RU2255730C1 - Stable pharmaceutical azithromycin suspension and method for its preparing - Google Patents

Abstract

FIELD: medicine, pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to an antibacterial preparation azithromycin. The stable pharmaceutical suspension of azithromycin comprises the therapeutically effective dose of azithromycin and special additives - sorbitol, sodium benzoate, aromatic principles, glycerol, glutamic acid, methylcellulose, polyvinylpyrrolidone and propylene glycol. Also, invention proposes a method for preparing the stable suspension of azithromycin that involves addition of mixture of azithromycin with glutamic acid as solution in glycerol or as dry form to an aqueous solution of methylcellulose containing propylene glycol and glycerol or propylene glycol and successively dissolved sodium benzoate, polyvinylpyrolidone and sorbitol followed by dilution with water up to the azithromycin concentration that is necessary for using. Invention provides creature of new stable suspension that is resistant for 1 year, not less, and useful for treatment of children being among them suffering with diabetes mellitus.

EFFECT: improved method for preparing, valuable medicinal properties of suspension.

4 cl, 4 tbl, 1 dwg, 4 ex

Description

The invention relates to medicine, specifically to the antimicrobial drug azithromycin and is suitable for the treatment of various infectious diseases caused by microorganisms sensitive to azithromycin: pneumonia, bronchitis, scarlet fever, tonsillitis, urethritis, etc.

Azithromycin is used in various dosage forms: tablets, capsules, powders for the preparation of suspensions.

Of considerable interest are children's dosage forms of azithromycin in the form of suspensions and syrups.

Azithromycin powder for suspension is described in European patent EP 0679400 A, 1995, several formulations are given (in grams):

- Azithromycin dihydrate - 838.57 - Sucrose - 15487.74 - Sodium phosphate trisubstituted anhydrous - 70.01 - Hydroxypropyl cellulose (Klucel EF) - 26.62 - Vegetable resin (gum) - 26.62 - Dye red -0.67
- Flavors: cherry - 59.94 vanilla - 133.28 banana - 99.96 Amount 16743.41

In the other five compositions described in this patent, in addition to these components, sorbitol, glycine, colloidal silicon dioxide, titanium dioxide, sodium benzoate, anhydrous sodium carbonate are given.

The disadvantages of this composition are:

- sugar content from 46 to 92%, which complicates the use of the drug in patients with diabetes;

- the suspension prepared from the powder is stored for no more than 5 days.

The aim of the invention is the creation of a new stable suspension containing azithromycin, stable for at least 1 year and suitable for the treatment of children, including those suffering from diabetes.

By theoretical and experimental selection of target additives in the claimed invention, a stable pharmaceutical suspension of azithromycin is created that meets the goal.

Sorbitol and glycerin have been proposed as a correcting agent for the bitter taste of azithromycin instead of sugar and sorbitol. To stabilize the suspension, methyl cellulose and polyvinylpyrrolidone were added. In addition, to increase the stability of azithromycin, which undergoes hydrolytic and oxidative degradation in aqueous media, glutamic acid is introduced. Glutamic acid also helps to improve the biomedical properties of the drug.

A stable pharmaceutical suspension of azithromycin is proposed, including a therapeutically effective amount of azithromycin and target additives, which are glycerol, glutamic acid, methyl cellulose, sodium benzoate, polyvinylpyrrolidone, propylene glycol, sorbitol, flavor in the following ratio, wt.%:

Azithromycin - Therapeutically Effective Amount

Glycerin - 15.0-25.0

Glutamic acid - 0.1-1.0

Cellulose - 1.0-3.0

Sodium benzoate - 1.0-3.0

Polyvinylpyrrolidone - 0.5-3.0

Propylene glycol - 5.0-10.0

Sorbitol - 5.0-10.0

Fragrance - 0.05-0.2

Water - up to 100.0

Methyl cellulose is mainly used for methylcellulose MTs-16, polyvinylpyrrolidone, mainly low molecular weight.

The azithromycin content in the pharmaceutical suspension is 2.0 ± 15%.

The claimed ratio of the components was found experimentally, it is optimal and allows to obtain a technical result that is appropriate for the task: the suspension of azithromycin has a shelf life of at least 1 year, can be used to treat children, including those suffering from diabetes. In addition, a stable suspension of azithromycin is suitable for use without dilution.

One of the ways to obtain suspensions is the method of mixing active and auxiliary substances and diluting them with water ("Technology of dosage forms", v.2, edited by L. Ivanova, M., Medicine, 1991, p. 491-492) .

