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    • 专利摘要:
    method and device for manufacturing micro or nanoparticles. The invention relates to a method for manufacturing water soluble or insoluble substance micro or nanoparticles by controlled precipitation, coprecipitation and self-organizing processes in microjet reactors, wherein a solvent containing at least one molecule target, and a non-solvent, are mixed as jets that meet the set pressure and flow rates in a microjet reactor, with very rapid precipitation, coprecipitation or a chemical reaction occurring within which micro or nanoparticles arise. . In order to generate such a method in which the particle size of the resulting micro and nanoparticles can be selectively controlled, it is proposed, within the scope of the invention, that the particle size be controlled by the temperature, which arises from the collision of the solvent, the solvent and non-solvent flow rate and / or the amount of gas, and at low temperatures, high solvent and non-solvent flow rates as well as complete particles.
    公开号:BR112012023983B1
    申请号:R112012023983-0
    申请日:2011-03-21
    公开日:2019-03-26
    发明作者:Bernd Baumstümmler；Bernd Penth；Felix Penth；Akif Emre Türeli
    申请人:Instillo Gmbh；
    IPC主号:
    专利说明:

    DESCRIPTION
    The invention relates to a method for the manufacture of micro or nanoparticles of substances soluble or insoluble in water by means of controlled precipitation, coprecipitation and self-organization processes in microjet reactors, where a solvent is mixed, containing at least a target molecule, and a non-solvent such as jets that meet defined pressure and flow rates in a microjet reactor, with very rapid precipitation, coprecipitation or a chemical reaction, in which micro or nanoparticles arise.
    It also refers to a device for manufacturing micro or nanoparticles of substances soluble or insoluble in water in microjet reactors, which have at least two injectors with pumps assigned to each of them and conductive tubes to inject a liquid medium into a reactor compartment closed by a reactor housing, at a common collision point, and a first opening is provided in the reactor housing, through which a gas can be inserted to maintain the gaseous atmosphere in the reactor compartment, mainly at the point of collision of the liquid jets, as well as for cooling the generated product, and another opening is provided to remove the generated product and excess gas out of the reactor housing.
    Several industrial sectors, mainly in the area of medicine and pharmacy, register a great need for micronization or nanonization of large particles. In particular, in the field of pharmacy, these methods are used with increasing frequency, to increase the bioavailability of active substances or to take one or more active substances selectively to their place of action.
    Bioavailability must be understood as the degree to which an active substance can be made available to the target tissue after its administration. Several factors are known to influence bioavailability, such as the solubility of the substance in water, the rate of release or particle size. Therefore, bioavailability can be improved by means of micronization or nanonization in the case of substances that are poorly soluble in water, by increasing solubility or the rate of release.
    Another possibility to increase bioavailability is the so-called “drug targeting” or “drug delivery”, which is based on the distribution of particles in the target tissue according to the size of the particles or through a particle structure in such a way that they they have adequate surface modifications, which make them able to selectively reach the site of absorption or action.
    2/13
    Such a method for the manufacture of microparticles and nanoparticles are described in different patent and patent registries, for example, US 5,833,891 A, US 5,534,270 A, US 6,862,890 B, US 6,177,103 B, DE 10 2005 053 862 A1, US 5,833,891 A, US 5,534,270 A, US 6,862,890 B, US 6,177,103 B, DE 10 2005 017 777 A1 and DE 10 2005 053 862 A1.
    WO 02/60275 A1 describes methods for making nanoparticles, in which two liquids are electrically charged which do not mix to obtain an encapsulation. In this case, the use of toxic substances is not eliminated, which can significantly influence the quality of the product. Furthermore, it is not possible with this method to control the particle size.
    In US 2009/0214655 A1 two liquids that do not mix are used again and, despite being used there, for the manufacture of nanoparticles, a micro-reactor, the manufacture of emulsions is only described in this patent. In addition, the fabrication is carried out in a liquid-filled compartment, in which it is also not possible to control the size or characteristics of the particle and, in addition, due to the fact that the reactions are carried out in microchannels, device blocking occurs easily.
    The known techniques for making nanoparticles, however, have many disadvantages.
