Method for preparing vaccine composition containing at least one antigen and at least one adjuvant
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to biotechnology and immunology. What is presented is a method for preparing a vaccine with using reverse latex. The first stage involves preparing an adjuvant composition by dispersion of reverse latex or polymer powder prepared by reverse latex spraying, in a physiologically acceptable solution. The second stage involves mixing the prepared adjuvant composition with an antigen-containing medium for preparing the vaccine composition.
EFFECT: reverse latex adjuvant is characterised by higher safety and possesses the high adjuvant effect both at the level of the humoral response, and at the level of the cell response.
8 cl, 2 dwg, 3 ex
The invention relates to a method of obtaining a vaccine composition comprising at least one antigen and at least one adjuvant.
Development of inactivated vaccines or vaccines containing purified antigens, is becoming an increasingly important problem, as it allows to eliminate the side effects in a patient undergoing treatment. However, improving the quality of the antigens develops to the detriment of their immunogenic nature. For this reason, antigens associated with immune adjuvants.
Immune adjuvants are products that enhance the immune response when they are introduced in the presence of viral antigens, bacterial or synthetic origin. They provoke mass appearance of macrophages at the site of injection, and then in the lymph nodes, increase the production of specific immunoglobulins, antibodies and stimulate numerous cells involved in the mechanisms of immune protection.
These adjuvants are of diverse nature. They may, for example, be an emulsion of the type water-in-oil S/N, or oil-in-water N/E, or water-in-oil-in-water E/N/E, or oil-in-water-in-oil N/E N/.
Very effective adjuvants's adjuvant; they are obtained from a combination of mineral oil and a complex ester of mannitol, whether or not containing killed is micobacteria. Vaccine produced by mixing equal parts of the adjuvant's adjuvant with antigenaemia water environment, remain standards in the world for laboratory research. They are in the form of emulsions, water-in-oil (S/N), i.e. emulsions in which the continuous phase is an oil or mixture of oils, and the dispersed phase is an aqueous phase, which may include solubilizing excipients, such as, for example, glycerol or dimethyl sulfoxide. The active principle is usually localized in the aqueous phase, which is often buffered saline solution. This phase is in the form of drops, separated between an oil film. This part allows you to get stronger and longer lasting in time biological responses.
However, emulsions of this type of E/N are usually highly viscous emulsions, and therefore create difficulties when introducing them by injection. These emulsions are often forced to use a syringe with a large bore needle that is causing pain when injecting and injure the injection.
The mass content of the aqueous phase in the emulsion E/N for intravenous infusion is in the range of 30-40% on 100% of the emulsion. The maximum content can sometimes be up to 50% of the mass. However, this limit is the brake is brilliant moment in particular, for the development of polyvalent vaccines, in which there are multiple antigens and for which it is more preferable to obtain emulsion E/N content of the aqueous phase above 50 wt%.
However, in the emulsion E/N with the low content of the aqueous phase, reaching up to 20 wt. -%, the viscosity of the emulsion is very close to the viscosity of the oil. The increase in the mass fraction of the aqueous phase increases the viscosity. For this reason emulsion with 20% of the mass. water, having a viscosity of 100 MPa·s, measured using a BROOKFIELD viscometer LVT with engine No. 2, rotating at 60 revolutions per minute, turns into a creamy mass, which with great difficulty administered by injection once the water content is increased to 50 wt%.
Some oil adjuvants produced in the sale are in the form of emulsions E/N, such as MONTANIDETMISA 70, which provide injectable emulsion E/N, containing about 30% of the mass. the aqueous phase, 70% of the mass. oil phase and having a viscosity of about 50 to 100 MPa·s, measured using a BROOKFIELD viscometer LVT with engine No. 2, rotating at 60 revolutions per minute. Other adjuvants, such as MONTANIDETMISA 50V2, allow to obtain injectable emulsion E/N, containing about 50 wt%. the aqueous phase, 50 wt%. oil phase and having a viscosity lower than 250 MPa·s, measured using viscos the meter BROOKFIELD LVT, equipped with engine No. 2, rotating at 60 revolutions per minute.
In the international patent application published under number WO 99/20305, disclosed the use of surfactants, including mannitol oleate, mineral oils, such as MARCOLTM52, to obtain emulsions, called liquidwith a viscosity of about 500 MPa·s, measured using a BROOKFIELD viscometer LVT with engine No. 2, rotating at 60 revolutions per minute.
The concept of liquid emulsion depends to a large extent on the scope of its application. As for injectable emulsions, the upper limit of viscosity for liquid emulsions are defined relative to the viscosity of the emulsion type E/N, is used as standard, which contains 50 wt%. the aqueous phase and 50 wt%. incomplete adjuvant's adjuvant (IFA); the viscosity measured using a BROOKFIELD viscometer LVT with engine No. 3, rotating at 30 rpm is about 2000 MPa·C. This emulsion is considered as a very viscous.
Emulsion type E/N will be called liquid, if its viscosity is 4 times smaller than the viscosity of a standard emulsion, i.e. below 500 MPa·s at 25°C. measured using a BROOKFIELD viscometer LVT with engine No. 2, rotating at 30 revolutions per minute.
However, liquid emulsions are generally less stable than more viscous emulsions, because after only a few days after their receipt of the observed phase separation at room temperature.
There are polymers, thickening the aqueous phase and are in the form of powders, such as homopolymers of acrylic acid in the sodium form or copolymers based on acrylic acid and its esters. Can be called, for example, polymers produced by a Noveon under the trademark CARBOPOLTMand PEMULENTM. They are described in particular in U.S. patents US 5373044, US 2798053 and in the European patent EP 0310532. These polymers were originally developed as thickeners designed for thickening compositions intended primarily for cosmetic purposes, and is described and used for several years. These polymers derived from monomer, such as, for example, acrylic, methacrylic acid, esters of acrylic acid or methacrylic acid, dissolved in a medium of an organic solvent. During the polymerization reaction occurring after the addition of various catalysts under specific conditions of temperature and pressure, the polymer becomes insoluble state from the initial environment of the solvent and precipitates on the bottom of the reactor. This method is called "polymerization deposition".
Obtained in such Obratnaya, of which the most famous are the polymers CARBOPOL brand®have proven to be very effective and are widely used in cosmetics. These polymers are also used for various pharmaceutical purposes:
- obtaining the polymer matrix to achieve a delayed release
- obtaining a polymer gel and the formation of complexes of these polymers with proteins,
- receiving polymer films that provide protection during contact with biological media,
- getting bioadhesive compositions, providing the greatest residual deformation when applied to mucous membranes,
- getting adjuvants for vaccines.
The use of polymers as adjuvant for vaccines at the end of the mass content of the polymer order "percent" is in the form of a liquid, transparent and easily injectable vaccine.
