RU2508094C1 - Methods for preparing transdermal therapeutic systems based on poly(lactic-co-glycolic acid) (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is a method for preparing a transdermal therapeutic system based on poly(lactic-co-glycolic acid) involving dissolving poly lactide-co-glycolide and a pharmaceutically active substance in an organic solvent, mixing the prepared solution until dissolved completely, hot air drying until dry completely and having a constant weight to prepare a film, cutting the film into sections and packing, with the relation of lactide and glycolide varying within the range of 95:5 to 5:95 (versions).

EFFECT: preparing the transdermal therapeutic system based on poly(lactic-co-glycolic acid) that is biodegradable.

33 cl, 1 dwg, 3 tbl, 6 ex

Description

The invention relates to the field of pharmaceutical industry, in particular to methods for producing transdermal therapeutic systems based on copolymers of lactic and glycolic acids.

The transdermal therapeutic system (TTC) is a unit dosage form for external use in the form of plasters, non-woven material or films. TTCs are able to continuously and atraumatically deliver a drug (PM) to the body at a rate that creates a constant level of drug concentration in the bloodstream that is close to the optimal therapeutic level.

Transdermal therapeutic systems are an alternative to parenteral and oral administration of drugs. Compared with oral administration, transdermal administration provides a quick action of the drug and helps to avoid a decrease in its activity as a result of passage through the liver. In addition, with such an introduction, it becomes possible to reduce the frequency of prescribing the drug, reduce the necessary doses and at the same time avoid fluctuations in its concentration in the blood, and if undesirable reactions develop, stop treatment immediately. For some drugs, transdermal delivery is the only route of administration.

The task underlying the creation of the present invention is the further improvement of transdermal therapeutic systems, while the technical result obtained by solving this problem is to create biodegradable transdermal therapeutic systems based on copolymers of lactide and glycolide.

To achieve this result, we propose options for methods for producing a transdermal therapeutic system (TTC) based on lactic and glycolic acid copolymers, the first of which involves dissolving the lactide-glycolide copolymer and a pharmacologically active substance in an organic solvent, mixing the resulting solution until it is completely dissolved, drying with hot air to complete drying and constant weight to obtain a film, cutting the resulting film into parts and packaging; the second includes dissolving the copolymer of lactide-glycolide and a pharmacologically active substance in an organic solvent, mixing the resulting solution in a magnetic stirrer until completely dissolved, pouring it into the feeder, applying 5-40 kV to the capillary, collecting the fiber to the receiving device to obtain a non-woven material, cutting received non-woven material for parts and packaging; the third of the process options includes the step of extruding the lactide-glycolide copolymer to obtain a yarn and then making a woven material from the yarn, the step of dissolving the lactide-glycolide copolymer in an organic solvent, dissolving the pharmacologically active substance, mixing and homogenizing such solutions to obtain a final solution, and the immersion step in the final solution of woven material with its subsequent cooling and drying; the fourth of the claimed process variants involves dissolving the lactide-glycolide copolymer in ethyl acetate, adding a pharmacologically active substance in a buffer, mixing, centrifuging the resulting mixture, removing the supernatant with dissolving the precipitate in ethyl acetate, obtaining a suspension and preparing a spray based on it.

Preferred, but not required, embodiments of the first, second, and third variants of the method involve a ratio of lactide and glycolide ranging from 95: 5 to 5:95, preferably 75:25, most preferably 50:50; using as a copolymer lactide-glycolide-polyethylene glycol (PEG) or - lactide-glycolide-polyvinylpyrrolidone (PVP), where PEG or PVP has a molecular weight of from 400 to 40,000 Da; additional use of substances from the ε-caprolactone group, dicarboxylic acid esters, glycerin as plasticizers, substances from the poloxamer group, tween-80 (polyoxyethylene-sorbitan monooleate) as emulsifiers; the use of aerosil and / or dimethyl sulfoxide and, as an organic solvent, substances selected from the group consisting of dichloromethane, chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, acetone or mixtures thereof to create predetermined release parameters of the pharmacologically active substance; in addition, the pharmacologically active substance may be a therapeutic or diagnostic agent, in this case, if the pharmacologically active substance is a therapeutic agent, it is selected from the group comprising wound healing agents; antimicrobial agents; local anesthetics and anesthetics; anti-inflammatory drugs; trophic factors; medicines for the treatment of addiction and drug abuse; medications for addiction and tobacco abuse; medicines for the treatment of addiction and alcohol abuse; hormonal drugs; stimulants; anti-obesity drugs; cardiotropic drugs, if the pharmacologically active substance is a diagnostic tool, then this is a tool for diagnosis in radiation medicine and / or radiation therapy; It should also be noted that to prevent the pH from changing to the acidic side, the first or third variants of the claimed method can be further characterized by the use of wollastonite or bioglass (bioglass 45S5).

