Method of preserving immunogenic composition availability for introduction to animal

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, namely to biopharmaceutics, and can be applied for the preservation of an immunogenic composition in the suitable condition for introduction to an animal. For this purpose the claimed composition contains an antigen of foot-and-mouth disease (FMD) and an emulsion, which is a single emulsion at the first temperature lower than the temperature of the animal body, and the said emulsion is used at the second temperature between the first temperature and the body temperature. The method includes: provision of the composition, freezing the composition and storing the frozen composition until it is required for introduction to the animal. A group of inventions also relates to a method of testing the immunogenic composition.

EFFECT: group of inventions makes it possible to reach an increase of the storage term of a vaccine against FMD, based on the emulsion as an adjuvant, and it is possible to apply the process of slow freezing, without rendering an impact on adjuvant properties of the emulsion.

13 cl, 6 dwg, 3 ex

 

The technical FIELD TO WHICH the INVENTION RELATES

This invention relates to a method of preserving the availability of immunogenic compositions for administration to an animal. The invention also relates to a method for testing immunogenic compositions and immunogenic compositions, optionally in combination with specific instructions for storage of the composition.

The LEVEL of TECHNOLOGY

In medicine often used in immunogenic compositions for administration to animals (including humans). Such compositions may, for example, be a vaccine or a diagnostic composition. Often, such a composition contains an adjuvant to enhance an immune response in the animal. An important class of adjuvants, especially in veterinary medicine, is of an emulsion containing oily substances, such as emulsion type of the so-called oil-in-water (O/W), water-in-oil (W/O) or water-in-oil-in-water (W/O/W), where the oil substance in General serves as a connection for stimulation of the immune response.

In daily practice is primary to immunogenic compositions had a long shelf life. This means that they can be stored for long periods of time while maintaining adequate effectiveness of demand for the introduction of the animal. It is well known that antigens, as such, are best preserved when n is skih temperatures. However, in particular, the emulsion cannot be frozen without adverse effect on their adjuvant properties. It is freezing may be disadvantageous for the quality of the emulsion and hence for the quality of the adjuvant properties. Consequently, available for purchase immunogenic compositions containing the adjuvant emulsion, always accompanied by instructions for storage of the composition above the temperature of freezing of the emulsion. In practice, since most of adjuvant emulsions are water-based, this means that the composition is usually stored between 2 and 8°C. Although it is ideal to maintain adequate quality of the emulsion, the temperature between 2°C and 8°C means that many antigens (which often contain complex protein or other biopolymer structure) is exposed to visible damage. Specifically, for antigens that are not very stable by nature, such as FMD antigens, it means that the immunogenic properties can easily fall below an adequate level within 12 months from the start of production.

In the prior art this problem has been noted and found several solutions. One of them is the storage of antigens separately from adjuvant emulsion. Thus, the antigens may be stored, for example, at a temperature RA is Noah -196°C, and emulsion at 4°C. In this case, both components can maintain their desirable properties for many years. The disadvantage of this method is that it takes some time to be immunogenic composition and distribute it if necessary for the introduction of the animal. It usually takes from 72 to 120 hours. In case of an emergency, it may be too long. Also, when there is an emergency situation and the composition should be delivered immediately after it was made, the safety and immunogenicity of the composition could not be tested.

Another solution is known from EP 1 201 251. This patent describes a method for stratified cryogenic stored vaccines (the so-called SACS). This method is based on the approach associated with layer-by-layer stacking of the individual components of the vaccine in the same primary container and then the product is stored at low temperatures (approximately -150°C). Although using this method, avoid adverse effect on the immunogenicity, the method is very complex, and the fact that the vaccine must be stored at extremely low temperatures, makes the method very expensive to apply.

The OBJECTIVE of the INVENTION

The invention aims to overcome or, at least, minimizera the th problems of the prior art, related to storage immunogenic compositions to their demand for the introduction of the animal, and to provide a convenient way of saving this song available for use. Another object of the invention is to provide a new method of testing immunogenic composition, a new combination of immunogenic compositions and instructions for storage of the composition, as well as a new liquid immunogenic composition.