A method of obtaining a stable pharmaceutical suspension of azithromycin according to the invention is as follows: a solution of methyl cellulose in water is diluted with glycerol and propylene glycol, sodium benzoate, polyvinylpyrrolidone, sorbitol are added to the resulting solution successively, after dissolution of these components, glutamic acid, azithromycin and flavor are added, the resulting solution is diluted with water until the necessary concentration of azithromycin; or a solution of methyl cellulose in water is diluted with propylene glycol, a pre-prepared solution of sodium benzoate, polyvinylpyrrolidone, sorbitol in water is added to the resulting solution, then a solution of azithromycin and glutamic acid in glycerol is added to the resulting solution and diluted with water to the required concentration of azithromycin.

All this together makes it possible to obtain a stable suspension of azithromycin that meets all the requirements of the State Pharmacopoeia of the 11th edition, regulatory documents for azithromycin, the suspension is used without dilution, shelf life of at least 1 year (table 1).

The following examples illustrate the invention.

Example 1. 350 ml of distilled water are added to 12.0 g of methyl cellulose. The mixture is stirred at room temperature for 4-5 hours to obtain a thick homogeneous mass. Separately, a solution of glycerol is prepared from 200 g of glycerol and 100 ml of distilled water. The resulting solution was poured into an aqueous solution of methylcellulose, the mixture was stirred and 80.0 g of propylene glycol was added to it, the mass was stirred for 30-40 minutes and filtered. 12.0 g of sodium benzoate are successively added to the resulting solution at room temperature with stirring; 8.0 g of polyvinylpyrrolidone; 54.65 g of sorbitol; 1.97 g of glutamic acid, 20.0 g of azithromycin (100%) and 1.0 g of flavoring.

Each subsequent component is added after obtaining a homogeneous mixture of the previous reagents.

The resulting suspension is diluted with purified water to a volume of 1 l and stirred for 1 hour.

The yield of suspension of azithromycin is 97.42%, counting on the initial azithromycin.

The resulting suspension complies with the regulatory requirements of the State Pharmacopoeia of the 11th edition and the regulatory documents for the suspension of azithromycin (infant dosage form). The content of azithromycin is 0.02 g in 1 ml. Shelf life at 10 ° C 1 year. The suspension is suitable for use without additional dilution.

Example 2. To 350 ml of distilled water, 12.0 g of methyl cellulose is added, stirred at room temperature until a homogeneous mass is obtained. Then add 80 g of propylene glycol, mix. A pre-prepared solution containing 150 ml of distilled water, 54.65 g of sorbitol, 12.0 g of sodium benzoate and 8 g of polyvinylpyrrolidone is gradually added to the resulting solution. The mass is mixed, then a solution containing 200 g of glycerol, 20 g of azithromycin and 1.97 g of glutamic acid is gradually added to it. The mass is thoroughly mixed, 1 g of flavor is added to it, diluted with distilled water to 1 liter. After thorough mixing, a suspension of azithromycin is obtained containing 0.02 g of azithromycin in 1 ml.

The yield on the starting azithromycin is 98.2%.

The resulting suspension complies with the regulatory requirements of the State Pharmacopoeia of the 11th edition and the regulatory documents for the suspension of azithromycin (infant dosage form). The content of azithromycin is 0.02 g in 1 ml. Shelf life at 10 ° C 1 year. The suspension is suitable for use without dilution.

Example 3. Analogously to example 1 load 10 g of methyl cellulose and 350 ml of distilled water, 150 g of glycerin and 110 g of distilled water, 10.0 g of sodium benzoate; 4.0 g of polyvinylpyrrolidone; 50.0 g of sorbitol; 1.0 g of glutamic acid, 20.0 g of azithromycin and 0.5 g of flavoring.

The resulting suspension complies with the regulatory requirements of the State Pharmacopoeia of the 11th edition and the regulatory documents for the suspension of azithromycin (infant dosage form). The content of azithromycin is 0.02 g in 1 ml. Shelf life at 10 ° C 1 year. The suspension is suitable for use without additional dilution.

Example 4. Analogously to example 2, load: 350 ml of distilled water, 30.0 g of methyl cellulose, 100 g of propylene glycol, add to 100 ml of distilled water 100.0 g of sorbitol, 30.0 g of sodium benzoate and 30.0 g of polyvinylpyrrolidone, add a solution containing in 250 g of glycerin 20 g of azithromycin and 10.0 g of glutamic acid. The mass is thoroughly mixed, 1 g of flavor is added to it, diluted with distilled water to 1 liter. After thorough mixing, a stable suspension of azithromycin is obtained.

The resulting suspension complies with the regulatory requirements of the State Pharmacopoeia of the 11th edition and the regulatory documents for the suspension of azithromycin (infant dosage form). The content of azithromycin is 0.02 g in 1 ml. Shelf life at 10 ° C 1 year. The suspension is suitable for use without additional dilution.

Biological studies of a stable pharmaceutical suspension of azithromycin are carried out in comparison with the known composition (according to European patent EP 0679400 A).

