RU2529179C1 - Liposome suspension stabiliser and method for production thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: stabiliser includes modified chitosan which is obtained by modifying chitosan particles located in an emulsion of an organic solvent - water, with pH 6.0-6.5, by first reacting a mixture consisting of a carboxylic acid in an organic solvent and a condensing agent, and then with an organic base, wherein the carboxylic acid used is either palmitic acid or stearic acid or dodecanoic acid, the condensing agent used is a mixture of hydroxysuccinimide and an aliphatic carbodiimide or formaldehyde and an aliphatic isocyanide, and the organic base used is triethylamine.

EFFECT: effective liposome composition stabiliser which can be obtained using a simple method.

8 cl, 3 tbl, 5 ex, 7 dwg

Description

The claimed group of inventions relates to biotechnology and the pharmaceutical industry and can be used to create systems, in particular, liposomal compositions with increased stability and designed to carry out targeted transport of physiologically active substances in order to increase the therapeutic activity of drugs.

Liposomes are widely used as carriers of various medicinal substances, including antiviral drugs. Over the years, both the advantages and disadvantages of liposomal dosage forms have been disclosed. Liposomes are capable of transferring any compounds in their structure (polar, nonpolar, amphiphilic, with large and low molecular weight). In addition, they have high biocompatibility and biodegradability.

In addition, in many cases, using liposomes, targeted drug delivery can be achieved through passive targeting or conjugation of liposomes with biomarkers.

At the same time, the disadvantages of liposomes as a dosage form are the difficulties associated not only with their production, but also arising during the long-term storage of liposome suspensions.

Liposomal suspensions are thermodynamically unstable colloidal systems that dissociate fairly quickly, sometimes within a few hours, to form two phases. Another disadvantage of liposome compositions is the high rate of absorption of liposomes by macrophages, which does not allow to achieve a specific effect of the liposomal dosage form.

Summarizing the data on the use of liposomal forms, we can conclude that many of these shortcomings are fundamental and cannot be eliminated without a fundamental change in the technology of liposome production.

One of the solutions that allows to eliminate some of the disadvantages of liposomal forms without losing all the advantages available is to obtain liposomes with composite membranes. An example is liposomes, in the membrane of which is embedded, for example, a polysaccharide, a polypeptide or a cross-linked synthetic polymer. In this case, a significant increase in the strength of the liposome membrane is achieved, since in this case the polymer compound performs the function of a kind of framework.

In addition, the resulting additional hydrophilic shell allows you to reduce the interaction with the plasma proteins of the patient and, accordingly, increase their stability.

Thus, composite liposomes in many respects resemble microorganisms having a cell wall, while biomarkers and other functional groups can be attached to the additional membrane with the aim of further targeted delivery of drugs to the lesion site.

An extremely important feature of liposomes with a composite membrane is their increased stability, which ensures long shelf life under normal conditions, as well as the possibility of implementation in the form of various dosage forms, for example, solutions, patches, transdermal therapeutic systems or capsules.

The increased stability of composite liposomes can significantly expand the list of medicinal substances that can be used in the form of liposomal forms.

Thus, the development of effective methods for obtaining stable liposome compositions is an urgent task.

The prior art method for producing a stable sterile liposome composition for the delivery of a pharmaceutical agent, comprising the following stages:

a) providing a suitable aquatic environment;

b) providing a suitable phospholipid;

c) providing at least one pharmaceutical agent capable of at least partially encapsulating in liposomes and selected from

i) a lipophilic amine and a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid is selected from an organic or inorganic acid, and

ii) a pharmaceutically acceptable salt of an organic acid of a lipophilic amine, optionally a pharmaceutically acceptable acid comprising a pharmaceutically acceptable organic acid;

where the amount of pharmaceutically acceptable acid present in the composition is such that the pH of the liposome composition is less than or approximately equal to the pK _{a of the} amino group of the pharmaceutically active lipophilic amine;

d) combining an aqueous medium, a phospholipid and a pharmaceutical agent to form a liposome composition; and

e) autoclaving said composition (see RF patent No. 2369384 for the invention “Stable liposomal compositions”, filing date November 22, 2004, published October 10, 2009).