The invention is illustrated in figure 1 with a graph of tissue regeneration.

The possibility of achieving the result is due to the fact that the copolymers of lactide and glycolide are biodegradable polymers, the chains of which consist of units of lactic and glycolic acids, the percentage of which affects the rate of decomposition and, as a consequence, the release of pharmacologically active substances. The polylactide molecule is optically active, D and L-isomers can be present in any proportions, with the exception of the copolymer of L-lactide and D-lactide with a relative content of units of 50/50. The molecular weight of the copolymers can vary from 30,000 to 100,000 Da (the masses were determined by gel permeation chromatography). It is also possible synthesis of oligomers with a molecular weight of from 2500 to 10000 Da. To increase biodegradability, copolymers can be used that contain, in addition to polylactide and / or polyglycolide copolymers, polyethylene glycols (PEGs) of various molecular weights ranging from 400 Da to 40,000 Da.

In general terms, according to the claimed variants of the method, transdermal therapeutically systems (TTC) can be obtained based on a lactide-glycolide copolymer and, if necessary, additionally polyethylene glycol and / or polyvinylpyrrolidone of various molecular weights and / or plasticizer and / or surface -active substances, and / or aerosil, and / or dimethyl sulfoxide (DMSO), in which a pharmacologically active substance is added, while in general terms such methods are divided into:

- method of evaporation of an organic solvent;

- electrospinning method;

- a method for producing composite materials;

- getting a spray.

Example 1. Obtaining biodegradable TTC by evaporation of an organic solvent.

1.1. 195 mg of a lactide-glycolide copolymer (50:50; M = 10,000 Da) and 10 mg of a pharmacologically active substance were dissolved in 10 ml of acetone; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, then the solution was dried with hot air until it completely dried, then it was placed in a vacuum oven, dried from acetone residues to constant weight. The resulting film was cut into pieces and placed in a sterile plastic bag, which was then sealed.

1.2. 486 mg of the lactide-glycolide-ε-caprolactone copolymer (71: 22: 7; M = 5000 Da) and 15 mg of the pharmacologically active substance in 10 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, then the solution was dried with hot air until it completely dried, then it was placed in a vacuum oven and dried from acetone residues to constant weight. The resulting film was cut into pieces and placed in a sterile plastic bag, which was then sealed.

1.3. 972 mg of a lactide-glycolide-PEG copolymer (50: 45: 5; M = 50,000 Da; M _PEG = 1000 Da) and 20 mg of a pharmacologically active substance in 60 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, then the solution was dried with hot air until it completely dried, then it was placed in a vacuum oven, dried from acetone residues to constant weight. The resulting film was cut into pieces and placed in a sterile plastic bag, which was then sealed.

1.4. 972 mg of a lactide-glycolide-PEG-ε-caprolactone copolymer (70: 20: 5: 5; M = 60,000 Da; M _PEG 1000 Da) and 20 mg of a pharmacologically active substance in 100 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, then the solution was dried with hot air until it completely dried, then it was placed in a vacuum oven and dried from acetone residues to constant weight. The resulting film was cut into pieces and placed in a sterile plastic bag, which was then sealed.

