System for substance delivery into oral cavity

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry, namely, represents a delivery system for the application in the oral cavity, application and method of obtaining the said delivery system. The delivery system includes a carrier, which includes a cellulose-based or starch-based material and has a surface, including oxygen-binding sites and one binding unit, bound to the carrier, where the said binding unit includes a sugar chain of the following formula: xylose-galactose-galactose-glucosamine.

EFFECT: realisation of the invention provides the possibility of the improved and simplified delivery of a wide range of biologically active substances, simultaneously providing a precise dose of the biologically active substance.

14 cl, 4 dwg, 3 ex

 

The technical field TO WHICH the INVENTION RELATES

The present invention relates to the delivery system used for the oral cavity, where this system includes a carrier for biologically active substances.

Background of the INVENTION

Known a number of problems associated with oral delivery of pharmaceuticals, the pharmaceutical drug is swallowed and passes through the gastrointestinal tract.

The main problem that occurs when oral delivery is the metabolic degradation of pharmaceutical drugs as they pass through the gastrointestinal tract. Metabolism can lead to splitting of the drug to inactive or even harmful metabolites. This means that the required therapeutic dose may be too high and cause unwanted side reactions. Another disadvantage relates to the difficulty of optimizing the dose for an individual. In addition, the metabolism of some pharmaceuticals is unacceptable for oral delivery.

The risk of intentional or unintentional overdose is also a concern, since the required therapeutic dose should be higher than theoretically calculated dose, order comp�to balance losses, associated with metabolic cleavage.

Taken by swallowing the medicinal substance only after a relatively long time may show a significant effect. This means that if a fast response is especially important, as in the case of painkillers or funds taken for the motor dysfunctions, there is a need for more sophisticated delivery system.

Nausea and vomiting may also be a barrier for oral administration of the drug. Migraine and movement disorders, which are accompanied by symptoms such are examples of conditions that often too late to take swallow the drugs to ensure that they had an impact when such symptoms occur.

In order to overcome these difficulties in oral delivery, has previously been proposed to use injection or spray means which are introduced into the oral or nasal cavity. Another alternative is anal the delivery path. However these methods are not free from drawbacks, determined by the complicated technical aspects of these procedures, their high cost, they cause discomfort or soreness.

In addition, it was proposed to introduce a pharmaceutical by means of tablets that dissolve�I in the oral cavity and release the appropriate pharmaceutical agent. This kind of tablet is described in EP 1295595 A1. However, decomposing in the mouth pills also have a number of serious inherent disadvantages associated with the fact that the level of absorption of pharmaceutical drugs through the oral mucosa may be low, and accordingly, a smaller or a large proportion of pharmaceuticals will be inadvertently swallowed by the subject undergoing treatment. In addition, in the case of the introduction of pharmaceuticals using tablets these pills definitely will contain excipients, such as fillers, flavoring substances, etc., in a mixture with the active substance. And when the tablets contain a small amount of active substance, there is the problem of achieving uniformity of distribution of active substance in tablets so that tablets contained the same amount of active substance.

In the case of tablets described in EP 1295595 A1, the exact dose that is actually injected in each case, cannot be controlled. Consequently, there is a risk that the administered dose will be too low to achieve the desired effect in the subject to treatment of an individual or it will be too high, if the tablet by accident will contain a greater quantity of the active substance than expected. Moreover, can also occur in�ü problems associated with metabolic decomposition of pharmaceuticals. To alleviate the problem associated with the absorption of the pharmaceutical if it means swallowing through saliva, in US2007/0031502 A1 has been proposed to mix the pharmaceutically active agent with a compound that promotes bioadhesive or mucoadhesive.

However, there is still a need for improved and simplified system of delivery, which could be used for a wide range of biologically active substances, including those substances which cannot be swallowed without subsequent metabolic collapse, and this solves the problem of accurate delivery of the dose, even in case of small doses of biologically active substances.

BRIEF DESCRIPTION of the INVENTION

The present invention relates to the delivery system in the oral cavity, where this system includes a carrier for biologically active substances. The specified media is a material the surface of which includes kislorodsvyazyvayushchei sites (X), and where at least one linking unit includes a pentose group and one or more additional sugar groups, where the specified pentose group attached to one of kislorodsvyazyvayushchei sites (X) and where one or more biologically active substances (R) are directly connected with one of sa�ary groups in at least one of the binding units or with one or more substituents on one or more sugar groups in at least one of the binding units.

One or more other sugar groups on the sugar binder unit can represent the pentose or gekozen if desired.

The present invention has more advantages relative to previously used drug-delivery systems, such as systems based on the swallowing of medicines, injection system, through the delivery of anal way, the aerosol delivery system, the delivery through the sublingual tablets and inhalation dose delivery.

When the carrier enters the oral cavity and comes into contact with saliva, the enzymes in saliva break down the connection on diabetes connection, which leads to the release of biologically active substance (R) in the oral cavity. The biologically active substance is released directly into the oral cavity in the form of a bioactive molecule that contains a sugar group associated with a biologically active substance (R). Hydrophilic sugar group, which is associated with the active substance (R), acts as the promoter, which facilitates the penetration and fast capture of bioactive molecules through the mucous membranes in the oral cavity. Accordingly, the bioactive molecules are immediately transferred into the blood vessels of the mucosa and then transported into the bloodstream and then to the brain, bypassing the gastrointestinal tract.

