Self-gelatinised alginate systems and application thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, more specifically to biocompatible alginate systems with the delayed gelatinisation process. There are offered sets and compositions for making a self-gelatinised alginate gel containing sterile water-soluble alginate and particles of sterile water insoluble alginate with a gelling ion. There are offered methods for dosing self-gelatinised alginate dispersion for making the self-gelatinised alginate gel. The methods can include dosing the dispersion in an individual. There is offered the self-gelatinised alginate gel of the thickness more 5 mm and not containing one or more sulphates, citrates, phosphates, lactates, EDTA or lipids. There are offered implanted devices coated with the homogeneous alginate gel. There are offered methods for improving viability of pancreatic islets or other cell aggregate or tissue, after recovery and while stored and transported.

EFFECT: group of inventions provides creation of the alginate gelling system which contains alginate and the gelling ions with high biological compatibility; enables the gelatinisation process without pH variations, connected with the other systems, and requires minimum ingredients, thus provides variation of gelatinisation time and gel strength depending on the specific requirements.

62 cl, 11 dwg, 2 tbl, 27 ex

 

The technical FIELD

The present invention relates to alginate systems that have delayed the process of gelation, and compassites, devices, kits and methods of making and using these systems.

The LEVEL of TECHNOLOGY

This application claims priority in provisional application U.S. No. 60/617852, entitled "Self-Gelling Alginate Systems and Uses Thereof", filed October 12, 2004, which is incorporated herein by reference.

Alginates are hydrophilic marine biopolymers, with a unique ability to form stable gels that can be formed and dried at physiologically significant tempaerature. Alginates are a family of unbranched double copolymers residues of β-D-mannurone acid (M) and α-L-glucuronic acid (G), United 1-4 glycosidic bond. The relative amount of the two monomers of the uronic acid and the sequence of their arrangement in the polymer chain varies widely depending on the nature of the alginate. Alginate is a structural polymer of brown algae such as Laminaria hyperborea, Macrocystis pyrifera, Lessonia nigrescens and Ascophyllum nodosum. Alginate also produce some bacteria, such as Pseudomonas aeruginosa, Azotobacter vinelandii and Pseudomonas fluorescens (WO04011628 A1).

Alginate is eaten formed, when the divalent cation forms ionic bonds with the negatively charged group of the G residue of each of two different alginate polymers, resulting in two polymer to be cross stitched. The formation of multiple cross-links between numerous alginate polymers leads to the formation of the matrix, which represents the structure of the alginate gel.

Alginate gels can be a hydrogel, i.e. transversely crosslinked alginate polymers, which contain large amounts of water without dissolving. Biopolymer gels such as alginate hydrogels are attractive candidates for tissue engineering and other biomedical purposes. Because of this, as well as the ability to form gels in physiological conditions, alginates are widely used and studied for the purpose of encapsulation and as biostructures material. The inclusion of cells in alginate granules is widely used methodology. It was also shown that alginates are useful material for other types of biological structures, including tissue engineering, and as frameworks for the regeneration of nerves.

There are various methods for the production of alginate hydrogels. The most common method is a method of dialysis/diffusion, when what oterom alginate solution heliroute diffusion gel-forming ions from the external tank. This method is usually used for the manufacture of alginate gel pellets, as well as for food purposes. Production of alginate micro granules is a quick process, limited by the diffusion of gel-forming ions in the gel network. Although this process is well suited for encapsulation of cells in the microspheres, it is less suitable for the manufacture of other forms or structures. For the manufacture of gel structures of large dimensions diffusion gelling systems may have limited opportunities. This is because rapid gelation process limits the time required to form the gel structure.

Delay the gelation process can be used for injection of fluids in the body and/or to contact the cells or other biological material to a gel matrix until the formation of gel. Thus, alternative methods have been developed for the manufacture of other types of biocompatible alginate gel structures. The rate of gelation can be reduced by using existing inside gelling systems, of which the gel-forming ions are released inside the forming gel more slowly. It is described as hardening of the gel from the inside. Usually current inside the gel-forming system calcium salt with limited R is stoimosti or compassione ions of CA 2+mixed with alginate solution in which calcium ions are slowly released. Calcium sulfate is used in the media for delivery of cells on the basis of alginate for tissue engineering. Calcium release and the kinetics of gelation can be controlled by the use of calcium salts with a pH-dependent solubility and add a slow-acting acid, such as D-glucono-δ-lactone (GDL). When changing the pH of the calcium ions are released. Also liposomes containing calcium, used as a controlled gelling alginate systems. Alginate gel systems based on internal gelation may have more specific and limited supply of gel-forming ions in contrast to the diffusive systems, in which the calcium ions diffuse into the alginate solution with the formation of a saturated calcium gel.

Modern methods for the production of alginate gel structures have limitations. Some of the technology is suitable only for the manufacture of gels limited sizes and shapes. Depending on use, there may be problems associated with the control of the kinetics of gelation. In some cases, the gels are unwanted materials, as these materials represent residues and by-products the points of mechanisms of gelation, which was controlled by chemical means. In some cases, gelation requires non-physiological pH values, and such conditions may present limitations for use of these methods. Thus there is a need for other gelling systems and computesize.

The INVENTION

The present invention relates to kits for producing alginate gel. The kits comprise a first container containing a soluble alginate, and a second container containing particles of insoluble alginate/gelling ion.

The present invention relates also to compassites for production of alginate gels. Compatabile include directly soluble alginate and particles of insoluble alginate/gelling ion.

The present invention relates also to a method of dispensing camogliese alginate dispersion. The methods include forming a dispersion of particles of insoluble alginate/gelling ion in a solution of a soluble alginate and dosing dispersion, whereby the dispersion of the alginate forms a gel matrix.

The present invention relates also to a method of dispensing camogliese alginate dispersion of the individual. The methods include forming a dispersion of particles of rastvorimy alginate/gelling ion in a solution of a soluble alginate and dosing dispersion of the individual, whereby the dispersion of the alginate forms a gel matrix in the body of the individual.

The present invention relates also to a method of dispensing camogliese alginate dispersion of the individual for use as a material to increase the amount of fabric for use in the procedure embolization of vessels applying for preventing the formation of adhesions after surgery, for use in the routine treatment of wounds, use for the treatment of diabetes and use to treat arthritis.

The present invention relates also to a method of applying inatentive alginate gel. The methods include forming camogliese of alginate by dispensing camogliese alginate dispersion and after the formation of the gel inatentive inatentive alginate gel to the individual.

The present invention relates also to methods of manufacturing impatiantley devices.

The present invention relates to alginate gels, having a thickness of 5 mm and a homogeneous network alginate matrix.

The present invention relates to alginate gels with a thickness of more than 5 mm and not containing one or more of sulfates, citrates, phosphates, lactates, EDTA or lipids.

The present invention relates also to inatentive the output devices, including homogeneous alginate gel coating.

The present invention relates also to a method of sealing or repair of bone and cartilage defects resulting from osteoarthritis, by dispensing camogliese alginate dispersion, which contains chondrocytes, in the body of an individual or by impatiently biologically compatible matrix which contains the chondrocytes in the body of the individual.

The present invention relates also to methods for treating diabetes by dispensing camogliese alginate dispersion, which contains insulinproducing cells or multicellular aggregates, in the body of an individual or by impatiently biologically compatible matrix which contains insulinproducing cells or multicellular aggregates, in the body of the individual.

The present invention relates also to a method of improving the viability of pancreatic islets or other cellular aggregates or tissues after extraction and during storage and transportation by incorporating Islands or cell aggregates or tissue in camogliese alginate dispersion.

The present invention relates to ultrahigh-purity particles of insoluble alginate/gelling ion and methods for their manufacture.

The BRIEF DESCRIBED THE E SHAPES

Figure 1 contains data realtionship measurements. Oscillatory measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of the gels with the following different concentrations of alginate calcium (Protaweld TX 120) (concentration in blend/gel): 1.0% calcium alginate mixed with 1.0% sodium alginate and 1.5% alginate calcium, mixed with 1.0% sodium alginate, and 2.0% alginate calcium, mixed with 1.0% sodium alginate. As the sodium alginate used Protanal SF 120.

Figure 2 contains data realtionship measurements. Oscillatory measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of gels made by mixing equal quantities of sodium alginate (Protanal SF 120) and calcium alginate (Protaweld TX 120) with the following concentrations in the gel: 0,75%, 1%, to 1.25% or 1.5% of sodium alginate and calcium alginate.

Figure 3 contains data realtionship measurements. Oscillatory measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of gels containing calcium alginates (part a) and sodium alginates (part b) with different molecular weights. Gels on the graph And containing 1% of sodium alginate and 1.5% of calcium alginate and gels on the graph To contain 1% of calcium alginate and 1% alginate is the atrium. In the graph And used the following alginates: Alginate calcium: Protaweld TX 120 and Protaweld TX 120, decomposed in 33 days at 60°C. Viscosity (1% solution at 20°C) two Sa alginates, measured as sodium alginate, was 270 and 44 , respectively. Sodium alginate: Protanal SF 120. In the graph used In the following alginates: Alginate calcium: Protaweld TX 120. Sodium alginate: Protanal SF 120 and Protanal SF/LF. Viscosity (1% solution at 20°C) of sodium alginates were 95 and 355 , respectively.

Figure 4 contains data realtionship measurements. Oscillatory measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of gels made with strontium or calcium as the gel-forming ions. The amount of sodium alginate (Protanal SF 120) and strontium alginate/calcium drove up to 0.75% of the content in the gel for each. Used calcium alginate was obtained by mixing of alginic acid (the product of the process FMC) (65,2 g) with calcium carbonate (35.32 per g) in the laboratory meilke for 1 hour, then drying and grinding. Used strontium alginate was obtained by mixing of alginic acid (the product of the process FMC) (65,2 g) strontium carbonate (52,10 g) in laboratory stirrer for 1.5 hours, then drying and grinding.

Figure 5 contains data realtionship serenelli the measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of gels containing sodium alginate with high and low content guluronic acid. In figure 5, part a, the amount used of calcium alginate (Protaweld TX 120) and sodium alginate was brought up to 1.0% of the content in the gel. Used alginates, sodium Protanal SF 120 (69% G) and Protanal HF 60D (32% G MM: 119 000). In figure 5, part b, 5.5% of strontium alginate (example 14) was mixed with 1.25% sodium alginate in a ratio of 1:4 (the final concentration of alginate was 2.1%). Used alginates, sodium PRONOVA UP 100G (69% G MM: 122 000) and PRONOVA UP 100M (46% G MM: 119 000). Picked up as much as possible similar to MM (and viscosity) of the two parties of sodium alginate. Each curve in the figure 5, part b represents the average from three independent measurements (curves) with the standard error of the mean shown for each item.

Figure 6 shows the stability and Biodegradability alginate gels made with different content of calcium ions and stored for 6 months under physiological conditions. Gel disks were made by mixing autoclaved dispersions of calcium alginate (Protaweld TX 120) and sterile filtered of sodium alginate (PRONOVA UP LVG) to a final concentration of 1.0% each of alginate and variance reliabale in two Petri dishes. Gel disks in one Cup (labeled V) were washed in 50 mm chlorine is the home of calcium within 10 minutes after zastudnevaniju, and then in both cups were added to the medium for cell culture (DMEM with addition of 10% FBS). The cups were kept in sterile conditions in CO2-thermostat and the environment regularly changed three times a week. The size of the largest gel disc in each Cup were originally one and the same. Shows the pictures were taken six months later.

Figure 7 shows the data of the experiments using cells, prisoners in camogliese alginate. Figure 7, part a, shows the mouse cultured myoblasts SS 45 days after the conclusion in camogliese alginate gel. The gel is produced and stored, as described in figure 6, but with the included cells. The photo was taken using a fluorescent microscope after staining of cells with callainos (Molecular Probes, L-3224) as a marker of cell viability. Enlightened areas and spots indicate the presence of viable cells. Viable cells are located inside and on the surface of the gel structure. Figure 7, part b, shows human chondrocytes, prisoners in camogliese alginate gel. The gel is made from 5 ml mixed camogliese gel PRONOVA SLG 20 and calcium alginate (example 14), containing human chondrocytes. Three days after zastudnevaniju gels cut to 600 μm environment using vibratome. The gel slice is kept in growth medium for cells in CO 2-thermostat, and the photo was taken six months later. The photo was taken using a fluorescent microscope after staining of cells with callainos (Molecular Probes, L-3224) for viability and clearly shows the presence of a large number of viable cells (enlightened areas).