Adjuvant properties of synthetic substances are closely related to their physical form introduction. Thus, the size of the particles used to create a significant adjuvant effect, is the main parameter that can control the ability to perform the functions of immunocompetent cells. In addition, depending on the size of the particles also creates the possibility of orienting response to the production of antibodies (humoral immune response) and what and also to stimulate specific cells of the immune system (cellular immune response). Synthesis of microspheres of various polymers in the solvent environment in the form of dispersions are widely described in the literature and creates the possibility of encapsulating biologically active agent (which may be the antigen in the case of vaccines) or serves as an adsorption substrate for transport and presentation of the active agent connected to the external surface of the microspheres by using more or less strong interaction forces.
The regulation of the particle size of the adjuvant always remains an unsolved problem, since it must be solved simultaneously with the stability of the adjuvant particles in time. In particular, it is important to avoid aggregation of particles during storage and separation of phases. The regulation of the particle size must also be accompanied by the stability of the composition after injection of a living being, in particular, in connection with the stresses to which they are exposed because of a change in pH, presence of enzymes and temperature changes.
Therefore, the applicant has set a task to develop an original method of polymer synthesis, allowing you to control the size of the agglomerates of the polymer (or "microgels"), which would allow to achieve a very good adjuvant characteristics. To solve this problem, technology was used polymerization in emulsion water-in-oil S/N or inverse emulsion to obtain this floor is Mer. Thus, the size of the monomer droplets of the solution is controlled by the use of emulsifying surfactant system of the type water-in-oil adapted to the technology of producing emulsions E/N. We are talking mainly about the combination of lipophilic emulsifying surfactants having, for example, the number of products HLB of 2 to 7, with hydrophilic emulsifying surface-active substance with, for example, the number of products HLB of 10 to 15, with the average weightedproviding the achievement of a homogeneous emulsion E/N. Polymerization of the monomers occurs when adding catalysts and other cross-linking agents in the usual concentrations, under conditions of pH and temperature, suitable for complete reaction of the monomer prior to the formation of polymers.
The particle size of the adjuvant has a direct impact on the immunological properties of the compositions which contain them. In addition, depending on the patient, the subject of vaccination, and the type of the vaccine may vary, the optimal particle size. Thanks to special technology of preparation of emulsions (optimization products HLB, the nature of the surfactant concentration, method of production) became possible in the process of polymerization in inverse emulsion to affect the distribution of the particles of the emulsion in size and, thus, to adjust the average size and particle size distribution agglom the drugs. Under the variance of the mean, depending on the content of surface-active substances and energy shift arising from the emulsification, heterogeneous systems, which can be
These various dispersed forms allow you to adjust the dispersion of the particles of the microgels in the range from 50 nm to 100 μm.
Chemical conditions of synthesis of the polymer (type monomers, catalysts, initiators) allow you to control individual properties of the obtained polymer (average molecular weight, degree of crosslinking, anionic character).
Synthesized thus adjuvant is in the form of an emulsion type "drops of polymer in oil" or "reversible latex". When the emulsion is dispersed in an aqueous solution of the antigen containing physiological buffer is the address of the emulsion, it is dispersed to form a liquid and transparent dispersion of polymer microgels in water. For example, drops microgels polyacrylate sodium can have an average size in the range of 0.5-5 micrometers, such as about 2 micrometers.
Reversible latexes and methods for their preparation are described, for example, in WO 99/36445 (see, in particular, the examples on page 9 and subsequent WO 99/36445).
The invention relates to a method of obtaining a vaccine that uses reversible latex. More specifically, izaberete the s refers to the manner of receiving the vaccine, including
- stage a) receiving adjuvant compositions by dispersion in a physiologically acceptable aqueous solution of at least one reversible latex or polymer powder obtained by atomization of the specified reversible latex;
- phase b) mixing the composition obtained in stage a), in antigenaemia environment intended for the formation of a vaccine composition.
Under reversible understand latex emulsion polymer water-in-oil, in which the aqueous phase, dispersed in a continuous oil phase that contains the specified polymer. Reversible latex obtained by polymerization in inverse emulsion is thus in the form of a liquid emulsion. Subsequent dispersion obtained reversible latex, if necessary or if desired, may be carried out in order to obtain the above-mentioned powder. Sputtering is described, for example, in European patent EP 149081.
Under water physiologically acceptable solution is understood in the framework of the present invention aqueous solutions which are suitable for the production of vaccines, it may be, for example, water, the quality of which corresponds, for example, European and American pharmacopoeias, such as physiological serum, or it can be saline solutions and/or, if necessary, water-alcohol solutions, appropriate to eastwoodiae these pharmacopoeias.
Under the adjuvant composition mean the immune adjuvant composition.
You can also add at least one surfactant hydrophilic character before stage a) to improve the stability of such dispersions in time.
Under the surface-active substance is hydrophilic nature imply emulsifying surfactants having the number of products HLB, is quite high, from 10 to 15, in order to obtain a stable emulsion of oil-in-water, such as ethoxylated esters mannitan, ethoxylated esters sorbitan, such as oleate sorbitan, ethoxylated 20 mol of ethylene oxide, manufactured by SEPPIC under the name MONTANOXTM80.
Under antigenaemia environment means the environment including at least one antigen or at least one generatorin vivocompounds containing the amino acid sequence. Under the antigen or at least one generatorin vivocompounds containing the amino acid sequence, mean or killed microorganisms, such as viruses, bacteria or parasites, or purified fractions of these organisms, or living microorganisms, the pathogenicity of which Attenborough. As examples of viruses that represents the antigen according to the invention, the can is to call the rabies virus, the herpes viruses such as the virus of Aujeszky's disease, orthomyxovirus,such asinfluenza virus, picornaviruses such as virus aphthous fever, or retroviruses, such as HIV virus. As bacterial microorganism type, which may be an antigen according to the present invention, can be calledE. coliand microorganisms of the speciesPasteurella, Furonculosis, Vibriosis, Staphylococcus and Streptococcus. As examples of parasites can be called parasitesTrypanosoma, PlasmodiumandLeishmania. May also be called recombinant viruses, in particular viruses without shell, such as adenoviruses, vaccinia virus, the virusCanarypox, the herpes viruses or baculoviruses. You can also call thethe recombinant vector of the live virus without shell, the genome of which, built in, preferably, in minor part to replicate the corresponding virus with the envelope contains a sequence encoding a subunit antigen, inducing the synthesis of antibodies and/or protective effect against a given virus shell or pathogen; these subunits antigens can be, for example, protein, glycoprotein, peptide or peptide and/or protective faction against infections caused by a living microorganism such as a virus shell, bacterium or parasite. Exogenous gene introduced into a microorganism, may be the separation of the n, for example, the virus of Aujeszky's disease or HIV.