Oskolkova biologically active substances are hydrophobic in nature, they are mostly not captured hydrophilic oral mucosa or captured only to a very small extent, so that a large proportion of the administered dose is lost through the ingesting of biologically active substances to its possible penetration through the mucosa. When using the delivery system of the present invention the risk of loss of active substances in swallowing is eliminated due to the fact that saliva activates the release mechanism, once nerastvorim medium together with the active substance comes into contact with the oral mucosa, so that the release occurs precisely at the time when it is needed. In addition, increasing penetration effect of hydrophilic sugar groups in the bioactive molecule is released from the carrier, a rapid and nearly complete capture of the released substance, regardless of whether hydrophilic or hydrophobic. Basically, 98% or more of the active substance must be absorbed through the oral mucosa.

In connection with the hydrophilic nature of the biomolecules that contain a certain substance, and also in connection with high accuracy the introduction of the active substance delivery system of the present invention allows its use for a wider range of biologically active substances, injected oral way�, than was possible when using previously known tablets and compositions, which simply dissolve and release the substance into the oral cavity.

The media itself is not soluble in the oral cavity, but remains intact, being in contact with the mucous membrane, until its removal after completion of treatment.

The saliva is secreted in the salivary glands. Human saliva contains 98% water and contains substances, including electrolytes, mucus, antibacterial compounds and various enzymes.

There are three major enzyme and more minor enzymes found in saliva:

a) α-amylase. Amylase begins the breakdown of starch and lipase fat before the food is swallowed.

(b) Lysozyme. The action of lysozyme is directed to lysis of bacteria.

(c) Lipase language. Lipase has an optimum pH of about 4.0, and this means that it is not activated until then, until it enters an acidic environment.

(d) Minor enzymes include acid phosphatase (A+B saliva, N-acetylmuramyl-L-alanine-amidase, NAD(p)H-dehydrogenases quinones, lactoperoxidase saliva dismutase, glutathione-transferase, aldehyde dehydrogenase class 3, glucose-6-phosphate-isomerase, aldehyde dehydrogenase and tissue kallikrein.

All of the enzymes of saliva is able to break down sugar and to contact the substituents on the sugar chain�ies, contribute to the realization of the function of the release of the present invention. Constantly open up new enzymes, and it should be expected that in the future the list of known enzymes will be expanded.

The delivery system of the present invention enables the use of significantly lower doses than in the case of oral delivery, without losing the effect of the active component. In comparison with drugs intended for swallowing, the use of the drug delivery system of the present invention allows to reduce the dose to 1/10 relative to swallow the dose. The delivery mechanism is fast acting, highly effective, simple and painless and only includes a biocompatible components and substances such as sugar, even in the decay of produce metabolites that are harmless to the human body. Any of the sugar substitutes on the links or on the material carrier of the present invention should be selected so that they had produced only non-toxic metabolites.

The delivery system of the present invention has advantages with respect to standard sublingual tablets or other placed in the oral cavity of pharmaceutical forms that are designed to dissolve within the oral cavity. The delivery system of the present invention �can be made to achieve accuracy in delivery and transfer of a clearly defined and very low doses of biologically active substances. The structure of the carrier is placed in the oral cavity and will be in the right place, and while it will not dissolve or otherwise change, until its final disposal by the individual receiving this treatment, or watching the procedure with a specialist, upon completion of the treatment. Once the biomolecules composed of a sugar group associated with a biologically active substance released from the carrier, they are immediately transferred to the oral mucosa due to the hydrophilic nature of the sugar group. Therefore, in this case eliminates the risk of loss of any biologically active substance by swallowing his carelessness.

According to the present invention, the sugar binding units on the media can be so focused on its length, the branches and alternate, to directly contribute to the specific binding with one or more biologically active substances. You can also create a binder such units, which burst under the action of additives, which gives additional opportunities for the organization of the sugar binding units, in order to better control the release mechanism.

The length of the sugar binding units can vary from the simple binding units containing only related to the carrier of the pentose and one complete�first sugar group, up to longer and more complex sugar chains. The length of the sugar chains determines the number of one or more biologically active substances that may contact the media. In the case of large molecules, it is preferable to use a longer chain to achieve a sufficient space between the carrier surface and the individual molecules connected with specified binder unit.

Sugar binding units can be monosaccharides, disaccharides, etc., but is preferably unbranched oligosaccharides or polysaccharides.

Particularly preferred sugar binding unit is a sugar chain consisting of the following components: xylose - galactose - galactose - glucosamine. The specified binder unit is connected by xyloskalo the end of the media. Sugar binding unit of this kind has a high biocompatibility, because it is present naturally in the connective tissue of animals and humans, where it acts as a promoter in the transport of hydrophobic molecules across biological membranes. In that case, when the media containing the attached binder such unit is placed in the mouth, the enzymes in saliva to break down the sugar group, starting from the free end of the chain. Accordingly, the first linkage, �otara will fail will be the link between glucosamine and the next group of galactose. If the biologically active substance is associated with glucoamine, the bioactive molecule will consist of biologically active substances and glucosamine where glucosamine will be at the hydrophilic end of bioactive molecules.