Figure 8 contains data realtionship measurements. Oscillatory measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of gels containing 1,25% of sodium alginate (PRONOVA UP 100G) mixed with 5.5% of the strontium alginate (example 14) in the ratio of 4:1 (final concentration of alginate was 2.1%) in the presence or in the absence of sodium chloride or sodium hexametaphosphate. Each curve represents the average of three independent measurements (curves) with the standard error of the mean shown for each point.

Figure 9 contains the data realtionship measurements. Oscillatory measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of gels containing 1,25% of sodium alginate (PRONOVA UP 100G) mixed with 5.5% of the calcium alginate (example 14), made with different particle sizes in the ratio of 4:1 (final total concentration of alginate was 2.1%). Different particle sizes were obtained by grinding lio is alizirovannoj of calcium alginate and sieving to obtain the specified dimensions. Each curve represents the average of three independent measurements (curves) with the standard error of the mean shown for each point.

Figure 10 contains the data realtionship measurements. Oscillatory measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of gels containing 1,25% of sodium alginate (PRONOVA UP LVG) in a mixture of 10% calcium alginate (example 14), at various tempaerature in the ratio of 9:1 (final concentration of alginate was 2%).

Figure 11 contains the data realtionship measurements. Oscillatory measurements were carried out using a rheometer Physica MCR300. Shows the storage modules depending on the time of gels containing sodium alginate with different molecular weights. The gel contains a 1.25% of sodium alginate (PRONOVA UP 100G), decayed (control), or the same batch of alginate decomposed. Was also made gel is decomposed of sodium alginate concentration of 2.5% (upper curve). In all cases, alginates, sodium was mixed with 5.5% of the strontium alginate (example 14) in the ratio of 4:1. Each curve represents the average of three independent measurements (curves) with the standard error of the mean shown for each point.

A DETAILED DESCRIPTION of the PREFERRED embodiments

R is developed alternative alginate gelling system. This system is used in many biomedical purposes, as well as in other areas. The system can include alginate and gel-forming ions, which have a high degree of biocompatibility. The system provides for the variation of the time of gel formation and gel strength depending on the needs of a particular application. The system provides a gelation without changes in pH associated with other systems, and requires a minimum number of compatments.

The system includes two compatment: one is a soluble alginate; the other represents particles of insoluble alginate/gelling ion. When compatment combine in the presence of a solvent to obtain a dispersion is formed in alginate gel as the gel-forming ion particles starts cross-linking of the alginate polymers of the particles and soluble alginate polymers in solution. Two compatment can be mixed by stirring or using a suitable mixing device. The kinetics of gelation of compatabile depends on several factors, including: the concentration of the soluble alginate in solution, the concentration of particles of insoluble alginate in the dispersion, the content of gelling ion relative to algina is, the presence agileoresund ions or other carbohydrates, tempaerature, the particle size of insoluble alginate/gelling ion, the content of the cells, multi-cellular aggregates, tissues or other biological materials that should be placed in a gel or present during gelation (impurities), and the types used of alginates, as well as the process of making particles of insoluble alginate and post-processing alginate source materials. This alginate system, therefore, can be widely adapted for each specific purpose. To place cells, multi-cellular aggregates, tissues or other biological materials in forming the gel, the solvent, the alginate solution or dispersion can be pre-mixed with material that should be signed.

The variance can be dosed to the individual in the form of a liquid/mist in the area in which it is desirable to obtain alginate gel matrix. The formation of alginate gel triggered when a soluble alginate and particles of insoluble alginate/gelling ion mixed in the presence of a solvent, and continues alginate gel hardens in situ. Used herein, the term "camogliese" refers to the process of gelation, which OBS is given, when soluble alginate and particles of insoluble alginate/gelling ion are mixed in the presence of a solvent. "Camogliese alginate" is an alginate dispersion or gel, which includes or is formed soluble alginate and particles of insoluble alginate/gelling ion in the solvent.

Compatment used in the system, you can contain before use in any of several forms. For example, soluble alginate can contain, in solution or in powder form. In some embodiments, implementation of the present invention are soluble alginate can be kept in the form of a powder, which immediately dissolves, such as dried powder. Similarly, particles of insoluble alginate/gelling ion can be kept in the form of a dispersion or in the form of powder.

Alginate polymers or combinations thereof, used in a soluble alginate may be the same or different from the alginate polymers or combinations thereof in the particles of insoluble alginate/gelling ion.

The concentration of alginate as a soluble alginate and alginate in the form of particles of insoluble alginate/gelling ion in the dispersion relative to the amount of solvent effect on the gelation time, porosity, stability and Borislava the pany, the strength and elasticity of the gels, and can produce gels with specific properties, using specific ratios of soluble alginate and particles of insoluble alginate/gelling ion with the solvent. Usually, the lower the concentration of alginate (for a given ratio of soluble and insoluble alginate alginate), the more biodegradable will gel. In some embodiments, implementation of the present invention can be used approximately 0,5%, 0,75%, 1%, 1,25%, 1,5%, 2%, 2,5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or more alginate (soluble alginate and alginate in the form of particles of insoluble alginate/gelling ion).

The relative concentration of soluble alginate in relation to alginate in the form of particles of insoluble alginate/gelling ion in the dispersion effect on the gelation time, the pore size, the strength and elasticity of the gels, as well as the stability and Biodegradability, and can produce gels with specific properties, using specific ratios of soluble alginate and particles of insoluble alginate/gelling ion. In some embodiments, implementation of the present invention, the concentration of soluble alginate is approximately equal to the concentration of alginate in the form of particles of insoluble alginate/gelling ion (1:1). In nektarinukiniai implementation of the present invention, the concentration of alginate in the form of particles of insoluble alginate/gelling ion is twice the concentration of the soluble alginate (2:1). In some embodiments, implementation of the present invention, the concentration of alginate in the form of particles of insoluble alginate/gelling ion is half of the concentration of soluble alginate (1:2). In some embodiments, implementation of the present invention, the concentration of alginate in the form of particles of insoluble alginate/gelling ion relates to the concentration of soluble alginate as 1 to 0,7 (1:0,7). Typically, the smaller the presence of gel-forming ion, the more biodegradable will gel. You can apply a decrease in the concentration of insoluble alginate/gelling ion in the system to create gels with lower stability and higher Biodegradability, related to the fact that the gel network is less busy ions, providing cross-stitching. Simuliranje amends in the manufacture of gels with lower concentrations of gelling ion, to obtain gels, particularly well suited for such purposes, where required biological decomposition. In some preferred embodiments, the implementation of the present invention the relationship of alginates in the particles of insoluble alginate/gelling ion and soluble alginate are 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4 or 1:5.

The relative content of monomers G and M alginate polymers affects the time the EP long stability and Biodegradability, strength and elasticity of the gels. Alginate polymers have different variations of the total content of M and G, and the relative content of successive structures also varies widely (G-blocks, M-blocks and MG alternating sequence), as the length of the sequences along the polymer chain. Usually, the lower the content of G is compared with the content of M used in the alginate polymers, especially biodegradable will gel. Gels with a high content of G alginate tend to have larger pore sizes and are more durable compared to gels with a high content of M in the alginate, the size of the pores smaller, and the strength is lower. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix contains more than 50% α-L-guluronic acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix contain more than

60% α-L-guluronic acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix contain from 60% to 80% α-L-guluronic acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix contain from 65%to 75% α-L-guluronic acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix containing more than 70% α-L-guluronic acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix contains more than 50% With 5 epimer β-D-mannurone acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix containing more than 60% With 5 epimer β-D-mannurone acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix contain from 60% to 80% With 5 epimer β-D-mannurone acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix contain from 65% to 75% With 5 epimer β-D-mannurone acid. In some embodiments, implementation of the present invention one or more of the alginate polymers of the alginate matrix containing more than 70% With 5 epimer β-D-mannurone acid. Procedures for obtaining uronic units are described in U.S. patent No. 6121441. G-block alginate polymers and their use as modulators of the properties of alginate gels are described in U.S. patent No. 6407226. Some preferred embodiments of this the total of the invention, 30% G 35% G, 40% G 45% G 50% G, 55% G 60% G 65% G 70% G 75% G 80% G or 85% G.

The average molecular mass of the alginate polymers affects the gelation time, the pore size, the strength and elasticity of the gels. Alginate polymers may have an average molecular weight of from 2 to 1000 kDa. Molecular weight of alginates can affect gelation and final properties of the gel. Usually, the lower molecular weight used alginate, the more biodegradable will gel. Alginate polymers or combinations thereof, used in compatment soluble alginate may be the same or different from the polymers or combinations thereof, used in the particles of insoluble alginate/gelling ion. In some embodiments, implementation of the present invention the alginate polymers of the alginate matrix have an average molecular weight of from 5 to 350 kDa. In some embodiments, implementation of the present invention the alginate polymers of the alginate matrix have an average molecular weight of from 2 to 100 kDa. In some embodiments, implementation of the present invention the alginate polymers of the alginate matrix have an average molecular weight of from 50 to 500 kDa. In some embodiments, implementation of the present invention the alginate polymers of the alginate matrix have an average molecular weight of from 100 to 1000 kDa. In some the older variants of implementation of the present invention formulated gels, having a high degree of Biodegradability. Accordingly, gels, containing less of alginate less gelling ion, alginates with a lower content of G and lower molecular weights, can be produced using lower limits of these parameters, as described herein, to obtain gels with a higher degree of Biodegradability.

Alginate can have a viscosity in 1% solution, measured at 20 degrees Celsius, from 25 to 1000, and in some embodiments, implementation of the present invention, preferably, from 50 to 1000 (1% solution, 20°C).

In some embodiments, implementation of the present invention preferably, the methods of making particles of insoluble alginate/gelling ion provided products with the stoichiometric quantity (100% saturation) gel-forming ion. The use of these stoichiometric salts reports camogliese alginate systems higher reproducibility. In some embodiments, implementation of the present invention it is preferable that a method of making particles of insoluble alginate/gelling ion provided products with substochiometric amount (< 100% saturation) of the said gel-forming ion. The use of these substochiometric salts reports Samore yousince alginate systems Biodegradability.

In some embodiments, implementation of the present invention, the alginate is an ultrapure alginate. Ultrapure alginate is commercially available, for example, of various marine algae such as Laminaria Hyperborea. Commercial calcium salt of alginic acid is usually produced using processes in which calcium is added to the alginic acid in the solid phase by simple mixing and stirring of compatments. Examples of commercially available calcium salts of alginic acid are Protaweld (from FMC BioPolymer) and Kelset from ISP Corporation. Particles of insoluble alginate/gelling ion can be produced using ultrapure alginate by making alginate gel using ultrapure alginate and gel-forming ion, laundering from sodium and other ions that were present in the ultrapure alginate, drying the gel to remove water and production of particles from the dried gel. In some embodiments, implementation of the present invention particles of insoluble alginate/gelling ion represent stoichiometric salt. Particles of insoluble alginate/gelling ion preferably has high purity and special, regular and usually homogeneous content of the gel-forming ion, such as, for example, calcium or strontium, barium, zinc, iron, manganese, copper, lead, cobalt, Nickel or combinations thereof, so that the rate of gelation and the strength of the gel can be achieved with a higher degree of predictability. Insoluble alginic acid salts with alkaline earth metals such as calcium alginate or alginate strontium (depending on the gelling ion), or insoluble salts of alginic acid with transition metals (such as salt gelling ions of copper, Nickel, zinc, lead, iron, manganese or cobalt) can be produced using well-known and pre-defined amount of alkali metal ions by precipitation from solutions. In some embodiments, implementation of the present invention are commercially available sodium alginate is first used for the manufacture of a solution of sodium alginate. Optional, sodium salt, such as sodium carbonate, can be included in the solution of sodium alginate. Salt containing the desired gelling ion for particles of insoluble alginate/gelling ion, such as, for example, a salt of calcium or strontium salt such as calcium chloride or strontium chloride, used for making mortar. The solution of sodium alginate unite, preferably slowly with a solution of gel-forming ion. Predpochtite is) the combined solution is continuously stirred during the mixing process. Insoluble alginate, such as, for example, calcium alginate or alginate strontium (depending on the gelling ion), precipitates from United solutions. Precipitated insoluble alginate should then be removed from the solution and re-washed, e.g., 2-10 times with purified water to remove all soluble ions. The removal of soluble ions is confirmed, for example, by testing the conductivity of insoluble alginate in the treated water compared with the conductivity of purified water. After washing the insoluble alginate can be dried, for example under vacuum. The dried alginate can grind in some embodiments, implementation of the present invention sorted according to particle size.

In some embodiments, implementation of the present invention, the alginate is sterile. In some preferred embodiments, the implementation of the present invention, the alginate is a sterile ultrapure alginate. Terms that are often used for sterilization of the material can change alginate, for example to reduce the molecular weight. In some embodiments, implementation of the present invention sterile alginate is made using sterilization the x filters. In some embodiments, implementation of the present invention, the alginate has a level of endotoxin <25 in this case/g.

