EP1707256B1 - Device and method for continuously producing emulsions or dispersions - Google Patents

Device and method for continuously producing emulsions or dispersions Download PDF

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Publication number
EP1707256B1
EP1707256B1 EP06015110.7A EP06015110A EP1707256B1 EP 1707256 B1 EP1707256 B1 EP 1707256B1 EP 06015110 A EP06015110 A EP 06015110A EP 1707256 B1 EP1707256 B1 EP 1707256B1
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EP
European Patent Office
Prior art keywords
mixing vessel
emulsion
emulsions
mixing
wie
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EP06015110.7A
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German (de)
French (fr)
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EP1707256A1 (en
Inventor
Gerd Dahms
Helmut Hegmann
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Kemira Oyj
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Kemira Oyj
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Priority to EP06015110.7A priority Critical patent/EP1707256B1/en
Priority claimed from EP03816337A external-priority patent/EP1606044B2/en
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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40Mixing liquids with liquids; Emulsifying
    • B01F23/405Methods of mixing liquids with liquids
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40Mixing liquids with liquids; Emulsifying
    • B01F23/43Mixing liquids with liquids; Emulsifying using driven stirrers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/50Mixing liquids with solids
    • B01F23/53Mixing liquids with solids using driven stirrers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01FMIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00Other mixers; Mixing plants; Combinations of mixers
    • B01F33/80Mixing plants; Combinations of mixers
    • B01F33/81Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles

Definitions

  • the invention relates to an apparatus and a method for the continuous production of emulsions or dispersions, in particular for the production of nanoemulsions.
  • the preparation of emulsions and dispersions is usually carried out batchwise in stirred reactors.
  • the required amounts of the starting materials are metered into a mixing vessel and emulsified or dispersed with a high degree of stirring.
  • high-performance stirrers are used which allow the generation of cavitation forces.
  • high-pressure homogenization is performed.
  • a control of the emulsions and dispersions prepared and the process is usually carried out only on the finished product of the corresponding mixture batch. A continuous review of the manufacturing process is usually not possible.
  • the US-A-4539-139 discloses a batch process for the preparation of oil-in-water emulsions.
  • discontinuous Standsvornchtungen be designed to be large, in order to produce suitable product quantities. This is associated with significant investment costs.
  • high degree of stirring results in high energy costs.
  • solid lipid nanoparticles English solid lipid nanoparticles particles - SLN
  • SLN has not been able to assert itself on a large scale so far.
  • SLN dispersions The preparation of SLN dispersions is usually carried out by high-pressure homogenization. Depending on the lipid and surfactant used, different particle shapes are obtained. A distinction is made between hot homogenisation and cold homogenisation. After melting the lipid and dissolving or dispersing the active ingredient is dispersed in the hot homogenization in hot surfactant solution. Then, a high-pressure homogenization of this pre-emulsion is carried out, which is then converted into a hot O [W nanoemulsion. After cooling and recrystallization, solid lipid nanoparticles (SLN) are obtained. In cold homogenization, after melting the lipid and dissolving or dispersing the drug, the drug-lipid mixture is solidified and then ground to microparticles.
  • the particles are suspended in cold surfactant solution, and high-pressure homogenization of the particle suspension is carried out.
  • the cavitation and shear forces encountered in high pressure homogenization are sufficiently great to break the lipid microparticles into lipid nanoparticles.
  • the pre-emulsion is usually homogenized in a hot-melt piston-gap homogenizer at pressures between 200 bar and a maximum of 1500 bar. This produces an emulsion whose lipid phase recrystallizes on cooling to SLN.
  • a hot-melt piston-gap homogenizer at pressures between 200 bar and a maximum of 1500 bar.
  • the SLN technology is used in particular for the application of pharmaceutical, cosmetic and / or food technology active ingredients in a solid carrier.
  • the drug carrier can be adapted to the particular application and allows a suitable dosage and release of the drug.
  • the SLNs represent an alternative carrier system to emulsions and liposomes.
  • the nanoparticles may contain hydrophilic or hydrophobic pharmaceutical agents and may be administered orally or parenterally.
  • a solid lipid is used as the matrix material.
  • physiologically acceptable lipids or lipids from physiological components such as glycerides from the body's own fatty acids are used.
  • emulsifiers or surfactants are usually used as in the production of emulsions and dispersions.
  • a process for the preparation of SLN dispersions is for example in EP-B-0 167 825 described.
  • the lipid nano pellets are prepared by dispersing the molten lipid with water using a high speed stirrer. Subsequently, the desired particle size distribution is adjusted by ultrasonic treatment. The stirring is usually carried out at speeds in the range of 20 000 min -1 .
  • the US-A-5250-576 discloses a process for the continuous production of high internal phase emulsions suitable for polymerization into polymer foam.
  • the object of the present invention is to provide a continuous, inexpensive process for the preparation of emulsions and dispersions, which in particular allows the production of nanoemulsions with controlled particle size.
  • the device and method are intended to allow in-process / online quality controls.
  • the production compared to conventional batch processes should be simplified and accelerated.
  • the production of variable amounts of emulsions or dispersions should also be possible.
  • the object is achieved by a method according to claim 1 or by a device according to claim 4.
  • the mixing vessel is closed on all sides. This means that apart from inlets and outlets and stirrer feedthroughs or feedthroughs for analytical sensors, the mixing vessel is closed. If both the supply and discharge pipes are filled with flowable materials and stirring and possibly also analytical sensors are present, the mixing vessel is closed to the admission of air or oxygen. This design of the mixing vessel is covered by the term "closed on all sides".
  • the stirrer allows mechanical stirring into the emulsion or dispersion without generating cavitation forces and without high pressure homogenization.
  • suitable stirrer elements are arranged on a stirrer axis that is rotated.
  • the stirrer tool may be so-called rotor / stator systems in which a rotor is moved by a motor.
  • the stator is usually the housing, which may be provided with internals such as crushers.
  • Suitable stirrers are, for example, paddle stirrers, which may optionally be provided with scrapers.
  • kneaders and other suitable stirrers such as planetary stirrers, anchor stirrers, bar stirrers, propellers, blade stirrers, dissolver disks or Intermig can be used.
  • Other suitable stirrer configurations are known to those skilled in the art.
  • the stirring tool is operated in such a way that stirring is effected in the emulsion or dispersion without generation of cavitation forces and without high-pressure homogenization.
  • grinding tools such as grinding beads or balls. Suitable grinding tools are known in the art.
  • the mixing vessel may have any suitable geometry, as long as it allows a suitable mixing of the flowable substances or mixtures or the phases of the emulsions and dispersions to be prepared. Suitable geometries are known to the person skilled in the art.
  • the mixing vessel has a substantially cylindrical shape, wherein the axis of the stirring tool lies in the cylinder axis and the supply and discharge pipes are arranged substantially perpendicular to the cylinder axis in the upper and lower peripheral region of the cylinder spaced from each other.
  • the supply and discharge pipes are thus, as far as possible from one another along the cylinder axis, arranged in positions along the cylinder circumference. They are arranged substantially perpendicular to the cylinder axis.
  • Deviations of ⁇ 10 °, preferably ⁇ 5 ° are possible.
  • the arrangement can be adapted to the practical requirements.
  • the flowable substances or mixtures are introduced or supplied separately in the first mixing vessel.
  • the corresponding feed tubes preferably protrude somewhat into the mixing vessel.
  • the individual components of the oil phase and the individual components of the water phase can be premixed separately. It is also possible for the oil phase and the water phase to be combined in a premixing stage and introduced together into the mixing vessel.
  • the oil phase and the water phase or similar other phases are fed separately from each other into the mixing vessel.
  • One or more supply and discharge pipes can be provided.
  • two or more, in particular two or three feed tubes and a discharge tube are provided.
  • the size of the mixing vessel can be selected according to the respective practical requirements.
  • the internal volume (free volume) of the mixing vessel is preferably from 2 to 70 ml, particularly preferably from 3 to 50 ml, in particular from 5 to 15 ml.
  • the internal volume is preferably from 70 to 500 ml, more preferably from 100 to 400 ml Scale is the volume preferably more than 500 ml, for example 500 to 50 000 ml.
  • mixing vessels of about 7 ml volume can be used, which have a cylindrical shape and an inner diameter of 20 mm and an inner height of 25 mm.
  • the internal volume can also be controlled by the thickness or the diameter of the rotor axis. So it is also possible that configurations are obtained according to an annular chamber reactor.