DISCLOSURE of INVENTION

The first object of the invention is solved by providing a method in accordance with the introductory part of this description, where this composition comprises an antigen and emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and body temperature (including temperature near the body), this method includes providing the composition (i.e. the accessibility of the composition, for example, through its issuance or simply purchase it on the market), the freezing of the composition and the storage of frozen composition to its demand for the introduction of the animal. The second problem is solved by providing a method of testing immunogenic composition for administration to an animal, the composition comprises an antigen and emulsion, to the which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and body temperature, the method includes the preparation of immunogenic compositions, the freezing of the composition, the storage of frozen composition within a predetermined time, the defrosting of the composition and determine the immunogenicity of the thawed composition.

The third problem is solved by providing a combination of immunogenic compositions for administration to an animal, the composition comprises an antigen and emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and body temperature, and the statement that the composition can be stored at a temperature below the freezing temperature of this composition to its demand for the introduction of the animal.

The fourth objective of the invention is solved by providing a liquid immunogenic composition for administration to an animal, the composition comprises an antigen and emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and body temperature, this composition is frozen at approximately -20°C and then Otti is up to a liquid state.

DEFINITION

Rapid freezing: the process by which the sample temperature is quickly lowered to temperatures below -140°C by immersing the sample in a liquid having a temperature below -140°C (specifically liquid nitrogen at -196°C), or gaseous phase such liquid.

Freezing to approximately -20°C: for freezing under conditions similar to freeze in a standard household freezer compressor of the type having an internal temperature in the freezing compartment) is usually between -12 and -28°C.

Immunogenic composition:the composition, which has the ability to trigger the host immune system, when the composition is administered to this host.

Immunogenicity: measure of the ability to initiate the host immune system.

Vaccine:a composition, suitable for use on animals (including humans), containing one or more antigens (such as a weakened or killed microorganisms and/or their subunits, or any other substance, such as a metabolite of the body) in immunologically effective amount (i.e. capable of stimulating the immune system of the target animal), typically combined with a pharmaceutically acceptable carrier (such as, for example, a liquid containing water), optionally containing Immunostimulants (adjuvant is), which with the introduction of the animal induces an immune response that is sufficient for the treatment of diseases or disorders in an animal, that is, at least, to contribute to the prevention, alleviation or cure of diseases or disorders.

Adjuvant: a substance or composition which is able to exert a beneficial influence or weaken a particular process in the cascade of immunological events, ultimately leading to better immune response against the antigen.

Putto ensure delivery by appointment, for example, using regular mail or Express transportation using road transport, air transport, water transport or any means suitable for packaging, or other tangible object.

DETAILED description of the INVENTION

Unexpectedly, the applicant has found that contrary to common knowledge and the instructions of the suppliers adjuvant emulsions can be frozen immunogenic composition, when it is based on the emulsion, which is a single emulsion (essentially emulsion type O/W or W/O) at the first temperature below the body temperature of the animal, and this emulsion is drawn at the second temperature (i.e. at least begin to look at this second temperature between the first temperature and so is the temperature value of the body. Conversion in this sense means that the phase, which emulsify when the first temperature is induced to become the continuous phase at the second temperature, and at the same time, this phase, which is continuous with the first temperature is inspired to emulsification in the other phase at the second temperature. Such emulsions is currently used in industrial. For example, Intervet/Schering-Plough Animal Health sells the vaccine against foot and mouth disease (FMD), referred to as DECIVAC® FMD-DOE, which contains the emulsion, which is a (single) emulsion oil-in-water below 25°C, but which is drawn at a higher temperature, for example at 37°C. Since this conversion occurs in the animal body, no mixing is not possible and some water will be present as a continuous phase even after treatment. Therefore, the final inverted emulsion of water-in-oil will contain some amount of water present in a continuous phase even after treatment. The result is thus the emulsion of the type water-in-oil in the presence of some water in the form of an explicit continuous phase. Therefore, such an emulsion is often referred to as a double emulsion (although technically it is not). Despite the fact that the provider is definitely instructs not to freeze the composition, the authors found that the freezer etc is the W barely (or not even) has an impact on the adjuvant properties of the emulsion. The reason for this is not clear, but may be due to the fact that the emulsion should apply in any case, with the introduction of the animal. This may mean that the quality of the emulsion before the conversion is not important or less important for the quality of the emulsion after treatment. Thus, despite the fact that the quality of the emulsion can be greatly reduced by freezing, it seems, has little or even not have any effect on the adjuvant properties of the emulsion after treatment. The advantage found in the present effect is that the immunogenic composition can be stored at much lower temperatures and that, therefore, the rate of natural degradation of antigens in the composition may be characterized to be lowered (usually 2 times 10 degrees lower storage temperatures for normal chemical reactions or even to full lock for catalyzed reactions and enzymatic processes) regardless of which antigens are used. Note that the emulsion may contain one or more surface-active agents to obtain the converting properties. However, it may also be that the antigen serves to provide these properties, because the antigens can have properties similar to the surface-active cf is the funds. In any case in this area is well known how to obtain a single emulsion, which is drawn at a certain temperature (i.e. at this temperature or higher).