These sugar binding units can be derived from proteoglycans isolated from connective tissue, such as connective tissue of cows or pigs. Proteoglycans are compounds comprising a nuclear protein and one or more covalently attached sugar chains usually via a serine residue. If desired, the specified protein may be removed from the serine residue using proteinase before the procedure branch of the sugar binding units from serine. These sugar binding units can be released from proteoglycans ènzimatičeski, when processing an aqueous solution of proteoglycans by chondroitinase, followed by separation of the sugar binding units from the solution by centrifugation. Once the connection between serine group and a sugar binder unit will be destroyed by chondroitinase, xylosma group at the end of the chain immediately exposed, so that the oxygen formed in the xylitol group will be available for preferential connections with key�artsmediamag group such as the nitro group on the carrier surface.

If desired, these sugar binding units of biological origin can be shortened under the action of chondroitinase with obtaining a binder units containing fewer sugar groups after the initial group of xylose. Chondroitinase represent enzymes that are specific for different sugars.

Proteoglycans and their composition are described in the literature (Moses et al, 1997 a, 1997 b, 1998, and 1999, a and b (Doctoral Dissertation, Medical Faculty of Lund University, titled "Biosynthesis of the Proteoglycan Decorin, published 1999").

Another way to get a sugar binder units for use in the present invention is the synthesis. During the synthesis of the sugar binding units specified binding units can be designed with the desired composition and the desired length. Synthesized sugar binding units may be further attached to the carrier containing kislorodsvyazyvayushchei group, at the opening end of pentose group, for example, using an aqueous solution of sodium borate, NaBH4or in the processing of aqueous solution of NaCI, as is well known in this field. In addition to this initial additional pentose sugar group can be represented by a pentose or hexose.

Upon receipt of the carrier with the sugar binding units of the present invention preferred reaction�Stateline carried out at a pH of 5.6 or lower.

In oral communication in sugar binding units are broken by enzymes present in the saliva of most people. A special exception is made for individuals with Sjogren's syndrome, which do not have the right type of amylase, and in this regard they have not disintegrated sugar binding units. Other conditions that change the content of saliva or affect the production of saliva, can also affect enzyme activity. These conditions may be caused, for example, certain types of therapy, trauma, or tumors.

However, the delivery system of the present invention is not to be totally ineffective, even in the case of individuals with enzymatic deficiency, because relationships will be destroyed and not at such a low pH, as pH below about 5.6. The decrease of pH in the oral cavity to levels sufficient for the destruction of the sugar binding units, often occurs after eating, and leads to the release of biologically active substance from the delivery system.

The delivery system of the present invention has more advantages over the currently used delivery systems such as pills, injectable form, etc. the Main advantage is the ease of stopping treatment, while achieving the desired effect by simply removing the media from oral sex�STI. This means that treatment can be planned and conducted on an individual basis.

In addition, there is virtually no risk of overdose, since the carrier with the biologically active substance can be removed from the oral cavity at any time. Additionally, due to the high support of the ability of the delivery system of the present invention, the dose required to obtain the desired effect, so small that it is impossible the formation of harmful levels of substances.

The present invention may be implemented using any types of drugs and substances acting on the Central nervous system and the trigger signal from the brain. Accordingly, topically acting drug would be unacceptable for delivery according to the present invention, if such a drug would not have local activity for the oral cavity. In addition, drugs that are destroyed by saliva, such as paracetamol, unacceptable for delivery using the system of the present invention. A necessary condition is the fact that the bioactive molecule must include an active group capable of forming a bond with a sugar binder unit. Acting on CNS drugs was found among opioid agonists and OPIE�LiDE antagonists, of benzophenone and benzodiazepines. Other suitable drugs include funds that have an effect on the cardiovascular system and vascular system of the kidneys.

Some specific examples of drugs that are acceptable for delivery by the method of the present invention, include medicines used in disorders of motor function, such as scopolamine or citalopram. Other examples include analgesics such as ibumetin, codeine, morphines and tramadol, antihypertensives, antiarrhythmic, psychotropic pharmaceutical drugs, diuretics, bronchodilators, etc.

The specified media can be a carrier based on cellulose, such as nitrocellulose, or a media-based starch. The specified starch can be obtained by synthesis, or biochemically as a result of biosynthesis. Other suitable carriers include collagen, gelatin, elastin or other biomolecules that are able to form a similar matrix. The media is cellulose-based and media based on starch are preferred because of their low cost and easy availability of materials. The carrier material preferably remains inert in the oral cavity and is not soluble Il� otherwise does not change, at least, during the entire treatment period.

Due to the high efficiency of delivery of active substances, achieved when using the delivery system of the present invention, the specified media present in combination with a sugar binder units and the active substance, can be very small and still contain a sufficient dose of the active substance. To facilitate the manipulation of the media, which is placed in the oral cavity and then removed after completion of treatment, the specified media can be embedded in a manipulative device. Thus, the carrier can be attached to a material having a practical size. Without limitation it can be noted that the delivery system can be represented in a physical form such as foil, strip, patch, ball, ribbon, etc., where the specified system in the appropriate form may be attached to the carrier. It is also possible to use microspheres, etc., contained in the wrapper, permeable to saliva.

