Magnetic converters review

FIELD: chemistry.

SUBSTANCE: invention relates to obtaining biocompatible magnetic nano-particles and can be applied for therapeutic purposes, in particular, for fighting cancer. Method of obtaining nano-particles, including iron oxide and silicon-containing casing and having value of specific absorption rate (SAR) 10-40 W per g of Fe with field strength 4 kA/m and frequency of alternating magnetic field 100 kHz, contains the following stages: A1) preparation of composition of at least one iron-containing compound in at least one organic solvent; B1) heating of composition to temperature in range from 50°C to temperature 50°C lower than temperature of reaction of iron-containing compound according to stage C1 for minimal period 10 minutes; C1) heating composition to temperature between 200°C and 400°C; D1) purification of obtained particles; E1) suspending purified nano-particles in water or water acid solution; F1) addition of surface-active compound to water solution, obtained according to stage E1); G1) processing of water solution according to stage F1) by ultrasound; H1) purification of water dispersion of particles, obtained according to stage G1); I1) obtaining dispersion of particles according to stage H1) in mixture of solvent from water and water-mixable solvent; J1) addition of alkoxysilane into dispersion of particles in mixture of solvent according to stage I1); and K1) purification of particles.

EFFECT: invention makes it possible to obtain biocompatible magnetic particles with high value of specific absorption rate (SAR).

42 cl, 3 dwg, 9 ex

 

MAGNETIC TRANSDUCERS

The present invention relates to the production of biocompatible magnetic nanoparticles that generate a lot of heat when exposed to an alternating magnetic field. The generated heat can be used, among other things, for therapeutic purposes, in particular for the fight against cancer.

Magnetic nanoparticles can convert the energy of the magnetic field into heat in different ways. In addition to heating by the so-called hysteresis loss, the nanoparticles can generate heat through relaxation (relaxation method Neel and according to the method of brown, respectively). The number of generated thermal energy depends on the magnetic field strength (amplitude) and frequency of the AC field. The efficiency of heat generation can, at certain intensity and frequency of the magnetic field, to be assessed by the values of the so-called SAR (specific absorption rate) or SLP (low power loss). SAR values matter to normalize the mass (in grams)used to measure, and expressed in units of [W/g]. However, the SAR of the magnetic material depends on other factors such as particle size and shape of the particles, the anisotropy of the substance and the content of the metal. SAR preferably determined according to the method developed by Jordan et al. [International Journal of Hperthermia, 1993, Vol. 9, N1, 51-68], at a frequency of 100 kHz and a field strength of up to 18 kA/m Here, the SAR show normalization of the iron content in the substance in mW/mg Fe.

The level of technology

Biocompatible magnetic nanoparticles often get so-called deposition method. He describes many examples in the literature [for example, DE 196 14 136 A1]. Since these particles get in aqueous solution, they can easily functionalitywith, and they usually have good biocompatibility. However, the thus obtained particles show a relatively low SAR value and, therefore, cannot answer inventive with the requirements of this patent.

Magnetic nanoparticles can also get the so-called magnitostaticheskie bacteria WO 98/40049]. The nanoparticles obtained in this way have a higher SAR. However, the method of obtaining is very difficult and expensive. In addition, particles are deposited relatively quickly, thereby severely limiting the possible applications.

It has long been known that thermal decomposition of metal complexes in organic solvents leads to the formation of colloids or nanoparticles [e.g., Smith et al., J. Phys. Chem. 1980, 84, 1621-1629]. Monodisperse particles of different sizes can be obtained by the method published by Peng et al. [US 2006/0211152 A1] and Hyeon et al. [WO 2006/057533 A1]. However, particles polucen the e by this method, dispersed only in organic solvents and, therefore, are not biocompatible. Moreover, the SAR values of the particles obtained by this method are low. Dispersions of such (hydrophobic) particles in water can principally be achieved by modifying the shell [e.g., Wang et al., Nano Lett., 2003, 3(11), 1555-1559 or De Palma et al., Chem. Mater., 2007, 19, 1821-1831]. These methods are based on direct exchange of hydrophobic ligands on hydrophilic ligands. These methods cover provide only a thin (monocline) coating that does not meet the requirement of a stable biocompatible coating according to the invention. In addition, the colloidal stability of the particles is limited, so the particles according to the invention cannot be covered by this method. Moreover, it is possible to cover only very dilute dispersion of particles. Thus, on an industrial scale does not exist a satisfactory technical solution to a dispersion of particles according to the invention. Further, substances or solvents used for dispersion tend to have high toxicity, thereby limiting biocompatibility.

Biocompatible nanoparticles of iron oxide can also be obtained by coating with silanes according to DE 196 14 136 A1, however, this method is applicable only when the particles are already dispersed in water, whereas the hydrophobic particles may not b the be easily coated with silanes or kremnezemom.

Therefore, the purpose of the present invention is to offer a biocompatible magnetic particles with a high SAR value in a variable magnetic field, where the coating of the particles consists of stable silicon membrane with a thickness in the range from 0.5 to 10 nm, preferably, from 1 nm to 6 nm and, more preferably, 3 nm. The intensity of the alternating magnetic field used to determine SAR, is in the range of, preferably, between 3 and 18 kA/m and the frequency is in the range between 1 kHz and 100 MHz and, preferably, between 10 and 1000 kHz.

The described problem is solved by a method of obtaining under paragraph 1, the nanoparticles according to paragraph 26, the pharmaceutical composition according to item 28 and the use of nanoparticles in paragraph 31.

Further preferential options for implementation are derived from the dependent claims, examples, figures and descriptions.

The present invention relates to biocompatible nanoparticles with stable silicone shell, which has a preferred thickness in the range from 0.5 to 10 nm, more preferably from 1 nm to 6 nm, more preferably from 2 nm to 4 nm and, most preferably, 3 nm, and which has a high SAR value in a variable magnetic field, where the intensity alternating magnetic field, preferably, is between 3 and 18 kA/m, and where astate, preferably, is between 10 and 1000 kHz.

According to the present invention, the particles with a high SAR value can be obtained by a process comprising the following stages:

A1) preparation of the composition, of at least one iron-containing compound A in at least one organic solvent LM1,

B1) heating the composition at a temperature in the range from 50°C to 50°C below the actual reaction temperature iron-containing compound A according to stage C1 for at least 10 minutes

C1) heating the composition to a temperature between 200°C and 400°C,

D1) purification of the obtained particles,

E1) the suspension of purified nanoparticles in water or an aqueous acid solution,

F1) the addition of surfactants in aqueous solution, obtained according to stage E1),

G1) treatment aqueous solution according to stage F1) ultrasound,

H1) clean water dispersion of the particles obtained according to stage G1),

I1) obtaining a dispersion of particles according to the stage H1) in a mixture solvent containing water and a solvent miscible with water,

J1) adding alkoxysilane to the dispersion of the particles in the solvent mixture according to stage I1),

K1) cleaning particles.

Stage A1 to K1 usually follow one after the other, where an additional step A2 may take place after stage A1 and to the point B1, and/or additional the stage B2 can take place after stage B1 and to the point C1. Similarly, after the stages C1, D1, E1, F1, G1, H1, I1, J1 or K1 may not necessarily follow oxidation step C2, D2, E2, F2, G2, H2, I2, J2 or K2. Here, stage C2, D2, E2, F2, G2, H2, I2, J2 or K2, also referred to as stage X2. Additional stages A2, B2 and/or X2 are optional and not essential to the execution of the invention.

Further, the person skilled in the art is able to adapt and optimize the reaction parameters depending on the selected reaction temperature or selected from iron-containing compound A or from other selected components. For example, the person skilled in the art can optimize the duration of the heating period B1 corresponding reaction so that the formed particles with a maximum SAR. The minimum duration of the heating time is 10 minutes; to a person skilled in the art it is obvious that the heating time becomes shorter with increasing temperature. Similarly, the specialist in the art can adapt the heating rate, final temperature, and aging time of the end temperature in stage C1 so that the formed particles with a maximum SAR.

The particles preferably are nanoparticles having a mean particle diameter in the nanometer range, where the microparticles can also be obtained according to the method of the of the invention.

Used iron-containing compound or A used iron containing compound a is preferably selected from the group comprising or consisting of compounds of iron complexes, compounds CARBONYLS of iron, iron salts, especially salts of iron with saturated or unsaturated fatty acids, organic compounds of iron and sandwich complexes of iron.

As compounds of iron CARBONYLS can be called dicarbonyl iron (Fe(CO)2), tetracarbonyl iron (Fe(CO)4or PENTACARBONYL iron (Fe(CO)5), and examples of the salts of iron are iron dichloride, dibromide iron, differed iron, diode iron, trichloride iron, tribromide iron, iron TRIFLUORIDE, triode iron sulfate, iron (II)sulfate iron (III), iron acetate, iron oxalate, nitrate iron (II)nitrate iron (III), iron carbonate, hydroxide iron (II)hydroxide iron (III), iron phosphate, tregulatory diphosphate. Ferrocene is an example of an iron complex "sandwich", and iron acetylacetonate is an example of the connection of the iron complex. As the ORGANOMETALLIC iron compounds are discussed, for example, acetate, iron (II), acrylate iron (III)oleate iron (III), iron alkoxides, such as ethoxide (ethylate) iron (III), or compounds of iron CARBONYLS, such as ACE enciclopedie(tricarbonyl)iron, butadiene(tricarbonyl)iron and olefin(tetracarbonyl)iron.

