WO2014092596A1

WO2014092596A1 - Substances and pharmaceutical compositions based thereon for treating human diseases, including chronic hepatitis b and c

Info

Publication number: WO2014092596A1
Application number: PCT/RU2012/001057
Authority: WO
Inventors: Тамара Александровна ВИТКАЛОВА; Дмитрий Валерьевич ШПАК; Владимир Александрович ИСАЕВ
Original assignee: Vitkalova Tamara Aleksandrovna
Priority date: 2012-12-12
Filing date: 2012-12-12
Publication date: 2014-06-19

Abstract

The invention relates to particles which constitute a universal system for the delivery of genetically engineered proteins. The particles, containing interferons, interleukins, a colony-stimulating factor, poloxamers and fatty acids, have an average particle size of from 1 to 350 nanometres, where an interferon is selected from the group consisting of human interferon-alpha, -beta and -gamma, and an interleukin is selected from the group consisting of human interleukin-1 alpha and interleukin-1 beta, and a colony-stimulating factor is selected from the group consisting of granulocyte colony-stimulating factor, macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. The present invention further relates to pharmaceutical compositions for parenteral, external or peroral (oral) administration, characterized in that they contain particles comprising the particles per se and a pharmaceutically acceptable carrier. Particles containing interferon-alpha, interleukin-1 beta and a colony-stimulating factor can be used for treating human diseases, including chronic hepatitis B and C.

Description

SUBSTANCES AND PHARMACEUTICAL COMPOSITIONS BASED ON THEM FOR THE TREATMENT OF HUMAN DISEASES, INCLUDING, FOR THE TREATMENT OF CHRONIC VIRAL HEPATITIS

“B” and “C”

Field of Invention

[0001] The present invention relates to substances or particles consisting of poloxamer, fatty acid and / or phospholipids, which is a delivery system that increases the transport of any biologically active genetically engineered (recombinant) drugs (interferons, interleukins, cytokines, colony stimulating factors, growth factors, hormones) and peptides. The present invention relates to substances containing, in addition to a special delivery system, interferon, interleukin, colony stimulating factor (G-CSF, M-CSF, GM-CSF) and their pharmaceutical compositions for parenteral and oral administration with improved bioavailability for the treatment of human diseases, in including for the treatment of chronic viral hepatitis B and C.

Technical level

[0002] Human interferons, for example, interferon-alpha, interferon-beta, and interferon-gamma, as well as interleukins, for example, interleukin 1 alpha, interleukin 1 beta are widely used as therapeutic agents for the treatment of human diseases, including for the treatment of chronic viral hepatitis B and C. The only practical way to deliver interferons and interleukins to the systemic circulation is the parenteral route of administration. However, parenteral administration provides a rapid onset of action with a rapid decrease in the systemic level of interferon and interleukin. However, it is often desirable to maintain systemic interferon levels in therapeutically effective concentrations for as long as treatment requires. This requires frequent injections, which ultimately causes discomfort to the patient. For this reason, there is a need to create prolonged dosage forms that can reduce the total number of injections while maintaining the effectiveness of the treatment, improve the pharmacoeconomic performance of the treatment and will be more convenient for the patient. A colony stimulating factor has been added to the treatment of viral hepatitis B and C because it enhances the antiviral signaling of interferon alfa.

[0003] Encapsulating an active pharmaceutical substance in lipid particles is a promising approach to creating a pharmaceutical composition with improved pharmacokinetic characteristics (see, for example, Wissing SA, Kayser O, Muller RH, Solid lipid nanoparticle for parenteral drug delivery. Advanced Drug Delivery Review, 56. 2004. 1257-1272. Joshi Medha. Muller Rainer, Lipid nanoparticles for parenteral delivery of actives. Euro. J. of Pharm. And Biopharm., 71, 2009, 161-172). Therapeutic agents embedded in lipid-based particles have shown improved bioavailability. However, there are many practical problems limiting the use of lipid-based particles in the manufacture of pharmaceutical compositions. Some of the problems limiting the production and development of lipid-based particles include problems with stability, reproducibility from batch to batch, difficulty in sterilization, low capture of the substance, control of average particle size, production of large batch size, and short half-life of particles in the bloodstream (Sharma A, Sharma U, Liposomes in drug delivery: progress and limitations. International Journal of Pharmaceutics. 154, 1997, 123-140U. Thus, there is a need to develop lipid-based particles with improved stability, reproducibility from pa TII to the party, increased substance content in the particle, as well as an extended lifetime in the systemic circulation.

