in the technical eluate from 94 to 97%

Secondly, multiple and mnogochislenost process: the number of steps from 5 to 10, each of which spend several cycles of extraction from 13 to 35 at an expense of 30 min for each cycle. As a consequence, the lengthy process of sorption time, only on the net contact time QOL-sorbent prototype is required for gentamicin 6.5 10 h, for monomitsina to 17 h /7/, not counting the time required for the separation of waste in each cycle QOL on the sieve with the next movement of this portion of QOL to the next level for the next cycle.

In the proposed method, the contact of the sorbent with QOL are disposable, i.e. one cycle on one level with a total time of sorption from 4 to 6 hours outside the head of the e branch of the saturated portion of the sorbent on the sieve, as a consequence of the uneven saturation of each portion of the sorbent, such as gentamicin, from 12 to 339 mg/g on the cation exchanger, Viatic CF and from 18 to 258 mg/g on the cation exchanger KB-2 /7/.

In the proposed method is proposed for practically complete extraction of the antibiotic from QOL only one evenly saturated portion of the sorbent, which is on the cation exchanger KB-2 saturation 270 mg/g for gentamicin and even higher for other antibiotics.

Fourth, low productivity (efficiency) of the process. The extraction of the antibiotic from QOL using sorbent, as noted above, automatically assumes desorption (elution) of the antibiotic from the sorbent and obtain the desired product in the form of technical eluate, but desorption is used only maximally saturated cation exchange resin. The prototype in each operation extract the most saturated only one portion of the sorbent in the first stage, the second portion of the second stage has a much lower saturation. In example 4, the prototype saturation (capacity) on the first foot 339,2 mg/g at the second is less 234,6 mg/g, but the authors believe that both of these portions are saturated, i.e. 20 ml of the sorbent. On stage desorption can take only 20 ml of sorbent instead of 50 ml of sorbent taken in OTE 10 μg/ml and in the second experiment 15 µg/ml The yield of the target product in the form of technical eluate will be even less than 34% while in the proposed method to extract the same volume of QOL and with the same concentration of the desired one portion of the cation exchange capacity of 100 ml, which is immediately after 4 h of contact with QOL will be in the entire volume of 100 ml was used for desorption.

Fifthly, in the prototype there is a need for preliminary screening of sorbent, obtaining a narrow fraction of the sorbent with a grain size of 1.0 to 1.6 mm and the use of only this fraction, and the rest of the sorbent, which is approximately 50% (cation exchangers are manufactured standard with a grain size of 0.3 to 1.6 mm [8] ), probably as a consequence of this method goes to waste.

A high degree of sorption ("sbresny concentration") in the prototype obtained with the use of sorbents, not mass-produced by the domestic industry and not in the Guest; SG-1M, KB-2H-2,5, or foreign production Viatic CF. When using domestic mass-produced in accordance with GOST [8] sorbent KB-2 achieved a lower outlet of the sorption 76,7%

The purpose of the invention increase the yield of the target product, simplifying the process and creating a waste-free technologies. The objective is achieved by the fact that commodity Sarbinowo substances (surfactants) cationic nature, as well as already related in complex alkaline earth metals, and spend one-stage and agnoticisme extraction of the antibiotic with a uniform saturation of the entire portion of the sorbent.

The essence of the method consists in the following: directly in the apparatus equipped with a mixer, where QL antibiotic related in complex alkaline earth metals, such as oxalate ions, sodium tripolyphosphate, make 0,05 0,1% surfactant, for example, N-alkylpyridinium bromide (catesol), amitriltyline chloride (ALMAH), and the cation exchange resin in a salt form. After a few hours of mixing and achieve kinetic equilibrium in the system (4 to 6 h) cation sorbed target product is separated in a vibrating sieve with a mesh size of 0.25 mm by the method of screening. Separated on the sieve sorbent is transferred to the column for washing from mycelium and spend desorption (elution) of the antibiotic known techniques to obtain technical product (eluate). The yield of the target product on the content of the antibiotic in the eluate from 94 to 97% of the initial content of the antibiotic in QOL.

The major difference of the proposed method from the prototype is that in QOL before sorption add components (such as oxalate ions to tripolitsa antibiotic (reducing the saturation by antibiotics) and 0.05 to 0.1% of surface-active agents cationic nature. Found that the cationic surfactant nature increase the saturation and the selectivity of the sorbent with respect to the antibiotic, and partially are lysed cells of a microorganism producing the antibiotic in QOL, lowering the viscosity and crushing them, which contributes the most complete separation of waste QOL with the remnants of lysed cells (mycelium) from the cation sorbed target product even when using sieves with mesh size of 0.25 mm, This gives the opportunity to use the entire range of commodity grain size of the sorbent, manufactured with dimensions of 0.3 to 1.6 mm, as well as to carry out the extraction process in a single act of sorption per cycle and on one level with a high degree of saturation of the sorbent.