As the organic solvent LM1, you can use all the high-boiling solvents. Preferred are solvents from the group comprising or consisting of high-boiling amines, alkanes, olefins, alcohols or ethers. Moreover, you can use monetary and diesters of diols (landiolol)and monetary, diesters, truefire of trolov (Alcantara), monetary of alkalophilus, diesters alkalophilus, monoether of ethylene glycol, diesters of ethylene glycol, monetary propylene glycol, diesters of propylene glycol, monetary glycerol diesters of glycerol, truefire glycerol and glycol diesters (glime). The solvent L2 can also be selected from the group specified above.

Especially preferred solvents LM1 and LM2 are the diesters of glycol (also called "gimmi with a minimum boiling point of 200°C. To obtain nanoparticles of iron salts (e.g. chlorides) are also suitable glycol. In principle, the boiling point of the solvent should be above 150°C, more preferably higher than 175°C, particularly preferably higher than 200°C.

At least one iron containing compound a is dispersed, dissolved or suspended in a solvent LM1 and then the resulting composition is heated to a temperature in the range of the region from 50°C to 50°C below the actual reaction temperature iron-containing compound A according to stage C1 during a minimum period of 10 minutes. Under the actual reaction temperature see temperature of formation of particles, which is in the range between 200°C and 400°C. Thus, the temperature of nucleation according to stage B1 is in the range between 50°C and a maximum of 350°C, however, always at least 50°C below the temperature according to stage C1. Thus, the heating of one or more iron compounds in A organic solvent LM1 or mixture of organic solvents LM1, preferably, carried out at a temperature of about 50°C lower than the actual temperature of formation of particles of A connection according to stage C1.

This heating phase before the formation of particles according to stage B1 is used for forming the so-called seed crystals, which give the possibility of formation of the given particle. The period of time during the heating phase has a significant influence on the SAR of the resulting particles, preferably nanoparticles, generated at stage C1. To obtain particles or nanoparticles with a high SAR value achieved temperature is maintained for a minimum period of 10 minutes, preferably for a minimum period of 30 minutes and particularly preferably within a minimum period of about 40 minutes. Thus, the composition of at least one SalesOrderHeader A and, at least one solvent LM1 should be heated to the above temperature for preferably 30-50 minutes.

Depending on the iron-containing compound A, preferably, to achieve a temperature of about 100°C to 300°C, preferably about 130°C-270°C, more preferably, about 150°C to 250°C, even more preferably about 170°C to 230°C, even more preferably by about 180°C-220°C, more preferably about 190°C-210°C and, particularly preferably, about 200°C below the actual reaction temperature for the formation of particles according to stage C1, where the intended temperature is not lower than 70°C, preferably not lower than 90°C and particularly preferably not lower than 100°C. Preferably, the temperature during the first heating phase will be maintained at 100°C-150°C, according to the stage B1.

In order to influence the formation of seed crystals, or to contribute, you can add additives or surface-active compounds according to the stage A2). Used herein, the terms "additive" or "surface-active compound" are put in the context that most supplements is also a surface-active compounds which, however, is not necessary the case for all additives. Therefore, each surfactant is Obedinenie can be called additive, where, however, not every Supplement can be called surface-active compound. These include surfactants, silane, Si - or Al-containing organic compounds, phosphines, saturated or unsaturated fatty acids, amines, diamines, carboxylic acids and their salts, saturated or unsaturated fatty acids, and polymers. Examples of polymers are polyvinyl alcohol, polyethylene glycol, polyacrylic acid, dextran, PLGA (copolymer of lactic and glycolic acids), chitin, fibrin, heparin, chitosan and polyethylenimine.

After the heating phase according to the stage B1) forming a true particles spend in stage C1). The seed crystals are formed at the stage B1), heated up to 500°C, but preferably to a temperature in the range from 200°C to 400°C.

Through this from the seed crystals and excess iron compound A form of iron-containing particles, preferably iron-containing nanoparticles.

It was shown that it is advantageous to initiate and implement a heating phase according to B1) than the full amount of iron-containing compounds A and add more iron containing compound B in an organic solvent L2 at stage B2) after the stage of forming the seed crystals according to B1).

At least one iron containing compound B monoses to choose from the above group of iron-containing compounds, and it may be identical to at least one iron-containing compound A, or be separate from it.

The same refers to an organic solvent L2, which can be selected from the above group of solvents LM1, and it is identical to or different from the solvent LM1, where it is preferable if the solvent LM1 and LM2 are identical.

Thus, preferably, if after the stage of formation of seed crystals B1) add a new iron containing compound B, preferably in the same solvent (LM1=LM2) and the composition obtained by this means, according to C1) is heated to a temperature up to 500°C, preferably in the range from 200°C to 400°C. LM1 and LM2, preferably have a minimum boiling point of 200°C.

Thus, the true particles obtained after adding at least one iron-containing compound B in solvent L2. Together with the iron-containing compound B to the composition obtained after stage B1, you can also add additional additives. Any of these additives must be selected from the same additives that are already present in the solution, but it is preferred.

Here, also, the number of added iron-containing compounds B, of the additives, and the type and amount of solvent L2 can be the ü newly adapted by the person skilled in the art thus, so formed particles with a maximum SAR.

As already articulated, the total number of required iron-containing compounds can, however, add on A stage, that stage B2) is preferred, but not mandatory. Even if no additional iron containing compound B is no longer added after the first heating phase according to the stage B1), as a stage B2) you can add additional additive, which should be the same as the additive, already present in the composition. Thus, as a stage B2) you can only add an additive or only iron containing compound B, or both simultaneously or sequentially.

The duration of the second phase of heating according to stage C1) is at least 30 minutes, preferably 1-30 hours, preferably 10-20 hours and particularly preferably 15 hours.

Suddenly it became clear that SAR can be improved by lengthening the heating phase or simply a longer heating phase, so long the heating phase and especially the additional phase heat treatment (tempering) are preferred. In particular, in stage C1) is preferable for the heat-up phase, which is more than 10 hours and, more preferably more than 14 hours.

Phase heat treatment, not necessarily following the donkey stage D1 as D1* and/or D2*, can also increase the SAR, and therefore, also, preferably more than 10 hours, more preferably more than 14 hours, and especially preferably more than 18 hours. Thus, the phase of the heat treatment can take 1-30 hours, preferably 10 to 25 hours, more preferably 13-22 and particularly preferably 15-20 hours.

SAR the resulting particles can be adjusted, by varying the duration of the heating phase B1), the final temperature and the duration of keeping the final temperature at the stage C1), and the amount of added iron compounds or additives on stage C1) so that the formed particles with a maximum SAR. These parameters depend on the type of iron compounds and the type of solvent and additives. Therefore, the heating phase must be adapted to each system that can be easily carried out by a person skilled in the art, based on his special knowledge.

SAR obtained particles according to the invention is between 10-40 W in g Fe in the magnetic field of 4 kA/m, preferably 20-40 watts per g Fe in the magnetic field of 4 kA/m, more preferably 25-40 W in g Fe in the magnetic field of 4 kA/m and particularly preferably 30-40 watts per g Fe in the magnetic field of 4 kA/m and frequency of the alternating magnetic field of 100 kHz.

0, Fe+2, Fe+3.

td align="justify"> Trioctylamine (365°C)
Table 1
Examples of suitable components for receiving particles according to the invention
Iron containing compound aThe solvent LM1
(Boiling point)
Examples of additivesSAR
[W/g Fe]
PENTACARBONYL ironDiethylene glycol-disutility ether (256°C)Fatty acids, surfactants10-30
PENTACARBONYL ironDioctyloxy ether (287°C)Fatty acids, surfactants10-30
FerroceneDiethylene glycol-disutility ether (256°C)Fatty acids, surfactants, amines10-30
Acetylacetonate ironFatty acids, surfactants, amines15-30
Acetylacetonate ironEthylene glycol (197°C)The diamines, carboxylic acids, polymers
without additives
15-30
Acetylacetonate ironTriethylene glycol (291°C)The diamines, carboxylic acids, polymers
without additives
15-30
The oleate of iron (III)Polyglycol DME 500 (>250°C)Fatty acids, surfactants
without additives
15-35
The oleate of iron (III)Trioctylamine (365°C)Fatty acids, surfactants15-35
The iron oleate (II)Polyglycol DME 500 (>250°C)Fatty acids, surfactants
without additives
15-30
The iron oleate (II)Trioctylamine (365°C)Fatty acids, surfactants15-35
Chloride iron (III)Ethylene glycol (197°C)The diamines, carboxylic acids, polymers
without additives
20-40
Chloride iron (III)Triethylene glycol (291°C)The diamines, carboxylic acids, polymers20-35
Atoxic iron (III)Polyglycol DME 500 (>250°C)The diamines, carboxylic acids, polymers
without additives
10-25

In the above table 1, "no additive" means that the synthesis of this invention implemented with components named in the appropriate column, but without the addition of additives. The components listed in table 1, was used according to example 1 or 2 and 3A and 3A (stage A1-C2), and then all systems are then used according to examples 4-6, and 4-7. It was shown that application of additional phase heat treatment (example 7, step D1* or D2*) SAR can be increased by 5 W/g Fe at about 5 kA/m SAR Values are shown in table 1, relate to the magnetic field of 4 kA/m and frequency of the alternating magnetic field of 100 kHz.

