RU2277933C2 - Immobilized form of cephasoline for preventing postoperative infectious complications in otolaryngology - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides immobilized form of cephasoline wherein cephasoline is included into polymer matrix made of sodium-carboxymethylcellulose.

EFFECT: reduced (by three days) treatment time.

1 dwg, 5 tbl

Description

The invention relates to medicine, in particular to pharmacy, surgery and otorhinolaryngology.

The closest dosage form is cefazolin powder for the preparation of an injection solution, which is used intramuscularly or intravenously (in a jet or drip). For the prevention of postoperative infectious complications, cefazolin is prescribed 1.0 g 30 minutes before surgery, 0.5-1.0 g during surgery and 0.5-1.0 g every 6-8 hours for a day after surgery. The duration of treatment is 7-10 days. The consumption of cefazolin from 3.5 to 42 g [Piskunov G.Z., Piskunov S.Z. Medicines used in otorhinolaryngology. - M.: CJSC Finstatinform, 2000. - S.33-34; Mashkovsky M.D. Medicines: Manual for doctors: In 2 t. - T.2. - Ed. 14th, rev. and add. - M .: New wave, 2000 .-- 608 p .; Belousov Yu.B., Ushkalova E.A. Formular system in antibiotic therapy // Antibiotics and chemotherapy. - 2001. - T. 46. - No. 11. - S.23-35].

The indicated dosage form of cefazolin has disadvantages: side effects from the vital systems of the body, nausea, vomiting, diarrhea, pain in the epigastric region, pseudomembranous colitis, candidomycosis, impaired renal function, increased concentration of liver enzymes (ACT, ALT, alkaline phosphatase, LDH) in the blood, changes in the picture of peripheral blood (reversible leukopenia, neutropenia, thrombocytopenia, agranulocytosis, lymphocytosis, hemolytic anemia), allergic manifestations (skin rashes, itching, toxic epidermis ny necrosis, erythema multiforme, fever, angioneurotic edema, arthralgia, anaphylactic shock). Possible pain at the site of intramuscular injection, the formation of infiltrates, abscesses, phlebitis and thrombophlebitis [Piskunov GZ, Piskunov SZ Medicines used in otorhinolaryngology. - M.: CJSC Finstatinform, 2000. - S.33-34; Mashkovsky M.D. Medicines: Manual for doctors: In 2 t. - T.2. - Ed. 14th, rev. and add. - M .: New wave, 2000 .-- 608 p .; Register of medicines of Russia. 8th ed., Rev. and add. / Ch. ed. Yu.F. Krylov. - M .: RLS-2001, 2001. - 1503 p.].

Thus, the main disadvantages of cefazolin solution, administered intravenously or intramuscularly, are side effects and significant antibiotic consumption.

The objective of the invention is to expand the range of dosage forms of cefazolin for the prevention of postoperative infectious complications in otorhinolaryngology.

This object is achieved in that the immobilized form, in addition to cefazolin, contains sodium carboxymethyl cellulose and glycerin in the following ratio of components, wt.%:

Cefazolin 0.5-2.0 Sodium Carboxymethyl Cellulose 2.0-4.0 Glycerol 1.5-2.5 Purified water Rest

The invention is illustrated by the following tables and drawing.

Table 1. The effect of cefazolin in polymer matrices on the transport function of the ciliated epithelium of the nasal mucosa.

Table 2. Antimicrobial activity of polymer matrices with cefazolin.

Table 3. The effect of drying temperature on the stability of polymer matrices with cefazolin.

Table 4. The stability of the immobilized form of cefazolin during storage at (4 ± 2) ° C.

Table 5. The effect of the immobilized form of cefazolin on the regression of symptoms of inflammation of the nasal mucosa in the postoperative period.

Drawing. The release of cefazolin from polymer matrices.

The introduction of sodium carboxymethyl cellulose into the immobilized form of cefazolin can reduce the toxicity of cefazolin, increase the time and extent of its release from the dosage form, and therefore increase the efficiency.

To increase the elasticity of polymer matrices, glycerol was introduced into their composition.

