Imidised biopolymer adhesive and hydrogel
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a recovered imidised biologically compatible polymer functionalised by an imide group. The above polymer is selected from the group consisting of polyethylene oxide, partially or completely hydrolysed by polyvinyl alcohol, polyvinylpyrrolidone, polyethyloxazoline, polyoxypropylene oxide block copolymers (poloxamers and meroxapol), polyethylene oxide and poloxamine copolymer, carboxymethyl cellulose and hydroxyalkylated cellulose, polypeptides, polysaccharides, carbohydrates, polysaccharose, hyaluronic acid, dextran, heparin sulphate, keratan sulphate, chondroitin sulphate, heparin, alginate, gelatin, collagen, albumin, ovalbumin, complex polyphosphoesters, polylactides, polyglycolides, polycaprolactones, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, polymaleic acids, polyamino acids, polyvinyl alcohol, polyvinylpyrrolidone, polyhydroxy cellulose, chitin, chitosan, and copolymers, ternary copolymers, or combinations or mixtures of the aforementioned materials. Also, the invention refers to a composition for a tissue adhesive, a medical device and a pharmaceutical composition.
EFFECT: invention represents additionally modified or functionalised imidised polymers.
9 cl, 2 ex, 20 dwg
The LEVEL of TECHNOLOGY
Biopolymers natural origin do not always have structural or functional characteristics desired for biomedical applications. However, polymeric biomaterials used in biomedical application forms, including coverage of medical equipment, artificial implants and devices for drug delivery. Polymeric reticulated structure can be formed, for example, by stitching solutions of water-soluble polymers with the formation of water-insoluble polymeric reticulated structure. Mechanical and structural characteristics can be adjusted by modifying the density of cross-linking depends on the pore size of the mesh structure, water content and mechanical properties.
Polymers, matrices or gels are preferred for tissue engineering because of their materials can be encapsulated cells. Some polymers or gels have a high water content, comparable with the tissue moisture content, which allows the transport of nutrients and waste products.
In particular, the description of the present invention is a composition comprising at least one Monomeric link biologically compatible polymer, functionalized by imide for having formirovaniya tissue adhesive, hydrogel, or both.
In yet another embodiment, at least one of the Monomeric units of biologically compatible polymer is associated with the second functional group, which may be an imide. The second functional group, if not an imide may be any known functional group and can give the polymer orientation.
The monomer can be functionalized with at least two functional groups. In General, when the polymer contains several types of functional groups, the polymer can contain basically ravnomernye number of different functional groups, or the ratio may vary according to the chosen structure.
Next, functionalityand biologically compatible polymer composition may contain at least the second biocompatible polymer that reacts with the first imitirovannymi biological polymer. Thus, the second polymer may contain functional groups which are reactive with respect to the imide or another functional group in the first emalirovannoy the polymer. The functional group of the second polymer may constitute, for example, the amino group.
Compositions according to the description of the present invention can optionally contain biologically the active agent, such as nutrient, cell, such as a blood cell or chondrocyte, or undifferentiated cell such as a stem cell, such as a hematopoietic stem cell or mesenchymal stem cell.
In some embodiments, the implementation of the described compositions are hydrogels with adhesive properties.
The present invention is a composition comprising a first biocompatible polymer, functionalized kidney group, and, optionally, bridging molecule, such as functionalized second polymer, to create a medical adhesive. In some embodiments, the first polymer contains at least 10 Monomeric units, at least 100 of monomer units or at least 1000 or more Monomeric units. Bridging molecule can contain many functional groups to ensure the reaction of at least two molecules of the first polymer.
In the polymer not all of the monomers must be functionalized with reactive fragment.
The first polymer may be reactive with respect to the surface of the structure, such as a biological structure, such as an organ, tissue or cell, such as the surface of the cartilage or bone, or an artificial structure, such as a prosthesis. Second fu is clonally fragment in the first emalirovannoy polymer, which may be an imide can also be reactive towards the surface. The first polymer may be reactive towards bridging molecule. Reactions can proceed in any manner that provides a level of adhesion, such as the formation of covalent bonds, physical crosslinking, ionic binding or other molecular mechanism that fixes the molecules on the surface, structure or body that is reactive with respect to such, and associates them with the bridging molecule.
In some embodiments, the implementation of diverse polymers react with each other with the formation of multilayer polymer structures with exposed surfaces that are reactive towards the surface, such as fabric, and to bridge the molecule. Bridge molecule may also be a multilayer structure.
Additional characteristics and advantages of the present invention are presented in the following Detailed description of the Invention and will be apparent from such.
BRIEF DESCRIPTION of DRAWINGS
Fig. 1-20 depict various imides which may be used as reactants for derivatization described monomer or polymer.
DETAILED description of the INVENTION
The present invention in part relates to the SPO is trained plastic or repair of a tissue or organ, such as sealing of the incision or wound. The method includes overlaying the surface of the biocompatible polymer containing imide. Optionally, the surface may be first processed to generate reactive functional groups that can react with the described first imitirovannymi polymer.
Interest gels, mesh structures, structural media (scaffold), films and the like made from describe(s) the composition(s), promote the integration and growth of cells, tissues and organ. The optional presence of cells such as stem cells, enhances the integration and growth of cells, tissues and organ.
Essential for the described product is better integration with the surrounding tissue to improve the stability and binding of the biological surface and for the formation of new tissue. In vitro studies have confirmed the efficacy of the chemical mechanism of the reaction with the surface and high mechanical strength at an interface between the material and the cell/tissue/organ.
The present invention solves the problem of the formation of fibrous cartilage tissue in surgical practice. The present invention is applicable, for example, in the early stages of osteoarthritis of the joints by applying dressings and gels for preventive care is IKI enzymatic decomposition of synovial fluid during and after implantation. The present invention also provides the possibility of stimulation of bone marrow without violating the integrity of the subchondral bone. Describe the connection or connections can be used, for example, in the eye, spine, musculoskeletal system, in places where the cartilage, and so on.
The present invention provides a method of in situ polymerization for the formation of structural media (scaffolds) and the like, which may be formed into the desired shape according to the defect, contribute to the development of tissue by stimulating the recovery of native cells, and potentially can be implanted using minimally invasive injection.
This description of the invention is directed, at least in part, on the polymer matrix and gels, and methods of obtaining and application of matrices, polymers and gels. One of these aforementioned polymers contains imide.
For example, this description is functionalized biologically compatible with the first polymer, such as hyaluronate, keratan-sulfate, chondroitin-sulfate and the like, substituted imide. For example, see patent application WO 2006089119, WO 2004029137, WO 2006105161 and WO 2006036681 given in this description for information about the various options for use of similar, but unrelated to the described compounds. In that the OIC did not mention imides, or statement is clearly not for eating imides.
Biological surface refers to the outer, open to the environment part of the biological material or organism such as a microbe, virus, cell, tissue, organ and the like, with which a biologically compatible polymer can interact, respond and/or to which to adhere.
Biologically compatible polymer refers to a polymer that is functionalized to serve as compositions for application to the surface. The polymer is a polymer of natural origin, or which is non-toxic to the recipient. The polymer contains at least imide. The polymer may be homopolymers where all monomers are the same, or heteropolymers containing two or more types of monomers. The terms "biocompatible polymer", "biocompatible crosslinked polymeric matrix" and "biocompatibility"being used in relation to these polymers, are common in the technology and are considered equivalent to each other, including biologically compatible polymer. For example, biocompatible polymers include polymers that are as non-toxic to the recipient (e.g., animal or human), and do not decompose (if the polymer decomposes) to such an extent that the recipient of bresults the Monomeric or oligomeric subunits or other by-products in toxic concentrations.
The concept of "active agent" and "biologically active agent" are used in this description interchangeably to refer to a chemical or biological compound that creates a desired pharmacological and/or physiological effect that can be prophylactic or therapeutic. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of those active agents specifically mentioned in the present description, containing, but not limited to such salts, esters, amides, prodrugs, active metabolites, analogs, and the like. When the terms "active agent", "pharmacologically active agent" and "drug", it should be understood so that the invention includes the active agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogs, etc. Active agent can be a biological organism such as a virus or cell, whether naturally occurring or artificially modified, such as transformed.
The concept of "biocompatible polymer", "biocompatible crosslinked polymeric matrix" and "biocompatibility" is common in the technology. For example, biocompatible polymers include polymers, which is not toxic by themselves for the recipient (for example, the animal or human), not degrade (if the polymer is decomposed in such a degree, at which the recipient are formed Monomeric or oligomeric subunits or other by-products in toxic concentrations. In some embodiments, implementation of the present invention biodegradation in common includes the decomposition of the polymer in the body, for example, in its Monomeric structural subunit, which can be known as practically non-toxic. However, the intermediate oligomeric products resulting from such decomposition may have different Toxicological characteristics, or biodegradation may contain oxidation or other chemical reactions which form molecules other than Monomeric structural subunit of the polymer. Thus, in some embodiments, the implementation of toxicology biodegradable polymer, intended for use in vivo, such as implantation or injection, the patient may be determined after one or more tests for toxicity. There is no need for 100%purity of the investigated compositions, to read her biocompatible; indeed, it is only necessary that the investigated compositions were biocompatible, as described above. Thus, the analyzed composition may contain a polymer containing 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or the even less biocompatible polymers, for example, including described in the present description, the polymers and other materials and excipients, and continue to be biocompatible.
To determine whether a polymer or other biocompatible material, it may be necessary analyses for toxicity. Such testing is well known in the prior art. One example of such analysis can be performed on living cells, such as HeLa, 293, Cho, and the like. The sample is partially or completely decompose, as is known in the prior art, using, for example, a chemical reagent or enzyme preparation. An aliquot of the products of the processing of the sample is placed in a cultural tablets with pre-seeded cells. Product samples incubated with cells. The results of the analysis can be plotted on a graph as a percent (%) relative growth depending on the concentration of the degraded sample.
In addition, monomers, polymers, polymer matrices and compositions according to the present invention can also be assessed well-known in vivo tests, such as subcutaneous implantation in rats to confirm that they do not cause significant levels of irritation or inflammation in areas of subcutaneous implantation.
The term "biodegradable" is a recognized technology and includes monomers, polymers, polymer is the matrix gels, compositions and formulations, such as described in the present description, which is assumed to be degraded during use, such as in vivo. Biodegradable polymers and matrix typically differ from the biologically indecomposable polymer so that the first may be degraded during use. In some embodiments, the implementation of such use includes the use of in vivo, such as therapy in vivo, and in other certain embodiments of the exercise of such use includes the use of in vitro. In General degradation attributable to biorthogonal includes the degradation of the biodegradable polymer and its composite structural subunits or cleavage of the polymer, for example, as a result of biochemical process into smaller polimernye subunit. In some embodiments, the implementation in General can be identified two different types of biodegradation. For example, one type of biodegradation may include splitting relations (whether covalent or any other) in the frame of the polymer. In this biodegradation is typically formed monomers and oligomers, and even more typically, such biodegradation occurs by cleavage of the link connecting one or more structural subunits in the polymer. In contrast, another type of biodegradation may contain a breakdown of communication (whether covalent or any other), h is held in the side chain, or this, which binds to the side chain functional group, and the like with a polymer frame. For example, a therapeutic drug, a biologically active agent, or other chemical substance, which is attached as a side chain to the frame of the polymer, can be released as a result of biodegradation. In some embodiments, the implement during use of the polymer can be one or the other or both of the common types of biodegradation. As used in the present description, the term "biodegradation" covers both General types of biological decomposition.
The rate of degradation of biodegradable polymer often depends to some extent on many factors, including the chemical nature communications responsible for any decomposition, molecular weight, crystallinity, biostability, and the degree of crosslinking of such a polymer, the physical characteristics of the implant, the shape and size, and method and location of the injection. For example, the larger the molecular weight, the higher the degree of crystallinity and/or the higher biostability, the usually slower biodegradation any biodegradable polymer. The term "biodegradable" assumes containing materials and processes, also referred to as "biologically erodium".
In certain embodiments, the implementation rate of biodegradation of such a polymer can is to be characterized by the presence of enzymes for example, chondroitinase. Under such circumstances, the rate of biodegradation may depend not only on the chemical nature and physical characteristics of the polymer matrix, but also on the nature of any such enzyme.
In certain embodiments of the exercise of the polymer compositions according to the present invention are biologically degrade within a period that is acceptable in the desired version of the application. In certain embodiments of the implement, such as a therapy in vivo, such degradation occurs over a period of time, usually less than about five years, one year, six months, three months, one month, fifteen days, five days, three days or even one day of exposure to a physiological solution with a pH value between 6 and 8 having a temperature of between about 25 and 37°C. In other embodiments implement the polymer degrades within a period of between about one hour and several weeks, depending on the desirable use. In some embodiments, the implementation of the polymer or polymer matrix can contain detective tool, which is released during degradation.
The concept of "sewn" in the present description refers to a composition containing intermolecular crosslinking and, optionally, intramolecular crosslinking that occurs, in General, resulting in the formation of the Cove is build relationships. Covalent binding of two stitched components may be direct, in which case the atom in one component directly connected with atom in another component, or may be indirect, through a group-a bunch. Cross-linked gel or polymer matrix, in addition to covalent bonds, can also contain intermolecular and/or intramolecular non-covalent connection, such as hydrogen bonds and electrostatic (ionic) bond.
The term "functionalized" refers to the modification of an existing molecular segment or group to create, or to introduce a new reactive or more reactive group (for example, kidney group)that can react with another functional group (e.g. amino group) with the formation of covalent bonds. For example, carboxylic acid groups can be functionalized by reaction with carbodiimide and emenim reagent when using the known methods for the formation of new reactive functional group in the form of kidney group, with the substitution of a hydrogen atom in the hydroxyl group of the carboxyl function.
The term "gel" refers to the object's state between liquid and solid, and in General is defined as the cross-linked polymer reticulate structure, swollen in a liquid medium. Typically the spruce is a two-phase colloidal dispersion, containing both solid and liquid, in which the amount of solids exceeds such that in a two-phase colloidal dispersion is referred to as "Sol". As such, the "gel" has some of the properties of the fluid (i.e. the form is elastic and deformable) and some properties of a rigid body (i.e. the form is discrete enough to support the three-dimensional configuration on a two-dimensional surface).
The concept of "time gilotinirovaniya", also referred to in this description as "gelation time"refers to time spent on that song became stagnant in conditions of moderate stress. In General, this manifests itself as an achievement of the physical state in which the elastic modulus, G', is equal to or greater than the modulus of viscosity, G”, i.e. the coefficient of damping of mechanical vibrations (tan Delta) is equal to 1 (as may be defined using commonly used rheological methods).
The hydrogel is a swelling in water of the polymer matrix, which can absorb water with the formation of an elastic gel, in which the matrix represent the three-dimensional mesh structure of macromolecules held together by covalent or non-covalent ligaments. When placed in an aqueous environment with the ixe hydrogels swell in the seizing of liquids to the level permissible degree of crosslinking.
Hydrogels consist of hydrophilic polymers, crosslinked with the formation of swelling in water, insoluble polymeric reticulated structure. Crosslinking can be initiated by many physical or chemical mechanisms. Photopolymerization is a method of covalent cross-linking of polymer chains, in which photoinitiator and the polymer solution (referred to as solution "pledges") are subjected to exposure light source, specific photoinitiator. When you activate photoinitiator react with specific functional groups in the polymer chains, matching them with the formation of the hydrogel. The reaction proceeds quickly (3-5 minutes) and held at room temperature and body temperature. Photoinductive gilotinirovaniya enables the spatial and temporal control of the formation of structural media (scaffold), allowing correction form after injection and during gilotinirovaniya in vivo. Cells and bioactive factors can be easily embedded in the hydrogel us simply mixing with the polymer solution before photogelatine.
Alternatively, the reactants may contain complementary reactive group, such as midna and amino group, which produce the binding without the need for external initiator is.
Described hydrogels may represent a partially interpenetrating net structures that promote cell regeneration, tissue and organ at the same time inhibiting the formation of scar. Described hydrogels are derivationally to contain imide, reactive towards the surface and/or the second interest of the polymer. Described hydrogels also configured to have a viscosity that will allow gilotinirovaniya the hydrogel to remain fixed in or on the cell, tissue or organ, or on the surface. The viscosity can be controlled used monomers and polymers, water level, captured by the hydrogel, and put thickeners, such as biopolymers, such as proteins, lipids, saccharides and the like. An example of such a thickener is hyaluronic acid or collagen.