The table is 2
Examples of systems according to the invention
StageExample (I)Example (II)Example (III)Example (IV)
A1Chloride iron (III) + ethylene glycolChloride iron (III) + ethylene glycolChloride iron (III) + ethylene glycolChloride iron (III) + ethylene glycol
E1Chlorostoma-burly acidNitric acidChlorostoma-burly acidChloritoid-native acid
F1The sodium oleateCIS-11-Aksenova acid
(Na-salt)
The sodium oleateThe sodium oleate
I1Ethanol/waterEthanol/waterIsopropanol/waterIsopropanol/
water
J1Tetraethoxy-silaneTetraethoxy-silane Tetraethoxy-silaneBis(triethoxysilyl)ethane
StageExample (V)Example (VI)Example (VII)Example (VIII)
A1Chloride iron (III) + ethylene glycolThe oleate of iron (III) + trioctylamineThe oleate of iron (III) + dietilen-glycol disutility etherAcetylaceton-NAT Fe (III) + triethylene-glycol
E1Chlorostoma-burly acidChlorostoma-burly acidNitric acidChlorostoma-burly acid
F1The sodium oleateCIS-11 - octadecene-Wai acid
(Na-salt)
The sodium oleateThe sodium oleate
I1Isopropanol/waterEthanol/waterEthanol/waterIsopropanol/
water
J1Those whom ruatoki-silane Tetraethoxy-silaneTetraethoxy-silaneBis(triethoxysilyl)octane

Phase (A) and (C) can be done not necessary under normal pressure in air or under a protective gas atmosphere (argon, nitrogen) or in the reaction autoclave under pressure up to 400 bar.

After this second heating phase according to stage C1) may be followed by phase oxidation X2). The phase oxidation X2) is optional and does not have to follow immediately after the stage C1, and can also occur after one of the steps C1)-K1). The particles here are oxidized, preferably, a supply of atmospheric oxygen. Supply of atmospheric oxygen is carried out for 4-24 hours, preferably 8-16 hours, and more preferably at 20°C-50°C. However, it is also possible to use other volatile oxidants or oxidizers removed by distillation, such as oxygen (pure), hydrogen peroxide, or other organic oxidants such as aminoxide. Thus, preferably, if after one of the steps C1)-K1) should stage oxidation X2), where X represents a variable for the letters C-K in the matter, after which stage is oxidation. If the optional oxidation should be carried out after stage E1), called oxidation stage E2), and if it is of eBet carried out after K1, stage oxidation will call K2). Next, the phase oxidation can be repeated many times, or additional oxidation step X2' can be followed by additional treatment stage, which is possible, but not preferred. Therefore, the method according to the invention could include the first stage of oxidation X2 (for example, F2) and the second stage oxidation X2' (for example, H2'). For particles that are already partially or fully oxidized state, the further oxidation, of course, is not necessary. Typically, the oxidation under the action of atmospheric air is auto, so the extra stage, i.e. the stage of oxidation X2, additional to auto-oxidation, is not necessary. Stage oxidation X2 can be carried out even if it is not absolutely necessary, since it has been shown that it also will not harm.

Particles, preferably nanoparticles formed according to stage C1, it is necessary to clean. This stage is essential and important for the invention. The use of untreated particles will not give particles according to the invention, with a good dispersibility in water and, ultimately, with a high SAR. The cleaning implement according to stage D1), preferably by extraction in to conventional Soxhlet extractions up until the dispersibility of the particles in nonpolar is rastvoritelyakh will no longer be given. As it has been unexpectedly discovered, for subsequent dispersion in water [stage F1)] it is important that the additive and especially surface-active compound from stage A2) and/or B2) - to the extent possible - were completely washed away with particles, i.e. for the most part would be again removed. The terms "possible" and "mostly", respectively, see removing additives in the range of 70-100%, preferably up to 90%. Thus, the additive will be removed from the particles by more than 70%, preferably more than 80%, more preferably more than 90% and particularly preferably more than 95%. The above percentages refer to the additive adhering to the particles. Free additive, i.e. additive, freely floating in the solution, or adsorbed to particles, can largely be removed by centrifugation, i.e. with >95%, preferably >98%. The number of remaining additive adhering to the particles, it is possible to determine, for example, elemental analysis and IR spectroscopy. In the present description the percentage refers to the mass (mass%). Supplement, not adhering to the particles removed by centrifugation, and removal of the additive adhering to the particles, it is possible, it is preferable to carry out the extraction of the formed particles to conventional Soxhlet extractions, where you can also use the extraction, podderzhivaemoe the ultrasound. For the use of nanoparticles will first be separated by centrifugation before the next stage of treatment.

The solvent used for extraction in to conventional Soxhlet extractions, can be a widespread a polar organic solvent, such as alcohols, ketones, (simple) ethers or esters. Preferred are acetone, ethyl acetate or ethanol.

The duration of extraction is between 1 and 8 hours, preferably between 2 and 6 hours and particularly preferably about 4 hours. The important point is that the iron-containing particles, preferably nanoparticles, no longer dispersible in non-polar solvents, such as toluene, xylene or hexane, after extraction. However, for this to have occurred, the extraction time should be regulated. Powder nanoparticles treated thus dried under vacuum.

Several "phases of heat treatment can be followed by stage D1 to increase the crystallinity of the particles. Data phase heat treatment can be performed in high-boiling solvents at temperatures up to 400°C for several hours. The solvents referred to as high-boiling, if they have a minimum boiling point of 200°C, preferably 300°C. the heat treatment Process may be here for months what about on the air or in a protective gas (for example, argon). At temperatures from about 200°C to 250°C the reaction is preferably carried out without a protective gas and at temperatures higher than about 200°C to 250°C the reaction is preferably carried out under protective gas. Alternatively, the nanoparticles can be thermally processed into powder form (without solvent) at temperatures up to 1000°C under protective gas. Preferred protective gases are argon or CO2/H2of the mixture. This, at least one stage of heat treatment should be in the form of stage D1* after stage D1 or in the form of stage D2* after stage oxidation D2.

The oxidation according to the stage of X2, where X=C or D or E or F or G or H or I or J or K, preferably, to carry out suspendirovanie particles in 0.5-2M HNO3preferably 1M HNO3by adding Fe(NO3)3and followed by boiling under reflux. The ratio of Fe(NO3)3to FeOxor, in General, the ratio of Fe(III) to FeOxpreferably is 1:2. This oxidation process has a beneficial effect on SAR particles and, hence, is preferred. It should be noted that this stage is not limited to Fe(NO3)3and that it is also possible to use other salts of Fe(III), such as FeCl3, FePO (4etc.

Next, carry out the dispersion of the treated particles of the sludge the nanoparticles in water, reversible floor surface-active compound according to the stages E1 and F1).

At this stage, the purified powder particles or nanoparticles suspended in water, where the hydrophilic layer attached so that it is easy to make subsequent removal of the layer. At the beginning of the solids content (iron oxide) for this coverage set preferably 2-20%, more preferably 3-12%, even more preferably 5%-8%, even more preferably 6%-7% and especially preferably approximately 6.5%. To achieve a finer dispersion of the particles before the addition of surface-active compounds can be added to the acid, preferably a mineral acid according to stage F1), such as hydrochloric acid or nitric acid to obtain a pH of 2-6, preferably 3-5, and especially preferably about 4.

Acid can preferably be selected from mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid, Hydrobromic acid, boric acid or nitric acid. But it is important that the use of acid, preferably a mineral acid which does not bind irreversibly to the surface of the particle. In experiments it was shown that the preferred are mineral acids, and amino acids, and carboxylic acids, SL is blowing to avoid. However, in the method according to the invention mainly use the following acids: sulfonic acid, nitric acid, perchloric acid, methanesulfonate acid, econsultancy acid, hydroxyethanesulfonic acid, ethylenesulphonic acid, p-toluensulfonate acid, naphtalenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid and camphorsulfonic acid.

If the pH of an aqueous solution install acid or mineral acid to carry out the addition of at least one surface-active compounds according to the stage F1). At least one surface-active compound, preferably selected from the group comprising or consisting of salts of saturated and especially unsaturated fatty acids. Moreover, it is possible to use surfactants or polymers, such as polyvinyl alcohol, polyethylene glycol, polyacrylic acid, dextran, PLGA (copolymer of lactic acid and glycolic acid), chitosan and polyethylenimine.

Examples of the saturated fatty acids are acetic acid, propionic acid, butyric acid, hexanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, arachnid acid, Bekenova acid and Ognianova acid.