In some embodiments, implementation of the present invention alginate matrix can be coated with poly-polymer, such parliamentarisation the polymer or chitosan, after the formation of the gel matrix. In some embodiments, implementation of the present invention poly-polymer is polylysine. In some embodiments, implementation of the present invention polylysin associated with another part, and polylysin, thus, is used to facilitate connection of the specified portion with the gel. Examples of parts associated with the gel using poly polymers include, for example, drugs, peptides, contrast reagents, ligands that bind to receptors or other detected label. Some specific examples include growth factor vascular endothelial (VEGF), a growth factor, epidermal (EGF), transforming growth factor (TGF) and morphogenic protein bones (BMP). Medications may include anti-cancer chemotherapeutic agents such as Taxol, cisplatin and/or other derivatives containing platinum. Carbohydrate polymers may include hyaluronan, chitosan, heparin, laminarin, fucoidan, chondroitin sulfate. In some embodiments assests the of the present invention used alginates are modified alginate polymers, such as chemically modified alginate, in which one or more polymers are associated with a different alginate polymer. Examples of these modified alginate polymers can be found in U.S. patent No. 6642363, which is incorporated herein by reference.

In some embodiments, implementation of the present invention alginate polymer may include neoriginalno part, such as, for example, a drug, a peptide, a contrast agent, the ligand binding to the receptors, or other detektiruya tag. In one embodiment, the present invention alginate polymer includes RDG peptide (Arg-Asp-Gly), the radioactive portion (for example,131I), or a radio-opaque substance. Other examples of parts associated with alginate polymers include, for example, drugs, peptides, contrast reagents, ligands that bind to receptors or other detected label. Some specific examples include growth factor vascular endothelial (VEGF), a growth factor, epidermal (EGF), transforming growth factor (TGF) and morphogenic protein bones (BMP). Medications may include anti-cancer chemotherapeutic agents such as Taxol, cisplatin and/or other derivatives containing platinum. Carbohydrate polymers may include hyaluronan, chitosan, GE is ARIN, laminarin, fucoidan, chondroitin sulfate.

Soluble alginate may be a salt, such as, for example, Na+-alginate,+-alginate, PEG-alginate (polyethylene glycol-alginate), NH4-alginate or combinations thereof.

In some embodiments, implementation of the present invention are soluble alginate is liofilizirovannam or any other way dehydrated. Freeze-dried soluble alginate is "instant". "Instant" alginate is dissolved in water in less than one minute, preferably less than 30 seconds, more preferably less than 15 seconds. "Soluble" alginate dissolves more than one minute and usually within a few minutes.

Gel-forming ions used in the particles of insoluble alginate/gelling ion, influence the kinetics of gelation, the strength and elasticity of the gel. Gel-forming ions influence the growth of cells. Gel-forming ions used in the particles of insoluble alginate/gelling ion, can be a Ca++, Sr++, Ba++, Zn++, Fe++, Mn++, Cu++, Pb, Co, Ni or their combinations.

Compasses insoluble alginate/gelling ion represent particles. The particles usually are not fiber-based zootoxin the I L/D, when the particle shape is characterized by the maximum dimension (L) and the smallest dimension (D). Lint-free L/D ratio is less than 10, preferably less than 5, preferably less than 2. L/D of 10 or more is a shortened fiber. Insoluble alginate/gelling ion can be maintained in the form of a dispersion or in dry form. In the first case, the dispersion can be mixed with a solution containing a soluble alginate, or with the soluble alginate to form a dispersion of particles of insoluble alginate/gelling ion in the solution containing soluble alginate. If the particles of insoluble alginate/gelling ion are in the dry form, they can be mixed with dry soluble alginate and subsequently with a solution for forming a dispersion of particles of insoluble alginate/gelling ion in the solution containing soluble alginate, or dry particles of insoluble alginate/gelling ion can be combined with the solution containing the soluble alginate to form a dispersion of insoluble alginate/gelling ion in the solution containing soluble alginate.

Mixing that occurs upon mixing of compatments for the formation of the dispersion, leads to the distribution of solid particles in the solution. Thus obtained dispersion is s may be in the form of mist, which can be poured, injected, or some other way to Samolyot in the matrix or cavity to form said matrix or cavity.

After obtaining a dispersion of particles of insoluble alginate/gelling ion in the solution containing soluble alginate, its dosage are placed in a particular place, in which there is simuliranje with the formation of alginate gel. In some embodiments, implementation of the present invention the dispersion is metered placed in a specific location in vivo. In some embodiments, implementation of the present invention the dispersion is metered placed in a certain location for a certain organism. In some embodiments, implementation of the present invention the dispersion is metered placed in a matrix or other container or on the surface.

The concentration of gel-forming ions used in the particles of insoluble alginate/gelling ion affects the kinetics of gelation, the strength and elasticity of the gel. The higher the concentration of gel-forming ions, the higher the strength of the gel. The strength of the gel is the highest, when the gel is saturated gel-forming ions. On the contrary, the lower the concentration of gel-forming ions, the lower the strength of the gel and the higher the degree of Biodegradability.

The particle size of insoluble alginate/gelling ion can in order to influence the kinetics of gelation and the final properties of the gel. The smaller the particle size, the faster the ends gelation. Larger pieces give a stronger gels. The particle size can be controlled, for example, by sieving the particles of insoluble alginate/gelling ion through filters of different sizes so that the particles can be pre-defined limits. In some embodiments, implementation of the present invention, the particles have a size of <25 μm, 25-45 μm, 45-75 μm, 75-125 microns or >125 μm.

Used solvent can be, for example, water, saline solution, sugar solution, cell culture medium, a solution such as a solution of a medicinal product, protein or nucleic acid, the suspension, such as cell suspensions, liposomes or suspension of contrast reagent.

Formed alginate hydrogel may include, for example, drugs, nucleic acid molecules, cells, multicellular aggregates, tissues, proteins, enzymes, liposomes, contrast agent or biologically active material. Examples of biologically active material are hyaluronate and chitosan. Contrast reagents include tantalum and gadolinium. Some specific examples of proteins include growth factor vascular endothelial (VEGF), a growth factor, epidermal (EGF), transforming growth factor (TGF) and mo is Pogany bone protein (BMP). Medications may include anti-cancer chemotherapeutic agents such as Taxol, cisplatin and/or other derivatives containing platinum. Carbohydrate polymers may include hyaluronan, chitosan, heparin, laminarin, fucoidan, chondroitin sulfate.

Cells that can be used in gels, include non-recombinant and recombinant cells. In some embodiments, implementation of the present invention, in which cells are encapsulated in alginate matrix, encapsulated cells are mammalian cells, preferably human cells. In some embodiments, implementation of the present invention, in which the encapsulated cells represent or neproliferirute cells, or neproliferirute cells can be selected from the group consisting of pancreatic islets, hepatic cells, neural cells, renal cortex cells, vascular endothelium, thyroid and parathyroid cells, adrenal, thymic cells, ovarian cells, and chondrocytes. In some embodiments, implementation of the present invention, in which the encapsulated cells are proliferating cells, proliferating cells may represent stem cells, precursor cells, proliferating cells of specific organs, Feb Oblasty and keratinocytes or cells, obtained from established cell lines, such as, for example, cell lines 293, MDCK and SS. In some embodiments, implementation of the present invention encapsulated cells contain expressing vector that encodes one or more proteins that are expressed at the cell cultivation. In some embodiments, implementation of the present invention the protein is a cytokine, growth factor, insulin or an inhibitor of angiogenesis such as angiostatin or endostatin, other therapeutic proteins or other therapeutic molecules, such as drugs. Proteins with lower MM, less than about 60-70 kDa, are particularly good candidates due to the porosity of the gel network. In some embodiments, implementation of the present invention cells are present in the form multicellular aggregates or tissue.

Camogliese alginates can be used for the manufacture of alginate gels more than 5 mm with homogeneous alginate network. In some embodiments, implementation of the present invention a homogeneous alginate gel exceeds 10 mm Gels formed using diffusion, are usually inhomogeneous alginate gels more than 1 mm. In preferred embodiments, the implementation of the present invention a homogeneous alginate gel, about sovanny imagelinkwrap alginate gel, does not contain sulfates, citrates, phosphates (TSPP: ternatively pyrophosphate and polyphosphate used in the food industry for alginate puddings and the like), lactates, EDTA (ethylenediaminetetraacetic acid) and lipids in the liposomes used for encapsulating the gel-forming ion.

There are many types of application camogliese of alginate. In some embodiments, implementation of the present invention camogliese alginate is used in food products. Camogliese alginates, which are particularly suitable for food products that are made in the form of liquid/slurry mixture with other food ingredients and pour into containers. Capacity, preferably, is the form in which the gel/food product is solidified with the formation of solid or semi-solid product of the specified form. It is possible to make candy, edible decorations, puddings and other molded food products.

In some embodiments, implementation of the present invention camogliese alginates are used in biomedical purposes. Biologically compatible camogliese alginates can be applied topically. Biologically compatible camogliese alginates are particularly suitable for such biomedical purposes, in which it is desirable that the spruce matrix corresponded to the space in situ thus, to camogliese alginate was dosed in the form of a dispersion in the place in which it is desirable to place the matrix. Dispersion fills the cavity or space in the form of liquid suspension and hardens, forming a solid substance within the cavity or space. Alternatively, the dispersion can be applied locally, where it can be distributed to solidification. In some embodiments, implementation of the present invention camogliese alginates used for the manufacture of matrices, which can be given concrete form by manufacturing liquid/slurry mixture, which is placed in a mold, where it solidifies, forming a solid substance specified form, as well as for the manufacture of matrices with encapsulated cells suitable for replacement tissues or organs.

Developed alginate camogliese systems that are controlled, biologically compatible and specially designed for in situ gelation with inaternational purposes. Developed solutions that can easily be used for injection or applied in other ways on the surface or inside the body, which hardens, forming a solid gel matrix. By mixing the alginate in the presence of a solvent with a source of gelling ions, in which the gel-forming ions are connected in the om condition inside the gel network insoluble particles, the gel-forming material can be entered dosed in liquid form and harden, taking the desired shape within a certain time interval. The solution for a certain time hardens and forms a gel. Computesize is biologically compatible, since changes in pH and the presence of toxic compounds are eliminated. Significant deviations from the biological values of pH are unnecessary.

In some embodiments, implementation of the present invention camogliese alginate used in biomedical purposes, such as giving the tissue volume, as in the treatment of reflux problems (i.e. for the treatment of urinary incontinence, problems kidney reflux or esophageal reflux), embolization, as in the treatment of benign or malignant tumors, protivospaechnyj treatment as a post-surgical procedures and the treatment of wounds. Modern technology can be used for a variety of purposes, including the construction of tissues ex vivo or in vivo, since cells and other biomaterials can be added in the gelling system, thus creating a biological artificial extracellular matrix that serves as the basis for cells or tissue. According to some uses can be inatentive biocompatible solid depot, which gradually release the Akti the main ingredients, such as proteins and drugs.

Camogliese alginate is particularly suitable as material that adds volume to the tissues, because it can be put in place that is difficult to access, and dosed to enter in the form of liquid suspension to provide a more complete, compared with other types of impuissance, according cavity. The dispersion can be introduced in a quantity sufficient to replace and support other tissues or organs of the body, and after the formation of the gel in situ creates a structure to maintain and support other tissues or organs. Camogliese alginate may contain compatment that make it very appropriate for the purposes of giving volume to the tissues. For example, the use of strontium as a gelling agent leads to the formation of the gel, which inhibits excessive cell growth and the formation of undesirable tissue.

Camogliese alginate is particularly suitable for embolization procedures, because it can be inserted into a blood vessel, which is difficult to access, and dosed to enter in the form of liquid suspension to provide a more complete, compared with other types of closures, such as joints, compliance with the internal part of the blood vessel and a more complete and effective unit. The variance can be entered in the count of the operation, enough to block blood flow after gel formation in situ. Camogliese alginate may contain compatment that make it very appropriate for the purposes of embolization. For example, compasionate you can choose to ensure relatively rapid hardening and high strength. Camogliese alginate used for the purposes of embolization may contain contrast agents for monitoring its availability and localization.

Camogliese alginate is particularly suitable for protivoptichego treatment as a post-surgical procedures, because it can be applied to the area of surgical intervention in the form of liquid suspensions, to ensure complete coverage of exposed surfaces directly in places incisions or near them. Camogliese alginate may contain compatment that make it very suitable for the purposes protivoptichego treatment. For example, the use of strontium as a gelling agent leads to the formation of the gel, which inhibits excessive cell growth and the formation of undesirable tissue.

