Troxerutin with a high content of trihydroxyethylrutoside and method thereof

 

(57) Abstract:

The invention relates to enriched troxerutin containing at least 92 wt.% 7,3',4'-trihydroxyethylrutoside, from 2 to 4 wt.% 5,7,3',4'-tetrahydrochloride and from 1 to 3 wt.% 7,4'-dihydroxytoluene and how to obtain it. Also features a pharmaceutical composition for the treatment of symptoms associated with venous-lymphatic insufficiency and treatment of functional symptoms associated with hemorrhagic stroke, containing enriched troxerutin. Enriched troxerutin and compositions based on it have increased wettability and solubility in water, and improved biological activity. 4 C. and 8 C.p. f-crystals, 4 PL.

The present invention relates to a drug with a high content of 7,3’,4’-trihydroxyethylrutoside with high wettability, to pharmaceutical compositions on the basis of troxerutin, enriched 7,3’,4’-trihydroxyethylrutoside with improved solubility, as well as to a method for producing enriched troxerutin.

7,3’,4’-Trihydroxyethylrutoside is a major component of troxerutin, which is the composition used in the treatment train for the treatment of functional symptoms, associated with hemorrhagic stroke. Troxerutin is a mixture of several derived classes of flavonoids, more specifically a mixture of hydroxyethylene derived rutoside (or routine). The above therapeutic indications based on veno-toniziruushii and vascular-protective properties of troxerutin. Tests conducted on animals and on human subjects confirmed that hydroxyethylrutoside increase the tone of the veins and reduce capillary permeability.

In French patent 5072 M describes troxerutin, including a mix of trihydroxyethylrutoside and tetrahydrochloride and having the properties of strengthening the resistance of the capillaries, allowing it to be used for the treatment of diseases caused by disorders of the microcirculation. This troxerutin get from rutoside and ethylene carbonate resulting when heated in the presence of an alkaline catalyst. One variant of this method, described in the application for French patent A-2267327 related to 7-mono-hydroxyethylrutoside, which has comparable activity against the regulation of capillary permeability and increased resistance of the capillaries, and lies in the interaction of ethylene oxide and rutoside in the presence of the complex is the lo to the present time in therapy, usually contains about 80-85% trihydroxystilbene derived (7,3’,4’-trihydroxyethylrutoside), about 8-10% tetrahydroquinoline derived (5,7,3’,4’-tetrahydrochloride) and 4-5% dihydroxyethylene derived (7,4’-dihydroxyethylene), and the rest formed derivatives: 7,3’,4’- 7.5’,4’-trihydroxy-utilitarian-3-o-glucoside and 7,4’-dihydrokaempferol-3-rutinozide. Obtained by known methods, troxerutin poorly wetted in water, resulting spent considerable time at its dissolution, and this is a disadvantage in obtaining pharmaceutical form powder for solution for quick preparation before the time of use of the above solutions the users for whom these pharmaceutical forms are used.

Conducted by the applicant's studies have shown that it is possible to obtain troxerutin with a high content of 7,3’,4’-trihydroxyethylrutoside, and this drug (below called "enriched troxerutin" due to the high content of 7,3’,4’-trihydroxyethylrutoside) gives the best compromise between physico-chemical properties (wettability in water) and pharmacodynamic activity (farmacocinetica, the object of the present invention is enriched troxerutin containing at least 92 wt.% 7,3’,4’-tri-hydroxyethylrutoside and having wettability in minutes, equal to less than 10 minutes, if the wettability is determined in the test, which consists in measuring the time during which 3.5 g of powder enriched troxerutin disappear from the surface chemical beaker containing 100 ml of water, at a constant temperature of 20°C, after the powder enriched troxerutin poured on the surface of the water in this glass, and wettability on average less than 100 seconds, if the wettability is determined in the test, which consists in measuring the time during which enriched troxerutin wetted, contained in a vessel, such as a chemical glass, once enriched troxerutin was placed on the surface of the water in the form of a compacted cylindrical specimens of size 2 and 3 mm height and weight 63±2 mg at a constant temperature of 20°C.

Preliminary seal designs can be implemented using any type of appropriate device, such as a device for the production of gelatin capsules.

The invention relates to enriched troxerutin containing minority wt.% 7,4’-dihydroxyethylene, and more specifically to the enriched troxerutin the above type, which contains a reduced number of 5,7,3’,4’-tetrahydrochloride (not more than 5 wt.%) and 7,4’-dihydroxyethylene (not more than 4 wt.%).

