RU2391966C1 - Based on botanical phospholipids nanosystem for actuation of biologically active compounds, and method of its manufacture (versions) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention belongs to medicine and pharmacology, notably to stable in storage nanosystem with particle size up to 10-30 nm which includes plant-based phosphatidilcholine and maltose and designed for inclusion of medication into phospholipid particle, to method of nanosystem producing, to phospholipid composition of medication in form of phospholipid nanoparticles 10-30 nm, including phosphatidilcholine, maltose and medication, and to method of mentioned nanosystem manufacture.

EFFECT: storage stability of the system.

12 cl, 3 dwg, 1 tbl, 5 ex

Description

The invention relates to medicine and pharmacology, and relates to a storage-stable nanosystem with a particle size of up to 10-30 nm, obtained on the basis of plant phospholipids and intended for inclusion in the phospholipid nanoparticle of biologically active compounds, in particular medicines, and a method for its preparation.

One of the most pressing problems of modern pharmacology is the creation of dosage forms that, when introduced into the body, have sufficient bioavailability to reach the affected area. The bioavailability of drugs is determined among many factors by their solubility.

About 60% of pharmaceuticals under development and many of the commonly used drugs are poorly soluble compounds.

Solubilizers can be used to create soluble dosage forms, but their use often requires the solution of additional problems due to their possible toxicity.

It is known that most drugs are limited and slowly penetrate into cells through a natural barrier - a biological membrane. To overcome this barrier, a drug compound must have a certain degree of lipophilicity, and, as already noted above, lipophilic hardly soluble drugs require solutions to the solubilization problem.

Other undesirable properties of drugs include a rapid loss of activity when introduced into the body, a high rate of sorption and elimination. This leads to the need to increase the dose and / or frequency of administration of the drug, which, in turn, also increases side effects. This effect is especially pronounced for most cytostatics and drugs acting on the central nervous system.

In this regard, over the past decade, researchers have paid significant attention not only to the search for new biologically active substances, but also to increasing the effectiveness of drugs already created by designing systems for their transport in the body, increasing the bioavailability and effectiveness of a specific action.

The interest in the development of delivery systems is due to many reasons and, above all, the huge potential benefits from both the economic and medical side. Medicines equipped with a delivery system have several advantages over free drugs: a) the solubility of hydrophobic drugs increases; b) their penetration into cells improves; c) pharmacokinetics improves, many drugs have the ability to cross the membrane and blood-brain barriers.

Examples of drugs included in the biodegradable nanospheres based on polylactates, polyglutamylalanine, polyalkylcyanoacrylate, etc., are lidocaine (US Patent No. 5,543,158), cyclosporine (US Patent No. 6,800,296), tamoxifen (De Kozak Y., et all, Eur. Jur. . ImmunoL, 2004, 34, 3702-3712) and others. The use of nanosystems for the transport of drugs allows not only to increase the bioavailability of the latter, but also to ensure the prolonged delivery of the drug to certain organs and target cells. Polymer-based nanoparticles are highly stable in biological fluids and during storage, but can cause side effects when introduced into the body.

In this regard, phospholipid nanoparticles have a great advantage, the effectiveness of which is significantly contributed by the sizes of 10–20 nm. Phosphoslipid nanoparticles (liposomes, micelles) are biodegradable, biologically inert, do not cause allergic, antigenic or pyrogenic reactions. The surface of lipid nanoparticles, in comparison with other particles, is easily modified to ensure directivity of delivery.

The most common nanosystems in the modern pharmaceutical market are currently liposomes. Their main advantage is that liposomes, creating a hydrophilic and hydrophobic environment for the drug, increase its solubility, also protect the drug from premature degradation, reduce its clearance and act as a system that limits its release. The significant effect of liposomes on the pharmacokinetics of the drug makes it possible to use it in lower doses. Due to the encapsulation of the drug in the liposome, the distribution volume is significantly reduced, and the concentration of the drug in the target organ increases.

The main properties of liposomes and the nature of their interaction with cells are due to their phospholipid base, similar to the structure of biomembranes.

Currently, there are 10-15 certified nanosystems used as drug carriers in the world. There are several dozens of drugs on the global pharmaceutical market, mainly antitumor drugs (daunomycin, doxorubicin, vincristine, annamycin, and tretinoin) equipped with a liposomal transport system. The diameter of liposomes, as a rule, is 100-400 nm, and the form of release is a solution for injection.