As the use of the s preferred unsaturated fatty acids or their salts, you can specify any fatty acid, such as CIS-9-tetradecenoic acid (Mirandolina acid), CIS-9-hexadecanoate acid (palmitoleic acid), CIS-6-octadecenoate acid (Petroselinum acid), CIS-9-octadecenoate acid (oleic acid), CIS-11-octadecenoate acid (Aksenova acid), CIS-9-Aksenova acid (gadolinia acid), CIS-11-Aksenova acid (andonova acid), CIS-13-docosanoate acid (erucic acid), CIS-15-tetracosanoic acid (acetabula acid)t-9-octadecenoate acid (elaidic acid), t-11-octadecenoate acid (t-Aksenova acid), t-3-hexadecanone acid, 9,12-octadecadienoic acid (linolenic acid), 6,9,12-octadecatrienoic acid (γ-linolenic acid, 8,11,14-eicosatrienoic acid (di-Homo-γ-linolenic acid), 5,8,11,14-eicosatetraenoic acid (arachidonic acid), 7,10,13,16-docosatetraenoic acid, 4,7,10,13,16-docosapentaenoic acid, 9,12,15-octadecatrienoic acid (α-linolenic acid), 6,9,12,15-octadecatetraenoic acid (stereonova acid, 8,11,14,17-eicosatetraenoic acid, 5,8,11,14,17-eicosapentaenoic acid (EPA), 7,10,13,16,19-docosapentaenoic acid (DPA), 4,7,10,13,16,19-docosahexaenoic acid (DHA), 5,8,11-eicosatrienoic acid, Mead acid, 9c,11t,13t-aleocharinae acid, 8t,10t,12c-calendula acid, 9c,11t,13c-katalava acid, 4,7,9,11,13,16,19-dokozageksaenovoy Isleta (Stella heptane acid,), taxonomy acid, penaeidea acid, Sidorova acid, 6-octadecenoate acid (terinova acid), t11-octadecan-9-andnew acid (santalina or ximenia acid), 9-octadecenoate acid (caarolina acid), 6-octadecan-9-andnew acid (6,9-octadecadienoate acid), t10-heptadecan-8-andnew acid (prolinnova acid), 9-octadecene-12-andnew acid (grebenyova acid), t7,t11-octadecadiene-9-andnew acid (gastrinoma acid), t8,t10-octadecadiene-12-andnew acid, 5,8,11,14-eicosatetraenoic acid (ETYA) and t8,t10-octadecadiene-12-new acid. Salts of fatty acids, preferably, get with ions of alkali and alkaline earth metals.

The mass ratio of the nanoparticles to the surface-active compound, is preferably from 1:0.02 to 1:10, more preferably 1:0.1 to 1:2 and particularly preferably 1:0.5 in.

After adding surfactants, suspension according G1 phase), preferably, treated with ultrasound for a minimum period of 30 minutes.

Then the suspension is stirred for about 2 hours at a temperature preferably in the range from 30°C to 70°C, more preferably from 50°C to 60°C and particularly preferably at 40°C. followed by purification according to the stage I1). Redispersion particles will be separated, preferably, centrifuger the cation (1000 rpm./min.

The variance of the particles must be free from excess surfactant immediately after coating. This cleaning can be accomplished by dialysis or by extraction with diethyl ether. Alternatively, particles can be separated by centrifugation, using the ultracentrifuge, and washed with water and with a mixture of water and diethyl ether.

Then the coating on the basis of the fatty acid on the particles exchanged for silicon-containing biocompatible membrane in accordance stages I1 and J1).

To exchange membrane, the particles must be atomized in a mixture of water and at least one solvent, miscible with water, according to the stage I1). As solvents, miscible with water, you can specify alcohols, polyols, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide, dimethylsulfoxide (DMSO), acetone, acetic acid, formic acid, methyl ester of formic acid, ethyl ester of formic acid, methyl ester acetic acid, ethyl ester acetic acid, and others.

However, especially preferred are alcohols. Alcohol can preferably be selected from the group comprising or consisting of methanol, ethanol, propanol, isopropanol and ethylene glycol, where the ethanol is preferred.

The ratio of water and alcohol, and water and ethanol in the mixture, respectively, extending t is preferably 1:1 to 1:5 and particularly preferably 1:3, so remove membrane fatty acids and replacement by a silicon membrane can be carried out in parallel.

Further, preferably, if the mixture of alcohol and water contains 1-5% by weight, more preferably 1-3% by weight and particularly preferably 1.5% by weight of amine, preferably a primary amine, and particularly preferably ammonia.

Soon after adding the dispersion of the nanoparticles to a mixture of solvents, in particular, to a mixture of alcohol and water and, preferably, a mixture of water and ethanol, according to the stage I1), it is necessary to add a suitable alkoxysilane. Add alkoxysilane should occur under sonication. Suitable alkoxysilane are all tetraalkoxysilane, such as tetramethoxysilane and tertatolol, and tralkoxydim, dialkoxybenzene and monopolkommission, which preferably have a functional group associated Si-C bond, such as an amino group, Tolna group and/or epoxy group.

To exchange membrane proceeded smoothly, the molar ratio of iron and alkoxysilane should be 1:1 to 1:5 and preferably 1:3.

After adding reagents dispersion is treated with ultrasound for 1-8 hours, preferably for 3 to 5 hours, and particularly preferably within 4 hours, according to the stage of J1). Then spend cleaning particles, preferably by dialysis is Rotel water. Alternatively, purification can be performed by separating the particles by centrifugation at high value of g and sediment washing ultrapure water.

In addition, the present invention relates to particles, preferably nanoparticles, which can be obtained by the way described here.

Themselves of iron-containing particles according to the invention are ferromagnetic, ferrimagnetic or superparamagnetic particles. Such particles or nanoparticles can be heated by an alternating magnetic field. Possible heating of the tissue containing particles or nanoparticles, above 50°C, as particles or nanoparticles have high SAR values according to the invention.

Iron-containing particles made according to the invention have a minimum value of SAR 18, preferably 20 and particularly preferably 22 mW/mg Fe at field strength of 6 kA/m

The particles preferably have a diameter of less than 500 nm. The nanoparticles preferably have an average diameter of 20 nm or, preferably are in the size range 1-100 nm, and particularly preferably in the size range of 15-30 nm.

Stable silicon-containing shell nanoparticles has a thickness of between 0.5 and 10 nm, preferably 3 nm.

Silicon shell can be functionalitywith additional alkoxysilane to modify the properties of the particles. This, preferably,is tralkoxydim, functional group bonded Si-C bond. Examples are (3-acroloxidae)trimethoxysilane, triethoxysilane, 3-aminopropyltriethoxysilane and 3-isocyanatopropyltrimethoxysilane. Tralkoxydim may be attached to the Si-C bonds of the side chain of polyethylene glycol of different lengths. As an example of this is 2-[methoxy(polietilene)propyl]trimethoxysilane.

Iron-containing particles of this invention can be used in the field of medicine and, for example, to enter it in the form of an aqueous solution. Iron-containing particles of this invention can be used for the treatment and prevention of proliferative diseases, cancer, tumors, rheumatism, arthritis, arthrosis and bacterial infections.

Further, the present invention relates to pharmaceutical compositions containing nanoparticles according to this invention, as well as to the use of nanoparticles according to the invention for the preparation of such pharmaceutical compositions.

The data of the pharmaceutical composition, in particular, represent solutions for infusion or injection. Such solutions of the nanoparticles, for example, physiological saline solution, suitable for interstitial or intratumoral application. Moreover, intra-arterial or intravenous use system allows the option of tera is AI, affecting the whole body for heterogeneous and/or forming metastases tumor types.

Further preferred pharmaceutical compositions are powder, powder for inhalation and a lyophilisate containing iron particles according to the invention.

Nanoparticles and pharmaceutical compositions according to the invention are preferably used for the treatment and prevention of diseases that are characterized by degenerative types of cells or exogenous cells, and you can use the feature of nanoparticles to distinguish exogenous or degenerative cells from its own healthy cells. As degenerative cells, in particular, are treated cancer cells or cells with impaired razrostanie, as well as stenotic or destinationsa fabric. Examples of exogenous cells, in particular bacteria.

Therefore, the nanoparticles according to the invention and pharmaceutical compositions containing nanoparticles will be used for the prevention and treatment of tumors, carcinomas and cancers.