Can be called, in particular, a recombinant plasmid comprising the sequence of nucleotides in which the integrated exogenous nucleotide sequence originating from a pathogenic microorganism or virus. This latter nucleotide sequence is intended to ensure the expression of compounds containing the amino acid sequence, but this connection is used to start an immune reaction in the body-master.
Under generatorin vivocompounds containing the amino acid sequence, understand any biological product, capable to Express the connection specified in the body of the host, in which is entered the specified generatorin vivo. The compound containing the amino acid sequence may be a protein, peptide or glycoprotein. These generatorsin vivousually get methods based on genetic engineering. More specifically, these methods consist in the use of living organisms, usually of the virus, plays the role of a recombinant vector, which embed the nucleotide sequence, in particular an exogenous gene. These compounds are known as such and are used, in particular, as a recombinant subunit vaccine.On this issue can solat is concentrated in the article M. ELOIT et al., Journal of virology (1990) 71, 2925-2431, and international patent applications published under the numbers WO-A-91/00107 and WO-A-94/16681. Generatorsin vivoaccording to the invention can be a recombinant plasmid containing an exogenous nucleotide sequence, is able to Express in the body-the owner of the connection, comprising the amino acid sequence. Such recombinant plasmids and the method of their introduction into the organism-owner described in 1990, LIN et al., Circulation 82: 2217, 2221; COX et al., J. of VIROL, Sept. 1993, 67, 9, 5664-5667, and in the international application published under the number WO 95/25542. Depending on the nature of the nucleotide sequence located in the generatorin vivothe compound containing the amino acid sequence that is expressed inside the host body, may
(i) to be the antigen and initiate immune responses
(ii) to provide a therapeutic effect against the disease, mainly of the disease with functional character, which develops in the body of the host. In this case, the generatorin vivoallows to treat the master method of gene therapy.
For example, such therapeutic effect may lie in the synthesis generatorin vivoof cytokines such as interleukins, in particular interleukin 2. These substances can trigger or amplify an immune response directed aselective destruction of cancerous cells.
Vaccine composition described above, includes the antigen concentration, which depends on the nature of the antigen and the nature of the patient's body. Especially it should be noted that the adjuvant according to the invention can significantly reduce the usual dose of antigen. Adequate concentration of antigen can be determined by a specialist in the classical way. Usually this dose is 0.1 mg/cm3to 1 g/cm3more specifically, from 1 μg/cm3up to 100 mg/cm3. The concentration of the specified generatorin vivoin the composition according to the invention depends, inter alia, on the nature of the specified generator and the host body into which it is introduced. This concentration can easily be determined on the basis of routine experiment. For example, when a generator in vivo is a recombinant microorganism, its concentration in the composition according to the invention is, as a rule, the interval from 102up to 1015microorganisms/cm3preferably from 105up to 1012microorganisms/cm3. When generatorin vivois a recombinant plasmid, its concentration in the composition obtained according to the invention, may range from 0.01 g/DM3to 100 g/DM3. The vaccine described above, is prepared by mixing environment containing adjuvant, and environment, tereasa antigen, adding optional water or dilution pharmaceutically acceptable environment.
Continuous oil phase used to obtain reversible latex used in stage a) of the method according to the invention, includes one or more compounds selected from oils of mineral, vegetable or animal origin, complex alilovic esters of these oils, complex alilovic esters of fatty acids or simple alilovic esters of fatty acids, esters of fatty acids and polyols or ethers of fatty alcohols and of polyols, synthetic oils.
Can also be used commercially available mineral oil, i.e. commercially available mineral oil containing saturated hydrocarbons, such as paraffins, ISO, cycloparaffin having at room temperature a density of from 0.7 to 0.9 and a boiling point above 180°C, such as, for example, EXXSOLTMD 100 S or MARCOLTM52, manufactured by EXXON CHEMICAL, isohexadecane or isododecane or a mixture of several of the above mentioned oils.
According to a preferred aspect of the present invention the oil phase consists of MARCOLTM52 or isohexadecane; isohexadecane, which is identified in the registration system Chemical Abstracts number RN=93685-80-4, is a mixture of isoparaffins12With16and C20, with whom containing a series of not less than 97% isoparaffins 16among which the main component is 2,2,4,4,6,8,8-heptamethylnonane (RN=4390-04-9). It is produced in France by the firm BAYER. MARCOLTM52 is a commercially available oil, the appropriate definition of vaseline oils in the French Pharmacopoeia Codex. It is a white mineral oil meets FDA regulations 21 CFR 172.878 and CFR 178.3620 (a) and recorded in the Pharmacopoeia, the US XXIII (1995) and in the European Pharmacopoeia (1993).
As examples of oils of vegetable origin can be called peanut butter, olive oil, sesame oil, soybean oil, wheat germ oil, grape seed oil, sunflower oil, castor oil, linseed oil, soybean oil, corn oil, copra oil, palm oil, walnut oil, hazelnut oil, rapeseed oil or squalene or squalane plant origin, manufactured in France by the company SOPHIM under the name PHYTOSQUALANTMidentified registration system Chemical Abstracts number RN=11-01-3 and consisting of a mixture of hydrocarbons containing more than 80% of the mass. 2,6,10,15,19,23-hexamethyltetracosane.
As examples of oils of animal origin can be called spermaceti oil, oleic acid, squalane or squalene extracted from the liver of fish.
As examples of complex alilovic esters oilscan be called methyl complex is new, ethyl, propyl ethers, linear or branched, or butyl esters, linear or branched, these oils.
As fatty acids, are suitable for obtaining the above-mentioned esters, can be called, more specifically, fatty acids containing 12-22 carbon atoms, such as, for example, myristic acid, palmitic acid, oleic acid, ricinoleic acid or ezoterikova acid, and, mainly, fatty acid, which is liquid at 20°C.
As examples of esters of fatty acids or ethers of fatty acids is a complex alkalemia esters of fatty acids, such as etiloleat, methyl oleate, isopropylmyristate or octylpyrimidine, esters of fatty acids and polyols or ethers of fatty alcohols and polyols, such as monoglycerides of fatty acids, diglycerides of fatty acids, triglycerides of fatty acids, esters of fatty acids and polyglycerol or esters of fatty acids and propylene glycol, more specifically, esters of fatty acids with exolon, such as, for example, sorbitol or mannitol, esters of fatty acids with the anhydride of hexol such as sorbitan or mannitan.
As examples of synthetic oils can be called hydrogenated polydecene orhydrogenated polyisobutene manufactured in France by Ets B. Rosso et Cie under the name PARLEAM - POLYSYNLANETMquoted Michel and Irene Ash, “Thesautus of Chemical Products, Chemical Publishing Co., Inc. 1986, volume 1, str (ISBN 0 7131 3603 0).