[0004] We found that the combination of interferon + interleukin + colony stimulating factor, fatty acid, phosphotidylcholine and poloxamer gives stable and reproducible particles with high uptake of the active substance, which are interferons, interleukins and colony stimulating factors and an extended lifetime in the systemic circulation. The critical advantage of such particles formed by fatty acid, phosphotidylcholine and poloxamer compared to other lipid-based particles is the smaller average particle size, which provides increased bioavailability of interferon + interleukin + colony stimulating factor placed in these particles upon parenteral, oral and local administration a mammal in need of it.

[0005] The object of the present invention are particles with an average size of from 1 to 350 nanometers, containing interferon, interleukin, colony stimulating factor, poloxamer, phosphotidylcholine and fatty acids, as well as methods for their preparation and pharmaceutical compositions based on them.

Brief Description of the Drawings

[0006] Fig. 1 shows the distribution of the average size of a substance in particles consisting of interferon, interleukin, oleic acid and poloxamer 470, determined by photon correlation spectroscopy.

[0007] Fig. 2 represents the distribution of the average size of a substance in particles consisting of interferon, interleukin, oleic acid, lecithin and poloxamer 470 determined by photon correlation spectroscopy.

[0008] Figure 3 shows the levels of interferon in the systemic circulation after parenteral administration of the pharmaceutical composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention, in one embodiment, relates to substances or particles consisting of fatty acids, phospholipids and poloxamers, which are a universal system for the delivery of genetically engineered drugs and peptides.

The present invention according to the second of the options relates to particles containing (a) interferon; (b) interleukin; (c) colony stimulating factor; (e) poloxamer; (e) fatty acid for treating human diseases, including the treatment of chronic viral hepatitis B and C.

In particular, the present invention relates to particles containing in its composition:

1. (a) interferon, (b) interleukin; (c) poloxamer; and (g) fatty acid;

2. (a) interferon, (b) interleukin; (c) poloxamer; (d) fatty acid; and (e) phosphotidylcholine or lecithin;

3. (a) interferon, (b) interleukin, (c) colony stimulating factor; (g) poloxamer; (e) fatty acid; and (e) phosphotidylcholine or lecithin;

4. These particles with interferon alpha, interleukin 1 beta and a colony stimulating factor have been developed for the treatment of human diseases, including the treatment of chronic viral hepatitis B and C; 5. Poloxamer, fatty acid and phospholipids are a universal delivery system that increases the transport of any biologically active genetically engineered drugs and peptides.

[0010] As used herein, the term “particles” refers to particles having an average size of from 1 to 350 nanometers.

[OOP] As used herein, the term “interferon” refers to interferon obtained using an interferon expression system, for example, in E. coli or yeast. Non-exclusive examples of interferons include interferon-a1pa2b, interferon-beta and interferon-gamma. As used herein, the term “interleukin” refers to interleukin obtained using an interleukin expression system, for example, in E. coli or yeast. Non-exclusive examples of interleukins include interleukin 1 alpha, interleukin 1 beta, interleukin 2, interleukin 4, interleukin 6, interleukin 8, interleukin 18.

[0012] In some preferred embodiments of the invention, interferon is selected from the group consisting of recombinant human interferon-a1bb2b, interferon-beta, and interferon-gamma.

[0013] The term “analogue” as used hereinafter refers to any interferon that contains one or more amino acid substitutions, deletions, additions or permutations of amino acids compared to natural interferon at such positions that the interferon analogue still retains in vivo biological activity of interferon .

[0014] The term “derivatives” as used herein refers to natural interferon and an interferon analog that are chemically or enzymatically modified at one or more amino acid residues, including side chain modifications, backbone modifications, and N- and C-terminal modifications, such as acetylation, acylation, hydroxylation, methylation, amidation, phosphorylation, pegylation, or glycosylation, and which are retained in vivo biological activity of interferon. Examples of such interferon derivatives are myristoyl-interferon and HisTag-interferon.

[0015] In some preferred embodiments of the invention, the particles comprise from about 0.000001 to 10% by weight of interferon; from about 5 to 70% by weight of poloxamer, and from 3 to 60% by weight of fatty acid.