Camogliese alginate is particularly suitable for the treatment of wounds because it can be applied to the surface of the wound in the form of liquid suspensions, to ensure full coverage under ergasia impact surfaces. In addition, camogliese alginate can be entered inside the wound area, for example, in the form of liquid suspensions. The dispersion can be introduced in a quantity sufficient to fill the internal cavity, after which the gel formation in situ will close any internal wounds and prevent blood loss due to internal bleeding. Camogliese alginate may contain compatment that make it very suitable for treatment of wounds. For example, you can enable its members compatment that promote the clotting of blood and antiseptic and antibiotic of compatabile.

Camogliese alginate is particularly suitable for the manufacture of tissue constructs ex vivo or in vivo. Cells or other biomaterials can be added in the gelling system, thus creating a biological artificial extracellular matrix that serves as the basis for cells or tissue. The variance can be entered in situ in the form of a liquid mist to the place in which the tissue/cell can function to achieve therapeutic effect. Examples of tissue structures include bone, cartilage, connective tissue, muscle, liver, cardiac tissue, pancreatic tissue, and skin. Examples of these structures can be drugs, containing secreting insulin cells, for the treatment of diabetes, it is noisesize, containing chondrocytes to repair defective joints and cells for the treatment of Parkinson's disease. These cells can be incorporated into a liquid suspension and dosed to enter into that place, in which after the formation of the gel they will exist and function within biocompatible alginate matrix. The gel can also be used as an immune barrier, protecting prisoners in cells from the immune system of the host. Camogliese alginate can also be used to encapsulate cells ex vivo, and the gel can be formed in accordance with the intended purpose. In some embodiments, implementation of the present invention camogliese alginate can be used to encapsulate cells such as skin cells, and produce artificial skin, similar to that which is used for the treatment of burn patients and other patients who need skin grafts or with extensive healing wounds. In some embodiments, implementation of the present invention camogliese alginates can be used to encapsulate cells ex vivo and the formation of matrices that can be inatentive.

Treatment of diabetes may include the production of biologically compatible matrix containing insulinproducing cells, through the production variance is AI, containing particles of insoluble alginate/gelling ion and insulinproducing cells in a solution of a soluble alginate, and the introduction of the dispersion into the body of the individual, which produce a biologically compatible matrix. The body of the individual may be a cavity or structure, inatentive the individual. The variance can be put in the form, structure or container, where it forms a biologically compatible matrix which inatlantic in the body of the individual. Insulin is produced by cells in the matrix, secreted by cells and released from the matrix into the body of the individual, where it functions to facilitate impuestos diabetic condition. In some embodiments, implementation of the present invention insulinproducing cells are cells of pancreatic islets. In some embodiments, implementation of the present invention insulinproducing cells are recombinant cells are obtained for the expression and secretion of insulin.

Camogliese alginate is particularly suitable for manufacturing devices with a coating, such as devices for impatiently. In some embodiments, implementation of the present invention a device selected from the group consisting of a stent, a heart pacemaker, Kate the EPA, inatentive prosthesis, surgical screws, surgical wire, inatlanta to add volume to the tissues, inatlanta, the vast oesophageal reflux, inatlanta, the vast incontinence, inatlanta, the vast renal reflux, container, suitable for the maintenance of cells, which are deposited on the outer surface and/or encapsulated in alginate matrix, such as a rigid device or microcapsule, inatlanta breast cancer, inatlanta chin, inatlanta cheeks, inatlanta chest, inatlanta buttocks and dental inatlanta. Coverage of camogliese of alginate provides effective coverage regardless of form. The use of strontium as a gelling ion is particularly suitable for inhibiting excessive cell growth after impatiently.

Camogliese alginates can be used for the manufacture of matrices that can be inatentive. These matrices can be given concrete form by manufacturing liquid/slurry mixture, which is poured into a mould where it solidifies with the formation of the solid product of the specified form. Matrix made for impatiently may contain biologically active agents and/or cells. Gels can be produced and the pulse is to atlantikwall surgically, apply topically or in the body through the hole.

According to some variants of implementation of the present invention designed the sets for the production of alginate gel. The kits can include a first container containing a soluble alginate, and a second container containing particles of insoluble alginate/gelling ion. Individual containers can be a branch of United container systems.

In some embodiments, implementation of the present invention sets include soluble alginate in the form of a solution. In some embodiments, implementation of the present invention sets include soluble alginate, containing no solvent. In some embodiments, implementation of the present invention sets include an additional container containing the solvent.

In some embodiments, implementation of the present invention sets include particles of insoluble alginate/gelling ion in the form of powder. In some embodiments, implementation of the present invention sets include particles of insoluble alginate/gelling ion in the form of a dispersion.

In some embodiments, implementation of the present invention sets include an additional container containing a drug, a peptide, a protein, a cell, a detectable label is whether a contrast agent. In some embodiments, implementation of the present invention sets include drug, peptide, protein, cell, detectable label, or a contrast reagent, included in the container containing the solution or powder soluble alginate, and/or the container containing the powder or dispersion of particles of insoluble alginate/gelling ion.

According to some variants of implementation of the present invention developed compatabile for the manufacture of the gel. Computesize includes soluble alginate and particles of insoluble alginate/gelling ion. Computesize may further comprise a drug, peptide, protein, detectable label, or a contrast reagent. Computesize can be compatment in the set. Such a kit may further comprise a container with a solvent.

The kits preferably contain instructions for use.

In some embodiments, implementation of the present invention sets contain the mixing device. The mixing device can be a part of the container or container system. In some embodiments, implementation of the present invention the mixing device comprises a valve system that allows the dispersion to pass from one container to the other container to facilitate mixing.

In some embodiments, implementation of the present invention sets contain the metering device. The metering device can represent the applicator in connection with the mixing device and/or container, adapted to contain the dispersion. In some embodiments, implementation of the present invention the metering device comprises a catheter. In some embodiments, implementation of the present invention the metering device comprises a syringe.

EXAMPLES

Example 1: Gelation at various concentrations of calcium

In this experiment, the gels were made by mixing the solution of sodium alginate (Protanal SF 120) and dispersion of calcium alginate (Protaweld TX 120). The number of calcium alginate was changed to 1.0%, and 1.5% or 2% in the gel), while the amount of sodium alginate remained constant (1% gel). Solidification camogliese system over time was measured by a rheometer Physica MCR300 (measurement system: RR, toothed; tempaerature: 20°C; interval: 1 mm; frequency: 1 Hz; strain: 0,005). The solution and the dispersion was mixed directly before adding 3 ml of the sample in the rheometer and the oscillation test was carried out for 18-24 hours.

As shown in figure 1, the strength of the gel was rapidly increased within the first 1-2 hours, and then the change in gel strength decreased, as it is to the gel showed a tendency to stabilize. The data suggest that the strength of the gel was increased at higher concentrations of calcium.

Example 2: Gelation at various concentrations of alginate

Alginate camogliese system produced by mixing a solution of sodium alginate (Protanal SF 120) and a suspension of calcium alginate and measurements were made as described in example 1. Oscillatory measurements were carried out for 18-24 hours. Used equal amounts of sodium alginate (Protanal SF 120) and calcium alginate (Protaweld TX 120). The amount of sodium alginate and calcium alginate, every drove up to 0.75%, 1%, 1.25% and 1.5% in the final gel, respectively (figure 2). The kinetics of gelation had a similar pattern in all four cases. However, as in example 1, the strength of the gel clearly increased with increasing concentrations of alginate.

Example 3: Gelation using alginates of different molecular weight

In this experiment compared the kinetics of gelation using alginates, sodium and calcium of various molecular weights (figure 3). A sample of alginate (Protaweld TX 120) with reduced MM was obtained by increasing tempaerature in a few days (figure 3, part a). Compare also the sodium alginates Protanal SF 120 and Protanal SF/LF with different MM (figure 3, part b). Rheological measurements were carried out as described is about in example 1, and the data presented in figure 3. As shown in the figure, the process of gelation clearly depended on the molecular weight of alginate as sodium alginate and calcium alginate. In both cases, the strength of the gel increased faster with the use of high-molecular-weight alginate, and reached a higher level.

Like the fact that you can see in figure 3, figure 11 also shows the gelation of the sample of sodium alginate (PRONOVA UP G100) with reduced MM, obtained using increasing tempaerature. However, in this case, the gelation was initiated by mixing strontium alginate. As shown in figure 11, the process of gelation clearly depended on the molecular weight of alginate, because the strength of the gel has reached a higher level when using high-molecular-weight alginate. The data of figure 11, where used calcium alginate or alginate strontium at stoichiometry with a 100% saturation, also show that increasing the concentration of alginate can compresensive MM reduction in terms of gel strength.

Example 4: Gelation with different gelling ions

In this experiment, alginate calcium or strontium was mixed with sodium alginate (Protanal SF 120). Alginates calcium and strontium were obtained by mixing of alginic acid with the carbonate to LCIA. Rheological measurements were carried out as described in example 1, and the data presented in figure 4. The amount of sodium alginate and alginate strontium/calcium, every drove up to 0.75% gel. Obviously, the use of strontium as a gelling ion provided a stronger gel structure, as well as more rapid kinetics of gelation.

Example 5: Gelation with different content guluronic acid

Because it is known that the content guluronic acid alginates has a great influence on the strength of alginate gels, studied the effect of the use of sodium alginates (Protanal SF 120 and Protanal HF 60D) with different content guluronic acid. In figure 5, part a, shows the modules of storage depending on time for gels containing sodium alginate with a high or low content guluronic acid. For both curves the system reliabale mixed with a dispersion of calcium alginate (Protaweld TX 120) with a high content of guluronic acid. The amount used of calcium alginate and sodium alginate was brought up to 1.0% of the content in each gel. The measurements were carried out as described in example 1. Obviously, the use of sodium alginate with a high content of guluronic acid increases the strength of the gel system, although in both cases used the alginate calcium in the high content guluronic acid. In figure 5, part b, strontium alginate (a product of FMC process with a high content of guluronic acid of example 14) was also mixed with sodium alginates with high and low content guluronic acid. Used alginates, sodium PRONOVA UP 100G (69% G MM: 122 000) and PRONOVA UP 100M (46% G MM: 119 000). Picked up similar MM (and viscosity) of two series of sodium alginate (more similar). As the data clearly show, also when using the strontium alginate as a source of gelling ions using sodium alginate with a high content of guluronic acid increased the strength of the gel compared with the sodium alginate with low content guluronic acid.

Example 6: the stability of the gels made with different content of calcium in physiological conditions

In this example, studied the stability and Biodegradability alginate gels made with different content of calcium ions (figure 6). Gel disks were made by mixing the alginate calcium (Protaweld TX 120), autoclaved for sterility and sterile filtered of sodium alginate (PRONOVA UP LVG) to a final concentration of 1.0% and 0.7%, respectively. Dispersion reliabale in two Petri dishes. Gel disks in one Cup (labeled V) after the initial zastudnevaniju washed with 50 mm calcium chloride during the course the e 10 minutes and then in both cups were added to the medium for cell culture (DMEM with addition of 10% FBS). The environment in the cups then replaced with fresh medium regularly three times a week and cups were kept in sterile conditions in CO2-thermostat at 37°C. the Initial size of the largest gel disc in each Cup were the same. Six months later, the main fraction of the gel, not probivaucheisa calcium, as shown in figure 6, disappeared, while the gel discs, probivaucheisa additional amount of calcium, showed little change in size or no size changes over time. This clearly shows that alginate gel, made with limited calcium content, can greatly degrade under physiological conditions.

Example 7: the Holding cells

Encapsulation of cells in the alginate microspheres is a widely used technology that is currently being developed for various biomedical purposes. Alginate pellets are used as "biological factory for therapeutic substances. Alginate gel allows you to be the influx of essential nutrients such as oxygen and glucose, and after the desired therapeutic molecules and waste. Through the use of reactive cells, similar to the islet cell is m, "biological factory" responds to the needs of the host body. However, the gel network is necessary to protect the retained cells from the immune system of the host, which is very important when impatiently foreign cells in the body. It was, however, shown that cells can have a better hold in other alginate structures other than the microgranules.

