Method of coproporphyrin iii extraction and purification

FIELD: chemistry.

SUBSTANCE: method is performed by the following way: unfiltered culture liquid is acidated to pH 2-2.5, sorb on cationite KU-23/100 in pulsing fluidisated mode with subsequent desorption using elution systems with pH 6.0±0.1, containing sodium citrate 1.5% and carbamide 0.5%. Coproporphyrin III is precipitaled on produced eluate, reducing pH to 3.5±0.1. Produced precipitate is extracted with hydrochloric acid solution, thereafter chromatographic cleaning of extract on molecular sorbent follows. End product is precipitaled on eluate. Then extraction and chromatographic cleaning are repeated, whereupon end product is precipitaled on eluate and transformed into potassium salt.

EFFECT: technology allows for production of water-soluble preparation based unfiltered culture liquid.

3 ex

 

Usage: biotechnology, medicine. The essence of the invention: a new method of obtaining coproporphyrin III. For separation of the target product in a water soluble form are sorption coproporphyrin III from the culture fluid on the sorbent KU - 23/100 followed by desorption using suantai system containing sodium citrate and urea. From the obtained eluate of coproporphyrin III secreted by deposition at bringing the pH to 3.5±0,1. From the obtained precipitate of coproporphyrin III secreted by extraction 5-7%solution of hydrochloric acid. The extract obtained is subjected to chromatographic purification on silicagel CSC. From the obtained eluate of coproporphyrin III is precipitated by bringing the pH to 3.5±0,1. The precipitate is re-subjected to extraction 5-7%solution of hydrochloric acid and re-made chromatographic purification coproporphyrin III. From the obtained eluate target product precipitates and is translated in water-soluble form during the alkalization. This way when selected aggregate manufacturing methods makes it possible to obtain a highly purified preparation of water-soluble salts coproporphyrin III with a purity of 90-95%.

The invention relates to medical and microbiological industry, in particular to technology for coproporphyrin III.

The technical solution is s carried out by obtaining coproporphyrin III in water-soluble form, which can be used in medicine to diagnose and treat cancer more effectively and with fewer side effects than the known water-insoluble form.

Analysis of patent and scientific literature suggests that traditional methods of cleaning coproporphyrin III include the stage of esterification of porphyrins and their separation ether derivatives of aluminum oxide. This is due to the commonly expressed view that various forms of porphyrins can be effectively separated in the form of ether derivatives. So, get purified water-insoluble forms of coproporphyrin III (U.S. Pat. USA N 4436663, ed. St. USSR №1482946). Methods of obtaining water-soluble forms according to the detected sources associated with obtaining water-insoluble esters of porphyrins, their separation and their further conversion into water-soluble forms. There is also a way of obtaining water-soluble coproporphyrin III by direct his selection and translation into water-soluble state by alkalizing. So, the closest analogue (prototype) obtaining water-soluble forms of coproporphyrin III is the patent of the Russian Federation No. 2078138, whereby purification of the target product is performed using sequential resultant deposition rates of porphyrins from native solution by hydrochloric acid solutions with the respective chromatography on macroporous anion exchange resin with the desorption of the ammonia solution, deposition of coproporphyrin III of the eluate upon acidification and its transfer in water-soluble form during the alkalization. The described method is time consuming because it uses the stage of obtaining native solution from the culture fluid by centrifuging. In addition, for chromatographic purification provides the use of the anion an - 80, on which there is no evidence that this sorbent approved for use in the medical industry, or aluminum oxide, which is a fine powder with a large hydrodynamic resistance and therefore not suitable for use on an industrial scale.

The proposed method for the isolation and purification of coproporphyrin III is based on a combination of techniques resultant deposition rates by bringing the pH to 3.5±0.1 s by chromatographic purification on two different sorbents. This technology allows to obtain high-purity water-soluble form of coproporphyrin III directly from the culture fluid, bypassing the stage of separation native solution from biomass.