Note that on the basis of data obtained from frozen FMD vaccine in EP 1 201 251 suggest that rapid freezing of vaccines based emulsion and storage of vaccines in a frozen state may be an option for vaccines containing emulsion prepared with butter Montanide ISA 206 (available from SEPPIC, France), but it is clear that this option is generally not considered to have a reasonable chance of success, taking into account the specific instructions from the manufacturer (SEPPIC) - do not store the emulsion based on Montanide ISA 206 in the frozen state. Undoubtedly, the applicant EP 1 201 251 chose the path SACS instead of freezing and no other qualified not explored the path of freezing since the publication of the mentioned EP patent application in 2002, despite the huge need for adequate storage of unstable immunogenic compositions. The applicant, however, despite the clear recommendations not to follow the option of freezing, but to follow the path SACS, found that storage of the immunogenic composition in a frozen state, at least when using the emulsion, as indicated here above, is very simple and effective way is the preservation of the composition in a suitable condition for the introduction of the animal. In case of an emergency, the composition may simply activitise and be entered immediately, which is a significant advantage, especially in case of emergency, when you may need more immunogenic composition (within hours).

In the embodiment, the immunogenicity of the immunogenic compositions set before storage. Is very advantageous when the immunogenicity of the immunogenic compositions known before the introduction. In the prior art, when the immunogenic compositions comprise in the event of an emergency, no time to assess the immunogenicity of the composition. With the present invention can be conducted by the use of a composition with the approved quality.

In the embodiment, the composition is delivered to a third party (also covering postal address different from the residence of a third party) at its request before it is frozen. In this embodiment, the manufacturer is not required to freeze the composition prior to its delivery to a third party. Specified third party itself can store the composition in a frozen state. This variant is particularly advantageous when a third party provides that large amounts of the composition may be required in the available state immediately, when there is an emergency and should not be lost. Alternatively, the composition is delivered to a third party at its request after it has been frozen. In this embodiment, it may be that the manufacturer immunogenic composition is the party that keeps the song in the frozen state. This has the advantage that the manufacturer may have a permanent control over the circumstances in which the composition is stored prior to its delivery to a third party.

In the embodiment, the frozen composition through the use of the slow process of freezing. The process of rapid freezing has the important disadvantage that often requires special expensive device. Such a device may not be available in every place in which the party wants to keep the immunogenic composition. In addition, the process of rapid freezing requires trained operators taking into account risks included when working with liquids at ultra-low temperatures (choking, burn wounds, and so on). The applicant has unexpectedly found that the present invention can be applied to the slow process of freezing to freezing of the composition. It was found that conventional freezer compressor type, such as an ordinary household freezer, bodylotions. Despite the fact that freezing time is much longer in such a freezer and, thus, the negative impact on the quality of the emulsion can be huge, the applicant has unexpectedly found that in this way there is no or hardly has any negative impact on the immunogenicity of the immunogenic composition. Even, apparently, is adequate when the freezing occurs at approximately -20°C, i.e. at the temperature of freezing, which in a normal household freezer.