Liposomal compositions obtained in accordance with a known method are autoclaved in order to increase shelf life. In addition, the stable liposome suspensions of this invention do not settle, undergoing phase changes, they are resistant to oxidation and hydrolysis.

A known method of producing shells based on chitosan and salts of alginic acid for microcapsules containing phospholipid micelles, characterized by sequential exposure of the nuclei of microcapsules in 0.5 + 1.0% (weight / volume) chitosan solution of medium or low viscosity in 1.0% acetic acid, in a 2.5- + 3.0% solution of alkaline earth metal chloride, in a 0.5- + 1.0% (weight / volume) solution of sodium alginate and, again, in 2.5- + 3, 0% solution of alkaline earth metal chloride (see RF patent No. 2411077 for the invention "A method for producing shells based on chitosan and salt minutes alginic acid microcapsules containing phospholipid micelles ", filing date 09.06.2009, published 27.09.2011 g).

Chitosan is a (1 → 4) -linked glucosamine-acetylglucosamine copolymer obtained by N-deacetylation of chitin in a basic medium (see FIG. 1).

Chitosan is of constant interest due to its outstanding biological properties such as biodegradability, bioactivity and biocompatibility.

The known invention is directed to the creation of a technological process, the implementation of which allows to obtain a shell for microcapsules based on calcium alginate or barium alginate and chitosan with different viscosities, which affects the relative percentage of phospholipid micelles from the nucleus of capsules in environments that mimic the conditions of the human gastrointestinal tract.

This invention allows to create a shell for microcapsules based on chitosan and salts of alginic acid, through which phospholipid micelles penetrate at a certain speed due to the use of chitosan of different viscosity and different nature of the cation forming a salt with alginic acid.

In addition, there is a method of stabilizing liposomal compositions by attaching a stabilizing substance that non-covalently binds to the lipid and is present in an amount sufficient to coat the lipid, but not sufficient to increase the viscosity of the composition, polymers in which repeating units contain one or more hydroxyl groups (polyhydroxy polymers); polymers in which the repeating units contain one or more amino groups (polyamines); polymers in which the repeating units contain one or more carboxyl groups (polycarboxypolymers); and polymers in which the repeating units contain one or more saccharide residues (polysaccharides). The molecular weight of the polymers can vary and is usually from about 50 to about 5,000,000, preferably from about 100 to about 50,000. More preferred are polymers with a molecular weight of from about 150 to about 10,000, and most preferably from about 800 to about 8,000. Among the proposed polymers are natural and modified resin polysaccharides, such as xanthan gum, robinia bean gum, guar or carrageenan (from red seaweed Chondrus crispus); methoxylated pectin; starch; agarose; cellulose and semi-synthetic cellulose, for example methyl cellulose, hydroxyethyl cellulose, methoxycellulose and hydroxypropyl cellulose; agar; chitosan; carboxymethyl cellulose; alginic acid salts such as sodium and calcium alginates; salts of glycosaminoglycans, including salts of hyaluronic acid; phosphorylated and sulfonated carbohydrate derivatives (see RF patent No. 2181998 for the invention of "New compositions of lipids and stabilizing materials", filing date 03/27/1996, published 05/10/2002).

Such compositions have enhanced stability. When applied, blocking of small vessels is reduced.

The closest technical solution to the claimed invention is a method for stabilizing a liposomal composition in which a modified chitosan biopolymer is used.

The known stable liposome composition relates to the target chitosan derivative containing an octreotide, and more particularly the N-succinyl-M-alkylate chitosan derivative, and to the N-alkylate carboxymethyl chitosan. In addition, there is a known method for producing this composition (see patent CN 101396563 "Chitose derivates using octreotide as terget ligand and use thereof in medicalament", publication date 04/01/2009).