1.5. 195 mg of a lactide-glycolide copolymer (50:50; M = 70,000 Da), 10 mg of glycerol and 10 mg of a pharmacologically active substance were dissolved in 30 ml of acetone; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, then the solution was dried with hot air until it completely dried, then it was placed in a vacuum oven and dried from acetone residues to constant weight. The resulting film was cut into pieces and placed in a sterile plastic bag, which was then sealed.

1.6. 195 mg of a lactide-glycolide copolymer (50:50; M = 80,000 Da), 20 ml of poloxamer 188 and 15 mg of a pharmacologically active substance in 10 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, then the solution was dried with hot air until it completely dried, then it was placed in a vacuum oven and dried from acetone residues to constant weight. The resulting film was cut into pieces and placed in a sterile plastic bag, which was then sealed.

1.7. 195 mg of a lactide-glycolide copolymer (50:50; M = 90,000 Da), 10 mg of Aerosil and 10 mg of a pharmacologically active substance were dissolved in 10 ml of acetone; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, then the solution was dried with hot air until it completely dried, then it was placed in a vacuum oven and dried from acetone residues to constant weight. The resulting film was cut into pieces and placed in a sterile plastic bag, which was then sealed.

1.8. 195 mg of a lactide-glycolide copolymer (50:50; M = 100,000 Da), 10 ml of dimethyl sulfoxide (DMSO) and 10 mg of a pharmacologically active substance in 10 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, then the solution was dried with hot air until it completely dried, then it was placed in a vacuum oven and dried from acetone residues to constant weight. The resulting film was cut into pieces and placed in a sterile plastic bag, which was then sealed.

Example 2. Obtaining biodegradable TTS by electrospinning.

2.1. 1 g of a lactide-glycolide copolymer (50:50; M = 35000 Da) and 10 mg of a pharmacologically active substance were dissolved in 10 ml of ethyl acetate; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, poured into a feeder, fed to a 20 kV capillary and the fibers were collected on a receiving device. The resulting non-woven material was cut into pieces and placed in a sterile plastic bag, which was then sealed.

2.2. 1 g of a copolymer of lactide-glycolide-ε-caprolactone (75: 20: 5; M = 40,000 Da) and 15 mg of a pharmacologically active substance in 10 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, poured into a feeder, fed to a 20 kV capillary and the fibers were collected on a receiving device. The resulting non-woven material was cut into pieces and placed in a sterile plastic bag, which was then sealed.

2.3. 1 g of a lactide-glycolide-PEG copolymer (50: 45: 5; M = 50,000 Da; M _PEG = 1000 Da) and 10 mg of a pharmacologically active substance in 10 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, poured into a feeder, fed to a 20 kV capillary and the fibers were collected on a receiving device. The resulting non-woven material was cut into pieces and placed in a sterile plastic bag, which was then sealed.

2.4. Dissolve 1.0 g of the copolymer of lactide-glycolide-PEG-ε-caprolactone (70: 20: 5: 5; M = 60,000 Da; M _PEG = 1000 Yes) and 10 mg of the pharmacologically active substance in 10 ml of acetone; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, poured into a feeder, fed to a 20 kV capillary and the fibers were collected on a receiving device. The resulting non-woven material was cut into pieces and placed in a sterile plastic bag, which was then sealed.

2.5. 1 g of a lactide-glycolide copolymer (50:50; M = 70,000 Da), 0.2 mg of glycerol and 10 mg of a pharmacologically active substance were dissolved in 10 ml of acetone; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, poured into a feeder, fed to a 20 kV capillary, and fibers were collected on a receiving device. The resulting non-woven material was cut into pieces and placed in a sterile plastic bag, which was then sealed.

2.6. 1 g of a lactide-glycolide copolymer (50:50; M = 80,000 Da), 0.2 ml of poloxamer 188 and 10 mg of a pharmacologically active substance in 10 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, poured into a feeder, fed to a 20 kV capillary and the fibers were collected on a receiving device. The resulting non-woven material was cut into pieces and placed in a sterile plastic bag, which was then sealed.