The term "polymer" is used to refer to molecules composed of repeating Monomeric units, including homopolymers, block copolymers, heteropolymer, statistical copolymers, grafted copolymers, and so forth. "Polymers" include linear polymers and branched polymers, and branched polymers include highly branched, dendritic and star polymers.
The monomer represents the base p is toraysee link in the polymer. The monomer itself may be a monomer or may be a dimer or oligomer of at least two different monomers, each dimer or oligomer is repeated in the polymer.
The initiator of polymerization refers to any substance that can initiate the polymerization of monomers or macromeris, for example, generation of free radicals. The polymerization initiator is often an oxidizing reagent. Exemplary polymerization initiators include those that are activated when exposed to, for example, electromagnetic radiation or heat.
The concept of "put", "encapsulated" and "captured" are recognized in the technology, when it comes to therapeutic drug, dye or other material and polymeric compositions, such as composition according to the present invention. In certain embodiments of the implementation of these terms include introduction, preparation, composition, or otherwise introducing such a drug in the composition, which provides the possibility of long-term release of such drug in the desired version of the application. Terms can suggest any course of action, which is a therapeutic drug or other material introduced into the polymer matrix, including, for example, joining the monomer of this polymer (interaction about what adowanie covalent bonds or other types of binding) and the involvement of such monomer in the polymerization to obtain the polymer composition, distributed throughout the polymer matrix attached to the surface of the polymer matrix (covalent or other types of binding), encapsulated within a polymer matrix, etc. the Term "co-administration" or "joint encapsulation" refers to the introduction of therapeutic drug or other material and at least one other therapeutic agent or other material in the described composition.
More specifically, the physical form in which any therapeutic agent or other material is encapsulated in the polymer, can vary depending on the specific versions. For example, therapeutic agent or other material may be first encapsulated in the microsphere and then combined with the polymer in such a way that retains at least part of the structure of the microspheres. Alternatively, a therapeutic drug or other material can be completely immiscible with the polymer according to the invention, it is dispersed as small droplets, but is not soluble in the polymer. In the present invention any form of encapsulation or administration is considered such as how long the release of any encapsulated therapeutic agent or other material determines whether there is enough acceptable form of enkapsuliran the tion for any particular use.
The term "treatment" or "therapy" is widely recognized in the technology term that includes healing and decrease the intensity of at least one symptom of any condition or disease. Treatment includes preventing a disease, disorder or condition preventing the animal that may be predisposed to the disease, disorder and/or condition,but has not yet been diagnosed as sick; the suppression of the disease, disorder or condition, for example, by impeding its development; and facilitating the course of the disease, disorder or condition, for example, providing any degree of regression of the disease, disorder or condition. Further, the treatment of the disease or condition involves reducing the intensity of at least one symptom of the particular disease or condition, even if causing such pathophysiology is not affected, or other symptoms remain the same.
The term "pharmaceutically acceptable salt" is a recognized technology and includes relatively non-toxic salts formed by the joining of inorganic and organic acids to the compositions according to the present invention, containing, without limitation, therapeutic agents, excipients, other materials, and the like. Examples of FA is matemticas acceptable salts include derivatives of mineral acids, such as hydrochloric acid and sulfuric acid, and derivatives of organic acids, such as econsultancy acid, benzolsulfonat acid, para-toluensulfonate acid and the like. Examples of suitable inorganic bases for the formation of salts include the hydroxides, carbonates and bicarbonates of ammonium, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and the like. Salt can also be formed using a suitable organic bases, including those that are non-toxic and strong enough to form such salts. In terms of illustration, the class of such organic bases may include mono-, di - and trialkylamines, such as methylamine, dimethylamine and trimethylamine; mono-, di - or trihydroxystilbene, such as mono-, di -, and triethanolamine; amino acids such as arginine and lysine; guanidine; N-methylglucamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; Ethylenediamine; N-benzylpenicillin; three(hydroxymethyl)aminoethane; and the like, for example, see J. Pharm. Sci., volume 66: pp. 1-19 (1977).
The term "prophylactic or therapeutic treatment" is a recognized technology and includes an introduction to the recipient one or more of the described compositions. If it is entered before the clinical detection of adverse conditions (e.g. the, disease or other unwanted state of the animal-recipient), then the treatment is prophylactic, that is, it protects the recipient against developing the unwanted condition, whereas if it is entered upon detection of an adverse condition, the treatment is therapeutic (i.e., it is intended to reduce, mitigate or stabilizirovannye existing adverse condition or side effects thereof).
The term "aliphatic" is a recognized technology and includes linear, branched and cyclic alkanes, alkenes or alkynes. In certain embodiments of the implementation of the aliphatic group in the present invention are linear or branched and have from 1 to about 20 carbon atoms.
The term "alkyl" is a recognized technology and includes saturated aliphatic groups containing lineannotation alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl group and cycloalkylation alkyl groups. In certain embodiments of the implementation of the linear alkyl chain or branched-chain has about 30 or fewer carbon atoms in its skeleton (for example, C1-C30for linear chains, With3-C30for branched chain), and alternatively,about 20 or less carbon atoms. Similarly, cycloalkyl fragments are from about 3 to about 10 carbon atoms in its cyclic structure, and alternative about 5, 6 or 7 carbon atoms in the ring structure.
Moreover, the term "alkyl" (or "lower alkyl"includes both "unsubstituted alkyl groups and substituted alkyl groups, the latter of which refers to alkyl fragments having substituents replacing hydrogen atoms in one or more of the carbon atoms of the hydrocarbon skeleton. Such substituents can include, for example, halogen, hydroxyl, a carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as a complex tiefer, thioacetal or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino group, amide group, aydinbey fragment, aminogroup, a cyano, a nitro-group, azide group, sulfhydryl group, allylthiourea, sulfate, sulfonate, sulfamoyl fragment sulfonamidnuyu fragment, sulfonyl, heterocyclic fragment, arylalkyl, or an aromatic or heteroaromatic fragment. Qualified specialists in this field of technology will be clear that the fragments that serve as the substituents in the hydrocarbon chain, may themselves be substituted, if it is acceptable. For example, the substituents in the substituted alkyl may include substituted and unsubstituted who's form amino groups, azide group, aminogroup, amide group, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfamidihappo, sulfamoyl and sulfonate), and silyl groups, as well as ethers, allylthiourea, carbonyl group (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkali described below. Cycloalkyl fragments can be further substituted by alkyl, alkenylamine, CNS fragments, alkylthiophene, aminoalkyl, carbonization alkyl groups, -CF3, -CN and the like.
The term "aralkyl" is a recognized technology and includes aryl groups (for example, an aromatic or heteroaromatic group).
The terms "alkenyl" and "quinil are recognized in the technology and includes unsaturated aliphatic groups analogous in length and possible zamestnanosti the above-described alkyl groups, but which contain at least one double or triple bond, respectively.
The term "heteroatom" is recognized in the technology, and the organic molecule in General includes an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
The term "aryl" is recognized tehnologii and includes 5-, 6 - and 7-membered monocyclic aromatic groups that may include from zero to four heteroatoms, for example, fragments of benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the cyclic structure may also be referred to as "allheterocou" or "heteroaromatic group". Aromatic cycle can be substituted in one or more of the provisions of the ring such substituents as described above, for example, halogen, azide group, alkyl, arylalkyl, alkenylphenol, alkenylphenol, cycloalkyl, hydroxyl, CNS group, an amino group, a nitro-group, a sulphydryl group, aminogroups, amide, phosphonate, phosphinate fragment, carbonyl, carboxyl, silyl group, ether fragment, alkylthiol, sulfonyloxy sulfonamidnuyu, ketone, aldehyde, ester group, the heterocyclic fragment, an aromatic or heteroaromatic fragments, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic structures in which two or more carbons are common to two adjoining to each other cycles (cycles n is called "condensed cycles"), in which at least one of the rings is aromatic, e.g., the other cyclic fragments may represent cycloalkyl, cycloalkenyl, cycloalkenyl, aryl and/or heterocyclic fragments, or cycles connected acyclic fragments.
The terms "ortho", "meta" and "para-" are recognized in the technology and are used for 1,2-, 1,3 - and 1,4-disubstituted cyclohexane, respectively. For example, the name "1,2-xylene and ortho-xylene" are synonyms.
The terms "heterocycle" and "heterocyclic group" are recognized in the technology and include cyclic structures from 3 - to 10-membered, such as cycles from 3 - to 7-membered ring structure containing from one to four heteroatoms. Heterocycles may also be polycyclic. Heterocyclic groups include, for example, fragments of thiophene, thianthrene, furan, Piran, isobenzofuran, chromene, Xanten, femoxetine, pyrrole, imidazole, pyrazole, isothiazole, isoxazol, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, hemolysin, isoquinoline, quinoline, phthalazine, naphthiridine, cinoxacin, heatline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, phenarsazine, fenotiazina, furazan is, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, research, lactones, lactams, such as azetidinone and pyrrolidinone, solitary, sultone and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, arylalkyl, alkenylphenol, alkenylphenol, cycloalkyl, a hydroxyl group, an amino group, a nitro-group, a sulphydryl group, aminogroups, amide, phosphonate, phosphinate fragment, carbonyl, carboxyl, silyl group, ether fragment, alkylthiol, sulfonyloxy, ketone, aldehyde, ester group, the heterocyclic fragment, an aromatic or heteroaromatic fragment-CF3, -CN, or the like.
The term "polycyclic fragment" or "polycyclic group" are recognized in the technology and include patterns with two or more cycles (e.g., cycloalkyl, cloonkeelane, cycloalkenyl, aryl and/or heteryl fragments), in which two or more carbons are common to two adjoining to each other rings, for example, the cycles are "condensed cycles". Ring connected via adjacent atoms, for example, when both the cycle is in General there are three or more atoms, called "bridge" cycles. Each of the rings of polycyclic system may be substituted with such substituents as described above, as for example, halogen, alkyl, arylalkyl, alkenylphenol, alkenylphenol, cycloalkyl, a hydroxyl group, an amino group, a nitro-group, a sulphydryl group, aminogroups, amide, phosphonate, phosphinate fragment, carbonyl, carboxyl, silyl group, ether fragment, alkylthiol, sulfonyloxy, ketone, aldehyde, ester group, the heterocyclic fragment, an aromatic or heteroaromatic fragment-CF3, -CN, or the like.
The term "carbocycle" is a recognized technology and includes aromatic or nonaromatic cycle, in which each atom of the ring is a carbon. Below recognized in technology terms have the following meanings: "the nitrogroup" means-NO2; the term "halogen" designates-F, -Cl, -Br or-I; the term "sulfhydryl" means-SH; the term "hydroxyl" or "hydroxy" means -- HE; and the term "sulfonyl" means-SO2-.
The terms "amine" and "amino" are recognized in the technology and include both unsubstituted and substituted amines. The primary amine contains two hydrogen atoms, a secondary amine contains one hydrogen atom and another is one Deputy, and in the tertiary Amina both of the hydrogen atoms substituted. The substituents for one or both hydrogen atoms may constitute, for example, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocycle, politics and so on. If both hydrogen atoms replaced by carbonyl groups, concluded between the CARBONYLS of the nitrogen atom form the imide.
The term "alkylamino" includes an amino group, as defined above, having attached thereto a substituted or unsubstituted alkyl group.
The term "amido" is a recognized technology as aminosilanes carbonyl.
The term "alkylthio" is a recognized technology and includes an alkyl group, as defined above, having attached thereto the sulfur radical. In certain embodiments of the implementation of the "ancilliary" fragment represented by one of-S-alkyl, -S-altenloh, -S-akinrinola fragments and so on. Illustrative examples of alkylthio include metalcorp, ethylthiourea and the like.
The term "carbonyl" is a recognized technology and includes a structure With a=O. the Carbonyl group is part of esters; carboxylic groups; formate; thiocarbonyl groups; complex thioesters; thiocarbonic acids; thioformate; ketones and aldehydes.
The terms "alkoxy" and "alkoxy" are recognized in them the technology and include alkyl group, as defined above, having attached thereto the oxygen radical. Illustrative examples of CNS groups include methoxy, ethoxy-, propoxy-, tert-butoxypropyl and the like.
"Plain air" consists of two hydrocarbon fragment covalently linked an oxygen atom. Accordingly, the substituent in the alkyl, which makes this simple alkyl ether, is a CNS group or similar to that of, for example, which can be represented by one of-O-alkyl, -O-alkenylphenol, -O-alkenylphenol groups, and so on.
The term "sulfonate" is a recognized technology and includes the fragment in which the sulfur atom has two oxygen atoms connected by double bonds, and an oxygen atom connected therewith ordinary communication.
The term "sulfate" is a recognized technology and includes a fragment that resembles sulfonate, but consists of two atoms of oxygen United with him by the ordinary ties.
The term "sulfonamide", "sulfamoyl", "sulfonyl and sulfoxide are recognized in the technology, and each of them can contain a variety of group R as substituents, as in the present description is described.
The terms "phosphoramidic and phosphoramidic are recognized in the technology.
The term "selenology" one is recognized by technology and includes alkyl group, having attached thereto a substituted selectarray group. Exemplary simple selenoviy", which can be substituted in the alkyl group are selected from one of the-Se-alkyl, -Se-altenloh, -Se-akinrinola fragments and so on.
Substitution can be made in alkenyl or etkinlik groups to make them, for example, aminoacridine, aminoalkylsilane, aminoalkylsilane, aminoalkylsilane, aminoalkylsilane, aminoalkylsilane, dialkanolamine, trialkylamine, carbonization alkenylamine or alkenylamine groups.
"Hydrocarbon" is recognized in the technology term and includes all permissible compounds having at least one hydrogen atom and one carbon atom. For example, a valid hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds, which may be substituted or unsubstituted.
The expression "protective group" is generally recognized in the technology and includes temporary deputies, which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protective groups include esters for carboxylic acids, simple Silovye EPE is s for alcohols and acetals and ketals of aldehydes and ketones, respectively. The field of chemical protective groups was summarized, for example, in the book the authors Greene et al., Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis, 2nd edition, published by Wiley, new York, (1991).
The definition of each expression, for example, alkyl, aryl, etc. when such occurs more than once in any structure, it is assumed independent of its definition wherever it is in the same structure, unless otherwise something else explicitly or not implied in the context.
The terms "trifles", "toil", "mesyl" and "neatly are recognized in the technology and relate to trifloromethyl, para-toluensulfonyl, methanesulfonyl and nonafterburning groups, respectively. The terms "triplet", "toilet", "mesilate and nonflat are recognized in the technology and belong to the ester functional groups, representing ester triftormetilfullerenov acid, an ester of para-toluensulfonate acid, ester methanesulfonic acid and ester nonattributable acid, and to molecules that contain these groups, respectively.
The abbreviations Me, Et, Ph, Tf, Nf, Ts and Ms are recognized in technology and represent methyl, ethyl, phenyl, trifloromethyl, nonattributable the ing, pair-toluensulfonyl and methanesulfonyl groups, respectively. A more complete list of abbreviations used by chemists organically having ordinary skills in technology, published in the first issue of each volume of the journal of Organic Chemistry; this list typically consists of a table, entitled "Standard List of Abbreviations" ("List of standard abbreviations").
Certain Monomeric structural subunit according to the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers and other compositions according to the present invention may also be optically active. The present invention considers all such compounds containing CIS-isomers and TRANS-isomers, R-enantiomer and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. The Deputy, such as an alkyl group, there may be additional asymmetric carbon atoms. All such isomers and mixtures thereof are assumed to be included in the present invention.
If, for example, a desirable specific enantiomer of the compounds according to the present invention, it can be obtained by asymmetric synthesis or by education derived from chiral the first center, where is formed a mixture of diastereomers share, and the group with a chiral center otscheplaut to obtain the desired pure enantiomers. Alternatively, if the molecule contains ό functional group such as amino, or an acidic functional group, such as carboxyl, diastereomeric salt is obtained using a suitable optically active acid or base, followed by separation of the thus obtained diastereomers by fractional crystallization or chromatographic means well known in the technology, and the subsequent isolation of pure enantiomers.
It will be clear that the notion of "substitution" or "substituted" includes the implicit proviso that such substitution is in accordance with a permitted valence of the substituted atom and the substituent, and that the substitution results in a stable connection, for example, which does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination, or other reaction.