  • the residence times in the first mixing vessel are preferably 2 to 600 seconds, more preferably 4 to 100 seconds, in particular 8 to 40 seconds.
  • a mixing vessel Preferably, however, at least two mixing vessels are connected in series one behind the other, wherein the discharge from the first mixing vessel is introduced into the second mixing vessel and a further feed pipe is provided in the second mixing vessel. Also, the second (and following) mixing vessel has an agitator as described. It is accordingly also possible to provide longer cascades of mixing vessels, wherein the discharge of a mixing vessel is supplied to the next mixing vessel and optionally further entries in the additional mixing vessel can be registered. Preferably, two or three, in particular two mixing vessels connected in series, are used.
  • a tempering can be achieved by cooling or heating jackets or by integrating the mixing vessel in an oven or a cryostat. Suitable devices for heating / cooling or temperature control of the mixing vessels are known in the art
  • the ratio of the inflows in the first mixing vessel is set so that it is used in the first mixing vessel in the viscoelastic or highly viscoelastic region during mixing.
  • the viscoelastic region indicates the region in which the viscoelastic fluids exhibit non-Newtonian fluid behavior.
  • the dependence of the viscosity of an emulsion or dispersion on the volume fraction of the disperse phase usually corresponds to an exponential function.
  • the important viscoelastic region in which work is preferably carried out according to the invention is the region in which the viscosity increases very greatly with increasing volume fraction of the disperse phase.
  • the weight ratio of the phases is preferably in a range of 1:15 to 15: 1, preferably 1: 5 to 5: 1, preferably 1: 2 to 2: 1, especially 1: 1.5 to 1.5 : 1 chosen.
  • the weight fractions of the corresponding phases are preferably in this range.
  • this work is highly viscous in the first stage and low-viscosity in the subsequent second stage.
  • the setting of a finely divided emulsion or dispersion is achieved in the first reactor, while the dilution is carried out to the final concentration of the product in the second mixing vessel. Since in this case a supplementary amount of at least one of the phases or a further phase is introduced into the second mixing vessel, the residence time in the second mixing vessel is correspondingly shorter, if both mixing vessels have the same internal volume.
  • the microemulsion obtained when mixing the phases can be understood as a system of two interpenetrating networks, so that the microemulsion exhibits single-phase behavior.
  • At least one sensor for continuously measuring the temperature, conductivity and / or optical properties of the emulsion or dispersion is arranged in the discharge tubes of the mixing vessels or at least one discharge tube of a mixing vessel.
  • a corresponding sensor is usually provided in the vicinity of the mixing vessel in the discharge pipe.
  • Suitable sensors for determining the electrical conductivity, the temperature or optical properties such as turbidity are known in the art.
  • a sight glass can also be provided, by means of which an optical or visual control of the clarity or turbidity of the emulsion / dispersion is possible.
  • Machine-aided optical techniques include laser light scattering and absorbance measurements.
  • Optical methods for determining the particle size in the emulsions or dispersions can also be used for process control. Furthermore, it is possible to carry out viscosity measurements, for example according to Brookfield, for example in line. The visual / visual control can be carried out by suitable and trained personnel. Furthermore, it is possible to determine the amount of energy input by the stirrer. Here, too, can be reacted quickly in deviations of the energy input, as this may indicate a change in the composition of the emulsion / dispersion. Overall, the continuous determination of one or more of the mentioned parameters allows a continuous process control and a continuous control of the composition of the emulsion or dispersion. The quality assurance in the production is thus considerably improved or simplified. This is particularly important in pharmaceutical products of high importance.
  • phase volume ratio About the conductivity statements about the phase volume ratio are possible. By measuring the conductivity, it is therefore easy to determine changes in the emulsion composition or in the phase volumes.
  • the process control is preferably carried out online, ie continuously during the manufacturing process. This makes it possible to react immediately to deviations of the compositions of the emulsions or dispersions. If, for example, the volume flows of the phases used change, the mixing vessel becomes different Phase volume ratio obtained, resulting in a changed conductivity.
  • the adjustment of the volume flows can in turn also be controlled in order to ensure constant volume flows.
  • the supply of the flowable substances and the stirring and optionally the temperature of the mixing vessels are computer controlled.
  • a central computer can be used to control and control all process parameters.
  • the measured values supplied by the sensors can also be fed to the computer and evaluated computer-aided.
  • the dosage of the different flowable substances for example, by suitable pumps.
  • suitable pumps are known in the art. They are preferably independent of the back pressure and can be controlled in fine gradation.
  • suitable pumps are gear pumps, peristaltic / peristaltic pumps and other suitable pumps.
  • the combination of these pumps with the mixing vessels used according to the invention allows the bubbles and air-free production of emulsions. In the entire path of the flowable substances, the access of air is made difficult or impossible, since all process steps are carried out in a closed system. This is a further advantage of the process according to the invention, wherein expensive process steps such as evacuation of the emulsions can be dispensed with.
  • the device according to the invention can be operated at low pressure, in particular at a pressure in the range of 1 to 10 bar, more preferably 1 to 1.5 bar.
  • the process is accordingly carried out at a pressure in this range.
  • the mixing vessels and lines can be constructed of any suitable materials.
  • suitable inert materials are plastics, steels such as V2A or V4A steel or copper. Suitable materials or materials are known in the art.
  • the device can be constructed according to a modular principle of individual components. These individual components can be, for example, pumps, mixing vessels, sensor elements, stirring motors, tempering units and connecting elements. All pumps and stirring motors can be controlled via a central computer.
  • stirrer the size of the mixing vessels and the feed streams is based on the practical requirements and is to be determined by simple preliminary tests. Particularly in the two-stage procedure, low viscosity can be used in the first stage and low viscosity in the second stage, whereby a large number of different emulsions or dispersions can be obtained in a simple manner.
  • thickeners may optionally be added to the individual phases or flowable substances or mixtures of substances. This makes it possible in a simple manner to get into a suitable viscosity range, which allows the production of finely divided emulsions and dispersions with little stirring.
  • the advantages of the continuous versus discontinuous processes according to the invention are manifold:
  • the preparation of the emulsions or dispersions is substantially accelerated.
  • the production of 1 liter of an emulsion in a continuous batch process with heating, cooling and homogenizing takes at least about 1.5 hours.
  • no statements about the quality of the emulsions or dispersions are possible.
  • the inventive method allows a. corresponding production in a maximum of about 15 minutes, whereby the emulsions or dispersions can be analyzed and controlled in the process (in-process product control).
  • a variation of the product quantities is possible in a simple manner over the length of the production period.
  • very different approach sizes can be realized in a simple manner.
  • By varying the feed streams into the mixing vessels a variation of the composition of the emulsions or dispersions is possible in a simple manner.