2.7. 1 g of a lactide-glycolide copolymer (50:50; M = 90,000 Da), 0.2 mg of Aerosil and 10 mg of a pharmacologically active substance in 10 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, poured into a feeder, fed to a 20 kV capillary and the fibers were collected on a receiving device. The resulting non-woven material was cut into pieces and placed in a sterile plastic bag, which was then sealed.

2.8. 1 g of a lactide-glycolide copolymer (50:50; M = 100000 Da), 0.2 ml of DMSO and 10 mg of a pharmacologically active substance in 10 ml of acetone were dissolved; the resulting solution was thoroughly mixed on a magnetic stirrer until completely dissolved, poured into a feeder, fed to a 20 kV capillary and the fibers were collected on a receiving device. The resulting non-woven material was cut into pieces and placed in a sterile plastic bag, which was then sealed.

Example 3. Obtaining biodegradable TTC method of composite materials.

3.1. 5 g of a lactide-glycolide copolymer (50:50; M = 50,000 Da) were poured into an extruder heated to 100 ° C; then, at the exit from the spinneret, the thread was collected on a drum and woven material was prepared on a loom.

196 mg of a lactide-glycolide copolymer (50:50; M = 40,000 Da) was dissolved in 30 ml of chloroform; 10 mg of the pharmacologically active substance was dissolved in 4 ml of purified water; the resulting solutions were mixed and homogenized at 16,000 rpm. The woven fabric obtained on the loom was lowered into the resulting solution and immediately cooled with liquid nitrogen at -196 ° C. The resulting composite material with a pharmacologically active substance was placed in a freeze dryer and dried at -85 ° C.

3.2. 5 g of a lactide-glycolide copolymer (75:25; M = 50,000 Da) were poured into an extruder heated to 100 ° C; then, at the exit from the spinneret, the thread was collected on a drum and woven material was prepared on a loom.

196 mg of a lactide-glycolide copolymer (50:50; M = 60,000 Da) was dissolved in 30 ml of chloroform; 10 mg of the pharmacologically active substance was dissolved in 4 ml of purified water; the resulting solutions were mixed and homogenized at 16,000 rpm. Woven material was lowered into the resulting solution and immediately cooled with liquid nitrogen at -196 ° C. The resulting composite material with a pharmacologically active substance was placed in a freeze dryer and dried at -85 ° C.

3.3. 5 g of a copolymer of lactide-glycolide-ε-caprolactone (75: 20: 5; M = 70,000 Da) were poured into an extruder heated to 100 ° C; then, at the exit from the spinneret, the thread was collected on a drum and woven material was prepared on a loom.

196 mg of a lactide-glycolide copolymer (50:50; M = 80,000 Da) was dissolved in 30 ml of chloroform; 10 mg of the pharmacologically active substance was dissolved in 4 ml of purified water; the resulting solutions were mixed and homogenized at 16,000 rpm. Woven material was lowered into the resulting solution and immediately cooled with liquid nitrogen at -196 ° C. The resulting composite material with a pharmacologically active substance was placed in a freeze dryer and dried at -85 ° C.

3.4. 5 g of a lactide-glycolide-PEG copolymer (70: 25: 5; M = 90,000 Da; M _PEG = 1000 Da) were poured into an extruder heated to 100 ° C; then, at the exit from the spinneret, the thread was collected on a drum and woven material was prepared on a loom.

196 mg of a lactide-glycolide copolymer (50:50; M = 30,000 Da) was dissolved in 30 ml of chloroform; 10 mg of the pharmacologically active substance was dissolved in 4 ml of purified water; the resulting solutions were mixed and homogenized at 16,000 rpm. Woven material was lowered into the resulting solution and immediately cooled with liquid nitrogen at -196 ° C. The resulting composite material with a pharmacologically active substance was placed in a freeze dryer and dried at -85 ° C.

3.5. 5 g of a copolymer of lactide-glycolide-PEG-ε-caprolactone (70: 20: 5: 5; M = 50,000 Da; M _PEG = 1000 Da) were poured into an extruder heated to 100 ° C; then, at the exit from the spinneret, the thread was collected on a drum and woven material was prepared on a loom.