The disadvantages of this invention are due to the use of a complex multistage method for modifying chitosan, as well as the use of carboxymethyl chitosan, which impedes the loading of liposomes with anionic drugs.

The technical result to which the claimed invention is directed is to simplify the method for producing (synthesis) of modified chitosan, as well as to increase the stabilization efficiency of liposome compositions by introducing a stabilizer based on modified chitosan.

The specified technical result is achieved by the fact that in the stabilizer for liposomal suspensions, including the modified chitosan, according to the invention, chitosan is used as the modified chitosan, obtained by modifying the chitosan particles in the emulsion as an organic solvent - water with pH 6.0-6.5, by exposure first with a mixture consisting of a carboxylic acid in an organic solvent and a condensing agent, and then with an organic base, while either carboxylic acids are used or itinovuyu or stearic or dodecanoic acid as a condensing agent - a mixture of aliphatic hydroxysuccinimide and carbodiimide, or formaldehyde and an aliphatic isocyanide, and as an organic base - triethylamine.

As the organic solvent, either dichloromethane, or chloroform, or toluene, or benzene is used.

In the claimed invention using chitosan with a molecular weight of 20-150 thousand daltons and a degree of deacetylation of 85-98%.

As fatty acids, carboxylic acids with a chain length of C ₁₀ -C ₁₈ , preferably stearic and palmitic, are used.

The degree of substitution with residues of fatty acids is 0.5-4.0%.

The optimal concentration of the stabilizing agent is 0.5-2.0 g / L.

The specified technical result is achieved in that the method of obtaining a stabilizer for liposomal suspensions, including the modification of chitosan, according to the invention, the modification of chitosan is carried out by alkalizing a solution of chitosan hydrochloride to form a colloidal solution with a pH of 6.0-6.5, which is exposed to a mixture consisting of carbon acid in an organic solvent and a condensing agent, after which the composition is intensively mixed and maintained, and then the organic base is introduced into the emulsion until pH 8.5, after which the organic solvent is removed, while either carboxylic acids or palmitic, or stearic, or dodecanoic acid are used, as a condensing agent is a mixture of hydroxysuccinimide and aliphatic carbodiimide or formaldehyde and aliphatic isocyanide, and as organic the bases are triethylamine.

The organic solvent is removed by distillation or phase separation.

Thus, the essence of the proposed method consists in the synthesis of hydrophobically-modified chitosan at the interface between the organic solvent and water.

The invention is illustrated by drawings, where

Figure 1 - structure of unmodified chitosan.

Figure 2 - structure of the modified chitosan obtained by the acylation reaction.

Figure 3 - structure of the modified chitosan obtained by the reaction of Ugi.

4 is a graph of particle size distribution in a sample treated with a solution of unmodified chitosan.

Figure 5 is a graph of the size distribution of particles in a sample of liposomes aged in a solution of chitosan modified with palmitic acid with a viscosity of 45 cps.

6 is a graph of the particle size distribution of the original (Record 3) and coated (Record 4) samples.

Fig.7 is a graph of changes in the average size and polydispersity of liposomes with a stabilizer (1) and without it (2).

In the process of synthesis, chitosan molecules are located and oriented at the interface and therefore the modification reaction proceeds more selectively to obtain derivatives with pronounced surface-active properties. Similar molecules actively interact with liposomes with a larger specific surface area. Thus, hydrophobic fragments of modified chitosan dissolve in the lipid surface layer, while glucosamine residues are oriented towards the aqueous phase. Hydrated chitosan chains provide high steric stabilization of liposomes.