    The so-called “top-down” techniques that cover most mechanical reduction methods, such as dry or wet grinding, safeguard the risk of microbial infection, contamination through friction of the grinding spheres or substance degradation active, especially because this method requires long grinding periods for the micronization of the active substance. And even so, in the case of dry grinding, even after long grinding periods, only particle sizes of not less than approximately 100 micrometers can be achieved.
    There are a series of so-called “Bottom-up” preparations for the production of nanoparticles, such as reloading, emulsification, solvent evaporation or evaporation by spraying supercritical liquids.
    Regardless of which of these preparations are followed, in order to produce pharmacological nanoparticles, in any case an increase in the surface is obtained compared to particles with a size greater than 1 pm.
    The increase in surface and surface interactions can positively influence the rate of release and enable the pharmacokinetic characteristics of a drug to be controlled. Despite this, most of these methods have limitations because they need a high use of energy, provide few gains, show problems in “upscaling” (transfer of the laboratory experiment to industrial production), it is difficult to control the size and characteristics of the particle, need
    3/13 relatively toxic organic substances are used or the method itself is difficult to perform. These factors limit its use for commercial production of nanoparticles.
    Among these various methods, nanoprecipitation or solvent exchange method is described in US 5,118,529 A. This relatively simple method includes in one step the formation of nanoparticles by means of solvent precipitation with non-solvent. Ideally, the polymer and the active substance are diluted in the same solvent and then precipitate as nanoparticles upon contact with the non-solvent (usually water).
    The rapid formation of nanoparticles is conditioned by the Maragoni effect as a result of the turbulence at the point of collision of the solvent with the non-solvent and the diffusion of the solvent in the non-solvent.
    The precipitation results in the production of nanoparticles in the range of 100 to 300 nm with a relatively narrow particle size distribution using different polymers. Surface modifiers are not required in all cases. As solvents, toxic solvents are not normally used.
    The state of the art described reveals that, especially in the pharmaceutical industry, innovative methods are needed that avoid all the disadvantages associated with the conventional methods mentioned above.
    DE 10 2009 008 478 A1 describes a method in which solvent / non-solvent precipitation occurs with in-situ spray drying in the presence of surfactant molecules, where a microjet reactor according to EP 1 165 224 is employed B1. A microjet reactor of this type has at least two injectors with a pump assigned to each of them and conducting tubes to inject each liquid medium in a reactor compartment closed by a reactor housing at a common collision point, with a first opening in the reactor housing is foreseen, through which a gas, a vaporized liquid, a refrigerant liquid or a refrigerant gas can be inserted to maintain the gaseous atmosphere inside the reactor, mainly at the point of collision of the liquid jets, as well as for cooling the generated product, and another opening for removing the generated product and excess gas out of the reactor compartment. Therefore, a gas, a vaporized liquid or a refrigerant gas is inserted through an opening in the reactor compartment to maintain the gaseous atmosphere inside the reactor, especially at the point of collision of the liquid jets, as well as to cool the generated product. and the product generated and the excess gas are removed from the reactor housing through an opening by means of overpressure on the gas inlet side or by means of underpressure on the gas and product outlet side.
    In DE 10 2009 008 478 A1 the active substance is dissolved in an organic phase
    4/13 which is mixed in water, together with a surfactant molecule. This organic solution and water, which is applied as a non-solvent, are pumped with the axle of two pumps through proper stainless steel capillaries with constant flow and pressure rates and collide with each other, in the micro-reactor (the so-called reactor Microjet) as impinging jets. The solvent and the non-solvent are quickly mixed in there, the active substance precipitating as a nanoparticle and the nanoparticle suspension generated in this way is propelled out of the MicroJet reactor with compressed air heated to high temperatures or with an inert gas.
    The gas vaporizes the organic solvent and the water, and the nanoparticle of the active substance is coated with surface-modifying molecules, after both liquid phases have been vaporized. In the final stage of the method, the nanoparticles are present in powder form.
    The essential element in DE 10 2009 008 478 A1 is, therefore, the use of heated air or inert gas in conjunction with a surface modifier such that during the precipitation of the active substance, the solvent and the non-solvent are vaporized and the surface modifiers involve nanoparticles, thereby inhibiting further particle aggregation and Oswald growth.
