Chelate amphiphilic polymers
SUBSTANCE: group of inventions relates to a chelate amphiphilic polymer as a carrier, a particle as a carrier containing a self-assembling structure of a chelating amphiphilic polymer (polymersome), contrast agents for CEST MRT, SPECT, PET or Spectral CT, containing said particle, and a method of producing the particle. The chelate amphiphilic polymer is capable of aggregation and contains a hydrophilic block (MA), having a chelating moiety (X) as a terminal group and a hydrophobic block (MB), wherein the polymer has the formula X-[MA]n - [MB]m, (i), where n and m are integers ranging from 3 to 1000000, which represent the number of monomer links forming the corresponding blocks. The hydrophilic block is selected from polyethylene oxide, polymethacrylic acid, polyacrylamide derivatives, polyvinyl alcohol or polyhydroxyethylmethacrylate, hydrophilic polypeptides and sugar derivatives. The hydrophobic block is selected from polybutadiene, polyisoprene and polyethylethylene. The chelating moiety is selected from a group comprising polyphosphates, amino carboxylic acids, 1,3-diketones, hydroxy carboxylic acids, polyamines, amino alcohols, aromatic heterocyclic bases, phenols, amino phenols, oximes, peptides containing proximal chelate functional groups, Schiff bases, tetrapyrroles, sulphur compounds, synthetic macrocyclic compounds, phosphonic acid or a combination of two or more of said compounds.
EFFECT: invention provides chelate amphiphilic polymers which are capable of self-assembling and are suitable for use in vulcanisation methods.
14 cl, 7 dwg, 4 ex
The SCOPE of the INVENTION
The invention relates to amphiphilic polymers and nanoneedles, such as obtained from them polymersomes suitable for use as imaging contrast agents. In particular, the invention relates to contrast agents T1and/or T2for magnetic resonance imaging (MRI), radioactively labeled compounds for single photon emission computed tomography (SPECT) or positron emission tomography (PET), for elements with high atomic number (spectral) computed tomography (spectral CT) and contrast agents for MRI with transferring saturation depending on the chemical exchange (CEST). More specifically, the invention relates to the delivery of medicines under visual control based on polymersof as carriers for drugs.
BACKGROUND of the INVENTION
A link to the source in respect of amphiphilic compounds, which can include, for example, a radioactive isotope or Mr active metal is, for example, V. Torchilin, Chemtech 1999, Volume 29, Number 11, 27-34. This publication refers to polychelate amphiphilic polymers. These polymers are mainly polymers based on poly-L-lysine containing hydrophilic residue with multiple chelate groups and relative to the short, highly lipophilic phospholipid residues. The latter are used for embedding polymer inside liposomes and micelles.
The invention relates to various classes of amphiphilic polymers, namely, those that are able to aggregate in polymersomes, micelles or stabilized polymer emulsion. These polymers generally can be described as blocks of polymers containing at least one hydrophilic block (A)preferably has a chain with a molecular mass of more than 500 g/mol, and at least one hydrophobic block (B), also in the form of polymer block (i.e., not lipid). These polymers may take the form of a block copolymer AB, triple polymer ABA or BAB, or any additional block polymer having terminal hydrophilic block and the terminal hydrophobic blocks, including polymers containing circuit (C)with fuzzy properties of the solvent (i.e. neither hydrophilic nor hydrophobic), for example, the triple block copolymer ACB. Basically, this would mean that the block C forms or new hydrophilic block with A block, or a new hydrophobic block together with the block B.
In the result of the presence of hydrophilic and hydrophobic blocks, amphiphilic polymers have the ability to form samoupravlenie patterns. The most typical samoupravlenie structures I have are micelles and polymersomes, formed in the aquatic environment. In any case, however, depending on the environment in which they are formed, any type of unit (i.e. hydrophilic or hydrophobic) may form the inner or outer space. In respect of micelles internal space implies the concentration at one point, the direction of the polymer chains inside, and outer space contains divergent, directed outward in the polymer chain. In relation to polimerkom, samoupravlenie patterns contain a shell bounding the cavity. The shell is most reminiscent of liposomes formed polymer Balaam in the aquatic environment with hydrophobic blocks facing each other in the inner part of the bilayer and the hydrophilic blocks in the inner part of the cavity and the outer surface of polimerkom.
Compared to lipid media (e.g., liposomes), polymersomes chemically more stable, less fluid, less prone to interference with biological membranes and less dynamic due to their lower critical aggregation concentration. The result of these properties is less opsonization and longer circulation. On the other hand, liposomes provide the advantage of easy inclusion of radioactive compounds or compounds of target lipid layer. Liposomes which also can be used as contrast agents, in this case, they are equipped with, for example, paramagnetic label for MRI or radioactive isotope for SPECT or PET.
Despite the fact that liposomes are a very versatile approach, the main limitation is the low degree of Paglierani, i.e. the possibility to provide on the surface covalently-associated poly(ethylene glycol). Pegylation is a well-known method of masking introduced into the body of the individual particles, such as therapeutic proteins from the immune system of the individual. I believe that this is based on a lower degree of opsonization, resulting Paglierani surface less susceptible to uptake by macrophages. This provides increased circulation time Paglierani molecules. Thus, liposomes and other nanoneedles which is in fact suitable, is desirable hiding in a similar way, i.e. the provision, Paglierani nanoneedle.
It is preferable to provide amphiphilic polymers, which are able to form samoupravlenie structure comprising a hydrophilic block and a hydrophobic block, where the hydrophilic block provides for the presence of chelat forming fragment as an end group. In particular, it is preferable to provide masking (hiding) the structure of the ur from the immune system, which can be done using labels for use in visualization techniques.
Preferably, it is desirable to provide such materials, and even better to ensure that labels, such as metal ions or elements with high atomic number, paramagnetic or radioactive labels.
In order to better ensure the above preferences, the invention relates to chelating amphiphilic polymer, which is able to samegreloshi (polymersomes, micelle or stabilized polymer emulsion).
In one aspect, the amphiphilic polymer is carried out as a polymer containing a hydrophilic block, in particular, poly(ethyleneoxide) block and a hydrophobic block, where the hydrophilic block comprises chelate forming fragment as an end group.
In another aspect, the polymer particle (also referred to as nanoneedle) provide particles with a structure capable of samegreloshi, such as stabilized polymer emulsion (i.e. emulsion oil-in-water", where the polymer forms a layer around the oil droplets), the micelle or bilayer, bounding the cavity (poliorama), where the polymer is an amphiphilic polymer containing a hydrophilic block and a hydrophobic block, where the hydrophilic block comprises chelate forming fragment as an end group.
In another aspect, contrast agents for MRI are in the form of nanooxides containing savagegarden structure, as described earlier in this document, where the chelate forming fragment on the external surface of nanooxides associated with a paramagnetic metal.
In an additional aspect, the contrast agent to the transfer of saturation depending on the chemical exchange (CEST) for magnetic resonance imaging (MRI) is presented as the substance containing polymersomes containing polymer frame, bounding the cavity, where the cavity contains a supply of protons for analysis, and where the frame allows the diffusion of protons for analysis, frame, being amphiphilic polymer contains a hydrophilic block and a hydrophobic block, where the hydrophilic block comprises chelate forming fragment as an end group, and where the paramagnetic metal is associated with chelat forming fragment in the interior cavity.
In another aspect, a radioactive compound for labeling used in single photon emission computed tomography (SPECT) or positron emission tomography (PET) provide in the form of nanooxides containing samoupravlenie patterns, as described earlier in this document, where the chelate forming fragment on the external surface of nanoneedle and/or inside nem space cavity associated with a radioactive isotope.
In another aspect, the contrast agent to visualize if (spectral) CT provide in the form of nanooxides containing samoupravlenie patterns, as described earlier in this document, where the chelate forming fragment on the external surface of nanoneedle and/or in the interior space cavity, associated with a substance with a high atomic number (for example, with this element, as a heavy metal).
The invention further includes methods of obtaining and application of chelating amphiphilic polymers with a specific method of application, which will deliver medicines.
DETAILED description of the INVENTION
In a broad sense, the invention can be described as chelating amphiphilic polymer capable of samegreloshi. Different from other nanoneedle, the polymer according to the invention by itself is capable of helatoobrazovatel, i.e. formation of a coordination complex with a metal ion. Different from other chelating polymer, the polymer according to the invention capable of forming samoupravlenie patterns (for example, to form polymersomes, instead be attached to the existing liposome), making it suitable to use as nanoneedle.
In the most understandable form, the polymer can be described with reference to three major functional e is ment: a hydrophobic block, have the property to be rejected aqueous medium, the hydrophilic block having the property to make contact with an aqueous medium, and chelate forming fragment, which is an end group of the hydrophilic block, i.e. on the remaining functional residue limit hydrophilic monomer unit. You can imagine that the polymer chain contains an additional reactive side groups, which can also be provided chelat forming fragments, but, in this case, the disadvantage is impossible under normal conditions to ensure 100% modification of side groups, and, thus, it appears that the polymer will necessarily contain reactive, usually charged side groups. In the case of materials based on polylysine in real conditions it may negatively affect the ability to samegreloshi.
Chelate forming fragment can be secured using metal so as to form a coordination complex and, thus, to provide, essentially, 'metalized' polymer. Depending on the interest of metal-labeled polymers can be used as contrast agents for MRI (T1, T2, CEST), radionuclide imaging (SPECT, PET) or spectral CT.
This can be attributed to the micelles, where the hydrophobic ends are directed in the center, and hydrophilic ends spatial issued. In the case of micelles, the metal can be entered for the formation of coordination complexes with chelat forming fragment either before or after the formation of micelles, resulting in, essentially, one and the same.
The invention also relates to polymersomes, where the amphiphilic polymer in an aqueous environment provided in the form bilayer, bounding the cavity. In this document hydrophobic blocks are directed against each other inside the boundaries of the bilayer and hydrophilic blocks and directed towards the aquatic environment, and toward the internal cavity. In this case, there are two fundamentally different ways for the formation of coordination complexes containing metal, with amphiphilic polymer. In the first case, first, lead to formation of polymersomes, and then provide metal. In this case, in the inner cavity polymersomes no metal associated with the polymer. In another method, first ensure the metal, so that substantially all of hepatoblastoma fragments formed a coordination complex, and then form polymersomes. In this case, the metal involved in the interaction, is present on the inner surface polymersomes (i.e. the inner shell cavity) and on the outer surface of aimerai. In the latter case, depending on the applied coordination chemistry, it is also possible removal of metal from the outer surface or the substitution of another metal to ensure the presence of metal on the outer surface. This provides the desired flexibility of the design, for example, allowing polymersomes to perform different functions in different ways.