The term "substituted" is also considered as containing all permissible substituents as derivatives of organic compounds, such as interest reagent for the formation of amidnogo fragment. In a broad aspect, the permissible substituents include acyclic and cyclic, rasvet is Lenna and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative examples of substituents include, for example, those described above. Permissible substituents can be one or more and same or different for the respective organic compounds. For the purposes of the present invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or substitutes that are acceptable for the described in the present description of organic compounds, which fill the valences of the heteroatoms. The present invention is not intended to be limited in any way in terms of permissible substituents of organic compounds.
For the purposes of the present invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version (System of classification in Chemical Abstracts Service), the leadership Handbook of Chemistry and Physics, 67th edition, 1986-1987
Functional group or a fragment that can be used to replace are those that are able to mediate the formation of the polymer or the reaction with the surface or other molecule. Functional groups include a variety of radicals and chemical objects described in the present description, and include alkeneamine fragments, such as the AKP is armor, the methacrylates, dimethacrylates, oligoaniline, oligometric, ethacrylate, itaconate or acrylamide. Additional functional groups include aldehydes. Other functional groups can contain monomers with ethylene unsaturation, containing, for example, alkalemia esters of acrylic or methacrylic acid such as methyl methacrylate, ethyl methacrylate, butylmethacrylate, acrylate, butyl acrylate, hexidecimal, n-octylacrylate, laurenmarie, 2-ethylhexylacrylate, nasolacrimal, bezelmaterial, hydroxyalkyl esters of the same acids such as 2-hydroxyethylacrylate, 2-hydroxyethylmethacrylate and 2-hydroxypropylmethacrylate, the nitrile and amides of the same acids such as Acrylonitrile, Methacrylonitrile and methacrylamide, vinyl acetate, finalproject, vinylidenechloride, vinyl chloride and vinylsubstituted aromatic compounds such as styrene, tert-butalbiral and vinyltoluene, diallylmalonate, diallylmalonate, diallylmalonate, isoprene and butadiene. Suitable monomers with ethylene unsaturation containing carboxylic acid group include acrylic monomers such as acrylic acid, methacrylic acid, etakrinova acid, taconova acid, maleic acid, fumaric acid, monoalkylation, including monomethylfumarate, monoethylether and MES is butylmalonate, monoalkylated, including monometallic, monoethylether and monobutylether, Tarakanova acid and Tirolerhof acid. Suitable monomers with multiple ethylene double bonds include butadiene, isoprene, alismataceae, diacrylate of alkanediols, such as diacrylate butanediol and diacrylate of hexandiol, divinylbenzene and the like.
In some embodiments, the implementation of the Monomeric link biologically compatible polymer can be functionalized with one or more thiol fragments, the remnants of the carboxylic acid or alcohol fragments located on the monomer of the biopolymer. For example, in the case of chondroitin sulfate carbonyl group can be derivatization kidney group using, for example, carbodiimide reagent. The alcohol group can be derivatisation, for example, through reaction of Mitsunobu, see authors Procter et al., Tetrahedron Letters, volume 47 (No. 29), page 5151-5154, 2006.
In some embodiments, the implementation of the present description of the invention is directed to a composition comprising at least one Monomeric link biologically compatible polymer, such as hyaluronic acid, heparin-sulfate, keratan-sulfate and the like, functionalized by imide. Such original molecules are natural components of vnekletochnaya. However, in General, as the polymer can be any biologically compatible polymer which contains at least imide. Other suitable polymers include those that occur in nature, such as GAG (glycosaminoglycan), mucopolysaccharide, collagen or proteoglycan components, such as hyaluronic acid, heparin-sulfate, glucosamine, dermatan, keratan, heparan, hyaluronan, aggrecan and the like.
In some embodiments, the implementation of the present description of the invention is directed to a composition comprising at least one Monomeric unit of the saccharide or other biocompatible polymer or polymer in which the monomers have reactive points, which will provide the opportunity for at least the introduction of imide or other functional groups, such as chondroitin-sulfate. Chondroitin sulphate is a natural component of cartilage and may be a useful material scaffold for regeneration. Chondroitin-sulfate comprises structural units of glucosaminoglycans, having a molecular weight of 10-60 thousand Daltons (kDa). Recurring structural units or monomer units, chondroitin sulfate consists of a disaccharide of β(1→4)linked D-glucuronyl-β(1→3)-N-acetyl-D-galactosaminidase.
Imide according to the present invention is not limited aceveda any one reactant of those several of which are known in the technology and is applicable in the context of the present invention, that is, to obtain an intermediate derivative, which does not undergo rapid spontaneous decay, but is stable enough to react, for example, with the amino group in the desirable molecule, in which the imide being gidroksilirovanii and having an oxygen atom as the point of binding, is regenerated in the form of hydroxyamide and replaced with the functional group in the desired molecule. Examples of imides shown in Figures 1-20, for example, succinimide.
Cross-linked polymer matrix according to the present invention can contain and form hydrogels. The water content of the hydrogel can provide information on porosity structure. Further, the water content may be a factor, which determines, for example, the survival of cells encapsulated within the hydrogel. The amount of water that the hydrogel can absorb, can be correlated with the density of crosslinking and/or pore size. For example, the percentage imenik ligaments in the functionalized macromer, such as chondroitin-sulfate or keratin sulphate, may determine the amount of water that can be absorbed.
Compositions according to the present invention may contain monomers, macromer, oligomers, polymers, Il the mixture. The polymer composition may consist solely of covalently stitched polymers, or polymers, stitched ionic interactions, or polymers, can be stapled in the redox reaction, or polymers, stitched hydrogen bonds, or any combination thereof. Reagents should be mostly hydrophilic and biocompatible.
Suitable hydrophilic polymers that serve as first and second polymers include synthetic polymers such as polyethylene glycol, polyethylene oxide, partially or fully hydrolyzed polyvinyl alcohol, polyvinylpyrrolidone, politisation, block copolymers of polyethylene oxide and polypropyleneoxide (poloxamer and mericarol), poloxamine, carboxymethylcellulose and hydroxyethylamine cellulose such as hydroxyethylcellulose and methylhydroxypropylcellulose, and natural polymers such as polypeptides, polysaccharides or carbohydrates such as FicollTM(a synthetic copolymer of sucrose and epichlorohydrin), polysaccharose, hyaluronic acid, dextran, heparan-sulfate, chondroitin-sulfate, heparin, or alginate, and proteins such as gelatin, collagen, albumin, or ovalbumin or copolymers or mixtures thereof. As used in the present description, the term "cellulose" includes cellulose and derivatives videopix is the R types; "dextran" includes dextran and similar derivatives thereof.
Also applicable polysaccharides or other biocompatible polymers, which are very viscous liquid or which are thixotropic, and form a gel after a long time due to the slow development patterns. For example, can be used hyaluronic acid, which can form an injectable gel with a consistency similar to gel for hair styling. Particularly useful are modified derivatives of hyaluronic acid. As used in the present description, the term "modified hyaluronic acid" refers to a chemically modified hyaluronic acid. Modified hyaluronic acid can be designed and synthesized with a pre-selected chemical modifications to regulate the speed and degree of crosslinking and biodegradation. For example, can be designed and synthesized, modified hyaluronic acid, which tarifitsirovana relatively hydrophobic group, such as propionic acid or phenylacetic acid, to make the polymer more hydrophobic and gel-forming, or grafted amines to facilitate electrostatic self-Assembly. Thus can be synthesized is modificirovannye hyaluronic acid, which are injectable, i.e. they can be flowing when the voltage but keep the gel-like structure when the load is absent. Hyaluronic acid and hyaluronic derivatives available in the market from firms Genzyme, Cambridge, Massachusetts, and Fidia, Italy.
Alternatively, the biocompatible polymer may be introduced in the described matrix to form a composite. Thus the molecule, such as hyaluronic acid or collagen, can be introduced in the described matrix. It may be desirable reactivity introduced such biopolymer. Therefore, the amino groups introduced in the polymer can be reactive with respect to the components described matrix, which can give a composite structure with a high modulus. Alternatively, for predominant properties of the polymer in the composite without significant effect on the module, such as maintaining adhesion to the tissues, entered the polymer can be functionalized to reduce the activity of any reactive functional groups therein. Thus, for example, amino groups in the polymer, such as collagen, can be functionalized, for example, the introduction of alkyl groups, acetyl groups, and so forth, as described in the present description, to make the polymer less reactive is in relation to emenim groups.
The methods of synthesis described above polymers known qualified specialists in this field of technology, for example, see the edition of the Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammonium Salts, edited by E. Goethals (published by Pergamon Press, Elmsford, new York, 1980). Many polymers, such as polyacrylic acid, available commercially on the market. Polymers of natural origin can be isolated from biological sources, as is known in the technology, or available for sale on the market. Naturally occurring and synthetic polymers can be modified using chemical reactions, technologically developed and are described, for example, in the book the author March “Advanced Organic Chemistry”, 4th edition, 1992, Wiley-Interscience, new York.
Exemplary embodiments of the invention include a method of obtaining emalirovannoi of saccharide, Monomeric or polymeric fragment, where the method may include the application of, for example, carbodiimide intermediate product, and amidnogo reactant for education derivatizing the imide monomer. Examples of carbodiimides include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). In technology there are other ways of limitirovaniya molecule.
For the modification of polymers, which can then p is to dergatsya radical polymerization, there are a variety of chemical approaches. For example, for the introduction of methacrylate groups in one or more of the monomers in the polymer chain can be used methacrylic anhydride, metallorganic and glycidylmethacrylate. Glycidylmethacrylate can be applied, for example, to enhance the reaction efficiency. Further, the reagents for the modification can be selected to optimize the absence of cytotoxic by-products.
In some embodiments, the implementation of each of the functional groups on the polymer block may contain at least one fragment of about 10 Monomeric units, at least about 2 fragments about 10 Monomeric units, and up to one or more functional groups on the monomer. Alternatively, the number of functional groups on the polymer block may contain at least one fragment of approximately 12 Monomeric units, to about 14 Monomeric units or more. For example, there may be at least one kidna group of ten Monomeric units.
Moreover, the ratio between each of imides and another functional group may be 5:1, 9:2, 4:1, 7:2, 3:1, 5:2, 2:1, 3:2, 1:1, 2:3, 1:2, 2:5, 1:3, 2:7, 1:4, 2:9 or 1:5 along the entire length of the polymer. Preferably each of imides and another functional group evenly distribution is Lena along the length of the polymer. However, the location of the functional groups can be configured so that they were placed on a non-random or regularly, for example, being concentrated in certain places polymer frame for its intended use. Therefore, groups can be isolated in various provisions of the polymer. If aside from imide there are two or more other functional groups, for each of the functional groups to the other one may vary from one to any other relationship or relationships in accordance with the selected structure.
Presents a composition comprising a cross-linked polymer matrix, which is called cross-linked polymer matrix includes at least one imitirovannymi biologically compatible polymer. In some embodiments, the mentioned cross-linked polymer matrix further includes at least two emitirovannykh biocompatible polymer. In other embodiments, the implementation of the cross-linked polymer matrix further comprises a second biocompatible polymer containing one or more functional groups reactive towards functional groups named first emalirovannoi polymer, such as amino groups, which are, for example, in the protein.
Auxiliary molecule that can bind described imitirovannymi bi the polymers with each other, such as aminecontaining polymer, i.e. bridging molecule, in General, is a polymer that contains many reactive places called reactive sites are those which react with the points lying in the described emalirovannoy biologically compatible polymer. Bridging molecule is preferably biocompatible. Bridging molecule, as imitirovannymi biologically compatible polymer may be biodegradable. Bridging molecule can be configured in a multilayer structure, in which the inner layers may be the same or different, provided that the surface outer layers are present with an open functional group for reaction with points on emalirovannoy the polymer, which can be an adherent to the tissue of the polymer.
Suitable polymers for the described emalirovannoi polymer and bridging molecules include biocompatible monomers with recurring structural units in the complex polyphosphate, polylactide, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, complex polyetherimide, polyarthra, polydioxanone, polyacetale, policewala, polycarbonates, polycholorinated, polyphosphazene, poly is hydroxybutyrate, polyhydroxyvalerate, polyalkylacrylate, polyalkylacrylate, polimetinovymi acids, polyaminoamide, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyhydroxyalkanoate, chitin, chitosan, and copolymers, ternary copolymers or combinations or mixtures of these materials. For example, the polymer can be substituted to contain amino groups.
Other suitable synthetic polymers include polymers containing amino groups, such as chemically synthesized polypeptides. Such polypeptides may contain polynucleotide polypeptides, which were synthesized for the introduction of amino acids containing primary amino groups, for example, lysine, and/or amino acid containing tirinya group (such as cysteine). Further suitable synthetic polymers include polyaminoamide.
Other compounds, which may contain amino groups, include proteins such as albumin. Albumin may be of animal origin from mammals, but can also be used other sources of albumin. For example, can be used bovine serum albumin (BSA). Alternatively, the albumin may be recombinant albumin isolated from cells with downregulation of gene recombinant albumin, using known technology metagame fragments of albumin, containing at least 100 residues albumen sequence, whether it is obtained by partial proteolysis or by using recombinant means, can also be used as a bridging molecule instead of intact albumin. Alternatively, apply the fragments may contain at least 50 residues, and more preferably at least 75 albumen residue sequence. Finally, can also be applied to mixtures of different forms of albumin (such as human, bovine, recombinant, fragmented), and the fraction of plasma that is enriched with albumin. Albumin can be purified directly from tissues or cells using methods well known in the technology.
Being used, the polymerization initiators include Electromechanical radiation. Initiation of polymerization can be produced by irradiation of light with a wavelength between about 200 to about 700 nm, or more than about 320 nm or higher, or even about 365 nm.
Examples of other initiators are soluble in organic solvents, initiators, such as benzoyl peroxide, azobisisobutyronitrile (AIBN), di-tert-butylperoxide and the like, water-soluble initiators such as ammonium persulfate (APS), potassium persulfate, sodium persulfate, sodium thiosulfate, and the like, OK what slideline-reduction initiators, which are combinations of such initiator and tetramethylethylene, salt, ferrous iron (Fe2+), hydrosulfite sodium or similar reducing agents, etc.
Suitable photoinitiator are such that can be used to initiate polymerization of the monomers, with minimal cytotoxicity, generation of free radicals. In some embodiments, the implementation of the initiators can act within a short period of time, such as minutes or seconds. Exemplary dyes for initiating ultraviolet (UV) or visible light include atrasin, 2,2-dimethoxy-2-phenylacetophenone, 2-methoxy-2-phenylacetophenone, other derivatives of acetophenone and comparison.
Other fotoacademie and photovoltaikanlage dyes that can be used to initiate polymerization include acridine dyes, for example, the product “Acriblarine”; casinowe dyes, for example, thionin; xantinove dyes, for example, rose Bengal; and phenazine dyes, for example, methylene blue. They can be used with socialization, such as amines, such as triethanolamine; sulfur compounds; heterocycles, such as imidazole; Rostami; ORGANOMETALLIC compounds; and other compounds such as N-phenylglycine. On the other initiators include camporini and derivatives of acetophenone.
Can also be applied to system thermal initiation of polymerization. Such systems, which are unstable at 37°C and would initiate radical polymerization at physiological temperatures include, for example, potassium persulfate with tetramethylethylenediamine or without; benzoyl peroxide with triethanolamine or without; and ammonium persulfate with sodium bisulfite.
Alternatively, the first imitirovannymi polymer can spontaneously react with the surface, such as tissue or prosthesis. First imitirovannymi polymer can also react with a second biocompatible polymer. Two reactant can be mixed prior to application, applied simultaneously, and so forth, as is known in the technology, to ensure the polymerization of the two polymers. If necessary, can be applied to the initiator, according to the chosen version of the application.
Cross-linked polymer matrix according to the present invention can form and may contain hydrogels. The water content of the hydrogel can provide information on porosity structure. Further, the water content may be a factor, which determines, for example, the survival of cells encapsulated within the hydrogel. The amount of water that the hydrogel can absorb, can be correlated with the density of knitting or pore size. For example,the percentage of methacrylate groups in the functionalized polymer can affect the amount of water which can be absorbed.