Examples of cancers and tumors, for which you can use nanoparticles according to the invention, are: adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, cancer of the anal canal, astrocytoma, basal-cleoc the traveler carcinoma, pancreatic cancer, a tumor of the connective tissue, bladder cancer, bronchial carcinoma, non-small cell bronchial carcinoma, breast cancer, Burkitt's lymphoma, a tumor of the corpus callosum, CUP-syndrome, colon cancer, cancer of the small intestine, the small intestine tumor, ovarian cancer, endometrial carcinoma, ependymal glioma, epithelial cancers, abnormal Ewing tumor, tumors of the gastrointestinal tract, gallbladder cancer, carcinoma of the gallbladder, uterine cancer, cervical cancer, glioblastomas, gynecologic tumors, tumors of the ear, nose and throat, swelling of the blood, leukemia hairy cells, urethral cancer, skin cancer, brain tumors (gliomas), brain metastases, cancer of the testis, pituitary tumor, carcinoid tumor, Kaposi's sarcoma, cancer of the larynx, germinoma, bone cancer, colorectal carcinoma, head and neck tumors (tumors located in the neck, nose and ear), colon cancer, craniopharyngioma, cancer in the mouth area and on the lip, liver cancer, liver metastases, leukemia, eyelid tumours, lung cancer, malignant lymphoma (Hodgkin's/non-Hodgkin's), lymphomas, cancer stomach, malignant melanoma, malignant neoplasms, malignoma gastrointestinal tract, carcinoma, breast cancer, colorectal cancer, medulloblastoma, melanoma, meningioma, Hodgkin's disease, mushroom mi the lake, cancer of the nose, neurinoma, neuroblastoma, kidney cancer, carcinoma of renal epithelial cells, lymphoma non-Hodgkin's lymphoma, oligodendroglioma, carcinoma of esophagus, osteolytic tumors and osteopaticheskii tumor, osteosarcoma, carcinoma of the ovary, carcinoma of the pancreas, cancer of the penis, plasmacytoma, squamous cell head and neck cancer, prostate cancer, throat cancer, colorectal cancer, retinoblastoma, cancer of the vagina, cancer of the thyroid gland, cancer of the lung Neiburga, esophageal cancer, spinoletta carcinoma, T-cell lymphoma (mushroom mycosis fungoides), thymoma, cancer of the fallopian tubes, eye tumors, cancer of the urethra, prostate tumor, urothelial carcinoma, carcinoma of the vagina, the appearance of warts, soft tissue tumors, soft tissue sarcoma, the tumor Wilms ' tumor, cervical carcinoma and tongue cancer.

Homogeneous tumors are particularly preferred. Further preferred are carcinoma of the prostate, brain tumors, sarcomas, cancer of the cervix, carcinoma of the ovary, carcinoma, breast cancer, bronchial carcinoma, melanoma, head and neck tumors, esophageal cancer, colorectal cancer, carcinoma of the pancreas, bladder and kidney cancer, and metastases in the liver, brain and lymph nodes.

Especially preferred is the use of nanoparticles according to the invention in combination with TPA the investment hyperthermia, radiation therapy and/or in combination with conventional chemotherapy.

Next, one would discover that the magnetic and, preferably, super-paramagnetic particles according to the invention increase the activity of anticancer agents and, in addition, reduce their side effects.

Thus, the particles obtained according to the invention will be used, preferably in combination with anticancer drugs, i.e. with cytotoxic and/or cytostatic compounds, i.e. chemical compounds with cytotoxic and/or cytostatic properties. Examples of anticancer drugs include, without limitation, alkylating agents, antibiotics with cytotoxic properties, antimetabolites, microtubular inhibitors and topoisomerase inhibitors, platinum compounds and other cytostatics, such as asparaginase, tretinoin, alkaloids, podophyllotoxins, taxanes and miltefosine®, hormones, immunomodulators, monoclonal antibodies, signal transductor (molecules for signal transduction), inhibitors of kinases and cytokines.

Examples of alkylating agents include, among other things, harachaman, cyclophosphamide, trofosfamide, ifosfamide, melphalan, chlorambucil, busulfan, thiotepa, carmustin, lomustin, dacarbazine, procarbazine, temozolomide, Tr is osullivan, estramustin, nimustine.

Examples of antibiotics that have cytotoxic properties are daunorubicin, and liposomal daunorubicin, doxorubicin (adriamycin), dactinomycin, mitomycin C, bleomycin, epirubicin (4-EPI-adriamycin), idarubitsin, dactinomycin, mitoxantrone, amsacrine and actinomycin D.

As examples of antimetabolites (antimetabolites drugs) you can specify methotrexate, 5-fluorouracil, 6-tioguanin, 6-mercaptopurine, fludarabine, cladribine, pentostatin, gemcitabine, cytarabine, azathioprine, raltitrexed, capecitabine, cytosine arabinoside, tioguanin and mercaptopurine.

To the class of alkaloids and podophyllotoxin belong, inter alia, vincristine, vinblastine, vindesine, etoposide, and teniposide. Moreover, according to the invention can be used platinum compounds. Cisplatin, carboplatin and oxaliplatin are examples of compounds containing platinum. Among the microtubular inhibitors take into account, for example, alkaloids, such as Vinca alkaloids (vincristine, vinblastine, vindesine, vinorelbine and paclitaxel (Taxol®)and derivatives of paclitaxel. Examples of topoisomerase inhibitors include etoposide, teniposide, camptothecin, topotecan and irinotecan.

Paclitaxel and docetaxel are examples of compounds Texan is, among other cytotoxic agents (other drugs) take into account, for example, hydroxycarbamide (hydroxyurea), imatinib, Miltefosine®, amsacrine, topotecan (an inhibitor of topoisomerase I), pentostatin, bexarotene, tretinoin and asparaginase. Representatives of the class of compounds, monoclonal antibodies include trastuzumab (also known as Herceptin®), alemtuzumab (also known as Mabcampath®) and rituximab (also known as MabThera®). Representatives of kinase inhibitors are sorafenib (Nexavar®) and sunitinib (Sutent®). Examples of hormones are glucocorticoids (prednisone), estrogens (fosfestrol, estramustin), LHRH (buserelin, goserelin, leuprorelin, triptorelin), flutamide, cyproterone acetate, tamoxifen, toremifene, aminoglutetimid, formestane, exemestane, letrozole, and anastrozole. Among the classes of immunomodulators, cytokines, antibodies and signal transduction take into account interleukin-2, interferon-α, erythropoietin, G-CSF, trastuzumab (Herceptin®), rituximab (MabThera®), gefitinib (Iressa®), ibritumomab (Zevalin®), levamisole, and retinoids.

Thus, the present invention also relates to combinations of particles obtained in accordance with the invention, at least one anticancer agent, such as actinomycin D, aminoglutaric the ID, amsacrine, anastrozole, purine antagonists and pyrimidine bases, anthracyclines, aromatase inhibitors, asparaginase, antiestrogens, bexarotene, bleomycin, buserelin, busulfan, derivatives camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, alkylating cytostatic agents, dacarbazine, dactinomycin, docetaxel, doxorubicin (adriamycin), doxorubicin lipo, epirubicin, estramustine, etoposide, exemestane, fludarabine, fluorouracil, folic acid antagonists, formestane, gemcitabine, glucocorticoids, gecelerin, hormones and hormone antagonists, histamine, hydroxyurea, idarubitsin, ifosfamide, imatinib, irinotecan, letrozole, leuprorelin, lomustin, melphalan, mercaptopurine, methotrexate, miltefosine, mitomycin, inhibitors of mitosis, mitoxantrone, nimustine, oxaliplatin, paclitaxel, pentostatin, procarbazine, tamoxifen, temozolomide, teniposide, testolactone, thiotepa, tioguanin, topoisomerase inhibitors, topotecan, treosulfan, tretinoin, triptorelin, trofosfamide, vinblastine, vincristine, vindesine, vinorelbine, cytostatic active antibiotics, and pharmaceutical compositions containing a combination of the above.

The above drugs can be used not only in combination with particles is about invention, but they can also covalently bind to particles, preferably nanoparticles, in order more effectively to import in cancer cells.

Thus, a further aspect of the present invention is aimed at particles obtained according to the method according to the invention, in which therapeutically active substance is covalently associated with the particle or nanoparticle. Therapeutically active substance can be selected from antiproliferative, antimigratory, antiangiogenic, anti-thrombotic, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic, anticoagulant, antibacterial, antiviral and/or antifungal drugs, where antiproliferative, antimigratory, antiangiogenic, cytostatic and/or cytotoxic drugs, as well as nucleic acids, amino acids, peptides, proteins, carbohydrates, lipids, glycoproteins, glikana or lipoproteins with antiproliferative, antimigratory, antiangiogenic, anti-thrombotic, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic, anticoagulant, antibacterial, antiviral and/or antifungal properties are preferred. Moreover, these compounds can also contain radio sensibilizators or sensitizers Il the amplifiers from other traditional cancer treatments, which also incorporate or include sensitizers.

Linking therapeutically active substances can be accomplished, for example, by hydroxyl groups, amino groups, carbonyl groups, tylnej groups or carboxyl groups, depending on what functional group is the appropriate drug. Hydroxyl group, preferably, are connected in the form of esters, acetals or ketals, tirinya group, preferably in the form of complex thioesters, thioacetals or tionately, amino group, preferably in the form of amides and partly also in the form of Eminov (Schiff bases), carboxyl groups, preferably in the form of esters or amides and carbonyl groups, preferably in the form of ketals. In addition, functionalization of the surface of the nanoparticles, so that, using known methods on the surface of nanoparticles can be obtained amino group, a hydroxy-group, carboxyl group or a carbonyl group.