Getting polymersomes or micelles in an aqueous environment, such as the human body, determines the hydrophilic fraction (fphil) amphiphilic copolymer (fphil=Mw,phil/(Mw,phil+Mw,phob)). Herein Mw,philand Mw,phobrepresents a weighted average molecular weight of hydrophilic and hydrophobic fractions of the polymer, respectively. In aqueous conditions polymersomes (i.e. vesicles with the blocks of the copolymer) formed at 0.2<fphil<0,4, whereas polymeric micelles determine when fphil>0.5 in. In case polimerkom, amphiphilic block copolymers are going in bishojou structure type head-tail and tail-head.
Kamagraviagra structure according to the invention may also be stabilized using polymer emulsion oil-in-water". In this case, a monolayer of amphiphilic polymer is formed around the oil droplets, the hydrophobic part is directed to the surface of the oil, and guide Oficina part directed towards the surrounding aqueous phase. It finds application, for example, by CT (using iodirovannoi oil), functional MRI (using perfluorinated oils) and drug delivery (there are several emulsions used for delivery of drugs approved by the FDA, for example, based on soybean oil).
Different parts according to the invention are described later in this document.
Amphiphilic polymers capable of samegreloshi themselves known, as well as the resulting nanoneedle, such as samoupravlenie structure of polimerkom. The specialist in this area has appropriate laboratory equipment to obtain data of the polymers. Links included in these patent documents such as WO 2005/016259, US 6835394, US 2005/180922, EP 1279682, US 2008/166382, WO 2008/58963, as well as various secondary references mentioned in these papers.
The polymer according to the invention generally contains at least one end of the hydrophilic block (A) and at least one terminal hydrophobic block (B). In the preferred, most simple form, the polymer is a block copolymer, having only two of the above units, i.e. a polymer with the General structure of AB. The units themselves are preferably mainly composed of a single povtoreaiusi the Xia of monomer units (M A, MBrespectively). The resulting structure of the block copolymer, thus, satisfies the General structural formula (i).
where X represents a chelate forming fragment; MAis a repetitive hydrophilic link; MBis a recurring hydrophobic link; n and m each independently are integers representing the number of monomer units constituting the block. In relation to the number of repeating units, they should be enough to increase affilinet polymer should be, as a rule, at least 3. The maximum number of, in particular, is not critical and is determined by the standard score associated with the method of producing the polymer. Thus, the standard upper limit is 1000000. The preferred range for n and m is from 4 to 40,000, preferably from 5 to 5000, and most preferably from 10 to 225.
However, it is possible that any or both of the hydrophilic and hydrophobic blocks contain two or more different repeating units, thus providing a polymer that satisfies General formula (ii):
Herein MA1, MA2and MA3represent different hydrophilic repeat what iesa links and MB1, MB2and MB3represent different hydrophobic repeating units. The letters p, q, r, x, y and z each independently represents an integer from 0 to 1000000 with the proviso that (p+q+r) and (x+y+z) are in the range of from 3 to 1000000, preferably from 4 to 40,000, more preferably from 5 to 5000, and most preferably from 10 to 225. In a similar multiblock polymers may have a large number of different repetitive hydrophilic and hydrophobic units, however, is not preferred.
Also in the polymers by any of the above formulas (1) and (2) you can enable the block (C), a solvent with amphiphilic properties, i.e. the block that is neither hydrophilic nor hydrophobic. The hydrophilic block or blocks, as a rule, are blocks, soluble in water, and preferably selected from the group consisting of polyethylene oxide, polymethacrylic acid, derivatives of polyacrylamide, polyhydric alcohols, such as polyvinyl alcohol or polyhydroxyethylmethacrylate, hydrophilic polypeptides and derivatives of sugar. Most preferably, the hydrophilic block is a block of polyethylene oxide (PEO, PEG), as this polymer according to the invention, essentially, is "Paglierani in water by human or animal, hydrophilic polyethylene oxide block,i.e. the PEG, will form the outer surface camogregorian patterns (such as poliorama), thus providing a surface Pegylation on 100%, and thus, the optimal malozemelnoj (leading to longer circulation in the less opsonization). With reference to the above fraction fphil, it is preferable that the average molecular weight of polyethylene oxide ranged from 500 to 10000. Longer hydrophilic blocks will lead to the need for sufficiently long hydrophobic blocks, which are less desirable due to lower ability to biodegradation and more complex process of obtaining (high viscosity). Typically, the hydrophobic block or blocks no affinity to water, and preferably chosen from polymers with a Tg below 70°C, such as polybutadiene, polyisoprene, politisation. Basically, all polymers with a skeleton of carbon atoms and side groups of hydrophobic nature, can be used as a hydrophobic block.
The above preferred Tg, inter alia, associated with the production method, since polymers with a Tg greater than the Tg value are more complex when receiving because of their high viscosity and/or the degree of crystallization under the conditions obtaining. If h is some Tg polymers, preferably the use of plasticizers during the process of obtaining (for example, organic solvents such as THF (tetrahydrofuran) or dichloromethylene. These plasticizers are used as a method of obtaining and removed before application of the polymer. This method of obtaining typically available to a person skilled in the art of polymer science.
As is clear to a person skilled in the art, a large degree of design flexibility reach the standard methods of influence on the molecular mass and molecular mass distribution of amphiphilic polymers. It can also be viewed from the point of view of the number of end groups per weight unit of the polymer, thus, provides a simple way of varying the number of chelating groups on the weight unit of the polymer. A particular advantage can be achieved by combining chelat forming amphiphilic polymer with a relatively short hydrophilic chain (namely, chain PEG) with amphiphilic polymer with a sufficiently large chain PEG. As a result of samegreloshi, chelate forming agent, thus, will be contained in the polymer layer, forming savagegarden structure, whereas chain PEG will form the outer surface of the structure, thus ensuring the entire surface with PEG, leaving it untouched is chelat forming fragments.
Chelate forming fragment
Chelate forming fragment can be obtained and/or to choose from fragments that contain atoms that are electron donors. These fragments can be, for example, polyphosphates such as sodium tripolyphosphate and hexametaphosphate acid; aminocarbonyl acids, such as ethylenediaminetetraacetic acid, N-(2-hydroxyethyl)etilendiamintetrauksusnoy acid, nitrilotriacetic acid, N,N-di(2-hydroxyethyl)glycine, ethylenebis(hydroxyphenylglycine) and Diethylenetriamine pentauksusnoi acid; 1,3-diketones, such as acetylacetone, triflluoroacetylacetone and thenoyltrifluoroacetone; and hydroxycarbonic acids, such as tartaric acid, murinova acid, citric acid, gluconic acid and 5-sulfosalicylic acid; polyamines, such as Ethylenediamine Diethylenetriamine, Triethylenetetramine and trigeminothalamic; aminoalcohols, such as triethanolamine and N-(2-hydroxyethyl)Ethylenediamine; aromatic heterocyclic bases, such as 2,2'-dipyridyl, 2,2'-diimidazole, Amin dipicolinic acid and 1,10-phenanthroline; phenols, such as salicylaldehyde, desulfoviridin, chromatophobia acid; aminophenols, such as 8-hydroxyquinoline and oxysulphate acid; Akimov, such as dimethylglyoxime and salicylaldoxime; peptides containing proximal elitnye functional group, such as polizistin, polyhistidine, poliasparaginovaya acid, polyglutamine acid or combination of amino acids, each polyaminoamide contains from 2 to about 20 amino acids in the polymer; Schiff bases, such as disalicylidene 1,2-Propylenediamine; tetrapyrroles, such as tetraphenylporphin and phthalocyanine; sulfur compounds, such as colordither, meso-2,3-dimercaptopropane acid, dimercaptopropanol, thioglycolate acid, ethylxanthate potassium, sodium diethyldithiocarbamate, ditson, diethyl-dithiophosphoric acid and thiourea; synthetic macrocyclic compounds such as dibenzo-18-crown-6, (CH3)6 --4,11-diene-N4 and (2.2.2)-cryptit, and phosphonic acids, such as nitrilotrimethylphosphonic acid, ethylenediaminetetra(methylenephosphonate acid) and hydroxyethylidenediphosphonic acid, or combinations of two or more of the above compounds.
The preferred hepatoblastoma fragments contain one or more carboxylic acids or carboxylic groups and include elements present in: Ethylenediamine-N,N,N',N'-tetraoxane acid (EDTA); N,N,N',N",N"-diethylaminopentane acid (DTPA); 1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraoxane acid (DOTA); 1,4,7,10-tetraazacyclododecane-N,N',N"-acetylacetonate acid (DO3A); l-oxa-4,7,10-triazacyclononane-N,N',N"-acetylated kusnoy acid (OTTA); TRANS-(l,2)-cyclohexanedimethanol pentauksusnoi acid (CDTPA).
The most preferred chelat forming fragments are DOTA, DTPA, HYNIC (6-hydrazinoacetate used for chelating technetium) and desferoxamine (for example, available as nelfinavir desferoxamine under the brand name of Desferal)used for helatoobrazutee with gallium.
Specialist in this field, it is clear that the above examples are chelat forming compounds and that hepatoblastoma fragments, when compared with these compounds, in fact, are their derivatives in the sense that they include a link with the polymer.
Linking chelat forming fragment
Although it is not excluded other sequence of receipt, it is preferable to first obtain amphiphilic copolymer and then to its hydrophilic unit to connect a chelate forming fragment. The person skilled in the art it is clear that the strict linkage between the hydrophilic end chelat forming monomer and a fragment is determined by the functional groups available on the end of the monomer and chelat forming the connection that is used for education chelat forming segment in the polymer. The standard, most commonly used type of connection is an amide bond.
Preferred the Lok poly(butadiene)-poly(ethylene oxide) polymers according to the invention can be obtained as follows, as depicted in scheme 1 below. First, provide a block polymer, in this case, poly(ethylene oxide)-block-poly(butadiene) (1). Primary alcohol polymer is converted into the corresponding tosylate copolymer (2). Then, toilet subjected to reaction with NH3to obtain the amino-functionalized poly(ethylene oxide)-block-poly(butadiene) (3). Then, the amino group on poncho 3 is subjected to reaction with N-Succinimidyl ether DOTA (4) to obtain functionalized with DOTA poly(ethylene oxide)-block-poly(butadiene) (5).
Herein the compounds participating in the reaction, and the solvents indicated below: (i) pTsCl, KOH, DCM; (ii) 7 N NH3, toluene/MeOH; (iii) Et3N, DMF.
Depending on the desired application, functionalized with DOTA block copolymer (5) can be mixed with defunctionalization block copolymers in the ratio of at least one chelate polymer up to a maximum of 100% in the system (i.e. all molecules present polymer are chelate polymers). A method of synthesis can be applied for a wide range of copolymers with different molecular weight and different values of fphilenabling a wide range of savagegarden structures. In addition, a similar strategy of synthesis and p is to change any for chemical modification of block copolymers with other related metals ligands, such as DTPA, and ligands on target, such as antibodies, peptides, etc.