The difference of the proposed method is that the target product is obtained in the form of technical eluate and high output by the claimed method already takes into account all losses during desorption of the target product from the sorbent and equal 94 - 97% against an estimated 34% of the prototype.

The advantage of the proposed method is the following.

First, a high yield of the desired product in the form of technical eluate from 94 thudercats and mnogochislennogo act sorption prototype (from 5 to 10 steps) sorption, each of which is carried out from 13 to 35 cycles), which is a significant simplification of the process.

Thirdly, reducing the retrieval time from 4 to 6 hours instead of 6.5 17 h of the prototype.

Fourth, adioactive (disposable) saturation of only the necessary quantity of sorbent to extract from a given amount QOL (getting all of the target product in sorbed form for subsequent elution) in contrast to the separation of the total portion of the sorbent into separate aliquots with uneven saturation of each and obtaining only some fraction of the finished product in sorbed form of the prototype, which leads to high productivity (efficiency) of the process.

Fifth, the proposed method commodity sorbent is used as such without prior screening, at that time, as in the prototype use only a small fraction of the grain size of 1.0 to 1.6 mm, as well as all the sorbents produce a wider range of sizes of 0.3 to 1.6 mm, the prototype fraction of 0.3 to 1.0, which is about 50% of all grains, is a waste of production.

A high degree of sorption and subsequent desorption, the proposed method obtained on the available mass-produced by the domestic industry si sorption and using sorbents, missing Guest or foreign.

Example 1.

To 500 ml of the culture fluid of sizomitsin activity 350 µg/ml contribute 3.25 g of ammonium oxalate binding of calcium salts present in the culture liquid, insoluble complex. The mass is stirred for 10 to 15 minutes, then 12 n sulfuric acid solution was adjusted pH of the culture fluid to a value of 6.0 to 6.2. Then in the treated culture liquid add 5 ml of 10% aqueous solution of celazole[CnH2n+1NC6H5]+Br-where n= 16oC20} i.e. 0.1% of the surfactant to the volume of QOL; then add 10 ml of commodity cation KB-2 is in salt form with a grain size of the full range of serial production of 0.3 to 1.6 mm, leave for 4 hours under stirring. Then separate the waste QOL on a sieve with a mesh size of 0.25 mm Get 480 ml waste QOL activity 4 µg/ml, adsorbed 99% of the antibiotic with the saturation of the sorbent 15610-3mcg/g

The cation sorbed target product is transferred to a desorption column, washed with water, through the water upward in the column. After washing through the column from top to bottom pass 2 n solution of ammonia at a speed of 5 ml/h

Receive a 20 ml technical ale is liturally liquid.

Example 2. Differs from example 1 in that as a surfactant to add a 10% aqueous solution of alkyltrimethylammonium of chloride (ALMAH)[CnH2n+1N(CH3)3] +Cl-where n= 10 - 16} yields of the target product are the same as in example 1.

Example 3. Differs from examples 1 2 the fact that add 2.5 ml of 10% aqueous solution of celazole or ATMAH, i.e. 0,05 surfactant relative to the amount of QOL. Indicators of yield of the target product are the same as in examples 1 2.

Example 4. Differs from examples 1 to 3 that add 1.5 ml of 10-aqueous solution cerasola or ATMAH i.e. 0.03% of surfactant relative to the amount of QOL. Get 470 ml waste QOL activity of 52 µg/ml, adsorbed only 86% of the antibiotic with the saturation of the sorbent 135103µg/g After desorption receive a 20 ml technical eluate activity 7260 µg/ml, which is the total yield of the target product 83%

Example 5. Differs from examples 1 to 4 that added to 6.5 ml of a 10 aqueous solution of celazole or ATMAH, i.e. 0.13% of the surfactant relative to the amount of QOL. Get 470 ml waste QOL activity 48 μg/ml, adsorbed only 87% of the antibiotic with the saturation of the sorbent 137 mg/g After desorption receive a 20 ml technical eluate activity 7440 µg/ml, which is orstore surfactants anionic character-Las sodium [CnH2n+1C6H4SO3] -Na+where n=12oC18} i.e. 0,1 surfactant relative to the amount of QOL. Get 450 ml waste QOL with an activity of 70 µg/ml, adsorbed 82% of the antibiotic with the saturation of the sorbent 129 mg/g After desorption receive a 25 ml technical eluate activity 5250 μg/ml with the yield of the target product 75% of the initial content of the antibiotic in QOL.

Example 7. Differs from examples 1 to 6 that add 5 ml of 10 aqueous solution of nonionic surfactant of Sintimid-5 or N-mono-(2-polietilenglikoli)amide III (synthetic fatty acids). [CnH2n+1CONHCH2CH2O(C2H4O)mH, where n=10oC16, m=5oC6] i.e. 0.1% of the surfactant relative to the amount of QOL. Get 460 ml waste QOL activity 65 μg/ml, adsorbed 83% of the antibiotic with the saturation of the sorbent 131 mg/g After desorption receive a 25 ml technical eluate activity 5390 μg/ml with the yield of the desired product 77% of the initial content of the antibiotic in QOL.