    Although using the method described in patent DE 10 2009 008 478 A1 it is possible to efficiently control the size of the particles, the need for the use of surface modifiers means a limitation in the use of technology for various strategies for the production of microparticles or nanoparticles.
    It is the task of the invention, therefore, to generate a method according to the general term, in which the particle size of the generated nano or microparticles can be selectively controlled. In this case, they must have a narrow size distribution and also allow the manufacture of surface modifying formulations for use in Drug Delivery and Drug Targeting.
    This task is solved according to the invention by controlling the particle size by means of the temperature, which appears in the collision of the solvent with the non-solvent, the flow rate of the solvent and non-solvent and / or the amount of gas, being that with low temperatures, high flow rate of solvent and non-solvent as well as full gas presence small particles are obtained.
    On that occasion it is possible that the particle size is controlled only by means of temperature, only by means of the flow rate or only by means of the amount of gas or by means of the desired combinations of two parameters.
    It is within the scope of the invention, that the target molecule is selected from the group composed of substances of biological use, substances for image formation, cosmetic substances, dyes, pigments, foods, food supplements, biocides, insecticides,
    5/13 fungicides, pesticides, herbicides, substances for pharmaceutical use, in particular human or veterinary pharmaceutical products.
    An advanced formation of the invention consists in the fact that the non-solvent contains at least one auxiliary additive.
    However, the non-solvent can also be composed exclusively of water.
    In this context, the weight ratio of the target molecule in relation to the auxiliary additive of at least 1: 100 was proven to be advantageous.
    In a preferred embodiment of the invention, it is provided that the solvent and the non-solvent are vaporized exclusively from the resulting suspension.
    Within the scope of the invention there is also a device for the manufacture of nano and microparticles of substances soluble or insoluble in water in the microjet reactors, which have at least two injectors with a pump assigned to each of them and conductive tubes to inject respectively a medium liquid in a reactor compartment closed by a reactor housing at a common collision point, and a first opening is provided in the reactor housing, through which a gas is inserted to maintain the gaseous atmosphere in the reactor compartment, mainly in the collision point of the liquid jets, as well as for cooling the generated product, as well as another opening for removing the generated product and excess gas out of the reactor housing, where means are provided to control the temperature of the liquids, the flow rate of liquids and / or means to control the amount of gas in the reactor compartment.
    Within the scope of the invention it has surprisingly been discovered that the size of the particles can be relevantly controlled by means of the temperature, which arises in the collision of liquids. Particle sizes to be reduced are achieved in this case by means of low temperatures. Likewise, particle sizes to be reduced are obtained by reducing the amount of gas in the reactor compartment or even the complete absence of gas in the reactor compartment.
    The present invention is also based on the surprising knowledge that with increasing amounts of air, the interactions of the formed diffusion layers are influenced in such a way that, finally, with various applications nanoparticles can be generated and in some cases it can reach a growth unwanted crystals. On the contrary, it was surprisingly discovered that the complete lack of air or inert gas leads to the formation of smaller particles. For the case in which no gas stream is used, the rapid precipitation of the particles apparently ends as soon as the liquid streams reach the outer edge of the liquid dish, which is formed by colliding the liquid streams as impinging jets. This probably results in an early termination of particle growth and in smaller particles with a homogeneous size distribution.
    6/13
    The effect of the gas flow together with the aggravation of the heating for vaporization of the solvent can be clarified provisionally, with regard to the particle size, as follows.
    At low temperatures, the solubility is reduced and the metastability zone is narrow, so that over-saturation can easily be achieved by injecting the solvent into the anti-solvent.
    The nucleation process is a process of loss of free energy and releases heat, thereby promoting a high rate of nucleation at very low temperatures.
    A low temperature can inhibit particle growth. For this reason smaller particles are formed, due to the high rate of nucleation and the slow growth rate at low temperatures.
    The knowledge that with increasing temperatures the particle size and the degree of aggregation also increases, can be deduced from the fact that the substance or additive is closer, with higher temperatures, to its glass transition temperature.
    The particle size can also be controlled by means of the flow rate of solvent and non-solvent, and with a high flow rate small particles are obtained and with a low flow rate large particles.
    The term precipitation reactor or microjet reactor encompasses all geometries as described in EP 1 165 224 B1 and DE 10 2009 008 478 A1.