In the embodiment, the composition is stored for more than 4 months, specifically more than 12 months. It was found that the storage for such periods of time does not or hardly affects the adjuvant properties of the emulsion. In the embodiment, a single emulsion is an emulsion of oil-in-water, preferably by emulsion, where the oil contains a mixture of manygreat and mineral oil. This emulsion was ideal in this invention. Specifically, this invention is suitable for immunogenic composition comprising the antigen of foot and mouth disease (FMD). It is well known that the FMD antigens are characteristic way unstable and best preserved at very low temperatures. The present invention provides the t option when testing a vaccine against FMD is available, while maintaining its potency for a long time when compared with the present situation where the test FMD vaccine stored at 4°C.

This invention also relates to a method for testing immunogenic composition for administration to an animal, where the specified composition comprises an antigen and emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and the temperature of the body, where the method includes the preparation of immunogenic compositions, the freezing of the composition, the storage of frozen composition within a predetermined time, the defrosting of the composition and determine the immunogenicity of the thawed composition.

This invention also relates to the combination of immunogenic compositions for administration to an animal, where the specified composition comprises an antigen and emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and body temperature, and the statement that the composition can be stored at a temperature below the freezing temperature of this composition to vostrebovani is to introduce the animal. In the embodiment, the combination of a package (e.g., box, bubble, bulb or any other container)containing the composition, and instructions in a tangible form (for example, in the form of a sheet of printed instructions on the packaging or in the form of a sticker glued to the packaging). In an alternative embodiment, the combination is a recommendation made publicly available in oral form or in the form of written descriptions, for example the recommendation that the immunogenic composition "X" can be frozen and stored in this condition until the demand for the introduction. The recommendation may, for example, be shown on the web site of the distributor or manufacturer specific immunogenic compositions or made public in the journal, presentation at the Congress, or other equivalent event, or presented either orally or in writing, or in combination of oral and written forms, commercial presentations, such as a television commercial, or presentation at the booth medical or scientific Assembly.

The invention also relates to a liquid immunogenic composition for administration to an animal, the composition comprises an antigen and emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn when the second rate is the atur between the first temperature and body temperature, this composition is frozen at approximately -20°C and then thawed to a liquid state.

EXAMPLES of the INVENTION

Example 1 in combination with figures 1, 2 and 3 shows the effect of freezing on the quality of the emulsion of various emulsions.

Example 2 describes the effect of different types of freezing on the macroscopic texture of the emulsion.

Example 3 shows the effect of storage on the immunogenicity of the immunogenic compositions with adjuvant emulsion oil-in-water.

Example 1

This example shows the effect of freezing on the quality of the emulsion variety available for purchase emulsions. For this purpose, the authors used the following emulsion FMD vaccines: CEDIVAC®-FMD (available from Central Institute for Animal Diseases Control, Lelystad, the Netherlands), AFTOVACIN® OLEOSA (available from Intervet/Schering-Plough Animal Health, Moinho Velho, Brazil) and DECIVAC® FMD DOE (available from Intervet/Schering-Plough Animal Health, Boxmeer, the Netherlands). The quality of the emulsion evaluated microscopically. Each emulsion are as such, when it was stored at 4°C and after the emulsion was frozen in a standard household freezer compressor type at -20°C, kept for 5 consecutive days in the freezer, thawed and heated to 4°C.

The results are shown in figures 1, 2 and 3. Figure 1A shows the emulsion CEDIVAC®-FMD after standard storage (in accordance with instructions what s provider) at 4°C. You can see that the emulsion is a double emulsion (in this case, the type water-in-oil-in-water). Figure 1B shows the corresponding picture of the emulsion during storage in the frozen state, as indicated here above. Obviously, the quality of the emulsion is greatly influenced. Explicitly occurs multiple coagulation.

Figure 2A shows the emulsion AFTOVACIN® OLEOSA after standard storage (in accordance with the supplier's instructions) at 4°C. one Can see that the emulsion is a single emulsion (in this case the type water-in-oil). Figure 2B shows the corresponding picture of the emulsion during storage in the frozen state, as indicated here above. Obviously, the quality of the emulsion is barely affected.