This delivery system may also include amplifiers of action of drugs and/or means to facilitate penetration and/or flavoring substance.

BRIEF description of the DRAWINGS

Further, the present invention is described in more detail using the attached to the description of drawings. Should�of divinity, that all the drawings and diagrams are given only for illustration purposes, and should not be interpreted as defining the boundaries of the field of the present invention, since the scope defined in the attached claims.

In the drawings:

Fig.1 is a diagram illustrating the results of a comparative test;

Fig.2 contains a description of the test groups A, b and C according to the procedure of the first example;

Fig.3 is a diagram illustrating a testing procedure according to the second example; and

Fig.4 shows an example of the carrier surface with powdered binder units.

DETAILED description of the INVENTION

Example 1

In order to demonstrate the effect of a delivery system comprising a carrier with attached sugar binding units of the present invention, in comparison with the media without sugar binding units, conducted the following tests.

The test results are given in the diagram shown in Fig.1. In these tests as a biologically active substance was taken citalopram, and the carrier was a carrier based on the matrix of nitrocellulose in the presence of sugar chains attached to the carrier, and without them. All media in the samples A, b, C and D were treated with the same amount of active substance (R) on the surface but�of RER. Processed substance carriers then subjected to a processing enzyme of saliva to restore any substance connected with the media.

Tests conducted with other substances such as scopolamine and ibumetin showed results similar to those shown in Fig.1.

Column in the diagram of Fig.1 illustrates the binding of citalopram with a native connected with nitrocellulose sugar binder unit of the present invention. The media is saturated with citalopram, so that all available binding sites were occupied with citalopram, as shown by the result of the restoration of citalopram at the level of 99.6% at release again when processing enzyme of saliva. Accordingly, almost the entire citalopram recovered from nitrocellulose/sugar membrane.

Column b shows the binding of citalopram with nitrocellulose medium without any sugar binding units. As shown in Fig.1, only about 24.8% of citalopram recovered in the processing of native enzyme of saliva. This experience shows that the carrier material itself, without sugar binding units, has a limited ability to contact with the substance.

Column C illustrates the result of the test conducted for the purpose of binding and release of substance from the carrier with nitrocellulose chains, containing sugar binding units, blocked by pre-saturation of another substance. Specified pre-saturation was performed by methylation of the sugar groups in a sugar binder units.

Column D illustrates the result of a comparative test conducted by only using pre-saturated media, without attached sugar binding units.

The tests show that, when all potential binding sites on the media blocked, citalopram is not absorbed or otherwise not captured by carriers, as can be seen from the fact that the media is not restored then the substance.

Example 2

The procedure of example 2 was conducted in order to demonstrate the release of citalopram in vivo using delivery system of the present invention.

For these tests used a standard white laboratory (white/white) rats. The animals were divided into three studied groups A, b and C consisting of 10 rats per group, as shown in Fig.2. In the study group A rats were given scopolamine. The indicated active substance has been associated with sugar chains, which, in turn, were associated with simple starch matrix, in accordance with the present invention. The matrix was fixed on the column, and �acharnae chain marked tritiumed the xylose according to the described procedure (Moses et al, 1997 a, 1997 b, 1998, and 1999, a and b (Doctoral Dissertation, Medical Faculty of Lund University, titled "Biosynthesis of the Proteoglycan Decorin, published 1999"), which enabled later to keep track of the sugar chains in the body of the rat.

The group served as the control, and the animals in this group were given unrelated scopolamine and starch matrix without sugar chains.

Animals in group C did not give neither the media nor the active substance.

All selected rats was characterized by normal production of saliva, and saliva of rats were also tested (results not shown) for determining the ability to release the connection from sugar media.

The size of the membrane was 1×1 mm, and the membrane was made of starch. With it linked sugar chain, and one such membrane is placed under the upper lip of each rat.

In this test used three equally calibrated centrifuge, one for each group of rats: A, b and C. Each centrifuge was placed in a box having an inlet/outlet through which rats could freely pass when moving between the cell and the centrifuge box. Initially, the rats were allowed to find their way into the centrifuge box, after which they were lifted and placed into the centrifuge.

Then rats were subjected to centrifugation at a speed of 3 G for 30 seconds.

After centrifugation monitored the ability of animals in each group And, In is to identify the exit of the centrifuge box and return to the cage and in General evaluated their stability.

In animals in group a, who were given 1/10 of the normal dose of scopolamine associated with the carrier of the present invention, it was not observed any deviations in normal behavior, such as signs of motor weakness, and they could immediately determine the output of the centrifuge box.

In animals in group b received the same amount of the substance, but this substance was not connected via a sugar chain with the matrix, was observed obvious signs of motor weakness, and they could not find the exit within 1-hour period of time.

The behavior of animals in the group, which gave neither the matrix nor the substance, it was about the same as the animals in group B.