Example 8. Differs from examples 1 to 7, in that the surfactant is not added at all. Get 460 ml waste QOL with the activity of 53 µg/ml, Sarbinowo 86% of the antibiotic with the saturation of the sorbent 135 mg/g After desorption get 22 ml technical eluate with aktivnost from the culture fluid is carried out in the presence of calcium salts, magnesium, i.e., the culture fluid is not treated with either oxalic acid or ammonium oxalate or chelating agents of another nature. Get 470 ml waste QOL with the activity of 130 μg/ml adsorbed 65% of the antibiotic with the saturation of the sorbent 102 mg/g After desorption receive a 20 ml technical eluate concentration of antibiotic 5425 µg/ml yield of the target product in the technical eluate 62% of the initial content of the antibiotic in QOL.

Example 10. Differs from examples 1 to 3 by the fact that in 400 ml of culture liquid gentamicin activity 625 µg/ml contribute 3.6 g of ammonium oxalate. The mass is stirred for 10 to 15 minutes, then 12 N. a solution of sulfuric acid adjusted pH of the culture fluid to a value of 6.0 to 6.5. Then 10 ml of sorbent KB-2H-2,5 contribute to QOL and spend sorption. Get 390 ml waste QOL activity of 6.4 μg/ml Adsorbed 99% at saturation of the sorbent 223 mg/g

Desorption is conducted as in example 1. Receive a 20 ml technical eluate activity 12000 μg/ml, the Yield of the target product in the technical eluate is 96% of the content of the antibiotic in the culture fluid.

Example 11. Differs from example 10 that the desorption of gentamicin carried out by passing downward through the layer arbetslivet 12000 μg/ml The yield of the target product from the content in QOL is 96%

Example 12. Different from example 1 3 the fact that take 250 ml QL gentamicin activity 1200 mcg/ml After binding of salts of alkaline earth metals in the complex and adding a surfactant bring the total volume of the suspension demineralized or distilled water to 500 ml and Then make 10 ml of sorbent KB-2 is in salt form and leave for 4 hours. Get 980 ml waste QOL activity of 3.2 µg/ml, adsorbed 99% saturation of the sorbent 267 mg/g

After desorption receive a 20 ml technical eluate concentration 14550 µg/ml yield of the target product in the technical eluate 97%

Example 13. Different from example 1 3 the fact that in 100 ml of the culture fluid of streptomycin activity 15000 µg/ml add 19 ml of a saturated solution of oxalic acid. After stirring for 10 to 15 minutes, add 10 ml of saturated solution of sodium tripolyphosphate and then after 15 min stirring bring the pH of the culture fluid 12 N. sodium hydroxide solution to a value of 6.0 to 6.2 and diluted with demineralized water to 3.5 times. Added to 350 ml of the diluted culture fluid 10 ml of sorbent KB-2H-2.5 or CB-2 in the sodium form. The mass is stirred for 6 hours Getting 340 ml atributa is sorbsil carried out as in example 1. As eluent using 1 n sulfuric acid solution, which is passed through the layer of sorbent with a speed of 3.5 to 4 ml/hour. Receive a 20 ml technical eluate activity (concentration) 72000 mg/ml Total yield of the antibiotic in the technical eluate is 96% of the content in the culture fluid.

Example 14. Different from example 1 3 the fact that 100 ml of a culture liquid of kanamycin activity 3000 µg/ml add 3.7 g of oxalic acid. After deposition of calcium salts bring the pH of the culture fluid 12 N. sodium hydroxide solution to a value of 6.0 to 6.2. As sorbents used KB-2, KB-2H-2,5 KB-4. Receive 150 ml of waste QOL activity 32 µg/ml, adsorbed 99% of the antibiotic at saturation of the sorbent 428 mg/g After desorption receive a 20 ml technical eluate activity 23280 µg/ml, which is 97% of the content of the antibiotic in QOL.

Example 15. Differs from examples 1 to 3 that to 320 ml of culture liquid of polymyxin b with a concentration of 1500 µg/ml added 1.6 g of oxalic acid. After deposition of calcium salts bring the pH of the culture fluid 12 N. sodium hydroxide solution to a value of 6.0 to 6.2. Sorption was carried out for 6 hours Get 300 ml of spent culture fluid with conceal in example 1. As eluent using 1 n sulfuric acid solution, which is passed through the layer of sorbent at a speed of 2 to 4 ml/h After desorption get 22 ml technical eluate concentration 20727 µg/ml, which is 95% of the content of the antibiotic in the culture fluid.

The method of selection of antibiotics by sorption them from the culture fluid on the cation exchanger and separation of the target product, characterized in that the culture fluid pre-add components, linking the alkaline earth metals, and 0.05 to 0.1% surfactant cationic nature, and sorption was carried out on the cation exchange resin with a grain size of 0.3 to 1.6 mm

 

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