Pharmaceutical structures possessing antibiotic activity

FIELD: medicine; pharmacology.

SUBSTANCE: application of Sodium citratum dihydrate or potassium Citras dihydrate, or Sodium hydrogenum or bicarbonate of potassium, carbonate of sodium, arginine or their admixture as the antibiotic stabiliser fosfo-mitsina tromethamole, and their pharmaceutical structures for granulating is proposed. The invention allows for lowering destruction reaction of tromethamole fosfomicin in granulate by 35-70% (which provides stability of structure ready to use), and also in the presence of a gastric juice.

EFFECT: possess improved efficiencyof the structures.

8 cl, 3 ex

 

The present invention relates to the use of certain salts and amino acids as stabilizers antibiotic fosfomicin of trometamol (Fosfomycin Tromethamol), as well as pharmaceutical compositions containing them. Fosfomicin trometamol (Fosfomycin Tromethamol), denoted by FT (The Merck Index, XIII Ed., No 4277, page 755), is a known antibiotic which used to treat urinary tract; it is the active ingredient, for example, medicines MONURIL®.

Fosfomicin trometamol is a relatively unstable compound, since it represents a reactive functional group and can easily collapse under the action of temperature and humidity.

This makes difficult the storage of raw materials, the development and preparation of pharmaceutical compositions (at present only in the form of water-soluble granules), and the preservation of the finished packages.

To use a specific granules dissolve it in water and drink. The acidity of the stomach can also cause significant damage, which reduces the actual amount of active ingredient available for absorption.

It is known the use of succinic acid as a stabilizer sodium or calcium salts fosfomicin (Vecchio S et al. Thermal stability of disodium and calcium phosphomycin and the effects of theexcipients evaluated by thermal analysis. J. Pharm Biomed nal. 2001 Mar; 24 (5-6): 1111-23).

Also known pharmaceutical compositions in the form of water-soluble solid granules based fosfomicin of trometamol (GB 2234245 And 30.01.1991). However, the problem of stabilization fosfomicin of trometamol not resolved.

Presently, we have unexpectedly found that certain substances, when applied in a mixture with fosfomicin the trometamol is also able to stabilize the antibiotic while making the operations associated with the manufacture of pharmaceutical products, as well as ensuring the stability of the ready-to-use packages for a longer period of time.

In addition, the destruction of fosfomicin of trometamol pH corresponding to the pH of gastric juice, is reduced if fosfomicin trometamol connect with the mentioned substances.

According to the invention, there is the use of sodium citrate or potassium citrate dihydrate or sodium bicarbonate, or potassium bicarbonate, or sodium carbonate, or arginine, or a mixture thereof as a stabilizer fosfomicin of trometamol.

Preferred is the use as a stabilizer sodium citrate or sodium carbonate, or arginine.

These compounds as stabilizers can be used in different molar ratios relative to fosfomicin of trometamol, I preferred what is the molar ratio of the stabilizer to fosfomicin the trometamol 50%.

Here and further substances, the use of which is the subject of the present invention, will be referred to as "stabilizers", this means that this term also applies to a mixture of two or more substances.

The required amount of stabilizer in moles is from 10 to 100% relative fosfomicin of trometamol, preferably from 30% to 70%, and even more preferably approximately 50%.

Currently, among the above-mentioned stabilizers are preferred rejonowy sodium citrate, carbonate (or bicarbonate) sodium or potassium and arginine.

Pharmaceutical compositions which are the subject of the present invention, receive from fosfomicin of trometamol and stabilizer by adding to them in order farmacevticheskogo use of fillers.

Currently, the preferred pharmaceutical form fosfomicin of trometamol are water-soluble granules. The reason for this is that due to the relatively high content of input fosfomicin of trometamol (5,631 g) solution, which is obtained by dissolving the granules in water, the most suitable for patients and is well tolerated by them.

Using the new compositions according to the present invention can be obtained formulation granules, but water-soluble compounds can also be prepared Rostam mixing fosfomicin of trometamol, stabilizer, as well as other fillers (if present).

Fillers suitable for obtaining water-soluble compounds that contain fosfomicin trometamol and stabilizer are, for example, natural and synthetic sweeteners or flavorings.

Even if you can add more fillers, which, for example, useful for granulating process, their use is not necessary.

The preparation of the compositions according to the present invention may be of different easy ways.

You can, for example, prepare the cake mix granulate fosfomicin of trometamol, which has successfully blended stabilizer, flavor and sweetener, and in the end the product is distributed in small packages.

Or all the ingredients of the composition can directly mix.

The following examples are intended to better illustrate the present invention.

Example 1

Stabilization fosfomicin of trometamol selected stabilizers was evaluated experimentally, it was performed using the method of differential scanning calorimetry.

A mechanical mixture fosfomicin of trometamol (0,02 mol) with each of the stabilizers (0,01 mol) was mixed with 0.05% of water (with respect to the contents fosfomicin of trometamol).

Differential scan is based on calorimetry, used for each mixture (scanning speed of 10°C/min), allowed to measure the heat of reaction allocated after the melting point fosfomicin of trometamol due to the destruction.