Additional coverage activated conjugates of nanoparticles-drug (e.g., a polymer), as described in patent WO 98/58673, it is also possible and can be used to improve the biological properties of conjugates of nanoparticles-drug. You can also attach an additional molecule that provides the target issue for lighting the properties of the whole structure (for example, polyclonal antibodies, monoclonal antibodies, humanized antibodies, human antibodies, chimeric antibodies, recombinant antibodies, bespecifically antibodies, antibody fragments, aptamers, Fab fragments, Fc fragments, peptides, peptidomimetics, gaps, ribozymes, CpG oligomers, DNA-winter, RIBO-switches or lipids). It is essential that all further modification does not inhibit activated the release of therapeutically active substance to the target site.

Further preferably, therapeutically active substance would not directly associated with a nanoparticle, and immobilized using the linker-molecule. As the linker can serve a variety of molecules containing up to 50 carbon atoms, provided that the linker contains a group which can decompose thermally, photochemically or enzymatically, acid-unstable group or a group which can easily be split by other methods. Communication within the linker-molecule and/or the relationship of the linker with the medicinal product and/or link the linker to the surface of the nanoparticles should be split directly or indirectly by the action of an alternating magnetic field. Indirect gap is set if, for example, stimulates enzymes, such as peptidases, esterase or hydrolases, or if they increase their activity or Express the alternating magnetic field at the target site, for example, in a cell of a malignant tumor, and if these enzymes can then carry out the above-mentioned gap. Moreover, the indirect gap can also occur when using magnetic nanoparticles if they are heated by an alternating magnetic field, and thereby cleaved thermally unstable group. You can also increase the pH at the target site the influence of an alternating magnetic field in order to break the acid-unstable communication within the linker-molecules.

As enzymatic tsepliaeva groups within or linker-molecules must specify the amide group. The group split thermally or by acid include, for example, phosphate groups, thiophosphate groups, sulfate groups, phosphamide groups, urethane groups, or imine groups.

A linker is a molecule can be a molecule of nucleic acid, polypeptide, peptide-nucleic acid aptamers, DNA, RNA, lacinova clasp, oligonucleotide, Biotin, avidin, streptavidin, bridge the hapten-antibody or bridge Biotin-avidin.

The drug should not be covalently linked to a linker, and may also be associated ionic or hydrogen bonds, or interkorean, or insecure.

Various possibilities binding therapeutically active substances, such the AK antitumor drug, monoclonal antibody, aptamer, nucleic acid, amino acid, peptide, protein, carbohydrate, lipid, glycoprotein, glycan, lipoprotein, or antiproliferative, antimigratory, antiangiogenic, anti-thrombotic, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic, anticoagulant, antibacterial, antiviral or antifungal drug, microparticles and nanoparticles are described in detail in WO2006108405A.

Thus, the method according to the invention may include the additional step L1), which refers to the binding of the anticancer drug, a monoclonal antibody, aptamer, nucleic acid, amino acid, peptide, protein, carbohydrate, lipid, glycoprotein, picana, lipoprotein, or antiproliferative, antimigratory, antiangiogenic, anti-thrombotic, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic, anticoagulant, antibacterial, antiviral or antifungal drug from the particles according to the stage K1).

Moreover, it is also possible to associate drugs with the surface of the nanoparticles by adsorption and cover them with a barrier layer, which mainly prevents the release of drug up until the barrier layer is not mo is oficerowie or partially destroyed by the influence of an alternating magnetic field so that what can happen the release of the drug.

Description of the drawings

Figure 1 shows the grain size distribution (obtained by transmission electron microscopy) nanoparticles of iron oxide according to the invention.

Figure 2 shows the values of SAR nanoparticles of iron oxide according to the invention in water compared with the values of traditional SAR nanoparticles of iron oxide, manufactured by deposition according to the description of the patent DE19614136A1. SAR values relate to an alternating magnetic field with a frequency of 100 kHz.

Figure 3 shows a schematic diagram of iron-containing nanoparticles according to the invention with a core and shell.

General description of synthesis for the preparation of particles according to the invention

Stage A1)

To obtain the seed crystal particles in an organic solvent LM1 with a boiling point from about 200°C to about 400°C, in a glass flask add 0,02 mole of iron-containing compound A and 100 ml of solvent.

Stage A2)

Now you don't need to add one of the additives described in the present description, in the amount of from 0.008 to 0.05 mol.

Stage B1)

The solution is heated for a minimum period of 10 minutes and, preferably, within 1 hour to a temperature between 50°C and 350°C, which is approximately 50°C below the temperature of subsequent reactions.

Stage B2)

You can now optional on the removed additional additive, as well as additional iron containing compound B.

Stage C1)

The resulting mixture is heated in a three-neck flask with reflux condenser, flowing protective gas to the boiling point of the respective solvent LM1 or LM2, which must be at least 50°C higher than the temperature of the heating phase according to the stage B1), and maintained at this temperature for a minimum period of about 1 hour.

Stage C2)

You can now optionally oxidizing the obtained particles of iron oxide.

Stage D1)

Now clean the particles by centrifugation, washing and, preferably, the extraction in to conventional Soxhlet extractions.

Stage D1*)

Optional you can perform at least one phase of the heat treatment, the nanoparticles of iron oxide.

Stage D2)

If you haven't already done, nanoparticles of iron oxide can now be optional to oxidize.

Stage D2*)

Optional you can perform at least one phase of the heat treatment, the nanoparticles of iron oxide.

Stage E1)

For dispersion or suspension of purified particles, they will be re-suspended in water with a neutral pH or acidic aqueous solution, preferably containing a mineral acid. The concentration of the acid is from 0.002 to 0,1M. To maintain the dispersion or suspension can be done at travelway processing.

Stage E2)

If you haven't already done, nanoparticles of iron oxide can now be optional to oxidize.

Stage F1)

Now have the addition of surface-active compounds in an amount of from 3 to 8 mmol.

Stage F2)

If you haven't already done, nanoparticles of iron oxide can now be optional to oxidize.

Stage G1)

This need not necessarily be mixed, preferably within 1 to 2 hours at a temperature of from 50°C to 90°C. With stirring, followed by sonication for 1-3 hours.

Stage G2)

If you haven't already done, nanoparticles of iron oxide can now be optional to oxidize.

Stage H1)

Now carry out the purification of the obtained particles by centrifugation, washing, extraction and/or dialysis, depending on which method or combination of methods is better.

Stage H2)

If you haven't already done, nanoparticles of iron oxide can now be optional to oxidize.

Stage I1)

The obtained particles are re-suspended in a mixture of water and alcohol (1:1 to 5:1), which does not necessarily contain amine and preferably ammonia at low concentrations.

Stage I2)

If you haven't already done, nanoparticles of iron oxide can now be optional to oxidize.

Stage J1)

Now perform the add alkoxysilane in the number is the firmness of from 0.04 to 0.08 mol.

Stage J2)

If you haven't already done, nanoparticles of iron oxide can now be optional to oxidize.

Stage K1)

Now carry out the purification of the obtained particles by centrifugation, dialysis, washing, extraction and/or re-dispersion depending on which method or combination of methods is better.

Stage K2)

If you haven't already done, nanoparticles of iron oxide can now be optional to oxidize.

Stage L1)

Now optional, you can bind drugs with nanoparticles of iron oxide.

Examples

Example 1

To obtain the seed crystal particles in debutalbum ether of diethylene glycol in a glass flask 0.3 g PENTACARBONYL iron was dissolved in 50 ml dibutylamino ether of diethylene glycol. To the solution was added 1.7 g of oleic acid. The solution was heated up to 150°C for 1 hour.

Example 2

To obtain the seed crystal particles in polyglycol DME 500 (the company Clariant) in a glass flask, 8 g of iron oleate (III) was dissolved in 50 ml of polyglycol DME 500. To the solution was added 1.5 g of oleic acid. The solution was heated to 120°C for 30 minutes

Example 3A

For nanoparticles of iron oxide solutions of examples 1-2 was heated in a three-neck flask with reflux condenser, when the transmittance of the protective gas (argon) until the temperature of the tours boiling point of the respective solvent and kept at this temperature for a minimum period of 1 hour. Because of this, the solution became red. After cooling, the particles were oxidized during the night the supply of atmospheric oxygen.

Example 3B

For nanoparticles of iron oxide solutions of examples 1-2 was heated in a three-neck flask with reflux condenser, when the transmittance of the protective gas (argon) up to the boiling point of the respective solvent and kept at this temperature for a minimum period of 1 hour. Here the solution became black.

Example 4

Particles from example 3 was separated by centrifugation at high values of g and washed with ethanol. 500 mg of the washed product was weighed into the extraction socket (603 g company Whatman) and placed to to conventional Soxhlet extractions. Into the flask for extraction to conventional Soxhlet extractions were filled with 200 ml of ethanol as extractant. The extractant was heated to its boiling point. Continuous extraction was carried out for 8 hours, and it included about 16 cycles of extraction. Because of this, the ethanol was yellowish. After completion of the extraction cartridge was removed, the powder was transferred into a flask Slinka and dried in vacuum for 1 hour.