For example, a polyethylene oxide-diacrylate (PEODA), carrying the imide may be used in the polymeric system for tissue engineering, and cross-linked polymer matrix can contain together gilotinirovaniya CS-I (chondroitin-sulfate-imide) and polyethylene oxide-diacrylate (PEODA).
Mechanical properties of cross-linked polymer matrix, such as the us, can also be associated with a porous structure. For use in tissue engineering may be desirable scaffold with different mechanical properties depending on the desired clinical application. For example, scaffold for tissue engineering of cartilage in the artificial joint must withstand higher mechanical stresses than the tissue engineering of cartilage in other places of the body. Thus, polymers with mechanical properties that are easily adjustable, can be desirable and can be obtained according to the chosen version of the application.
The cytotoxicity of the biopolymer system of scaffold can be estimated using any suitable cells, such as fibroblasts, for example, using fluorescent cell cycle analysis of live and dead cells, and MTT (bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazole), compounds that actively metabolized in the cell with ismaningerstrasse from yellow to purple, as described above, and as is known in the technology.
In one aspect of the present invention can be prepared with a composition comprising a cross-linked polymer matrix or gel, and one or more biologically active agents. The biologically active agent can vary widely depending on the intended use of the composition. The term "active" is a recognized technology and refers to any substance that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. Examples of biologically active agents that can be named as "medicines", are described in well-known literary sources such as the Merck Index, The Physician''s Desk Reference, and The Pharmacological Basis of Therapeutics, and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; substances which affect the structure or function of the body; or a prodrug, which become biologically active or more active after they have been placed in physiological environment. Can be used in various forms of biologically active agent that is capable of visvabharati the described compositions, for example, in the adjacent tissue or fluids when administered to a subject. In some embodiments, the implementation of the biologically active agent can be applied in a cross-linked polymer matrix according to the present invention, for example, to facilitate formation of cartilage. In other embodiments, implementation of the biologically active agent can be used in cross-linked polymer matrix according to the present invention for the treatment, enhance, suppress or prevent a disease or symptom, in combination, for example, contribute to the formation of cartilage.
Further examples of biologically active agents include, without limitation, enzymes, antagonists or agonists of the receptors, hormones, growth factors, autologous bone marrow, antibiotics, antibacterial agents and antibodies. The term "biologically active agent" is also expected to contain a variety of cell types and genes that can be incorporated into compositions according to the invention.
In certain embodiments of the implementation of the described compositions containing biologically active agent in an amount of from about 1% to about 75% or more by weight of the total composition, alternatively about 2,5%, 5%, 10%, 20%, 30%, 40%, 50%, 60% or 70%.
Non-limiting examples of biologically active agents include means blocking adrenergicheskie inepsy, anabolic drugs, androgenic steroids, antacids, anti-asthma remedies, anti-allergenic materials, anticholesterolemic antilipidny drugs, anticholinergic and sympathomimetic agents, anticoagulants, anticonvulsants, antidiarrheal drugs, antiemetics, antihypertensive agents, anti-infective tools, anti-inflammatory drugs, such as steroids, non-steroidal anti-inflammatory drugs, antimalarials, protivoradikulitnye drugs, antiemetic, antineoplastics agents, anti-obesity drugs, antiparkinsonian drugs, antipyretic and analgesic drugs, antispasmodic agents, antithrombotic drugs, drugs against uricemia, anti-angina, antihistamines, antitussives, appetite suppressors, benzophenantridin alkaloids, biological agents, cardiotonic tools, cerebral straddling, coronary straddling, decongestants diuretics; diagnostic preparations, eritropoeticescoe tools, estrogens, expectorants, gastrointestinal sedatives, agents, hyperglycemic drugs, hypnotic drugs, hypoglycemic agents, ion exchange resins, laxatives, mineral supplements, m is Totti, mucolytic agents, growth factors, neuromuscular drugs, nutrients, peripheral vasodilators, drugs, contributing to the onset or continuation of the pregnancy, prostaglandins, anti-depressants, psychotropic drugs, sedatives, stimulants, thyroid and antithyroid drugs, tranquilizers, uterine relaxants, vitamins, antigenic materials, and prodrugs.
Specific examples of applicable biologically active agents of the above categories include: (a) antineoplastic, such as inhibitors of androgen receptors, antimetabolites, cytotoxic agents and immunomodulators; (b) antitussives, such as dextromethorphan hydrobromide, noscapine, carbetapentane citrate and chlophedianol hydrochloride; (C) antihistamines such as chlorpheniramine, phenindamine tartrate, pyrilamine, doxylamine succinate and phenyltoloxamine citrate; (d) decongestants tools, such as hydrochloride, hydrochloride phenylpropanolamine, pseudoephedrine hydrochloride, and ephedrine; (e) various alkaloids such as codeine phosphate, codeine sulfate and morphine; (f) mineral supplements such as potassium chloride, zinc chloride, calcium carbonate, magnesium oxide and other alkali metal salts and alkaline earth metals; (g) ion exchange resins, such as the N-acetylprocainamide; (i) antipyretics and analgesics such as acetaminophen, aspirin and ibuprofen; appetite suppressors, such as phenylpropanolamine or caffeine; (k) expectorants such as guaifenesin; (l) antacids such as aluminum hydroxide and magnesium hydroxide; biological additives, such as peptides, polypeptides, proteins and amino acids, hormones, interferons or cytokines and other bioactive peptidic compounds, such as calcitonin, ANF (trially natriuretic peptide), EPO (erythropoietin) and insulin; (n) anti-infective drugs, such as antifungal agents, antivirals, antiseptics and antibiotics; and (m) antisense funds and antigenic materials such as tools, applicable for vaccinations.
More specifically, non-limiting examples of applicable biologically active agents include the following therapeutic categories: analgesics, such as nonsteroidal anti-inflammatory drugs, opiate agonists of receptors and salicylates; antihistamines, such as H1-blockers and H2-blockers; anti-infective agents such as antihelmintic, antianaerobic drugs, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, broad-spectrum antibiotics dei is the major, penicillin antibiotics, quinolone antibiotics, sulfonamidnuyu antibiotics, tetracycline antibiotics, antimycobacterial drugs, anti-TB antimycobacterial drugs, Antiprotozoal drugs, antimalarial Antiprotozoal drugs, antiviral agents, antiretroviral agents, agents that kill scabby mites and anti-infective drugs for the treatment of urinary infections; antineoplastics agents, such as alkylating tools, alkylating funds on the basis of the nitrogen mustard alkylating funds on the basis of nitrosamine, antimetabolites, purine analogs, antimetabolites, pyrimidine analogs, antimetabolites, hormonal antineoplastics tools, natural antineoplastic, antibiotic natural antineoplastics and natural antineoplastic group of Vinca alkaloids; anti-vegetative disorders, such as anticholinergic drugs, protivopanikovye anticholinergic drugs, ergot alkaloids, parasympathomimetic, parasympathomimetics cholinergic agonists, parasympathomimetics cholinesterase inhibitors, sympatholytic tools, sympatholytic alpha-blockers, sympatholytic, sympathomimetics and sympathomimetic adrenergicheskie agonists; cardio-soudes what's drugs, such as anti-angina drugs against coronary heart disease, antianginal means the group of calcium channel blockers, nitrate antianginal tools, antiarrhythmic drugs antiarrhythmic drugs group of cardiac glycosides, antiarrhythmic drugs class I antiarrhythmic drugs class II, anti-arrhythmic drugs class III, anti-arrhythmic drugs class IV, antihypertensive agents, antihypertensive α-blockers, antihypertensive group of angiotensin-converting enzyme inhibitor (ACE-inhibitor), antihypertensive L3-blockers, antihypertensive group of calcium channel blockers, adrenergicheskie antihypertensive means of a Central, diuretic antihypertensive agents, antihypertensive agents group peripheral vasodilators, antilipemics funds antilipemics funds on the basis of substances that increase the excretion of bile acids, antilipemics based tools reductase inhibitors, inotropy, isotropy group of cardiac glycosides and thrombolytic means; dermatological drugs, such as antihistamines, anti-inflammatory agents, corticosteroid anti-inflammatory agents, anesthetics, antibacterial, p is aparaty local actions antibiotics topical application, antiviral anti-infective drugs local action and antineoplastic local action; electrolytic and renal agents, such as acidifying means, alkalizing diuretics, diuretics group of carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, accumulating potassium diuretics, thiazide diuretics, electrolytic deputies and tools that promote the excretion of uric acid; enzymes, such as pancreatic enzymes and thrombolytic enzymes; gastrointestinal drugs, such as anti-diarrhoeal remedies, antiemetics, gastrointestinal anti-inflammatory agents, salicylate gastrointestinal anti-inflammatory drugs, antacids anti-ulcer drugs, antiulcer drugs group of proton pump inhibitors in acid secretion of gastric juice, antiulcer drugs acting on the mucous membrane of the stomach, antiulcer drugs group H2-blockers, cholinergic assets, stimulating digestion, emetics drugs, laxatives and stool softeners, and prokinetics funds; General anesthetics actions, such as inhalation anesthetics, halogenated inhalation anesthetics, int the public anesthetics, barbiturate intravenous anesthetics, intravenous benzodiazepine anesthetics and intravenous anesthetics group of agonists of opioid receptors; hematological drugs, such as Antianemic tools, hematopoietic Antianemic funds coagulatory tools, anticoagulants, hemostatic coagulatory funds coagulatory capital of the group of platelet aggregation inhibitors, coagulatory means on the basis of thrombolytic enzymes and extenders plasma volume; hormones and modifiers hormones, such as abortifacients, adrenal funds adrenal corticosteroid drugs, androgens, antiandrogens, anti-diabetic drugs, anti-diabetic drugs on the basis of sulfonylureas, antihyperglycemics funds, oral contraceptives, progestin-only contraceptives, estrogens, productiveness drugs, tools, enabling clan activities, parathyroid tools, pituitary hormones, progestins, anti-thyroid drugs, thyroid hormones and tocolytic; immunobiological preparations, such as immunoglobulins, immunosuppressor, toxoid and vaccines; local anesthetics, such as amide local anesthetics and ester local anesthetics; anti-musculo-skeletal pain, such as protivoyadii the definition anti-inflammatory drugs, corticosteroid anti-inflammatory agents, anti-inflammatory agents based on gold compounds, immunosuppressive anti-inflammatory agents, non-steroidal anti-inflammatory drugs, salicylate anti-inflammatory agents, relaxants skeletal muscle relaxants skeletal muscle groups of neuromuscular blocking agents and skeletal muscle relaxants groups reversible neuromuscular blockers; neurological drugs, such as anticonvulsants, barbiturate anticonvulsants, benzodiazepine anticonvulsants, drugs against migraine, anti-Parkinson drugs, anti-vertigo, agonists opiate receptors and antagonists of opioid receptors; ophthalmic drugs such as anti-glaucoma, mitotic agents, mydriatic, mydriatic group of agonists adrenergic receptors, antimuskarinovoe act occurs mydriatic, ophthalmic anesthetics, ophthalmic anti-infective tools, ophthalmic aminoglycoside anti-infective tools, ophthalmic macrolide anti-infective tools, ophthalmic quinolone anti-infective tools, ophthalmic sulfonamidnuyu anti-infective tools, tetracycline ophthalmic anti-infective cf is DSTV, ophthalmic anti-inflammatories ophthalmic corticosteroid anti-inflammatory drugs and ophthalmic nonsteroidal anti-inflammatory drugs; psychotropic drugs such as antidepressants, heterocyclic antidepressants, tricyclic antidepressants on the basis of monoamine oxidase inhibitors and selective inhibitors of serotonin reuptake, protivoradikulitnye drugs, neuroleptic drugs, phenothiazine neuroleptic drugs, anxiolytics, sedatives, and hypnotics; barbiturate sedatives and sleeping pills, benzodiazepine anxiolytics, sedatives and hypnotics, psychostimulants, respiratory equipment, such as antitussives, bronchodilators, bronchodilators group of agonists adrenergic receptors, antimuskarinovoe act occurs bronchodilators, expectorants, mucolytic agents, respiratory anti-inflammatory drugs and respiratory corticosteroid anti-inflammatory drugs; toxicology tools, such as antidotes, the means of fixation of heavy metals, drugs against drug or alcohol abuse, a deterrent against abuse of alcohol or drugs, and money is the notion of abstinence when the abuse of alcohol or drugs; minerals; and vitamins, such as vitamin a, vitamin b, vitamin C, vitamin D, vitamin E and vitamin K.
