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The method of stabilization solution for infusion ciprofloxacin

The method of stabilization solution for infusion ciprofloxacin
IPC classes for russian patent The method of stabilization solution for infusion ciprofloxacin (RU 2229884):
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The invention relates to the pharmaceutical industry. Infusion solution ciprofloxacin stabilize lactic acid, sodium chloride and a buffer system, which includes citric acid - sodium phosphate, in the following ratio of components, g: ciprofloxacin 0,2; sodium chloride 0,9; citric acid of 0.615 - 1,845; sodium phosphate 0,385 - 1,150; lactic acid of 0.00006-0,00012; purified water to 100 ml. of the Invention allows to obtain the product in the form of a solution. 12 table.

The invention relates to the field of pharmacy, namely, solutions for infusion containing antimicrobial drugs.

According to a recent statement by the world health organization, many infectious diseases threaten to become incurable, because bacteria in recent years evolved to full immunity to antibiotics (Pokrovsky Century. And., Pozdeev O. K. Medical Microbiology/Medical: GEOTAR, - 1998, S. 5-6). The drug of choice for treatment of many infectious diseases caused by resistant microflora is ciprofloxacin. Because of the high antibacterial activity of ciprofloxacin issued abroad in the form of different Lecanora convention. 2003 - ciprofloxacin assay inection).

In Russia ciprofloxacin is available only in pill form. In this regard, it is urgent development and other dosage forms ciprofloxacin. Infusion solution ciprofloxacin is made isotonic sodium chloride solution or glucose solution 5%. Known patent (DE No. 10018783 A1) Stable infusion solution ciprofloxacin.

In this infusion solution is included as an active substance is present in the amount of 0.015 to 0.5 g per 100 ml of solution and the sulfuric acid in the amount of 0.9 mol per 1 mol of the active substance. The disadvantages of this prototype, in our opinion, is that as the active substance used ciprofloxacin - in base, which is further transferred to salt (more stable form), which increases the number of stages of production of a solution of ciprofloxacin, resulting, of course, is the cost of the final product.

Our proposed solution ciprofloxacin differs from the prototype in that for the preparation of dosage forms used ciprofloxacin as hydrochloride, for its stabilization is applied phosphate-citrate buffer. To maintain the pH Katsina produces. The aim of the invention is the creation of solution for infusion ciprofloxacin, stable over a long period of time, using buffer solutions that are close to physiological blood components. However, for the preparation of a solution of ciprofloxacin use of ciprofloxacin hydrochloride, registered in Russia that, in contrast to the German counterpart does not require translation of ciprofloxacin Foundation in its salt that decreases the stage of the process of obtaining.

Distinguishing the essential features of the claimed invention is:

1. Use as buffer solution buffer Macilwaine (phosphate-citrate buffer) is closest in content to the physiological composition of the blood.

2. When using phosphate-citrate buffer solution increases the stability of the solution.

3. The reduction steps in the manufacture of a solution of ciprofloxacin, resulting in a reduction of cost of infusion solution ciprofloxacin.

To improve the stability of ciprofloxacin proposed solution of the following composition: ciprofloxacin 0.2 g (as hydrochloride), sodium chloride (0.9 g, lactic acid of 0.00006-0,00012 g to a pH of 3.6 to 4.6, citric acid of 0.615-1,844 W ith more stable dosage form of ciprofloxacin solution for infusion and thereby to increase shelf life, using a physiological buffer. With this purpose were composed of various compositions using different buffer systems. From the available buffer solutions we have used buffer solutions, most often used in medical practice, containing citric acid - sodium phosphate (Mcilvaine), citric acid - sodium citrate, acetic acid - sodium citrate (Reference Biochemist under the editorship of R. Dossena, D. Elliott, U., Elliott, K. Jones. - M.: Mir, 1991, S. 48-57).