Figure 3A shows the emulsion DECIVAC® FMD DOE after the standard storage (in accordance with the supplier's instructions) at 4°C. the Emulsion is a single emulsion of the type oil-in-water (where the oil contains a mixture of manygreat and mineral oil, available for purchase as MONTANIDE® ISA 206, from SEPPIC, Paris, France), but refers to the type water-in-oil when heated to 37°C. Figure 3B shows the corresponding picture of the emulsion during storage in the frozen state, as indicated here above. Obviously, the quality of the emulsion is greatly influenced. Explicitly is the centre of the public coagulation.

These results indicate that the emulsion type, as is present in available for purchase vaccine DECIVAC® FMD DOE under serious loss of quality of the emulsion when the emulsion is frozen, specifically during slow freezing, as used in this example. It is usually assumed that this corresponds to a significant loss adjuvant properties.

Example 2

This example describes the effect of various types of freezing on the macroscopic texture of a single emulsion. In this case, the experiment was carried out with the emulsion, available for purchase vaccines DECIVAC® FMD DOE. One sample of the emulsion was rapidly frozen when placed in a glass vial containing the emulsion in liquid nitrogen and keep it within 24 hours. A second sample of the emulsion was subjected to the slow process of freezing when placed in a vial containing emulsion, in a standard household freezer having an internal temperature of -20°C, and the contents of the vial in the freezer for 24 hours. Then both samples were thawed by exposure bubbles ambient conditions (normal air is 21°C, atmospheric pressure). Then the quality of the emulsion macroscopically evaluated by exposing the vesicles to the visual examination. It is revealed that the emulsion is subjected to nebest the WMD freezing, showed significantly greater coagulation oil phase. From this we can conclude that slow freezing has a greater impact on the quality of the emulsion for this type of emulsion than rapid freezing.

Example 3

This example shows the effect of storage on the immunogenicity of the immunogenic compositions with adjuvant emulsion oil-in-water. In this example, the selected case worse case scenario, namely immunogenic composition, containing three of FMD antigen, which are notoriously unstable. Therefore, the effect that storage has on the immunogenicity of the composition, can be recognized in a temporary format months. For sustainable antigens that may require several years. The principles, however, remain the same: to show the presence (absence) of the effect of freezing on the adjuvant properties of the emulsions used in the present invention.

For the experiment, the inventors used the vaccine DECIVAC® FMD DOE, in this case containing antigens 01 Manisa, A22 Iraq and Asia 1 Shamir. Samples of the vaccines were stored either at 4°C (Liquid) or frozen in a standard freezer at approximately -20°C (Frozen) and stored in this freezer. Immunogenicity stored vaccines define (after 4 and 12 months of storage) through vaccination 5 animals (cattle RMSE is) a single dose (2 ml) and blood withdrawal in cattle after 28 days. Serum obtained from the blood. The titer of neutralizing antibodies against FMD virus homologous serotype determined in serum samples by an animal. The average titer corresponds to the immunogenicity of the vaccine. The results shown here below in Figures 4, 5 and 6.

From Figure 4 it is obvious that the antigen 01 Manisa is relatively stable in the observed period of time. You can still see that the immunogenicity of frozen vaccine after 12 months of storage is somewhat better than the immunogenicity of the vaccine stored at 4°C. Therefore, the adjuvant properties of the frozen emulsion are still adequate.

For antigen A22 Iraq becomes clear that storage at 4°C is unfavorable for immunogenicity. Obviously, the antigen loses its immunogenic properties, and no adjuvant emulsion as the emulsion remains stable for at least about 5 years, when stored at 4°C. When stored at -20°C, immunogenicity hardly reduced. Obviously, the antigen is fairly stable at -20°C. Also, the emulsion explicitly retains its immunogenic properties when it is stored in a frozen state.