196 mg of a lactide-glycolide copolymer (50:50; M = 30,000 Da) was dissolved in 30 ml of chloroform; 10 mg of the pharmacologically active substance was dissolved in 4 ml of purified water; the resulting solutions were mixed and homogenized at 16,000 rpm. Woven material was lowered into the resulting solution and immediately cooled with liquid nitrogen at -196 ° C. The resulting composite material with a pharmacologically active substance was placed in a freeze dryer and dried at -85 ° C.

3.6. 5 g of a lactide-glycolide copolymer (50:50; M = 30,000 Da), 0.1 g of aerosil was poured into an extruder heated to 100 ° C; then, at the exit from the spinneret, the thread was collected on a drum and woven material was prepared on a loom.

196 mg of a lactide-glycolide copolymer (50:50; M = 60,000 Da) was dissolved in 30 ml of chloroform; 10 mg of the pharmacologically active substance was dissolved in 4 ml of purified water; the resulting solutions were mixed and homogenized at 16,000 rpm. Woven material was lowered into the resulting solution and immediately cooled with liquid nitrogen at -196 ° C. The resulting composite material with a pharmacologically active substance was placed in a freeze dryer and dried at -85 ° C.

4. Obtaining a spray with a pharmacologically active substance based on copolymers of lactic and glycolic acids

5 g of a lactide-glycolide copolymer are dissolved in 20 ml of ethyl acetate, 20 mg of a pharmacologically active substance are added in a buffer, intensively mixed, the resulting mixture is centrifuged, the supernatant is removed, the precipitate is dissolved in 40 ml of ethyl acetate to obtain a suspension based on which a spray suitable for spraying onto the skin is prepared .

To study the effectiveness of the obtained transdermal therapeutic systems in the form of films, non-woven material, patches containing a lactide-glycolide copolymer and acexamic acid as a wound healing pharmacologically active substance, the wound surface was simulated by removing animal hair from the wound site, then a piece of skin was cut with a scalpel to obtain a full-layer wound measuring 225 mm ² .

For the experiment, adult male Wistar rats weighing 200-250 g were used for 1 week, kept in order to acclimatize in cells in groups of 5 individuals. Animals were divided into 3 groups of 6 animals in each group:

1 group control; animals with standard full-layer wounds (225 mm ² ) on the lateral surface of the body, which are not affected by any physical and chemical factors on the defect area.

Group 2, animals with standard full-layer wounds (225 mm ² ) on the lateral surface of the body, to which Panthenol spray is applied to the defect area.

3 group, animals with standard full-layer wounds (225 mm ² ) on the lateral surface of the body, to which a polymer film containing a lactide-glycolide copolymer (50:50 M = 30,000 Da) and acexamic acid in accordance with the claimed process variants ( figure 1).

The study was conducted for 15 days. The area of wounds was measured daily in all experimental animals. All animals were taken smears from the surface of the wounds after 6, 12 and 24 hours. A biopsy was taken from all animals after 5, 10 and 15 days, followed by the manufacture of histological preparations according to standard prescriptions.

The following examples also illustrate the feasibility of the claimed TTC with various pharmacologically active substances.

Example 4. Analgesic activity of substances released from TTC.

Tail pull test. The animal was placed in an individual plastic chamber, the tail was immersed 5 cm in water with a temperature of 55 ± 1 ° C. In the test, the latent period of getting rid of the pain stimulus was recorded — the period of time (sec) during which the animal pulled its tail out of the water completely. The maximum time for presentation of a pain stimulus is 30 seconds. The initial pain sensitivity was determined as the arithmetic mean of the indicators recorded at 60, 40, and 20 minutes before the use of TTC. The latent period of getting rid of the pain stimulus was fixed 20, 40, 60 and 120 minutes after application. Analgesic activity was assessed by the change in the latent period of the reaction according to the formula: A = LPop-LPis, where LPop is the latent period of recovery after using TTC, and LPis is the arithmetic mean of latent periods of recovery before using TTC.

TTC was applied to males of non-linear white rats weighing 200-300 g. Control animals were not applied. The results are shown in table 1.