Coordination complexes based
chelat forming fragments
Hepatoblastoma connection represented in the amphiphilic polymer according to the invention, can be used to create coordination complexes with metals in accordance with the methods of helatoobrazutee known in this field.
As amphiphilic polymers according to the invention, essentially ensured coordination sites, there is great freedom of choice in regard to the extent of chelation, which can vary from one chelating ion to the maximum achievable (with the ability to achieve a much higher degree of helatoobrazutee than standard polymers, which themselves do not form a chelate compound).
For example, the copolymer based on DOTA, as described above, in the same way, this polymer is capable of samegreloshi in polymersomes, with the subsequent formation of the complex with Gd(III). In the second method, the reaction with Gd(III) and a copolymer on the basis of DOTA is performed on the first stage and, subsequently, functionalityand using Gd(III)DOTA copolymers samearearule in polymersomes. In the first method, Gd(III) is present only on the outer surface polymersomes, i.e. complexes with Gd(III) extending the s out in the water column, whereas in the second method, the complexes with Gd(III) directed outward on both sides of the shell polymersomes.
Contrast agent for T1/T2MRI
The polymers according to the invention can be used as contrast agents for MRI. Typically, this refers to a weighted contrast agents for T1and/or T2.
When magnetic resonance study of the body of a mammal, such as man, the image of the organ or tissue in vivo receive, placing at least part of the body, the subject of visualization, in a strong external magnetic field excited by the energy of the radiation, and observing the effect of excitation on the magnetic properties of photons contained in the organ or tissue and surrounding them. This is especially useful when imaging blood flow of the body (i.e. blood). You can measure the number of magnetic parameters. Time proton relaxation, T1and T2are the parameters of primary importance. T1also called spin-lattice or longitudinal period of relaxation, and T2also called spin-spin, or the period of transverse relaxation are functions of the chemical and physical water environment the internal environment of an organ or tissue, and they are measured using radiopulse ways. This information analyze karfunkle spatial location using the computer, which converts the information to obtain the image.
Often, the resulting images lack the proper contrast, for example, between normal and damaged tissue, which reduces the efficiency of diagnosis. To overcome this disadvantage of the use of a contrast agent. Magnetic resonance contrast agents are magnetoactive compounds that affect the parameters of the magnetic resonance related nuclei of the molecules. Theoretically, a contrast agent, if mainly to examine a specific part of the body or a specific type of tissue, such as cancerous tissue, may provide for the modification or enhancement of the contrast of the resulting image in this tissue.
Because magnetic resonance image is strongly influenced by changes of the parameters T1and T2it is desirable to have a contrast substance, affecting any of the two or both. Research is concentrated mainly in two classes magnetoactive materials, i.e. paramagnetic materials, which reduce T1and T2and super-paramagnetic materials, which mainly reduce T2. In low concentration of paramagnetic materials have a greater influence on T1than T2.
Paramagnetism fuss is AET in materials containing electrons with unpaired spins. Paramagnetic materials are characterized by a weak magnetic susceptibility (response to an external magnetic field). Paramagnetic materials become magnetic in the presence of a magnetic field and quickly lose this type of activity when removing the external field, i.e. demagnetized. For a long time have established that the addition of paramagnetic materials to water causes a reduction of the parameters T1hydrogen nuclei.
As contrast agents for MRI preferred paramagnetic materials containing, for example, paramagnetic lanthanides, especially materials containing Gd+3primarily through their influence on T1.
Due to the presence of chelat forming fragment in amphiphilic polymers according to the invention, the paramagnetic material can simply be included in the polymer, allowing it to form a coordination complex with chelat forming fragment.
In the case of contrast agents for T1/T2preferably, if they are based on savagegarden structures with paramagnetic material present on the outer surface. In this case, the micelles are thus suitable. However, it is preferable that nanosail according to the invention were in the form of polimerkom is.
Contrast agents for SPECT and PET
Similarly, as in the case of formation of coordination complexes with paramagnetic, the polymers according to the invention can also be used to enable radionuclides.
In single photon emission computed tomography (SPECT) images are reflecting the distribution of descent nuclides gamma radiation. This method of obtaining the image has a very high sensitivity and the lack of background signal, allows to obtain quantitative data on the biodistribution of the radionuclide. SPECT is usually used in a hospital environment for visualization and quantitative evaluation of regions of the tumor and, then, to assess bearsdley potentially new drugs or contrast agents. Recent developments include the synthesis of stabilized lipid emulsions for SPECT using111In as a radionuclide. The inclusion of functionalized with DTPA or DOTA copolymers in polymersomes, polymeric micelles and stabilized copolymer emulsion allows for effective radioactive tagging savagegarden particles with radioactive isotopes (such as177Lu or111In) for use in the field of radionuclide imaging.
The present invention includes a method floor the treatment and radioactive labeling stabilized polymer emulsion using amphiphilic polymer, as previously described herein, for example with functionalized with DOTA poly(ethylene oxide)-block-poly(butadiene) as the emulsifier.
As a proof of concept, has been stabilizatio emulsions using the copolymer obtained by the authors of the present invention, loaded DOTA, and these patterns were labeled with radioactive isotope111In. The biodistribution of the compounds studied in mice. In Fig. 7 tomography SPECT/CT shows the presence of111In the heart, liver and kidneys. The presence of111In blood 4 hours after administration is a sign of a long circulation time in the blood emulsions, radiolabelled. In addition, accumulation in the liver reflects the elimination of the nanoparticles of the hepatobiliary route, which later was confirmed by the absence of111India in the bladder. The results show that the emulsion of radiolabelled with the authors of the present invention copolymer DOTA, can be used as contrast agents for SPECT.
Similarly, the present invention finds application in PET, providing helatoobrazovateli with radionuclides typically used in PET, such as Rubidium-82, Gallium-68, cu-64 and Zirconium-89.
Contrast agent for CEST MRI
The polymers according to the SNO invention, samoupravlenie in polymersomes, are an appropriate basis for obtaining a contrast agent for CEST MRI. The way CEST used to implement the contrast of an image by transferring saturation depending on the chemical exchange (CEST) from a separate, pre-saturated by magnetic protons to the molecules of the water column, as determined by MRI.
CEST in combination with a paramagnetic chemical shift reagents (ParaCEST) is a technique in which the magnetization pool of protons, chemical shift which is caused by paramagnetic, a contrast agent for CEST is selectively saturated by applying high-frequency radiation (RF). The transfer of this saturation to the molecules of the water column through the proton exchange leads to a reduction in the number of excited protons of water surrounded by a CEST contrast agent. Thus, the observed decrease in the intensity of the signal molecules of the water column, which can be used to create (neutralization) of contrast enhancement on MRI images.
The approach for obtaining high efficiency CEST when based on the use of a large number of water molecules from a solution containing paramagnetic shift reagents for, for example, Na[Tm(dotma)(H2O)]), where "H4dotma is a(lpha), a',a,a'-tetramethyl-1,4,7,19-tetraoxane acid, and dotma performance, which provides a corresponding fourfold deprotonirovannoi Tetra-anionic form of the ligand to provide a pool of protons, which are subjected to chemical shift and, thus, can be selectively saturated with RF pulse. If this system be encapsulated in a carrier, in this case, polymersomes, magnetic saturation can be transferred to the molecules of the water column outside of the media, which are not subjected to chemical shift. The number of transfer magnetization and, thus, the degree of contrast enhancement, determined by the diffusion coefficient of water through the shell of the carrier (i.e. the ratio of water exchange), and also with the amount of water inside the media.
The optimal rate of water exchange is strictly correlated with the difference in chemical shift between the pool of protons inside of media and water from outside media. In the paramagnetic shift induced on the water molecules inside polimerkom, contribute two main processes: chemical shift caused by direct interaction of dipoles between water molecules and the chemical shift (δdip), and the chemical shift caused by the volumetric effect of the magnetic susceptibility (δbms). Overall paramagnetic shift is the sum of the above processes:
δbmsfor spherical particles is equal to zero, but for anisotropic particles, it can be significant. Expericne particles undergo strengthening inanaga field, which causes them to line up, coinciding with the lines of force of the magnetic field. In the case of liposomes was shown that the total paramagnetic shift can be further increased, if you create a paramagnetic molecules associated with the phospholipid membrane.
Reference to the use asperity liposomes for CEST is Terreno, E. et al. Angew. Chem. Int. Ed. 46, 966-968 (2007).
Due to the presence of amphiphilic polymer according to the invention chelat forming fragment, the paramagnetic material can easily be incorporated into the polymer, allowing it to form a coordination complex with chelat forming fragment. This facilitates the inclusion in the polymer of a suitable paramagnetic material (preferably the lanthanide, and most preferably Tm or Dy) in any proportion.
Similar to the above process for the preparation of contrast agents for MRI (T1/T2) the lanthanides is possible to provide on the outer surface or the inner surface polymersomes. It should be noted that in relation to CEST, the invention is successful in relation to freedom of choice of design. Polymersomes can be used as a more or less standard contrast agent for CEST, providing a pool of protons inside the cavity of a suitable paramagnetic material, such as a lanthanide in liquid form or in suspension. External gelatinous the surface polymersomes can be used to create a coordination complex with additional paramagnetic metal, whereby you can increase the difference in chemical shift for the transfer of saturation of the protons in the environment polimerkom (thus, increasing the above-mentioned effect of the magnetic susceptibility). Additionally, paramagnetic materials inside the cavity can be provided in the form of a coordination complex with chelat forming fragments in the polymer according to the invention.
In addition, in any of the above embodiments, implementation, polymersomes can give asferico form to enhance the effect CEST. Polymersomes, as a rule, are spherical. Giving polymersomes aspherical forms of exercise, subjecting them to the process of dialysis against hypertonic buffer, i.e. a buffer solution with a higher osmollnosti compared with the solution inside polimerkom. Dialysis is the reason the net diffusion of water from the interior of polimerkom in the main volume of the solution. This reduces the total volume of the internal space of polimerkom. As the surface polimerkom remains unchanged, the reduction in volume makes polymersomes to deform, to take asferico form such as the form of a disk, cigars or any other asferico form.
It should be noted that, in the case asperity polimerkom, effect CEST also can be fully achieved on the basis of the effect risperidnoe form, i.e. the ez reagent with a paramagnetic shift, mainly interacting with analyzed using an Mr material present in the cavity, or selected for analysis using an Mr material lacking in interaction with the reagent with a paramagnetic shift present in the cavity. In the present invention this provides additional flexibility of design: as indicated above, it is possible to choose the cavity, so that it was filled with metal. In this case polymersomes provided in aspherical form, can be used as contrast agents for CEST, however, to introduce additional contrast, for example, on the basis of T1and/or T2you can use helatoobrazovateli involving metals on the outer surface.