Other classes of biologically active substances from the above categories include: (1) analgesic drugs in General, such as lidocaine, other kainic" analgesics or derivatives thereof, and analgesic non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, ibuprofen, Ketoprofen, and naproxen; (2) analgesics group of agonists of opioid receptors, such as codeine, fentanyl, hydromorphone, and morphine; (3) salicylate analgesics, such as aspirin (ASA) (aspirin with intersolubility coating); (4) antihistamines group H1-blockers, such as clemastine and terfenadine; (5) antihistamines group H2-blockers, such as cimetidine, famotidine, nysatin and ranitidine; (6) anti-infective agents such as mupirocin; (7) antianaerobic anti-infective drugs, such as chloramphenicol and clindamycin; (8) antifungal antibiotic anti-infective drugs, such as amphotericin b, clotrimazole, fluconazole, and ketoconazole; (9) a macrolide antibiotic anti-infective drugs, such as azithromycin and erythromycin; (10) antibiotic anti-infective drugs with a broad spectrum of action, such as imipenem; penicillin the s antibiotic anti-infective drugs, such as nafcillin, oxacillin, penicillin G and penicillin V; (12) quinolone antibiotic anti-infective drugs, such as ciprofloxacin and norfloxacin; (13) tetracycline antibiotic anti-infective drugs such as doxycycline, minocycline and tetracycline; (14) TB antimycobacterial anti-infective agents such as isoniazid and rifampin; (15) Antiprotozoal anti-infective drugs such as atovaquone and Dapsone; (16) antimalarials Antiprotozoal anti-infective drugs, such as chloroquine and pyrimethamine; (17) antiretroviral anti-infective drugs, such as ritonavir and zidovudine; (18) antiviral anti-infective drugs, such as acyclovir, ganciclovir, α-interferon and rimantadine; (19) alkylating antineoplastics tools, such as carboplatin and cisplatin; (20) alkylating antineoplastics funds on the basis of nitrosamine, such as carmustine (BCNU); (21) antimetabolites antineoplastics tools, such as methotrexate; (22) pyrimidine analogues antineoplastics drugs, such as fluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastics tools, such as goserelin, leuprolide, and tamoxifen; (24) natural antineoplastics tools, such as aldesleukin interlac is n-2, docetaxel, etoposide, α-interferon, paclitaxel, other taxonomie derivatives, and tretinoin (ATRA); (25) antibiotic natural antineoplastics tools, such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin; (26) natural antineoplastics means of a group of Vinca alkaloids such as vinblastine and vincristine; (27) means acting on the autonomic nervous system, such as nicotine; (28) anticholinergics effects on the autonomic nervous system, such as benztropine and trihexyphenidyl; (29) antimuskarinovoe act occurs anticholinergics effects on the autonomic nervous system, such as atropine, oxybutynin; (30) the impact on the autonomic nervous system on the basis of ergot alkaloids, such as parlodel; (31) parasympathomimetic group of agonists of cholinergic receptors, such as pilocarpine; (32) parasympathomimetic group of cholinesterase inhibitors such as pyridostigmine; (33) sympatholytic group-blockers, such as prazosin; (34) sympatholytic group D-blockers, such as atenolol; (35) adrenergic sympatholytic, such as albuterol and dobutamine; (36) cardiovascular drugs, such as aspirin (ASA) (aspirin with intersolubility coating); (37) antianginal drugs of group D-blockers, such as atenolol and propranolol; (38) antianginal means the group of calcium channel blockers such as nifedipine and verapamil; (39) nitrate antianginal tools such as the isosorbide dinitrate treatment (ISDN); (40) antiarrhythmic agent group of cardiac glycosides, such as (41) antiarrhythmic agent of class I, such as lidocaine, meksiletin, phenytoin, procainamide, and quinidine; (42) antiarrhythmic agent of class, such as atenolol, metoprolol, propranolol, and timolol; (43) antiarrhythmic agent of class, such as amiodarone; (44) IV antiarrhythmic agent of class, such as diltiazem and verapamil; (45) antihypertensive agents such as prazosin; (46) antihypertensive group of angiotensin-converting enzyme inhibitor (ACE inhibitor)such as captopril and enalapril; (47) antihypertensive agents such as atenolol, metoprolol, nadolol and propanolol; (48) antihypertensive groups of calcium channel blockers, such as diltiazem and nifedipine; (49) adrenergic antihypertensive Central actions, such as clonidine and hydrochlorothiazide methyldopa; (50) diuretic antihypertensive agents, such as amiloride, furosemide, hydrochlorothiazide (HCTZ) and spironolactone; (51) antihypertensive group peripheral vasodilators such as Minoxidil; (52) antilipemics tools, such as Hampi resil and probucol; (53) antilipemics funds on the basis of substances that increase the excretion of bile acids, such as cholestyramine; (54) antilipemics based tools reductase inhibitors, such as lovastatin and pravastatin; (55) inotropy, such as amrinone, dobutamine and dopamine; (56) isotropy group of cardiac glycosides, such as (57) thrombolytic agents such as alteplase (TRA), anistreplase, streptokinase and urokinase; (58) dermatological drugs, such as colchicine, isotretinoin, methotrexate, Minoxidil, tretinoin (59) dermatological corticosteroid anti-inflammatory agents such as betamethasone and dexamethasone; (60) antifungal anti-infective drugs local actions, such as amphotericin b, clotrimazole, miconazole, and nystatin; (61) antiviral anti-infective drugs local actions, such as acyclovir; (62) antineoplastic local actions, such as (63) electrolytic and renal agents, such as lactulose; (64) loop diuretics, such as furosemide; (65) accumulating potassium diuretics, such as triamterene; (66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67) to contribute the excretion of uric acid, such as probenecid; (68) enzymes, such as (69) thrombolytic enzymes, such as alteplase, anistreplase, streptokinase and urokinase is; (70) antiemetics, such as prochlorperazine; (71) salicylate gastrointestinal anti-inflammatory agents, such as sulfasalazin; (72) antiulcer drugs group of proton pump inhibitors in acid secretion of gastric juice, such as omeprazole; (73) antiulcer drugs group H2-blockers, such as cimetidine, famotidine, nizatidine, and ranitidine; (74) agent stimulating digestion, such as pancrelipase; (75) prokinetics drugs, such as erythromycin; (76) intravenous anaesthetics group of agonists of opioid receptors, such as fentanyl; (77) hematopoietic Antianemic agents such as G-CSF, granulocyte colony-stimulating factor) and (GM-CSF, granulocyte-macrophage colony-stimulating factor); (78) coagulatory tools, such as antihemophilic factors 1-10 (AHF 1-10); (79) anticoagulants, such as warfarin; (80) coagulatory means on the basis of thrombolytic enzymes, such as alteplase, anistreplase, streptokinase and urokinase; (81) hormones and modifiers hormones, such as parlodel; (82) abortifacients, such as methotrexate; (83) antidiabetic drugs, such as insulin; (84) oral contraceptives, such as estrogen and progestin; (85) progestin-only contraceptives, such as levonorgestrel and norgestrel; (86) estrogens such as resistivity is defined estrogens, diethylstilbestrol (DES), estrogen (estradiol, estrone and estropipate); (87) the fruitfulness drugs, such as clomiphene, human chorionic gonadotropin (HCG) and menotropin; (88) parathyroid agents such as calcitonin; (89) pituitary hormones, such as desmopressin, goserelin, oxytocin, and vasopressin (ADH); (90) progestins, such as medroxyprogesterone, norethindrone and progesterone; (91) thyroid hormones, such as levothyroxine; (92) immunobiological drugs, such as interferon beta-lb and interferon gamma-lb; (93) immunoglobulins, such as immune globulin IM, IMIG, IGIM and immune globulin IVIG, IGIV; (94) amide local anesthetics like lidocaine; (95) ester local anesthetics, such as benzocaine and procaine; (96) musculoskeletal corticosteroid anti-inflammatory agents, such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone, and prednisone; (97) musculo-skeletal immunosuppressive anti-inflammatory drugs, such as azathioprine, cyclophosphamide, and methotrexate; (98) musculoskeletal nonsteroidal anti-inflammatory drugs, such as diclofenac, ibuprofen, Ketoprofen, Ketorolac and naproxen; (99) skeletal muscle relaxants, such as diazepam; (100) skeletal muscle relaxants groups reversible neuromuscular blockers, such as p is redetermine; (101) neurological drugs, such as nimodipine, riluzole, taken and ticlopidine; (102) anticonvulsants, such as carbamazepine, gabapentin, lamotrigine, phenytoin and valproic acid; (103) barbiturate anticonvulsants, such as phenobarbital and primidone; (104) benzodiazepine anticonvulsants, such as clonazepam, diazepam and lorazepam; (105) antiparkinsonian drugs, such as parlodel, levodopa, carbidopa and pergolid; (106) anti-vertigo, such as meclizine; (107) agonists opiate receptors, such as codeine, fentanyl, hydromorphone, methadone, and morphine; (108) antagonists of opioid receptors, such as naloxone; (109) anti-glaucoma, such as timolol; (110) mitotic anti-glaucoma, such as pilocarpine; (111) ophthalmic aminoglycoside anti-infective agents such as gentamicin, neomycin and tobramycin; (112) ophthalmic quinolone anti-infective agents such as ciprofloxacin, norfloxacin and ofloxacin; (113) ophthalmic corticosteroid anti-agents, such as dexamethasone and prednisone; (114) ophthalmic nonsteroidal anti-inflammatory drugs such as diclofenac; (115) neuroleptics, such as clozapine, haloperidol, and risperidone; (116) benzodiazepine anxiolytics, sedatives and with otbornye drugs such as clonazepam, diazepam, lorazepam, oxazepam and prazepam; (117) psychostimulants, such as methylphenidate, pemoline; (118) such as codeine; (119) bronchodilators, such as (120) bronchodilators group of agonists adrenergic receptors, such as albuterol; (121) respiratory corticosteroid anti-inflammatory drugs, such as dexamethasone; (122) antidotes, such as flumazenil and naloxone; (123) means of fixation of heavy metals, such as penicillamine; (124) deterrent against abuse of alcohol or drugs such as disulfiram, naltrexone and nicotine; (125) withdrawal symptoms when alcohol or drugs, such as parlodel; (126) minerals, such as iron, calcium and magnesium; (127) derivative of vitamin b, such as cyanocobalamin (vitamin B12) and Niacin (vitamin B3); (128) connection of vitamin C such as ascorbic acid; and (129) vitamin D, such as calcitriol.
Further, there may be used a recombinant or isolated from cell proteins, such as recombinant beta-glucan; concentrate bovine immunoglobulin; bovine superoxide dismutase; composition containing fluorouracil, epinephrine and bovine collagen; recombinant hirudin (r-Hir), HIV-1 immunogen; recombinant human growth hormone, recombinant erythropoietin (r-EPO); gene-activated Erie is repeatin (GA-EPO); recombinant human hemoglobin (r-Hb); recombinant human mecasermin (r-IGF-1); recombinant β-interferon; lenograstim (G-CSF); olanzapine; recombinant thyroid-stimulating hormone (r-TSH); and topotecan.
Still further, can also be applied to the following peptides, proteins and other large molecules, such as interleukins 1 through 18, including mutants and analogues; interferons α, β, and which may be useful for the regeneration of cartilage, gonadotropin-releasing hormone (LHRH) and analogues; gonadotropin-releasing hormone, transforming growth factor (TGF), fibroblast growth factor (FGF); tumor necrosis factor α and β; nerve growth factor (NGF); the factor that stimulates growth hormone (GHRF), epidermal growth factor (EFG), osteogenic factors, activated by a connective tissue factor, homologous to fibroblast growth factor (FGFHF); a growth factor for hepatocytes (HGF), insulin-like growth factor (IGF); factor-2 inhibition of invasion (IIF-2); bone morphogenetic proteins 1-7 (BMP 1-7); somatostatin; thymosin-α-γ-globulin; superoxide dismutase (SOD); and complementary factors, and biologically active analogs, fragments and derivatives of such factors, for example, growth factors.
Members supergene family of transforming growth factors (TGF), which are multifunctional regulatory proteins, mouthbut introduced in the polymer matrix according to the present invention. Members supergene family of transforming growth factors (TGF) include transforming growth factors beta (for example, TGF-β1, TGF-β2, TGF-β3); bone morphogenetic proteins (for example, BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9); heparin-binding growth factors (e.g. fibroblast growth factor (FGF), epidermal growth factor (EFG), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF)), (for example, Inhibin A, Inhibin B), the differentiation factors of growth (for example, GDF-1); and Actively (for example, Activin A, Activin B, Activin AB). The growth factors can be isolated from a native, or natural sources, such as mammalian cells, or can be prepared synthetically, such as the technique of recombinant DNA, or by using a variety of chemical processes. In addition, can be applied analogs, fragments and derivatives of these factors, provided that they exhibit at least some biological activity of the native molecule. For example, the analogs can be obtained by expression of genes that are changed in the site-specific mutagenesis or other methods of genetic engineering.
Can be used in various forms of biologically active agents. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, etc the simple esters, esters, amides, proletarienne forms and the like, which are biologically active, being implanted, injected or otherwise placed into the subject.
In certain embodiments of the implementation in the described compositions can be introduced other materials in addition to one or more biologically active agents. For example, in the composition according to the present invention can be implemented plasticizers and stabilizers known in the technology. In certain embodiments of the exercise of such additives as plasticizers and stabilizers, are chosen for their biocompatibility or the final physical properties of the agents, thickening or gelling matrix or frozen or generovanou matrix.
The composition according to the present invention may further contain one or more auxiliary substances, or the like. Such additional materials may affect the characteristics of the final composition. For example, the polymer composition can be associated with such fillers as bovine serum albumin (BSA) or mouse serum albumin (MSA). In certain embodiments of implementation, the amount of filler can vary from about 0.1 to about 50% or more by weight of the composition. The introduction of such fillers may determine the speed duration is a high release of any encapsulated substance. Other fillers known qualified specialists in this field of technology, such as carbohydrates, sugars, starches, sugars, cellulose and polysaccharides, including sucrose, can be used in certain embodiments to implement the present invention.
In the composition for adjusting the pH value can be input buffer reagents, acids and bases. May also include means for increasing the distance of diffusion agents released from the composition.
The charge, lipophilicity or hydrophilicity of the described compositions can be modified by use of the additive. For example, surfactants can be applied to enhance Miscibility poorly miscible liquids. Examples of suitable surfactants include dextran, Polysorbate and sodium lauryl sulfate. In General, surfactants are used in low concentrations, usually less than about 5%.
The specific method used to obtain the described in the present description of the new compositions is not critical to the present invention and can be selected from a physiological buffer (authors Felgner et al., U.S. patent No. 5589466 (1996)).
Therapeutic formulations of the product can be prepared for storage as lyophilized formulations or in the solutions mix of product, having the desired degree of purity with optional pharmaceutically acceptable carriers, diluents, auxiliary additives or stabilizers typically used in technology, that is, buffer agents, stabilizing agents, preservatives, agents to ensure isotonicity of solutions of non-ionic detergents, antioxidants, and other various additives, see publication Remington''s Pharmaceutical Sciences, 16th edition, edited by Osol (1980). Such additives are in General non-toxic to the recipient used in the dosages and concentrations, therefore, excipients, diluents, carriers and so on are pharmaceutically acceptable.
"Isolated" or "purified" described polymer mainly contains no contaminating proteins originating from the environment or tissue from which was obtained a polymer, or substantially free from chemical precursors or other chemicals or reactants used in the environment, or the reaction mixture, which contains chemically synthesized components. Thus, the isolated and purified imitirovannymi polymer mainly contains no nakedyoung polymeric material and includes in its composition less than about 30%, 25%, 20%, 10%, 5%, 4%, 3%, 2,5%, 2%, 1,5% or 1% or less (dry weight) nakedyoung biopolymer dirt.
As the line is used in the present description, the terms "stability" and "stable" in the context of a liquid composition containing the described biopolymer mean that it is resistant to thermal and chemical aggregation, degradation or fragmentation under given conditions of manufacture, preparation, transportation and storage, such as within one month two months three months four months five months six months or more. Stable compositions according to the invention remain biologically active in a degree equal to or greater than 80%, 85%, 90%, 95%, 98%, 99% or 99,5% under the conditions of manufacture, preparation, transportation and storage. The stability of the above mentioned composition can be assessed by degrees of aggregation, degradation or fragmentation techniques known qualified specialists in this field of technology.
The term "carrier" refers to a diluent, auxiliary additive, excipient or environment, which introduces a therapeutic tool. Such physiological media can be a sterile liquid such as water or oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a suitable carrier, when FA the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol can also be used as liquid carriers, particularly for injectable solutions. suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. If desired, the composition may also contain small amounts of wetting or emulsifying agents, or buffering agents to control pH.
Compositions can take the form of solutions, suspensions, emulsions, powders, formulations with prolonged-release depot and the like. Examples of suitable carriers are described in the publication “Remington''s Pharmaceutical Sciences”, Martin. Such compositions will contain an effective amount of the described biopolymer, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration patient. As is known in the technology of preparing for compliance with the method of administration.
Buffer agents help to maintain the pH value in the range that approximates physiological conditions. The buffer means is preferably present in concentrations that are in the range from about 2 mm to about 50 mm. suitable buffering agents for use in the present invention include both organic and inorganic acids and salts thereof such as citrate buffers (e.g., a mixture of monosodium salt of citric acid and disodium salt of citric acid, a mixture of citric acid and trinitarios salt of citric acid, a mixture of citric acid and monosodium salt of citric acid, etc), succinate buffers (for example, a mixture of succinic acid and monosodium salt of succinic acid, a mixture of succinic acid and sodium hydroxide, a mixture of succinic acid and disodium salt of succinic acid, etc), tartrate buffers (for example, a mixture of tartaric acid and sodium tartrate, a mixture of tartaric acid and tartrate of potassium, a mixture of tartaric acid and sodium hydroxide, and so on), fumaric buffers (for example, a mixture of fumaric acid and monosodium salt of fumaric acid, a mixture of fumaric acid and disodium salt of fumaric acid, a mixture of monosodium salt of fumaric acid and disodium salt of fumaric acid, etc), gluconate buffers (for example, a mixture of gluconic acid and sodium gluconate, a mixture of gluconic acid and sodium hydroxide, a mixture of gluconic acid and gluconate potassium, etc), oxalate buffer (for example, a mixture of oxalic acid and sodium oxalate mixture, oxalic acid and sodium hydroxide, the mixture of oxalic acid and potassium oxalate, etc), lactate buffers (e.g., a mixture of lactic acid and sodium lactate, a mixture of lactic acid and sodium hydroxide, a mixture of lactic acid and potassium lactate, etc) and acetate buffers (e.g., a mixture of acetic acid and sodium acetate, the mixture of acetic acid and sodium hydroxide, and so on). Can be used phosphate buffers, carbonate buffers, his-tag buffers, salts of trimethylamine, such as Tris, HEPES, and other such well-known buffers.
To slow down the growth of microorganisms can be added preservatives, and can be included in amounts ranging from 0.2% to 1% (weight parts by volume). Preservatives suitable for use in the present invention include phenol, benzyl alcohol, meta-cresol, chloride of octadecyltrimethylammonium, benzalkonium halides (e.g. chloride, bromide and iodide), chloride hexadecane, alkylarene, such as methyl - or propylparaben, pyrocatechol, resorcinol, cyclohexanol and 3-pentanol.
Means to ensure isotonicity of the solution are present to maintain physiological isotonicity of liquid compositions according to the present invention and contain complex carbohydrate alcohols, preferably trivalent or higher carbohydrate alcohols, such as glycerin, aritra, Arabic, xylitol, sorbitol and mannitol. Polyhydric alcohols can Preece is to act in amounts of between about 0.1% to about 25%, by weight, preferably from 1% to 5%, based on the relative amounts of the other ingredients.