    At this point it is important to mention that a microjet reactor operated without air, as it is known from EP 1 165 224 B1, cannot be replaced by a common micro-reactor for the imposed task, since mixing with a common micro-reactor, for example, designed as a mixer T, leads to very high mixing periods, because he works regularly in the laminar section. For the execution of the method according to the invention, the microjet reactor can be executed in such a way that the jets of liquids are at an angle other than 180 ° or that the jets mix in a common impact area. However, in these cases the particle size that can be reached increases.
    In addition, it can be determined that the microjet reactor is the only reactor in which precipitation or other types of reactions are carried out freely in a gas-filled compartment. Through this it is possible to determine the particle size by changing the process parameters such as temperature, pressure or flow rate. Due to the fact that the reaction is carried out in a free compartment, it is possible that the product or the by-products block the reaction and can thus bring the entire system to a standstill.
    Nanoparticle or microparticle formulations are also manufactured according to the invention for Drug Targeting and Drug Delivery. For this it is necessary to formulate
    7/13 water-soluble substances with auxiliary additives suitable for nano or microparticle systems. However, in existing methods, it was only possible to formulate active substances insoluble in water, the production of which is based exclusively on the precipitation of these particles due to their low solubility at high temperatures with the use of inert gas or heated air.
    In the present construction of the test, in which no gas flow is used during the operational cycle, it is also possible to manufacture nanoparticles from water-insoluble molecules and this with simultaneous reduction in the temperatures of the liquids used as non-solvents, the microjet reactor and / or the solvent containing the substance in such a way that the solubility of the substance in question in the mixture of solvent and non-solvent is also reduced, so that the substance precipitates as a nanoparticle, which can then be coated with use of a second microjet reactor, which is coupled directly to the first microjet reactor in a two-step method, with a suitable additive. The generated nanoparticles can be coated with auxiliary additives or biologically active substances through absorption or integration into the surface, for example, to make them resistant to gastric juice or mucoadhesives.
    The particles generated in the precipitation can be subjected, for example, immediately after the precipitation (eg within 0.1 to 5 s) in a second cascade microjet reactor or afterwards to a mechanical treatment. This mechanical treatment can occur by means of ultrasound, pressure of the dispersion with pressure by means of injectors or by means of strong agitation, for example, by means of an UltraTurrax or as “Impinging Jets” (jets that are) by means of treatment single or multiple. In this way the particles can be stabilized in a continuous process.
    It is also possible to generate magnetic particles using the method according to the invention.
    In addition, it is also possible to precipitate highly water-soluble substances such as nanoparticles through a process of self-organization, in which insoluble derivatives are precipitated after a reaction such as neutralization or reloading, which takes place inside the microjet reactor. An active target molecule can, for example, be managed by reacting with one or more auxiliary additives in order to generate particles that are insoluble in the solvent / non-solvent mixture. It is also possible that a target molecule active with an insoluble reaction product of two or more auxiliary additives is co-precipitated.
    Another advantage of the absence of heated gas is due to the fact that sensitive molecules including, but not limited to, proteins, peptides, biological marker and biopharmaceuticals, can also be formulated and without losing their biological activities.
    The present invention also enables the coprecipitation of a substance of
    8/13 low solubility with a pharmaceutical additive without surfactant and the modification of the surface of these nanoparticles with biologically active molecules for use in Drug Delivery and Drug Targeting.
    Thus, it is the task of the present invention to provide a method and a device that allow, based on a solvent / non-solvent precipitation using a microjet reactor, to generate stabilized nanoparticles or microparticles in the form of suspensions of soluble and insoluble substances in water with high profit. It is within this context that they have a narrow size distribution and also enable the production of formulations for use in Drug Delivery and Drug Targeting. The construction with the use of devices makes it possible to manufacture an optimized process through the use of statistical test planning and automated parameterization in connection with an online determination of the particle size.
    The method is robust, can be scaled and used in several water-soluble and insoluble substances including biological substances.
    The invention is explained in more detail below.