Also shown is the effect of the gel on the cells, prisoners in camogliese alginate matrix according to the present invention (figure 7). In one of the experiments (figure 7, part a) mouse myoblast cells SS was mixed with a solution of alginate PRONOVA UP MVG before mixing with autoclaved dispersion of calcium alginate (Protaweld TX 120). The mixture containing the cells and 0.7% of sodium alginate and 1.0% of calcium alginate, were injected with in Petri dishes and were cast out of her disks. After a few minutes, the gel was washed with 50 mm calcium chloride for 10 minutes in order to prevent degradation of the gel (see example 6), and then the gel was added to the cell growth medium (DMEM with 10% FBS). Alginate gel/cell culture was kept in CO2-thermostat at 37°C under sterile conditions and the medium was changed on a regular basis three times a week. After 45 days of cultivation viable cells were identified under the microscope after staining callainos. For visualization of living cells used fluorescent micro is down

In figure 7, part a, shows the presence of viable cells both outside and inside the gel. Due to various focus the microscope on different parts of the gel various spots in the picture are seen more or less clearly. Numerous viable cells or small cell colonies can be seen inside the gel in the form of small enlightened spots. Most enlightened, covering a large part of the picture shows the viable cells that have penetrated the surface of the gel and there has multiplied. This part of the surface of the gel is completely covered by cells growing as monolayers. A number of cell aggregates, however, is also present in other areas.

In another experiment (figure 7, part b) human chondrocytes were concluded in camogliese alginate gel. In this case, the gel is made from 5 ml mixed camogliese gel PRONOVA SLG 20 (lyophilized sterile low viscosity alginates with a high content of guluronic acid) and calcium alginate (a product of FMC process, example 14), containing human chondrocytes. Three days after curing gels cut to 600 μm environment using vibratome. Gel slices were kept in growth medium for cells in CO2-thermostat, and the photo was taken six months later. The photo was DM is Lana using a fluorescent microscope after staining of cells with kalayna on the subject of sustainability. The photograph clearly shows the presence of a large number of viable cells. Alginate gel network, therefore, should be a good matrix for maintaining the cell for a long period of time. In conclusion, the data clearly show that the gel may be a biologically compatible matrix for cells and cell growth.

He was also made a number of different alginate samples contained human chondrocytes. In this case, were selected more high molecular weight alginates, in order to preserve the strength of the gel at low concentrations of gelling ion and alginate. Alginates was a PRONOVA SLG 100 and PRONOVA SLM 100 (lyophilized sterile high viscosity alginates with high and low content guluronic acid, respectively). The chondrocytes were mixed with 2% solution of alginates in the cellular environment. The alginate/cell suspension was then kept for about half an hour to free the air bubbles prior to further use. Cell suspension was mixed with sterile insoluble alginates calcium or strontium (product of FMC process of example 14 in vials containing 5 ml of 10% alginate dispersion, 0.5 mg of alginate). Each bottle of insoluble alginate contained a magnet for stirring and was used after opening the same on the HB. Insoluble products are also grinded and sieved with the aim of controlling the particle size and were made as alginates strontium or calcium with a high or low content guluronic acid. Mixing the alginate/cell suspension and dispersion of insoluble alginate was carried out in small volumes in small test tubes. Dispersion of insoluble alginates were subjected to a constant magnetic stirring, when the bottles were selected desired volume. Different samples were mixed as described in table 1, below.

Gel systems containing cells (initial concentration in parentheses)

Table 1
GroupAlginate solutionAlginates-ion sourcesMixing
Sal. 11.6% of PRONOVA SLG 100 (2,0%)2.0% strontium, high G (10%)4:1
Sal. 21.6% of PRONOVA SLG 100 (2,0%)2.0% calcium, high G (10%)4:1
Sal. 31.6% of PRONOVA SLM 100 (2,0%) 2.0% strontium, high G (10%)4:1
ALG1.6% of PRONOVA SLG 100 (2,0%)2.0% strontium, high M (10%)4:1

After initial gelation in the mixture for several minutes, small pieces of gel was kept in a cell culture environment in CO2-thermostat and checked the cell viability by staining callainos (as described previously) a week later. In this study, there was good cell viability in all samples alginate gel/cell. Alternatively, samples algina/chondrocytes can be made in situ. Depending on the purpose of use of various camogliese compatabile can be adapted for specific applications. The gel may contain cells directly, but also may contain microspheres or other biological structures containing cells. Computesize can be injected before complete gelation, but can also allow the gel to harden ex vivo in whole or in part to impatiantly. In addition, the gel can be made more or less solid or porous, to allow or not to allow the cells to proliferate inside the gel, in order to adapt to the environment or ensure the process of immunological protection. Depending on the type of gelling ion and the type of alginate gel can be drawn up so that it was less attractive to excessive cell growth. Gel structure can be made more or less biodegradable, using low concentrations of calcium (as shown in example 6 and figure 6), low molecular weight alginate or low concentrations of alginates. The gel can also be mixed with other biopolymers, such as hyaluronate or chitosan to improve its properties. You can also add additional gel strength with the use of additional quantities of calcium in the design by means of a suitable procedure impregnation or spraying.

Example 8: Systems controlled release

Was shown the suitability of alginate in systems with controlled-release delivery of drugs or other therapeutic molecules. The type of gel preparations, which are shown herein can also be used in similar ways, and they have advantages in different computesize. One example is the use of biodegradable gels, i.e. the use of a low concentration of gelling ions to limit the treatment period. In the treatment of patients with malignant tumors of filling the space in the gel, containing, in addition to the public funds or radioactive isotopes, can be used during surgical interventions for the prevention of relapse. After the active substance is released or after the radioactivity disappears, it may be desirable that the gel has dissolved and excretionary from the body. Camogliese the alginate compatabile controlled delivery is possible, of course, also be injected directly into the body without any surgical procedures, and the solution gel/alginate can also be used for oral drug delivery. Currently, for oral use is known, the use of alginate in computesize as a remedy against reflux. Thus, it is also possible that alginate camogliese compatabile will be applied in a similar manner.

Example 9: the Application in the field of tissue engineering

The conclusion of cells in alginate gel described herein can also be used for the manufacture of impatiantley "biological factories", ekskretiruyutsya active substances for the treatment of several diseases. However, the conclusion of cells in alginate gel can also be used in the field of tissue engineering. For the purposes of tissue engineering the necessary growth of cells inside or on the three-dimensional structures and, thus, on the one required good materials. Delayed release transversely cross-linking ions allows to produce a suspension of gel-forming ion/alginate with obtaining complex geometric designs before the solidification. In ex vivo specified alginate structure can be used as a growth substrate during the development of tissues or artificial organs. Cells grow on the surface of the granules of the alginate gel, because the surface of the gel may be a growth substrate for cells. The growth of cells on alginate gels was found to depend on the alginate and gel-forming ions. This camogliese computesize can be used to create multiple layers of cells growing on the inside or on the surface of alginate plates or gel structures other form. In addition, the alginate gel can later be removed by treatment with citrate, phosphate, or other chelating gel-forming ions agents. This gives you the ability to combine several cell layers in the design of tissues or organs. Several types of cells within or on the surface of the gel structures can be combined, if it is desirable to develop a design.

Nerve regeneration is an interesting example of the use of alginate for tissue engineering. Filling artificial neural channels itself is generousity alginate can be used to create structures with improved napravljaemost and biological compatibility for regrowth of the nerve. This system can provide greater flexibility and improved control compared to molding processes and improved the properties of the structure in comparison with other methods.

Injectable alginate/cell suspension system can also be delivered in a defective or damaged areas of tissue even without surgical intervention. For these purposes, a very important may be the presence of a certain time for work, to give material shape before it hardens. However, the rate of gelation is also required reasonable so that you can avoid the problems associated with long waiting time for the patient, or problems with the application of the gel/solution. Camogliese system, as shown herein and as described previously, can be adapted to different periods of time for gelation and to different properties of strength and stability. This variability can thus be used to adapt to each type of injection procedures. As an example, the restoration of cartilage defects is a possible area of application camogliese alginate structures. It was found that alginate is a useful biomaterial for use in tissue engineering of cartilage, and it was found that alginate m which can stimulate the formation of cartilage tissue. Thus, camogliese alginate solutions with chondrocytes or without chondrocytes or other cells can be directly injected for the treatment of defects of the joints. Currently, patients with osteoarthritis also treated using "liquid therapy of joints", and available in two product - sodium hyaluronate (Hyalgan) and hylan G-F 20 (Synvisc), which are believed to act as lubricating agents, delivering hyaluronic acid, a substance that gives the viscosity of joint fluid. In some people the pain relief lasts from six to 13 months. Drugs were most effective in people with osteoarthritis of the knee from mild to moderate severity. However, since it is known that hyaluronic acid is decomposed in the body, the use of other biopolymers such as alginate, less Biodegradability and good biological compatibility has advantages.

Alginate hydrogels can be liofilizirovanny, or water may be removed partially or completely by other means to create a biological compatible structures such as sponge or fiber. The technology presented in this document uses camogliese alginate system, may also be a stage production by the biological the key compatible sponges or other structures, which are suitable for tissue engineering or other purposes.

Camogliese the alginate compatabile can be used for coating stents or impatiently or other impatriation device. Depending on the type of alginate compatabile covering layer can be made more or less biodegradable and provide more or less support for growing inside the host cells, or cell growth, added to the device.

Example 10: adding volume to the tissue

Alginate can be delivered into the submucosal layer, proximal to the urethral sphincter to create a volume for the treatment of urinary incontinence, and similar procedures are already in place in hospitals. Another example might be shipping alginate computesize at the junction of the esophagus and stomach, to help in the treatment of gastroesophageal reflux. High degree of compatibility of alginates makes use of injectable solution for cosmetic procedures attractive alternative to other materials.

Compatabile based camogliese alginate systems can be used to create injectable solutions or pastes with a predetermined solidification time to fill a predetermined volume. As noted earlier, g is left compatabile can produce more or less biodegradable, what does giving the amount of compatabile desirable properties.

Example 11: Embolization of blood vessels

Methods of forming endovascular occlusions can be used to treat conditions such as arterial-venous malformations, aneurysms, excessive blood supply to tumors, struggle with massive bleeding and other conditions that require embolization for help. Some embolic systems include the use of polymer solutions, which begin to cure or to precipitate upon contact with blood or other body fluids. These systems, however, face the same problem as the migration of polymer solution in unwanted areas of the body, as for solidification or precipitation of solid polymer takes time. The migration of these systems of polymer solutions is particularly problematic when the solution is injected in the "high-flow" areas, such as the vascular system. Fibers, which form a system of polymer solutions, also create problems, such as insufficient embolization, excessive brittleness or lack of biological compatibility. The use of particles or pellets in PVA (polyvinyl alcohol) or gelatin granules, as shown, is suitable for embolize the AI and is currently in clinics.

Compatabile on the basis of alginates are also available for use in embolization procedures. It has been suggested that endovascular occlusion can be induced with the use of calcium alginate by controlling the injection of alginate liquid and calcium chloride, that are polymerized in the area within the vascular system, scheduled for occlusion. Compared with these systems use camogliese alginate computesize of the present invention has advantages. Treatment can be done in a single injection, and the strength of self-curing of compatabile can be adjusted to provide the best control system. In particular, camogliese the alginate compatabile are useful when you want to control the time until gelation and Biodegradability.

Example 12: Protivospaechnyj compatabile

The formation is accompanied by surgery, trauma, infection, etc. Adhesions often occur after abdominal operations and represent a major clinical problem that causes intestinal obstruction, infertility, and pain. Attempts to prevent or reduce the formation of adhesions were almost completely unsuccessful; however, recently developed mechanical is their barriers, using different biopolymers, demonstrated clinical progress in terms of preventing the formation of adhesions.

Compatabile on the basis of alginates have also been proposed as protivospaechnyj barriers. Protivospaechnyj barriers can be created using camogliese alginate system presented in this document. Computesize solution/gel mixed immediately before use and make it with a suitable Biodegradability. Compatabile these types can also contain other polymers, medicines, or other auxiliary connections. Additional polymers can be used to improve the properties of the gel, among other things, to increase the adhesion between the gel structure and fabric.

Example 13: Compatabile for wound healing

Alginate dressings are widely used for the treatment of wounds with separable bleed and have exudate. Modern alginate products for wound healing consists of a soft non-woven fibers or champoiseau. Alginates can adsorb mass many times greater than their own weight, and form a gel in the wound to fill the dead space and maintain humidity environment. It has been suggested that the alginates may affect the wound-healing process in which redstem others, unknown, mechanisms, and it has been suggested that the calcium present in the alginate dressing material, can affect the process of wound healing by affecting certain cells.

Camogliese alginate structure is able to adapt to the three-dimensional structure of the tissue surface during the healing process. Additional area can be achieved creating computesize more controlled and specific content of calcium, as well as structures with a high degree of resistively.