[0016] As used herein, the term "poloxamer" refers to any non-ionic copolymer consisting of three blocks, namely a central hydrophobic chain of polyoxypropylene (polypropyleneoxide) located between two hydrophilic chains of polyoxyethylene (polyethylene oxide). Non-exclusive examples of poloxamer include 124 poloxamer, 188, 237, 338 and 407, which have been included in the US National Pharmacopoeia since 1990. Other examples of poloxamer are disclosed in US patent 3740421 and in the Handbook of biodegradable polymers. Domb AJ et al. Harwood Academic Publisher, 1997.

[0017] As used herein, the term "fatty acids" refers to any saturated or unsaturated aliphatic carboxylic acid consisting of 4-28 carbon atoms. Saturated fatty acids are long chain carboxylic acids, which typically have 12-24 carbon atoms and no double bonds. Non-exclusive examples of saturated fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid and arachidonic acid. Unsaturated fatty acids, unlike saturated fatty acids, have one or more double bonds. Non-exclusive examples of unsaturated fatty acids include myristoleic acid, palmitoleic acid, sapmenic acid, oleic acid, linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid.

[0018] Particles of the present invention may further comprise other ingredients. Such optional ingredients are typically used individually at a level of from about 0.0005% to 80.0% by weight of the particles.

[0019] Examples of optional suitable ingredients include, but are not limited to, phospholipids such as lecithin, phosphotidylcholine, and polymers such as poly (D, L-lactide) poly (ethylene glycol) -poly (D, L-lactide ) and polyvinylpyrrolidone.

[0020] Further, the present invention provides a method for producing particles comprising interferon, interleukin, poloxamer, and fatty acid, comprising the steps of: (a) preparing particles of a fatty acid emulsion in water; (b) the embedding of interferon and interleukin in the particles of the emulsion; (c) embedding the poloxamer in the particles of the emulsion; and (d) isolating the particles.

[0021] In some embodiments of the invention, the step of producing particles of a ^• fatty acid emulsion in water with a reproducible average particle size of 1 to 350 nanometers can be implemented using the Microfluidizer Processor MHO EN-30 (USA) device as described in Mayhew E. Lazo R, Vail WJ, King J, Green AM. Characterization of liposomes prepared using a microemulsifier. Biochim Biophys Acta. 1984, 775 (2): 169-74. Briefly, the emulsion is passed through a ceramic chamber of a specific shape at a speed of 500 m / s to obtain the desired particles of the emulsion.

[0022] In some embodiments of the invention, the step of incorporating interferon and interleukin into the emulsion particles can be implemented by methods well known in the art. Such methods include extruding an aqueous mixture of interferon and interleukin and lipids through filters with a progressive decrease in pore size from 400 nm to 200 nm, and then 100 nm; ultrasonic disintegration, as described in Martins S, et al., Lipid-based colloidal carriers for peptide and interferon delivery - liposomes versus lipid nanoparticles. Int J Nanomedicine. 2007; 2 (4: 595-607; and conjugation methods of interferons and interleukins with lipids.

[0023] In a preferred embodiment of the invention, the solubilized interferon with interleukin can be mixed with a fatty acid emulsion and the mixture is passed at a speed of 500 m / s through a Microfluidizer Processor MHO EN-30 ceramic chamber (USA) to obtain emulsion particles incorporated with interferon and interleukin with a reproducible average particle size of 1 to 350 nanometers.

[0024] In another preferred embodiment, the solubilized interferon with interleukin can be mixed with a fatty acid in water and the mixture is passed at a speed of 500 m / s through a ceramic chamber Microfluidizer Processor MHO EN-30 (USA) to obtain emulsion particles incorporated with interferon and reproducible average particle sizes of 1 to 350 nanometers.

[0025] In some embodiments of the invention, the step of embedding the poloxamer in the particles of the emulsion can be implemented by mixing the poloxamer with particles of a fatty acid emulsion with embedded interferon and interleukin and passing the mixture through Micro fluidizer Processor MHO EN-30 (USA) to obtain particles of a fatty acid emulsion with embedded interferon and interleukin and poloxamer with a reproducible average particle size of 1 to 350 nanometers.