The effect CEST can be further configured using the natural properties of the block copolymer and/or density of the polymer layer, as these parameters affect the rate of exchange of water through the membrane; for example, the amphiphilic nature of the polymer can be used to influence the exchange ratio of protons through polymersomes. This usually can be done by changing the ratio of the lengths of the more hydrophilic or more hydrophobic blocks.
Regarding exchange of water, it is clear that the effect CEST you can also reach other analyzed using an Mr materials, such as small organic molecules, as well as molecules able to exchange through the membrane bilayer polymersomes.
Various diseases, which are mainly localized in specific tissues, treat systemic drug delivery. Well-known examples of standard anticancer therapy is systemic chemotherapy followed by significant side effects for the patient due to unwanted bearsdley and toxicity. therapeutic window for these medicines, with one hand, usually determine the minimum required therapeutic concentration in the affected tissue, and, on the other hand, toxic effects on organs that are not targets, such as the liver, spleen. Local impact, for example through the local release of drugs from nanoneedles, promises a more effective treatment and a wider therapeutic window compared with standard treatment. Local delivery of drugs is also important if other types of therapeutic treatment, such as surgical, too dangerous, as often happens in the case of malignant liver tumors. Local delivery of drugs may also be the preferred method of treatment for many indications in cardio-the vascular diseases (CVD), such as atherosclerosis of the coronary arteries.
Magnetic resonance imaging is an important diagnostic method, commonly used in hospitals to diagnose diseases. MRI allows noninvasive visualization of soft tissues with fine spatial resolution.
As a useful extension of the diagnostic application also proposed to use MRI to monitor the delivery of biologically active agents, such as therapeutic or diagnostic compounds. I.e. MRI can be used not only for treatment planning, but also to oversee the local delivery of drugs with visual management. Reference to this is Ponce et al., J Natl Cancer Inst 2007;99: 53-63. In this document, drug, doxorubicin, is enclosed in a temperature-sensitive a liposome, which is in a solid state at normal body temperature, and melts when the temperature rises a few degrees (41-42°C). Thus, the release of drug can be facilitated by applying heat, which will take place the opening of the liposomes, resulting in the release of a drug is no longer determined by diffusion (if provided) through the membrane of the liposomes. For observed what I am for the release of drugs using MRI, drugs used as a contrast medium, add salt manganese.
Polymersomes according to the invention can be used as a carrier for drugs. For the introduction and delivery of medicines introduced into the body through such media can be monitored with T1/T2and/or CEST MRI, depending on (as clearly described above, according to the present invention, the type and location of the paramagnetic metal, formed a complex with amphiphilic chelating polymer.
Media for the medicinal product to be injected into the body of the person subjected to MRI. Through, for example, injection into the bloodstream, or other ways of introducing media into the liquid environment of the body.
A drug is a chemical compound used for the treatment, cure, prevention or diagnosis of diseases or disorders, or used other means to enhance physical or mental well-being. Managed software delivery envisaged in the present invention mainly effective against therapeutic agents (i.e. in the strict sense, medicines intended for the treatment or prevention of diseases or disorders), but also in terms of connections, the input for di the Gnostic purposes. Although, other biologically active funds, i.e. funds that are not therapeutic or diagnostic, such as food, are not, as a rule, managed and/or controlled delivery, but if desired, this can be done by applying the present invention.
The most optimal method of use according to the invention achieves in the case of directed therapeutic effects, i.e. in the case of medicinal products intended for targeted delivery, such as delivery by nature has the greatest benefit from observation, is available through the invention. This applies, for example, connections with local delivery in the treatment of tumors, to compounds for the treatment or prevention of cardiovascular diseases such as atherosclerosis of the coronary arteries, or antithrombotic compounds (for example, local dissolution of blood clots), or compounds that need to cross the blood-brain barrier, such as neuromodulators that can be used in the treatment of such neurological diseases such as epilepsy, Alzheimer's disease, Parkinson's disease or stroke. Benefit from management and monitor the delivery of the address of medicines are appropriate for the address of the events for diagnostic purposes. As with targeted therapy, there are also tumors are the area where essential site-specific delivery.
Biologically active products, suitable for use in the present invention include biologically active products, including therapeutic drugs, endogenous molecules and pharmacologically active substances, including antibodies, molecules, intended for power supply; connection for diagnostics; and additional contrast agent for visualization. As used herein, the active agent includes pharmacologically acceptable salts of the active assets.
Carriers for drugs of the present invention, based on polymersof may contain both hydrophilic and hydrophobic biologically active products. Hydrophilic bioactive agent can be included in the aqueous compartment of the carrier or may be associated with more hydrophilic part of the shell particles, or the distribution may include a combination of these possibilities, whereas hydrophobic biologically active products can be included in the hydrophobic domains of media, for example, in the shell polymersomes. Nucleic acids, carbohydrates and mostly proteins and peptides are water soluble or hydrofilm the mi. For example, you can also consider biologically active products, which are low molecular weight compounds, lipids, lipopolysaccharides, polynucleotide and antisense nucleotides (connection for gene therapy). Biologically active products, which can be included, thus, includes drugs that are not peptides and proteins. In the framework of the present invention can include medicines polymeric nature, but also include drugs with a small enough molecular weight of less than 1500 g/mol, or even less than 500 g/mol.
Thus, compounds considered for use as biologically active agents, in the context of the present invention include any compounds with therapeutic or prophylactic properties. This may be the connection, influence, or participates in tissue growth, cell growth, cell differentiation, a compound that is able to invoke a biological action such as an immune response, or compound that can play any other role in one or more biological processes. A non-limiting list of examples includes antimicrobial agents (including antibacterial, antiviral compounds and antifungal compounds), antiviral agents, protiva wholesae means, thrombin inhibitors, antithrombotic agents, thrombolytic tools, fibrinolytic tools, inhibitors of angiospasm, calcium channel blockers, vasodilator, antihypertensive, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet funds antimitoticescoy tools, inhibitors of microtubules, antisecretory funds inhibitors, actin inhibitors, remodeling, antimetabolites tools, antiproliferative funds (including inhibitors of angiogenesis), anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory drugs, IMMUNOSUPRESSIVE tools, antagonists of growth hormone, growth factors, dopamine agonists, means for radiotherapy, components of the extracellular matrix, ACE inhibitors, traps for free radicals, chelating compounds, antioxidants, inhibitors of the polymerase and means for phototherapy.
Mention can be made sufficiently small peptides according to the number of amino acids (such as di-, tri-, tetrapeptide). The peptide with a fairly small number of amide bonds can also be called an Oligopeptide of up to 50 amino acids), whereas the peptide with a sufficiently large number (more than 50 amino acids) can be called the polyp is the Chida or protein. In addition to the existence of a polymer of amino acid residues, some proteins, in addition, can be characterized by the so-called Quaternary structure, the combination of several polypeptides that are not necessarily chemically bonded amide bonds, but with the help of forces of interaction, as a rule, well-known experts in this field, such as electrostatic forces and van-der Waals forces. The term peptides, proteins or mixtures thereof, as used herein, includes all the above features.
Typically, protein and/or peptide is chosen on the basis of their biological activity. Depending on the type of the selected polymer, the product obtained by the present method is extremely suitable for a controlled release of proteins and peptides. In a specific embodiment, the protein or peptide is a growth factor.
Other examples of peptides or proteins or compounds containing peptides or proteins that can be successfully included in the loaded polymer include, as non-limiting examples, the immunogenic peptides or immunogenic proteins, which include, as non-limiting examples, the following:
Toxins, such as diphtheria toxin and tetanus toxin.
The surface antigens of the virus or parts of viruses, such as hell is overuse, the virus of Epstein-Barr, hepatitis A virus, hepatitis B virus, herpes viruses, HIV-1, HIV-2, the virus T-cell human leukemia-III, influenza virus, Japanese encephalitis virus, measles virus, papilloma virus, paramyxoviruses, poliovirus, rabies virus, rubella virus, cowpox viruses (smallpox) and yellow fever virus.
The surface antigens of bacteria or part of takari, such as Bordetella pertussis, Helicobacter pylori, Clostridium tetani, Corynebacterium reagent grade, Escherichia coli, Haemophilus influenzae, Klebsiella species, Legionella pneumophila, Mycobacterium bovis, Mycobacterium leprae, Mycrobacterium tuberculosis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus species, Pseudomonas aeruginosa, Salmonella species, Shigella species, Staphylococcus aureus, Streptococcus pyogenes Vibrio cholerae and Yersinia pestis.
The surface antigens of pathogenic parasites or parts of parasites, such as Plasmodium vivax (malaria), Plasmodium falciparum (malaria), Plasmodium ovale (malaria), Plasmodium malariae (malaria), Leishmania tropica (leishmaniasis), Leishmania donovani (leishmaniasis), Leishmania branziliensis (leishmaniasis), Trypanosoma rhodescense (sleeping sickness), Trypanosoma gambiense (sleeping sickness), Trypanosoma cruzi (Chagas disease), Schistosoma mansoni (sistematis), Schistosomoma haematobium (Sistemas), Schistosoma japonicum (Sistemas), Trichinella spiralis (trichinosis), Stronglyloides duodenale (the hookworm), Ancyclostoma duodenale (hookworm), Necator americanus (hookworm), Wucheria bancrofti (filariasis), Brugia malaya (filariasis), Loa (filariasis), Dipetalonema perstaris (filariasis), Dracuncula medinensis (filariasis) and Onchocerca volvulus (filariasis).
Immunoglobulins such as IgG,IgA, IgM, rabies immunoglobulins and antibodies to vaccinia virus.
Toxoids, such as botulinum toxoid, diphtheria toxoid, gas-gangrenous toxoid, tetanus toxoid.
The antigens that trigger an immune response against FMDV.
Hormones and growth factors, such as follicle-stimulating hormone, prolactin, angiogenin, epidermal growth factor, calcitonin, erythropoietin, thyrotropic releasing hormone, insulin, insulin-like growth factor 1 and 2, the growth factor bone tissue, chorionic gonadotropic hormone human luteinizing hormone, nerve growth factor, adrenocorticotropic hormone (ACTH)releasing factor, luteinizing hormone (RF-LH), parathyroid hormone (PTH), thyrotropin-releasing hormone (TRH), vasopressin, cholecystokinin and corticoliberin; cytokines, such as interferon, interleukins, colony-stimulating factor and necrosis factor tumors: fibrinolytic enzymes, such as urokinase, kidney plasminogen activator; blood clotting factors such as protein C, factor VIII, factor IX, factor VII and antithrombin III.