    They are shown in the figures:
    FIG. 1- construction with the addition of air for the production of microparticles and nanoparticles,
    FIG. 2 - the construction without adding air to produce microparticles and nanoparticles,
    FIG. 3 - the effect of the flow rate proportion on the particle size,
    FIG. 4 - the representation of the effect of temperature on the particle size, with the x axis indicating the temperature in ° C and the y axis the particle size in nm,
    FIG. 5 - the representation of the effect of gas pressure on the particle size, with the x-axis indicating the pressure in bar and the y-axis the particle size in nm,
    FIG. 6 - images by electromagnetic tomography of nanoparticles that were generated with a microjet reactor,
    FIG. 7 - 3D diagram of the effect of gas and temperature on the particle size, with the x axis indicating the temperature in ° C, the y axis the particle size in nm and the z axis the pressure in bar.
    The present invention makes use of solvent / non-solvent precipitation in such a way that solvent and non-solvent streams with flow rates above 0.1 ml / min as impinging jets (colliding jets) and which collide at a higher speed that, preferably, 1 m / s, better still above 50 m / s and with a Reynold coefficient above 100, preferably above 500. The solvent and the non-solvent are formed in the jet injectors, which are preferably less than 1000 pm, especially preferred less than 500 pm, but the best is below 300 pm with pressure
    9/13 usually 1 bar, preferably more than 10 bar and especially preferred above 50 bar, the pressure in the present method being controlled by means of a pressure regulator.
    These two impinging jets collide in the microjet reactor in such a way that precipitation occurs at the meeting point of the jets, which there, depending on the geometry of the reactor, forms a structure in the shape of a double plate of liquid streams moving rapidly, in whose area from the edge of the dish, rapid mixing occurs, usually with mixing speeds below 1 millisecond, often below 0.5 milliseconds, most often below 0.1 milliseconds.
    In the present invention, the solvent concept means a solvent with one or more target substances contained therein with one or more auxiliary additives including, but not limited to, pharmaceutical additives, surfactant molecules, polymers, co-polymers or block polymers.
    The non-solvent concept also means a solvent with one or more target substances or auxiliary additives contained therein, which find use in the manufacture of nanoparticles or microparticles.
    These liquids can be heated or cooled by external heating or directly at the pump, to allow the target substances and / or auxiliary additives to dissolve or to enable the formation of nanoparticles of the desired size or to stabilize the obtained molecules.
    The present invention includes methods for manufacturing particles from water-soluble or insoluble substances by means of a microjet reactor with simultaneous stabilization of the particles with one or more auxiliary additives or surface modifiers and a resulting particle size of up to 2,000 nm, preferably below 1000 nm, especially preferred below 500 nm and better below 200 nm with polydispersity index normally below 2.0, preferably 1.0 and especially preferred below 0.4.
    Alternatively, another embodiment of the invention includes a method and equipment that enable self-organization processes, in which one or more active target molecules react with one or more auxiliary additives, soluble in non-solvent, and thus result in a product that it is not soluble in the mixture of solvent and non-solvent and thus allows the formation of microparticles or nanoparticles of different sizes, depending on the parameter, including, but not limited to, flow rate or concentration of substances.
    It is also possible to co-precipitate one or more active target substances with a non-soluble reaction product of one or more auxiliary additives.
    The present invention further includes methods for co-precipitation of one or more
    10/13 active target substances with one or more suitable auxiliary additives, in which the substance is dissolved in the auxiliary additive in a molecular dimension in such a way as to form particular systems and include coating the surface of those systems with suitable target molecules, including antibodies, but not limited to them.
    In the case of the active substances mentioned above are included substances for biological use, substances for imaging, pharmaceutical substances, cosmetic substances, food substances or food supplements and, mainly, medicines for use in humans or veterinary medicines.
    The solvent and the non-solvent are solutions or mixtures as liquid components, which can contain their mass-produced component both in solution and in suspension form.
    The solvent and the non-solvent, employed in the present invention, can be a liquid or organic phase or a solution, mixture, emulsion or suspension or also a combination of them.
    Organic solvents of this type can be of the type that mix with water or not. Suitable organic solvents include, but are not limited to, substances that mix well in water such as ethanol, methanol, tetrahydrofuran, dimethyl sulfoxide, acetone, 2-isopropanol and substances that do not mix well, such as toluol, hexan, heptan, pentan and methylene chloride.