  • nanoemulsions with particle or droplet sizes in the range of 15 to 300 nm, at most 1000 nm is possible in a simple manner.
  • the amount of emulsifier used can be significantly reduced. Often you can work with less than half of the usual amount of emulsifier.
  • the device according to the invention can be inexpensively adapted to a variety of applications by selecting suitable stirring tools.
  • a cleaning of the device according to the invention is possible because of the small size in a simple and fast manner.
  • changing the emulsions or dispersions to be produced can also be dispensed with a cleaning.
  • the materials or streams used are varied according to the new product composition, and the first output from the mixing vessels is discarded.
  • the change in the emulsion until the constant desired product composition is obtained can in turn be monitored via the online process control.
  • the apparatus and method of the present invention are applicable to a variety of emulsions or dispersions.
  • emulsions or multiple emulsions are prepared according to the invention.
  • examples are OW emulsions, WO emulsions, PO emulsions, multiple emulsions, LC gels, liposomes or pearlescent concentrates. Since working air-free, oxidation-sensitive active ingredients can be introduced into the emulsions in an advantageous manner.
  • the inventive method allows the production of highly viscous systems such as gels. Liposomes can also be made at low pressure. Thus, the production of emulsions, ointments, gels for all customary pharmaceutical, cosmetic, food technology or detergent technology areas is possible. Other fields of application are accessible according to the invention.
  • Nanoemulsions have emulsion droplets having an average diameter in the range of 5 to 1000 ⁇ m, preferably 15 to 300 nm.
  • a finely divided primary emulsion is generally prepared in the first mixture under high-viscosity conditions, which is diluted in the second mixing vessel with one of the two phases to the desired final concentration.
  • an OW emulsion can be prepared in the first mixing vessel with high oil contents, wherein the primary emulsion thus obtained is diluted in the second mixing vessel with the addition of water to the desired final concentration. In this procedure, the main part of the external phase is diluted in the second mixing device.
  • the active substance and the lipid-based active substance carrier and at least one emulsifier which forms lamellar structures can first be at a temperature above the melting or softening point of the active ingredient carrier be mixed.
  • a phase B is formed.
  • this phase B can be mixed with an aqueous phase A at a temperature above the melting or softening point of the active ingredient carrier.
  • This mixture is carried out, for example, in the first mixing vessel.
  • the mixed phase can then be diluted with an aqueous phase to the desired final concentration. This dilution can be carried out in the second mixing vessel.
  • the active ingredient carrier particles used are lipid-based particles. These include lipids and lipid-like structures.
  • suitable lipids are the mono-, di- and triglycerides of the saturated straight-chain fatty acids having 12 to 30 carbon atoms, such as lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, cerotic, meleinic, as well as their esters with other polyhydric alcohols such as ethylene glycol , Propylene glycol, mannitol, sorbitol, saturated fatty alcohols having 12 to 22 carbon atoms, such as lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, saturated wax alcohols having 24 to 30 carbon atoms, such as lignoceryl alcohol, ceryl alcohol, cerotyl alcohol, myrizyl alcohol.
  • synthetic mono-, di- and triglycerides are used as individual substances or in the form of a mixture, for example in the form of a hard fat.
  • Glycerol trifatty acid esters are, for example, glycerol trilaurate, glycerol trimyristate, glycerol palmitate, glycerol tristearate or glycerol tribehenate.
  • Suitable waxes are, for example, cetyl palmitate and Cera Alba (bleached wax, DAB 9).
  • lipids it is also possible to use polysaccharides with or in individual cases or polyalkyl acrylates, polyalkyl cyanoacrylates, polyalkylvinylpyrrolidones, acrylic polymers, polylactic acids or polylactides.
  • the amount of active ingredient carrier particles, based on the total aqueous active ingredient carrier dispersion, is preferably 0.1 to 30 wt .-%, particularly preferably 1 to 10 wt .-%.
  • dispersion stabilizers can be used. They can be used, for example, in amounts of from 0.01 to 10% by weight, preferably from 0.05 to 5% by weight.
  • Suitable substances are surfactants, in particular ethoxylated sorbitan fatty acid esters, block polymers and block copolymers (such as poloxamers and poloxamines), polyglycerol ethers and esters, lecithins of various origins (for example egg or soya lecithin), chemically modified lecithins (for example hydrogenated lecithin) as well Phospholipids and sphingolipids, mixtures of lecithins with phospholipids, sterols (for example cholesterol and cholesterol derivatives and stigmasterol), esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols (for example sucrose monostearate), sterically stabilizing substances such as poloxamers and poloxamines (polyoxyethylene-polyoxypropylene) Block polymers), ethoxylated sorbitan fatty acid esters, ethoxylated mono- and diglycerides, ethoxylated lipids and lipid
  • viscosity-increasing substances such as cellulose ethers and esters (for example methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose), polyvinyl derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetate, alginates, polyacrylates (for example carbopol), xanthans and pectins.
  • cellulose ethers and esters for example methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose
  • polyvinyl derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetate, alginates, polyacrylates (for example carbopol), xanthans and pectins.
  • aqueous phase A water, aqueous solutions or mixtures of water with water-miscible liquids such as glycerol or polyethylene glycol can be used.
  • Further additional components for the aqueous phase are, for example Mannose, glucose, fructose, xylose, trehalose, mannitol, sorbitol, xylitol or other polyols such as polyethylene glycol and electrolytes such as sodium chloride. These additional components can be used in an amount of 0.5 to 60, for example 1 to 30 wt .-%, based on the aqueous phase A.
  • viscosity increasing agents or charge carriers can also be used, as described in US Pat EP-B-0 605 497 are described.
  • emulsifiers forming lamellar structures natural or synthetic products can be used.
  • the use of surfactant mixtures is possible.
  • suitable emulsifiers are the physiological bile salts such as sodium cholate, sodium dehydrocholate, sodium deoxycholate, sodium glycocholate, sodium taurocholate.
  • Animal and plant phospholipids such as lecithins with their hydrogenated forms as well as polypeptides such as gelatin with their modified forms can also be used.
  • Suitable synthetic surface-active substances are the salts of sulfosuccinic acid esters, polyoxyethylene acid betanesters, acid betanesters and sorbitan ethers, polyoxyethylene fatty alcohol ethers, polyoxyethylene stearates and corresponding mixed condensates of polyoxyethylene-methopolyoxypropylene ethers, ethoxylated saturated glycerides, partial fatty acid glycerides and polyglycides.
  • suitable surfactants are Biobase® EP and Ceralution® H.
  • emulsifiers are also glycerol esters, polyglycerol esters, sorbitan esters, sorbitol esters, fatty alcohols, propylene glycol esters, alkylglucositesters, sugar esters, lecithin, silicone copolymers, wool wax and mixtures thereof or derivatives.
  • Glycerol esters, polyglycerol esters, alkoxylates and fatty alcohols and isoalcohols can be derived, for example, from castor fatty acid, 12-hydroxystearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, myristic acid, lauric acid and capric acid.
  • succinates, amides or ethanolamides of the fatty acids may also be present.
  • Particularly suitable fatty acid alkoxylates are the ethoxylates, propoxylates or mixed ethoxylates / propoxylates.
  • Emulsifiers are also generally used to prepare the cosmetic emulsions according to the invention.
  • suitable emulsifiers are glycerol esters, polyglycerol esters, sorbitan esters, sorbitol esters, fatty alcohols, propylene glycol esters, Alkylglucoside esters, sugar esters, lecithin, silicone copolymers, wool wax and their mixtures and derivatives.