Other examples of peptides and proteins are albumin, atrial naturethese factor, renin, superoxide dismutase, alpha 1-antitripsin, pulmonary surfactant proteins, bacitracin, bestatin, cylosporin, peptide, causing the Delta is he (PWDs), endorphins, glucagon, gramicidin, melanotropin-inhibitory factor, neurotensin, oxytocin, somatostatin, terpreted (terprotide), Timothy factor serum, thymosin, desmopressin, dermorphin, met-enkephalin, peptidoglycan, Steichen, chymopapain, the breakdown products of fibrin, mesencephalon-alpha-endorphin, gonadotropin releasing hormone, leuprolide, MSH-alpha and madarame.
Antineoplastic agents, such as altretamine, fluorouracil, amsacrine, hydroxycarbamide, asparaginase, ifosfamide, bleomycin, lomustin, busulfan, melphalan, chlorambucil, mercaptopurine, chlormethine, methotrexate, cisplatin, mitomycin, cyclophosphamide, procarbazine, cytarabine, teniposide, dacarbazine, thiotepa, dactinomycin, tioguanin, daunorubicin, treosulfan, doxorubicin, thiotepa, estramustin, vinblastine, etoposide, vincristine, etoposide, vindesine and paclitaxel.
Antimicrobial agents include:
Antibiotics such as ampicillin, nafcillin, amoxicillin, oxacillin, azlotillin, penicillin G, carbenicillin, penicillin V, dicloxacillin, fenetylline, floxacillin, piperacillin, mecillinam, sulbenicillin, methicillin, tikarcillin, mezlocillin. Cephalosporins: cefaclor, cephalothin, cephalo-Smoking, cephapirin, cefamandole, cefradine, cefatrizine, cefalotin, Cefazolin, ceftazidime, ceforanide, Ceftriaxone, cefoxitin, cefuroxime, cefacetrile, latamoxef and C is phalexin. Aminoglycosides, such as amikacin, neomycin, dibekacin, kanamycin, gentamicin, netilmicin, tobramycin. Macrolide antibiotics, such as amphotericin B, novobiocin, bacitracin, nystatin, clindamycin, polymyxin, colistin, rovamycin, erythromycin, spectinomycin, lincomycin, vancomycin. Tetracyclines, such as chlortetracycline, oxytetracycline, demeclocycline, rolitetracycline, doxycycline, tetracycline and minocycline. Other antibiotics, such as chloramphenicol, rifamycin, rifampicin and thiamphenicol.
Chemotherapeutic agents, such as the sulfonamides sulfadiazine, sulfamethizole sulfadimetoksin, sulfamethoxazole, sulfadimidine, sulfamethoxypyridazine, sulfafurazole, sulfaphenazole, sulfalen, sulfisomidine, sulfamerazine, sulfisoxazole and trimethoprim with sulfamethoxazole or sulfometuron.
Rosatti, such as methylamine, quinolones (norfloxacin, cinoxacin), nalidixic acid, nitro compounds (nitrofurantoin, niforeika) and oxolinic acid.
Drugs against anaerobic infections, such as metronidazole.
Medicines to treat tuberculosis, such as aminosalicylate acid, isoniazid, cycloserine, rifampicin, ethambutol, Ciocarlia, ethionamide and viomycin.
Drugs for treatment of leprosy, such as amitiza, rifampicin, clofazimine, sulf the XON sodium and diaminodiphenylsulfone (DDS, Dapsone).
Antifungal drugs such as amphotericin B, ketoconazole, clotrimazole, miconazole, econazole, natamycin, flucytosine, nystatin and griseofulvin.
Antiviral medicines such as acyclovir, idoxuridine, amantadine, methisazone, cytarabine, vidarabine and ganciclovir.
Drugs for treating amoebic dysentery, such as chloroquine, iodoquinol, kliohinol, metronidazole, dehydroemetine, paromomycin, diloxanide, furoatetinidazole and emetine.
Antimalarial drugs such as chloroquine, pyrimethamine, hydroxychloroquine, quinine, mefloquine, sulfadoxine/pyrimethamine, pentamidine, suramin sodium, primaquine, trimethoprim and proguanil.
Antihelminthic drugs, such as antigenically salt of tartaric acid, niridazole, dimercaptosuccinic of nutrisource, complementary, bephenium, piperazine, dichlorophen, praziquantel, diethylcarbamazine, Pyrantel, pamoate, Gigantor, pyrivium pamoate, levamisole, stibophen, mebendazole, tetramisole, metrifonate, thiabendazol and niclosamide.
Anti-inflammatory medicines, such as azetilsalicilovaya acid, mefenamovaya acid, iclofenac, naproxen, isopropanol, niflumova acid, benzydamine, oxyphenbutazone, diclofenac, piroxicam, fenoprofen, pirprofen, flurbiprofen, sodium salicylate ibuprofen, sulindac, indomethacin, tiaprofenic acid, Ketoprofen, tolmetin.
Medicines for treating gout, such as colchicine and allopurinol.
The centrally acting analgesics (opioids)such as Alfentanil, methadone, Bezitramide, morphine, buprenorphine, Nicomorphine, butorphanol, pentazocine, codeine, pethidine, dextromoramide, piritramid, dextropropoxyphen, Sufentanil and fentanyl.
Local anesthetics, such as articaine, mepivacaine, bupivacaine, prilocaine, etidocaine, procaine, lidocaine, and tetracaine.
Medicines to treat Parkinson's disease, such as amantadine, diphenhydramine, apomorphine, ethopropazine, benztropine mesilate, lergotrile, biperiden, levodopa, parlodel, lisuride, carbidopa, meteksan, chlorphenoxamine, orphenadrine, cycrimine, procyclidine, dexetimide and trihexyphenidyl.
The centrally acting muscle relaxants, such as baclofen, carisoprodol, chlormezanone, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, debarbat, mephenoxalone, mephenesin, metaxalone, Methocarbamol and tolperison.
Mineralcorticoid, such as cortisol, hypertension and fluorohydrocarbon.
Corticosteroids include beclomethasone, betamethasone, cortisone, dexamethasone, fluotsinolon, fluocinonide, fluocortolone, fluorometholone, fluprednisolone, Florentino the ID, halcinonide, hydrocortisone, Madison, methylprednisolone, paramethasone, prednisolone, prednisone and triamcinolone (acetonide).
Such therapeutic androgenic steroids, as danazol, fluoxymesterone, mesterolone, methyltestosterone, testosterone and their salts.
Such therapeutic anabolic steroids, as calusterone, nandrolone and their salts, drostanolone, oxandrolon, ethylestrenol, oxymetholone, methandriol, stanozolol, methandrostenolone and testolactone.
Antiandrogens, such as ciproteron acetate.
Such therapeutic estrogens, including estrogenic steroids, as diethylstilbestrol, estradiol, estriol, ethinylestradiol, mestranol, Ginestra.
Antiestrogens, such as chlorotrianisene, clomiphene, Atomoxetine, nafoxidine and tamoxifen.
Progestins, such as allylestrenol, desogestrel, dimethisterone, dydrogesterone, ethinylestradiol, ethisterone, ethynodiol diacetate, ethynodiol, hydroxyprogesterone, levonorgestrel, lynestrenol, medroxyprogesterone, megestrol acetate, norethindrone, norethisterone, norethynodrel, norgestrel and progesterone.
Thyroid hormones include:
Such therapeutic thyroid drugs, like elevation and lotion.
Such therapeutic anti-thyroid drugs, as carbimazole, methimazole, thiuragyl and propylthiouracil.<> In addition to biologically active agents which are soluble in water, it is possible to include other water-soluble substances, such as antioxidants, ions, chelating tools, dyes, imaging tools.
Preferred therapeutic means are means for use in the tumors (e.g., anticancer), and cardiovascular diseases.
Methods of obtaining derivatives of lipophilic drugs suitable for drug nanoparticles or polimerkom known in the art (see, for example, US 5534499 describing the covalent joining of therapeutic agents to chain fatty acids of phospholipid). Medicines according to the present invention can also be prodrugs.
The drug may be present in the inner, outer or both compartments of the carrier, for example, in the cavity and/or in the shell polymersomes. The distribution of the medicinal product does not depend on the distribution of any other compounds contained in the carrier medicines, such as paramagnetic compound to chemical shift or paramagnetic. You can use a combination of medicines, and any of these drugs can be inside, outside or both compartments of the carrier of drugs, e.g. the R, in the cavity and/or in the shell polymersomes.
As noted above, the chelating amphiphilic polymers according to the invention can be combined with amphiphilic polymers, non-chelate.
Also, in the case of polimerkom based chelating amphiphilic polymers, specific diseases molecules can be provided in the shell polymersomes, for example, in the presence of compounds having a hydrophobic tail, suitable for penetration into the surface polymersomes, where the other end of the connection contains the desired ligand. This allows you to apply polymersomes as contrast agents, which may preferably be localized desired or anticipated areas in the body, which then can be visualized using MRI.
It should be understood that the invention is not limited to the implementation and formulas, as described herein previously. It is also understood that in the claims the word "comprising" does not exclude other elements or steps. In the case of an indefinite or definite article, referring to a single number, such as "a" or "an", "the", this includes a plural of that noun, if, in particular, do not report anything else.
The present invention is illustrated with reference n the following non-limiting examples and figures.
BRIEF DESCRIPTION of DRAWINGS
Fig. 1. Nanostructures capable of samegreloshi containing amphiphilic copolymers. Polymersomes (left), stable polymer emulsion (in the middle), and polymeric micelles (right).
Fig. 2. Schematic representation of functionalized with Gd(III)DOTA-polimerkom as T1,2-weighted contrast agents for magnetic resonance imaging (MRI).
Fig. 3. Schematic representation of functionalized using the DOTA polimerkom. Spherical polymersomes containing terminorum with DOTA copolymers in the polymer layer (6, left). In the reaction of DOTA molecules with paramagnetic metals are formed spherical polymersomes (10, middle), in which the paramagnetic complexes are directed outward to the volume of water. Warp polimerkom (10) in response to osmotic pressure allows to obtain expericne polymersomes (11, right).
Fig. 4. Schematic representation of functionalized using the DOTA polimerkom containing compound for chemical shift in the internal aqueous compartment. Spherical polymersomes containing terminorum with DOTA copolymers in the polymer layer (12, upper left). In the reaction of DOTA molecules 12 with paramagnetic metals are formed spherical polymersomes (13, upstairs in the middle), in which the paramagnetic set is XY directed outward to the volume of water. Using deformation 12 in response to the osmotic pressure can be obtained expericne polymersomes (15, below). Expericne polymersomes containing compounds with a chemical shift inside, and paramagnetic complexes, directed outwards to the volume of water (14, top right), can be obtained using either 13 or 15.
Fig. 5. Schematic diagram contrasting connections CEST MRI containing paramagnetic complexes of copolymers DOTA on both sides of the polymer layer polimerkom. Spherical polymersomes (16, upper left), expericne polymersomes (17, top right), spherical polymersomes containing compound for chemical shift in the internal aqueous compartment (18, bottom left), and expericne polymersomes containing compound for chemical shift in the internal aqueous compartment (19, bottom right).