The test was repeated with new groups of animals, divided into groups A, b and C, but they were given citalopram instead of scopolamine. The results of the second test were similar to the results obtained in the first test. Accordingly, the rats in group a centrifugation had no adverse effects, whereas rats in groups b and C showed clear signs of motor weakness.

Rats killed with carbon dioxide 4 hours after centrifugation, and then was selected to study the internal organs. The presence of scopolamine or citalopram in the body of rats was determined� according to the method of spectrophotometrically and using digital images as described by Goncalves, Diaz and Moses et al.

In animals in group A of the kidneys contain less than 0.1%, the liver is less than 0.2% and brain - 99% of the active substance. The remainder of the drug was distributed in other parts of the body.

Animals in the group found less than 4% of active substances in the brain, more than 75% in the kidney or the liver, and the remainder was distributed throughout the body.

The animals in group C, as expected, the active substance was not found anywhere else.

Thus, the results are the same for the scopolamine and citalopram, indicate that, in itself, the substance has no guiding effect.

Example 3

The following test was carried out on human volunteers.

Specified test involved a group of 19 people. Each subject, regardless of gender, were given 2 litres of red wine. Specified wine was taken in the evening for 3 hours before testing. The next morning all participants in the test were divided into two groups: A and B, respectively. Subjects in group A were given 40 mg (1/10 of normal oral administered dose) of ibumetin associated with the carrier, in accordance with the present invention. Subjects in group b were given a blank membrane only with sugar chains, but without active substance. The participants of the tests in group A feel my anger ... �Wali full relief from headaches, caused by red wine, for 5 minutes, whereas the trial participants in group b did not experience relief of a bare membrane with sugar chains. And in this regard the subjects in group b took 400 mg bumetanide by standard oral delivery. Noted different degrees of relief in 45 minutes - 1 hour. The test procedure is illustrated in Fig.3 in the form of a diagram.

Accordingly, experiments have shown that the delivery system of the present invention is fast and accurate. In addition, the released substance penetrates quickly through the oral mucosa and transported directly to the brain, without metabolic loss substances.

Fig.4 in schematic form shows the structure of the carrier (membrane) 1, containing sugar binding unit 2 connected to kislorodsvyazyvayushchei sites (X) in the carrier 1. Kislorodsvyazyvayushchei sites (X) may represent a P, C, S or N. Sugar binding units contain substituents, such as OH, NH, SO4or PO4that contributes to the formation of binding sites (B) for compounds of biologically active substance (R) with sugar chains.

The carrier can be any non-toxic material containing kislorodsvyazyvayushchei group, and may be based on cellulose or n� the basis of starch. Starch can be obtained by synthesis, or biochemically as a result of biosynthesis. Other suitable carriers include collagen, gelatin, elastin or other biomolecules, are able to form a similar matrix. Media based on cellulose, such as nitrocellulose, are preferred because of their low cost and availability of materials. Preferably, the specified media is essentially insoluble or insoluble in saliva, at least during that period of time, which, presumably, corresponds to the duration of the course of treatment.

According to the present invention binding sites (B) in the sugar-binding units contain 2 attached thereto a biologically active substance Specified R. biologically active substance may be any pharmaceutical agent or other substance acting on the Central nervous system and the trigger signal from the brain, as soon as it comes.

Sugar binding units may contain one or more sugar groups. Depending on the number of desirable binding sites (B), and the size and stereochemistry of bioactive molecules that are attached to the sugar chain can be constructed of a sugar chain, specifically suitable for each of the goals of their application.

When �omideyi of the drug in the oral cavity healthy individual enzymes of the salivary glands begin to act on the sugar chain and split link between sugar groups which leads to the release associated bioactive molecules, including sugar fragment and the biologically active substance (R) in the oral cavity, where said bioactive molecules can pass directly through the mucosa, as described above.

1. Delivery system for use in the oral cavity, where the system includes a carrier (1) for biologically active substances, characterized in that the carrier (1) comprises a material based on cellulose or material based on starch and has a surface that includes kislorodsvyazyvayushchei sites, and the fact that the system includes at least one binding unit (2) attached to the carrier (1), where the specified binding unit includes one or more sugar groups, where one or more bioactive molecules (R) attached directly to one or more sugar groups or by one or more substituents on one or more sugar groups by at least one connecting unit (2), where the binding unit
(2) represents a non-branched oligosaccharide or polysaccharide, where the binding unit (2) comprises a first end that is attached to kislorodsvyazyvayushchei group on the media,
(1) and where the first end contains a pentose group and where a connecting unit (2) comprises a sugar chain of the following formula: xylose-galactose�-galactose glucosamine.

2. The delivery system according to claim 1, characterized in that said kislorodsvyazyvayushchei sites (X) on the carrier (1) is selected from: R, C, S or N.

3. The delivery system according to claim 1, characterized in that the carrier (1) comprises nitrocellulose.

4. The delivery system according to claim 1, characterized in that said at least one linking unit (2) comprises a second end at which is glucosamine.

5. The delivery system according to claim 1, characterized in that said at least one linking unit (2) includes at least one Deputy, selected from HE, NH, SO4and PO4that comprises the binding site (C) biologically active substance (R).