Feature of the objects:

Cefazolin * (Cefazolin *) - (6R-trans) -3 - [(5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl] -8-oxo-7 - [(1H-tetrazol-1 -yl-acetyl) amino] -5-thio-1-azabicyclo [4.2.0.] oct-2-en-2-carboxylic acid (and in the form of sodium salt). Synonyms: Cefazolin sodium salt, Cefazolin sodium (Cefazolinum-natrium) ABOLmed (Russia) (FS 42-3477-98), Antsef (Ancef), Vulmizolin (Vulmizolin), Kefzol (Kefzol), Intrazoline (Intrazoline) and others. Li powder white or white with a yellowish tint. It is soluble in water, in an isotonic solution of sodium chloride and 5% glucose solution, very slightly soluble in ethyl alcohol. Pharmacological action - antibacterial, bactericidal. It has a wide spectrum of antimicrobial action: it is active against both gram-positive (staphylococci that do not produce and produce penicillinase; green and hemolytic group A streptococci, pneumococci, diphtheria bacilli, anthrax), and gram-negative microorganisms (meningococcus sigella, gonella, stick, Klebsiella, Proteus, etc.). Cefazolin prevents the formation of a bacterial wall by competitively blocking the enzymes involved in the synthesis of mucopeptide, which is part of the cell membrane. The elimination half-life of 1.8 hours after intravenous and 2 hours after intramuscular administration, the maximum concentration in the blood is reached after 1 hour. It binds to plasma proteins by 80%, is not biotransformed, excreted by the kidneys [Russian Drug Register. Encyclopedia of drugs. 8th ed., Revised and supplemented. / Ch. ed. Yu.F. Krylov / M .: "Radar-2001". - 2001. - 1504 s .; State Register of Medicines / Ministry of Health of the Russian Federation. - M., 1998. - 1004 p.]. The selected amount of cefazolin is due to the absence of a negative effect on the transport activity of the ciliated epithelium of the nasal mucosa and the optimal antimicrobial activity when administered locally (Tables 1 and 2).

Sodium carboxymethyl cellulose (Na-CMC) is the sodium salt of cellulose ether and glycolic acid. It is a white or slightly yellow, powdery, odorless product. In addition to domestically produced Na-CMC, Na-CMC is currently used by the Dutch company Hercules Blanose Cellulose Gum Type 7M31CF (Blanose), which is a granular product. Na-CMC is soluble in hot and cold water, a 50% aqueous solution of ethanol, forms highly viscous aqueous solutions. Na-CMC is physiologically inert and not irritating. In pharmaceutical practice, Na-CMC is used as a prolongator of the action of drugs in eye drops and injection solutions, an emulsifier, a binding and disintegrating agent in the manufacture of tablets, the basis of drug films [Polymers in Pharmacy / A.I. Tentsova, M.T. Alyushin. - M .: Medicine, 1985. - S.10-20]. Na-CMC and Blanose provide maximum, uniform dissolution and release of cefazolin from the polymer matrix as compared to methyl cellulose (MC) and hydroxypropyl methyl cellulose (OPMC) (see drawing), storage stability (Table 4) and, therefore, increase the therapeutic effect . In the polymer compositions of cefazolin with HMPC and MC during the drying process, the antibiotic is destroyed, as evidenced by a color change, a shift in the absorption maximum, a significant decrease in the zones of inhibition of growth of the test microorganism and quantitative content (Table 3). The selected amounts of Na-CMC and Blanose are due to the fact that, at a concentration below 2 wt.%, The strength of the polymer matrix and contact time with the mucous membrane are reduced, and at a content of more than 4 wt.%, The gel formed upon dissolution of the matrix reduces the transport activity of the ciliated epithelium of the mucous membrane of the cavity nose.

Introduction to the polymer matrix of 1.5-2.5 wt.% Glycerol (FS 42-2202-99) provides elasticity and strength of the matrices (table 4).

Thus, the optimal immobilized form of cefazolin is a polymer matrix of 2-4 wt.% Sodium carboxymethyl cellulose containing 0.5-2.0 wt.% Cefazolin and 1.5-2.5 wt.% Glycerol.