    Suitable drug target molecules can be selected from a variety of known drug classes, including, but not limited to, painkillers, anti-inflammatory substances, anthelmintics, antiarrhythmics, antibiotics (including penicillin), anticogulants, antidepressants, antidiabetic substances, antiepléptics, antihistamines, antihypertensive substances, antimuscarinics, antimycobacterial substances, antineoplastic substances, immunosuppressive substances, antithyroid substances, antiviral substances, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor products, blood products blood, inotropic substances for the heart, contrasts, corticosteroids, cough suppressant substances (expectorants and mucolytics), diagnostic substances, diagnostic imaging substances, diuretics, substances dopaminergic substances (substances against Parkinson's disease), hemostatics, immunological substances, substances for regulating fat, muscle relaxants, parasympathomimetics, parathyroid calcitonin and bisphosphonate, prostaglandin, radiopharmaceuticals, sex hormones (including steroids), antiallergic substances, stimulants and anorexics, anorexics and anorexics , thyroid substances, vasodilators and xanthines.
    11/13
    The substances are obtained commercially and / or can be obtained using techniques known worldwide. Provided that they are employable, the active substances mentioned above can be used as a free base or as one or more of their salts.
    The active substances mentioned above can be processed in such a way that they can be used in a variety of pharmaceutical compositions and formulations, for example, for oral administration in the form of tablets, capsules or suspensions, for pulmonary or nasal administration, topical administration , administered as emulsions, lotions or creams, parental administration in the form of suspensions, microemulsions or deposit formulations.
    Within this scope, auxiliary additives may be included, for example, inert diluents, solubilizing substances, suspending substances, adjuvants, humidifying substances, sweetening, perfuming or flavoring substances, isotonic substances, colloidal dispersants and surfactants including, but not limited to, electrically phospholipids loaded, for example, dimiristoyl-phosphatidyl-glycerol, alginic acid, alginate, acacia resin, gum arabic, 1,3-butylene glycol, benzalkonium chloride, colloidal silicone dioxide, emulsifying wax, ketomacrogol, casein, calcium stearate, chloride of cetyl-pyridine, cetyl alcohol, cholesterol, calcium carbonate, CRODESTAS F-110, which is a mixture of sucrose stearate and disaccharose stearate (Croda Inc.), tone, kaolin and bentonite, cellulose derivatives and their salts as , for example, hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose, carboxymethylcellulose and its salts such as, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, non-crystalline cellulose, dicalcium phosphate, dodecyltrimethyl ammonium bromide, dextran, sodium sulfosuccinate dialkylester (e.g. ex. AEROSEL OT, American Cynamid), gelatin, glycerin, glycerin monostearate, glucose, Pisononylphenoxypoli (glycidol), also known as OLIN 10-G or 10-GR surfactant (Olin Chemicals, Stamford, Conn.); glucamide such as octanoyl-N-methylglucamide, decanoyl-Nmethylglucamide, heptanoyl-N-methylglucamide, lactose, lecithin (phosphatide), maltosides such as n-dodecyl-BD-maltoside, mannitol, magnesium stearate, magnesium oil silicate, magnesium oil silicate cotton, seed oil, olive oil, castor oil and sesame oil; paraffin, potato starch, polyethylene glycol (eg CARBOWAX 3350, CARBOWAX 1450 and CARBOPOL 9340 (Union Carbide)), polyethylene alkyl ester (eg macrogol ether like KETOMACHROGOL 1000), polyoxyethylene sorbitol fatty acid ester ( eg TWEENS, ICI Specialty Chemicals), polyoxyethylene castor oil derivatives, polyoxyethylene stearate, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), phosphate, 4 (1,1,3,3-tetramethylbutyl) -phenol -polymer with ethylene oxide and formaldehyde (also known as ASTYLOXAPOL, SUPERIONE and TRITON), poloxamers and polaxamines (p.
    12/13 ex. PLURONICS F68LF, F87, F108 and TETRONIC 908 available from BASF Corporation, Mount Olive, NJ), pyranosides such as n-hexyl-BD-glucopyranoside, n-decyl-B-Dglucopyranoside, n-octyl-BD-glucopyranoside, quartz compounds ammonium, silicic acid, starches, starches, sorbitolester, sodium carbonate, solid polyethylene glycols, sodium dodecyl sulphate, sodium lauryl sulphate (eg DUPONAL P, DuPont), stearic acid, sucrose, tapioca starch, talc, thioglucosides as n -heptyl-BD-thioglucoside, tragant, triethanolamine, TRITON X-200 (Rohm und Haas); and the like.