6. The use of media (1), which contains material based on cellulose or material based on starch and has a surface that includes kislorodsvyazyvayushchei sites, and additionally includes at least one binding unit (2) attached to the carrier (1), where the specified binding unit includes one or more sugar groups, where the binding unit (2) is an unbranched oligosaccharide or polysaccharide and where the binding unit (2) comprises a first end that is attached to kislorodsvyazyvayushchei group on the carrier (1), and where the first end contains a pentose group, where the binding unit (2) comprises a sugar chain of the following formula: Xylo�a-galactose-galactose-glucosamine, to obtain a delivery system for the release of biologically active substances in the oral cavity, where the delivery system is characterized in that one or more biologically active substances (R) attached directly to one or more sugar groups or by one or more substituents on one or more sugar groups specified in the connecting unit (2) and the carrier (1) with a biologically active substance (R) is placed in the oral cavity and arranged so that upon contact with saliva enzyme is the release of biologically active substances (R).

7. The use according to claim 6, where enzymes in saliva break down the linkages between the sugar groups in the junction unit (2), leading to the release of at least one bioactive molecules, including biologically active substance (R) attached to a sugar group in the specified binder unit (2).

8. The method of producing a delivery system for releasing a biologically active substance (R) in the oral cavity, characterized by the fact that
(a) receive carrier (1) which has a surface comprising kislorodsvyazyvayushchei sites (X);
(b) perform linking at least one connecting unit (2) with the carrier (1), where the specified binding unit (2) at a first end contains a pentose group, and also includes one or more sugar groups, where the binding� unit (2) comprises a sugar chain of the following formula: xylose-galactose-galactose-glucosamine, and where the specified pentose group attached to one of the above kislorodsvyazyvayushchei sites (X);
c) conduct the binding of one or more bioactive molecules (R) directly from one or more sugar groups or with one or more substituents on one or more sugar groups in at least one of the binding units (2).

9. A method according to claim 8, in which the binding of at least one connecting unit (2) with the carrier (1) is carried out in an aqueous solution having a pH of 5.6 or lower.

10. A method according to claim 8 or 9, in which the specified kislorodsvyazyvayushchei sites (X) on the carrier (1) is selected from P, C, S, and N.

11. A method according to claim 8, wherein said carrier (1) comprises a material based on cellulose or material based on starch.

12. A method according to claim 8, wherein said carrier (1) comprises nitrocellulose.

13. A method according to claim 8, in which the specified binding unit (2) is an unbranched oligosaccharide or polysaccharide.

14. A method according to claim 8, in which the specified sugar binding unit (2) include at least one Deputy, selected from HE, NH, SO4or PO4that comprises the binding site (S) for biologically active substances.



 

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26 cl, 8 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: amlodipine base or its pharmaceutically acceptable salt, preferentially amlodipine besylate, bisoprolol fumarate, a disintegrating agent, a wetting agent, and if necessary additional excipients are homogenised; an antiadhesion agent is added, and the homogenisation procedure is continued; the homogenate is then tabletted by direct compression, or solid gelatine capsule is filled in; the prepared tablets or capsules are packed in moisture-proof protective packaging. The prepared tablets or capsules contain less than 0.5 wt % of active ingredients of compounds of formula

.

EFFECT: what is described is a method for preparing the stable solid pack dosage form containing the amlodipine base or its pharmaceutically acceptable salt and bisoprolol fumarate.

3 cl, 6 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the pharmaceutical industry and provides a multilayered tablet, containing an effervescent layer, containing hydrochlorothiazide or amlodipine or its salt as an active ingredient, carbonate salt and organic acid, and a telmisartan-containing layer.

EFFECT: obtaining the multilayered tablet, containing the effervescent layer.

1 dwg, 9 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns a hot-melt extruded pharmaceutical dosage form with controlled-release pharmaceutically active ingredient (A) enclosed in a matrix containing polymer (C). A core of the pharmaceutical dosage form is morphologically oriented according to the holt-melt extrusion, which is substantially orthogonal to a long direction of the dosage form; and/or a release per a unit area of the pharmacologically active ingredient (A) through a front side and an opposite back side is faster than that through an annular ring.

EFFECT: dosage form shows min breaking strength 300 H; it has an oblong shape with the long direction and the cross direction orthogonal to the long one, with the front side opposite to the back side, and the annular rim between the above front and back sides.

11 cl, 20 tbl, 3 ex, 13 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine. What is described is a pharmaceutical composition containing licarbazepine acetate, preferentially eslicarbazepine acetate, in a combination with acceptable excipients, particularly a binding agent and a disintegrating agent. What is also described is a method for wet granulation for preparing the pharmaceutical composition.

EFFECT: composition is compacted as a tablet, which has reduced size and volume density.

79 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for producing a tablet by (i) compressing a powder mixture in a mould plate of one device for producing a tabletted form with the powder mixture comprising a pharmaceutically active substance and a fusible binding agent, and (ii) exposing the above tabletted form to radio-frequency radiation generated by the above device over a period of time adequate to soften or melt the binding agent inside the above tabletted form to produce a tablet. Oral absorption of the produced tablet placed on the tongue takes less than approximately 30 s.