[0026] In a preferred embodiment of the invention, the solubilized interferon with interleukin can be mixed with fatty acid and poloxamer in a predetermined ratio and the mixture is passed at a speed of 500 m / s through a ceramic chamber Microfluidizer Processor Ml 10 EN-30 (USA) to obtain particles of the invention with a reproducible average size of 1 to 350 nanometers.

[0027] Further, the present invention provides a pharmaceutical composition for parenteral administration, characterized in that the composition contains (a) particles that contain interferon, interleukin, poloxamer, and a fatty acid, and (b) a pharmaceutically acceptable carrier.

[0028] As used herein, the term "parenteral" refers to subcutaneous, intradermal, intravenous, intramuscular injection, as well as various infusion methods.

[0029] Due to the fact that proteins such as interferon and interleukin are embedded in the particles, the pharmaceutical compositions of the present invention have increased therapeutic efficacy. Compared with conventional injections of interferon and interleukin taken in the same dose, the introduction of interferon and interleukin embedded in the particles ensures a longer stay of interferon and interleukin in the systemic circulation in therapeutically effective concentrations, reduces the total number of injections to achieve an effective cure, improves the pharmacoeconomic indicators of treatment and provides convenience for the patient.

[0030] Due to the high stability and reproducibility of the particles consisting of fatty acid and poloxamer, the pharmaceutical compositions of the present invention do not have the usual practical problems associated with the use of particles containing drugs, such as problems with stability, reproducibility from batch to batch , difficulties with the choice of sterilization methods, low concentration of interferon in the particle, control of the average particle size, difficulty in producing large industrial quantities and is not long enough fractional lifetime of particles in the bloodstream.

[0031] Due to the fact that the particles formed by the fatty acid and poloxamer are biodegradable, the pharmaceutical compositions of the present invention are safe and well tolerated by the patient.

[0032] Due to the smaller average particle size of the particles formed by fatty acids and poloxamers compared to particles based on other lipids, the pharmaceutical compositions of the present invention can be effective for oral and external administration.

[0033] Further, the present invention provides a pharmaceutical composition for oral administration, characterized in that the composition comprises (a) particles that contain interferon, interleukin, poloxamer, and a fatty acid, and (b) a pharmaceutically acceptable carrier. [0034] Due to the fact that the particles formed by fatty acid and poloxamer are a delivery system that increases the transport of biologically active genetically engineered drugs, for example, active interferon and interleukin through the mucosa into the systemic circulation, the pharmaceutical compositions of the present invention can be orally administered in the form of tablets, capsules, dragees, powders, gels, syrups, and other conventional oral forms.

[0035] Further, the present invention provides a pharmaceutical composition for external administration, characterized in that the composition comprises (a) particles that contain interferon, interleukin, poloxamer, and a fatty acid, and (b) a pharmaceutically acceptable carrier.

[0036] Due to the fact that the particles formed by the fatty acid and poloxamer are a delivery system that increases the transport of biologically active interferon through the mucosa into the systemic circulation, the pharmaceutical compositions of the present invention can be administered externally in the form of gels, solutions, drops and other conventional external forms.

[0037] The compositions of the present invention can be obtained using procedures well known in the art. Such procedures include, but are not limited to, mixing particles with other ingredients of the composition in the usual way. Guidance on the preparation of the pharmaceutical compositions of the invention can be found in "Remington: The science and practice of pharmacy" 20th ed. Mack Publishing, Easton PA. 2000 ISBN 0-912734-04-3 and "Encyclopedia of Pharmaceutical Technology", edited bv Swarbrick. J . & JC Boylan. Marcel Dekker. Inc .. New York. 1988 ISBN 0-8247-2800-9 "or a newer version of this book. [0038] The term "pharmaceutically acceptable carrier" refers to a carrier that is compatible with active interferon, active interleukin, and is not harmful to the subject to be treated. Non-exclusive examples of such carriers include, but are not limited to, water for injection, mannitol, lactose, starch, talc, magnesium stearate, etc.

[0039] The following examples are presented to demonstrate the invention. The examples only illustrate the invention and do not limit the claimed scope.

Example 1

[0040] Preparation of particles containing human interferon-a1bpa2b (table 1) and particles containing interferon-a1bba2b and interleukin 1 beta (table 2).