Example 14: Production of insoluble calcium alginate

Alginate calcium were made using ultrapure (low endotoxin) commercial alginate. In addition, the calcium content was stoichiometric in nature. Specifically, 60 g of sodium alginate PRONOVA UP LVG (series FP-008-04)having a molecular weight of approximately 130 000, a viscosity of approximately 150 (1% solution, 20°C), the content of guluronate 64% and the content of endotoxins 260 in this case/g, was dissolved in 5 liters of purified water. Added 26 grams of sodium carbonate. 165 g of dihydrate of calcium chloride was first dissolved in 500 ml of purified water, and then brought the pH to neutral with nitric acid. Caution was added to the alginate solution to a solution of calcium chloride with tandom stirring. Precipitated precipitated calcium alginate was then washed 4-8 times in a row purified water up until the conductivity was reduced to levels similar to the conductivity of the purified water. The washed calcium alginate was then dried under vacuum, and then grinded. Insoluble alginate strontium can be obtained similarly using strontium salt instead of calcium chloride. The obtained insoluble alginates contain controlled stoichiometric or substochiometric calcium or strontium, which when used in gelling systems give gels with more reproducible consistency than gels made with the use of insoluble alginates obtained by other means.

Example 15: Gelation in the presence of other ions and agents, calcium-binding

In the experiments, the applicants was carried out by oscillatory measurements, as described previously (example 1). Module storage was measured in dependence on time for gels containing 1,25% of sodium alginate (PRONOVA UP 100G)mixed with 5.5% strontium alginate (example 14) in the ratio of 4:1 (final concentration of alginates amounted to 2.1%). Solidification of the gel was measured in the presence or absence of sodium chloride or sodium hexametaphosphate (figure 8). Studied two different concentrations of sodium chloride, and data Yas what about the show the increase in the rate of gel formation when the concentration of sodium ions. The presence of the agent, a calcium-binding, such as sodium hexametaphosphate, also clearly alters the kinetics of gel formation and reduces the ultimate strength of the gel. Thus, the data show that the presence of agileoresund ions, such as sodium, or kompaziciya calcium compounds, such as sodium hexametaphosphate, can be used to modify the kinetics of gelation and final properties of the gel.

Example 16: Gelation of particles of calcium alginate in various sizes

During the process of manufacture of insoluble alginates can control the particle size of the final product. In this example, the applicants have produced one batch of alginate calcium, which was grinded and sieved through a variety of filters to separate from each other, particles of different sizes. When gelation was carried out with particles of strontium alginate in various sizes and sodium alginate, otherwise identical conditions, there was a large difference in the gelation process and the final properties of the gel (figure 9). While gelation was very fast in the case of smaller particles, the total gelation time was significantly longer in the case of larger particles, and they also gave a much stronger gels. However, in the case of smaller castilleae be noted, that there is some degradation of the gel, probably, was observed during the mixing of the two compatments, since the rate of gelation was very high (in particular, for particles less than 25 microns). The effect, therefore, also contributes in varying the strength of the final gel. However, in conclusion, the data of the applicants show that the size of the particles must be taken into account and can be used actively with the aim of obtaining the desired properties.

Example 17: Gelation at various tempaerature

Applicants also studied the ability of selecting tempaerature to control solidification of the gel system. The figure 10 shows the rheological data for a mixture of calcium alginate and sodium alginate at different tempaerature. It is obvious that the rate of gelation was decreased at 10°C, and were grown at 37°C compared with room tempaerature. Thus, the data show that tempaerature can actively be used to monitor the kinetics of gelation. Among other things it can be used actively by reducing tempaerature to win time for the manufacture and processing of the gel before the introduction in vivo.

Example 18: Gelation using unsaturated particles of alginate calcium or strontium

Izhota ivali alginates and calcium alginates strontium, which was stoichiometric unsaturated gelling ions (less than 100% saturation). These particles, in contrast to the saturated particles, registrationis very quickly when in contact with solutions containing water. Unsaturated particles, therefore, can be used to generate instant gel structure consisting of gel particles (non-solid gel). Although the gel structure was unstable, it was easy to shape for a long period of time. Cells or other materials can be easily added in the gel structure is simple they are added to the solution containing the water, before mixing with the powder. Also other particles or materials can be added in the gel structure by pre-mixing with the unsaturated particles before adding the solution containing the water. One example is the pre-mixing dry sodium alginate, which is rich in insoluble alginate and unsaturated insoluble alginate before adding a solution containing water. Upon contact with water the mixture, as previously, to give a gel structure, instantly absorbing water, but the strength of the gel will also increase with time, as the particles of soluble and insoluble alginate saturated alginate gel gradual the NGOs begin to hydrogenate itself and give gelation after dissolution. Compatabile mentioned in this document that uses a water-absorbing properties of unsaturated of insoluble alginates can also be used in combination with cells or other materials and can be very useful for tissue engineering and for other purposes.

Example 19: FP-411-03, manufacture of calcium alginate with the stoichiometric amount of calcium (100% saturation), the alginate with a high content of G, using sodium carbonate and nitric acid

50 grams of sodium alginate PRONOVA UP LVG, series FP-008-04 (contents guluronic acid 64%, a molecular weight of 130 000 g/mol, viscosity of 1% solution at 20°C 146 , the content of endotoxin in this case a 400/g), was dissolved in 3 liters of purified water. Added 15 grams of sodium carbonate. Solution was added calcium, which consisted of 139 grams CaCl2∙2H2Oh, dissolved in 300 ml of purified water with the addition of 12 ml of HNO3(65%). Observed loss of fine sediment. The conductivity of the specified solution was 55 MS/see the Precipitate was washed several times (8 times) purified water to obtain a conductivity of 0.08 MS/see the Residue was dried under vacuum.

Example 20: FP-411-04, manufacture of calcium alginate with substochiometric calcium (50% saturation), the alginate with a high content of G, using sodium carbonate and nitric acid

2∙2H2O)=6,84 g CaCl2∙2H2O. 6,84 g CaCl2∙2H2O dissolved in 150 ml of purified water and 6 ml of HNO3(65%). Add to 7.5 grams of sodium carbonate to the alginate solution. There is loss of fine sediment. The specified conductivity of the solution is 8 MS/see the Precipitate is washed several times (6 times) to obtain a conductivity of 0.4 MS/see the Residue dried under vacuum.

Example 21: FP-411-05, manufacture of strontium alginate with the stoichiometric amount of strontium (100% saturation), the alginate with a high content of G, using sodium carbonate and nitric acid

47 grams of sodium alginate PRONOVA UP LVG, series FP-008-04 (contents guluronic acid 64%, a molecular weight of 130 000 g/mol, viscosity of 1% solution at 20°C 146 , the content of endotoxin in this case a 400/g), was dissolved in 3 liters cleaned up the th water. Added 15 grams of sodium carbonate. Solution was added strontium, consisting of 252 grams SrCl2∙6N2Oh, dissolved in 300 ml of purified water with the addition of 12 ml of HNO3(65%). Observed loss of fine sediment. The conductivity of the specified solution was 78 MS/see the Precipitate was washed several times (8 times) purified water to obtain a conductivity 0,0159 MS/see the Residue was dried under vacuum.

Example 22: FP-411-06, manufacture of strontium alginate with substochiometric number of strontium (50% saturation), the alginate with a high content of G, using sodium carbonate and nitric acid

23.3 grams of PRONOVA UP LVG (description given in example 19) was dissolved in 1.5 liters of purified water. To calculate the required quantities of calcium 23.3 grams of alginate is 0,136 mol of alginate (using the molecular weight of the monomer 171 g/mol). Used alginate, PRONOVA UP LVG, series FP-008-04 has a content guluronic acid 64%, which gives 0,087 mol cellisvisible sites (0,136 mol of alginate × 64% of monomers guluronic acid). For 50% substitution of strontium is required 0,0435 mol of strontium (0,087/2=0,0435 mol). 0,0435 mol strontium salt, by calculation, is 11.6 grams of uranyl (0,0435 mol × 266,62 g/mol (SrCl2∙6H2O)=11.6 g SrCl2∙6H2O. 11.6 g SrCl2∙6H2O dissolved in 150 ml of purified water and 6 ml of HNO 3(65%). Add to 7.5 grams of sodium carbonate to the alginate solution. There is loss of fine sediment. The specified conductivity of the solution is 22 MS/see the Precipitate is washed several times in a row (3 times) to obtain the conductivity of 0.6 MS/see the Residue dried under vacuum.

Example 23: FP-506-03, manufacture of strontium alginate with the stoichiometric amount of strontium (100% saturation), the alginate with a high content of M, without sodium carbonate and nitric acid

50 grams of sodium alginate PRONOVA UP LVM, series FP-408-01 (contents guluronic acid 44%, a molecular weight of 220 000 g/mol, viscosity of 1% solution at 20°C 127 , the content of endotoxins <25 in this case/g), was dissolved in 3 liters of purified water. Solution was added strontium, consisting of 252 grams SrCl2∙6N2Oh, dissolved in 400 ml of purified water. Observed loss of fine sediment. The conductivity of the specified solution was 43 MS/see the Precipitate was washed several times (8 times) purified water to obtain a conductivity 0,143 MS/see the Residue was dried under vacuum, grinded and fractionally.

Example 24: FP-505-05, manufacture of strontium alginate with the stoichiometric amount of strontium (100% saturation), the alginate with a high content of G, without sodium carbonate or nitric acid

50 grams of sodium alginate PRONOVA UP LVG, series FP-408-02 (soda the abolition guluronic acid 69%, molecular weight of 219 000 g/mol, viscosity of 1% solution at 20°C 138 , the content of endotoxins <25 in this case/g), was dissolved in 3 liters of purified water. Solution was added strontium, consisting of 252 grams SrCl2∙6N2Oh, dissolved in 400 ml of purified water. Observed loss of fine sediment. The specified conductivity of the solution was 40 MS/see the Precipitate was washed repeatedly (7 times) purified water to obtain a conductivity of 0.1 MS/see the Residue was dried under vacuum, grinded and fractionally.

Example 25: FP-505-02, manufacture of calcium alginate with the stoichiometric amount of calcium (100% saturation), the alginate with a high content of M, without sodium carbonate and nitric acid

50 grams of sodium alginate PRONOVA UP LVM, series FP-408-01 (contents guluronic acid 44%, a molecular weight of 220 000 g/mol, viscosity of 1% solution at 20°C 127 , the content of endotoxins <25 in this case/g), was dissolved in 3 liters of purified water. Solution was added calcium, which consisted of 137 grams CaCl2∙2H2Oh, dissolved in 300 ml of purified water. Observed loss of fine sediment. The conductivity of the specified solution was 45 MS/see the Precipitate was washed several times (8 times) purified water to obtain a conductivity 0,0129 MS/see the Residue was dried under vacuum, grinded and fractionally.

Example 26: FP-504-02, manufactured Olenye of calcium alginate with the stoichiometric amount of calcium (100% saturation), the alginate with a high content of G, without sodium carbonate and nitric acid

50 grams of sodium alginate PRONOVA UP LVG, series FP-408-02 (contents guluronic acid 69%, a molecular weight of 219 000 g/mol, viscosity of 1% solution at 20°C 138 , the content of endotoxins <25 in this case/g), was dissolved in 5 liters of purified water. Solution was added calcium, which consisted of 231 grams CaCl2∙2H2Oh, dissolved in 500 ml of purified water. Observed loss of fine sediment. The conductivity of the specified solution was 43 MS/see the Precipitate was washed several times (8 times) purified water to obtain a conductivity 0,0068 MS/see the Residue was dried under vacuum, grinded and fractionally.

Example 27: Additional examples of products made with different stoichiometric amounts of calcium and strontium, as well as variations in the type of alginate with a high content of guluronate (G) or with a high content of mannuronate (M)) are presented in table 2.

Table 2
SeriesSaltThe type of alginate
The viscosity
Saturation%Na%Ca %SrParticle size,
mcm
FP-508-03CaG
113
100%125,75,
45,25
FP-506-03SrM
127
100%125,75,
45,25
FP-505-05SrG
425
100%125,75,
45,25
FP-505-02CaM
410
100%125,75,
45,25
FP-504-02CaG
993
100%
FP-502-02SrM
663
100%0,1221,675
FP-502-01CaM
663
100%0,169,275
FP-501-06SrG
149
100%0,5820,5
FP-501-05CaG
149
100%0,448,0
FP-501-03SrM
110
100%
FP-501-02CaM
110
100%0,228,6
FP-412-01SrM
110
90%3,114,5
FP-411-06SrG
146
64%
FP-411-05SrG
146
100%0,4620,0
FP-411-04CaG
146
64%3,46,4
FP-411-03CaG
146
100%0,169,5
16.09.2004CaG
190
100%0,2110,3

1. Set for making camogliese alginate gel containing:
the first container containing sterile water-soluble alginate; and a second container containing particles of sterile water-insoluble alginate with gel-forming ion.