In addition, the polymer carries a charge, leading to electrostatic repulsion between them. The introduction of modified chitosan can improve the mechanical properties of the liposomal membrane, including increasing the elasticity and viscosity of the lipid layer. In general, all these effects lead to a significant increase in the stability of liposomal dosage forms. For example, liposomes with a stabilizer in aqueous solutions are not subject to coaculation and the formation of conglomerates for several weeks and even months. In addition, the rate of absorption of liposomes by macrophages decreases, which leads to a more pronounced drug effect of the liposome preparation. In particular, stabilized liposomes are able to pass through the mucous membrane without destroying the lipid layer, which opens up great opportunities for practical use in medical practice.

In the claimed invention, a mixture of carboxylic acids is used in the presence of condensing agents — phenols and aliphatic carbodiimides or formaldehyde and aliphatic isocyanides. In both cases, the yield of the modified product reaches 75-80%. The interaction is as follows. The solution of chitosan hydrochloride is made alkaline to form a colloidal solution, then a solution of the starting reagents in an organic solvent is added to it, which is used either dichloromethane, or chloroform, or toluene, or benzene. Both phases are mixed until a stable emulsion is obtained using an effective mixer or homogenizer. At the end of the reaction, the emulsion is destroyed spontaneously, otherwise phase separation is achieved by adding dilute hydrochloric acid or removing the solvent.

The final products in all cases are hydrophobically modified chitosan-based polymers (see FIG. 2), the structure of which is confirmed by PMR spectra. The reaction mechanism includes the formation of an activated ester and subsequent nucleophilic substitution with the formation of an amide bond. The derivatives obtained in this way showed a pronounced ability to stabilize the emulsions of organic solvents in water at low concentrations (less than 2 g / l). The result is biocompatible and biodegradable emulsion stabilizers that are sensitive to changes in pH and ionic strength of solutions, which are used to stabilize liposomal suspensions and as components of liposomal compositions in the food and medical industries.

Using the starting reagents palmitic acid, hydroxysuccinimide and dicyclohexylcarbodiimide (<0.5 mmol / L), a product soluble in water and hydrochloric acid solutions was isolated. Intense absorption bands were observed in the IR spectrum in the regions of 1613 and 1550 cm ^-1 . Peaks of 1.55 2.76 and 2.85 ppm were observed in ¹ H NMR. These peaks correspond to palmitic acid signals, which indicates the passage of the acylation reaction.

Similar data were obtained using stearic and dodecanoic acids. At a low concentration of the starting reagents in the organic solvent, chitosan particles are easily desorbed from the interface and the reaction proceeds in the aqueous phase. At a high concentration of the starting reagents, particles cannot easily be desorbed from the surface; therefore, they accumulate on it and the reaction occurs at the interface between the aqueous and organic phases.

When using another combination of condensing agents - formaldehyde and aliphatic isocyanides, the products of the Ugi reaction are formed. The advantage of this option is the absence of reaction by-products. At the same time, the main reaction product - modified chitosan (see figure 3) has pronounced surface-active properties.

Modification of chitosan with aliphatic acids improves its ability to stabilize liposomal suspensions.

So, for example, unmodified chitosan (Fig. 1) has poor adhesion to liposomal membranes (membranes), as a result of which the main polymer content is in solution and only a small part is deposited on the membranes.

Figure 4 shows a graph of the distribution of particle size in the sample treated with a solution of unmodified chitosan.

The sample is polydisperse, while the polydispersity index averaged 0.46, which is significantly higher than 0.2, which is taken as the upper value for monodisperse samples. Two main peaks are clearly visible in the distribution: one at about 320 nm and the second at about 37 nm. A peak in the region of 30–40 nm is characteristic of samples of the initial polymer, which allows us to conclude that a significant part of chitosan is in solution and does not participate in the formation of the shell. In addition, the particle size increased significantly (from 243 to 320 nm), which indicates the formation of a loose shell on the surface of liposomes.

Figure 5 presents a graph of the size distribution of particles in a sample of liposomes aged in a solution of chitosan modified with palmitic acid with a viscosity of 45 cps. The sample is monodisperse, while the polydispersity index averaged 0.17, which slightly differs from the sample in figure 4.