Emulsions were obtained from a mixture of oleic acid and water in a mass ratio of 1: 4, pH 4.9 and using a Microfluidizer Processor MHO EN-30 device (USA). Lyophilized recombinant human interferon alpha2b was added to the emulsion and the mixture was subjected to a second particle preparation procedure using the Microfluidizer Processor Ml 10 EN-30 (USA). Emulsions underwent ultrafiltration. Pre-ultrafiltered poloxamer gel 470 was embedded in the particles of the emulsion. The particles thus obtained were lyophilized. Figure 1 shows the particle size distribution determined by photon correlation spectroscopy. The average particle size was about 50 nm and about 80% of the particles had an average particle size of 10 to 100 nm for particles derived from oleic acid and poloxamer 470 taken in a mass ratio of 1: 5. If desired, lecithin may be added during the preparation of the emulsion. Fig.1b shows the distribution of the average particle size prepared using lecithin in a mass ratio of 5: 1: 5 for lecithin, oleic acid, and poloxamer 470, respectively. The average particle size was about 75 nm. Thus, the use of fatty acid in combination with poloxamer provides smaller particles than those produced with the addition of lecithin. Tables 1 and 2 show the content of lyophilized particles in a dosage form.

Table 1

Ingredient Content of rh-Interferon alpha2b 3 million Units.

Oleic acid 20%

Poloxamer 470 about 80%

table 2

Ingredient Content of rh-Interferon alpha2b 3 million Units.

rh-Interleukin 1 beta 1.0 * 10 ⁵ units

Oleic acid 9%

Poloxamer 470 45%

Lecithin up to 100%

Example 2

[0041] Particles containing granules of an oocyte colony stimulating factor, human recombinant interferon beta, and gamma interferon.

Tables 3 and 4 show the lyophilized particles obtained by the method as described in example 1 in a dosage form.

Table 3 Ingredient rh-Interferon beta la content 30 mcg

Oleic acid 20%

Poloxamer 470 about 80%

Table 4

Ingredient Content of rh-interferon gamma 50 mcg

Oleic acid 20%

Poloxamer 470 about 80%

Table 5

Ingredient Content

G-CSF 2 million units.

Oleic acid 20%

Poloxamer 470 about 80%

Example 3

[0042] Improving the pharmacokinetics of a pharmaceutical composition containing particles according to Example 1.

A pharmaceutical composition containing particles in accordance with example 1 was prepared by dissolving a single dose of lyophilized particles containing 3 million Units. HR-interferon-alpha2b in 2 ml of water for injection (Table 6).

Table 6

Ingredient g-Interferon-a1bba2b (particles) 3 million units

Sodium Chloride 0.9%

The resulting solution was administered once subcutaneously to mice weighing 20-22 grams (n = 20) at a dose of 57 ng of interferon per mouse. Other mice received a single subcutaneous injection of physiological saline (n = 20), a control solution of interferon-a1bb2b 57 ng / mouse (n = 20), or pegylated interferon as a long-acting interferon (positive control). Plasma interferon levels were measured over 7 days. Although the administration of a control solution of interferon-a1ppa2b showed a significant increase in its plasma level on the first day, there was no difference in blood plasma on day 2 between the group receiving physiological saline and a solution of interferon-a1pa2b. This result indicates that interferon-a1bb2b is completely eliminated within 24 hours. However, the interferon-αlp2b embedded in the particles of the present invention showed a long-term increase in the level of interferon in the blood. Fig. 3 shows that a single administration of interferon-a! Pn2b embedded in the particles maintains a therapeutically effective level of interferon-alp2b in the blood for at least 5 days, which is comparable to the duration of action of pegylated interferon. Thus, an interferon pharmaceutical composition containing particles in accordance with the present invention has improved pharmacokinetic properties compared to a conventional interferon composition, maintains the desired therapeutic levels of interferon in the bloodstream for a long time, and can reduce the total number of injections, while maintaining the effectiveness of the treatment and pharmacoeconomic indicators.

Example 4 [0043] Demonstrates the oral pharmaceutical compositions of the present invention containing particles in accordance with examples 1 and 2. Table 6 shows an example of sublingual tablets containing particles with a therapeutically effective amount of interferon and interleukin.