For the proposed composition, taking into account the properties of the incoming ingredients, the optimum drying temperature of the polymer composition (30 ° C) was established, which allows preserving the antimicrobial activity, the quantitative content of the antibiotic within normal limits, and a manufacturing technology (with step-by-step quality control) has been developed, which consists of the following steps.

1. Sanitary processing of production. Preparation of premises, personnel, auxiliary materials, equipment, raw materials.

2. Obtaining a medicinal composition.

2.1. Preparation of a solution of sodium carboxymethyl cellulose and glycerin in a portion of purified water.

2.2. Dissolution of cefazolin in the remaining portion of purified water.

2.3. Mixing a polymer solution with an antibiotic solution.

2.4. Deaeration

3. Obtaining a polymer matrix.

3.1. Bottling of the drug composition on a substrate.

3.2. Drying.

3.3. Dosage

4. Packing and packaging of polymer matrices.

An example of the method of obtaining.

In order to increase stability, polymer matrices are prepared under aseptic conditions in accordance with the requirements of regulatory documents using sterile dishes. A portion of Na-CMC (or Blanose) is poured with part of sterile purified water, heated to 50-70 ° C, and periodically mixed until the polymer is dissolved, glycerin is added. Cefazolin is dissolved in the remaining amount of sterile water and thoroughly mixed with a polymer solution cooled to (20 ± 2) ° C until uniform. After deaeration, a homogeneous polymer drug composition is poured onto substrates and dried at a temperature of (30 ± 3) ° C for 5-6 hours. The dried polymer matrices are removed from the substrates, dispensed and packaged in sterile glass bottles from a drug drain (TU 62-2-1077) (HC-1 glass), sealed with rubber stoppers of the IR-119 grade (TU 38-006108-90) and metal caps "run-in". Vials are placed in cardboard boxes. Store at a temperature of (4 ± 2) ° С in a dark place (in the refrigerator) for 12 (24) months (Table 4).

A decrease in toxicity and an increase in the effectiveness of cefazolin in immobilized form in the prevention of postoperative infectious complications is confirmed by the results of use (table 5).

The method of use of the immobilized form of cefazolin.

Polymeric matrices with cefazolin 2 × 1 cm in size were placed on the surface of the mucous membrane of the lower nasal concha and nasal septum, and 1.5 × 1 cm matrices were placed on the middle nasal concha. The first injection of polymer matrices with cefazolin was carried out 2 hours before the operation. After removal of the tampons one day after the operation, the administration of the immobilized form of cefazolin was performed daily once a day for 5-6 days. No allergic reactions, inflammation and ulceration of the mucous membranes of the nasal cavity were detected.

An example of how to use it.

Patient M., 25 years old, medical history No. 1348 02/18/04, performed submucosal resection of the nasal septum, bilateral submucosal vasotomy. After removing tampons from the nasal cavity, the next day, an immobilized form of cefazolin was introduced according to the method described above. The introduction of cefazolin was carried out for 4 days. After a day, a patient with rhinomanometry had a sufficient degree of nasal breathing, there were no inflammatory phenomena, there was no excessive production of nasal secretion, the surface temperature of the mucous membrane was approaching control indicators, there was no need to use decongenants.

In order to identify the effect of the carrier polymer on the therapeutic activity of the immobilized form of cefazolin, a group of patients after surgery introduced polymer matrices of cefazolin from Blanose into the left half of the nose and Na-CMC into the right half. Differences during the postoperative period have not been established. The regression of the symptoms of inflammation was the same in both halves of the nose, indicating the same activity of the polymer matrices from Na-CMC and Blanose.

Thus, the proposed immobilized form of cefazolin has high therapeutic efficacy, low toxicity to tissues of the nasal mucosa and cost-effectiveness. The antibiotic consumption per treatment course is 0.2-0.8 g. An optimal method for the manufacture of an immobilized form of cefazolin has been developed, which excludes changes in the structure and physicochemical properties of the drug.

The proposed immobilized form of cefazolin allows you to expand the range of available drugs for the prevention of postoperative infectious complications.