For the third antigen, Asia 1 Shamir, you can see the situation corresponding to the situation of antigen A22 Iraq. Considering the fact that vaccines are stored in a frozen state,immunogenicity remains unchanged during storage, must be concluded that adjuvant properties of the emulsion not have negative impacts through a process of freezing and storage.

In short, from these experiments it can be concluded that adjuvant properties of the emulsion remain completely unaffected when the emulsion as defined in the attached claims, or the vaccine on the basis of this emulsion freeze. Specifically, the slow process of freezing, despite the fact that is adverse to quality emulsion, apparently, is sufficient even when using a freezing temperature, as high as about -20°C. Advantages of the present invention can be applied to increase the retention period of any immunogenic composition, which is based on emulsion adjuvant.

1. The method of saving the immunogenic composition in a suitable condition for the introduction of the animal, where the specified composition comprises antigen of foot and mouth disease (FMD) and the emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and the temperature of the body, where the method includes:
- providing composition,
- freeze compositions and
- storage of the frozen composition to its enterprise's designs the project for the introduction of the animal.

2. The method according to claim 1, wherein before storing immunogenic compositions set its immunogenicity.

3. The method according to claim 1 or 2, characterized in that before freezing the composition is delivered to a third party upon request.

4. The method according to claim 1 or 2, characterized in that after freezing the composition is delivered to a third party upon request.

5. The method according to claim 1, characterized in that the composition is frozen through the use of the slow process of freezing.

6. The method according to claim 5, characterized in that the composition is frozen in a freezer compressor type.

7. The method according to claim 1, characterized in that the freezing occurs at approximately -20°C.

8. The method according to claim 1, characterized in that the composition is stored for more than 4 months, specifically more than 12 months.

9. The method according to claim 1, characterized in that the single emulsion is an emulsion of oil-in-water.

10. The method according to claim 9, characterized in that the oil contains a mixture of manygreat and mineral oil.

11. The way to test immunogenic composition for administration to an animal, where the composition comprises antigen of foot and mouth disease (FMD) and the emulsion, which is a single emulsion at a first temperature below the body temperature of the animal and this emulsion is drawn at a second temperature between the first temperature and the temp is the temperature of the body, where the method includes:
- preparation of immunogenic compositions,
- freeze compositions,
- storage of frozen composition within a predetermined time,
- defrosting compositions and
- determine the immunogenicity of the thawed composition.

12. The combination of immunogenic compositions for administration to an animal, where the composition comprises antigen of foot and mouth disease (FMD) and the emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and body temperature, and the statement that the composition can be stored at a temperature below the freezing temperature of this composition to the demand for the introduction of the animal.

13. Liquid immunogenic composition for administration to an animal, where the composition comprises antigen of foot and mouth disease (FMD) and the emulsion, which is a single emulsion at a first temperature below the body temperature of the animal, and this emulsion is drawn at a second temperature between the first temperature and body temperature, the specified composition is frozen at approximately -20°C and then thawed to a liquid state.



 

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FIELD: biotechnology.

SUBSTANCE: method of production of vaccine against foot and mouth disease comprises culturing virus antigen in suspension culture of cells BHK-21 at a temperature of 36-37°C, purification of the viral suspension from ballast impurities, inactivation, concentration of the obtained foot and mouth disease virus antigen, and connection of the antigen concentrate with an adjuvant. Purification of the virus suspension from ballast impurities is carried out by adding derived polyguanidines at a final concentration of 0.005-0.01%, or the mixture of chloroform and derivatives of polyguanidines taken in weight ratios of (40-160):1, respectively, at a final concentration of 0.4-0.8. As derivatives of polyguanidines dihydrochloride 1,12 diguanidinohexane or dihydrochloride bis (3-guanidinopropyl) piperazine, or dihydrochloride 3,6-dioxaoctane-1,8-diguanidine, or dihydrochloride 4,9-dioxadodecane-1,2-dibiguanide.

EFFECT: improvement of purification level of virus suspension from ballast impurities and increase in immunogenicity of the target product.

2 cl, 1 tbl, 16 ex

FIELD: biotechnology.

