Pharmaceutical composition for the treatment and control of convulsive states


(57) Abstract:

Use: medicine for the treatment and control of epilepsy and other types of convulsive States. The inventive aqueous solution for injection contains 35-180 mg/ml dinatriumfosfaatti 3-hydroxymethyl-5,5'-diphenylhydantoin, 0.05 to 0.2 M buffer, pH 8.3 creating-a 9.4. In particular, the buffer is tromethamine. Preferably 3-hydroxymethyl-5,5'-diphenylhydantoin is contained in the amount of 75 mg/ml, and the solution pH to 8.3-9. 3 C.p. f-crystals, 3 tables.

The invention relates to pharmaceutical compositions for the treatment and control symptoms of convulsive States in the form of an aqueous solution for injection.

Known 5,5-diphenylhydantoin (or phenytoin), commonly used for the treatment and control of epilepsy and other types of convulsive States. Although phenytoin is widely used for the treatment of these conditions, it has extremely low solubility and, consequently, low bioavailability. Phenytoin is a high-melting, weakly acidic substance poorly soluble in water. These properties lead to uneven absorption after administration in the form of the free acid, in the form of sodium salt. (S. A. Varia et in aqueous-alkaline medium with a pH of 12, containing 40% propylene glycol and 10% ethanol. Rapid intravenous parenteral dosage forms can be painful, because, as it turned out, education in places intramuscular injection of free acid precipitates.

In critical situations when the use of the parenteral forms of phenytoin, namely, to control seizures in patients with severe injuries, you may need to enter the drug intramuscularly. Intramuscular use of the drug should cause minimal tissue damage at the injection site. However, it was reported that intramuscular injections of sodium phenytoin painful, possibly due to precipitation of phenytoin. And they cause hemorrhage, hematoma and necrosis at the injection in cats and rats.

The above-mentioned work (S. A. Varia et al. Journal of Pharmaceutical Science) and (U.S. patent No. 4 260 7769, published. 7.04. 1981) describe the various drug precursors of phenytoin with more favorable physicochemical characteristics. In particular, the mentioned publications disclose predecessor phenytoin-3-(hydroxymethyl)-5,5-diphenylhydantoin-centripetal, and indicated that its physical and chemical characteristics suitable for parenteral the e connection does not detect tissue damage after subcutaneous or intramuscular injection, and, therefore, should be a good candidate for intramuscular delivery of phenytoin. However, the predecessor of phenytoin tends to decay with subsequent precipitation of phenytoin. To slow down the formation of point precipitation usually modify the structure of the active compounds or enter the additives which could solubilisate large quantities of decomposition products. Such additives include alcohol, propylene glycol, L-arginine, sodium deoxycholate, Polysorbate-80, as well as various combinations of the listed compounds.

It was found that the predecessor - 3-(hydroxymethyl)-5,5-diphenylhydantoin-centripetal stable in aqueous medium while maintaining the pH at a certain interval at a certain concentration in the composition of the precursor with education as a decomposition product of diphenylglycine with a minimum number of phenytoin. All this allows to minimize precipitation.

The pharmaceutical composition of the present invention, is intended for the treatment and control of convulsive States in the form of an aqueous solution for injection, and includes 3-(hydroxymethyl)-5,5-diphenylhydantoin-centripetal in the amount of 35 mg/meimei)-5,5-diphenylhydantoin-dinatriumfosfaatti 75 mg/ml, and the pH of the solution is preferably maintained in the range of 8.3 to 9.0 using as buffer tromethamine.

The inventive aqueous composition is a form of low-concentration dosage. This is a commercial product approved for sale in the United States and in other countries. It is administered intravenously in micrograms /kg/min

Preferred pharmaceutical composition should contain:

predecessor medications 35-180 mg/ml

alcohol USP 0-25%

propylene glycol 0-25%

L-arginine 0-0,2 M

the sodium deoxycholate 0-0,1 M

Polysorbate-80 0-1,5%

tromethamine 0,05-0,2 M

in water for injection with pH in the range of 8.3 to 9.4, the magnitude of which is governed by hydrochloric acid or sodium hydroxide.

It is determined that the interval of pH values, providing the greatest stability, it is from 8.3 to 9.4. In this range the choice of buffers is limited, in the sense that the buffer should effectively maintain the pH within the specified range. In addition tromethamine (Tris-(hydroxymethyl)aminomethane) can be used in other buffers, such as Bizen or N,N-bis(2-hydroxyethyl)-2-aminoetansulfonovaya acid; tricin or N-[Tris(hydroxymethyl) methyl]glycine; sodium bicarbonate; glycylglycine; F. the zine-N'-3-propanesulfonic acid); as well as taps, 3{ [Tris(hydroxymethyl)methyl]-amino} propanesulfonate acid. It is preferable to use tromethamine, bicin or tricin. As wetting additives, addition of Polysorbate-80, you can use: poloxamer 188 and ethers of polyoxyethylene and fatty acids. A more specific example of the composition: 75 mg/ml predecessor; 0.1 M tromethamine and approximately pH of 8.3, and 9.0, the pH was brought to the desired values using HCl.

Initially it was assumed that the decomposition of the precursor phenytoin just flows, in two stages, with the formation of phenytoin. However, determined that phenytoin is not the only decomposition products. It is established that the decomposition of the precursor of phenytoin is formed formaldehyde, 5,5-diphenyl-4-imidazolidinone (DIZ), diphenyl-glycinamide, benzophenone and phenytoin in the diagram below.