It should be noted that this particle size makes the drug "accessible" for lysis, the reticuloendothelial system (RES) of the cell, which significantly reduces the effectiveness of the drugs, and the liquid dosage form complicates their storage and transportation.

Lysis of the drug is most often overcome by stabilizing the surface with polyethylene glycol (PEG). So, the Kelix preparation is a pegylated liposomal form of doxorubicin with a particle size of about 100 nm. Pegylated liposomes have a low permeability lipid matrix and an internal aqueous buffer system, which allows you to keep doxorubicin inside the liposome during its circulation in the bloodstream, excluding its contact with plasma components. At the same time, the use of PEG can lead to additional side effects.

There is a method that reduces the exposure of phospholipid particles to RES cells and thereby contributes to prolonged circulation - this is a reduction in particle size.

For example, when comparing liposomes of three sizes with diameters of 400, 200 and 50 nm, it turned out that the ratio of their clearance time significantly exceeds the size ratio and is 1: 5: 38, i.e. a decrease in size of 8 times prolongs their circulation in the bloodstream by almost 40 times (Drummond D. Et al., Pharmacol.Rev., 1999, 51, 691-743). A decrease in particle size also increases the solubility of an encapsulated hydrophobic substance in them: an antimicrobial hydrophobic agent dissolves twice as much when moving from 2.4 microns (2400 nm) particles to 800 nm particles (Muller R., Peters Int J. Pharm. 1998, 160, 229-237), which is due to an increase in the total particle surface area and surface tension (Kesisoglou F. et al., Adv Drug Delivery Rew, 2007, 59, 631-644).

A natural logical continuation of such developments is the transition from a liposomal dosage form to a drug composition based on phospholipid nanoparticles with a diameter of up to 100 nm, i.e. to the development of a nanosystem for the inclusion of biologically active compounds, which is currently receiving much attention.

The effectiveness of phospholipid nanoparticles as colloidal drug carriers is determined mainly by their size - optimally 10-20 nm, which provides a large "working surface" of the particle and, therefore, high capacity.

Phospholipid nanoparticles are lyotropic liquid crystals, which, due to their chemical structure, can serve as carriers for both soluble and insoluble (hydrophobic) drugs in biological fluids. The incorporation of drug compounds into the lipid matrix of nanoparticles allows one to obtain new nanoforms of drugs with high efficiency, bioavailability and reduced side effects.

The high total surface area, in combination with nanoscale, creates optimal conditions for the interaction of such particles with the cell. In addition, nanoscale creates a unique opportunity for the introduction of particles in the region of gap intercellular junctions, the width of which in some areas can be 30-50 nm. Due to this, it becomes possible to deliver therapeutic agents to inaccessible to other dosage forms parts of the affected tissue, for example, tumor.

Close sizes, along with the general nature of the surface, phospholipid nanoparticles and lipoproteins also create optimal conditions for their interaction with each other. In this case, the phospholipid particles carrying the drug are included in the system of lipoproteins of blood plasma, with the participation of lipid transport proteins, as a result of which the molecules of the lipophilic drug together with phospholipids can be transported to the particles of lipoproteins.

The penetration of a drug, together with a lipoprotein or phospholipid particle into the cell, creates conditions for its cytosolic delivery and access to subcellular structures, which are often the target of many drugs (Wasan, et.al., Antimicrob Agents Chemother. 1998, 42 (7): 1646- 53; Wasan, et.al., Nat Rev Dmg Discov. 2008, 7 (1): 84-99).

All of the above convincingly illustrates the promise of developing phospholipid nanosystems incorporating drug compounds.

Dispersible phospholipid-stabilized microparticles are known from the state of the art, which are a fast-dispersible solid dosage form consisting of a water-insoluble compound in the form of nanoscale or micromeric solid particles, the surface of which is stabilized by surface modifiers, for example a phospholipid, and the particles are dispersed in a volume-creating matrix (patent RF 2233654). The size of the resulting particles is 0.66-10.6 microns (660-10000 nm).

There is also known a method for producing submicron particles of a water-insoluble or poorly soluble organic pharmaceutically active compound, comprising the steps of dissolving this compound in a water-miscible first solvent, mixing this solution with a second solvent into which phosphatidylcholine can be added, and homogenizing or homogenizing in countercurrent to the obtained suspensions or exposure to it by ultrasound (RF patent 2272616). The size of the resulting particles is 0.1-2.46 microns (100-2500 nm).