In the distribution, there is one peak at 302 nm, which indicates an increase in the size of liposomes due to the formation of the membrane (see Fig.6). At the same time, the increase in volume is not as significant as in the case of unmodified chitosan, which confirms the formation of a denser shell.

Two factors are crucial for this method: the rate of deposition of chitosan on the liposome membrane and the stability of the resulting suspensions. Both values can be determined by the rate of disappearance of small particles in the range of 30-80 nm in the light scattering spectra of the samples.

The results of the deposition rate of chitosan samples differing in viscosity (10, 20, 45 and 120 cps) are shown in Table 1.

Table 1 The deposition rate of chitosan modified with 2% palmitic acid, depending on the viscosity of chitosan. Viscosity cps 10 twenty 45 120 The deposition rate, hour 0.5 1,5 5,0 14.0

As can be seen from Table 1, with an increase in viscosity, the deposition rate of chitosan on the surface of liposomes decreases rapidly. At the same time, higher viscosity chitosan provides better liposome stabilization. Thus, the inventive stabilizer provides reliable stabilization of the liposome membrane.

Technical solutions that coincide with the totality of the essential features of the claimed invention have not been identified, which allows us to conclude that the claimed invention meets such a patentability condition as “novelty”.

The claimed essential features that predetermine the receipt of the specified technical result, do not explicitly follow from the prior art, which allows us to conclude that the claimed invention meets such a patentability condition as "inventive step".

The patentability condition "industrial applicability" is confirmed by examples of specific applications.

The inventive stabilizer for liposomal suspensions is prepared and used as follows.

The synthesis of modified chitosan is carried out, in which 250 mg of chitosan is dissolved in 100 ml of a 0.2% solution of hydrochloric acid in water. The resulting solution is titrated with a 0.2% solution of sodium hydroxide in water until the solution becomes cloudy (pH 6.0-6.5). To the resulting solution add the calculated amount of fatty acid (or palmitic, or stearic, or dodecanoic) and a condensing agent (a mixture of hydroxysuccinimide and dicyclohexylcarbodiimide or aliphatic isocyanide and formaldehyde) in 20 ml of an organic solvent (or dichloromethane, or chloroform, or benzene) .

The mixture is stirred vigorously until a homogeneous emulsion is obtained. Then the pH of the mixture was adjusted to 8.5 by the addition of triethylamine and the emulsion was maintained for another 1 hour. After that, the organic solvent is distilled off with heating and vigorous stirring. The aqueous phase is filtered and concentrated to 10-15 g / l by evaporation on a rotary evaporator. The resulting solution can be directly used for deposition on the surface of liposomes.

Surface modification of liposomes. An aqueous solution of hydrophobically-modified chitosan with a concentration of 10-15 g / l is added to the liposomal suspension until its concentration in the suspension reaches 1 g / l. The resulting solution was incubated for 3 hours at room temperature.

The parameters of stabilizer liposomes were evaluated using a Malvem Zetasizer Nano SL dynamic light scattering spectrophotometer. For the experiment, the liposome composition was diluted with distilled water to a hydrophobic-modified chitosan concentration of 1 g / l and placed in a spectrophotometer cuvette. The evaluation results confirmed that the inventive liposomal suspension into which the stabilizer obtained by the inventive method was introduced has the characteristics necessary for medical use, in particular, up to 95% of the liposomes had a diameter in the range of 150-450 nm.

The main parameters of the claimed liposomal composition are shown in Table 2.

table 2 Parameter Parameter value The total concentration of lipids in solution, g / l 10-50 The content of antioxidant, g / l 0-4.0 The content of the stabilizer, g / l 0.5-2.0 Shelf life at t = 20 ° C up to 6 months The average particle size, nm 150-450

In addition, comparative studies were conducted on the change in the average size and polydispersity of liposomes, into which the inventive stabilizer was introduced, and liposomes without a stabilizer.