Table 1 Cefazolin content
in the polymer matrix, wt.% Transport time, minutes Before introduction After uninstall 0.5 24.5 ± 1.65 25.2 ± 1.45 1,0 23.4 ± 1.85 24.8 ± 1.58 1,5 27.8 ± 1.58 28.6 ± 1.65 2.0 25.2 ± 1.45 26.8 ± 1.86 2,5 28.8 ± 1.65 29.2 ± 2.48 Note: each average value was obtained for 6 subjects.

table 2 Test microorganisms The diameter of the zones of inhibition of growth of test microorganisms (mm) when the content of cefazolin, wt.% 0.5 1,0 2.0 3.0 Staphylococcus aureus ATCC-6538 30.5 ± 0.3 35.5 ± 1.5 39.8 ± 1.2 41.5 ± 1.4 Bacillus subtilis ATCC 6633 34.1 ± 0.7 38.5 ± 1.8 44.3 ± 1.2 47.5 ± 1.7

Table 3 Quality indicators Drying temperature, ° С Shelf life Carrier Polymers Blanose Na-CMC OPMC MC Coloring (30 ± 2) Fresh White White White White 6 months White Yellowish White Yellowish (45 ± 2) Fresh White White White White 6 months Yellowish Light yellow Yellow Light yellow Quantitative content, rel. % (30 ± 2) Fresh 100.04 100.30 97.33 100.67 6 months 98.70 98.33 89.33 63.67 (45 ± 2) Fresh 95.67 98.67 100,20 97.67 6 months 86.33 90.33 58.00 50.33 Maximum adsorption at a wavelength, nm (30 + 2) Fresh 272 274 274 274 6 months 272 280 295 295 (45 ± 2) Fresh 272 272 274 277 6 months 295 295 300 300 Zones of inhibition of growth of Bacillus subtilis, mm (30 + 2) Fresh 37.0 37.0 36.5 38.5 6 months 36.5 34.0 34.5 28.5 (45 ± 2) Fresh 36.0 36.5 36.0 35.0 6 months 32,0 30,0 28.7 25.7

Table 4 Quality indicators Carrier Polymers Blanose Na-CMC Freshly prepared matrices After storage Freshly prepared matrices After storage 12 months. at 4 ° C 12 months at 4 ° C 24 months at 4 ° C Coloring White White White White Light yellow Average weight, g 0.0409 ± 0.0015 0.0416 + 0.0042 0.0411 ± 0.0031 0,0399 ± 0,0017 0.0408 ± 0.0028 Elasticity Elastic Elastic Elastic Elastic Elastic Solubility, min 10 ± 3 20 ± 3 22 ± 5 12 ± 4 20 ± 6 Quantitative content, rel.% 98.67 ± 1.27 94.99 ± 1.70 90.76 ± 0.74 99.83 + 1.47 90.60 ± 1.37 Maximum adsorption at a wavelength, nm 272 272 272 272 272 Rf value 0.67 + 0.02 0.68 + 0.03 0.68 + 0.03 0.67 ± 0.01 0.68 + 0.02 The diameter of the zones of inhibition of growth of Bac.subtilis ATCC 6633, mm 37.0 ± 1.0 35.0 ± 1.0 34.0 ± 0.8 37.0 ± 1.0 35.0 ± 1.5

Table 5 Symptoms of inflammation
mucous membrane of the nasal cavity The first day after removal of tampons The third day after removal of tampons The traditional way of prevention Using an immobilized form of cefazolin The traditional way of prevention Using an immobilized form of cefazolin Hyperemia Expressed Expressed Expressed Weakly expressed Edema Expressed Weakly expressed Weakly expressed Absent Exudation Plentiful Moderately expressed Moderately expressed Missing or mild Average surface temperature 35.4 ± 0.3 35.4 ± 0.4 34.9 ± 0.5 34.0 ± 0.3

Claims (1)

A means for the prevention of postoperative infectious complications in otorhinolaryngology, containing cefazolin, polymer and glycerin, characterized in that cefazolin is enclosed in a polymer matrix of sodium carboxymethyl cellulose in the following ratio, wt.%: Cefazolin 0.5-2.0 Sodium Carboxymethyl Cellulose 2.0-4.0 Glycerol 1.5-2.5 Purified water Rest