EP 0 556 394 A1 describes a method for preparing a lyophilized preparation for the delivery of drug substances based on refined soybean oil and refined egg phosphatylcholine. The drug is easily soluble in water with the formation of particles with a size of 10-100 nm and is a fat emulsion.

The objective of the present invention is to develop a technology for producing a non-greasy phospholipid composition with an average diameter of liposomal micellar particles of 10-30 nm, having low toxicity, able to withstand long-term storage and transport of drugs in the body.

In accordance with the invention describes a phospholipid composition of the drug in the form of phospholipid nanoparticles with a size of 10-30 nm, including phosphatidylcholine, maltose and the drug in the following ratio, wt.%:

Phosphatidylcholine 20-43

Maltose 55-78

Medicines 2-8

Also described is a method of producing a phospholipid composition of a drug in the form of phospholipid nanoparticles with a size of 10-30 nm, including 20-43 wt.% Phosphatidylcholine, 55-78 wt.% Maltose, 2-8 wt.% Of the drug, which, in the case hydrophobic drug phospholipid and hydrophobic drug are dissolved in ethanol, ethanol is distilled off, water is added, suspended, maltose is added and the resulting suspension is subjected to several homogenization cycles under high pressure of 800-1500 bar at a temperature round 40-50 ° C followed by lyophilization.

In the case of a hydrophilic drug, the phospholipid, hydrophilic drug and maltose are suspended in water and the resulting suspension is subjected to several homogenization cycles under high pressure of 800-1500 bar at a temperature of 40-50 ° C followed by lyophilization.

The number of homogenization cycles is usually 10-25 cycles, and the pH of the water used is in the range of 6.0-7.5.

Also described is a composition for embedding a drug in a lipid matrix in the form of lyophilized phospholipid nanoparticles 10-30 nm in size, including plant phospholipid with a phosphatidylcholine content of 78-95% and maltose in the following ratio of components, wt.%

Phosphatidylcholine 20-43

Maltose 57-80

Also described is a method of producing a phospholipid composition in the form of phospholipid nanoparticles with a size of 10-30 nm, including 20-43 wt.%. Phosphatidylcholine and 57-80 wt.% Maltose, which consists in the fact that the phospholipid and the aqueous solution of maltose are suspended, then the suspension is subjected to several homogenization cycles under high pressure of 800-1500 bar at a temperature of 40-50 ° C, followed by lyophilization. The number of homogenization cycles is usually 10-30 cycles, and the pH of the water used is in the range of 6.0-7.5. The developed pharmaceutical composition can be used to obtain new dosage forms of both hydrophilic and hydrophobic drugs of different spectrum of action (anti-inflammatory, anti-tumor, etc.).

The proposed technology will allow introducing into the medical practice highly effective drugs of a new generation and, above all, for the treatment of cancer.

Used phosphatidylcholine is the main component of highly purified plant soybean phospholipid, the content of phosphatidylcholine in which is not less than 78-95 wt.%. Other phospholipid components may be contained in amounts not exceeding permissible (lysophosphatidylcholine up to 4 wt.%, Trace amounts of other phospholipids).

As auxiliary pharmacologically acceptable substances, the composition contains maltose for the possibility of obtaining a lyophilisate capable of completely recovering its structure (in particular, particle size) after dissolution in physiological saline or water.

According to the invention, the proposed technology allows to obtain pharmaceutical preparations with greater bioavailability compared to the original drug.

Materials and methods

The following materials were used in the work:

1. Soya phospholipid brand Lipoid C 100 company Lipoid, Germany.

2. Maltose monohydrate company MERCK, Germany.

3. Water for injection (according to FS No. 42-4587-95).

Technological stages of obtaining:

I. Composition for embedding a drug in a lipid matrix in the form of lyophilized dried phospholipid nanoparticles

A portion of soybean phospholipid is added to an aqueous solution of maltose, homogenized by rotor-stator homogenization for 3 minutes at a temperature not exceeding 40 ° C until a homogeneous finely divided primary suspension is obtained.