The data obtained are shown in Table 3.

Table 3 Change in the parameters of a sample of stabilized liposomes depending on storage time Time months The average size of liposomes, im Polydispersity index After receiving 221 0.215 2 231 0.217 3 236 0.221 5 235 0.236

Analysis of the data shown in Table 3 allows us to conclude that the change in the size and polydispersity of liposomes does not exceed 2% per month.

A comparative analysis of changes in the parameters of liposome samples with a stabilizer (1) and without it (2) is shown in Fig.7. The analysis showed that the average size of liposomes without a stabilizer increased over 20 days from 264 to 336 nm, which corresponds to an aging rate of approximately 35% per month. At the same time, the polydispersity index increased one and a half times, which allows the use of these suspensions only within 3-4 days after receipt. At the same time, the parameters of liposomes with a stabilizer did not undergo significant changes during storage at room temperature for 5 months.

All of the above confirms the practical use of the inventive stabilizer for liposomal suspensions.

The implementation of the claimed invention is confirmed by examples of specific performance.

Example No. 1.

Obtaining a stabilizer of liposomal suspensions using the acylation reaction.

The synthesis of modified chitosan is as follows. Chitosan in an amount of 250 mg is dissolved in 100 ml of a 0.2% solution of hydrochloric acid in water. The resulting solution is titrated with a 0.2% solution of sodium hydroxide in water until the solution becomes cloudy (pH 6.0-6.5). To the resulting solution was added the calculated amount of a mixture of hydroxysuccinimide, dicyclohexylcarbodiimide and palmitic acid in 20 ml of dichloromethane. The mixture is stirred vigorously until a homogeneous emulsion is obtained. Then the pH of the mixture by adding an organic base - triethylamine is adjusted to 8.5 and incubated for 1 hour. After that, dichloromethane is distilled off with heating and vigorous stirring. The precipitate of dicyclohexylurea formed is filtered off and the aqueous phase is concentrated to 10-15 g / L. The resulting solution can be used for deposition on the surface of liposomes.

Example No. 2.

Obtaining a stabilizer of liposomal suspensions using the acylation reaction.

The synthesis of modified chitosan is as follows. Chitosan in an amount of 250 mg is dissolved in 100 ml of a 0.2% solution of hydrochloric acid in water. The resulting solution is titrated with a 0.2% solution of sodium hydroxide in water until the solution becomes cloudy (pH 6.0-6.5). To the resulting solution was added the calculated amount of a mixture of hydroxysuccinimide, dicyclohexylcarbodiimide and dodecanoic acid in 20 ml of benzene. The mixture is stirred vigorously until a homogeneous emulsion is obtained. Then the pH of the mixture by adding triethylamine is adjusted to 8.5 and incubated for 1 hour. After that, the benzene solution is separated on a separatory funnel. The aqueous phase is filtered from the resulting precipitate of dicyclohexylurea and concentrated to 10-15 g / L. The resulting solution can be used for deposition on the surface of liposomes.

Example No. 3.

Obtaining a stabilizer of liposomal suspensions using the Ugi reaction.

The synthesis of modified chitosan is as follows. Chitosan in an amount of 250 mg is dissolved in 100 ml of a 0.2% solution of hydrochloric acid in water. The resulting solution is titrated with a 0.2% solution of sodium hydroxide in water until the solution becomes cloudy (pH 6.0-6.5). To the resulting solution was added the calculated amount of a mixture of methoxyethylisocyanide, formaldehyde and stearic acid in 20 ml of toluene. The mixture is stirred vigorously until a homogeneous emulsion is obtained. Then the pH of the mixture by adding triethylamine is adjusted to a value of 8.5, after which the resulting emulsion is incubated for 1 hour. During this time, spontaneous separation of the emulsion occurs. After the reaction, toluene is separated on a separatory funnel, and the aqueous phase is concentrated to 10-15 g / L. The resulting solution can be used for deposition on the surface of liposomes.