The proposed method for water-soluble forms of coproporphyrin III is as follows:

the pH of the culture fluid containing the target product is brought to 2-2 .5 by adding 35%hydrochloric acid at the rate of 20 ml per 1 liter of the culture liquid is Then sorption coproporphyrin III from the culture fluid on macroporous cation exchanger KU - 23/100 in pulsating fluidized bed mode. After washing the sorbent is desorption of coproporphyrin III suantai system containing 1.5% of sodium citrate, 0.5% of urea and a pH equal to 6.0±0,1. the pH of the resulting eluate containing coproporphyrin III, is brought to 3.5±0,1 to precipitate the desired product. The precipitate is separated by centrifugation, followed by extraction coproporphyrin III of sediment 5-7%solution of hydrochloric acid. The use of hydrochloric acid with a concentration of more than 7% leads to emulsification suspension (due to protein impurities), poor separation, contamination of the extract. When the acid concentration is below 5% increased acid consumption and duration of its impact on porphyrinogenic intermediate product. The extract obtained is applied on the column with silicagel CSC (you can also use silagra C-80 or kilogram CX - 2,5) for the Department of ballast substances. Then the column is washed with 5%hydrochloric acid solution. From the obtained eluate of coproporphyrin III is precipitated by bringing the pH to 3.5±0.1, the precipitate is separated by centrifugation. Next is the extraction of porphyrin 5-7%solution of hydrochloric acid and re-chromatographic purification on silicagel also, as described above. the pH of the obtained eluate is brought to 3.5±0,1 for deposition of aproper is Irina III. The precipitate is separated by centrifuge and washed with distilled water with a pH equal to 3.5±0,1 (pH brought hydrochloric acid) to remove mineral salts. Then the washed precipitate coproporphyrin III converted into water-soluble form by dissolving it in an aqueous solution of potassium hydroxide. The content of potassium hydroxide in this solution should be equal to the equivalent amount of carboxylic groups received drug coproporphyrin III. Then the solution is dried at a temperature of 80°C. the Purity of the thus obtained preparation is 90-95%.

The feasibility of the proposed method is illustrated by the following examples.

Example 1. The isolation and purification of the target product received 5450 ml of the culture fluid with the concentration of coproporphyrin III 209 mg/L. this culture fluid was added 35%hydrochloric acid solution with a volume of 110 ml the pH of the culture fluid was equal to 2.3. Then this culture fluid was filtered through a column of cation exchange resin KU - 23/100 in pulsed, fluidized bed mode. Then, the column was washed with water volume of 8 liters. After that conducted the desorption process suantai system, which is an aqueous solution of sodium citrate and 1.5%, urea 0.5% and pH is equal to 6.05. The volume of the eluate was 6820 ml. Content coproporphyrin III in it SOS is avilo 134,1 mg/L. Then the pH of the eluate was brought to 3,45, when it fell precipitate containing the target product. The precipitate was separated by centrifugation, the volume of the mother liquor was approximately 6820 ml containing coproporphyrin III in the amount of 0,78 mg/l is the loss of the target product at this stage. Next of the selected sediment were extracted coproporphyrin III 5%solution of hydrochloric acid. The volume of the extract was equal 6190 ml, content of coproporphyrin III which amounted to 146.2 mg/L. the extract Obtained was subjected to a first chromatographic purification on silicagel CSC. The volume of the eluate was 21400 ml containing coproporphyrin III - 40,1 mg/L. Then the pH of the eluate was reduced to 3.5 and the precipitation with coproporphyrin III was isolated by centrifugation. Amount of liquor was 21400 ml, in which the content of the target product was equal 0,41 mg/L. Coproporphyrin III contained in the mother liquor, is a loss at this stage. From the resulting precipitate, containing coproporphyrin III, was produced by extraction of the target product, a 5%solution of hydrochloric acid. The volume of the extract was 630 ml containing coproporphyrin III in the amount of 1335,8 mg/L. the extract Obtained was subjected to a second chromatographic purification on silicagel CSC. The volume of the eluate was equal 3485 ml with the concentration of coproporphyrin III equal 237,4 mg/L. pH of the obtained eluate b is l brought to 3,55 using ammonia water with a concentration of 25%. Coproporphyrin III dropped into the sediment, which was separated using a centrifuge. Amount of liquor was 3485 ml. content of the target product in the mother liquor was equal 1,054 mg/l loss of coproporphyrin III at this stage. The precipitate removal of mineral salts was washed with distilled water and the pH brought hydrochloric acid to 3.5. The washed precipitate is transferred to the potassium salt by dissolving in a solution of potassium hydroxide and bringing sustainable solution pH to 7.8. The solution was dried at 80°C. Mass drug coproporphyrin III tetracylines salt after drying was 1004,8 mg with a moisture content of 10.5% or without water: 899,3 mg content of the target product 902,0 µg/mg (90.2 per cent).