  • Glycerol esters, polyglycerol esters, alkoxylates and fatty alcohols and isoalcohols can be derived, for example, from castor fatty acid, 12-hydroxystearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, myristic acid, mauric acid and capric acid.
  • succinates, amides or ethanolamides of the fatty acids may also be present.
  • Particularly suitable fatty acid alkoxylates are the ethoxylates, propoxylates or mixed ethoxylates / propoxylates. It is also possible to use emulsifiers which form lamellar structures.
  • emulsifiers examples include the physiological bile salts such as sodium cheolate, sodium dehydrocheolate, sodium deoxycheolate, sodium glycochelate, sodium taurochalate.
  • physiological bile salts such as sodium cheolate, sodium dehydrocheolate, sodium deoxycheolate, sodium glycochelate, sodium taurochalate.
  • Animal and plant phospholipids such as lecithins with their hydrogenated forms as well as polypeptides such as gelatin with their modified forms can also be used.
  • Suitable synthetic surfactants are the salts of sulfosuccinic, Polyoxiethylenchurebethanester, pressureurebethanester and sorbitan, Polyoxiethylenfettalkoholether, Polyoxiethylenstearinklareester and corresponding mixture condensates of Polyoxiethylen-methpolyoxipropylenethern, ethoxylated saturated glycerides, partial fatty acid glycerides and polyglycides.
  • suitable surfactants are Biobase ® EP and Ceralution ® H.
  • Lipids and emulsifiers are preferably used in a weight ratio of 50: 1 to 2: 1, preferably 15: 1 to 30: 1.
  • the pharmaceutical, cosmetic and / or food-technological active ingredients are, based on the phase B, preferably used in an amount of 0.1 to 80 wt .-%, particularly preferably 1 to 10 wt .-%.
  • Suitable active ingredients are, for example, also dichlorphenac, ibuprofen, acetylsalicylic acid, salicylic acid, erythromycin, ketoprofen, cortisone, glucocorticoids.
  • cosmetic active ingredients which are particularly susceptible to oxidation or hydrolysis, for example polyphenols.
  • Catechins such as epicatechin, epicatechin-3-gallate, epigallocatechin, epigallocatechin-3-gallate
  • flavonoids such as luteolin, apigenin, rutin, quercitin, fisetin, kaempherol, rhametin
  • isoflavones such as genistein, daidzein, glycitein, Prunetin
  • coumarins such as daphnetin, umbelliferone
  • emodin emodin
  • resveratrol oregonin.
  • vitamins such as retinol, tocopherol, ascorbic acid, riboflavin, pyridoxine.
  • whole extracts from plants that. including the above molecules or classes of molecules.
  • the active substances are, according to one embodiment of the invention, light protection filters. These can be present as organic sunscreen at room temperature (25 ° C) in liquid or solid form.
  • Suitable light protection filters are, for example, compounds based on benzophenone, diphenylcyanoacrylate or p-aminobenzoic acid.
  • organic sunscreen filters are octyltriazone, avobenzone, octylmethoxycinnamates, octylsalicylates, benzotriazoles and triazines.
  • anti-dandruff agents are used as active ingredients, as they are usually present in cosmetic or pharmaceutical formulations.
  • An example of this is Piroctone Olamine (1-hydroxy-4-methyl-6- (2,4,4-dimethylpentyl) -2 (1H) -pyridone, preferably in combination with 2-aminoethanol (1: 1)).
  • Other suitable agents for the treatment of dander are known in the art.
  • emulsions are hydrophilic coated micropigments, electrolytes, glycerol, polyethylene glycol, propylene glycol, barium sulfate, alcohols, waxes, metal soaps, magnesium stearate, vaseline or other ingredients.
  • perfumes perfume oils or perfume flavors.
  • Suitable cosmetic agents for example polyphenols and compounds derived therefrom.
  • Suitable vitamins are retinol, tocopherol, ascorbic acid, ribovavin and pyridoxine.
  • active ingredients for example, all oxidation-sensitive active ingredients such as tocopherol come into consideration.
  • organic dyes are used as active ingredients or instead of active substances.
  • water-in-oil emulsions or oil-in-water emulsions can be prepared by the process according to the invention. These can be used after the emulsifiers described and other ingredients. Furthermore, the preparation of polyol-in-oil emulsions is possible. Any suitable polyols can be used here.
  • the proportions of the two main phases can be varied within wide limits. For example, from 5 to 95% by weight, preferably from 10 to 90% by weight, in particular from 20 to 80% by weight, of the respective phases are present, the total amount being 100% by weight.
  • The. described P / O emulsion can also be emulsified in water or a water-in-oil emulsion. This results in a polyol-in-oil-in-water emulsion (P / O / W emulsion) containing at least one described emulsion and additionally at least one aqueous phase.
  • P / O / W emulsion polyol-in-oil-in-water emulsion
  • Such multiple emulsions may correspond in structure to the emulsions described in DE-A-43 41 113.
  • the weight ratio of the individual phases can be varied within wide limits.
  • the weight fraction of the P / O emulsion is preferably from 0.01 to 80% by weight, particularly preferably from 0.1 to 70% by weight, in particular from 1 to 30% by weight. %, based on the total P / O / W emulsion.
  • the proportion of the P / O emulsion is preferably 0.01 to 60% by weight, particularly preferably 0.1 to 40% by weight, in particular 1 to 30 wt .-%, based on the finally obtained P / O / W emulsion.
  • the oil content is preferably 1 to 80% by weight, particularly preferably 1 to 30% by weight, based on the O / W emulsion used.
  • a W / O emulsion can also be introduced, which leads to a W / O / W emulsion.
  • the individual phases of the emulsions may still have conventional ingredients known for the individual phases.
  • the individual phases may contain further pharmaceutical or cosmetic active substances which are soluble in these phases.
  • the aqueous phase may contain, for example, organic soluble sunscreen, hydrophilically coated micropigment, electrolytes, alcohols, etc.
  • any or all of the phases may contain solids which are preferably selected from pigments or micropigments, microspheres, silica gel, and the like.
  • the oil phase can For example, organically modified clay minerals, hydrophobic coated (micro) pigments, organic oil-soluble sunscreen, oil-soluble cosmetic agents, waxes, metal soaps such as magnesium stearate, Vaseline or mixtures thereof.
  • Titanium dioxide, zinc oxide and barium sulfate, as well as wollastonite, kaolin, talc, Al 2 O 3 , bismuth oxychloride, micronized polyethylene, mica, ultramarine, eosin dyes, azo dyes, may be mentioned as (micro) pigments.
  • Titanium dioxide or zinc oxide in particular, are customary in cosmetics as light protection filters and can be applied particularly smoothly and evenly to the skin by means of the emulsions according to the invention.
  • Microspheres or silica gel can be used as carriers for drugs, and waxes can be used, for example, as a base for polishes.
  • the water phase may further contain glycerin, polyethylene glycol, propylene glycol, ethylene glycol and the like, as well as derivatives thereof.
  • aqueous phase water, aqueous solutions or mixtures of water with water-miscible liquids such as glycerol or polyethylene glycol can be used. Further, electrolytes such as sodium chloride may be contained in the aqueous phase. If desired, it is also possible to use viscosity-increasing substances or charge carriers, as described in US Pat EP-B-0605497 are described.
  • Emulsification of an acrylate resin (80% in EEP) sample Phase A: Protelan LS 9011 Sodium lauroyl sarcosinate 0.38% Brij 35 P Nena Laureth-23 0.41% Brij 700 Steareth-100 0.41% demin. water 6.00% WorléeCryl product acrylate 63.0% demin. water 29.8% 100.0% Speed level 1 [min-1] 3000 Speed level 2 [min-1] 2400 Dwell time level 1 [s] 25 Dwell time level 2 [s] 16 Median [ ⁇ m] 0.67 ⁇ 1 ⁇ m [%] 82.0 m 2 / cm 3 11.0
  • Phase A Protelan LS 9011 Sodium lauroyl sarcosinate 0.75% Brij 35 P Nena Laureth-23 1.30% Pricerine 9091 glycerin 2.25% demin. water 2.25%
  • Phase B Cutina CP Cetyl palmitate 44.8% a-tocopherol tocopherol 11.2%
  • Phase C demin. water 37.5% 100.0% Speed level 1 [min-1] 4000 Speed level 2 [min-1] 3200 Dwell time level 1 [s] 12 Dwell time level 2 [s] 8th.
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Description