2. The kit according to claim 1, containing a mixing device and/or the metering device.

3. The kit according to claim 2, in which the mixing device is a T-connector.

4. The kit according to claim 1, additionally containing an additional container containing the solvent.

5. The kit according to claim 1, additionally containing a drug, a peptide, a protein, a cell, a multicellular aggregate, fabric, detektiruya a label or a contrast reagent.

6. The kit according to claim 1, in which there is an excess of sterile soluble alginate compared with sterile insoluble alginate.

7. The kit according to claim 1, in which the ratio of the concentration of sterile soluble alginate and concentration sterile insoluble alginate is from 5:1 to 1:5.

8. The kit according to claim 1, in which the particle sizes of sterile insoluble and is iginate with gelling ion selected from the group consisting of <25 μm, 25-45 μm, 45-75 μm, 75-125 microns and >125 μm.

9. The kit according to claim 1, in which sterile soluble alginate and/or sterile insoluble alginate comprises alginate containing at least 50% G.

10. The kit according to claim 1, in which sterile soluble alginate and/or sterile insoluble alginate has a molecular mass of approximately 5-350 kDa.

11. The kit according to claim 1, in which sterile soluble alginate and/or sterile insoluble alginate includes the following levels of endotoxins <25 in this case/year

12. The kit according to claim 1, in which sterile soluble alginate and/or sterile insoluble alginate contains levels of endotoxins in this case a 400/year

13. The kit according to claim 1, in which sterile soluble alginate includes one or more of Na-alginate, alginate, PEG-alginate or NH4the alginate.

14. The kit according to claim 1, in which sterile insoluble alginate includes one or more of calcium, strontium, barium, copper, manganese, lead, cobalt or Nickel.

15. Composition for the manufacture of camogliese alginate gel containing sterile soluble alginate in water and sterile particles of water-insoluble alginate with gel-forming ion.

16. The composition according to item 15, further containing a drug, peptide, protein, detektiruya a label or a contrast reagent.

17. The composition is indicated in paragraph 15 in which sterile soluble alginate and/or sterile insoluble alginate comprises alginate containing at least 50% G.

18. The composition according to item 15, in which sterile soluble alginate and/or sterile insoluble alginate has a molecular mass of approximately 5-350 kDa.

19. The composition according to item 15, in which sterile soluble alginate and/or sterile insoluble alginate includes the following levels of endotoxins <25 in this case/year

20. The composition according to item 15, in which sterile soluble alginate and/or sterile insoluble alginate contains levels of endotoxins in this case a 400/year

21. The composition according to item 15, in which sterile soluble alginate includes one or more of Na-alginate, alginate, PEG-alginate or NH4the alginate.

22. The composition according to item 15, in which sterile insoluble alginate includes one or more of calcium, strontium, barium, copper, manganese, lead, cobalt or Nickel.

23. The composition according to item 15, in which there is an excess of sterile soluble alginate compared with sterile insoluble alginate.

24. The composition according to item 15, in which the ratio of the concentration of sterile soluble alginate and concentration sterile insoluble alginate is from 5:1 to 1:5.

25. The composition according to item 15, in which the particle sizes of sterile insoluble alginate is gelling ion selected from the group consisting of <25 μm, 25-45 μm, 45-75 μm, 75-125 microns and >125 μm.

26. Method of dosing camogliese alginate dispersion to obtain camogliese alginate gel, including:
a) forming a dispersion by mixing i) a solution containing sterile water-soluble alginate, sterile particles of water-insoluble alginate with gel-forming ion, or (ii) soluble in sterile water of alginate particles sterile water-insoluble alginate with gelling ion and solvent, and (b) dispensing the dispersion, whereby the dispersion of the alginate forms a gel matrix.

27. The method according to p in which the specified dispersion further comprises one or more components selected from the group consisting of a drug, peptide, protein, cells, multicellular aggregate, fabric, detectable labels and contrast reagent.

28. Method of dosing camogliese alginate dispersion of the individual to obtain camogliese alginate gel, including:
a) forming a dispersion by mixing i) a solution containing a soluble alginate, with particles of insoluble alginate with gel-forming ion, or (ii) dissolving the alginate particles of insoluble alginate with gelling ion and solvent, and
b) dosing var is rsii individual, whereby the dispersion of the alginate forms a gel matrix.

29. The method according to p, in which the dispersion is dosed to the individual for the formation of alginate gel matrix in the tissue, where the tissue includes bone, cartilage, connective tissue, muscle, liver, heart, pancreas, or skin.

30. Method of application camogliese alginate gel as a material for making the volume of tissue in an individual, comprising dosing camogliese alginate dispersion of the individual on p.

31. The method according to item 30, in which camogliese alginate gel is used as a material for imparting amount of tissue for the treatment of urinary incontinence, in which the specified camogliese alginate dispersion is administered to the individual in the submucosal layer, proximal to the urethral sphincter, or alginate gel is used as a material for imparting amount of tissue for the treatment of gastro-oesophageal reflux, in which the specified camogliese alginate dispersion is administered to the individual at the junction of the esophagus and stomach.

32. Method of application camogliese alginate gel procedures for vascular embolization of the individual, including the introduction camogliese alginate dispersion of the individual on p in which the specified camogliese alginate dispersion is injected and is dividuum in a blood vessel.

33. The method according to p in which the procedure vascular embolization is carried out for the treatment of benign or malignant tumors, in which the specified camogliese alginate dispersion is administered to the individual in a blood vessel that supplies blood to the tumor.

34. Method of application camogliese alginate gel for preventing the formation of adhesions after surgical intervention at the individual, including the introduction camogliese alginate dispersion of the individual on p in which the specified camogliese alginate dispersion is administered to the individual in the area of surgical intervention.

35. Method of application camogliese alginate gel for the treatment of a wound in an individual, comprising the introduction camogliese alginate dispersion of the individual on p in which the specified camogliese alginate dispersion is administered to the individual in the area of the wound.

36. Method of application camogliese alginate gel for the treatment of wounds on the skin of an individual including the introduction camogliese alginate dispersion of the individual on p in which the specified camogliese alginate dispersion is applied on the specified skin of an individual in the area of the wound.

37. The method of using the implantable alginate gel, including the formation of camogliese of alginate PU is eat dosing camogliese alginate dispersion of the individual on p, and, after gel formation, implantation of implantable alginate gel to the individual.

38. A method of manufacturing the implantable device, including the application of camogliese alginate dispersion on p on the device.

39. Alginate camogliese gel, having a thickness of 5 mm and a homogeneous network alginate matrix, and not containing one or more of sulfates, citrates, phosphates, lactates, EDTA or lipids.

40. Alginate gel according to § 39, having a thickness more than 10 mm

41. Alginate camogliese gel, having a thickness more than 5 mm and not containing one or more of sulfates, citrates, phosphates, lactates, EDTA or lipids.

42. Alginate gel according to paragraph 41, having a thickness more than 10 mm

43. Implantable device comprising a coating of homogeneous alginate camogliese gel.

44. Implantable device according to item 43, in which said device is selected from the group consisting of a stent, a heart pacemaker, a catheter, an implantable prosthesis, surgical screws, surgical wire, the implants add volume to the tissue, the implant, the vast oesophageal reflux, implant, vast incontinence, implant, vast renal reflux, container, suitable for the maintenance of cells, which are deposited on the outer surface and/or in opalyuyetsya in alginate matrix, such as a rigid device or microcapsule, implant breast, chin implant, cheek implant, the implant of the chest, buttocks implant and a dental implant.

45. Method of completion or repair of bone and cartilage defects resulting from osteoarthritis, by dispensing camogliese alginate dispersion on p in which the specified imagelibrary alginate dispersion contains chondrocytes.

46. The method according to item 45, in which the chondrocytes are autologous.

47. A method of treating diabetes by dispensing camogliese alginate dispersion of the individual on p in which the specified imagelibrary alginate dispersion contains insulin-producing cells or multicellular aggregates.

48. The method according to p, in which the insulin-producing cells or multicellular aggregates represent pancreatic islets or cultivated lines insulin-producing cells.

49. Method for improving the viability of pancreatic islets or other cellular aggregates or tissues after extraction and during storage and transportation by incorporating these Islands or cell aggregates or tissue in camogliese alginate dispersion obtained by p.

50. A method of making particles of insoluble alginate with g is loprazolam ion to obtain alginate camogliese gel, incorporating the following stages:
dissolution of ultrapure sodium alginate in water and adding sodium salt;
salt dissolving a gelling ion in water and bring the pH to neutral values;
combining alginate solution with a solution of calcium chloride with continuous stirring;
collect fallen in the precipitate of insoluble alginate and washing with water up until its conductivity does not decrease to a level similar to the conductivity of the purified water;
drying the washed insoluble alginate:
the formation of particles of the specified dry insoluble alginate.

51. The method according to item 50, in which the gel-forming ion is calcium or strontium.

52. The method according to item 50, which includes stages:
dissolution of ultrapure sodium alginate in water and adding sodium carbonate;
dissolution of dihydrate of calcium chloride in water and bring the pH to neutral values using nitric acid;
combining alginate solution with a solution of calcium chloride with continuous stirring;
collect fallen in the precipitate of calcium alginate and washing with water up until its conductivity does not decrease to a level similar to the conductivity of the purified water;
drying the washed calcium alginate; and
grinding dry calcium alginate particles.

53. Ultrapure insoluble particles is about the alginate to gel-forming ion to obtain alginate camogliese gel, manufactured by a method according to paragraph 52.

54. Ultrapure particles of insoluble alginate with gelling ion to obtain alginate camogliese gel with the levels of endotoxins <25 in this case/year

55. Ultrapure particles of insoluble alginate with gelling ion in item 54, in which the alginate is saturated gel-forming ion.

56. Ultrapure particles of insoluble alginate with gelling ion in item 54, in which the gel-forming ion is calcium or strontium.

57. Sterile dispersion comprising a solution of a soluble alginate in the solvent and particles of insoluble alginate with gel-forming ion.

58. Variance § 57, in which the particles of insoluble alginate with gelling ion contain calcium.

59. Dosing device containing a dispersion according to § 57.

60. Dosing device according to p, where the metering device is a syringe.

61. The method of implantation of alginate gel matrix in the tissue of an individual comprising introducing into the fabric of the specified individual alginate gel matrix, obtained from the dispersion according to § 57.

62. The method of implantation of alginate gel matrix in the tissue of an individual, comprising the stage of: receiving alginate gel matrix of the variance in § 57 and the introduction of this alginate gel matrix in the tissue at asanoha of the individual.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing biologically compatible gel which is thickened with cross-linked polymer by cross-linking a given amount of at least one biologically compatible natural polymer in a solution by adding a defined amount of cross-linking agent, an additional amount of polymer with molecular weight over 500000 dalton in a solution, in which the reaction mixture is diluted to reduce concentration of polymer in the solution, and the cross-linking reaction is stopped by removing the cross-linking agent.

EFFECT: gel and its use for separating, replacing or filling biological tissue or for increasing volume of such tissue, or supplementing or replacing biological fluid.

11 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine. Particles of the viscoelastic material chosen from group, consisting of polysaccharides and their derivatives which are suitable for injection with gel particles having the size in a range from 1 to 5 mm at action of a physiological saline solution are described. An implant for increase of volume of the soft tissues, containing particles of the viscoelastic material chosen from group, consisting of polysaccharides and their derivatives where the basic volume of the specified particles represents the gel particles, suitable for injection and having the size in a range from 1 to 5 mm at action of a physiological saline solution, is described. The way of increase of volume of soft tissues at a mammal, including a human being, including subepidermal introduction in a place of a body of the specified mammal in which it is desirable to enlarge volume of soft tissues is described.

EFFECT: augmentation of volume of soft tissues at a mammal.

24 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine. Claimed is composition with hyaluronic acid (HA), which includes gel particles of bound water-insoluble hydrated HA. HA includes bindings, represented with the following structural formula: HK'-U-R2-U-TK'. Where each group HA' represents the same or other molecule of bound HA'; each U independently represents optionally substituted 0-acylisourea or N-acylurea; and R2 represents optionally substituted alkyl, alkenyl, alkinyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkinyl, aryl, heteroaryl, heterocyclic radical, cycloaliphatic alkyl, aralkyl, heteroaralkyl or heterocyclolalkyl. Also claimed is method of developing tissues in individual, including introduction of needle into individual in place where development of tissues is necessary, needle is connected to syringe filled with composition with HA, and applying force to syringe in order to supply composition with HA to individual. Method of obtaining composition with HA includes formation of water-insoluble dehydrated particles of bound HA, separating insoluble in water particles by their average diameter, selection of subset of particles by average diameter and hydration of subset of dehydrated particles by means of physiologically compatible water solution. Other method of obtaining composition with bound HA includes binding precursor of bound HA by means of bis-carbodiimide in presence of pH buffer and dehydration of bound HA. Also included is method of developing tissues in individual that needs tissue development. Method of stabilisation of bound HA includes hydration of water-insoluble dehydrated bound HA by means of physiologically compatible water solution which includes local anesthetic, so that value of elasticity module G' for stabilised composition constitutes not less than approximately 110% from value G' for non-stabilised composition.