Reduced heat means higher stabilization, and the number fosfomicin of trometamol remains the same.

Were obtained the following values:

Fosfomicin trometamol (individual substance) = 271,03±16,73 (j/g)

Fosfomicin trometamol + rejonowy sodium citrate (dihydrate) = 119,19±7,47 (j/g)

Fosfomicin trometamol + sodium bicarbonate = 143,32±4,92 (j/g)

Fosfomicin trometamol + sodium carbonate = 115,84±9,89 (j/g)

Fosfomicin trometamol + arginine = 175,25±9,41 (j/g)

The data obtained show that fosfomicin trometamol effectively stabilized with the addition of the above-mentioned substances. Heat of reaction of destruction when the same number of FT decreased by approximately 35-70%.

Example 2

Stabilization fosfomicin of trometamol in conditions simulating the gastric juice was evaluated by vosproizvedeniya these conditions for the patient: to 5,631 g fosfomicin of trometamol was added to 0.01 mol of the selected stabilizer, and then dissolved in water (180 ml).

The solution was poured into the simulator gastric juice (100 ml, pH 1); destruction was determined as a percentage of the recovery active ingredient is and in time.

Already after 30 min recovery fosfomicin of trometamol in the absence of the stabilizer was 82%, while with stabilizer restoration was carried out by 90%.

Example 3

Below, the pharmaceutical compositions were obtained by simple mixing of the ingredients.

Part 1

Fosfomicin trometamol 5,631 g

The dihydrate sodium citrate 1,125 g

Aspartame 0,100 g

Tangerine flavor 0,100 g

Orange flavor 0,100 g

Part 2

Fosfomicin trometamol 5,631 g

The dihydrate sodium citrate 0,500 g

Sodium bicarbonate 0,840 g

Aspartame 0,100 g

Tangerine flavor 0,100 g

Orange flavor 0,100 g

Part 3

Fosfomicin trometamol 5,631 g

Sodium bicarbonate 1,127 g

Sodium carbonate 0,200 g

Sucrose 2,00 g

Tangerine flavor 0,100 g

Orange flavor 0,100 g

Part 4

Fosfomicin trometamol 5,631 g

The dihydrate sodium citrate 0,734 g

Acidic sodium citrate 0,987 g

Fructose 2,500 g

Tangerine flavor 0,100 g

Orange flavor 0,100 g

Part 5

Fosfomicin trometamol 5,631 g

L-arginine 1,470 g

The sodium saccharinate 0,010 g

Sucrose 2,100 g

Tangerine flavor 0,100 g

Orange flavor 0,100 g

Part 6

Fosfomicin trometamol 5,631 g

L-arginine 0,500 g

Lysine 0,100 g

Aspar what am 0,100 g

Tangerine flavor 0,100 g

Orange flavor 0,100 g

Part 7

Fosfomicin trometamol 5,631 g

The dihydrate sodium citrate 0,500 g

Sodium carbonate 0,500 g

Aspartame 0,100 g

Tangerine flavor 0,070

Orange flavor 0,070

Part 8

Fosfomicin trometamol 5,631 g

The dihydrate sodium citrate 1,000 g

L-arginine 0,050 g

Aspartame 0,070

Orange flavor 0,150 g

Lemon flavor 0,030 g

Part 9

Fosfomicin trometamol 5,631 g

The dihydrate sodium citrate 1,800 g

The sodium saccharinate 0,040 g

Sucrose 1,500 g

Tangerine flavor 0,100 g

Lemon flavor 0,100 g

Part 10

Fosfomicin trometamol 5,631 g

The dihydrate sodium citrate 1,125 g

Aspartame 0,070

Tangerine flavor 0,100 g

Orange flavor 0,100 g

1. The use of sodium citrate, or potassium citrate dihydrate or sodium bicarbonate, or potassium bicarbonate, or sodium carbonate, or arginine, or a mixture thereof as a stabilizer fosfomicin of trometamol.

2. The use according to claim 1, characterized in that the stabilizer is the dihydrate of sodium citrate, sodium carbonate or arginine.

3. The use according to claim 1, characterized in that the said compounds as a stabilizer in a molar ratio relative to fosfomicin Trametal the La is 50%.

4. Antibiotic pharmaceutical composition for granulation containing fosfomicin trometamol, dihydrate sodium citrate, or potassium citrate dihydrate or sodium bicarbonate, or potassium bicarbonate, or sodium carbonate, or arginine, or a mixture thereof and suitable for pharmaceutical use fillers.

5. Antibiotic pharmaceutical composition according to claim 4 in the form of soluble granulate.

6. Antibiotic pharmaceutical composition according to claim 5, characterized in that it contains fosfomicin of trometamol in a single dose in the amount of 5,631,

7. Antibiotic pharmaceutical composition according to claim 4, characterized in that it contains as stabilizer dihydrate sodium citrate, or sodium carbonate, or arginine.

8. Antibiotic pharmaceutical composition according to claim 4, characterized in that the said compounds as stabilizers 50% in molar ratio relative to fosfomicin of trometamol.



 

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