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The General direction of the decomposition shown in the diagram. Many of his stage associated with the transformation of the hydroxyl group, which should lead to decrease over time, the pH of the composition. This phenomenon was observed when studying the stability of the product in the usual manner. To prevent a significant fall in pH relative to its initial value during trocme decomposition. It is seen that with decreasing pH increases the rate of formation of phenytoin and the rate of formation DIZ is reduced. This suggests that the proposed disclosure gigantinho rings phosphate is, apparently, the limiting stage of the core schema decomposition of the precursor of phenytoin. However, when the pH decreases, the quantity of generated phenytoin increases and the solubility decreases, which greatly reduces the shelf life of the composition due to the saturation of the aqueous solution and the possible precipitation of phenytoin when used. The selected range of pH of the final product provides such a direction decomposition that the main decomposition product is diphenylglycine with minimal amounts of phenytoin that maximizes the lifetime of your predecessor.

The composition of the decomposition products.

With the aim of determining the composition of the decomposition products were analyzed several samples at room temperature and at 40oC. analysis of the effectiveness of the predecessor of phenytoin, the concentration of formaldehyde, 2,2-diphenylglycine, 5,5-diphenylhydantoin, 5,5-diphenyl-4-imidazolidinone and benzophenone was performed using gradiento method GHFR. Isokinetically), 5,5-diphenylhydantoin and 5,5-diphenyl-4-imidazolidinone was performed using isocratic method GHUR. Calculated molar equivalents, were determined and compared the contents of the products.

Statistical method and comparison method.

Method I the gradient method.

Took several standard curves chromatography for each connection to determine the linearity of the method. To obtain calibration curves, constructed a plot of peak areas and heights from the respective concentrations. As a rule, all standard curves had a correlation coefficient > 0,99. It is shown that all standard floor area or height of the peaks were within 4% of the linear regression that satisfies the specified requirements compliance schemes. Filmed chromatography repeated portions of a standard solution of each compound. The relative standard deviations did not exceed 1.7% using peak areas and 2.2% for the peak heights. The results obtained confirm the accuracy of the method.

The same dilution of the standard solutions used for the determination of limit of detection and limit of quantitation.

All standards who took the data obtained from standard solutions before and after a series of injections of the samples to determine the adequacy and effectiveness of the system GHUR.

Experimentally determined limits of quantitation (table. A and B).

Several times took the curves of the combined standards containing 2,2-diphenylglycine, 5,5-diphenylhydantoin and 5,5-diphenyl-4-imidazolidone, to determine their consistency with the curves of the individual standards. To obtain calibration curves were constructed dependency areas and peak heights of concentration. The angles and points of intersection with the Y-axis compared with the individual standards, confirming their compliance. Took chromatography repeated portions of the combined standard solution. The relative standard deviations did not exceed 1.7% for the peak areas and 2.0% for the heights of the peaks, except diphenylglycine for which (peak heights) relative standard deviation amounted to 3.09% This confirms the precision of a method of using a combination of the standard curve.

Mass composition.

To determine the mass composition of the analyzed several samples maintained during the various Prohm is achene source of efficiency and effectiveness in the moment, as well as data on the changing concentration of formaldehyde. Using Method 1 chromatographic determined concentration diphenylglycine, diphenylhydantoin, diphenyl-4-imidazolidinone and benzophenone. Based on these data, calculate the mass composition. The original and subsequent current values of efficiency were made in the original and the current number of moles of the predecessors of phenytoin. The concentration of formaldehyde, diphenylglycine, diphenylhydantoin, diphenyl-4-imidazolidinone and benzophenone was counted in a molar equivalents. Using the obtained number of moles of formaldehyde, diphenylglycine, diphenylhydantoin and benzophenone, using equation 1 to calculate the number of moles of the unknown connection (which was later identified as diphenylglycine).

The percentage of regeneration of 212 analyzed samples ranged from 98,0 to 102,6% that ensures the convergence of the composition (table 1).

Method II Isocratic method

Linearity of the method

Prepared and introduced standards to determine linearity isocratic method. In each case, the linear regression line for diphenylglycine, 5,5-diphenyl-4-imidazolidinone and phenytoin differed correlation coefficient above 0,999. As is diphenylglycine there is no standard, to determine the concentration of samples used curve diphenylglycine.

Precision isocratic method is implemented only in the analysis of several series decomposition of the precursor and the comparison of the obtained results with the gradient method (see Tables II and III). For all products of the decomposition results showed a very close match. The biggest difference obtained for diphenylglycine (formerly known as Unknown). Because the quantity was estimated using as a standard diphenylglycine, not the difference (equation I), was observed a slight increase. The results show that the quantitative assessment of the difference affects only the variance analysis for formaldehyde.

1. Pharmaceutical composition for the treatment and control of convulsive States in the form of an aqueous solution for injection, including 3-hydroxymethyl-5,5'-diphenylhydantoin centripetal and an additive, wherein the additive it contains 0.05 to 0.2 M buffer, creating a pH of 8.3 to 9.4, and the number of 3-hydroxymethyl-5,5'-diphenylhydantoin of dinatriumfosfaatti is 35 180 mg/ml.

2. The composition according to p. 1, characterized in that the image quality is hydroxymethyl-5,5'-diphenylhydantoin of dinatriumfosfaatti is equal to 75 mg/ml

4. The composition according to PP.1 to 3, characterized in that the pH of the solution is equal to 8.3, and 9.0.


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SUBSTANCE: one should perform puncturing of epidural space at Th12-L1 level. Through the lumen of puncture needle one should introduce catheter to move it cranially at the depth of 3 cm. After that one should inject 10 ml 05%-marcaine solution to perform repeated injections per 5.0 ml every 4 h during 1-8 d. The effect is achieved due to unloading minor cycle of circulation.

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