Stabilizers refer to broad categories of excipients which may vary in functionality from bulking up supplements that solubilities therapeutic agent or helps to prevent denaturation or adhesion to the wall of the container. Typical stabilizers can be a complex carbohydrate alcohols; amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, and so on; organic sugar or carbohydrate alcohols, such as lactose, trehalose, stachyose, Arabic, aritra, mannitol, sorbitol, xylitol, ribitol, monoset, galactic, glycerin and the like, including cyclically, such as Inositol; polyethylene glycol; polymers of amino acids; sulfur-containing reducing agents such as urea, glutathione, lipoic acid, thioglycolate sodium, thioglycerol, α-monothioglycerol and sodium thiosulfate; the polypeptides of low molecular weight (i.e. < 10 residues); proteins such as human serum albumin, bovine serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, sugars, monosaccharides, such as xylose, mannose, fructose, or CH the goat; disaccharides, such as lactose, maltose and sucrose; trisaccharide, such as raffinose; polysaccharides, such as dextran, and so on. The stabilizers can be present in the range from 0.1 to 10,000 weight parts per weight part of the biopolymer.
An additional variety of excipients include fillers (e.g. starch), chelating reagents (for example, ethylenediaminetetraacetic acid (EDTA), antioxidants (e.g. ascorbic acid, methionine or vitamin E) and the cosolvent.
As used in the present description, the term "surfactant" refers to organic substances having amphipatic structure, namely, composed of groups of opposing solubility characteristics, typically oil-soluble hydrocarbon chain and a water-soluble ionic group. Surfactants can be classified, depending on the charge of the surface-active fragment, anionic, cationic and nonionic surfactants. Surfactants are often used as wetting agents, emulsifiers, solubilization and dispersant for a variety of pharmaceutical compositions and compounds of biological materials.
Non-ionic surfactants or detergents (also known as "moisten what their agents") can be added to facilitate dissolution of therapeutic agent, and to protect therapeutic protein from the conditioned mixing aggregation, which also allow the composition to be subjected to surface shear stresses without causing denaturation of the protein. Suitable nonionic surfactants include Polysorbate (20, 80, and so on), poloxamer (184, 188, etc.), Pluronic polyols®and simple monetary of polyoxyethylenesorbitan (TWEEN-20®TWEEN-80®and so on). The nonionic surfactant may be contained in the range from about 0.05 mg/ml to about 1.0 mg/ml, preferably from about 0.07 mg/ml to about 0.2 mg/ml
As used in the present description, the term "inorganic salt" refers to any compound that does not contain carbon, which is obtained by substituting some or all of the acidic hydrogen atoms or acid metal or a group acting as metal, and is often used as a connection for adjusting toychest pharmaceutical compositions and compounds of biological materials. The most common inorganic salts are NaCl, KCl, NaH2PO4etc.
The present invention is a liquid biopolymer compositions having a pH ranging from about 5.0 to around 7.0, or from about 5.5 to about 6.5, or from about 5.8 to about 6.2, or about 6.0, or from about 6.0 to about 7.5, or from about 6.5 d is around 7.0.
The present invention encompasses compositions, such as liquid formulations having stability at temperatures in commercial refrigerators and freezers that are in the physician's office or in the laboratory, such as from about -20°to about 5°C, and named the stability estimate, for example, microscopic analysis, for storage purposes, such as within about 60 days 120 days 180 days, within about a year, for about 2 years or more. Liquid compositions according to the present invention are also showing stability, which is estimated, for example, particle size analysis at room temperature at least for a few hours, for example, one hour, two hours, or about three hours before use.
Examples of diluents include buffered phosphate buffer saline, buffer tebufelone against gastric acid in the bladder, such as citrate buffer (pH 7.4)containing sucrose bicarbonate buffer (pH 7.4) by itself or bicarbonate buffer (pH 7.4)containing ascorbic acid, lactose or aspartame. Examples of carriers include proteins, for example, which are removed in the milk, sugar, e.g. sucrose, or polyvinylpyrrolidone. Typically these carriers should be used at a concentration of about 0.1-90% (relative is giving weight parts by volume), but preferably in the range of 1-10% (ratio by weight parts by volume).
The compositions used for administration in vivo, must be sterile. This can be achieved, for example, by filtration through sterile filtration membranes. For example, the compositions according to the present invention can be sterilized by filtering.
Biopolymer composition will be formulated, dosed and injected by appropriate conventional medical practice. The determining factors in this context include the particular curable disease specific mammal treatable clinical condition of the individual patient, the cause of the disorder, the place of delivery means, the method of administration, scheduling of administration and other factors known to medical professionals. "Therapeutically effective amount" input biopolymer will be determined by such considerations and may constitute the minimum number required for the prevention, improvement or treatment considered disorders. As used in the present description, the term "effective amount" equivalent to the expression related to therapeutic level (e.g., prophylactic or therapeutic agent)which is sufficient to reduce the severity and/or duration of the disease weakening of one or more symptoms thereof, prevention of disease progression or provide regression of the disease, or which is sufficient to result in prevention of the development, recurrence, occurrence or progression of the disease or one or more symptoms thereof, or enhance or improve the prophylactic(-fir) and/or therapeutic(-fir) effect(-s) of another therapy (e.g., another therapeutic agent), applicable to the treatment of the disease. For example, the described treatment may increase the possibility of using joint recipient based on the initial condition of a damaged or diseased joint, at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In yet another embodiment, an effective amount of the described therapeutic or prophylactic remedy relieves symptoms of the disease, such as arthritis symptoms, by at least 5%, preferably at least 10%, by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. Also used in the present description as equivalent to the term "therapeutically effective amount".
If necessary, the composition may also contain a solubilizer and a local anesthetic such as lidocaine or other "kainic" anesthetic to relieve pain at the injection site.
In General, the ingredients are supplied either separately or mixed together in a single dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active funds. When the composition should be introduced by infusion, it can be distributed from an infusion bottle containing sterile pharmaceutical water purity or saline. When the composition is administered by injection, an ampoule of sterile water for injection or saline is placed, for example, set so that the ingredients can blend up call is to be placed.
Industrial product containing materials, applicable to the treatment of the above diseases. Industrial product includes a container and a label. Suitable containers include, for example, bottles, microtube (Wielki), syringes, and test tubes. The containers can be formed from various materials, such as glass or plastic materials. The container holds a composition which is effective for prevention or treatment, for example, wounds or disease of the joint, and may have a sterile input channel (for example, the container may be vialco with tube, sharp hypodermic needle for injection). The label applied to the container or associated with such, shows that the composition is used for treatment of the chosen state. Industrial product may further comprise a second container containing a pharmaceutically acceptable buffer, such as phosphate buffered buffered saline, ringer's solution and dextrose. It may further include other materials desirable from a commercial or custom of reasons, including buffers, diluents, filters, needles, syringes, and packaging inserts with instructions for use.
Biologically active agents and other additives can be incorporated in the crosslinked synthetic is kind of the polymer composition by blending in or added to the mixture of reagents. Alternatively, the agents can be introduced into the cross-linked polymer matrix by linking these agents with functional groups on the described polymers. Such compositions may contain ligaments, which can easily be subjected to biodegradation, for example, by enzymatic cleavage, leading to the release of the active agent or additive in the target tissue, where it will exhibit its desired therapeutic effect.
A simple way of introducing biologically active agents containing nucleophilic groups in the crosslinked polymeric composition includes mixing the active agent with polyelectrolytes component to add polynucleotides component. By varying the relative molar quantities of the various components of the reaction composition can change the total charge of the final cross-linked polymer composition, to prepare a matrix for the delivery of charged compounds, such as protein or an ionisable drug. As such, the delivery of charged proteins or drugs, which usually have to quickly diffuse from the neutral matrix-carrier can be controlled.
For example, if you use a molar excess of the component which is polynucleotides, the resulting matrix can have a positive net charge structures and can be used for ion binding and delivery of negatively charged compounds. Examples of negatively charged compounds that can be delivered from these matrices include a variety of drugs, cells, proteins and polysaccharides.
If you use a molar excess of the component which is polyelectrolytes, the resulting matrix has a net negative charge of the structure of charge and can be used for ion binding and delivery of positively charged compounds. Examples of positively charged compounds that can be delivered from these matrices include a variety of drugs, cells, proteins and polysaccharides.
Composition cross-linked polymer matrices according to the present invention can also be used for delivery of various types of living cells or genes to the desired injection for the formation of new tissue. As used in the present description, the term "genes" is supposed comprising genetic material from natural sources, synthetic nucleic acids, DNA, antisense DNA and RNA.
For example, mesenchymal stem cells can be delivered using polymeric matrices for the production of cells of the same type as the tissue in which they are delivered. Mesenchymal stem cells may be undifferentiated and therefore can differentiate with education is the use of various types of new cells by the presence of the active agent or agents (chemical, physical and so on) of the specific tissue. Examples of mesenchymal stem cells include osteoblasts, chondrocytes and fibroblasts. For example, osteoblasts can be delivered to the site of the bone defect to create new bone; the chondrocytes can be delivered to the site of the cartilage defect to create new cartilage; fibroblasts can be delivered for the formation of collagen whenever you want a new connective tissue; neuroectodermal cells can be delivered to the formation of new nerve tissue; epithelial cells can be delivered to the formation of new epithelial tissues, such as liver, pancreas, etc.
Cells can be allogeneic, or xenogeneic origin. The composition can be used to deliver the cells of interest, which are genetically modified.
In some embodiments, the implementation of the compositions according to the invention may not be easy degradation in vivo. Thus, cells captured within the compositions cross-linked polymer matrix, will be isolated from the cells of the recipient and, as such, will not provoke or will delay the immune response of the host.
To capture cells or genes within a cross-linked polymer matrix cells or genes can be, for example, pre-mixed with R the agent composition or optional, with the mixture prior to the formation of cross-linked polymer matrix, thereby introducing cells or genes inside the matrix.
In General the way of effective treatment of the surface of the hinge joint or disc or joint, spine and so on, within the body of a mammal subject components of the reaction composition are put into place that needs treatment. The present invention can be adapted to include appropriate media for this injection, implantation, infusion or delivery. Once in this place of the body, imitirovannymi biologically compatible polymer reacts with the surface and is associated with such, for example, cloth or prosthesis. Thus, imitirovannymi polymer is biologically fixed" on the fabric of the recipient and can then react with other surfaces, or polymers, such as described bridging molecule.
Alternatively, the polymer matrix may be formed from a semi-solid or solid object, suitable for implantation in an anatomical region, or in the form of a film or mesh that can be used to cover the segment area or surface. Various methods of implantation of solid objects into the appropriate anatomical region most likely familiar to a qualified specialist in this field the minute technology.
In some embodiments, the implementation disclosed in the present description of the composition can be placed in a surgically created defect, which must be reconstructed, and should be left in this position after the reconstruction was completed. The present invention may be suitable for use in the local reconstructions tissue reconstruction of the pedicle flaps, sealing corneal flaps or reconstructions of free plastic flaps.
In some embodiments implementing the present invention relates to kits for rapprochement between tissues or parts of tissues, such as for sealing or healing.
Disclosed in the present description sets will contain a container that is used to describe emalirovannoi polymer. The set can contain the device delivery. The set does not necessarily contain a container used for the second of the described polymer. Can be included instructions on their application.
Applications such kits include, for example, therapeutic use. The invention is kits for use in treating the disease or condition. For example, a set may contain imitirovannymi biologically compatible polymer, such as imitirovannymi chondroitin-sulfate, and biocompatible polymer or compound containing AMI is hydrated fragment, such as the aminecontaining glycol.
In certain embodiments of the implementation of the described polymer can be formed with desired structures, such as films, foams, scaffold or other three-dimensional structures of interest. Under such circumstances, in the described composition can be included with other materials in addition to one or more biologically active agents. For example, in the composition according to the present invention can be introduced known in the technology of plasticizers and stabilizers. Component set can be a solid structure. Thus, the described imitirovannymi biologically compatible polymer may be applied to a biological surface in the form of a solid structure with capability to react with the biological surface. Then bridge molecule may be closer to fixed biologically compatible polymer to interact with the latter.
In other embodiments, the implementation of a biologically compatible polymer is used without bridging molecules. Thus, imitirovannymi biologically compatible polymer is used as the adhesive. The polymer may be applied in liquid form on the biological surface. Alternatively, the polymer can be combined with an inert structure that is may provide support or to serve as a carrier for the polymer, such as a substrate for an adhesive bandage or structure or device having a desirable destination.
Described imitirovannymi polymer can be brought into interaction with the first and second cloth if possible to simultaneously respond to those. Kidnie groups react with functional groups of tissue, such as free amino groups of the lysine of the protein fragments.
In yet another embodiment, kidny fragment or one of imenik fragments or other functional group is reactive with respect to not only the fabric, but also to another substance used in an organism, such as a prosthesis, a hydrogel, us), matrix and so on. Thus, the described functionalized polymer can be used for fixing the substance to the tissue or to a particular place in the body.
Disclosed in the present description of the composition can be used in any number of variants of tissue repair, such as, but not limited to such, prevention seroma and bruises, accession skin or muscle flap, eliminating, or preventing endoprotease, eliminating stratification of the aorta, the restoration of the volume of the lung, the restoration of the neural tube, the sealing corneal incisions, reconstructive retina and holding microvascular is about and neural anastomosis.
In one embodiment, the restoration of damaged tissue can be carried out within any standard surgical process, providing access to restore tissue, including open surgery and laparoscopic techniques. Once the damaged tissue is available, the composition according to the invention is placed to contact with the damaged tissue, together with any surgical dressing or implant if necessary. Being used to restore broken or separated tissues, such as when connecting two or more tissue surfaces, for example, with subsequent surgical intervention, the composition may be applied to one or more tissue surfaces, and then the surface brought into contact with each other, and between such adhesion occurs.
Being used to restore the protruding tissue, surgically acceptable bandage may be applied to the area of tissue surrounding the protruding fabric to cover the protruding region, thereby strengthening the damaged tissue and eliminating the defect. While the bandage on the surrounding tissue composition according to the invention can be applied to either a bandage on the surrounding tissue, or on a bandage after bandage was applied to the protruding tissue. When the behavior of the lubricant and the fabric will be brought into contact with each other, among these may occur adhesion.
The surface that you want to glue that can hold together manually, or using other suitable means such as adhesive tape, temporary stitch and so on, until the crosslinking reaction does not take place until completion. Joining typically flows enough for adhesion within about 5 to 60 seconds after mixing of the components of the adhesive composition, unless the desired slow curing. However, the time required for full flow of stitching depends on a number of factors, including the type and molecular weight of each reaction component, the degree of functionalization and the concentration of the components in stitched composites (for example, higher concentrations are the result of more rapid binding).
In one embodiment, the composition according to the present invention are delivered to the injection site using a device that allows components to act separately, for example, sequentially or simultaneously. Such delivery systems may include a multi-chamber sputtering device.
Alternatively, the components can be delivered separately using any type of controlled extrusion system, or they can be delivered manually in the form of a separate pastes, liquids which she or dry powders and mixed with each other manually at the injection site. Many devices which are adapted for delivery of multicomponent tissue adhesives/hemostatic means well known in the technology and can also be used in the practice of the present invention.
Another way of delivery of the compositions according to the present invention is the preparation of the reaction components in the inactivated form of liquid or powder. Such compositions can then be activated after the application in the proper place on the fabric, or just before it, by hydration or application of, for example, activator. In one embodiment, the activator is a buffer solution having a pH value at which you want to activate the composition being mixed with it. Another way of delivery of the compositions is in the preparation of pre-formed sheets and drawing sheets as such in the introduction. A qualified specialist in this field of technology can easily determine the appropriate methodology introduction for the use of any specific composition with a known strength of the gel and the gelation time
Described in the present description of the composition can be used for therapeutic conditions that require coating or sealing layer to prevent the deposits of gas leakage, liquid or solid substances. The method involves the application of a reagent(tov) on the damaged tissue or organ for sealing 1) vascular and/or other tissues or organs to stop or minimize bleeding; 2) tissue in the chest to stop or minimize the leakage of air; 3) gastrointestinal tract or pancreatic tissue to stop or minimize the leakage of faeces or tissue content; 4) the bladder or ureters to stop or minimize the leakage of urine; 5) Dura to stop or minimize the leakage of cerebrospinal fluid (CSF); and 6) skin or serous tissue to stop the leakage of serous fluid. These compositions can also be used for bonding with each other tissues such as small vessels, nerves or skin tissue. The material can be used 1) by applying it to the surface of one fabric, and then the second fabric can be quickly pressed against the first tissue, or 2) putting tissues in close contact and then applying the material. In addition, the composition can be used to fill cavities in soft and hard tissues that occur as a result of disease or surgical intervention.