II. For hydrophobic drug substances

Samples of phospholipids and hydrophobic drug substance are dissolved in a sufficient volume of ethanol (96%), then the alcohol is distilled off on a rotary evaporator. A 10% aqueous solution of maltose is added to the resulting mass, homogenized by rotor-stator homogenization for 3 minutes at a temperature not exceeding 40 ° C until a homogeneous finely divided primary suspension is obtained. Then the suspension is placed in the receiving funnel of a high pressure homogenizer. Homogenize cyclically at a pressure of 1000 bar ± 10%. The solution between subsequent cycles is passed through a water-cooled refrigerator, preventing it from heating above 55 ° C. The homogenization process is continued until transparency> 60% is achieved (they control the light transmission at 660 nm in a cuvette with an optical path length of 1 cm).

III. For hydrophilic drug substances

Samples of the starting components are mixed in water, homogenized by rotor-stator homogenization for 3 minutes at a temperature not exceeding 40 ° C until a homogeneous finely divided primary suspension is obtained.

IV. Obtaining phospholipid nanoparticles

The production of phospholipid nanoparticles is carried out in two ways: high pressure homogenization and fluodization.

Homogenization is carried out using a high-pressure homogenizer Ranie MiniLab 7.30 VH (Denmark) or microfluodizer Microfluidizer Processor, M110 EN-30K (USA).

The primary suspension obtained in the previous step (I, II or III) is passed through a homogenizer / microfluodizer at a pressure of 1000 bar ± 10%. The temperature of the suspension is maintained within the range of 40-50 ° C.

The process of homogenization (5-7 cycles) or microfluodization (4-5 cycles) is repeated until the transmittance of the working solution reaches> 60% (control by transmittance at 660 nm in a cuvette with an optical path length of 1 cm).

V. Filtration and sterile bottling

The resulting solution is filtered through a 5 μm filter, then through a 0.22 μm sterile filter (sterilizing filtration) and poured into 10 ml vials under sterile conditions.

VI. Lyophilization

Vials with the drug are pre-cured with rubber stoppers, placed on the shelves of freeze drying. The product is frozen to -40 ° C, then the shelves are heated to + 10 ° C. Under vacuum of 150 mTorr, the product is sublimated for 30 hours. Then the temperature of the shelves is increased to + 50 ° C and the preparation is dried under a vacuum of 50 mTorr for 8-10 hours. The dried preparation is corked under vacuum, sealed with aluminum caps, labeled and samples are taken for quality control by analytical and microbiological methods.

Determining the particle size of the phospholipid composition for incorporating the drug and the phospholipid composition with the substance included.

1. 20 μl of the preparation after homogenization (or after dissolving the freeze-dried preparation) is added to 3 ml of water.

2. The resulting solution is degassed (by ultrasound or under vacuum), filtered through a filter with a pore size of 0.45 μm into a measuring glass cuvette.

3. Particle size analysis is performed by photon correlation spectroscopy on a N5 Beckman submicron particle size analyzer.

Determination of the content of drug substances in the liposome fraction of the phospholipid composition.

1. The phospholipid preparation with the drug substance is quantitatively introduced into the ultrafiltration cartridge with a membrane passing the compounds with mol. weighing less than 3000 daltons and centrifuged at 3000 rpm for 5-10 minutes As a result, the free drug (with a solvent) passes through the membrane to the lower part - the receiver-cartridge, and the drug in the composition of nanophospholipid particles is retained by the filter and remains in solution above the membrane.

2. The content of free drug in the volume introduced into the cartridge is determined by HPLC on a Millichrom A-02 chromatograph, analyzing it in a solution that has passed through the membrane. To determine the amount of substance, the results of HPLC are compared with a calibration curve for standard drug solutions. The ratio of this value to that for a solution that has not undergone ultrafiltration indicates the ratio of the drug that is free and incorporated into the phospholipid nanoparticles. The absence of substance in the filtrate indicates its 100% incorporation.

The invention is illustrated by the following examples.

Example 1. Obtaining a phospholipid composition with a soluble substance (diclofenac)

0.625 g of diclofenac, 6.25 g of phosphatidylcholine, 25 g of maltose are mixed, the volume is adjusted to 250 ml with water for injection. Homogenize for 6 minutes to obtain a primary suspension using a Braun household blender. The resulting finely dispersed suspension is placed in a microfluidizer Microfluidizer Processor, MHO EN-30K (USA), cyclically fluodized (4-5 cycles) to achieve transparency> 60% (control by light transmission at 660 nm in a cuvette with an optical path length of 1 cm), at a pressure 1000 bar ± 10%, at a temperature not exceeding 50 ° C. After sterilization of the solution by successive passing through a 0.45 μm filter and a 0.22 μm sterile filter, the solution is poured under sterile conditions into 10 ml vials. According to Beckman-Coulter No. 5 laser correlation spectrometer, the particle size is (11 ± 5) nm. The incorporation of diclofenac into phospholipid nanoparticles is 96.4 ± 0.3%. Then the drug is freeze-dried. For intravenous administration to animals, the contents of one vial are dissolved in 10 ml of water for injection. The particle size after rehydration of the freeze-dried powder is maintained.