Table 1 Test sample Tail pullback (sensitivity change, sec) 20 minutes 40 min 60 min 90 min 120 min The control 0.5 ± 0.1 0.5 ± 0.1 0.3 ± 0.1 0.2 ± 0.1 -0.1 ± 0.1 TTS obtained by evaporation 1 mg / kg 11 ± 1.2 * 12.4 ± 1.6 * 12.8 ± 1.4 * 6.7 ± 0.7 * 4.5 ± 0.3 * TTS obtained by electrospinning 1 mg / kg 5.7 ± 0.7 * 7.5 ± 0.8 * 5.3 ± 0.6 * 4.1 ± 0.5 * 4.3 ± 0.4 * TTS, which is a composite material 1 mg / kg 4.7 ± 0.9 * 5.2 ± 1.4 * 4.3 ± 0.7 * 2.1 ± 0.6 0.2 ± 0.1 pharmacologically active substance - indomethacin 10 mg / kg 4.2 ± 1.6 * 3.9 ± 1.2 * 2.9 ± 1.9 1.9 ± 1.2 0.7 ± 0.3 * - reliability compared to control at P <0.05.

From the presented results it follows that the use of TTC causes a significant increase in the latent period of the tail withdrawal reaction in response to pain irritation.

Example 5. Tests of the effectiveness of TTC in the test of inflammation caused by concanavalin A.

The inflammatory response to concanavalin A (Con A) is based on the ability of plant pectins to release inflammatory mediators. TTS was applied or a well-known anti-inflammatory agent was injected intravenously 20 minutes before Con A. Con A was administered subplanarly at a dose of 100 μg / 20 g body weight (20 μl of the solution at a concentration of 5 mg / ml), the same volume in the contralateral limb saline solution. After 1 hour, the mice were sacrificed, the mass of paws was determined, and the inflammation reaction index (Ir) was calculated according to the formula: Ir = (Rop-Rk) * 100 / Pk, where Rop is the mass of the foot of the hind paw, Kon A was introduced into the pad, and Pk is physiological solution. A statistically significant difference between the data of the experimental and control groups, exceeding 20%, was considered significant (Lyubimov B.I. et al. 2000).

Control animals were injected intraperitoneally with distilled water. The results are shown in table 2.

table 2 Test sample Concanavalin A inflammation (reaction index) The control 16.4 ± 1.5 TTS obtained by evaporation 10 mg / kg 9.2 ± 1.1 * TTS obtained by electrospinning 10 mg / kg 13.1 ± 2.4 * TTS, which is a composite material 10 mg / kg 8.7 ± 2.2 * pharmacologically active substance - diclofenac Na 10 mg / kg 13.7 ± 1.6 * * - reliability compared to control at P <0.05.

The results show that the use of an anti-inflammatory agent in TTC compared with its intravenous administration causes a significant decrease in the index of the inflammatory response in response to the administration of concanavalin A.

Example 6. Study of antimicrobial activity Chloramphenicol 3% was taken as the active component for TTC. The study of antimicrobial activity was carried out in accordance with the requirements of the Global Fund XI, in vitro by diffusion into agar. Sterile Petri dishes were placed on a strictly horizontal surface, 2% meat-peptone agar (pH = 7.2-7.4) was poured into them in an amount of 20 ml to create an optimal layer thickness of 4-5 mm. For those types of microbes that do not grow on meat-peptone agar, such as streptococci, pneumococci and others, 5% blood or serum agar was used. Before seeding, plates with medium were dried in a thermostat.

A thick layer of agar was inoculated with 1-2 ml of suspension of the tested microorganisms and ground with a spatula until the microorganisms were evenly distributed over the entire surface of the Petri dish and at the same distance. The excess suspension was completely removed, dried for 30 minutes. Then, with a drill (d = 6 mm), holes were made at a distance of 2.5 cm from the wall of the Petri dish and at equal distances from each other, which were then filled with the objects under study. After this, the cups were placed in a thermostat at 37 ° C without turning, strictly horizontally, so that round zones formed.