For example, the composition of the polymer matrix according to the invention can be used in owani to block or fill various voids or pores in the body of a mammal subject. The composition can also be used as a biological adhesive means for sealing cracks or breaks inside the tissue or structure (such as a vessel), or joints between adjacent tissues or structures, to prevent leakage of blood or other biological fluid.
The composition can also be used as a device to fill large openings to bias the body in the body cavity during a surgical or radiological procedures, for example, to protect the intestines during the planned course of radiation therapy to the pelvic region.
Compositions according to the invention can be also applied in the form of a coating on the inner surface of a physiological lumen such as a blood vessel or fallopian tube, thereby fulfilling the function of a seal to prevent restenosis of the lumen after therapeutic treatment, such as balloon catheterization to remove deposits of arterial plaques with the inner surface of the blood vessel, or remove scar tissue or endometrial tissue from inside the fallopian tubes. A thin layer of the reaction mixture is preferably applied to the inner surface of the vessel (for example, through a catheter) immediately after mixing the first and second synthetic polymers. Because of the composition according to the invention do not undergo the easy degradation in vivo, possible restenosis due to degradation of the coating is minimized.
Compositions according to the invention can also be used for augmentation of soft or hard tissue within the body of a mammal subject. Examples of applications for soft tissue augmentation include sphincter augmentation (for example, urinary, anal, ezofagealnogo) and removing wrinkles and scars. Examples of applications for hard tissue augmentation include restoration and/or replacement of bone and/or cartilage.
Now, when the invention is in General described, it will be more understandable with the involvement of the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.
Receive donor corneoscleral discs unsuitable for transplantation. The cornea is stored in standard conditions of the eye Bank Optison-GS (Bausch & Lomb, Inc., San Dimas, CA) at 4°C. the Procedure is performed for no longer than 10 days after death, as stated in the work of authors Reyes et al., Invest. Ophthal. Vis. Sci., volume 46 (No. 4), pages 1247 (2005)who report the use of derivatizing aldehyde group chondroitin-sulfate with polyvinyl alcohol to have is latania corneal incisions. However, the toxicity of these reagents has not been determined.
To perform keratectomy with a hinged flap use manual microkeratome (LSK One; firm Moria USA, Doylestown, Pennsylvania) just outside the center hole of the eye camera method, which obtained a large flap. This hole is like artificial unexpanded the pupil, which could be a reference point in a medical facility. For all corneas use a cylinder with a thickness of 300 μm. As is known in the technology, to maintain corneoscleral discs used artificial anterior chamber (ALTK System; firm Moria USA). Gearless guides on the base plate of the artificial anterior chamber is designed to fit to the head of the microkeratome, to pass along the cornea was maintained in the same plane and direction. All discs with rear stroma, shell Descemet and layer endotelialnyj cells obtained with the use of 6.25 mm round trephine drills manual.
Infusion of isotonic sodium chloride conduct before corneoscleral discs placed at the base of the anterior chamber, to remove residual air from the infusion tube, and from under the cornea. The bottle with the solution rises to a height of 1.5 m above the level of the camera to achieve the proper chamber pressure (60-70 mm Hg) PE is ed pass microkeratome. Corneal center according to the circular guide in the base of the camera. Mechanical epithelial scraping performed using 2.5 mm vertical sickle knife with a rounded end (Beaver, Becton Dickinson Surgical Systems, Franklin lakes, new Jersey), in order to avoid surface irregularities due to the free epithelium, which may cause errors in each videokeratography measurements.
Artificial anterior chamber is configured to achieve the maximum diameter of the graft in all cases. Manipulation is regarded as a larger area in the stromal bed to perform trepidatio and closing of the flap. All surgical operations are performed by the same surgeon in order to avoid variability typical of different surgeons, using a surgical microscope (Ophthalmic 900S; firm Moeller-Wedel, Hamburg, Germany).
To simulate clinical conditions on the corneal surface before passing through the microkeratome put a few drops of hydrochloride of proparacaine. The keratectomy with partial flap carried out by passing the head microkeratome with its oscillating blade at a relatively constant speed along the plate, stopping just behind the Central aperture of the camera. This approach differs from previously published techniques in attempts is to get wide hinged flap with a relatively low probability of displacement of the flap, to add more stability to the flap of the cornea and reduce a hole in the cornea. The remaining stroma under the hinged flap is separated using a 2-millimeter eye spatula of Caller (Sparta Surgical Corporation, Concord, California), to leave adequate space to perform the Central trepidatio. The internal chamber pressure return to the value of 18 to 20 mm Hg by reducing the height of the lift the bottle with the solution isotonic solution of sodium chloride up to 25 cm above the level of the cornea, and trepan center according keratectomy and pupillary" edge created artificially Central hole camera. For complete circular incision stromal bed use manual trephine diameter of 6.25 mm Blade round trephine drills gently pull up to the perforation, and the rest of the circular section complete with corneal scissors. Donor drives are placed in the recipient bed, leave unembroidered, and is placed back.
The experiment consists of two groups of four of the cornea in each. In one group (Group 1) flap is fixed with five interrupted sutures (10/0-nylon, firm Sharpoint Surgical Specialties Corporation, reading, Pennsylvania). The technique of seam is the same for all corneas for consistency.
In the second group (Group 2) flap is fixed with the use of tissue adhesive on navalnogo on emalirovannoy chondroitin-sulfate and aminecontaining polyethylene glycol.
Bridge component, 10%of aminecontaining polyethylene glycol, are used to cover the chondroitin-sulfate-imide (CS-I). Polyethylene glycol (PEG) intentionally colored in blue color using biocompatible dye (Cibacron Blue; firm Sigma-Aldrich). The embellishment of the bridge component allows to observe directly polymerized adhesive means relative to the incision and ensures that the adhesive agent does not have access to the front of the camera.
For the deposition of chondroitin-sulfate-imide (CS) on the wound edges using a 2.5 mm vertical sickle knife with rounded end (Beaver, BD Surgical Systems). A thin layer is applied to cover the cut surface and the inner edges of the wound. Then, using the second sickle knife apply a thin layer bridging component adhesive (aminecontaining polyethylene glycol, PEG-amine) on top of the first layer. Two components leave to cure for 30 seconds. As soon as the adhesive agent hardens, producing infusion of saline solution.
In both groups transplantirovannam drive leave without sewing or adhesive means, as he tends to stay in place due to surface tension after the internal chamber pressure reaches 15-18 mm Hg
After removal of the epithelium infusion of isotonic chloride is sodium stop and measure the corneal thickness using ultrasonic pachymetry (Pach IV, the firm Accutome Inc., Malvern, Pennsylvania) in the center of the cornea. The second measurement is carried out after the creation of the hinged flap and bending it from the stromal bed. Then calculate the thickness at the center of the flap.
For analysis of surface curvature apply commercial videokeratography (firm EyeSys Laboratories, Inc., Houston, Texas). Manual keratoscope ("Placido disk") is placed in a vertical position, and the camera center, respectively, to control the monitor. Observe caution in maintaining orientation in the preoperative and postoperative registrations. For each cornea before surgery and after surgery performed in three dimensions.
To assess the stability of the graft gradually increase in chamber pressure. Monitor for leaks, and the pressure is recorded by a digital manometer (Digimano 1000, firm Netech Corp., The Hicksville, New York).
Calculations performed using StatsDirect, version 1.9.0 for Windows (CamCode, Asheville, England). Describe the average value, standard deviation (SD), minimum and maximum values.
Fabric glue tool provides a good seal and less astigmatism than the other messages on the back lamellar keratoplasty using a microkeratome. Further, the lack of seams makes the technique easier and significantly reduces the straps.
The composition according to the present invention can be used for bonding two separate surfaces, at least one of which is a biological surface. Thus, the present composition can be used to seal wounds or holes by closing the open edges close to each other. The seal may be long-term or maybe short-term, depending on the degree of biorthogonal components of the adhesive. Briefly, the seal can provide adequate time for healing or leakage of natural closing holes. Alternatively, the described adhesive may be applied for bonding non-biological, but biocompatible surface to the biological surface. Such non-biological surface may be, for example, prosthesis, medical device and so on.
The method of synthesis of N-hydroxysuccinimide derived chondroitin sulfate (CS-NHS) using carbodiimide was known in the technology. Emenee derived significantly improves the efficiency and biocompatibility. Also synthesized derivatives of chondroitin sulfate (CS-Amin)to act as a donor of amino groups. For example, chondroitin sulphate (CS), succinimide and deemed in a ratio of about 3:3:1, the COO is responsible, can be introduced into the reaction in a small volume of saline solution within a short period of time. Suitable ratio of the three reactants may be about 75:100:38, as the choice of methods.
In yet another embodiment, chondroitin sulphate (CS) (750 mg) was dissolved in 6 ml of buffered phosphate buffer saline (PBS). 1.5 ml of PBS solution was dissolved 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 1,572 g, 8.2 mmol). Preparing a solution of 3.3 mmol of N-hydroxysuccinimide (NHS) by dissolving 380 mg in 1.5 ml PBS. A solution of N-hydroxysuccinimide (NHS) and carbodiimide (EDC) dobavliali to a solution of chondroitin sulfate (CS), and the mixture was stirred vortex stirring and left to react for 10 minutes at 37°C. the Reaction mixture is then cooled for 30 minutes at a temperature of -80°C, and precipitated with ethanol. The solution is then centrifuged for 5 minutes, and the supernatant was removed and washed.
Crosslinked chondroitin sulfate (CS) net structures synthesized in a variety of ratios NHS:NH2as shown in the Table below. The polymer solutions with a concentration of 10% (weight parts by volume) were prepared at the ratios of CS-NHS to PEG-(NH2)6comprising 1:1, 1:2 and 2:1. The reactants PEG-(NH2)6and CS-NHS was dissolved in DMEM with the formation of three different concentrations: 1,3%, 10% and 6.67% (ratio by weight parts by volume). Reagent CS-NHS (50 ml) was added into the mold, then add 50 ál of aminecontaining of polyethylene glycol (PEG-(NH2)6) and was stirred. After 10 minutes, the mesh was removed from the mold and transferred into a solution of PBS for measuring the degree of swelling.
|Description||50 μl of CS-NHS (wt.% per unit volume)||50 μl of amino-polyethylene glycol (PEG-amine) (wt.% per unit volume)|
|1:2 CS-NHS:PEG-amine||to 6.67||13,3|
|2:1 CS-NHS:PEG-amine||13,3||to 6.67|
Stitched mesh structure is then evaluated against swelling and cytocompatibility (cells encapsulated in mesh structures or cultivated close to those). The swelling characteristics are critical for applications as eye adhesive means, as excessive swelling may disclose reinforced wound or cause stigmatism. Mesh patterns were created with encapsules the private cells and without them. Potential delivery of cells within the adhesive applicable for large wounds of the cornea, which require the formation of some new fabrics in addition to seal wounds. Chondroitin sulphate (CS) net patterns were comparable with polietilenglikolya (PEG) control net structures in all reports.
Fibroblasts were encapsulated in the net structure of CS-PEG-amine with different ratios, 1:1, 1:2 and 2:1. The control PEG-net patterns were obtained at a concentration of 5%, 10% and 20% (weight parts by volume). Cells were stained for survival analysis using a commercially available kit. The number of living cells in all gels was comparable, indicating that the gels based on chondroitin-sulfate-imide (CS-I) were biocompatible.
In another experiment reagents CS-NHS and branched polyethylene glycol (PEG) was dissolved in PBS containing various amounts of HEPES buffer, for example, 10 mm, 100 mm, 500 mm and 1000 mm HEPES buffer. The reagents were stirred until gelation occurred, until, when to take a sample of the reagent pipette was impossible. It was noted that the time curve of gelation goes on gently sloping land with approximately 100 mm HEPES buffer. With increasing concentration of HEPES buffer was low decrease in the volume of the gel, presumably as a result of increasing the degree with which ivci with increasing concentrations of HEPES buffer. Module, or the strength of the gel, in General also increased with increasing concentration of HEPES buffer. At a concentration of 500 mm module in a small degree has declined, with a large standard deviation.
Cells from the nucleus pulposus, the annulus, chondrocytes, keratocyte, endothelial cells of the cornea, the epithelial cells of the cornea and mesenchymal stem cells were tested for cytotoxicity with a variety of gels according to the present invention. Cells were encapsulated in diverse described gels. Monitoring cells was at least over a period of more than 21 days. As a control, cells were treated with 5%diacrylates of polyethylene glycol. Gels contained chondroitin sulphate (CS) and polyethylene glycol (PEG) at the ratios of CS:PEG 1:2, 1:1 and 2:1. Some gels contain hyaluronic acid (ON) or glucosamine (GlcN), in General the gel ratio CS:PEG 1:1 contained an equal part of hyaluronic acid (ON) or glucosamine (GlcN). In all circumstances, the viability of cells was maintained throughout the 21-day test period. Endothelial cells of the cornea on the 8th day showed the level of cell proliferation was observed anti-apoptotic effect.
In another series of experiments to CS-PEG-gels, prepared as described above was added collagen to final concentrations OK the lo of 0.15% (weight parts by volume). Observed an increase in module 1.75±0.08 fold compared with CS-PEG-gels without collagen. It was hypothesized that the collagen acts as a dispersion included in the gel matrix and thus gives the gel properties of the composite.
The primary amino groups of collagen can interact with imename groups CS-NHS in the described gel. Therefore, the collagen may be crosslinked with gel matrix by covalent binding. This reinforcement stitching may lead to reduced adhesion of the gel due to the reduced number of available imenik groups in CS-NHS. One approach to prevent covalent binding between collagen gel matrix is to use functionalized collagen, such as collagen, in which the amino group is substituted, to minimize the reactivity of the amino group. For example, the amino group may be modified by the introduction of acetyl groups, alkyl groups, and so forth, as described above. This should lead to a gel with a high modulus without sacrificing adhesion to tissues.
Putative equivalents of polymers, polymer matrices, subunits and other compositions described in the present description, include such materials which otherwise correspond to those, which have the same General properties thereof, in colorimetery one or more simple variations of substituents, which do not render harmful influence on the effectiveness of such molecules or compositions in achieving its intended purpose. In General, the compounds according to the present invention can be obtained by methods illustrated in the General reaction schemes as, for example, described above, or by modifications thereof, using readily available starting materials, reagents and common synthetic methods. In these reactions is also possible to use variants which are known in themselves, but in the present description not mentioned.
All publications and patents mentioned in the present description, hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually listed as incorporated by reference.
1. Selected imitirovannymi biologically compatible polymer, functionalized kidney group, with specified polymer selected from the group consisting of polyethylene oxide, partially or fully hydrolyzed polyvinyl alcohol, polyvinylpyrrolidone, polisiloksanovye, block copolymers of polypropyleneoxide (poloxamers and maroccolo), copolymer of polyethylene oxide and poloxamine, carboxymethylcellulose and hydroxyacetylamino cellulose, polypeptides, polysaccharides, carbohydrates, polishers, hyaluronic is acid, dextran, heparin sulfate, keratan-sulfate, chondroitin sulfate, heparin, alginate, gelatin, collagen, albumin, ovalbumin, complex polyphosphatase, polylactide, polyglycolides, polycaprolactones, polyamides, polyurethanes, complex polyetherimides, polyarteritis, polydioxanone, polyacetale, policewala, polycarbonates, polycholorinated, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerate, polyalkyleneglycol, polyalkyleneglycol, polimetinovymi acids, polyaminoacid, polyvinyl alcohol, polyvinylpyrrolidone, polyhydroxyalkanoate, chitin, chitosan, and copolymers, ternary copolymers or combinations or mixtures of these materials.
2. The polymer under item 1, in which gidroksietilirovanny cellulose is hydroxyethyl cellulose and/or methylhydroxypropylcellulose.
3. The polymer under item 1 or 2, which contains at least ten Monomeric units.
4. The polymer under item 1, in which the named imide contains succinimide.
5. Composition for tissue adhesive containing a polymer according to any one of paragraphs. 1-4 and the second biocompatible polymer according to claim 1, reactive with respect to the first polymer.
6. Composition under item 5, which is called the second polymer contains amine.
7. Medical device containing a non-biological surface on rituu composition by p. 5 or 6.
8. The device according to p. 7, containing the prosthesis.
9. Pharmaceutical composition suitable for tissue adhesive and/or hydrogel containing polymer according to any one of paragraphs. 1-4 and a pharmaceutically acceptable carrier, excipient or diluent.