Fig. 6. Polymersomes, stable emulsion polymers and polymeric micelles for radionuclide imaging, exhibiting a label, for example, radionuclide imaging, on the outer surface of the structure.
Fig. 7. SPECT/CT tomography using emulsion labeled with111Indium later, 4 hours after the injection. Projection with maximum intensity value of the CT image is registered with tomography SPECT (top left); coronary SPECT/CT slice, allowing to visualize the series is CE and liver (upper right); sagittally SPECT/CT slice, allowing to visualize the heart and the liver and kidneys (lower left); cross-SPECT/CT slice (bottom right).
Synthesis of functionalized with DOTA poly(ethylene oxide)-block-poly(butadiene) (5)
PBD(2500)-b-PEO(1300) (1) was dissolved in acetone (18 ml),Yu and the solution was concentrated under reduced pressure to remove excess isopropanol. To remove residual water, the copolymer was dissolved in toluene (15 ml) and the solution was concentrated in vacuum. Subsequently, PBD(2500)-b-PEO(1300) (4,90 g, 1,29 mmol) was dissolved in DHM (15 ml) under a nitrogen atmosphere. The resulting solution was cooled to 0°C was added p-taillored (0,497 g, 2.6 mmol). The mixture was stirred for 30 min at 0°C and carefully added KOH (0,640 grams, or 11.4 mmol). The mixture was stirred over night at room temperature. The reaction mixture was washed with water (2×30 ml) and brine (2×15 ml). The aqueous layer was removed using DHM (30 ml), and mixed organic layers were dried over MgS4filtered content and the solution was concentrated under reduced pressure to obtain 2 (62%, 3.2 g, 0.81 mmol). Functionalized using tosilata copolymer (2) (3.2 g, 0.81 mmol) was dissolved in toluene (12 ml) and the solution was added 7 N NH3in MeOH (12 ml, 84 mmol). The reaction was conducted at 50°C for 63 hours Then the solvent prowess and under reduced pressure. The crude mixture was dissolved in DHM (10 ml). The resulting solution was washed with water (2×20 ml), brine (2×10 ml), and saturated NaHCO3(water.) (10 ml). The aqueous layer was removed with DHM (40 ml). Mixed organic layers were dried over MgSO4.The suspension was filtered and the filtered contents were concentrated under reduced pressure to obtain 3 (1.55 g, 0.41 mmol) with a yield of 50%. Functionalized with amine copolymer (3) (1.2 g, 0.31 mmol) was dissolved in DMF (12 ml) and subsequently added structural units based on DOTA (4) (0,347 g, 0.35 mmol) and Et3N (0.9 ml, 6.5 mmol). The mixture was stirred for 26 h at room temperature in a nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The crude mixture was dissolved in toluene, and the solution was concentrated under reduced pressure. Functionalized with DOTA poly(ethylene oxide)-block-poly(butadiene) (5) was obtained with quantitative yield.
Semiregular functionalized with DOTA copolymers and the formation of complexes with Gd(III)
Polymer vesicles with a mean diameter of 100-150 nm were obtained using the method of hydrating the thin film together with the subsequent eviction. Briefly, functionalized with DOTA poly(butadiene(l,2-addition)-b-ethylene oxide) (Mn(g/mol): PBD(2500)-b-PEO(1300), PD=1,04, and fEO=0,34)was dissolved in CHCl 3. The solvent was carefully removed under reduced pressure, and got a thin polymer film. The film was subjected to the hydrating solution of 20 mm HEPES (pH 7,4). After heating overnight to 50°C, followed by 10 cycles of freezing and thawing at a temperature -177°C and 70°C, the colloidal solution was repeatedly subjected to displacement through polycarbonate filters with a pore diameter of 1 μm to 0.4 μm, 0.2 μm and 0.1 μm. Subsequently, the solution GdCl3(5 equivalents) in 20 mm HEPES solution, pH of 7.4) was added to the colloidal solution polimerkom at 50°C for 2 hours. Subsequently, polymersomes dialyzed overnight to remove excess Gd(III). Dialysis was performed against 20 mm HEPES solution, pH of 7.4. Minimum average radius of polimerkom were determined using dynamic light scattering (ODCs). The form of polymer vesicles were determined using cryo-TEM. The concentration of gadolinium were determined using ICP-MS. Longitudinal and transverse periods of relaxation (T1and T2) was determined at 60 MHz.
Expericne polymersomes containing compound with the chemical shift and paramagnetic complexes terminorum with DOTA polymers (14).
Polymer vesicles with a mean diameter of 100-150 nm were obtained using the method of hydrating the thin film together with the subsequent displacement, as described in example 1. In this case, the AU film was subjected to hydrating in 20 mm HEPES solution (pH 7,4), containing 65 mm [Tm(hpdo3a)(H2O)]. After heating to 50°C during the night, followed by ten cycles of freeze-thawing at -177°C and 70°C, the colloidal solution was repeatedly subjected to displacement through a polycarbonate filter with a pore diameter of 1 μm to 0.4 μm, 0.2 μm and 0.1 μm. Received polymersomes (12) dialyzed overnight to remove [Tm(hpdo3a)(H2O)], which was not captured after hydrating the lipid film, and received expericne polymersomes (15). Dialysis was performed using 20 mm HEPES buffer containing 0.3 M NaCl. Then the solution TmCl3(5 equivalents) in 20 mm HEPES buffer containing 0.3 M NaCl, was added to the colloidal solution polimerkom at 50°C for 2 hours. Polymersomes (14) dialyzed overnight to remove excess Tm. Dialysis was performed against 20 mm HEPES buffer containing 0.3 M NaCl (pH of 7.4). Minimum average radius of polimerkom (14) were determined using dynamic light scattering. The form of polymer vesicles was studied using cryo-TEM. The concentration of gadolinium were determined using ICP-MS. Longitudinal and transverse periods of relaxation (T1and T2) was determined at 60 MHz.
Radiolabelled polymersomes and emulsions
Obtaining a stabilized polymer emulsion
The emulsion was received from Octan-2-yl-2,3,5-triiodobenzoate (25% weight/volume)using 2% weight/in the poly(butadiene(l,2 accession)-block-poly(ethylene oxide) (f EO0,61; Mwphil=2033 g/mol; Mwphob= 1305 g/mol) and 5 mol % of functionalized with DOTA copolymer (5). The emulsion was obtained 2.1 mm THAM buffer containing 152 mm NaCl at a pH of 7.4, using a system of microfluidizer high pressure (microfluidizer M110S, Microfluidics Int. Corp., Newton, MA) at 70°C. for three days conducted extensive dialysis against the buffer THAM (1 l)containing Chelex (2 g/l). Then stabilized with a polymer emulsion was filtered through a filter with pores of 450 nm.
Radioactive labeling of the emulsion
The emulsion is stabilized using DOTA-copolymer (300 µl) were incubated with111InCl330 MBq of 0.05 M HCl (4 ml)for 1 hour at 70°C. Then the reaction mixture was added the free DTPA removal free111In. 1 μl of the reaction mixture were applied to the coated silica plate for TLC. As used additionally separated by 200 mm EDTA solution containing 9.0 g/l NaCl. TLC was analyzed using a phosphoimager FLA-7000 (Fuji Film, Tokyo, Japan), and the introduction of radioactive particles was quantitatively evaluated using the software Aida (Fuji film). The efficiency of introducing a radioactive label using111InCl330 MBq was 65%. The introduction of radioactive substances on a smaller scale (111InCl34,6 MBq in 100 μl of emulsion) gave a yield of 97%. Although this result is more for visualization 4.6 MB is not enough. Thus, the described method with111In 30 MBq used for studies in-vivo. Radiolabelled emulsion was tested on male Swiss mice (Charles River, Maastricht, the Netherlands) for scanning using doodley SPECT/CT. Radiolabelled emulsion (200 μl) with activity 20,5 MBq was injected intravenously. Scanning with SPECT/CT was performed using NanoSPECT/CT (Bioscan).
Experiment on animals was approved by the expert ethical Committee of the University for animal experiments of the University of Maastricht (Maastricht, Netherlands).
1. Chelating amphiphilic polymer as a carrier, capable of samegreloshi containing hydrophilic block and a hydrophobic block, where the hydrophilic block contains the chelate forming fragment as an end group,
where the hydrophilic unit selected from the group comprising polyethylene oxide, polymethacrylic acid, derivatives of polyacrylamide, polyhydric alcohols, such as polyvinyl alcohol or polyhydroxyethylmethacrylate, hydrophilic polypeptides and derivatives sugar,
where the hydrophobic block is selected from the group comprising polybutadiene, polyisoprene, politisation and all polymers with a skeleton of carbon atoms and side groups of hydrophobic nature,
where chelate forming fragment selected from the group including polyphosphates, aminocarbonyl key is lots 1,3-diketones, hydroxycarbonate acid, polyamine, aminoalcohols, aromatic heterocyclic bases, phenols, aminophenols, oximes, peptides containing the proximal chelating functional groups, Schiff bases, tetrapyrroles, sulfur compounds, synthetic macrocyclic compounds, phosphonic acid, or a combination of two or more of the above compounds,
where chelating amphiphilic polymer satisfies the General structural formula (i):
where X represents a chelate forming fragment; MAis a repetitive hydrophilic element, forming a hydrophilic block; MBrepresents a hydrophobic repeating unit, and forming a hydrophobic block; n and m each independently are integers from 3 to 1000000, preferably from 5 to 5000, representing the number of monomer units constituting the respective blocks.
2. Chelating amphiphilic polymer according to claim 1, where the hydrophilic block is a block of poly(ethylene oxide), preferably with srednevekovoi molecular weight of from 500 to 10000.
3. Chelating amphiphilic polymer according to claim 1, where the hydrophobic block has a Tg below 70°C, and preferably selected from the group consisting of poly(butadiene), poly(isoprene) and poly(ethylethylene).
4. Chelating amphiphilic polymer according to claim 1, where he is matoobrazuyushchei fragment selected from the group consisting of DOTA, DTPA, HYNIC and desferoxamine.
5. Particle as a carrier, capable of containing samegreloshi structure chelat forming amphiphilic polymer according to any one of the preceding paragraphs.
7. Particle according to claim 6, containing a combination of chelating amphiphilic polymer according to any one of claims 1 to 4 and amphiphilic polymer, non-chelate.
7. Particle according to claim 6, where the non-chelating amphiphilic polymer has a chain of poly(oxyethylene) as the hydrophilic block, the length of this circuit is greater than the length of the hydrophilic block chelating amphiphilic polymer.