    Inert diluents, diluent substances, emulsifiers, adjuvants, humidifying substances, isotonic substances, colloidal detergents and humidifiers are obtained commercially or can be prepared according to methods known to those skilled in the art.
    These additives, as they are employed in the present invention, can potentially also have their own activities, including antioxidant molecules, and these additives are not limited to the group of antioxidant molecules.
    EXAMPLES
    EXAMPLE 1
    Nanoparticles were manufactured by using nifedipine as a model substance and Eudragit S 100 as a model auxiliary additive. Eudragit S 100 at a concentration of 10 mg / ml was dissolved in acetone together with nifedipine at a concentration of 1 mg / ml. As a non-solvent, water was used. The temperatures of the solvent, non-solvent and the microjet reactor were adjusted to 40 ° C. Particles with different particle sizes could be produced by changing the flow rate of the solvent and the non-solvent. The particle sizes obtained are shown in the table (FIG. 3).
    EXAMPLE 2
    Nanoparticles were manufactured as described in example 1, and at different temperatures the flow rate of the solvent and the non-solvent was fixed at 10 ml / min, to observe the influence of temperature on the particle size. The particle sizes obtained are shown in the diagram (FIG. 4). The x-axis provides the particle size, the y-axis the corresponding temperature. As the temperature rises, an increase in particle size can be observed.
    EXAMPLE 3
    Nanoparticles were manufactured as described in example 1, and at different gas pressures the flow rate for the solvent and the non-solvent was fixed at 10ml / min, to observe the influence of the gas pressure on the particle size. For this experiment, an additional gas conductor tube was included in the test construction, as described in figure 1, through which inert nitrogen gas can be added. With this assay construction, an increase in particle size can be seen
    13/13 with increasing gas pressure. The results of the experiment in this example are shown in the diagram (FIG. 5). The x-axis shows the particle size [nm], the y-axis the gas pressure [bar]. This example shows that with the increase in the gas pressure an increase in the particle size can be observed.
    An exemplary construction of the device according to the invention is shown in figures 1 and 2, the device comprising a calculation and control unit (1), gas and air inlets (2), a pressure sensor for regulating the air pressure (3), a pressure sensor for regulating the pressure (3; 21) of the addition of reactants, a filter (5, 20), pumps (6, 19), a container for non-solvent reactors (7, 8 , 9) a container for solvent reactors (16, 17, 18, 24, 25), a temperature control (10, 15, 23), a heating / cooling unit with tempered container (11, 14), a microjet reactor (12), fractionated product outlet collector (13) and an online measurement of particle sizes (22).
    EXAMPLE 4
    Nanoparticles were produced by using fenofibrate as a model substance and Pluronic F68 as a model auxiliary additive. Fluronic 68 at a concentration of 10 mg / ml was dissolved in ethanol together with Fenofibrat at a concentration of 10 mg / ml. As a non-solvent, water was used. The temperatures of the solvent, non-solvent and the microjet reactor were adjusted to 40 ° C. The particle size can be adjusted to 320 nm through changes in the solvent and non-solvent flow rates, and because of Ostwald's maturation, the precipitated nanoparticles without further stabilization formed agglomerations within a short time. The particle size of the clusters was greater than 1,000 nm. The particles were stabilized by means of multiple treatments in cascade microjet reactors or by a new path in the same microjet reactor. The particle size can be kept at 320 nm and has not changed over time.