Example 2. Obtaining a phospholipid composition with a hydrophobic drug substance (budesonide or prednisolone)

0.2 g of the substance and 2.0 g of phospholipid are dissolved in 80 ml of ethanol (96%). The alcohol is distilled off on a rotary evaporator. To the resulting mass add 150 ml of a 10% solution of maltose in water and homogenize for 8 minutes to obtain a primary suspension using a household Braun blender. The resulting fine suspension is placed in a receiving funnel of a high-pressure homogenizer Ranie MiniLab 7.30 VH (Denmark). Homogenize cyclically (6-7 cycles) to achieve transparency> 60% (control by light transmission at 660 nm in a cuvette with an optical path length of 1 cm), at a pressure of 1000 bar ± 10%, at a temperature of no higher than 50 ° C. After sterilization of the solution by successive passing through a 0.45 μm filter and a 0.22 μm sterile filter, the solution is poured under sterile conditions into 10 ml vials. According to Beckman-Coulter No. 5 laser correlation spectrometer, the particle size is 22 ± 5 nm for budesonide and 18 ± 3 nm for prednisolone. Embedding in phospholipid nanoparticles is 100% for budesonide and 95% for prednisolone. Then the drug is freeze-dried. For intravenous administration to animals, the contents of one vial are dissolved in 10 ml of water for injection. The particle size after rehydration of the freeze-dried powder is maintained.

Example 3. Comparison of the bioavailability of Budesonide free and Budesonide in the form of nanophospholipid particles (NF-Budesonide) in a rat experiment

Budesonide free and NF-Budesonide are prepared in the form of a 1% alcohol solution. The concentration of budesonide is 2 mg / kg. The injected volume is 1 ml.

Animals weighing 400-500 g are injected intraperitoneally with solutions of Budesonide and NF-Budesonide at a dose of 2 mg / kg. After 5, 10, 20 and 40 minutes, blood is drawn from the tail vein into test tubes with heparin (5: 1). Then, 880 μl of methanol is added to 120 μl of heparinized blood, it is intensively mixed, centrifuged, proteins and other blood components insoluble in methanol are precipitated, and analyzed by HPLC. Quantitative measurements are carried out by comparing the data obtained with the calibration curve.

The data shown in figure 1 indicate that budesonide in the composition of phospholipid nanoparticles has a significantly better bioavailability than its free counterpart. Thus, a nanophospholipid composition based on budesonide and soybean phospholipids can be recommended for further tests in order to create a new dosage form of budesonide.

Example 4. Comparison of the bioavailability of intravenous preparations of Prednisolone-Nycomed (Pr-Nycomed) and Prednisolone in the composition of nanophospholipid particles (NF-Pr) in a rat experiment

Pr-Nycomed and NF-Pr are prepared in the form of a 1% alcohol solution. The prednisone concentration is 2 mg / kg. The injected volume of 1 ml.

NF-Pr and Pr-Nycomed solutions are administered intravenously to animals weighing 400-500 g at a dose of 2 mg / kg. After 5, 10, 20 and 40 minutes, blood is drawn from the tail vein into test tubes with heparin (5: 1). Then, 880 μl of methanol is added to 120 μl of heparinized blood, it is intensively mixed, centrifuged, proteins and other blood components insoluble in methanol are precipitated, and analyzed by HPLC. Quantitative measurements are carried out by comparing the data obtained with the calibration curve.

With the intravenous administration of both drugs for prednisolone in the composition of nanophospholipid particles, elimination from the systemic circulation is much slower than for its free analogue (figure 2).

Table 1 shows the accumulation in the liver of rats of prednisolone and prednisolone in the phospholipid particles after 15 minutes. after their intravenous administration. It was shown that the accumulation of prednisolone in the composition of phospholipid particles is less than free.