The drug substance diffuses from the polymer carrier into agar, forming a zone of inhibition of growth of sensitive microorganisms around the disk, which clearly stands out against the background of continuous growth. After 24 hours, the diameters of the growth inhibition zone were measured. The results are shown in table 3.

Table 3 Test culture Size of growth retardation in diameter, mm Evaporation TTC Electrospinning TTC TTS, which is a composite material pharmacologically active substance - chloramphenicol Staphylococcus aureus 209p twenty eighteen 22 21 Staphylococcus aureus type 16 fourteen fourteen fifteen Staphylococcus epidermidis Wood-46 27 25 33 32

Escherichia coli 675 10 9 12 eleven Escherichia paracoli 10 12 12 eleven Proteus vulgaris 25 twenty 22 22 Bacillus subtillus l ₂ 23 23 24 23 Bacillus anthracoides 96 fifteen 13 16 17

Kruskal-Wallis test P> 0.05

More than 10 - high activity, 10 - moderate activity, less than 10 - lack of activity.

The experimental results indicate the antimicrobial activity of the active component that is part of the TTC. The antimicrobial activity in the form of TTC is not inferior in magnitude to the antimicrobial activity of chloramphenicol.

Claims (33)

1. A method of obtaining a transdermal therapeutic system based on copolymers of lactic and glycolic acids, including dissolving a copolymer of lactide-glycolide and a pharmacologically active substance in an organic solvent, mixing the resulting solution until it is completely dissolved, drying with hot air until it completely dries and constant weight to obtain a film, cutting the resulting film into parts and packaging, while the ratio of lactide and glycolide is selected in the range from 95: 5 to 5:95, preferably 75:25, most respectfully 50:50. 2. The method according to claim 1, in which a copolymer of lactide-glycolide-polyethylene glycol (PEG) is used, where the PEG has a molecular weight of from 400 to 40,000 Da. 3. The method according to claim 1, in which additionally used as plasticizers substances from the group ε-caprolactone, esters dicarboxylic acids, glycerin, polyvinylpyrrolidones of various molecular weights. 4. The method according to claim 1, in which additionally used as emulsifiers substances from the group of poloxamer, tween-80 (polyoxyethylene-sorbitan monooleate). 5. The method according to claim 1, in which aerosil and / or dimethyl sulfoxide are additionally used to create predetermined release parameters of the pharmacologically active substance. 6. The method according to claim 1, wherein the organic solvent is a substance selected from the group consisting of dichloromethane, chloroform, methylene chloride, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, acetone, or mixtures thereof. 7. The method according to claim 1, in which the pharmacologically active substance is a therapeutic or diagnostic agent. 8. The method according to claim 7, in which the pharmacologically active substance is a therapeutic agent selected from the group comprising wound healing agents; antimicrobial agents; local anesthetics and anesthetics; anti-inflammatory drugs; trophic factors; medicines for the treatment of addiction and drug abuse; medications for addiction and tobacco abuse; medicines for the treatment of addiction and alcohol abuse; hormonal drugs; stimulants; anti-obesity drugs; cardiotropic drugs. 9. The method according to claim 7, in which the pharmacologically active substance is a diagnostic tool for diagnosis in radiation medicine and / or radiation therapy. 10. The method according to any one of claims 1 to 9, in which additionally use wollastonite or bioglass to prevent changes in pH in the acidic direction. 11. A method of obtaining a transdermal therapeutic system based on copolymers of lactic and glycolic acids, including dissolving a copolymer of lactide-glycolide and a pharmacologically active substance in an organic solvent, mixing the resulting solution in a magnetic stirrer until completely dissolved, applying 5-40 kV to the capillary, collecting fiber on the receiving device with the receipt of non-woven material, cutting the resulting non-woven material into parts and packaging. 12. The method according to claim 11, in which the ratio of lactide and glycolide is selected in the range from 95: 5 to 5:95, preferably 75:25, most preferably 50:50. 13. The method according to claim 11, in which a copolymer of lactide-glycolide-PEG or PVP is used, where PEG or PVP have a molecular weight of from 400 to 40,000 Da. 14. The method according to claim 11, in which additionally used as plasticizers substances from the group ε-caprolactone, esters dicarboxylic acids, glycerin. 