Table 6

Ingredient Content,%

Particles of Examples 1 or 2 0.001-1

Citric Acid 0.8

Croscamelose Sodium 3.6

Magnesium Stearate 1.6

Mannitol to 100

Ingredients (other than the lubricant) were added to the V-blender (Patterson-Kelly V-blender) and mixed for about 15 minutes. After homogenization, a lubricant was added and the mixture was further stirred for about 3 minutes. The mixture was loaded into a press (Ayush Minipress-II, with Natoli punches and 0.2969 inch die) and adjusted to the desired tablet weight and thickness. The tablets were tested for pH, hardness, degradation, and impurity content.

Example 5

[0044] Demonstrates an external pharmaceutical composition of the present invention containing particles according to examples 1 and 2. Table 7 shows the composition of the external gel containing particles with a therapeutically effective amount of interferon.

Table 7

Ingredient Content,% Particles of Examples 1 or 2 0.100

Sodium Carboxymethyl Cellulose 2.400

Sodium Chloride 0.809

Sodium acetate trihydrate 0.157

Glacial acetic acid 0.007

Methylparaben 0.162

Propylparaben 0.018

t-cresol 0.090

L-Lysine hydrochloride 0.500

Water for injection up to 100

The gel is prepared by mixing the ingredients in water and gradually adding sodium carboxymethyl cellulose with constant stirring.

Example 6

[0045] Demonstrates the improved pharmacokinetics of the oral pharmaceutical composition of the present invention containing particles in accordance with example 1.

Particles according to example 1, filled with r-interferon-a1pn2b were injected into the oral cavity of mice (20-22 g of weight) at a dose of 57 ng interferon per mouse (n = 6). A control solution containing the same amount of rh-interferon-a1bba2b was administered to control mice. Plasma concentrations of interferon-αlp2b were measured 1 hour after administration. The plasma levels of interferon in the group receiving the particles turned out to be 47 ± 17% (the levels achieved by subcutaneous injection were taken as 100%), while the levels in the control group were below the detection limit of the method. Example 7

[0046] Demonstrates the improved pharmacokinetics of the external pharmaceutical composition of the present invention containing particles in accordance with example 1.

The gel according to example 5, containing particles filled with rh-interferon-a1pa2b was applied to the shaved back of mice (20-22 g weight) at a dose of 57 ng interferon per mouse (n = 6). A control gel containing the same amount of gp-interferon-a1ppa2b was applied to mice of the control group. Concentrations of interferon-a1bba2b in plasma were measured 1 hour after topical application. The plasma levels of interferon in the group receiving the particles turned out to be 21 ± 10% (the levels achieved by subcutaneous injection were taken as 100%), while the levels in the control group were below the detection limit of the method.

Distribution of results

Distribution of results

SUBSTITUTE SHEET (RULE 26)

Claims

CLAIM

1. Particles consisting of fatty acid, phospholipids and poloxamers, which are a universal delivery system for genetically engineered drugs and peptides.

2. Particles containing (a) interferon; (b) interleukin; (c) colony stimulating factor; (d) poloxamer; (e) fatty acid used to treat human diseases, including the treatment of chronic viral hepatitis B and C.

3. Particles according to 1 or 2, characterized in that they have an average particle size of from 1 to 350 nanometers.

4. Particles according to claim 2, characterized in that they contain from about 0.000001 to 10 wt.% Interferon; from 0.000001 to 10% by weight of interleukin, from about 5 to 70% by weight of poloxamer, and from 3 to 60% by weight of fatty acid.

5. Particles according to claim 2, characterized in that the interferon is selected from the group consisting of human recombinant interferon-a1ppa2b, interferon-beta or interferon-gamma.

6. Particles according to claim 2, characterized in that the interleukin is selected from the group consisting of human recombinant interleukin 1 alpha or interleukin 1 beta.

7. Particles according to 1 or 2, characterized in that the poloxamer is selected from the group consisting of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407.

8. Particles according to 1 or 2, characterized in that oleic acid is used as the fatty acid.

9. A method of producing particles according to claim 2, characterized in that it comprises the steps of: (a) preparing particles of a fatty acid emulsion in water; (b) the embedding of interferon and interleukin in the particles of the emulsion; (c) embedding the poloxamer in the emulsion particles; and (d) isolation of particles containing genetically engineered drugs.

10. A pharmaceutical composition for parenteral administration characterized in that it contains particles according to claims 1 or 2 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition for oral administration (oral administration) characterized in that it contains particles according to claims 1 or 2 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition for external use characterized in that it contains particles according to claims 1 or 2 and a pharmaceutically acceptable carrier.