The compositions of solutions for infusion ciprofloxacin, g:

Example 1

Ciprofloxacin (as hydrochloride) 0,2

Glucose 5,0

Purified water to 100 ml

Example 2

Ciprofloxacin (as hydrochloride) 0,2

Glucose

The lactic acid to 5.0

Purified water to 100 ml of 0.00006

Example 3

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride

Citric acid 0,9

Sodium phosphate 0,123

Purified water to 100 ml 0,077

Example 4

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride

Citric acid 0,9

Sodium hydrogen phosphate of 0.615

The lactic acid 0,385

Purified water to 100 ml of 0.00006

Example 5

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride

Citric acid 0,9

Sodium chloride

Citric acid 0,9

Sodium phosphate 1,844

The lactic acid 1,15

Purified water to 100 ml 0,00012

Example 7

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride

Citric acid 0,9

Sodium citrate 0,295

Purified water to 100 ml 0,205

Example 8

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride

Sodium acetate 0,9

Acetic acid 0,09

Purified water to 100 ml 0,41

Example 9

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride

Sodium acetate 0,9

Acetic acid 0,18

Purified water to 100 ml 0,82

Example 10

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride

Citric acid 0,9

Sodium citrate 0,590

The lactic acid 0,410

Purified water to 100 ml 0,00012

Example 11

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride 0,9

Sodium acetate 0,09

Acetic acid 0,41

The lactic acid 0,00012

Purified water to 100 ml

Example 12

Ciprofloxacin (as hydrochloride) 0,2

Sodium chloride

The lactic acid 0,9

Purified water to 100 ml of 0.00006

The resulting solutions were analyzed for the following parameters: pH, color solution, related impurities and quantitative the historical method [U. S. P. 26 The National Formulary 19. - Rockwill: United States Pharmacopoeia convention. 2003]. The color of the solutions was determined spectrophotometrically at=430 nm, where the optical density (D) shall be not more than 0.01. As the reference solution used purified water [U. S. P. 26 The National Formulary 19, - Rockwill: United States Pharmacopoeia convention. 2003]. Related impurity ethylendiamine (ED) similar ciprofloxacin analyzed by high performance liquid chromatography (HPLC) [U. S. P. 26 The National Formulary 19. - Rockwill: United States Pharmacopoeia convention. 2003]. Quantitative determination of the solution for infusion ciprofloxacin were also carried out by high performance liquid chromatography (HPLC) on a column of 2x80 mm, filled with dearbom C-16, as the eluent used 60% acetonitrile, the feed rate of the mobile phase of 50 ál/min relative error for quantitative determination did not exceed ±3% [U. S. P. 26 The National Formulary 19. - Rockwill: United States Pharmacopoeia convention. 2003]. The study of stability of solutions of ciprofloxacin, prepared on the basis of different buffer systems were conducted according to the “Instructions for carrying out works for the purpose of determining the shelf life of medicines on the basis of the method of accelerated aging at elevated temperatures”. In parallel p. The obtained data are given in tables 1-12.

On the basis of the obtained data shows that the compositions 7 and 8 were stable for at least 2.5 years (table. 7, 8). Solutions of compositions No. 1, 2, 9 were stable over the 3 years (table. 1, 2, 9). Composition No. 3, 10, 11, 12 remained stable over 3.5 years (table. 3, 10, 11, 12), and composition of No. 4, 5, 6 proved to be the most stable and remained stable during the 4 years (table. 4, 5, 6).

For the proposed compositions was calculated theoretical osmolarity of the solutions. The calculation was performed according to the formula:

where m is the concentration, g/l;

M - molar mass of substance (g/mol;

n is the number of particles formed during dissolution.

The value of n for citric acid and sodium hydrogen phosphate were calculated at pH 4.5. For this purpose, we first calculated the proportion dissociatively molecules for each of the steps of dissociation (P. R. Bonchev Introduction to analytical chemistry: Bulgarian/ edited by B. I. Lobov. - L.: Chemistry, 1978. - 496 C.). It was found that theoretical osmolarity for these compositions range from 320 to 325 mOsm/l, which meets the requirements of perfusions (239-376 mOsm/l).

This composition proposed the om offer the composition while maintaining equivalent to prototype pharmacological action is to enhance the stability of the solution and thereby increase the shelf life of the drug, and also serves as a stabilizer to use buffer solution, similar in content to the physiological composition of the blood.

Claims

The way to stabilize the solution for infusion ciprofloxacin, characterized in that the stabilizer is used as the lactic acid, sodium chloride and a buffer system: citric acid - sodium phosphate in the following ratio of components, g:

Ciprofloxacin 0,2

Sodium chloride 0,9

Citric acid of 0.615 - 1,845

Sodium phosphate 0,385 - 1,150

The lactic acid of 0.00006-0,00012

Purified water To 100 ml

 

 

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