Die Erfindung betrifft eine Vorrichtung und ein Verfahren zur kontinuierlichen Herstellung von Emulsionen oder Dispersionen, insbesondere zur Herstellung von Nanoemulsionen.The invention relates to an apparatus and a method for the continuous production of emulsions or dispersions, in particular for the production of nanoemulsions.

Die Herstellung von Emulsionen und Dispersionen erfolgt in der Regel diskontinuierlich in Rührreaktoren. Dabei werden die erforderlichen Mengen der Einsatzstoffe in ein Mischgefäß dosiert und unter hohem Rühreintrag emulgiert oder dispergiert. In der Regel werden dazu Hochleistungsrührer eingesetzt, die die Erzeugung von Kavitationskräften erlauben. Alternativ wird eine Hochdruckhomogenisierung durchgeführt. Eine Kontrolle der hergestellten Emulsionen und Dispersionen und des Verfahrens erfolgt in der Regel erst am fertigen Produkt der entsprechenden Mischungscharge. Eine kontinuierliche Überprüfung des Herstellungsprozesses ist in der Regel nicht möglich.The preparation of emulsions and dispersions is usually carried out batchwise in stirred reactors. The required amounts of the starting materials are metered into a mixing vessel and emulsified or dispersed with a high degree of stirring. As a rule, high-performance stirrers are used which allow the generation of cavitation forces. Alternatively, high-pressure homogenization is performed. A control of the emulsions and dispersions prepared and the process is usually carried out only on the finished product of the corresponding mixture batch. A continuous review of the manufacturing process is usually not possible.