Example 2. The isolation and purification of the target product received 5930 ml of the culture fluid with the concentration of coproporphyrin III 251 mg/L. this culture fluid was added 35%hydrochloric acid solution with a volume of 120 ml pH of the culture fluid was equal to 2.1. Then this culture fluid was filtered through a column of cation exchange resin KU - 23/100 in pulsed, fluidized bed mode. Thereafter, the column was washed with water to a volume of 9 liters. Then held the desorption process suantai system, which is an aqueous solution of sodium citrate and 1.5%, urea 0.5% and pH equal to 6.1. The volume of the eluate was 7230 ml. Contents coprop is hirin III it was 175,8 mg/L. Then the pH of the eluate was reduced to 3.5, when it fell precipitate containing the target product. The precipitate was separated by centrifugation, the volume of the mother liquor was approximately 7230 ml, containing coproporphyrin III in the amount of 0,63 mg/l is the loss of the target product at this stage. Next of the selected sediment were extracted coproporphyrin III 5%solution of hydrochloric acid. The volume of the extract was 6740 ml, content of coproporphyrin III which is equal to 146.2 mg/L. the extract Obtained was subjected to a first chromatographic purification on silicagel CSC. The volume of the eluate was 25100 ml containing coproporphyrin III - to 48.3 mg/L. Then the pH of the eluate was reduced to 3.5, and the precipitation with coproporphyrin III was isolated by centrifugation. Amount of liquor was about 25100 ml, in which the content of coproporphyrin III equal to 0.65 mg/l Target product contained in the mother liquor, is a loss at this stage. From the resulting precipitate, containing coproporphyrin III, was produced by extraction of the target product a 5%solution of hydrochloric acid. The volume of the extract was 780 ml containing coproporphyrin III in the amount of 1524,1 mg/L. the extract Obtained was subjected to a second chromatographic purification on silicagel CSC. The result was obtained eluate volume 6790 ml and the concentration of coproporphyrin III, equal 171,4 mg/L. Molokanova of the eluate was brought to 3.5 with ammonia water with a concentration of 25%. Coproporphyrin III dropped into the sediment, which was separated using a centrifuge. Amount of liquor was 6790 ml. content of the target product in the mother liquor was equal to 1.45 mg/l loss of coproporphyrin III at this stage. The precipitate removal of mineral salts was washed with distilled water and the pH brought hydrochloric acid to 3.5. The washed precipitate coproporphyrin III transferred to the potassium salt by dissolving in a solution of potassium hydroxide and bringing sustainable solution pH to 7.8. The solution was dried at 80°C. the dried Mass drug coproporphyrin III tetracylines salt was 1379,6 mg with moisture content of 12.4%, or excluding moisture: 1208,5 mg content of the target product 943,6 µg/g (94.2 percent).