The accumulation in the liver of rats of prednisolone and prednisolone in the composition of phospholipid particles

Table 1 Sample Weight / weight Mg Ex / g tissue Liver / NF-Pr 11.832 g / 138 mg 11.7 Liver / Pr-Nycomed 12.813 g / 180 mg 14.0

Example 5. The study of the distribution of Prednisolone-Nycomed (Pr-Nycomed) and Prednisolone in the composition of nanophospholipid particles (NF-Pr) by plasma components in an in vitro experiment.

In vitro experiments showed that upon incubation of Nf-Pr and Pr-Nycomed at a concentration (0.5 mg / ml) with 3.7 ml of human blood plasma at a temperature of 37 ° C for 30 min, a redistribution of the drug substance over blood components is observed (figure 3). The greatest amount of prednisolone in the composition of phospholipid particles is found in low and high density lipids. The greatest amount of free prednisolone is contained in dilipidated plasma.

Summary of drawings.

Figure 1 presents the kinetics of elimination of budesonide from the blood of experimental animals with intraperitoneal administration of free budesonide and budesonide in the phospholipid particles (NF-Budesonide).

Figure 2 shows the elimination of prednisolone after its intravenous administration in the form of free prednisolone (Pr-Nycomed) and prednisolone in the phospholipid particles (Nf-Pr).

Figure 3 presents the incubation of free prednisolone (Pr-Nycomed) and prednisolone in the composition of phospholipid particles (Nf-Pr) with blood plasma in an in vitro experiment. Conditional Abbreviations:

VLDL - very low density lipoproteins

LDL - low density lipoproteins

HDL - high density lipoproteins

DLP - delipidated plasma

Claims (12)

1. The phospholipid composition of the drug in the form of phospholipid nanoparticles with a size of 10-30 nm, including plant-derived phosphatidylcholine (78-95%), maltose and the drug in the following ratio, wt.%:
Phosphatidylcholine 20-43 Maltose 57-80 Medicine 2-8 2. The phospholipid composition according to claim 1, characterized in that the drug is diclofenac, budesonide or prednisolone. 3. The method for producing the phospholipid composition according to claim 1, wherein, in the case of a hydrophobic drug, phosphatidylcholine and a hydrophobic drug are dissolved in ethanol, ethanol is distilled off, water is added, suspended, maltose is added and the resulting suspension is subjected to several high-pressure homogenization cycles 800-1500 bar at a temperature of 40-50 ° C followed by lyophilization. 4. The method according to claim 3, characterized in that the drug is budesonide or prednisone; the number of homogenization cycles is 10-25 cycles and water with a pH of 6.0-7.5 is used. 5. The method for producing the phospholipid composition according to claim 1, wherein, in the case of a hydrophilic drug, phosphatidylcholine, the hydrophilic drug and maltose are suspended in water and the resulting suspension is subjected to several homogenization cycles under high pressure of 800-1500 bar at a temperature of 40-50 ° C followed by lyophilization. 6. The method according to claim 5, characterized in that the drug is diclofenac; the number of homogenization cycles is 10-25 cycles and water with a pH of 6.0-7.5 is used. 7. Phospholipid composition for embedding a drug in a lipid matrix in the form of lyophilized phospholipid nanoparticles 10-30 nm in size, including plant phosphatidylcholine (78-95%) and maltose in the following ratio, wt.%:
Phosphatidylcholine 20-43 Maltose 57-80 8. The method for producing the phospholipid composition according to claim 7, wherein phosphatidylcholine and maltose are suspended in water and the resulting suspension is subjected to several homogenization cycles under high pressure of 800-1500 bar at a temperature of 40-50 ° C followed by lyophilization. 9. A method for producing a phospholipid composition of a medicine according to claim 1, wherein the composition for incorporating the drug into the lipid matrix according to claim 7 in the case of a hydrophobic drug is dissolved in water and added to a rotary evaporator dissolved in alcohol and evaporated to dryness drug substance, then suspended, the resulting suspension is subjected to several homogenization cycles under high pressure of 800-1500 bar at a temperature of 40-50 ° C, followed by lyophilization. 10. The method according to claim 9, characterized in that the drugs are budesonide and prednisone. 11. The method for producing a phospholipid drug composition according to claim 1, wherein the composition for incorporating the drug into the lipid matrix according to claim 7 in the case of a hydrophilic drug is dissolved in water together with the drug substance, then suspended, the resulting suspension is subjected to several homogenization cycles under high pressure of 800-1500 bar at a temperature of 40-50 ° C followed by lyophilization. 12. The method according to claim 11, characterized in that the drug is diclofenac.

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