Studies were performed on male chinchilla rabbits with a body weight of 3.0-3.2 kg. The animals were kept in standard cages with a 12-hour lighting regime and free access to food and water.

The pharmacokinetics and bioavailability of the preparations of the present invention (A) and the known (European patent EP 0679400 A) (B) were studied for 8 hours after a single administration of a suspension of per os at a dose of 160 mg / kg (Lukehart A., Fohn MJ // J Antimicrob. Chemother - 1990. - Vol.25. - P.91-99 .//).

After oral administration of drugs, blood was taken from the marginal vein of the rabbit ear at discrete time intervals (0.5; 1; 1.5; 2; 3; 4; 5; 6 and 8 hours after drug administration) (table 2).

Blood samples were kept at room temperature until a clot formed, after which the samples were centrifuged for 10 min at n = 2500 rpm and 0.5 ml of serum was taken.

The analysis of the content of azithromycin in the blood serum was carried out by the microbiological method of diffusion into agar with the Micrococcus lutea test microbe. The detection limit is 0.2 μg / ml. In this case, the following composition was used: casein hydrolyzate - 4 g, yeast extract - 3 g, anhydrous glucose - 1 g, agar - 15 g, meat and peptone broth up to 1000 ml. pH after sterilization of 7.7-8.0.

The seeding dose of the test microbe was 200 million microbial bodies per 1 ml of medium. 15 ml of seeded medium (1 layer) was poured into each Petri dish. After serum was instilled into the wells, Petri dishes were incubated at 36 ° C for 18-20 hours (Marzo A. - Pharmacol.Res. - 1995. Vol.32, No.2 - P.237-240; Laub PB, Gallo JM // J. Pharmaceut. Sci. - 1996. - Vol. 85, No.4. - P.393-395).

Pharmacokinetic data were analyzed using the out-of-model method of integral moments using the ASKID computer program.

The following pharmacokinetic parameters were calculated:

AUC _t is the area under the pharmacokinetic curve (0-8 h), μg · h / ml;

T _max - time to reach C _max , h;

MRT is the average residence time of the drug in the body, h;

T _{1 / 2β} is the half-life.

The relative bioavailability of the suspension according to the proposed patent (A) compared with the suspension according to the well-known patent EP 0679400 (B) of the company was determined using the equation:

f = [AUC (A) · D (B)] / [AUC (B) · D (A)],

where AUC is the area under the concentration – time curve, μg · h / ml;

D is the administered dose, mg / kg.

The profiles of the pharmacokinetic curves of the averaged concentrations in the blood after the introduction of a new suspension and the known are shown in the drawing in Cartesian coordinates.

It was found that the drug is rapidly absorbed into the systemic circulation when taking both studied forms, for a short time it is in submaximal concentrations and excreted with a half-elimination period in the β-phase of the order of 3.16-3.18 hours.

Table 2 contains individual and average values of the main pharmacokinetic parameters characterizing the relative bioavailability of the studied dosage forms of azithromycin. It was found that the values of AUC, MRT, C _max , T _max and T _{1 / 2β} in the studied dosage forms of azithromycin did not statistically significantly differ from each other. Statistical analysis included the calculation of average values, standard unbiased deviation. A comparison of the average of the two populations was carried out on the basis of the t-criterion for student distribution (Table 3).

Since both dosage forms were administered in the same average dose, the relative bioavailability of preparations A and B was determined by the ratio of the areas under the AUC pharmacokinetic curve, which were calculated by the trapezoidal method.

Therefore, according to the degree of bioavailability and the absence of significant differences in other parameters that determine the relative bioavailability of the compared dosage forms of azithromycin, both drugs are therapeutically equivalent.

Thus, the inventive suspension of azithromycin, not inferior in quality or pharmacological properties to a known sample, has a shelf life of at least 1 year and can be used in the treatment of children, including those suffering from diabetes. In addition, it is ready for use and does not require additional dilution.

Table 1 Name of quality indicators Quality Standards Actual Quality Indicators example
one example
2 example
3 example
4 Description White or slightly colored suspension of bitter taste with a fruity odor White fruity suspension White fruity suspension White fruity suspension White fruity suspension Sedimentation stability time
Within 1 hour, the separation of the suspension does not occur Suspension is stable for more than 24 hours. Suspension is stable for more than 24 hours. Suspension is stable for more than 24 hours. Suspension is stable for more than 24 hours. pH 7.0 to 9.0 8.0 7.5 8.5 8.5 Quantitative content In 1 ml: - azithromycin from 0.018 to 0.022 g; - sodium benzoate from 0.0113 to 0.0127 g azithromycin 0.02 g sodium benzoate 0.117 azithromycin 0.02 g sodium benzoate 0.117 azithromycin 0.02 g sodium benzoate 0.117 azithromycin 0.02 g sodium benzoate 0.117 Bioavailability,% 75-125 110 115 98 98.5 Shelf life Not less than 1 year 1 year 1 year 1 year 1 year