EFFECT: more effective method for producing the tablet by (i) compression.

18 cl, 14 dwg, 7 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention provides a composition having antioxidant properties in the form of a tablet, comprising an active agent based on nicotinamide adenine dinucleotide in reduced form (NADH) and inert filling agents, characterised by that the active ingredient is a complex which is a mixture of 10 wt % NADH with 63 wt % vegetable fats, 17 wt % beeswax and 10 wt % chlorophyll, and the inert filling agents are in the form of microcrystalline cellulose, Macrogol 6000, intense sweetener and a food flavourant.

EFFECT: invention provides a new tablet form of NADH.

1 ex

FIELD: food industry.

SUBSTANCE: invention relates to food products having prophylactic effect. The fat-binding composition contains an inclusion complex with a host molecule and a guest molecule. The guest molecule is represented by alpha and beta cyclodextrins. The guest compound may be represented by one or more quantities of compounds from the following list: amino acids, vitamins, flavouring substances and their related compounds, rutin, betanin and their derivative compounds and mixtures. The guest molecule is bound to the host molecule weakly and reversibly so that to enable substitution of the guest compound molecule with a fat molecule in a physiological medium, binding of such fat molecule being virtually irreversible. The proposed fat-binding composition may exist, for instance, in the form of a tablet or powder and may be included into the formula of a food product such as beverage. The proposed fat-binding composition (if prepared in the form of a tablet of powder) may optionally include a component providing for carbon dioxide release , with the composition to be dissolved in fizzy carbonated or still water.

EFFECT: proposed fat-binding composition may be used in a method for binding fat consumed by an animal, such method involving the animal consuming the proposed fat-binding composition or a food product or beverage containing it.

17 cl, 3 dwg, 6 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention represents an encapsulated liposomal antiviral agent based on human interferon alpha-2b for vaginal application, characterised by the fact that each capsule is made in the form of a hollow coating, which encloses a powder excipient and liposomes distributed in the excipient, and sodium alginate, a water-soluble polymer gel former; the excipient consists of lactose, sodium chloride, 12-aqueous disodium hydrogen phosphate and sodium dihydrogen phosphate, whereas each of the liposomes represents a hollow coating containing lecithin, cholesterol and alpha-tocopherol, and a nucleus inside the coating and containing recombinant human interferon alpha-2; the ingredients of the agents are taken in a certain ratio, mg.

EFFECT: maintaining the storage activity of recombinant human interferon alpha-2 and prolonged action in vaginal application.

2 cl, 3 dwg, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a polymeric carrier molecule, a complex of a polymeric carrier with a load, a method of producing a polymeric carrier molecule, a pharmaceutical composition and a vaccine. In one of the versions, the polymeric carrier molecule has the following formula (I): L-P1-S-[S-P2-S]n-S-P3-L and additionally contains in the structure at least one amino acid component (AA)x, wherein AA is an amino acid, x is an integer selected in the range of 1 to 100. If the amino acid component (AA)x is present in the structure, then it is a linker between P1 or P3 and component L. If component L is absent, then at least one amino acid component (AA)x is part of P1 or P3. Components P1 and P3 are different or identical and are a linear or branched chain of a hydrophilic polymer of polyethylene glycol (PEG); P2 is a cationic or polycationic peptide or a protein with length of 3 to 100 amino acids, or a cationic or polycationic polymer with molecular weight of 0.5 kDa to 30 kDa; -S-S is a disulphide bond; L is an optional ligand, n denotes an integer selected from 1 to 50. According to the second version, the polymeric carrier molecule has the formula (Ia) l-P1-S-{[S-P2-S]a[S-(AA)X-S]b}-S-P3-L, where a+b=n, where n equals 1, 2, 3, 4 or 5 to 10; a is an integer selected independent of integer b in the range of 1 to 50, b is an integer selected independent of integer a in the range of 1 to 50. Separate components [S-P2-S] and [S-(AA)x-S] are present in any order in the subformula {[S-P2-S]a[S-(AA)x-S]b}. The complex of the polymeric carrier with a load is formed by the polymeric carrier molecule and a nucleic acid. A pharmaceutical composition and a vaccine include the complex of the polymeric carrier with a load and optionally a pharmaceutically acceptable carrier and/or solvent. Polymeric carrier molecules and the complex of the polymeric carrier with a load are used as a medicinal agent for treating various diseases.

EFFECT: invention enables to obtain a stable polymeric carrier which enables efficient transfection of nucleic acids in cells in vivo and in vitro.

20 cl, 16 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention represents an agent for treating septic wounds, pus pockets and trophic ulcers containing betaine hydrochloride, methyluracil, trimecaine, pepsin powder and polyethylene oxide 400 with the ingredients taken in certain proportions, wt %, and polyethylene oxide 400 is taken in an amount of 87.0-84.0 ml.

EFFECT: invention provides fastening necrolysis, intensifies bactericidal action, stimulates regeneration, prevents secondary infection.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to prodrug preparations of glucagon superfamily peptides, in which the glucagon superfamily peptide is modified by binding a dipeptide with the peptide of the glucagon superfamily by an amide bond.