In the framework of the present invention a continuous oil phase used to obtain reversible latex used in stage a) of the method according to the invention may contain only one of the compounds listed above, or a mixture of several compounds, above.
The proportion of oil phase in the inverse latex is 10-50 wt. -%, preferably, 15-25% of the mass. from the total mass reversible latex.
At least one of the above polymer obtained by polymerization in inverse emulsion, leading to reversible latex underlyingreceiving adjuvant composition at the stage a) of the method according to the invention are selected from anionic polyelectrolytes, branched or crosslinked selected from copolymers of acrylic acid and 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid (AMPS), copolymers of acrylamide and 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid, copolymers of 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid and (2-hydroxyethyl)acrylate, homopolymer 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid, partially or completely translated into salt, homopolymer acrylic acid, partially or completely translated into salt, homopolymer m is acrylaway acid, partially or fully translated in salt, copolymers of chloride of acrylonitrilebutadiene and acrylamide, copolymers of AMPS and of vinylpyrrolidone, copolymers of AMPS and of N-methylacrylamide, copolymers of AMPS and N,N-dimethylacrylamide, copolymers of AMPS and of methacrylamide, copolymers of AMPS and of N-isopropylacrylamide, copolymers of AMPS and of N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]propenamide [or Tris(hydroxymethyl)acrylamidoethyl, or N-Tris(hydroxymethyl)methylacrylamide, also denoted TNUM], copolymers of acrylic acid and acrylamide, copolymers of acrylic acid and N-methylacrylamide, copolymers of acrylic acid and N,N-dimethylacrylamide, copolymers of acrylic acid and methacrylamide, copolymers of acrylic acid and N-isopropylacrylamide, copolymers of acrylic acid and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]propenamide [or Tris(hydroxymethyl)acrylamidoethyl, or N-Tris(hydroxymethyl)methylacrylamide, also denoted TNUM], copolymers of acrylic acid and alkylacrylate, hydrocarbon chain containing from ten to thirty carbon atoms, copolymers of AMPS and of alkylacrylate, hydrocarbon chain containing from ten to thirty carbon atoms.
Under the branched polymer understand the non-linear polymer which has side chains, which are able, when this polymer is water in plants is arandom condition, to create a highly branched structure,which leads to very high viscosities at low velocity gradient.
Under the crosslinked polymer understand the nonlinear polymer, in the form of three-dimensional mesh structure, insoluble in water, but capable in the water to swell and, therefore, form a chemical gel.
If this crosslinked polyelectrolyte, preferably, sew it Diethyleneamineor polyethyleneimine compound, the molar content of which is expressed relative to the monomers used is 0.005 to 1%, preferably from 0.01 to 0.2%, more preferably from 0.01 to 0.1%. Preferably, a crosslinking agent and/or Razorbladeagent, preferably selected from ethylenglykolether, dietilenglikoluretan, diallylamine sodium, etilenglikolevye, dialymotion, triallylamine, trimethylolpropane or methylene-bis-(acrylamide), allilohreos.
When reversible latex is used at the stage of receiving adjuvant composition, i.e. stage a) of the method according to the invention, it contains, as a rule, from 1 to 5% of the mass. emulsifying system of the type water-in-oil (S/N).
Under the emulsifying system of the type water-in-oil (S/H) mean in the context of the above definitions or only one surfactant or mixture of surfactants, provided the above mixture should be set to the number of products HLB, low enough to initiate the formation of emulsions, water-in-oil. As the emulsifying agent of the type water-in-oil may be called, for example, esters sorbitan, such as oleate sorbitan, such as the oleate sorbitan manufactured by the company SEPPIC under the name MONTANETM80, isostearic sorbitane, as, for example, isostearic sorbitan manufactured by the company SEPPIC under the name MONTANETM70, or sesquioleate sorbitan, as, for example, sesquioleate sorbitan manufactured by the company SEPPIC under the name MONTANETM83. There are also some polyethoxysiloxane esters sorbitan, for example ethoxylated (5 mol) monooleate sorbitan, such as manufactured by SEPPIC under the name MONTANETM81, or ethoxylated (5 mol) of isostearic sorbitan, such as manufactured by SEPPIC under the name MONTANETM71. Also include ethoxylated (2 mol) ileocecectomy alcohol, such as manufactured by SEPPIC under the name SIMULSOLTMOC 72, polyesters with molecular weight from 1000 to 3000, representing the condensation products of poly(isobutene)salcinovic acid or its anhydride with diethanolamine, such as HYPERMERTM2296, manufactured by UNIQEMA, or block copolymers with a molecular weight of from 2500 to 3500, such as HYPERMERM V manufactured by UNIQEMA, or SIMALINETMIE 200, manufactured by SEPPIC.
When reversible latex is used at the stage of receiving adjuvant composition, i.e. at the stage a) of the method according to the invention, it usually contains 2-8% of the mass. emulsifying system of the type oil-in-water (H/E).
Under the emulsifying system of the type oil-in-water (H/E) denote in the context of the above definitions or only one surface-active agent or mixture of surface-active substances, provided that the mixture should be set to the number of products HLB, high enough to initiate the formation of emulsions of oil-in-water. As the emulsifying agent of the type oil-in-water can be called, for example, ethoxylated esters sorbitan, such as oleate sorbitan, polyethoxysiloxane 20 mol of ethylene oxide, manufactured by SEPPIC under the name MONTANOXTM80, laurate sorbitan, polyethoxysiloxane 20 mol of ethylene oxide, manufactured by SEPPIC under the name MONTANOXTM20, castor oil, polyethoxysiloxane 40 mol of ethylene oxide, sold under the name SIMULSOLTMOL50, ethoxylated 10 mol readarray alcohol, manufactured by the company SEPPIC under the name SIMULSOLTMOC 710, ethoxylated (7 mol of lauric alcohol, sold under the name SIMULSOLTMP7, or monostearate sorbitan, p is latexjerry 20 mol of ethylene oxide, manufactured by SEPPIC under the name MONTANOXTM60.
Used a polymer obtained by the emulsion polymerization, leading to reversible latex underlying receiving adjuvant compositions obtained in stage a) of the method according to the invention, primarily selected from the group consisting of homopolymer acrylic acid, partially or completely translated into salt, homopolymer methacrylic acid, partially or completely translated into salt, copolymers of acrylic acid and 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid, copolymers of acrylamide and 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid, copolymers of 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid and (2-hydroxyethyl)acrylate, and more preferably, sodium polyacrylate.