8. The use of particles according to any one of pp.5-7 as a contrast agent for visualization.
9. Contrast agent for CEST MPT containing particles according to any one of pp.5-7, which is capable of samegreloshi structure represents polymersomes having a shell formed by Bilaam of one or more amphiphilic polymer bilayer contains chelating amphiphilic polymer, where the shell is enclosed cavity containing a supply of protons for analysis capable of diffusion through the shell, and where the chelate forming fragment chelating amphiphilic polymer stretching in the direction into the cavity, provide with chelating paramagnetic material.
10. Contrast agent for CEST MPT according to claim 9 form, which is not what I spherical.
11. Contrast agents for SPECT or PET, containing particle according to any one of pp.5-7, which is capable of samegreloshi structure is a stabilized polymer emulsion oil-in-water", and where hepatoblastoma fragments chelating amphiphilic polymer provide using chelating radionuclide suitable for SPECT or PET.
12. Contrast agent for spectral CT containing particles according to any one of pp.5-7, where the chelate forming fragment chelating amphiphilic polymer provide using Gd.
13. Particle according to any one of pp.5-7, where one or more chelat forming fragments contain a metal ion to form a coordination complex metal ions to form chelate complexes inside.
14. A method of producing particles according to item 13, where the chelating amphiphilic polymer should be in the aqueous medium to form a bilayer surrounding the cavity, and where hepatoblastoma fragments are subjected to formation of coordination complexes with metal ions before forming the bilayer.
SUBSTANCE: method of producing membranes involves preparing a solution containing an organic solvent and a unneutralised block-copolymer in a micellar form. At least one amine is added to the solution. The amine is a polyfunctional amine containing two to four nitrogen-containing functionalities, and contains at least two nitrogen-containing functionalities bonded to each other through a linear, branched or cyclic aliphatic bridge fragment. Said solution is then moulded into a membrane containing a sulphonated block-copolymer. Before neutralisation, said sulphonated block-copolymer has at least one terminal block A and at least one inner block B. Each block A essentially does not have any sulphonic acid or sulphonate ester functional groups, and each block B is a polymer block containing from about 10 to about 100 mol % sulphonic acid or sulphonate ester functional groups with respect to the amount of monomer links of block B, which are unneutralised, where each block A contains one or more segments selected from polymerised (i) para-substituted styrene monomers, (ii) ethylene, (iii) alpha-olefins containing 3 to 18 carbon atoms, (iv) 1,3-cyclodiene monomers, (v) monomer conjugated dienes with pre-hydrogenation vinyl content of less than 35 mol %, (vi) acrylic esters, (vii) methacrylic esters and (viii) mixtures thereof. Each block B contains segments of one or more vinyl aromatic monomers selected from polymerised (i) unsubstituted styrene monomers, (ii) ortho-substituted styrene monomers, (iii) meta-substituted styrene monomers, (iv) alpha-methylstyrene, (v) 1,1-diphenylethylene, (vi) 1,2-diphenylethylene and (vii) and mixtures thereof.
EFFECT: obtaining a membrane with improved physical and chemical properties.
24 cl, 3 tbl
SUBSTANCE: invention provides a crystalline coordination copolymer, a method for production thereof and a method for use thereof. Production involves assembling multiple organic molecules to obtain porous materials with frame structures having layered configurations or "core-shell" configurations. Said materials are synthesised by step-by-step growing methods such as seed growing methods. The disclosed coordination copolymer includes at least a first region of a first coordination polymer, characterised by a first X-ray diffraction pattern, and a second region of a second coordination polymer, characterised by a second X-ray diffraction pattern, where the first and second coordination polymers are not identical, and where the X-ray diffraction pattern of the coordination copolymer simultaneously includes a set of peaks of the first X-ray diffraction pattern and a set of peaks of the second X-ray diffraction pattern.
EFFECT: invention provides a simple method of controlling functionality depending on the field of use.
10 cl, 5 dwg, 7 ex
SUBSTANCE: present invention relates to resorbable block copolymers for producing resorbable surgical or therapeutic implants for humans and animals. The block copolymer is of type AB or ABA. Block A is formed by polyester and block B is formed by polyether. Type AB has the formula: E-(O-D-CO-)n-(O-CH2-CH2-)m-O-F, where the structural link E-(O-D-CO-)n forms block A, and link -(O-CH2-CH2-)m forms block B. Type ABA has the formula: E-(O-D-CO-)n-(O-CH2-CHr)m-O-(CO-D-O-)n'-E, in which links E-(O-D-CO-)n and E-(O-D-CO-)n. form block A, and link -(O-CH2-CH2-)m forms block B. Content of block B ranges from 0.1 to 4 wt %. The invention also relates to a method of producing and cleaning said block copolymers contaminated with monomers.
EFFECT: obtaining block copolymers or implants from said block copolymers, characterised by high mechanical strength, elasticity, viscosity and fast kinetic resorption.
42 cl, 3 tbl, 4 ex
SUBSTANCE: invention relates to a polymer of formula (I): In-[(A)x-(B)y-( A')x-(E)z]n, obtained via controlled free-radical polymerisation using nitroxyl radicals with excess acrylate. In is a fragment of an initiator. A and A' are identical or different monomers selected from a group comprising methylacrylate, ethylacrylate, ethylhexylacrylate, propylacrylate, cyclohexylacrylate, hydroxyethylacrylate, n-butylacrylate, styrene and vinylpyridine. The amount of unsubstituted C1-C22 alkyl acrylic esters and/or C1-C22 alkyl methacrylic esters is more than 30 wt %. B is propargylacrylate. E is a group containing at least one stable nitroxyl free radical.
EFFECT: obtaining polymers suitable for use as a wetting or dispersing agent for dyes, as well as starting material for all reactions starting with alkyne or for hydrosilylation reactions.
8 cl, 1 tbl, 3 ex
SUBSTANCE: method for preparation of functionalised, bound or star-block copolymer used in sulphur-cured rubber composition containing carbon char and having in cured state decreased hysteresis with at least one of said blocks containing polyisoprene and at least one other block consisting of diene elastomer different from polyisopren with mole content of repeating units of one or more of conjugated dienes exceeding 15% includes: copolymerisation of one or more monomers containing at least one conjugated diene different from polyisoprene with catalitycal system containing hydrocarbon solvent halogenated or unhalogenated metal-organic compound A of the group IIIA metal, alkaline-earth metal compound B and polymer initiator C containing bound C-Li formed by unfunctionalised monolythium-containing polyisopren intended for formation of the said block or every polyisoprene block and (ii) adding to the product of the said polymerisation of the functionalising, binding or star-shape forming agent containing acetoxy group of formula Rn-Sn-(O-CO-R')4n> whereat n is integer natural number from 0 to 4 and R and R' each represents following groups: alkyl, cycloalkyl, aryl, aralkyl, same or different, for functionalisation or binding or forming of star-shape structure of the said block consisting of dien elastomer different from polyisopren. The said one or more polyisopren blocks have number average molecular mass Mn1 from 2500 to 20000 g/mole, the said one or more dien elastomer blocks have number average molecular mass Mn2 from 65000 to 350000 g/mole. Functionalised, bound or star-block copolymer, curable or cured rubber composition with lowered hysteresis in cured state, containing reinforcing filler completely or partially consisting of carbon char and containing aforementioned functionalised, bound or star-block copolymer are described also. Pneumatic tyre tread containing aforementioned rubber composition is described as well as pneumatic tyre containing described above tread.
EFFECT: hysteresis decrease of cured the rubber composition.
36 cl, 5 ex
FIELD: chemistry, medicine.
SUBSTANCE: complex matrix consists of at least one biologically compatible polymer of natural origin, structured with sewing agent, which represents two- or multi-functional molecule, selected from epoxides, epihalohydrines and divinyl sulphone, on said polymer inoculated are chains with molecular weight less than 50000 daltons, selected from polymers of natural origin of small size, preferably, derivatives of cellulose or other biological polymer derivatives which naturally are not present in human organism, and/or non-polymerised chains with properties of oxidation inhibitors or ability to inhibit reactions of matrix decomposition, preferably, vitamins, enzymes or molecules, consisting of one or several cycles, degree of inoculation, expressed as ratio of moles of inoculated molecules and quantity of moles of polymer units, constitutes from 10 to 40%. Also described are method of obtaining such matrix and its application for separation, replacement, filling or addition of biological fluid or tissues.
EFFECT: increase of application efficiency.
20 cl, 7 ex, 2 tbl, 1 dwg
SUBSTANCE: invention refers to radical polymerization method of halogenated polymers production. Radical polymerization method is applied for halogenated polymers production. Besides radical polymerization method is used for polymer production of chlorinated vinyl monomer(s). Method implies usage of (A) one or more ethylene non-saturated monomers at least one of which is selected from chlorinated vinyl monomers group, (B) molecular iodine and (C) one or more radical generating agents selected from diazo-compounds, peroxides and dialkyldiphenylalkans. Method includes stages according to which at least a part of each compound (A), (B) and (C) are placed into reactor. Then reactor content interacts as optional residue of each compound (A), (B) and (C) is added until at most 70 moles % chlorinated vinyl monomer(s) placed into reactor react(s), if ethylene non-saturated monomer or monomers placed into reactor are exclusively chlorinated vinyl monomer(s), or until at most 95 moles % chlorinated vinyl monomer(s) placed into reactor react(s), if at least one ethylene non-saturated monomer placed into reactor is non-halogenated monomer. Then reaction is carried through. This method is used for production of polymer with number-average molecular weight Mn more than 1,0x104 and ratio Mz/Mw lower than 1.65. Radical polymerization method is applied for block-interpolymer production at least one block of which is polymer block of chlorinated vinyl monomer(s) containing (A') one or more ethylene non-saturated monomers and (B') one or more polymers of chlorinated vinyl monomer(s) selected from polymers produced by stated method and intermediate block-interpolymer. Block-interpolymer characterized with number-average molecular weight Mn more than 1.5x10 and polydispersity ratio Mw/Mn lower than 1.60. Product is made of one or more specified chlorinated vinyl monomer(s) and block-interpolymer. It is possible to reactivate polymer chain growth from chlorinated vinyl monomer(s) by additional mutual reaction, even after release from polymerization medium that makes possible to produce block-interpolymers containing at least one polymer block of chlorinated vinyl monomer(s). Products based on specified polymers have improved mechanical properties.
EFFECT: method enables to synthesize polymers from chlorinated vinyl monomer.
18 cl, 2 tbl, 8 ex
FIELD: chemistry of polymers, chemical technology.