Example 3. The isolation and purification of the target product received 5340 ml of the culture fluid with the concentration of coproporphyrin III 236 mg/l of this culture liquid was added 35%hydrochloric acid by volume 110 ml. pH was equal to 2.0. Then this culture fluid was filtered through a column of cation exchange resin KU - 23/100 in pulsed, fluidized bed mode. Then, the column was washed with water volume of 8.5 liters. After that conducted the desorption process suantai system, which is an aqueous solution of sodium citrate and 1.5%, urea 0.5% and pH equal to 6.1. The volume of the eluate was 7050 ml Contents coprop is hirin III it was 155.8 mg/L. Then the pH of the eluate was reduced to 3.5, when it fell precipitate containing the target product. The precipitate was separated by centrifugation, the volume of the mother liquor was approximately 7050 ml containing coproporphyrin III in the amount of 1.05 mg/l is the loss of the target product at this stage. Next of the selected sediment were extracted coproporphyrin III 5%solution of hydrochloric acid. The volume of the extract was equal 6830 ml, content of coproporphyrin III which was 158,9 mg/L. the extract Obtained was subjected to a first chromatographic purification on silicagel CSC. The volume of the eluate was 22600 ml containing coproporphyrin III - 45,9 mg/L. Then the pH of the eluate was reduced to 3.5, and the precipitation with coproporphyrin III was isolated by centrifugation. Amount of liquor was 22600 ml, in which the content of the target product was totaled 0.83 mg/L. Coproporphyrin III contained in the mother liquor, is a loss at this stage. From the resulting precipitate, containing coproporphyrin III, was produced by extraction of the target product, a 5%solution of hydrochloric acid. The volume of the extract was 700 ml containing coproporphyrin III in the amount of 1445,3 mg/L. the extract Obtained was subjected to a second chromatographic purification on silicagel CSC. The volume of the eluate was equal 4740 ml with the concentration of coproporphyrin III equal 210,3 mg/L. pH of the obtained eluate b is l brought to 3.5 with ammonia water with a concentration of 25%. Coproporphyrin III dropped into the sediment, which was separated using a centrifuge. Amount of liquor was 4740 ml. Content coproporphyrin III in the mother liquor was equal to 0.97 mg/l is the loss of the target product at this stage. The precipitate removal of mineral salts was washed with distilled water and the pH brought hydrochloric acid to 3.5. The washed precipitate is transferred to the potassium salt by dissolving in a solution of potassium hydroxide and bringing sustainable solution pH to 7.6. The solution was dried at 80°C. Mass drug coproporphyrin III tetracylines salt after drying was 1196,0 mg with humidity 11.9 per cent or without water: 1053,7 mg content of the target product 911,1 µg/mg (for 91.1%).

Sources of information

1. U.S. patent 4436663, 1984.

2. The patent of Russian Federation №2078138, 1993.

3. Copyright certificate №1482946, 1978.

The isolation and purification of coproporphyrin III from the culture fluid, including adsorption on macroporous sorbent and extraction of 5-7%hydrochloric acid solution, wherein the unfiltered culture liquid is acidified to a pH of 2-2,5, perform sorption on cation marks KU-23/100 in pulsating fluidized bed mode, followed by desorption with suantai system with a pH of 6.0±0,1 containing 1.5% of sodium citrate and 0.5% urea, from the obtained eluate wasp who give coproporphyrin III, bringing the pH to 3.5±0,1, the precipitate is extracted with hydrochloric acid, the extract is subjected to chromatographic purification on a molecular sorbent, produces the precipitation of the desired product from the eluate, followed by re-extraction and chromatographic purification, target product precipitated from the eluate and translate it into potassium salt.



 

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SUBSTANCE: method involves intravenously introducing chlorine row photosensitizer in water-soluble form at a dose of 0.8-1.1 mg/kg x 0.7 during 10 min. Spectral fluorescent diagnostic procedure for determining photosensitizer accumulation in intraocular neoplasm, is carried out in 1 h after having finished chlorine row photosensitizer introduction. Then, chlorine row photosensitizer in liposomal form is intravenously introduced in bolus dose of 0.8-1.1 mg/kg x 0.3. 10 min later, tumor periphery is transpupillarily exposed to laser radiation of 670 nm wavelength all over its perimeter with power density of 60-80 J/cm. Next to it, the whole neoplasm surface is transpupillarily irradiated with laser radiation of 662 nm wavelength and power density of 100-120 J/cm. Irradiation is carried out in circularly moving from periphery towards the center. The treatment is applied field-by-field with neighboring fields overlay by 5% of area. The intraocular neoplasm is removed 2 weeks later.

EFFECT: enhanced effectiveness in destroying blood vessels feeding the tumor; destroyed tumor cells; complete removal of intraocular neoplasm; no intraoperative bleeding from tumor blood vessels; reduced risk of tumor cells revival, relapses and metastases.

2 cl

FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

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