Mass fraction of at least one reversible latex in the adjuvant compositions obtained in stage a) of the method according to the invention is 0.5 to 30% by weight of the total adjuvant compositions, mainly, 5-15% of the total mass of the adjuvant composition.
At the stage a) of the method according to the invention can be added immunostimulatory substance. Immunostimulatory substance may be selected, for example, from one or more well-known agents, immune stimulants, such as AvridineTMN,N-deok Adell-N',N'-bis(2-hydroxyethyl)propandiamine, derivatives of MDP (muramyldipeptide), in particular threonyl-MDP derived mullinavat acid or derivatives of Lipid-A. More specifically, this substance is a substance inisheer. Ionithermie substance is chosen, for example, from one or more water-soluble organic salts formed with metal cations,such as, for example, soluble calcium gluconate, magnesium gluconate, salicylate of aluminum or aluminum acetate.Whenadjuvant composition according to the invention includes pharmaceutically acceptable salt, this salt is at a concentration of 0.02-3000 mg/cm3preferably 0.1 to 1000 mg/cm3more preferably, 0.1 to 150 mg/cm3. You can also use and insoluble salts, usually as immune adjuvants such as aluminum hydroxide or phosphate of calcium.
According to a variant of the invention at the stage a) add at least one surfactant with hydrophilic character, intended to stabilize the emulsion. The value of products HLB number of at least one surfactant with hydrophilic character is from 10 to 15.
The composition obtained in stage a)contains 0.1 to 15% of at least one surfactant, preferably 0.1 to 5% of at least one surface-active substance.
In the context of Exte of the present invention is the number of products HLB surfactants are calculated according to the formula products HLB=20(1-I s/Ia), where Isdenotes the index of saponification and Iadenotes the index of the acidity of the fatty acid used to obtain the surface-active substances. In the case of using a mixture of surface-active substances, the products HLB value of the mixture is calculated as the weighted average sum of products HLB of each surfactant. These two indicators, i.e. the index of saponification and the acidity index, determined according to the methods described in the European Pharmacopoeia.
According to another specific variant of the invention, the composition obtained in stage a) of the method according to the invention has a mass content of the oil phase from 0.1 to 5% by weight of the total composition obtained in stage a) of the method according to the invention, preferably, 0.2 to 1% of the mass.
Used surfactant with hydrophilic character is usually chosen from the modified fatty substances.
Modified fatty substances used in the present invention, can be of mineral, vegetable or animal origin. As modified fatty substances of mineral origin used oil received from the oil.
As modified fatty substances of vegetable origin used, for example, peanut, olive, sesame, soy wheat germs, grapeseed, sunflower, castor, linseed, soybean, corn, copra, palm, hazelnut oil, walnut oil or modified rapeseed oil.
As modified fatty substances of animal origin are used, for example, modified squalane, modified squalene, modified spermaceti oil or modified animal fat.
Under the modified fatty substances implies, in particular, alkoxysilane derivatives of fatty substances, more specifically, alkoxysilane derived oils or alkoxysilane derivatives complex alilovic esters of oils, more specifically, ethoxylated and/or propoxycarbonyl derived oils or ethoxylated and/or propoxycarbonyl derivatives of methyl, ethyl, propyl, linear or branched esters or butyl, linear or branched esters of these oils. More specifically, the invention relates to the composition described above, in which a modified fatty substance selected from the ethoxylated derivatives of the oils, in which the number of moles of ethylene oxide is 1-10.
Under the modified fatty substances include esters of fatty acids and polyols or ethers of fatty alcohols and polyols, is more specifically esters of fatty acids with exolon, such as, for example, sorbitol or mannitol, or esters of fatty acids with the anhydride of hexol,such as sorbitan or mannitan, alkoxysilane derivatives of esters of fatty acids and polyols or alkoxysilane derivatives ethers of fatty alcohols and polyols, such as triglycerides alkoxysilane fatty acids, alkoxysilane esters of polyglycerol and fatty acids, more specifically, alkoxysilane esters of fatty acids with exolon, such as, for example, sorbitol or mannitol, or alkoxysilane esters of fatty acids with the anhydride of hexol, such as sorbitan or mannitan with the number of mol of ethylene oxide of 1 to 20.
Under the esters of fatty acids and polyols mean in the scope of the present invention complex monetary fatty acids and polyols or polyesters of fatty acids and polyol, such as, for example, a complex diesters of fatty acids and polyols or complex truefire fatty acids and polyols. The same applies to polyalkoxysiloxanes derived above esters.
Under ethers of fatty acids and polyols mean in the scope of the present invention a simple monetary fatty acids and polyols or polyether fatty acid and a polyol, such as, for example, simple on the esters of fatty acids and polyols or simple truefire fatty acids and polyols. The same applies to polyalkoxysiloxanes derived above ethers.
Modified fatty substances can be chosen from ethoxylated derivatives of esters of fatty acids and polyols or ethoxylated derivatives ethers of fatty alcohols and of polyols, more specifically, of ethoxylated esters of fatty acids with exolon, such as, for example, sorbitol or mannitol, or ethoxylated esters of fatty acids with the anhydride of hexol, such as sorbitan or mannitan with the number of mol of ethylene oxide from 5 to 10.
As fatty acids suitable for the production of modified fatty substances described above, suitable fatty acids containing 12-22 carbon atoms, such as, for example, fatty acids containing 16 to 18 carbon atoms, such as oleic acid, ricinoleic acid or ezoterikova acid, and, mainly, fatty acid, which is liquid at 20°C.
According to a variant of the invention at the stage b) add at least one immunostimulating agent is selected from saponin, animal and/or vegetable and/or mineral and/or synthetic oils, surfactants, aluminum hydroxide, lecithins and derived lecithin.
According to a particular variant of the invention, the vaccine obtained in stage b), with the holds from 10 to 20% of the drug, obtained in stage a), and from 80 to 90% antigenaemia environment.
Vaccine composition described above, can be used as a prophylactic or therapeutic agent. Depending on the nature of the antigen or generatorin vivothe composition according to the invention can be introduced fish, crustaceans, such as shrimp, domestic birds, particularly geese, Turkey, pigeons and chickens, animal family dog, such as dog, an animal of the cat family, such as cat, pigs, primates, cattle, sheep, horses, rodents such as rat, lagomorphs, such as rabbit, the family of goats and sheep, large mammals such as elephants. The composition according to the invention can also be entered to people.
The introduction of the composition can be performed by classical routes, such as parenteral, in particular, by subcutaneous, intramuscular or intravenous injection. The introduction may also be administered by oral, nazalnam through the eyepiece by immersing or rinsing.
The invention relates also to the use of the adjuvant composition, obtained according to stage a) of the method described above for obtaining a vaccine composition.
The percentage of ingredients given in the text of the invention, represent the mass fraction.