SUBSTANCE: method of production of antirabic vaccine for animals comprises preparing of inoculum from the strain of rabies virus, infection contamination with the inoculum of the culture of the continuous cells, culturing the rabies virus, collection of virus-containing suspension with its subsequent inactivation and preparation of the target product, at that the inactivation is carried out by adding the virus-containing suspension to ethanol in the final concentration of 18-20%, exposure for 20-22 hours at a temperature of 36-37°C under constant stirring, then 4-6% aluminium hydroxide is added in a ratio to the reaction mixture of 1:(4.5-5.0).

EFFECT: simplification of the method and improvement of quality of the product by increasing the shelf life of the target product.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining suspension of polymorphic form I of salt of methanesulfonic acid and dabigatran etexilate of formula I . Method is characterised by the following: polymorphic form I of dabigatran etexilate methanesulfonate with melt temperature tmelt 180±3°C is suspended in mixture with talc in solution of hydroxypropylcellulose in isopropyl alcohol at temperature in the range from 12 to 22°C with obtaining suspension by method of circulation dispersion at temperature not higher than 30°C. Invention also relates to obtained in said way suspension for obtaining dabigatran etexilate methanesulfonate pellets. Invention also relates to dabigatran etexilate methanesulfonate pellets used for thrombin inhibition, and to method of obtaining said pellets by dispersion of said suspension on isolated tartaric acid cores in fluidised bed.

EFFECT: claimed invention provides industrial method of obtaining pellets of dabigatran etexilate methanesulfonate, presents only in one polymorphic form.

27 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is described is using a pharmaceutical composition in the form of an orally disintegrated tablet containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as an active substance and crospovidone as a disintegrating agent in ratio 2:1 respectively, as a motor stimulating and anorectic agent.

EFFECT: preparing motor stimulating and anorectic agent.

16 dwg, 34 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical oil-in-water emulsion contains mometasone or mometasone furoate, propylene glycol and water. The propylene glycol concentration makes from 20 to approximately 45 wt %. A mass ratio of propylene glycol and water in the oil-in-water emulsion makes from 1:1 to approximately 1:3. A portion of mometasone or mometasone furoate is found insoluble in the emulsion.

EFFECT: composition is characterised by stability and therapeutic effect.

27 cl, 6 dwg, 5 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an herbal formulation of topical nanoemulsion for treating acne-related skin disorders. The above formulation contains an aqueous phase comprising a therapeutic agent, rose water and/or lemon juice, and an oil phase containing an essential oil, a non-ionic surfactant and an accessory surfactant. The aqueous and oil phases are related within the range of 1:1 to 1:2, while a particle size of the herbal formulation is less than 5 nm. The essential oil is presented by tea tree oil, basil oil, rosemary oil, lavender oil, jojoba oil, bergamot oil, clove oil and peppermint oil. The invention also refers to a method for preparing the herbal formulation which involves providing the aqueous and oil phases, mixing the above phases to produce a mixture to be emulsified with the non-ionic surfactant to prepare a macroemulsion. The prepared macroemulsion is mixed with ethanol to produce a nanoemulsion with a particle size less than 5 nm.

EFFECT: invention provides the herbal formulation with good penetration, prolonged effect causing no irritation.

8 cl, 4 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a pharmaceutical submicron suspension and to a method for preparing the submicron suspension and is applicable for ophthalmic (local or intravitreal) and nasal application. The ophthalmic aqueous pharmaceutical submicron suspension contains a hydrophobic therapeutic agent prepared in the form of submicron particles with the hydrophobic therapeutic agent presenting nepafenac; where a low-molecular charged polymer contains one or more cellulose polymers which jointly or individually have a molecular weight of less than 200000 kilodalton, and wherein the low-molecular charged polymer has an average degree of polymerisation (DP) making approximately min. 100 and up to approximately 4000; and one or more additives. The low-molecular charged polymer inhibits submicron particle aggregation in the suspension; the submicron particles have an average hydrodynamic radius making less than 1 mcm, and the low-molecular charged polymer represents carboxymethyl cellulose.

EFFECT: using the group of inventions enables preparing the high-active therapeutic agent for ophthalmic application.