Die US-A-4539-139 offenbart ein diskontinuierliches Verfahren zur Herstellung von Öl-in-Wasseremulsionen.The US-A-4539-139 discloses a batch process for the preparation of oil-in-water emulsions.

Darüber hinaus ist eine Variation der Produktmengen nur in sehr begrenztem Umfang möglich, da die mögliche Ansatzgröße bei einem Chargenmischer in einem eng begrenzten Bereich liegt. Die minimale Ansatzgröße darf in der Regel die Hälfte der maximalen Ansatzgröße nicht unterschreiten.In addition, a variation of the product quantities is possible only to a very limited extent, since the possible batch size in a batch mixer is within a narrow range. The minimum batch size must not be less than half of the maximum batch size.

Auch im Hinblick auf eine sterile Verarbeitung ist ein diskontinuierliches Verfahren problematisch. In der Regel wird in offenen Rührkesseln gearbeitet, so dass Kontaminationen von außen nicht ausgeschlossen werden können. Sofern unter Luftausschluss gearbeitet werden soll, ist ein aufwändiges Verfahren zur Evakuierung der Mischgefäße zum Arbeiten unter Vakuum notwendig.Also in view of a sterile processing, a batch process is problematic. As a rule, work is done in open stirred kettles, so that contamination from the outside can not be ruled out. If you want to work under exclusion of air, a complex process for evacuating the mixing vessels to work under vacuum is necessary.

Darüber hinaus müssen diskontinuierliche Mischungsvornchtungen groß ausgelegt werden, um geeignete Produktmengen erzeugen zu können. Dies ist mit erheblichen Investitionskosten verbunden. Zudem führt der hohe Rühreintrag zu hohen Energiekosten. Insbesondere bei der Herstellung von Nanoemulsionen, speziell festen Lipidnanopartikeln (englisch solid lipid nano particles - SLN) fehlen bislang großtechnische Herstellungsverfahren. Daher konnten sich SLN bislang nicht in größerem Umfang durchsetzen.In addition, discontinuous Mischungsvornchtungen be designed to be large, in order to produce suitable product quantities. This is associated with significant investment costs. In addition, the high degree of stirring results in high energy costs. In particular, in the production of nanoemulsions, especially solid lipid nanoparticles (English solid lipid nanoparticles particles - SLN) lack so far industrial production processes. As a result, SLN has not been able to assert itself on a large scale so far.

Die Herstellung von SLN-Dispersionen erfolgt üblicherweise durch Hochdruckhomogenisation. In Abhängigkeit vom eingesetzten Lipid und Tensid erhält man dabei unterschiedliche Partikelformen. Man unterscheidet die Heißhomogenisation und die Kalthomogenisation. Nach dem Schmelzen des Lipids und Lösen oder Dispergieren des Wirkstoffes wird bei der Heißhomogenisation in heißer Tensidlösung dispergiert. Sodann wird eine Hochdruckhomogenisation dieser Präemulsion durchgeführt, die sodann in eine heiße O[W-Nanoemulsion überführt wird. Nach Abkühlen und Rekristallisation werden feste Lipidnanopartikel (SLN) erhalten. Bei der Kalthomogenisation wird nach Schmelzen des Lipids und Lösen oder Dispergieren des Wirkstoffs die Arzneistoff-Lipidmischung erstarrt und sodann zu Mikropartikeln vermahlen. Anschließend werden die Partikel in kalter Tensidlösung suspendiert, und eine Hochdruckhomogenisation der Partikelsuspension wird durchgeführt. Die bei der Hochdruckhomogenisation auftretenden Kavitations- und Scherkräfte sind ausreichend groß, um die Lipidmikropartikel zu Lipidnanopartikeln zu zerbrechen. Bei der Heißhomogenisation wird die Präemulsion in der Regel in einem Kolben-Spalt-Homogenisator bei Drücken zwischen 200 bar und maximal 1500 bar im heißen Zustand homogenisiert. Hierbei entsteht eine Emulsion, deren Lipidphase beim Erkalten zu SLN rekristallisiert. Für eine Beschreibung der Verfahren kann auf R.H. Müller, G. E. Hildebrandt, Pharmazeutische Technologie: Moderne Arzneiformen, wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 1998, 2. Auflage, Seiten 357 bis 366 verwiesen werden.The preparation of SLN dispersions is usually carried out by high-pressure homogenization. Depending on the lipid and surfactant used, different particle shapes are obtained. A distinction is made between hot homogenisation and cold homogenisation. After melting the lipid and dissolving or dispersing the active ingredient is dispersed in the hot homogenization in hot surfactant solution. Then, a high-pressure homogenization of this pre-emulsion is carried out, which is then converted into a hot O [W nanoemulsion. After cooling and recrystallization, solid lipid nanoparticles (SLN) are obtained. In cold homogenization, after melting the lipid and dissolving or dispersing the drug, the drug-lipid mixture is solidified and then ground to microparticles. Subsequently, the particles are suspended in cold surfactant solution, and high-pressure homogenization of the particle suspension is carried out. The cavitation and shear forces encountered in high pressure homogenization are sufficiently great to break the lipid microparticles into lipid nanoparticles. In the hot homogenization, the pre-emulsion is usually homogenized in a hot-melt piston-gap homogenizer at pressures between 200 bar and a maximum of 1500 bar. This produces an emulsion whose lipid phase recrystallizes on cooling to SLN. For a description of the procedure can be up RH Müller, GE Hildebrandt, Pharmaceutical Technology: Modern Pharmaceutical Forms, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 1998, 2nd edition, pages 357-366 to get expelled.

Die SLN-Technolgie dient insbesondere der Applikation von pharmazeutischen, kosmetischen und/oder lebensmitteltechnologischen Wirkstoffen in einem festen Träger. Der Wirkstoffträger kann dabei an die jeweilige Anwendung angepasst werden und erlaubt eine geeignete Dosierung und Freisetzung des Wirkstoffs. Die SLN stellen ein alternatives Carriersystem zu Emulsionen und Liposomen dar. Die Nanopartikel können hydrophile oder hydrophobe pharmazeutische Wirkstoffe enthalten und können oral oder parenteral verabreicht werden. Als Matrixmaterial wird dabei im Gegensatz zu den bekannten Emulsionen ein festes Lipid eingesetzt. Zur Gewährleistung einer hohen Bioakzeptanz und guter In-Vivo-Abbaubarkeit werden überwiegend physiologisch verträgliche Lipide oder Lipide aus physiologischen Komponenten wie Glyceride aus körpereigenen Fettsäuren verwendet. Bei der Herstellung werden wie bei der Herstellung von Emulsionen und Dispersionen üblicherweise Emulgatoren oder Tenside mit verwendet.The SLN technology is used in particular for the application of pharmaceutical, cosmetic and / or food technology active ingredients in a solid carrier. The drug carrier can be adapted to the particular application and allows a suitable dosage and release of the drug. The SLNs represent an alternative carrier system to emulsions and liposomes. The nanoparticles may contain hydrophilic or hydrophobic pharmaceutical agents and may be administered orally or parenterally. In contrast to the known emulsions, a solid lipid is used as the matrix material. To ensure high bio-acceptance and good in vivo biodegradability predominantly physiologically acceptable lipids or lipids from physiological components such as glycerides from the body's own fatty acids are used. In the production of emulsifiers or surfactants are usually used as in the production of emulsions and dispersions.