SUBSTANCE: invention relates to a method for synthesis of block-copolymers based on vinylaromatic monomers and monomers representing derivatives of (meth)acrylic acid. Invention describes a method for synthesis of block-copolymers by means of radical polymerization involving the following steps: (a) polymerization of vinylaromatic monomer at temperature 120°C or above in the presence of the radical-initiating system consisting of a compound of the general formula (I) given in the invention description and wherein R1 and R2 are similar or different and represent methyl or ethyl radical; X1 represents hydrogen atom; X2 represents hydrogen atom or hydroxyl, or X1 and X2, similar or different, represent (C1-C4)-(iso)alkyl radicals, or they form in common aromatic ring; n = 0 or 1; R3 represents radical chosen from one of the following groups: -C(CH3)2-CN, -CHCH3-Ph, or R3 is absent as unpaired electron occupies its place, and used in mixture with compounds (G) generating radicals chosen from peroxides, peracid esters, percarbonates, azobisdialkyldinitriles in the molar ratio (I)/(G) less 4 up to the conversion degree of monomer from 5 to 99.9%; (b) feeding a monomer representing a derivative of (meth)acrylic acid to polymerization mixture from step (a) after the necessary conversion degree in the amount providing the total mass of block-copolymer Mw is less 500000 Da, and this step is carried out at the same temperature and in the presence of the same initiating system; (c) isolation of synthesized block-copolymer after termination of the polymerization reaction. Also, invention describes a block-copolymer. Invention provides synthesis of block-copolymer comprising the decreased amount of homopolymer and statistic copolymer, elimination of the precipitation step and isolation of the first polymeric block.
EFFECT: improved method of synthesis.
11 cl, 11 ex
FIELD: polymer production.
SUBSTANCE: invention provides a method for preparing "living" vinyl polymer via "living" radical polymerization characterized by that vinyl monomer is polymerized using organotellurium compound depicted by formula (1) and azo-type polymerization initiator, where R1 represents C1-C8-alkyl, optionally substituted aryl, or aromatic heterocyclic group; each of R2 and R3 represents hydrogen atom or C1-C8-alkyl; and R4 optionally substituted aryl aryl, aromatic heterocyclic group, acyl, oxycarbonyl, or cyano; said organotellurium compound and said azo-type polymerization initiator being used at molar ratio 1:(0.1-100), respectively. "Living" vinyl polymer is also described as well as mixture of organotellurium compound depicted by formula (1) and azo-type polymerization initiator wherein the two components are present at weight ratio as above.
EFFECT: achieved preparation of "living" vinyl polymer with precisely controlled molecular mass and molecular mass distribution.
5 cl, 2 tbl, 32 ex
FIELD: organic chemistry, polymers, chemical technology.
SUBSTANCE: invention relates to a method for synthesis of polymers by method of "living" radical polymerization and to "living" polymers synthesized by this method. Invention describes a mixture of initiating agent of "living" radical polymerization represented by the formula (1): , and compound represented by the formula (2): (R1Te)2 used for polymerization of vinyl monomers taken in the ratio from 0.1 to 100 moles of compound of the formula (2) per one mole of initiating agent of the formula (1) wherein R1 means (C1-C8)-alkyl, aryl or aromatic heterocyclic group; each among R2 and R3 means hydrogen atom or (C1-C8)-alkyl group; R4 means aryl, substituted aryl, hydroxycarbonyl group or cyano-group wherein R has value given above. Also, invention describes a method for synthesis of "living" polymer by method of "living" radical polymerization wherein vinyl monomer is polymerized by using a mixture of initiating agent of "living" radical polymerization represented by the formula (1) and compound represented by the formula (2). Invention describes polymer synthesized by polymerization of vinyl monomer by using initiating agent mixture given above. Also, invention describes methods of synthesis of diblock-copolymer and triblock-copolymer and these diblock-copolymers and triblock-copolymers are described. Invention provides a method for synthesis of polymers comprising "living" chain allowing carrying out the precise control of molecular masses and molecular-mass pattern. Polymers synthesized by the proposed method allow easy conversion of their terminal groups to other functional groups useful for preparing macromonomers that can be used as places for pouring off and useful as agents providing compatibility and as materials for producing block-polymers.
EFFECT: improved method of synthesis, valuable properties of polymers.
15 cl, 3 tbl, 42 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to pharmaceutics, namely to a pharmaceutical composition (a solid oral dosage form (a tablet or a capsule)) of tyrosine kinase Bcr-Abl inhibitor - imatinib(4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylamino)phenyl]benzamide). The pharmaceutical composition contains 25-45 wt % of imatinib, preferentially imatinib mesylate, more preferentially an α-crystalline form of imatinib mesylate, a binding agent representing povidone, and at least two desintegrant representing low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.
EFFECT: invention provides the min 80% imatinib release from the tablet for 15 minutes after oral administration and enables extending the range of drugs used for leukaemia.
14 cl, 4 dwg, 3 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to microcapsulation of cephalosporins related to β-lactam antibiotics. A method for preparing cephalosporin microcapsules is implemented by physicochemical non-solvent addition. That involves using two non-solvents that are carbinol and isopropyl alcohol taken in ratio 1:4. The microcapsule yield makes more than 90%.
EFFECT: method for cephalosporin microcapsules provides accelerating the process for preparing and simplifying the method.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to microcapsulation of drug preparations, vitamins, herbicides, flavouring agents and polysaccharides. The microcapsules are prepared by physical-chemical nonsolvent addition with using benzol as a precipitator.
EFFECT: invention provides simplifying and accelerating the process of preparing the microcapsules, reducing losses in preparing the microcapsules (higher weight yield).
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to microcapsulation of drug preparations of cephalosporins referred to β-lactam antibiotics in konjac gum by physical-chemical precipitation in a non-solvent. Konjac gum is used as a microcapsule membrane. The microcapsules are prepared by physical-chemical precipitation in the non-solvent with using two precipitation agents - carbinol and chloroform. The process of microcapsules is carried out at 25°C with no special equipment required.
EFFECT: method according to the invention provides simplifying and accelerating the process of microcapsules of drug preparations of cephalosporins, and reducing losses (higher weight yield).
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to microencapsulation of drugs through the example of rivanol which can be used as an antimicrobial, antifungal topical preparation. A method for preparing microcaplues of rivanol in a water-soluble polymer representing polyvinyl alcohol or polyvinyl pyrrolidone is implemented by physical-chemical precipitation with a solvent wherein a precipitant is acetone. The process is carried out at 25°C with no special equipment required.
EFFECT: method for preparing the microcapsules of rivanol provides simplifying the process of microencapsulation.
13 dwg, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical microcapsulation of cephalosporins related to β-lactam antibiotics. As a microcapsule shell, the method of pharmaceutical microcapsulation of cephalosporins uses konjac gum; the microcapsules are prepared by physical-chemical technology implying the precipitation in a non-solvent using two precipitants - carbinol and diethyl ester in ratio 1:3; the method is conducted at 25°C with no special equipment.
EFFECT: invention provides simplified and accelerated preparation of the water-soluble pharmaceutical microcapsules of cephalosporins in konjac gum, loss reduction in preparing the microcapsules (higher yield-mass).
FIELD: medicine, pharmaceutics.
SUBSTANCE: declared group of inventions refers to a pharmacological composition for intranasal introduction for cerebral delivery, and a method for preparing said composition. The declared composition comprises a container base formed by porous particles of calcium carbonate and titanium dioxide of particle size 100-5000 nm and a pharmacologically active component - loperamide. The container surface is modified by surfactants specified in polysorbates, or by polymers specified in a group containing glycosaminoglycanes and polypeptides, or their combination. A method for preparing the pharmacological composition consists in preparing the container base by porous particle synthesis, sorption of loperamide in its pore spaces and modification of the container surface by polymers and surfactants by container incubation in their solutions.
EFFECT: invention provides preparing the pharmacological composition which is applicable for cerebral loperamide delivery after the intranasal introduction.
5 cl, 5 dwg, 1 ex
SUBSTANCE: invention relates to composition for peroral introduction, which possesses properties of modified release. According to invention composition includes pharmaceutically acceptable excipients and complex medication-ion-exchanging resin with coating with modified release, which contains pharmaceutically active medication, combined with pharmaceutically acceptable ion-exchanging resin. Complex has solidified barrier coating with high rupture strength, water-permeable, water-insoluble, which contains polyvinyl acetate polymer, stabiliser and efficient amount of plastifier. Said coating is in fact non-sticky, when applied onto complex in absence of anti-adhesive preparation, if composition presents tablet, complex medication-ion-exchanging resin with coating additionally contains release-retarding substance in matrix together with complex medication-ion-exchanging resin. Invention also relates to product with modified release, including package which contains composition described above.
EFFECT: invention ensures regulated prolonged active agent release without breaking coating integrity, without application of water-soluble impregnating substances and without agglomeration of complex particles during application of coating.
27 cl, 22 ex
SUBSTANCE: there are described oral dosage forms of risedronate containing safe and effective amount of a pharmaceutical composition containing risedronate, a chelating agent and an agent for effective delayed release of risedronate and the chelating agent in small intestine. The pharmaceutical composition is directly released in a small intestine of a mammal with ensuring pharmaceutically effective absorption of bisphosphonate together with or without food or drinks. Present invention essentially reduces interaction between risedronate and food or drinks which leads to that the active component of bisphosphonate becomes inaccessible to absorption. Thus, the final oral dosage form can be taken with and without food. Further, present invention covers delivery of risedronate and the chelating agent in a small intestine, essentially reducing irritation of upper gastrointestinal tract associated with bisphosphonate therapy. These advantages simplify previous, complicated regimens and can lead to more complete observance of the bisphosphonate therapy regimen.
EFFECT: present invention essentially reduces interaction between risedronate and food or drinks which leads to that the active component of bisphosphonate becomes inaccessible to absorption.
23 cl, 12 ex
SUBSTANCE: invention refers to a carrier for drugs, biologically active substances, biological objects used in medicine for diagnostics and treatment in pharmaceutical industry. The carrier represents a material sensitive to external magnetic or electric fields and consisting of magnetic or ferroelectric material filmed with biocompatible thermosensitive, biodegradable polymer and/or dispersed in thermosensitive medium properties of which change with varying temperature relative to that of human body within 15.9 to 42°C. The magnetic or ferroelectric materials are made of substance with great magnetocaloric or electrocaloric component effect 1 to 13 K, have temperature of magnetic or ferroelectric phase transition within temperature range 33 to 37°C, and are chosen from the group including rare-earth, transition and precious metals, their alloys and compounds.
EFFECT: invention also concerns methods of controlled drug delivery by means of such carrier with enabling release thereof (regulated desorption) in the preset point.
32 cl, 9 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a contrast agent in the form of an aqueous solution for magnetic resonant tumour diagnosis. The agent represents sulpho-substituted phthalocyanine metal complex sodium salt in the form of a mixture of manganese and gadolinium complex sulpho-acids of different degrees of sulphatation (di, tri and tetra) and average substitution n=2.5-3, containing sulphogroups both in position 3, and in position 4 of a phthalocyanine ring and described by the following formula: . In the specified formula, R=H or SO3Na, M=Mn or Gd, X=CH3COO.
EFFECT: invention provides a higher contrast of magnetic resonant diagnostic tumour images.
2 cl, 2 dwg, 4 ex