The object of the invention is also a pharmaceutical composition comprising as an active beginning enriched troxerutin containing at least 92 wt.% 7,3’,4’-trihydroxyethylrutoside, and this active principle may also contain not more than 5 wt.% 5,7,3’,4’-tetrahydrochloride and not more than 4 wt.% 7,4’-dihydroxyethylene, these pharmaceutical compositions have improved pharmaceutical activity and possess good properties of wettability and solubility in water.

The invention relates in particular to pharmaceutical compositions, with a higher solubility and high speed of dissolution containing enriched troxerutin associated with accipiendum favouring his oral introduction, for example, with an equal weight of mannitol, the time of dissolution which, on average, less than 140 seconds, if the time measured in the test, which consists in the introduction of 7.25 g of the granules in chemical beaker 250 ml (diameter of the neck of the Noah mixer 35 mm×6.5 mm speed 4 on the device (IKAMAG)) and in the time dimension solubilize the pellet.

Another object of the present invention is a method of obtaining enriched troxerutin with high wettability and high output.

The method of receiving according to the present invention consists in the introduction in cooperation with the heating routine with an excess of ethylene oxide in water in the presence of a base, then in the implementation of crystallization from alcohol and differs in that the reaction medium was concentrated to obtain in the environment for crystallization water content lower than 8% and preferably 1-6%.

According to a preferred variant of the method, the crystallization is carried out alcohol selected from methanol and isopropanol, taken individually or preferably in a mixture, at a temperature of completion of crystallization from 35 to 15°C. the Crystallization is particularly preferable to carry out when the profile temperature reduction, adapted to the kinetics of crystallization trihydroxystilbene derived than the kinetics of di - and tetrahydroquinoline derived rutoside. In fact, under the operating conditions of the method according to the invention by a rapid decrease in temperature hydroxyethylene derivative and limit the deposition of Tetra - and dihydroxyethylene derivatives, thus the final concentration of the latter compounds in the environment should be sufficient for crystallization of these compounds.

As mentioned above, the speed reduction temperature should be fast in an industrial environment, the method, preferably above about 20°C in h, preferably 30°With in the hour.

Introduced in the reaction medium base may be selected from sodium hydroxide or potassium hydroxide or carbonate of sodium, potassium, lithium or calcium.

So get enriched troxerutin containing at least 92 wt.% 7,3’,4’-trihydroxyethylrutoside, not more than 5 wt.% 5,7,3’,4’-tetrahydrochloride and not more than 4 wt.% 7,4’-dihydroxyethylene. Preferably the content of 7,4’-dihydroxyethylene is 1-3 wt.%, while the content of 5,7,3’,4’-tetrahydrocarboline is 2-4 wt.%.

Enriched troxerutin according to the invention mainly contains at least 93% 7,3’,4’-trihydroxyethylrutoside, from 2 to 3.5% of 5,7,3’,4’-Tetra-hydroxyethylrutoside and 1.7 to 4.5% 7,4’-dihydroxyethylene. As indicated above, it may contain some traces of derivatives: 1,3’,4’- 7.5’,4’-trihydroxyethylrutoside-3-glucose is retenu contains at least 92 wt.% 7,3’,4’-trihydroxyethylrutoside, as specified above. It may also contain isomer representing 5,7,4’-trihydroxy-ethylbutane, which cannot be easily distinguished from the above isomer using conventional methods of analysis. According to the present description agree that the name of 7,3’,4’-trihydroxyethylrutoside optionally comprises a second isomer. Similarly, the name of 7,4’-dihydroxyethylene may include, if necessary, isomer 7,3’-dihydroxyethylene.

Enriched troxerutin obtained according to the invention and having the above-mentioned content of di-, tri - and tetrahydroquinoline derived rutoside, has valuable properties. In particular, enriched troxerutin according to the present invention has good wettability in water and greater inhibition of aggregation of red blood cells compared with normal troxerutin.