15. The method according to claim 11, in which additionally used as emulsifiers substances from the group of poloxamer, tween-80 (polyoxyethylene-sorbitan monooleate). 16. The method according to claim 11, in which aerosil and / or dimethyl sulfoxide are additionally used to create predetermined release parameters of the pharmacologically active substance. 17. The method according to claim 11, in which the organic solvent is a substance selected from the group consisting of dichloromethane, chloroform, methylene chloride, ethyl acetate, tetrahydrofuranethyl acetate or acetone. 18. The method according to claim 11, in which the pharmacologically active substance is a therapeutic or diagnostic agent. 19. The method according to p, in which the pharmacologically active substance is a therapeutic agent selected from the group comprising wound healing agents; antimicrobial agents; local anesthetics and anesthetics; anti-inflammatory drugs; trophic factors; medicines for the treatment of addiction and drug abuse; medications for addiction and tobacco abuse; medicines for the treatment of addiction and alcohol abuse; hormonal drugs; stimulants; anti-obesity drugs; cardiotropic drugs. 20. The method according to p, in which the pharmacologically active substance is a diagnostic tool for diagnosis in radiation medicine and / or radiation therapy. 21. The method according to any one of paragraphs.11-20, in which additionally use wollastonite or bioglass to prevent changes in pH in the acidic direction. 22. A method of obtaining a transdermal therapeutic system based on copolymers of lactic and glycolic acids, including the step of extruding a lactide-glycolide copolymer to obtain a yarn and subsequent manufacture of a woven material from a yarn, the steps of dissolving the lactide-glycolide copolymer in an organic solvent, dissolving the pharmacologically active substance, mixing and homogenization of the obtained solutions to obtain the final solution and the stage of immersion in the final solution of the woven material with its subsequent cooling and drying. 23. The method according to item 22, in which the ratio of lactide and glycolide is selected in the range from 95: 5 to 5:95, preferably 75:25, most preferably 50:50. 24. The method according to item 22, which uses a copolymer of lactide-glycolide-PEG, where the PEG has a molecular weight of from 400 to 40,000 Da. 25. The method according to item 22, in which additionally used as plasticizers substances from the group ε-caprolactone, esters dicarboxylic acids, glycerin. 26. The method according to item 22, in which additionally used as emulsifiers substances from the group of poloxamer, tween-80 (polyoxyethylene-sorbitan monooleate). 27. The method according to item 22, in which to create predetermined parameters for the release of pharmacologically active substances using aerosil and / or dimethyl sulfoxide. 28. The method according to item 22, in which, as an organic solvent, a substance is selected from the group consisting of dichloromethane, chloroform, methylene chloride, ethyl acetate, tetrahydrofuranethyl acetate or acetone. 29. The method according to item 22, in which the pharmacologically active substance is a therapeutic or diagnostic agent. 30. The method according to clause 29, in which the pharmacologically active substance is a therapeutic agent selected from the group including wound healing agents; antimicrobial agents; local anesthetics and anesthetics; anti-inflammatory drugs; trophic factors; medicines for the treatment of addiction and drug abuse; medications for addiction and tobacco abuse; medicines for the treatment of addiction and alcohol abuse; hormonal drugs; stimulants; anti-obesity drugs; cardiotropic drugs. 31. The method according to clause 29, in which the pharmacologically active substance is a diagnostic tool for diagnosis in radiation medicine and / or radiation therapy. 32. The method according to any of paragraphs.22-31, which additionally use wollastonite or bioglass to prevent changes in pH in the acidic direction. 33. A method of obtaining a transdermal therapeutic system based on lactic and glycolic acid copolymers, comprising dissolving a lactide-glycolide copolymer in ethyl acetate, adding a pharmacologically active substance in a buffer, mixing, centrifuging the resulting mixture, removing the supernatant with dissolving the precipitate in ethyl acetate, preparing a suspension and preparing for its base spray.

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