SUBSTANCE: fish roe is homogenised. Fish roe hydrolysis is carried out with a ferment preparation "Collagenase" in presence of an inhibitor for 10-12 hours. Chitosan is added to the produced hydrolysate at the ratio of 0.5-1.0:1.0. Components are mixed.
EFFECT: invention makes it possible to accelerate process of chitosan-nucleic complex production.
1 dwg, 1 tbl, 3 ex
SUBSTANCE: method includes depolymerisation of a high-molecular chitosan with hydrogen peroxide. The process of chitosan depolymerisation is carried out in a double-phase system. The solid phase is activated chitosan with Mav = 450-650 kDa and the average particle size of 0.05-0.20 mm. The liquid phase is a water solution of H2O2 with concentration of H2O2 in a reaction system equal to 1-7%. The reaction is carried out for 120-180 minutes at 70°C. Then phase separation of produced chitosan homologs is carried out by means of filtration via paper or textile surface of the produced reaction mixture. The produced filtrate contains water-soluble chitosan oligomers.
EFFECT: invention makes it possible to quantitatively control extent of conversion of an initial high-molecular chitosam into oligomer and low-molecular structures of its homologs.
1 tbl, 1 ex
SUBSTANCE: invention relates to a method of purifying chondroitin sulphate and can be used in food and cosmetic industry and in medicine. The method involves electrochemical deposition to obtain a hydrogel of chondroitin sulphate, stabilisation, removal from the electrode, washing and drying. The chondroitin sulphate is dissolved in a 0.01-0.1 n alkali solution in ratio of 1:50-1:200 and deposited in an alkaline medium with constant cooling and stirring. The solution is stirred at a rate of 10-20 rpm. Current density is equal to 1-10 A/m2. Voltage is preferably not lower than 2.7 V. The hydrogel of chondroitin sulphate is stabilised in a 0.05-0.5 n HCl solution.
EFFECT: invention enables to obtain chondroitin sulphate with high weight ratio of the basic substance and increases output of the end product.
5 cl, 1 ex
SUBSTANCE: present invention relates to a method of producing a N,S-cyclo-containing chitosan derivative. Described is a method of producing a chitosan-based N,S-cyclo-containing polymer (I) which contains in the macrochain 1-oxa-6-thia-4,8-diazocycloundecane fragments: I, by reacting chitosan with formaldehyde and a S-containing compound, characterised by that the S-containing compound used is hydrogen sulphide, the formaldehyde solution is pre-saturated with H2S and the reaction is carried out with molar ratio chitosan: formaldehyde: hydrogen sulphide of 1:2:1, at temperature of 0-60°C in a chloride medium for 24 hours.
EFFECT: obtaining modified chitosan which exhibits properties of a highly efficient heavy metal sorbent for waste water treatment, an extractant for separating rare, noble and precious metals and a complexing agent for biological molecules.
1 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to biochemistry. What is presented is a conjugate of hyaluronic acid and novocaine of a structure as defined in the patent claim containing 20-50% residues of novocaine.
EFFECT: conjugate is water-soluble; it possess the amphoteric properties and contains no side O-acylisourea.
3 tbl, 3 ex
SUBSTANCE: disclosed are versions of a method of producing cross-linked polysaccharides, involving reaction of at least one polysaccharide selected from amino-polysaccharide, amino-functionalised polysaccharide containing one or more amino groups which can be cross-linked by reducing sugar, and combinations thereof, with at least one reducing sugar. The invention also discloses polysaccharides obtained using the disclosed method, a method of producing cross-linked matrices based on polysaccharides and matrices obtained using this method. The obtained matrices may include polysaccharide matrices and composite cross-linked matrices, including polysaccharides cross-linked with proteins and/or polypeptides.
EFFECT: obtained polysaccharides have satisfactory resistance to enzymatic degradation coupled with rheological properties of the preparation for injection, obtained matrices exhibit various physical, chemical and biological properties.
29 cl, 12 dwg, 6 tbl, 11 ex
SUBSTANCE: chitosan is dissolved in an organic acid: 4-6% citric acid or 2-8% lactic acid in the relation of the ingredients chitosan: the organic acid 1:2-1:4 to prepare a forming solution. Chitosan has molecular weight 80-500 kDa. The forming solution is added with vitamin B1 in the amount of max. 0.5 wt %. The prepared forming solution is applied on a substrate in the amount of 0.2-0.25 ml/cm2 and kept to achieve a film structure. Said method is used to form the chitosan film coating having the thickness of 50-250 mcm and the breaking elongation of 42 to 470%.
EFFECT: group of inventions allows preparing high-elastic chitosan citrate or lactate films possessing bactericidal action.
2 cl, 1 tbl, 13 ex
SUBSTANCE: method involves preparation of material for enzymatic hydrolysis. Alkaline hydrolysis is carried out with proteolytic enzyme preparations with neutralisation of the obtained solution to pH=7. A salt is added to the obtained enzymatic hydrolysate to a value of not less than 0.1 mol/l. Successive ultrafiltration is carried out, first on a membrane with maximum retention of 50 kD with separation of high-molecular weight impurities, and then on a membrane with maximum retention of 5 kD with separation of low-molecular weight substances. The chondroitin sulphate solution retained at the membrane is washed on the same membrane with distilled water until complete removal of salts. Final washing with distilled water is carried out on a membrane with maxim retention of 50 kD.
EFFECT: invention enables to obtain a chondroitin sulphate preparation with weight ratio of the basic substance.
SUBSTANCE: method involves activation of hyaluronic acid using a cross-linking agent and an auxiliary cross-linking agent. The activated hyaluronic acid then reacts with a nucleophilic cross-linking agent. The pH of the reaction medium ranges from 8 to 12. The nucleophilic cross-linking agent contains at least 50 wt % oligopeptide or polypeptide. Further, pH of the reaction medium is regulated to 5-7 and cross-linked hyaluronic acid is precipitated in the organic solvent. The invention also relates to use of the cross-linked hyaluronic acid obtained using this method in plastic surgery to make implants and to a hedrogel containing said cross-linked hyaluronic acid in a buffer aqueous solvent.
EFFECT: invention enables to obtain cross-linked hyaluronic acid in dry form, having high resistance to decomposition factors such as temperature, free radicals and enzymes.
18 cl, 3 tbl, 3 ex
SUBSTANCE: disclosed is a method of determining antibacterial properties of chitosan by estimating its minimum bacteriostatic and/or bactericidal concentration. Complex buffer solutions based on three organic acids MES, ACES and TES with different pH values are prepared. The ready buffer solutions are poured into a vessel. Double dilutions of chitosan are then prepared in vessels with the buffer solutions. Aliquots of a bacterial suspension in a fluid medium are added to the chitosan solutions in the buffer. The solutions are incubated for 24 hours at temperature which is optimum for bacterial growth. The minimum bacteriostatic and/or minimum bactericidal concentration of chitosan is then determined after incubation by determining growth of the culture or a drop in the number of living cells, respectively.
EFFECT: invention enables to determine antibacterial properties of chitosan in a wide pH range from 5,50 to 8,00 without the need to use buffers of different chemical composition.
5 dwg, 2 ex
SUBSTANCE: invention relates to medicine, namely to surgery, traumatology and orthopedics and can be used for treatment of early paraprosthetic infection in endoprosthetics of hip joint. For this purpose performed are multiple sanitising processing of wound, during each of which clinical-laboratory monitoring of wound process is carried out, encrectomy is performed. Dislocation of hip endoprosthesis component into wound is carried out, stability of fixation of endoprosthesis components is estimated. In case of stable fixation wound lavage with aseptic solution is performed in volume not less than 2 l with pulsing jet. Wound and endoprosthesis bed are filled with antiseptic with 15 minute exposure. Hip component of endoprosthesis is reset. Wound is tightly tamponed with sorption bandage material based on polyacrylate, wound is tightly sutured. Sanitising processing of wound is performed with one day interval. When signs of regeneration in wound, absence of microflora growth in bacteriological test, normalisation of laboratory blood parameters are achieved, delayed secondary suture of wound is performed.
EFFECT: method ensures stopping of infection process without application of washing drainages, preservation of maximal volume of soft tissues for wound covering, makes it possible to performed delayed secondary suture and preserve endoprosthesis stability.
SUBSTANCE: invention refers to nanotechnology of new materials applicable in biology, veterinary science and medicine, particularly for laser hyperthermia of new growths. What is presented is a method differing from known ones by agent concentrations, pH values of a reaction mixture, and particle surface functionalisation. At the first stage, gold spherical particles of the diameter of 1-3 nm used as a templates for the further growth of non-spherical particles are synthetised. At the second stage, gold is additionally reduced by ascorbic acid on the particles in cetyl trimethyl ammonium bromide in an acid medium (pH=1). At the third stage, cetyl trimethyl ammonium bromide molecules on the particle surface are substituted by polyethylene glycol for reducing biotoxicity of gold nanorods. The method uses the ingredients taken in specific molar ratios. What is also presented is a thermal sensitiser which is produced by the method above and representing a gold nanorod suspension. The rods are 30-45 nm long, 9-12 nm wide and coated by polyethylene glycol molecules.
EFFECT: invention provides higher stability and reproducibility of the gold nanorod synthesis with biotissue infrared absorption, as well as reduced toxicity of the thermal sensitiser.
2 cl, 6 dwg
SUBSTANCE: group of inventions refers to medicine, particularly pharmaceutical compositions, methods for applying for treating the patients suffering celiac disease. The composition contains a high-molecular synthetic polymer which contains (a) a copolymer of hydroxyethylmetacrylate (HEMA) and 4-styrenesulphonic acid or its salt; (b) a copolymer of HEMA and sulphopropylmetacrylate or its salt, (c) a polymer of 4-styrenesulphonic acid or its salt, or (d) a polymer of sulphopropylmetacrylate or its salt. Said polymer is able to form electrostatic couplings at pH lower than an isoelectric point of gluten and peptides formed with gluten splitting, and is able to bind with gluten or peptides formed with gluten splitting in the gastrointestinal tract.
EFFECT: invention provides using the polymer substance for binding gluten or peptide formed with gluten splitting for the purpose of decreasing gluten splitting to toxic peptides or for the purpose of decreasing gluten or peptides formed with gluten splitting with a gastric mucosa that leads to decreased adverse effect of gluten.
83 cl, 34 ex
SUBSTANCE: what is offered is a gastric swelling oral composition for appetite suppression containing at least one cross-linked polycarboxylate homopolymer, cross-linked polycarboxylate copolymer or their combination wherein polymer is cross-linked by means of a non-vinyl cross-linker; polymer particles or grains have the pre-swelling average particle size within 100 nm to 1 mm, and a pharmaceutically acceptable excipient, a gastric swelling composition of polymeric hydrogel for the same purposes, a method for appetite modulation in an individual, a gastric swelling agent prepared by the method involving monomer or monomer mixture polymerisation for polymerisation involving at least one ethyl-unsaturated carboxyl containing monomers and at least one non-vinyl cross-linking agent and a method for making the swelling agent of said composition. What is shown is a synergetic character of the ability to intensify the water-swelling characteristics of superabsorbent polymer hydrogels (SAPH) by stearic acid or its magnesium salt.
EFFECT: invention provides the material unable suppress hunger or suppress as much as possible with the ability to provide weight reduction and/or weight control.
20 cl, 5 dwg, 4 tbl
SUBSTANCE: invention refers to medicine. What is described is an antimicrobial and wound healing agent of hydrogel polymeric matrix used for wounds, burns and dermatologic disorders. The agent has the following formulation, wt %: polyvinylpyrrolidone - 2-10, agar - 1, polyethylene oxide - 1-3, an antimicrobial pharmaceutical substance selected from gentamycin and miramystine - 0.02-1,0, water - the rest. The agent is prepared by cross-linking medical polymers under ionising radiation. The hydrogel polymeric matrixes of the various area are sterile and ready for application on open wound surfaces.
EFFECT: agent exhibits elasticity, breaking strength, sorption properties in relation to wound exudate, transparency that enables following a course of wound process, painless removal from wound surface, creates an optimum microclimate in a wound (humidity, temperature).
3 cl, 3 ex
SUBSTANCE: invention relates to medicine, surgery. Purulent-necrotic foci are ablate, nasointestinal intubation, small intestinal lavage are performed, enterosorbent is introduced intraintestinally. Intestine loops are step-by-step put on probe, probe traction is performed closer to ligament of Treitz, it is pulled out of stomach and probe is installed in such a way that last 1-2 holes are in stomach. Loops of small intestine are laid in oblique-horizontal position. Recanalisation of umbilical vein with its cannulation is performed for carrying out intraportal infusion therapy in dose 40-45 ml/kg of patient's weight per day. Treatment is carried out until complete recovery of small intestine peristalsis.
EFFECT: method makes it possible to increase efficiency of treatment of patients with pancreonecrosis by impact on aerobic and anaerobic flora in portal system, prevents syndrome of intestinal failure, reduces intoxication syndrome.
1 ex, 7 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: one aspect of invention relates to improved method of obtaining particles, which consist of polymer with molecular impressions (PMI), which includes enrichment of initially obtained composition, which include insoluble particles of PMI, with PMI particles, binding particular target molecules, thus excluding from initial composition non-binding and low-binding particles. Enrichment is usually carried out by chromatographic methods, acceptable for separation of powder-like material, or by agglutination. Other aspect of invention relates to preparation of improved insoluble PMI by intensified milling of unpurified PMI in order to create a great number of binding centres per weight unit of PMI particles. Preferable aspects of invention include combination of two said aspects.
EFFECT: obtained improved PMI can be applied for diagnostic, analytical and therapeutic purposes, in particular, as per orally introduced medications, which can bind substances, for instance, cholesterol, gall acids and salts of gall acids, present in gastrointestinal tract.
17 cl, 5 dwg, 2 tbl, 6 ex
SUBSTANCE: invention relates to medicine and can be applied for bimodal impact on human injured tissue. Volume of tissue defect is filled in and/or interpolyelectrolite complex of sulfated glycoaminogolicans (sGAG) with proteins of collagen and/or elastin series and/or positively charged biologically compatible polymers, taken in equimolar ratios. For stimulation of reparative processes quantity from 10-6 mg to 10-1 mg is used, and for suppression of reparative processes quantity from 1 mg to 100 mg is used.
EFFECT: method makes it possible to modulate reparative processes.
11 ex, 2 dwg
SUBSTANCE: invention relates to transdermal therapeutic system, which contains, at least, one easily volatile and/or thermolabile biologically active substance and/or auxiliary substance, which can be obtained by limiting on each other of, at least, three components, namely, polymer matrix layer, acceptor layer, absorbing with high speed biologically active substance and/or auxiliary substance, as well as donor-layer, which by the moment of manufacturing contains volatile and/or thermolabile biologically active substance and/or auxiliary substance. During or immediately after lamination process, donor-layer by means of migration of volatile and/or thermolabile substances combines with acceptor layer.
EFFECT: transdermal therapeutic system ensures improved gastrointestinal tolerance.
12 cl, 1 tbl, 1 dwg, 1 ex
SUBSTANCE: invention relates to medicine, ophthalmology and can be used as drainage for surgical treatment of refractory glaucoma. Explantodrainage presents 10-20 mcm thick track membrane from polyethylene terephthalate or polycarbonate, irradiated by heavy charged particles and processed by ultraviolet irradiation and chemical etching in water solution of sodium hydroxide until through canals with 0.3-0.4 mcm diameter are obtained. Superficial layer of membrane is nanostructured by processing in oxygen-containing medium.
EFFECT: explantodrainage makes it possible to preserve formed during antiglaucoma operation intrascleral cavity, achieve high level of biocompatibility, filtering ability, areactivity with minimum of complications, reduce adsorption of blood cells, proteins and other constituents of intraocular fluid on drainage surface.
4 ex, 3 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a composition possessing analgesic, anti-inflammatory and locomotor function improving action. The composition contains 1-20 wt % of glucosamine sulphate, 1-10 wt % of chondroitin sulphate, 0.0001-10 wt % of methylsulphonylmethane, 0.01-5 wt % of L-proline, ascorbic acid, magnesium. The declared composition additionally contains zinc gluconate, citric acid, a sweetening agent, a flavour, a preserving agent and water.
EFFECT: composition is presented in the liquid form and possesses improved bioavailability and extended pharmacological action.