In fact, studies in the test ex vivo, carried out with the use of human blood showed that the inhibition of aggregation of red blood cells is greatly enhanced in the presence of three or tetrahydroxytrilead and that trihydroxystilbene derived more efficiently than tetrahydroquinoline preisvorteil (content trihydroxyethylrutoside close to 95%) compared with commercially available troxerutin (contents close to 84%). The value of reducing aggregation of red blood cells is that the reduced viscosity of whole blood and, therefore, improves blood circulation. This property is expressed in increasing venous flow and increase microcirculation blood volume (density increase perfuziruemah capillaries).

Wettability enriched troxerutin, obtained according to the invention, compared with the wettability commercially available troxerutin containing about 84% trihydroxystilbene derivative, about 8% tetrahydroquinoline derived and about 4% dihydroxyethylene derived rutoside, and the residue formed above hydroxyethylene derived isoquercitrin-3-glucoside and kaempferol-3-rutinoside.

Studied enriched troxerutin in the amount of 3.5 g poured in chemical beaker 250 ml (low), containing 100 ml of water whose temperature is stabilised at the temperature of the laboratory (20°C). In the beginning of the test the temperature increase and measure the time required for complete wetting of the enriched troxerutin, i.e. so that it completely down to the bottom of the glass.

The following table 1 indicates the time, n is according to the invention and commercially available troxerutin. Each test was carried out while maintaining the temperature of the aqueous solution at 20°C, without stirring.

Similarly enriched troxerutin in the form of a compacted cylindrical sample of the powder size 2 and 3 mm height and weight of 63±3 mg is placed on the surface chemical beaker with 80 ml containing 100 ml of water. Raise the water temperature in the beginning of the test and measure the time required for complete wetting of the enriched troxerutin, that is, that he has completely changed color.

The following table 2 indicates the average time required for wetting of these samples enriched troxerutin according to the invention and commercially available troxerutin.

The results of the two above tests show that enriched troxerutin according to the invention differs from the standard troxerutin clearly improved wettability.

The study, conducted with the use of pharmaceutical compositions based on the enriched troxerutin according to the present invention showed that the observed rheological properties depend mainly on high doses of 7,3’,4’-trihydroxyethylrutoside, i.e. the systematic correction (improvement of the kinetics of aggregation and disaggregation constants of red blood cells) and the concentration of 7,3’,4’-trihydroxyethylrutoside.

Moreover, it was found that enriched troxerutin according to the invention is less related to plasma proteins, which limits the risk of drug interaction. This advantage is very important in the case of elderly patients, when they are forced to take several medications.

Pharmaceutical compositions based on the enriched troxerutin have improved solubilization, in particular, it can be seen at work in the following conditions.

Prepare a mixture containing, for example, 500 g of the investigated enriched troxerutin, 500 g of mannitol, and 0.035 g of saharinata sodium. Compounds are mixed and granularit using a mixture of ethanol with water.

The obtained granules are dried in a drying Cabinet. Dry granules are calibrated using sieves, nominal diameter of the hole which is 800 μm, and then added to them 35,71 g of orange flavor. Stirred to homogenize for 5 minutes. of 7.25 g of granules pour in chemical beaker 250 ml (diameter of the neck of 78 mm, height 95 mm), which contains 200 ml of water (room temperature about 20°C, stirring with the magnetic stirrer size 35×6.5 mm, 4 speed on the machine (IKAMAG)). Measure the time that the mu is stabilizing the solution of the final product, obtained with enriched troxerutin according to the invention. Finished pharmaceutical compositions on the basis of the enriched troxerutin require smaller amounts of the wetting fluid for the implementation required for pelleting operations, if the final product must be received in the form of granules. So, for wetting 1000 grams of the drug on the basis of the classical troxerutin and close to it the weight of mannitol using 150 g of water, while for wetting the same amount of the composition according to the invention based on purified troxerutin spent less than 100 g of water (table 4).

The following examples in more detail to explain the invention without limiting the scope of patent protection. Unless nothing else, all parts and percentages are expressed relative to the mass.

Example 1

100 g of rutin treated by heating at a temperature of about 75°C, using 28 g of ethylene oxide in 100 ml of water to which was added 1.1 g of sodium hydroxide, and the reaction mixture was kept under stirring for about 6 hours. Over the course of the reaction is monitored by high performance liquid chromatography (HPLC) and the end of the reaction is determined by the fact that when the relative quantities of islet by adding sulfuric acid to neutralize the alkali present.

The aquatic environment concentrated under reduced pressure (approximately 2·104PA) at a temperature of 60-70°C. so that the concentration of water in the destination environment for crystallization was close to 2%.