EFFECT: produgs, disclosed in the claimed invention, have an increased half-life and transfer into an active form in physiological conditions as a result of a non-enzymatic reaction, caused by chemical instability.

30 cl, 15 dwg, 8 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention represents an agent for accelerating wound healing and tissue regeneration, containing oxymethyluracil, loratadine, sodium alginate, glycerol, a stabilising agent, a preserving agent and distilled water; the ingredients of the agent are taken in certain proportions, wt %.

EFFECT: accelerating wound healing and tissue regeneration, as well as possesses the pronounced immunomodulatory, anti-inflammatory, anti-allergic, anti-pruritic, anti-edematous and wound-healing action.

2 cl, 3 ex, 1 tbl

FIELD: biotechnology.

SUBSTANCE: invention relates to a biodegradable synthetic polymer, namely to the polymer of the general formula (I) , where NA has the structure: , AN has the structure: , where n is an integer >2; Z is either absent or is an amino acid residue -NH-(CH2)i-CO-, where i - is an integer from 1 to 5; D represents a linear or branched alkyl C1-C5 or benzyl; B represents a residue of aliphatic diamine -NH-(CH2)k-NH-, where k is an integer from 2 to 6; X and Y can simultaneously have the following meanings: X=H-B, Y=H, or X=Nα-(D-OCO)-L-arginyl-Z-B, Y=Nα-(D-OCO)-L-arginyl-Z, or X=R1-AN-B, Y=NA-R1, where R1 is carboxamide-alkyl of the type H2NCO-CH2- or H2NCO-CH2CH2-. Such a polymer is capable of delivering the natural L-arginine into the tissues of human, animals, through biological membranes and can be used alone or in a combination with other active compounds.

EFFECT: invention enables to obtain the polymer soluble in water, which has no cytotoxicity and enhances the level of nitrogen oxide in the tissues of humans and animals.

2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, more specifically to a method for producing a mixture of mono- and di-pegylated IL-10, and can be used in medicine. The above method consists in carrying out a reaction of IL-10 protein in the concentration of 1 to 12 mg/ml with activated PEG-linker, wherein the relation of IL-10 and PEG-linker makes 1:1 to 1:7.7 in the presence of 25 to 35 mM of the reducing agent. The appropriate cases may require purifying the produced mixture of IL-10. The invention also refers to a pharmaceutical composition for treating a proliferative condition or disorder, containing a therapeutically effective amount of the mixture of mono- and di-pegylated IL-10 produced as described above, and a pharmaceutically acceptable carrier.

EFFECT: invention enables producing the mixture of mono- and di-pegylated IL-10 accompanied by no side products produced and keeping the protein dimer structure non-destructive.

16 cl, 2 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biochemistry, particularly to a recovered monoclonal anti-LOXL2 antibody or its antigen-binding fragment, as well as conjugates containing them. What is disclosed is a pharmaceutical composition for treating a disease related to angiogenesis, fibrosis, tumour or metastases, containing the above recovered monoclonal anti-LOXL2 antibody or its antigen-binding fragment in an effective amount. The invention also refers to a method for determining and/or measuring LOXL2 in a biological sample, to a method for inhibiting LOXL2 activity, to a method for reducing growth of LOXL2-expressing tumour in an individual in need thereof, to a method for inhibiting angiogenesis in the individual in need thereof, to a method for suppressing a fibrous disease in the individual in need thereof, as well as to a method for monitoring an individual's response to an anti-LOXL2 therapy with using the above antibody or its antigen-binding fragment and the above conjugate.

EFFECT: invention enables treating the LOXL2-related diseases effectively.

28 cl, 6 dwg, 6 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry and presents a conjugation product, comprising polysaccharides T1 and T2, where the monosaccharides which form the polysaccharides T1 and T2 are bonded to each other by alpha-1,4-glycosidic links. At least one of the polysaccharides T1 and/or T2 comprises at least one amino group. T1 and T2 are bonded to each other covalently by a linker. T1 and/or T2 carry m groups -(L-A), wherein A is glucosaminoglycan or a derivative of glucosaminoglycan, glucosaminoglycan or a derivative of glucosaminoglycan with fluorescence labels, L is a second linker, by which T1 and/or T2 are covalently bonded to A, and m is at least 1.

EFFECT: invention also relates to a pharmaceutical composition, comprising a bonded product; use of the product in medicine and cosmetology and to the method of preparation of the bonded product.

22 cl, 5 ex

FIELD: biochemistry, pharmaceutical chemistry.

SUBSTANCE: invention relates to preparing conjugate of naturally occurring or recombinant urate oxidase (uricase) bound covalently with poly-(ethylene glycol) or poly-(ethylene oxide) (both are designated as PEG) wherein in average from 4 to 10 PEG strands are conjugated with each subunit of uricase and molecular mass of PEG is about between 20 and 40 kDa. Prepared PEG-uricase conjugates are nonimmunogenic practically and retain at least 75% of uricolytic activity of nonmodified enzyme.

EFFECT: improved preparing method, valuable properties of conjugates.

22 cl, 17 dwg, 12 ex

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