The applicant Noida is but found that compared adjuvant properties of dispersions of reversible latex with polymers of the same chemical composition but obtained by polymerization in the environment of the solvent followed by precipitation, showed a very high adjuvant effect on the level of humoral response (figure 1), and at the level of cellular response, accompanied with high security adjuvant (chart 2).
The following examples illustrate the invention without limiting its scope.
Example 1: Adjuvant composition based on sodium polyacrylate, obtained in the emulsion water-in-mineral oil
Use liquid mineral oil Marcol® 52”manufactured by EXXON. The emulsion polymer obtained after polymerization is in the form of white viscous oil gel. The composition of the emulsion is 30% mineral oil (continuous phase), 5% surface-active substances, intended to stabilize the emulsion, 25% of sodium polyacrylate and 40% water. When contacting with an aqueous solution of the antigen, buffered to pH 7, and when the concentration of the buffer 3%, is the treatment of the emulsion polymer in the oil to form a liquid dispersion containing traces of oil.
Example 2: Vaccine adjuvant based on sodium polyacrylate obtained by emulsion polymerization
Dispersion in water, sotiriadou the 10% polymer, described in example 1, get with satisfactory mechanical stirring. The viscosity of the dispersion adjust by adding inert inisheer substances (salts) (e.g., sodium chloride) or immunostimulating agents (such as magnesium gluconate). The obtained gel ready for use, can be re-dispersed to the desired concentration in a given antigenaemia environment. The gel can also add additional surfactants, designed to stabilize the dispersion of oil in water.
Example 3: Vaccine containing sodium polyacrylate obtained by the emulsion polymerization
A vaccine consisting of 85% antigenaemia environment, enter 15% of the preparation described in example 2. You can add other immunostimulatory substances, such as, for example, saponins, animals, and/or vegetable and/or mineral and/or synthetic oils, surfactants, aluminum hydroxide, lecithin and derivatives of lecithin.
1. The method of obtaining the vaccine, including
- stage a) receiving adjuvant composition by dispersing in an aqueous physiologically acceptable solution reversible latex or polymer powder obtained by atomization of the specified reversible latex;
- phase b) mixing the composition obtained in stage a), with the anti-Christ. esterase environment, intended to receive the vaccine composition.
2. A method of obtaining a vaccine according to claim 1, characterized in that at least one designated reversible latex contains at least one anionic polyelectrolyte, branched or crosslinked selected from the group consisting of homopolymer acrylic acid, fully or partially translated into salt, homopolymer methacrylic acid, fully or partially translated into salt, copolymers of acrylic acid and 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid, copolymers of acrylamide and 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid, copolymers of 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid and (2-hydroxyethyl)acrylate.
3. A method of obtaining a vaccine according to claim 2, characterized in that the anionic polyelectrolyte, branched or crosslinked, obtained by polymerization in inverse emulsion, leading to reversible latex, is a homopolymer of acrylic acid, fully or partially translated into salt.
4. A method of obtaining a vaccine according to claim 1, characterized in that stage a) add at least one immunostimulatory substance.
5. A method of obtaining a vaccine according to claim 1, comprising at least stage
mix 10-20% of the adjuvant composition obtained in stage a), with 80-90% antigenaemia environment.
Cab getting the vaccine according to claim 1,
additionally, including the implementation of stage b)
- the stage at which introduce at least one immunostimulatory substance is selected from saponin, animal and/or vegetable and/or mineral and/or synthetic oils, surfactants, aluminum hydroxide, lecithins and derived lecithin.
7. The use of adjuvant compositions obtained in stage a) of the method according to any one of claims 1 to 6, to obtain the vaccine composition.
8. Applying at least one reversible latex or polymer powder obtained by atomization of the specified reversible latex, to obtain the vaccine method according to claim 1.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry, namely to an extract of one or more bacterial strains Lactobacillus. The extract of one or more bacterial strains Lactobacillus representing a soluble extract, wherein the extract contains chemically modified bacterial molecules prepared by the action of an alkaline medium on one or more bacterial strains Lactobacillus; the extract is effective in treating diseases associated with the anti-inflammatory cytokine production imbalance. A method for preparing the extract of one or more bacterial strains Lactobacillus. A pharmaceutical composition effective for reducing at least one symptom associated with at least one condition specified in a respiratory disorder, an allergic condition, an urinary disorder and a gastric disorder, containing the extract. A nutritional composition. A pharmacological composition effective in treating the diseases associated with the anti-inflammatory cytokine production imbalance, containing the extract. A method of relieving the above symptoms. The extract prepared by the above method.
EFFECT: extract is effective in treating the diseases associated with the anti-inflammatory cytokine production imbalance.
21 cl, 7 dwg, 23 tbl, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to medicine, namely immunology and may be used for immune system stimulation. That is ensured by administering a composition containing a complex of isolated carbonic anhydrase IX (CA9) protein and an antigen, wherein the isolated CA9 proteins and the antigen are noncovalently linked to each other, into an individual. The group of inventions also refers to a composition containing a purified population of dendrite cells coming into contact with the above composition.
EFFECT: group of inventions provides immune cell stimulation by enhancing the antigen immunogenicity ensured by adding the complex with the CA9 protein which can function as a chaperone protein.
18 cl, 6 dwg, 8 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to pharmacology and medicine and concerns an immunostimulating composition, and methods for using it for enhancing the immune response, particularly for treating infections caused by bacterial and viral pathogens, to adjuvant compositions and methods for enhancing the antigen immunogenicity when used as an adjuvant of vaccines. The pharmaceutical composition of pattern-recognising receptor ligands contains muramyl peptide of structural formula N-acetylmuramyl-L-alanyl-D-isoglutamine and lipopolysaccharide or lipid A in the following proportions, wt %: muramyl peptide of structural formula N-acetylmuramyl-L-alanyl-D-isoglutamine 0.00001 to 0.01, lipopolysaccharide or lipid A 0.00001 to 0.01, a solvent - the rest.
EFFECT: group of inventions provides high immunostimulating activity and prolonged action of the composition.
7 cl, 5 ex, 1 tbl, 9 dwg
SUBSTANCE: invention refers to medicine, namely to pulmonology and may be used in treating the patients with chronic bronchitis in combination with secondary immunodeficiency. For this purpose, the patient with the remitting disease undergoes 6 procedures of ozone therapy every second days by the intravenous introduction of ozonised physiological saline with the ozone concentration 600 mcg/l in the ozone-oxygen gas mixture. One week after the ozone therapy, patient's venous blood is sampled and exposed to UV light for 2 procedures every 7 days. At the first procedure, the blood volume to be exposed makes 0.8 ml/kg of patient's body weight, and at the second procedure - 1 ml/kg.