The concentrate is treated with 240 ml of methanol, then filtered to remove the salts formed. To the solution was added 220 ml of isopropanol and, after monitoring the water content carry out crystallization for about 8 hours, reducing the temperature from 65°C to 25°C during the first two hours and maintaining the temperature in the range of 25-20°C within the next 6 hours.

So get 89,4 g (yield 80%) troxerutin, containing 92% trisemester derivative, 4% Tetra-substituted derivative and 3% of the disubstituted derivative, and the residue formed above hydroxyethylene derived isoquercitrin-3-glucoside and kaempferol-3-rutinoside.

Example 2

Follow the procedure of example 1, but the crystallization is carried out for about 3-4 hours, during which reduces the temperature from 65 to 30°C, and then keep the temperature in the range 30-25°C for approximately 2 hours.

So get 87,2 g (yield 78%) troxerutin, containing 93% triseme the IAOD the same derivative, as the above.

Example 3

Follow the procedure of example 1, but the aqueous solution before filtration is passed through an ion exchange resin type strong cation resin, then a strong anionic resins. Wednesday then concentrate in order to bring the water content in the target environment to the average of approximately 5.2%.

The concentrate is treated with 800 ml of methanol and to the solution was added 30 ml of isopropanol. The crystallization is carried out, as described above, for about 2 hours, maintaining the temperature in the range 25-15°C for about 1 hour at the end of crystallization.

So get 84,2 g (yield 75%) troxerutin, containing 95% trisemester derived, 2.8% of Tetra-substituted derivative and 1.7% of the disubstituted derivative, and the remainder formed the same derivative, as specified above.

1. Enriched troxerutin containing at least 92 wt.% 7,3',4'-trihydroxyethylrutoside, from 2 to 4 wt.% 5,7,3',4'-tetrahydrochloride and from 1 to 3 wt.% 7,4'-dihydroxytoluene.

2. Enriched troxerutin under item 1, characterized in that the content 7,3',4'-trihydroxyethylrutoside greater than or equal to 93 wt.%, and the content of the 7th, that it contains at least 93 wt.% 7,3',4'-trihydroxyethylrutoside, 2-3,5 wt.% 5,7,3',4'-tetrahydrochloride and 1.7-2.5 wt.% 7,4'-dihydroxytoluene.

4. Pharmaceutical composition for the treatment of symptoms associated with venous-lymphatic insufficiency and treatment of functional symptoms associated with hemorrhagic stroke, containing enriched troxerutin according to any one of paragraphs.1-3 and pharmaceutical excipient.

5. Pharmaceutical composition for the treatment of symptoms associated with venous-lymphatic insufficiency and treatment of functional symptoms associated with hemorrhagic stroke, containing enriched troxerutin under item 1 and excipient suitable for oral administration, the time of dissolution which is on average 140 measured in the test, consisting in the introduction of 7.25 g of the granules of the composition in chemical beaker 250 ml (diameter of the neck of 78 mm, height 95 mm) containing 200 ml of water, and stirring with a magnetic stirrer and in determining the time solubilize the pellet.

6. The pharmaceutical composition according to p. 5, characterized in that the enriched troxerutin has a composition under item 2 or 3.

7. Enriched troxerutin according to any one of paragraphs.1-3 for receiving the motion in the legs, pain, primary bedsores) and treatment of functional symptoms associated with hemorrhagic stroke.

8. The method of obtaining troxerutin containing at least 92 wt.% 7,3',4'-trihydroxyethylrutoside, 2-4 wt.% 5,7,3',4'-tetrahydrochloride and 1-3 wt.% 7,4'-dihydroxytoluene, consisting in the interaction when heated routine with an excess of ethylene oxide in water in the presence of a base, then in the implementation of crystallization from alcohol, wherein the reaction medium was concentrated to obtain in the environment for crystallization water content of 1.8 wt.%.

9. The method according to p. 8, characterized in that the water content is 1-6%.

10. The method according to any of paragraphs.8 and 9, characterized in that the solvent for crystallization is methanol or isopropanol, used individually or in a mixture.

11. The method according to any of paragraphs.8-10, characterized in that the crystallization is carried out with the speed of the temperature approximately 20°C per hour for 1-2 hours

12. The method according to any of paragraphs.8-11, characterized in that the crystallization is carried out at a temperature 35-15°C.



 

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