Example 5

For dispersion of the particles after extraction, 0.5 g of the powder of the nanoparticles of example 4 are suspended in 20 ml of 0,01M HCl. Then the nanoparticles were treated with ultrasound for 30 minutes. Then 0.5 g) was added TBE the Dogo oleate sodium.

Stage G1

Then was stirred at 70°C for 1.5 hours, followed by ultrasonic treatment under stirring for 2 hours. After the successful dispersion, the dispersion was centrifuged at low values of g for the Department redispersion particles. Alternatively, the remaining dispersion was washed to remove excess sodium oleate. This was carried out by centrifugation at high values of g, and washed with diethyl ether and re-dispersible in the water. Alternatively, it is possible to carry out the extraction in diethyl ether or dialysis. For a complete re-dispersion dispersion was treated with ultrasound.

Example 6

of 3.3 ml of a dispersion of particles according to example 5 (0.97 mol/l Fe) and 2.14 ml of tetraethoxysilane was added to 120 ml of a mixture of water and ethanol (3:1) and 1.5% by weight of ammonia. During adding the dispersion was stirred and then treated with ultrasound for 6 hours. The dispersion was purified by centrifugation and re-dispersion in water.

Example 7 (phase heat treatment)

The particles obtained in example 4, suspended in 200 ml dibutylamino ether of diethylene glycol. Then fuegirola air at 80°C for 12 hours and then boiled under reflux for 8 hours (boiling point of about 256°C). Then the suspension was slowly cooled to room te is the temperature (within 8 hours). This procedure was repeated twice.

Obtained in this way (thermally processed) particles were washed and suspended in 20 ml of 1M HNO3. Then added 0.3 mmol of iron nitrate (Fe(NO3)3·9H2O) and boiled under reflux for 1 hour (100°C). The particles three times washed with water, 100 ml each time.

Then the particles were coated as in examples 4-6.

Example 8A (oxidation/without fumigation air)

For nanoparticles of iron oxide in ethylene glycol, 0.1 mol FeCl3·6H2O and 0.2 mol FeCl3(anhydrous), 50 g of sodium acetate and 195 g of diaminohexane was dissolved in 900 ml of ethylene glycol and heated to 60°C for one hour.

Then the solution was heated to boiling point for 30 minutes. The boiling temperature was maintained for 6 hours. The resulting dispersion was slowly cooled to room temperature.

The particles three times washed with a mixture of ethanol and water. Then the particles are re-suspended in 900 ml of ethylene glycol. The suspension was heated to the boiling point of ethylene glycol and kept at this temperature for 24 hours.

After cooling, the particles were washed with a mixture of water and ethanol and re-suspended in 900 ml of 1M HNO3. Then was added 450 ml of a 0.7m solution of iron nitrate (Fe(NO3)3·9H2O) and boiled under reflux for od the CSOs hours (100°C). The particles three times washed with water, 500 ml each time.

These particles were coated as in examples 4-6.

Example 8B (without oxidation/fumigation air)

For nanoparticles of iron oxide in ethylene glycol, 0.1 mol FeCl3·6H2O and 0.2 mol FeCl3(anhydrous), 50 g of sodium acetate and 195 g of diaminohexane was dissolved in 900 ml of ethylene glycol and heated to 60°C for one hour.

Then the solution was heated to boiling point for 30 minutes. The boiling temperature was maintained for 6 hours. The resulting dispersion was slowly cooled to room temperature.

The particles three times washed with a mixture of ethanol and water. Then the particles are re-suspended in 900 ml of ethylene glycol and fuegirola atmospheric oxygen. The suspension was heated to the boiling point of ethylene glycol and kept at this temperature for 24 hours.

After cooling, the particles were washed with a mixture of water and ethanol and re-suspended in water.

These particles were coated as in examples 4-6.

Example 8C (oxidation/fumigation air)

For nanoparticles of iron oxide in ethylene glycol, 0.1 mol FeCl3·6H2O and 0.2 mol FeCl3(anhydrous), 50 g of sodium acetate and 195 g of diaminohexane was dissolved in 900 ml of ethylene glycol and heated to 60°C for one hour.

Then the solution was heated to the point and boiling for 30 minutes. The boiling temperature was maintained for 6 hours. The resulting dispersion was slowly cooled to room temperature.

The particles three times washed with a mixture of ethanol and water. Then the particles are re-suspended in 900 ml of ethylene glycol and fuegirola atmospheric oxygen. The suspension was heated to the boiling point of ethylene glycol and kept at this temperature for 24 hours.

After cooling, the particles were washed with a mixture of water and ethanol and re-suspended in 900 ml of 1M HNO3. Then was added 450 ml of a 0.7m solution of iron nitrate (Fe(NO3)3·9H2O) and boiled under reflux for one hour (100°C). The particles three times washed with water, 500 ml each time.

These particles were coated as in examples 4-6.

Example 8D (without oxidation/without fumigation air)

For nanoparticles of iron oxide in ethylene glycol, 0.1 mol FeCl3·6H2O and 0.2 mol FeCl3(anhydrous), 50 g of sodium acetate and 195 g of diaminohexane was dissolved in 900 ml of ethylene glycol and heated to 60°C for one hour. Then the solution was heated to boiling point for 30 minutes. The boiling temperature was maintained for 6 hours. The resulting dispersion was slowly cooled to room temperature.

The particles three times washed with a mixture of ethanol and water. Then the particles are re-suspended in 90 ml of ethylene glycol. The suspension was heated to the boiling point of ethylene glycol and kept at this temperature for 24 hours.

After cooling, the particles were washed with a mixture of water and ethanol and re-suspended in water.

These particles were coated as in examples 4-6.

Example 9

For nanoparticles of iron oxide a solution of 96 g of sodium hydroxide and 680 ml of oleic acid in 2000 ml of methanol was added to a solution of 216 g of uranyl chloride Fe (III) in 500 ml of methanol. The resulting solid was washed with methanol and dissolved in diethyl ether. Then it was extracted several times with water. The solid is precipitated with acetone, washed and dried under vacuum.

75 g of this solid was dissolved in 250 ml of trioctylamine and was heated to 120°C for one hour.

Then the solution was heated in an autoclave to a temperature of 380°C for 30 minutes. This temperature is maintained for 4 hours. The resulting dispersion was slowly cooled to room temperature.

The particles three times washed with a mixture of ethanol and water.

Then the particles were suspiciously 300 ml dibutylamino ether of diethylene glycol and fuegirola atmospheric oxygen. The suspension was heated in an autoclave to a temperature of 300°C and kept at this temperature for 24 hours.

These particles were oxidized as in example 8C and then arrival as in examples 4-6.

1. Method of producing nanoparticles comprising iron oxide and silicon shell and having a value of specific absorption rate (SAR) 10-40 watts per g Fe at field strength of 4 kA/m and frequency of the alternating magnetic field of 100 kHz, which contains the following stages:
A1) preparation of a composition of at least one iron-containing compound And at least one organic solvent LM1;
B1) heating the composition to a temperature in the range from 50°C to 50°C below the actual reaction temperature of iron-containing compounds And according to the stage S1 for a minimum period of 10 min;
C1) heating the composition to a temperature between 200°C and 400°C;
D1) purification of the obtained particles;
E1) the suspension of purified nanoparticles in water or an aqueous solution of an acid;
F1) the addition of surfactants in aqueous solution, obtained according to stage E1);
G1) treatment aqueous solution according to stage F1) ultrasound;
H1) clean water dispersion of the particles obtained according to stage G1);
I1) obtaining a dispersion of particles according to the stage H1) in a mixture solvent of water and a solvent miscible with water;
J1) adding alkoxysilane in the dispersion of the particles in the solvent mixture according to stage I1); and
K1) cleaning particles.

2. The method according to claim 1, additionally containing stage A2), the following is Yu for stage A1):
A2) adding an additive selected from the group comprising surfactants, silane, Si - or Al-containing organic compounds, phosphines, saturated or unsaturated fatty acids, amines, diamines, carboxylic acids and their salts, saturated and unsaturated fatty acids, polymers.

3. The method according to claim 1, additionally containing stage B2), the next stage B1):
B2) adding an additive selected from the group comprising surfactants, silane, Si - or Al-containing organic compounds, phosphines, saturated or unsaturated fatty acids, amines, diamines, carboxylic acids and their salts, saturated and unsaturated fatty acids, polymers, or
B2) adding the composition of at least one iron-containing compound In at least one organic solvent L2,
or
B2) adding the composition of at least one iron-containing compound In at least one organic solvent L2 and adding additives selected from the group consisting of surfactants, silane, Si - or Al-containing organic compounds, phosphines, saturated or unsaturated fatty acids, amines, diamines, carboxylic acids and their salts, saturated and unsaturated fatty acids, polymers.

4. The method according to claim 3, in which the mentioned at least one iron containing compound selected from the group consisting of compounds of complexo the iron, compounds CARBONYLS of iron, iron salts, organic compounds of iron, iron salts and saturated/unsaturated fatty acids and sandwich complexes of iron.