EFFECT: method provides the effective treatment in the given category of patients that is ensured by the activation of the cell, phagocytic and humoral immunity without the use of aq drug-induced therapy as a result of the combined selected regimen.
2 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry and represents using probiotic bifidus bacteria in preparing a nutritional composition for improving IgA secretion in the infants born by cesarean section for the first four months of life.
EFFECT: invention provides improving specific and non-specific IgA secretion thereby enhancing the mucosal immune protection in the infant.
11 cl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: given invention refers to medicine, biopharmaceutics, and may be used to prepare vaccines. For this purpose, the immunogenic composition contains: 1) an antigen Neisseria autotransporter protein representing NadA or Hsf; 2) an antigen Neisseria protein involved in iron absorption and representing Lipo28 or low-molecular or high-molecular TbpA; and 3) a vesicle preparation of an outer membrane containing immunotype L3 Neisseria lipopolysaccharide (LPS); and wherein the above antigens if present in the outer membrane vesicle are positively regulated in accordance with recombinant technology in the above outer membrane vesicle.
EFFECT: using the given vaccine that is a combination of the various class Neisseria antigens generates the immune response which occurs to be stronger if expressed in bactericidal units.
17 cl, 11 dwg, 21 ex
SUBSTANCE: invention refers to medicine, and concerns a new multifunctional combined interferon drug preparation of broad spectrum of action. A preparation in the form of a suppository contains a synergistic combination of the immunomodulator interferon alpha-2b and the herbal biostimulant aloe extract; it contains vitamin E, glycine, buffer salts, tysol, lecithin and solid fat as a base in the specified proportions.
EFFECT: invention provides preparing the combined drug preparation in the form of long storage-stable suppository having the standard physical-chemical, structural and mechanical, multifunctional biological properties, higher bioavailability and synergistic therapeutic efficacy of interferon alpha-2b with the herbal biostimulant aloe extract.
1 cl, 5 tbl, 3 dwg
SUBSTANCE: disclosed are peptides which are isolated from the FOXM1 protein and are capable of activating cytotoxic (killer) human T cells by forming an antigen-presenting complex with a HLA-A2 molecule. Disclosed are compositions which contain the disclosed peptides, use of a peptide to produce an agent for inducing cancer immunity, treating and preventing cancer, and for producing antibodies which selectivity bind the disclosed peptides. The invention describes an exosome and an isolated antigen-presenting cell, which present a complex of the disclosed peptide with a HLA-A2 molecule, for inducing cytotoxic T cells, methods of inducing a antigen-presenting cell and a cytotoxic T cell, as well as a method of damaging FOXM1 and HLA-A2 expressing cells.
EFFECT: invention can further be used in treating tumours that are characterised by high FOXM1 expression.
14 cl, 2 ex, 1 dwg, 1 tbl
SUBSTANCE: disclosed are germanium complexes, having a general structural formula (I): Gex[AD][CA]y[AA]z (I), where AD denotes a purine nitrogenous base derivative, having antiviral activity; CA denotes a hydroxycarboxylic acid; AA denotes an amino acid selected from α-amino acids, where x=1÷2, y=2÷4, z=0÷2, wherein all CA in the complex are identical or different, all AA in the complex are identical or different. Also disclosed is a method of producing germanium complexes, a medicinal agent and an immunostimulant.
EFFECT: invention enables to obtain germanium complexes, having high antiviral and immunostimulating activity.
18 cl, 5 dwg, 3 tbl, 7 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to medicine, namely to paediatrics and may be used for preparing a drug or therapeutic nutritional composition for maturating an immune responses in a newborn infant. That is ensured by using an oligosaccharide specified in a group consisting of: lacto-N-tetrose, lacto-N-neotetrose, lacto-N-hexose, lacto-N-neohexose, para-lacto-N-hexose, para-lacto-N-neohexose, lacto-N-octose, lacto-N-neooctose, iso-lacto-N-octose, para-lacto-N-octose and lacto-N-decose. Also, the above oligosaccharide may be used for modulating the immune system of the newborn infant to ensure the developing beneficial intestinal microflora for the first weeks of life comparable to such found in breastfed infants.
EFFECT: group of inventions enables the developing beneficial intestinal microflora in the infant, and reduces the risk of a further allergy.
27 cl, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry, and represents a local skin composition which is an oil-in-water-in-oil emulsion containing a water phase with a dispersed lipophilic phase containing calcipotriol or monohydrate in the dissolved form; a non-ionic surfactant specified in a group consisting of polyethylene glycol glycerides and C6-20 fatty acids, polyoxyethylene C8-20 alkyl ethers or polysorbates and a lower alkanol as a co-solvent; the above water phase is dispersed in a pharmaceutically acceptable anhydrous lipophilic carrier or base.
EFFECT: invention provides the effective dissolution of calcipotriol with the lower content of a lower alcohol, as well as the good penetration of calcipotriol into the viable skin layers, higher biological activity and less skin irritation.
26 cl, 5 ex, 7 tbl, 6 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to immunology, and concerns preparing meningococcal vaccines. What is presented is a kit for preparing an immunogenic composition for serogroup B Neisseria meningitidis containing: (i) a first containing comprising an adjuvant containing an oil-in-water emulsion; and (ii) a second containing comprising a lyophilised antigenic composition containing an immunogen for inducing the immune response to serotype B Neisseria meningitidis. The lyophilized antigens Men-B may be reduced into an adjuvant form ready for administration into the patient at the moment of use. The lyophilised component may also contain one or more conjugated saccharides of serogroup A, C, W135 and/or Y N. meningitides.
EFFECT: invention enables preparing the storage-stable and effective compositions.
7 cl, 3 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention is intended for application in pharmacy and cosmetology. Microemulsive composition has water and oil phases for transdermal and/or transmucosal introduction, contains, at least, one water- or fat-soluble active substance, activator of transdermal or transmucosal transfer, and main and additional emulsifiers. As main emulsifier used is synthetic emulsifier, and as additional emulsifier non-polar emulsifiers and/or polar emulsifiers are used. Microemulsive composition can be applied for preparing transdermal cosmetic preparations, for preparing transdermal and/or transmucosal medications.
EFFECT: ensuring high bioavailability of transdermal and transmucosal forms of medications and cosmetic substances through intact skin and mucous membranes due to creation of stable and biocompatible microemulsive compositions, capable of transferring water- and fat-soluble medications and cosmetic substances with molecular weight to ~6000 Da through intact skin.
10 cl, 8 dwg, 3 tbl, 8 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention discloses pharmaceutical composition for controlled release regarding toxic active compounds, in particular, bioactive proteins from class of interferons. Composition contains bio-degradable block-copolymer made of poly(ethyleneglycol)terephthalate (PEGT) in amount from 50 to 95%, and poly(butyleneterephthalate) (PBT). Agent may be represented as injection microparticles, injection liquid, capable of independent gel or solid implant formation. Besides, invention provides a pharmaceutical set, including specified composition, methods of composition making and pharmaceutical versions of its application.