EFFECT: claimed composition of hyaluronic acid and method of preparation and application of HA composition are efficient for development of tissue and/or drug delivery.

27 cl, 22 ex, 2 tbl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to reconstructive surgery, traumatology-orthopedy, maxillofacial surgery, stomatology and can be applied at osteo-plastic operations. For delivery of medical products immediately in a zone of defect and their prolonged influence in the centre of a lesion medicinal preparations are dissolved in a normal saline solution in a dose providing local effect, collagen-containing component is added to a solution in the ratio 9-20 g: 100 ml of a solution also admix with the carrier from dispersed allotransplants in the ratio of 1:1-3.

EFFECT: method allows lowering a dose necessary for reception of medical effect in 10 times, and also allows accelerating reparative processes in a defect zone.

3 dwg

FIELD: medicine.

SUBSTANCE: method of antibiotics fixation within porous implants is described. Result of method application lies in possibility of reliable fixation of antibiotic solution within porous implant and arrangement of favourable conditions for haemostasis in operative wound due to application of 10% gelatine solution as antibiotic carrier. Specified result is achieved by filling porous implants with antibiotic solution in liquid gel. For this purpose implant is dipped in solution by 3/4. Filling occurs under the influence of capillary forces. After solution cooled to form dense gel, antibiotic is fixed in implant pores and gradually released after installation to bone defect area.

EFFECT: reliable fixation of antibiotic solution within porous implant and arrangement of favourable conditions for haemostasis in operative wound.

3 cl, 1 ex

FIELD: medicine-destination polymers.

SUBSTANCE: invention relates to biologically stable hydrogels to be employed as endoprosthesis consisting essentially of following components: polyacrylamide including acrylamide, crosslinked methylene-bis-acrylamide, wherein acrylamide and methylene-bis-acrylamide are linked at molar ratio from 150:1 to 1000:1. Hydrogel is rinsed with water or physiologic solution so that it contains about 0.5-3.5% polyacrylamide and less than 50 ppm acrylamide and methylene-bis-acrylamide monomers, while modulus of elasticity of hydrogel is approximately 10 to 700 Pa and its complex viscosity about 2 to 90 Pa*sec. Rinsing stage allows removal of nearly all amounts (even trace amounts) of above-indicated monomers resulting in lower toxicity and higher stability of hydrogel. Biologically stable hydrogel is used as injectable prosthesis to fill soft tissues and also to treat or prevent urinary incontinence or anal incontinence. Hydrogel, obtained in a few stages including combining acrylamide and methylene-bis-acrylamide, initiating radical polymerization, and rinsing with apyrogenic water or physiologic solution, is also useful in treatment or prevention of bladder-ureter reflux in mammalians. In all these cases biologically stable hydrogels contain between 0.5 and 25% polyacrylamide.

EFFECT: enlarged resource for manufacturing endoprostheses.

10 cl, 3 dwg, 7 tbl

The invention relates to medicine, in particular to plastic surgery
The invention relates to medicine, namely to a method for producing compositions for injection, for use in reconstructive and cosmetic surgery

The invention relates to medicine, namely to molecular-linked gel containing a variety of biological and non-biological polymers such as proteins, polysaccharides and synthetic polymers

The invention relates to a formulation and method for producing a biocompatible hydrogel based on cross-linked copolymer of acrylamide with cross-linking agents that can be used as a material for medical purposes, for example:

- when the endoprosthesis through targeted injections hydrogel for plastics soft tissues of the face, breast, penis, calf muscles, vocal cords and other tissues, the density of which corresponds to the density of the hydrogel;

- as a filler in the manufacture of implants, including implants breast;

- as a depot for drugs with long-term medication, such as tumors or abscesses;

- as a carrier for culturing human cells and animals with subsequent implantation of hydrogel containing cells in the mammalian organism

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining polysaccharide fibre for making materials, specifically for making surgical suture materials absorbable in a human and a mammal body, absorbable and non-absorbable dressing material and absorbable textile matrix materials. The method is characterised by that 2.4-4.0 wt % solution of polysaccharide in dimethylacetamide which contains 4.56-10.00 wt % lithium chloride is mixed with 1.0-5.0 wt % poly-N-vinylpyrrolidone with molecular weight of 8-35 kDa or a metallopolymer complex - fine-grained silver stabilised by poly-N-vinylpyrrolidone in such an amount that, content of fine-grained silver relative polysaccharide dissolved in spinning solution ranges from 0.07 to 0.87 wt %. Mass ratio of polysaccharide: metallopolymer complex equals 88.0-99.0:1.0-12 wt %. The mixture is intensely stirred, held, filtered, degassed and the obtained spinning solution is extruded at room temperature into an alcohol deposition tank in form of water-soluble aliphatic C2 and C3 alcohols. The fibre is then processed in plastification and washing tanks and dried.

EFFECT: obtaining fibre with good deformation and strength properties.

1 dwg, 4 tbl, 29 ex

FIELD: medicine.

SUBSTANCE: there is described method of manufacturing anti-microbial wet wound bandage with bound silver. Silver-containing compound is added to 0.1-30% water solution of alkaline solvent with dissociation of silver atoms from silver-containing compound, SD is dissolved in water or an organic solvent, obtaining SD solution, solution containing silver ions is mixed with SD solution in such way that hydrogen ions (HI) of SD hydroxyl groups are substituted by silver ions, obtaining silver-SD compound, said silver-SD compound is dispersed and absorbed in a substrate, the substrate is dried.

EFFECT: wound bandage does not stick to wound surface.

16 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry. The material for haemostasis contains dialdehyde cellulose of the oxidation level 6.5±0.33% - 1 g, gelatinol 60±3 mg - (0.75 ml), ε-aminocapronic acid 50±0.25 mg, lysozyme 5±0.25 mg, water 5.75 ml. The method for making the textile material expressing haemostatic action consists that ε-aminocapronic acid, gelatinol and lysozyme are successively dissolved in the distilled water at room temperature. After said components are dissolved completely, the prepared solution is placed into dialdehyde cellulose solution of the oxidation level 6.5%±0.33% in the form of a cloth and kept for 2 hours. Then the cloth is wrung out, air-dried to residual humidity no more than 10% with cutting out napkins of weight approximately 1 g and dimensions 7.5×5.0 cm, then sealed in polyethylene bags and sterilised by gamma irradiation in a dose 25 kGy. Besides for haemostasis of irregularly shaped deep stab, missile and shell fragment wounds, the prepared material is ground in a rotor impact mill to lint condition (cotton wool).

EFFECT: making the effective styptic (haemostatic) product of partially oxidised cellulose.

1 tbl, 5 ex, 3 cl

Adsorbent product // 2378020

FIELD: medicine.

SUBSTANCE: there is described adsorbent product, such as a diaper, a sanitary towel or a product used in incontinence and having a longitudinal and lateral direction, including a back sheet which is distal from the user's body while in use, and an upper sheet which is proximal to the user's body while in use. Herewith said product has a front part, a back part and a perineal part that lies between the front and back parts. The product in addition contains an adsorbent structure between the upper and back sheet passing longitudinally from the front to back parts. And the product contains at least one starch deodorising agent of the specific area at least 5 m2/g, preferentially at least 10 m2/g, more preferentially at least 50 m2/g, even more preferentially at least 100 m2/g, and the most preferentially at least 200 m2/g.

EFFECT: it ensures improved ability to absorb compounds with odour nuisance during long periods of time in damp and dry systems.

19 cl, 5 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: according to the invention there is provided a hemostatic composition comprising gelatin and hyaluronic acid or its derivative, wherein the specified hyaluronic acid or its derivative is included in the specified composition with final content of at least 10% (wt/wt) and/or wherein the specified hyaluronic acid or its derivative is cross-linked by the exposure to dry heat at a temperature of 110°C to 200°C. According to the invention, there are provided methods of obtaining the said compositions and their application.

EFFECT: invention ensures reduced swelling, which allows safer sponge application, improved hemostatic properties and improved adhesive properties decreasing therethrough post-operation tissue bond.

74 cl, 8 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine. The absorbing layered structure intended for use as the absorbing body in the absorbing product is described. The absorbing structure contains the first blanket consisting mainly from the fluffed crushed cellulose, the second blanket consisting mainly from the fluffed crushed cellulose, and the inside layer located between blankets and consisting of an admixture of the fluffed crushed cellulose and a 5-90 wt % material with ultrahigh absorbing ability. Thus the fluffed crushed cellulose in blankets has durability of a quill which is less than durability of a quill in an inside layer, at least, on 1 N, measured at mass on unit of the area, making 300 g/m2, and specific volume of 4.5 cm3/g or less, and preferably durability of a quill which is less than durability of a quill in an inside layer, at least, on 2 N, measured at mass on unit of the area making 300 g/m, and specific volume of 4.5 cm3/g or less.

EFFECT: development of the absorbing layered structure intended for use as the absorbing body in the absorbing product.

14 cl, 3 tbl, 3 ex

FIELD: medicine; hygiene.

SUBSTANCE: invention is intended to solve problem of body dehydration and irritation at areas contacting absorbing articles. Invention concerns absorbing article, such as hygienic towel, pad attached to lingerie, tampon, diaper, lip medium or incontinence protection medium, containing skin care agent with pectin for transport from absorbing article to user. Particularly, invention concerns absorbing article containing skin care agent for transport to mucosa and skin at lower abdomen area of women. Invention is also suitable for elderly people, whose skin is often dry and fragile and can become ulcerated, infected, or for infant diapers increasing skin irritation and dehydration risk. Pectin has humidity preservation effect and can be applied in acidification or pH level regulation.

EFFECT: good compatibility with skin, ease of contact and interaction with skin and mucosa.

9 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: used are films made of glycosaminoglycan conjugates with 4- or 5-aminosalicylic acids or alginate conjugates with 4- or 5-aminosalicylic acids or intermixed conjugates or mixed conjugates and at least one polymer chosen from group including carboxymethyl cellulose, glycosaminoglycan, alginate, gelatine, albumin with salicylate content not less than 50%. Specified mixtures are treated with 2-20% iron (III) chloride solution at room temperature within 1-5 minutes. Surface complex lowers water- and biological liquids solubility of the film.

EFFECT: prolonged of biomaterial activity is provided.

10 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention can be used at treatment of pyoinflammatory diseases and trophic ulcers, and also in gynecology - at a cervical pathology. After secondary crushing pectin is dissolved in water in the ratio accordingly 0.09÷0.1:1.0; then the colloidal solution in thickness of 2.0÷2.5 mm is applied on a fluoroplastic surface, dried and the pectinaceous film obtained for the medical purposes in tight packing is sterilised a method of ultra-violet radiation within not less than 15 minutes.

EFFECT: reduction of terms of healing wounds at the expense of their reliable isolation from an environment, reduction of terms of mediko-social rehabilitation of patients at the expense of creation of favorable conditions for tissue regeneration.

5 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention can be used for production human and mammal body absorbable surgical suture materials and absorbable wound textiles. Milled chitin-containing natural raw materials (for example, crab shells) are processed many times at 4-10°C, preferable at 4-5°C using aqueous solutions of hydrochloric acid and alkali, then rinsed with water, aqueous solution of weak acid, water, acetone. Produced dry product is dissolved in dimethylacetamide containing lithium chloride 4.56-10.0 wt % to produce chitin solution 2.4-4.0 wt %. Produced solution is extruded at room temperature to alcoholic setting bath, passed through aqueous stretch and rinsing baths; thus alcoholic setting bath is water-soluble aliphatic alcohols C1-C3, preferably C2 and C3.

EFFECT: sufficient elongation and durability especially for surgical suture material.

1 tbl, 1 dwg, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns a multi-purpose biomaterial. The biomaterial contains KH2PO4, metal oxide (namely, MgO), calcium-containing compound, sugar and water. Typical calcium-containing compounds include, but not limited, tricalcium phosphate.

EFFECT: biomaterial exhibits an excellent adhesive properties and also unexpected and essential osteoproliferative possibilities and is used as a bone graft, bulking agent, adhesive, binding agent, fastener and cement and can be easily introduced with a syringe.

26 cl, 1 dwg, 5 tbl, 3 ex

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