Example No. 4.

Obtaining a stabilizer of liposomal suspensions using the Ugi reaction.

The synthesis of modified chitosan is as follows. Chitosan in an amount of 250 mg is dissolved in 100 ml of a 0.2% solution of hydrochloric acid in water. The resulting solution is titrated with a 0.2% solution of sodium hydroxide in water until the solution becomes cloudy (pH 6.0-6.5). To the resulting solution was added the calculated amount of a mixture of cyclohexyl isocyanide, formaldehyde and palmitic acid in 20 ml of chloroform. The mixture is stirred vigorously until a homogeneous emulsion is obtained. Then the pH of the mixture by adding triethylamine is adjusted to a value of 8.5, after which the resulting emulsion is incubated for 1 hour. After this, chloroform is distilled off with heating and vigorous stirring. The aqueous phase is filtered and concentrated to 10-15 g / L. The resulting solution can be used for deposition on the surface of liposomes.

Example No. 5.

The use of a stabilizer of liposomal suspensions.

The surface of liposomes is modified, for which an aqueous solution of hydrophobically-modified chitosan with a concentration of 10-15 g / l is added to the liposomal suspension until its concentration in the suspension reaches 1 g / l. The resulting solution was incubated for 3 hours at room temperature.

The claimed group of inventions allows to obtain a stabilizer for liposomal suspensions with increased stability and intended for the implementation of targeted transport of physiologically active substances.

Claims (8)

1. A stabilizer for liposomal suspensions, including modified chitosan, characterized in that chitosan is used as the modified chitosan, obtained by modifying the particles of chitosan in the emulsion as an organic solvent - water with pH 6.0-6.5, by first applying the mixture, consisting of a carboxylic acid in an organic solvent and a condensing agent, and then an organic base, with either palmitic or stearic or dodecanoic acid being used as carboxylic acids, in as a condensing agent, a mixture of hydroxysuccinimide and aliphatic carbodiimide or formaldehyde and aliphatic isocyanide, and triethylamine as the organic base. 2. The stabilizer for liposomal suspensions according to claim 1, characterized in that either dichloromethane, or chloroform, or toluene, or benzene is used as the organic solvent. 3. The stabilizer for liposomal suspensions according to claim 1, characterized in that they use chitosan with a molecular weight of 20-150 thousand daltons and a degree of deacetylation of 85-98%. 4. The stabilizer for liposomal suspensions according to claim 1, characterized in that the degree of substitution by carboxylic acid residues is 0.5-4.0%. 5. The method of obtaining a stabilizer for liposomal suspensions according to claim 1, including the modification of chitosan, characterized in that the modification of chitosan is carried out by alkalizing a solution of chitosan hydrochloride to form a colloidal solution with a pH of 6.0-6.5, which is affected by a mixture consisting of carboxylic acid in an organic solvent and a condensing agent, after which the composition is intensively mixed and maintained, and then an organic base is introduced into it until a pH of 8.5 is reached, after which the organic solvent is removed spruce, while palmitic or stearic or dodecanoic acid is used as carboxylic acid, a mixture of hydroxysuccinimide and aliphatic carbodiimide or formaldehyde and aliphatic isocyanide as the condensing agent, and triethylamine as the organic base. 6. The method of producing a stabilizer for liposomal suspensions according to claim 5, characterized in that chitosan with a molecular weight of 20-150 thousand daltons and a degree of deacetylation of 85-98% is used. 7. A method of obtaining a stabilizer for liposomal suspensions according to claim 5, characterized in that the degree of substitution by carboxylic acid residues is 0.5-4.0%. 8. The method of obtaining a stabilizer for liposomal suspensions according to claim 5, characterized in that the organic solvent is removed by distillation or phase separation.

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