table 2
The values of the concentrations of azithromycin (μg / ml) after a single oral administration to rabbits at a dose of 100 mg / kg SUGGESTED SUSPENSION Time h 1 2 3 4 5 6 M m 0.5 0.8 1.3 1.4 0.9 1,1 0.9 1,07 0.10 1 1.4 1.9 3.3 1.8 1.7 2,5 2.10 0.28 1,5 1,1 2.7 2,8 1.3 2.7 2,3 2.15 0.31 2 1 2,8 2,3 1,2 2,4 2.1 1.97 0.29 3 0.8 2.2 2 0.5 1,5 0.8 1.31 0.29 4 0.5 1.8 1,1 0.8 0.7 0.6 0.91 0.19 6 0.4 0.8 0.9 0.5 0.7 0.5 0.64 0.08 8 0.4 0.5 0.7 0.3 0.5 0.3 0.45 0.06 KNOWN SUSPENSION Time h 1 2 3 4 5 6 M m 0.5 1.4 0.9 0.8 1,5 1.9 0.8 1.22 0.19 1 1.9 1,5 1.9 2.9 2,5 3.2 2,32 0.27 1,5 3.3 1,2 1,5 2,5 2,8 2,8 2,35 0.34 2 2.9 1,1 1,5 2,4 2,3 2.2 2.07 0.27 3 2.2 0.8 0.8 1,6 0.9 0.6 1.15 0.25 4 1,6 0.7 0.7 1,2 0.8 0.8 0.97 0.15 6 1,1 0.5 0.6 0.8 0.7 0.5 0.70 0.09 8 0.5 0.3 0.4 0.3 0.5 0.3 0.38 0.04

Table 3
The pharmacokinetic parameters of azithromycin after a single oral administration of the inventive suspension (A) and known suspension (B) to rabbits at a dose of 100 mg / kg The inventive drug (A) No. T _1/2 C _max T _max MRT Auc 1 3.9 1.4 1 5.93 6.81 2 2.23 2,8 2 4.16 13,4 3 3.19 3.3 1 5.02 14.2 4 3.92 1.8 1 5.7 7.04 5 3.32 2.7 1,5 5.11 10.3 6 2,53 2,5 1 4.01 7.63 M 3.18 2.42 1.25 4.99 9.90 m 0.283 0.285 0.171 0.319 Comparison drug (B) No. T _1/2 C _max T _max MRT Auc 1 2.44 3.3 1,5 4.32 14.3 2 3.36 1,5 1 5.22 7.2 3 3.65 1.9 1 5.62 8.47 4 2.16 2.9 1 3.67 11.2 5 4.35 2,5 1,5 5.89 11.7 6 3.02 3.2 1 4.46 7.82 M 3.16 2,55 1.17 4.86 10.12 m 0.33 0.30 0.08 0.35 1.12

Table 4
The results of a standard comparison of the averaged data of the pharmacokinetics of azithromycin after a single oral administration of drugs A and B T _1/2 C _max T _max MRT Auc A / B 100.6% 94.9% 106.8% 102.7% 97.8% t 0.05 0.31 0.42 0.27 0.13 p > 0.05 > 0.05 > 0.05 > 0.05 > 0.05

where t are the values of the student criterion; p - probability values, p> 0.05 indicates the absence of a significant difference between the average values of the compared samples.

Claims (4)

1. Pharmaceutical suspension of azithromycin with antimicrobial activity, including azithromycin, target additives - cellulose derivatives, flavoring, water, characterized in that it contains methyl cellulose and additionally contains glycerin, glutamic acid, sodium benzoate, polyvinylpyrrolidone, propylene glycol components, sorbitol, with wt.%: Azithromycin 1.7-2.3 Glycerin 15.0-25.0 Glutamic acid 0.1-1.0 Cellulose 1.0-3.0 Sodium benzoate 1.0-3.0 Polyvinylpyrrolidone 0.5-3.0 Propylene glycol 5.0-10.0 Sorbitol 5.0-10.0 Flavor 0.05-0.2 Water Up to 100 2. The suspension according to claim 1, characterized in that as methyl cellulose it contains predominantly methyl cellulose MC-16, polyvinylpyrrolidone, mainly low molecular weight. 3. The suspension according to claims 1 and 2, characterized in that it is suitable for use without additional dilution. 4. A method of obtaining a pharmaceutical composition of azithromycin with antimicrobial activity, characterized in that azithromycin with glutamic acid in the form of a solution in glycerol or in dry form is added to a solution of methyl cellulose in water containing propylene glycol and glycerin or propylene glycol and successively dissolved sodium benzoate, polyvinylpyrrolide sorbitol, followed by dilution with water.