16 cl, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a formulation of a perfluorinated blood substitute emulsion for biomedical applications, containing: perfluorinated hydrocarbons, emulsifying agents and an electrolyte solution differing by the fact that it contains a binary mixture of two perfluorinated hydrocarbons in ratio 1.55 to 1.99 in the concentration of 5 - 1000 g/l, with an average particle size of a perfluororganic compound of 25 - 250 nm; a binary mixture of the emulsifying agents in ratio 1.55 to 1.99 that are non-ionic block copolymers of ethylene oxide and propylene oxide - proxanoles: proxanole-268/proxanole-168; proxanole-268 in the concentration of 1 - 200 g/l with the molecular weight of 7 - 14 thousand Da; proxanole-168 in the concentration of 1 - 200 g/l with the molecular weight of 5 - 7 thousand Da; the electrolyte solution: NaH2PO4 - 0.18-0.25 g/l; NaCl - 5.5-6.5 g/l; and/or KCl - 0.37-0.41 g/l; and/or MgCl2 - 0.17-0.21 g/l; and/or NaHCO3 - 0.35-0.7 g/l; and/or glucose - 1.5-2.5 g/l.

EFFECT: invention ensures formulating the perfluorinated blood substitute with better aggregation and sedimentation stability and lower toxicity.

2 cl, 9 ex

FIELD: medicine.

SUBSTANCE: agent contains 0.2% Pyriton, an emulsifier, an emollient - isopropyl myristate, and a solvent. The emulsifier is presented by glycerol cocoate PEG-7; the emollient is presented by triglycerides of caprylic and capric acids; the solvent is water. Besides, the agent additionally contains glycerol, cyclomethicone, urea, allantoin and a flavouring agent. All the ingredients of the agent are taken in certain mass ratio.

EFFECT: invention enables eliminating side effects, recovering physiological properties of skin and providing high patient's satisfaction upon completion of the treatment.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention discloses a cream for external treatment of Graham-Little-Piccardi-Lasseur syndrome, which contains lanolin, peach oil and distilled water, and is characterised by that it further contains chloroquine, wherein components of the cream are in a defined ratio given in g%.

EFFECT: inhibiting progression of scarring without marked side effects.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of cosmetology, namely to a cosmetic composition for peroral introduction, which contains a combination of lycopene, vitamin C, vitamin E and at least one polyphenol compound, obtained from pine bark, in which the ratio of weight content of polyphenol compound to the sum of weight contents of lycopene, vitamin C and vitamin E constitutes from 0.3 to 0.7, as s single active ingredient.

EFFECT: invention is intended for prevention and/or treatment of wrinkles in the area of eyes and mouth angles, small wrinkles, eye bags and dark circles under eyes.

22 cl, 2 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention represents a pharmaceutical composition for treating local manifestations of herpes simplex infections and for preventing influenza and acute respiratory viral infections, containing green tea extract and epigallocatechin-3-gallate (EGCG) 70-90 wt %, colloidal silver and a gel-forming base with the ingredients of the composition taken in certain ratio, wt %.

EFFECT: high clinical effectiveness.

6 cl, 8 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to veterinary virology and biotechnology and concerns a type A foot-and-mouth disease vaccine. The vaccine contains an avirulent and purified antigen material of the viral strain Aphtae epizooticae, of the family Picornaviridae, of the genus Aphtovirus, of the serotype A, deposited in the collection of FGU VGNKI (Federal State Institution Russian National Centre for Quality and Standartisation of Drugs and Feed for Animals), registration No. 2045/Kirghizia/2007-DEPA No. 2045/Kirghizia/2007-DEP prepared in a passaged cell culture VNK-21, representing s suspension containing preferentially the immunogenic viral components 146S and 75S of foot-and-mouth disease, the adjuvants aluminium hydroxide with saponin and a supporting medium in effective proportions.

EFFECT: vaccine possesses high immunogenicity and is able to provide the effective protection against a foot-and-mouth disease agent circulating in the countries of Transcaucasus, Central Asia, Near and Far East.

12 cl, 14 tbl, 1 dwg, 4 ex

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