    权利要求:
    Claims (4)
    [1]
    1. Method for manufacturing micro or nanoparticles of substances soluble or insoluble in water by means of controlled precipitation, coprecipitation and self-organization processes in microjet reactors, one solvent, containing at least one target molecule, and one not -solvent are mixed like jets that meet, with defined pressure and flow rates, in a microjet reactor, with very rapid precipitation, coprecipitation or a chemical reaction, where micro or nanoparticles arise within them, characterized by the the particle size of the micro 10 or nanoparticles is controlled by means of the temperature, which arises due to the collision of the solvent with the non-solvent, the flow rate of the solvent and the non-solvent and / or the amount of gas in the microjet reactor compartment, temperature of 40 ° C, solvent and non-solvent flow rates above 0.1 ml / min as impinging jets handle a speed greater than, 1 m / s or greater than 50 m / s and 15 with a Reynold coefficient above 100 or above 500, as well as complete absence of gas, smaller particle sizes are obtained, in proportion to the weight of the target molecule relative to the auxiliary additive is at least 1: 100; the particles generated in the precipitation can be subjected, immediately after the precipitation (eg, within 0.1 to 5 s) in a second cascade microjet reactor or after a mechanical treatment, which can occur by means of ultrasound, pressure of the dispersion with pressure by means of injections or by means of strong agitation, in an UltraTurrax or as Impinging Jets by means of simple or multiple treatment, pressures of 1 bar or greater than 10 bar or above 50 bar, controlled by means of a pressure regulator and precipitation occurs at the meeting point of the jets, which, depending on the geometry of the reactor, forms a structure in the shape of a double plate of liquid currents moving rapidly, in whose area of the rim of the plate there is a fast mixing, usually with mixing speeds below 1 millisecond, below 0.5 milliseconds or below 0.1 milliseconds.
    2. Method according to claim 1, characterized in that the target molecule is selected from the group composed of substances of biological use, substances for image formation, cosmetic substances, dyes, pigments, foods, food additives, food supplements, biocides, insecticides, fungicides, pesticides,
    Petition 870180141153, of 10/15/2018, p. 12/13
    [2]
    2/2 herbicides, substances for pharmaceutical use, in particular human or veterinary pharmaceutical products.
    5
    [3]
    Method according to claim 1, characterized in that the solvent and the non-solvent are vaporized in sequence from the resulting suspension.
    [4]
    4. Device for the manufacture of micro or nanoparticles of substances soluble or insoluble in water in microjet reactors, which have at least two injectors with 10 pumps assigned to each of them and conducting tubes to inject a liquid medium into a reactor compartment, respectively. closed by a reactor housing, at a common collision point, and it is provided with a first opening in the reactor housing, through which a gas can be inserted to maintain the gaseous atmosphere in the reactor compartment, mainly at the point collision of the liquid jets, as well as for cooling the generated product, and it is also provided with another opening to remove the generated product and excess gas out of the reactor housing, characterized by temperature control agents of liquids, the flow rate of liquids and / or agents to control the amount of gas in the reactor compartment.
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    同族专利:
    公开号 | 公开日
    BR112012023983A2|2016-08-02|
    JP2013522028A|2013-06-13|
    CN102883798B|2016-02-24|
    KR20130062270A|2013-06-12|
    EA201201311A1|2013-03-29|
    AU2011232103A1|2012-10-25|
    DK2550092T3|2018-12-10|
    EA025562B1|2017-01-30|
    CN102883798A|2013-01-16|
    PT2550092T|2018-11-13|
    JP6025706B2|2016-11-16|
    CA2799519C|2017-04-25|
    CA2799519A1|2011-09-29|
    CL2012002625A1|2013-02-15|
    ZA201206810B|2013-05-29|
    ES2692651T3|2018-12-04|
    PL2550092T3|2019-01-31|
    NZ602674A|2013-10-25|
    TR201816320T4|2018-11-21|
    AU2011232103B2|2013-10-24|
    EP2550092A1|2013-01-30|
    MX2012010868A|2013-02-26|
    US20130012551A1|2013-01-10|
    KR101823706B1|2018-01-30|
    US8852644B2|2014-10-07|
    EP2550092B1|2018-08-15|
    WO2011116763A1|2011-09-29|
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    法律状态:
    2018-01-02| B25D| Requested change of name of applicant approved|Owner name: INSTILLO GMBH (DE) |
    2018-07-17| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
    2019-02-12| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2019-03-26| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/03/2011, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/03/2011, OBSERVADAS AS CONDICOES LEGAIS |
    优先权:
    申请号 | 申请日 | 专利标题
    DE102010010996|2010-03-22|
    DE102010010996.7|2010-03-22|
    PCT/DE2011/075044|WO2011116763A1|2010-03-22|2011-03-21|Method and device for producing microparticles or nanoparticles|
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