5. The method according to claim 3, in which the mentioned at least one solvent L2 has a minimum boiling point of 200°C.

6. The method according to claim 3, in which the mentioned at least one solvent L2 is selected from the group consisting of high-boiling amines, alkanes, olefins, alcohols or ethers, simple monetary of alkalophilus, simple diesters alkalophilus, simple monoether of ethylene glycol, simple diesters of ethylene glycol, simple monetary propylene glycol, simple diesters of propylene glycol, simple monetary glycerin, simple diesters of glycerin, simple truefire glycerin, simple diesters of glycol (glime).

7. The method according to claim 3, in which the mentioned at least one iron containing compound In is identical to the aforementioned at least one iron-containing compound and/or the at least one organic solvent LM1 identical to this at least one organic solvent LM2.

8. The method according to claim 1, additionally containing stage x2), following the stages C1 or D1, or E1 or F1 or G1 or H1, or I1 or J1 or K1:
X2) oxidation of the formed particles.

9. The method according to claim 1, additionally containing stage heat is th processing D1*), the next stage D1:
D1*) heat treatment of the obtained particles.

10. The method according to claim 1, in which the mentioned at least one iron containing compound And selected from the group consisting of compounds of iron complexes, compounds CARBONYLS of iron, iron salts, organic compounds of iron, iron salts and saturated/unsaturated fatty acids and sandwich complexes of iron.

11. The method according to claim 1, in which the mentioned at least one solvent has a minimum boiling point of 200°C.

12. The method according to claim 1, in which the mentioned at least one solvent LM1 selected from the group consisting of high-boiling amines, alkanes, olefins, alcohols, ethers, simple monetary of alkalophilus, simple diesters alkalophilus, simple monoether of ethylene glycol, simple diesters of ethylene glycol, simple monetary propylene glycol, simple diesters of propylene glycol, simple monetary glycerin, simple diesters of glycerin, simple truefire glycerin, simple diesters of glycol (glime).

13. The method according to claim 1, in which the heating stage according C1) is carried out for a minimum period of 30 minutes

14. The method according to claim 1, wherein the cleaning stage according D1) perform the extraction in to conventional Soxhlet extractions.

15. The method according to claim 1, in which at the stage of purification according to the stage D1) present additives are essentially removed.

16. The method according to claim 1, in which an aqueous solution of mineral acid has a pH from 2 to 6, preferably from 3 to 5.

17. The method according to claim 1, wherein the mineral acid according to the stage E1) is selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, Hydrobromic acid, boric acid or nitric acid.

18. The method according to claim 1, wherein the surface-active compound according to stage F1) is selected from the group consisting of fatty acids, salts of fatty acids, surfactants, polymers, polyvinyl alcohol, polyethylene glycol, polyacrylic acid, dextran, PLGA (copolymer of lactic acid and glycolic acid), chitosan and polyethylenimine.

19. The method according to claim 1, wherein the solvent mixture according to stage I1) represents sportowego mixture with a volume ratio of alcohol to water in the range from 1:1 to 1:5.

20. The method according to claim 19, in which the solvent mixture further comprises amine or ammonia.

21. The method according to claim 19, in which the alcohol is selected from the group consisting of methanol, ethanol, propanol and isopropanol.

22. The method according to claim 1, wherein the alkoxysilane according to the stage J1) selected from the group consisting of tetraalkoxysilane, tralkoxydim, dialkoxybenzene and monoatomically.

23. The method according to claim 1, in which the molar ratio of the particles to the alkoxysilane according to the stage J1) is in the range from 1:1 to 1:5./p>

24. The method according to claim 1, wherein the alkoxysilane according to the stage J1) add the ultrasonic processing.

25. The method according to claim 1, wherein the dispersion obtained according to stage J1), treated with ultrasound for 1-8 hours

26. The method according to claim 1, additionally containing phase L1):
L1) binding of anti-cancer compounds, monoclonal antibodies, aptamers, nucleic acid, amino acid, peptide, protein, carbohydrate, lipid, glycoprotein, picana, lipoprotein, or antiproliferative, antimigratory, antiangiogenic, anti-thrombotic, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic, anticoagulant, antibacterial, antiviral or antifungal drug from the particles obtained according to stage K1).

27. Iron-containing nanoparticles obtained by the method according to any one of claims 1 to 26.

28. Iron-containing nanoparticles according to item 27, and the nanoparticles have a minimum value of the specific absorption rate (SAR) 20 mW/mg Fe at field strength of 6 kA/m

29. Nanoparticles comprising iron oxide and silicon shell, and the nanoparticles have a value of specific absorption rate (SAR) 10-40 watts per g Fe at field strength of 4 kA/m and frequency of the alternating magnetic field of 100 kHz.

30. The nanoparticles according to clause 29, and cremniter the General shell has a thickness of between 0.5 and 10 nm, preferably from 1 to 6 nm, more preferably from 2 to 4 nm, and in particular 3 nm.

31. The nanoparticles according to any one of PP and 30, and the nanoparticles contain iron.

32. Nanoparticles on p, and the nanoparticles are ferromagnetic, ferrimagnetic or superparamagnetic particles.

33. The nanoparticles according to clause 29, the nanoparticles have a SAR value of 20-40 watts per g Fe, in particular 25-40 W in g Fe, more specifically 30-40 watts per g Fe, at field strength of 4 kA/m and frequency of the alternating magnetic field of 100 kHz.

34. The nanoparticles according to clause 29, and the nanoparticles are dispersible in nonpolar solvents or dispersible in water.

35. The nanoparticles according to clause 29, the nanoparticles have a diameter less than 500 nm, in particular 1-100 nm, preferably 15 to 30 nm.

36. The nanoparticles according to clause 29, and the silicon-containing shell functionalized with alkoxysilane.

37. Nanoparticles on p, and alkoxysilane are tralkoxydim, these tralkoxydim are
(i) bearing a functional group, bonded Si-C bond, preferably (3-acroloxidae)trimethoxysilane, triethoxysilane, 3-aminopropyltriethoxysilane, 3-isocyanatopropyltrimethoxysilane; or
(ii) a bearing attached to the Si-C bonds of the side chain of polyethylene glycol of different lengths, preferably 2-[methoxy(polietilene)propyl]trim oxsilan.

38. Nanoparticles comprising iron oxide and silicon membrane obtained by the method according to any one of claims 1 to 26, and the nanoparticles are characterized by any of PP-37.

39. Pharmaceutical composition comprising iron-containing nanoparticles according to any one of p and 28 or nanoparticles according to any one of p-38.

40. The pharmaceutical composition according to § 39 in the form of an infusion solution, solution for injection, powder, powder for inhalation, or freeze-dried.

41. The use of iron-containing nanoparticles according to any one of p and 28 or nanoparticles according to any one of p-38 to obtain a pharmaceutical composition for the treatment and/or prevention of proliferative diseases, cancer, tumors, rheumatism, arthritis, arthrosis and bacterial infections.

42. The application of paragraph 41 in combination with the anticancer drug.



 

Same patents:

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2 cl, 3 dwg, 1 ex

FIELD: chemistry.

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2 cl, 1 dwg, 3 tbl, 3 ex

FIELD: chemistry.

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2 ex, 1 tbl, 1 dwg

FIELD: chemistry.

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2 tbl, 6 ex

FIELD: chemistry.

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2 cl, 2 ex

FIELD: chemistry.

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1 dwg, 1 ex

FIELD: chemistry.

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1 dwg, 1 ex

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1 ex

FIELD: chemistry.

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2 tbl, 2 ex

FIELD: chemistry.

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9 cl, 3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention can be used in inorganic chemistry. In order to obtain a magnetoactive compound by oxidative condensation of an iron (II) salt solution, condensation is carried out in the presence of nitrosated lignosulphonates in conditions of exposure to a magnetic field.

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1 tbl, 22 ex

FIELD: medicine, pharmaceutics.

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16 cl, 4 tbl, 1 dwg, 26 ex

FIELD: chemistry.

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3 cl, 1 tbl, 57 ex

FIELD: chemistry.

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EFFECT: invention improves the quality of the end product, simplifies the method, reduces power consumption and improves environmental safety of the process.

1 ex, 1 tbl

FIELD: chemistry.

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EFFECT: invention increases specific surface area of magnetite to 130 m2/g.

1 ex

FIELD: chemistry.

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2 cl, 1 tbl, 19 ex

FIELD: process engineering.

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EFFECT: expanded applications.

16 cl, 4 ex

FIELD: chemistry.

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12 cl, 4 ex

FIELD: medicine, pharmaceutics.

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EFFECT: invention allows producing multiuseable steady magnetite nanoparticles.

3 cl, 2 dwg, 1 tbl, 5 ex

FIELD: chemistry.

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EFFECT: high stability of the magnetic liquid in gradient magnetic field, simple and cheap method.

3 cl, 5 ex

FIELD: chemistry.

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EFFECT: method enables to obtain a cheap inorganic chromatic pigment, reduces the cost of paint materials by simplifying the process of producing the pigment and using readily available and cheap production wastes, which enables to solve the problem of recycling sludge from clarification tanks of thermal power plants.

2 tbl, 6 ex

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