EFFECT: invention provides for initial release within 4 hours of not more than approximately 10% of included amount of one or more alpha-interferons and at least 80% of one or more alpha-interferons are released in monomer non-aggregated form.
31 cl, 8 ex, 2 dwg
SUBSTANCE: absorbing agent is specified from the group consisting of starch, talc, kaolin, aluminium stearate, magnesium carbonate, titanium dioxide, titanium dioxide or zinc oxide processed with methicone, dimethicone, cyclopentasiloxane, stearic or myristinic acid, or their mixture. Buffer agents consist of citrates, phosphates or their mixture. Besides the invention refers to medicinal agents containing mentioned compositions and used for treatment and/or prevention of mild skin irritations, especially of diaper dermatitis. Also the invention refers to the application of the mentioned compositions as anti-urease agents.
EFFECT: environmental improvement of skin condition in a diaper and prevention or treatment of the irritated skin, diaper dermatitis and miliaria caused by the presence of urine or excrements.
13 cl, 3 dwg, 11 tbl, 4 ex
SUBSTANCE: invention refers to medicine and can be used for prevention of inflammatory processes in animals. That is ensured by putting in a dark glass bottle at the relation g (wt %) of mixed dry powdered elecampane rhizomes and roots - 20.0 (5,9) plaster clover leaves, blossom, fruits, thin bodies - 14.5 (4.4), oak barks - 15.0 (4.4), touch-and-heal herb - 20.0 (5.9), calendula blossom basket - 20.0 (5,9), burnet bloodwort rhizomes and roots - 20.0 (5.9), lavender blossom clusters - 20.0 (5.9), peppermint leaves, bodies and blossom - 20.0 (5.9), costmary blossom baskets - 15.0 (4.4), common plantain leaves - 20.0 (5.9), horse gowan blossom - 20.0 (5.9), common licorice rhizomes, soboles - 20.0 (5.9), nosebleed herb - 20.0 (5.9), thyme herb - 20.0 (5.9), full-maturity hips - 20.0 (5.9), eucalyptus leaves - 20.0 (5.9), killwort leaves, bodies, blossom, fruits - 15.0 (4.4), and nonfrozen stoned sea-buckthorn fruits- 20.0 (5.9). Then agitated mixture is filled with 1500.0 g of corn or sunflower oils either plain or refined, or olive oil either plain or salad. The prepared mixture is kept at room temperature with constant mixing for 25-30 days with following separation of vegetable sediment and preparing of oil-vegetable agent. The prepared vegetable sediment is filled with 1500.0 g of 0.9% sterile solution of table salt at temperature no more than 50 C, and kept in agitation for 25-30 days to produce thereby an aqueous-vegetable agent. For each 100.0 g of prepared oil-vegetable or aqueous-vegetable agent, there are added in agitation natural may honey 6.0 g (6.0%) and formalin 0.6 g (0.6%); then the prepared agent is packed. The agent is applied externally, once or manifold on affected body part, or introduced internally.
EFFECT: invention allows ensuring higher clinical effectiveness with respect to inflammatory processes ensured by various actions of the components of the mixture.
SUBSTANCE: for preventing and treating of inflammatory processes in an animal's organism, the animal's body lesion is coated with a water-vegetative preparation, also to be introduced in a vaginal, uterine or intestinal cavity. Said preparation is made as follows. Powdered dry drug plants are placed in a dark glass bottle in a certain weight ratio. The plant mixture is covered with a vegetable oil 2500.0 g and kept at room temperature in continuous stirring for 30 days. Then a liquid component is separated to produce an oil-vegetative preparation. The water-vegetative preparation is made by covering the raw material with 2500.0 g of hot, but no more than 50°C, 0.9% sodium chloride brine, and kept in stirring for 30 days at a room temperature. Then formalin is added at 0.6 g per 100.0 g of water-vegetative infusion.
EFFECT: more effective prevention and treatment.
SUBSTANCE: invention relates to pharmacy. The method for making storage-stable multicomponent water/oil/water emulsions which contain one or more biologically active substances includes the stage a) that involves a biologically active substance added in an aqueous phase, the stage b) that involves the aqueous phase emulsified by addition to an oil phase through a loose membrane, and the stage c) that involves phase inversion in the emulsion from the stage b) by cooling the mixture at low rate 0.3 K/min. An emulsifier is added to the aqueous phase at the stage a) and/or to the oil phase at a stage b).
EFFECT: invention provides the identical external and internal aqueous phases containing the same amount of the active substance, with immediate release of the active substance from the external phase and slow release thereof from the internal phase.
12 cl, 1 tbl, 4 ex, 2 dwg
SUBSTANCE: invention concerns chemical-pharmaceutical industry, namely development of a therapeutic agent for external application to be used for prevention of thromboses and disturbed circulation. The therapeutic agent represents nanostructured gel containing n-3 polyunsaturated fatty acids, α-tocopherol-acetate, phospholipid concentrate, alkali, water and liquid paraffin.
EFFECT: advantages of such composition are thermodynamic stability, possibility to introduce biologically active substances of both hydrophilic and amphiphilic, and hydrophobic nature, ability to promote percutaneous substance delivery and ease of production.
9 ex, 2 tbl
SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns an oral drug delivery system including biliquid foam containing continuous hydrophilic phase 1 to 20 wt %, pharmaceutically acceptable oil 70 to 98 wt % producing discontinuous phase. A slightly water-soluble drug 0.1 to 20 wt % is dissolved or dispersed in said pharmaceutically acceptable oil. The drug delivery system also contains biliquid foam with included surface-active substance 0.5 to 10 wt % to produce stable biliquid foam with all the amounts specified in percentage of total composition.
EFFECT: drug delivery system ensures high bioavailability of slightly water-soluble oral drugs.
22 cl, 16 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a topical pharmaceutical composition in the form of an opaque emulsion gel. The composition contains 1.2-4 wt % of diclofenac diethylammonium salt, saturated or unsaturated C10-C18fatty alcohol, at least 40 wt % of water, C2-C4alkanol, glycol solvent, gelling agent, liquid lipid forming an oil phase of the emulsion gel, non-ionic surfactant and agent with the primary properties to reduce pH of the prepared composition to 6-9.
EFFECT: compositions under the invention are characterised by high skin permeability, extremely low systemic absorption, absence of human skin irritation after application, high chemical and physical stability, complete solubility of the active component and considerable relief of pain intensity.
8 cl, 4 tbl, 5 ex