Ein Verfahren zur Herstellung von SLN-Dispersionen ist beispielsweise in der EP-B-0 167 825 beschrieben. Die Herstellung der Lipid Nano Pellets erfolgt durch Dispergieren des geschmolzenen Lipids mit Wasser mit einem hochtourigen Rührer. Anschließend wird durch eine Ultraschallbehandlung die gewünschte Teilchengrößenverteilung eingestellt. Das Rühren erfolgt in der Regel mit Drehzahlen im Bereich von 20 000 min-1.A process for the preparation of SLN dispersions is for example in EP-B-0 167 825 described. The lipid nano pellets are prepared by dispersing the molten lipid with water using a high speed stirrer. Subsequently, the desired particle size distribution is adjusted by ultrasonic treatment. The stirring is usually carried out at speeds in the range of 20 000 min -1 .

Die Herstellung von festen Lipid-Nanoteilchen mit geringem mittleren Teilchendurchmesser gemäß dem Stand der Technik ist aufwendig, da in der Regel Hoch-druckhomogenisatoren eingesetzt werden müssen. Durch bloßes Rühren bei hoher Umdrehungszahl werden nur relativ große mittlere Teilchendurchmesser von etwa 3 µm erreicht.The preparation of solid lipid nanoparticles with a low average particle diameter according to the prior art is expensive, since usually high-pressure homogenizers must be used. By merely stirring at high speed only relatively large average particle diameter of about 3 microns can be achieved.

Die US-A-5250-576 offenbart ein Verfahren zur kontinuierlichen Herstellung von High-internal-Phase-Emulsionen die zur Polymerisation zu Polymerschaum geeignet sind.The US-A-5250-576 discloses a process for the continuous production of high internal phase emulsions suitable for polymerization into polymer foam.

Aufgabe der vorliegenden Erfindung ist die Bereitstellung eines kontinuierlichen, unaufwendigen Verfahrens zur Herstellung von Emulsionen und Dispersionen, das insbesondere die Herstellung von Nanoemulsionen mit kontrollierter Partikelgröße erlaubt. Die Vorrichtung und das Verfahren sollen eine In-Process/Online-Qualitätskontrölle erlauben. Zudem soll die Herstellung gegenüber üblichen Batch-Verfahren vereinfacht und beschleunigt werden. Auch die Herstellung variabler Mengen an Emulsionen oder Dispersionen soll möglich sein. Zudem soll unaufwendig luftfrei gearbeitet werden können.The object of the present invention is to provide a continuous, inexpensive process for the preparation of emulsions and dispersions, which in particular allows the production of nanoemulsions with controlled particle size. The device and method are intended to allow in-process / online quality controls. In addition, the production compared to conventional batch processes should be simplified and accelerated. The production of variable amounts of emulsions or dispersions should also be possible. In addition, it should be easy to work without air.

Die Aufgabe wird erfindungsgemäß gelöst durch ein Verfahren nach Anspruch 1 bzw. durch eine Vorrichtung nach Anspruch 4.The object is achieved by a method according to claim 1 or by a device according to claim 4.

In der erfindungsgemäßen Vorrichtung ist das Mischgefäß allseitig geschlossen. Dies bedeutet, dass abgesehen von Zu- und Abführungen sowie Rührerdurchführungen oder Durchführungen für Analytiksensoren das Mischgefäß geschlossen ist. Sofern sowohl die Zu- als auch Abführrohre mit fließfähigen Stoffen gefüllt sind und Rührwerkzeug sowie gegebenenfalls Analytiksensoren vorliegen, ist das Mischgefäß gegenüber dem Zutritt von Luft bzw. Sauerstoff abgeschlossen. Diese Auslegung des Mischgefäßes wird unter dem Ausdruck "allseitig geschlossen" erfasst.In the device according to the invention, the mixing vessel is closed on all sides. This means that apart from inlets and outlets and stirrer feedthroughs or feedthroughs for analytical sensors, the mixing vessel is closed. If both the supply and discharge pipes are filled with flowable materials and stirring and possibly also analytical sensors are present, the mixing vessel is closed to the admission of air or oxygen. This design of the mixing vessel is covered by the term "closed on all sides".

Das Rührwerkzeug erlaubt einen mechanischen Rühreintrag in die Emulsion oder Dispersion ohne Erzeugung von Kavitationkräften und ohne Hochdruckhomogenisierung. In bevorzugten Rührwerkzeugen werden auf einer Rührerachse, die gedreht wird, geeignete Rührelemente angeordnet Beim Rührwerkzeug kann es sich um so genannte Rotor/Stator-Systeme handeln, in denen motorbetrieben ein Rotor bewegt wird. Als Stator dient in der Regel das Gehäuse, das mit Einbauten wie Brechern versehen sein kann. Als Rührer kommen beispielsweise Flügelrührer in Betracht, die gegebenenfalls mit Abstreifern versehen sein können. Darüber hinaus können Kneter und andere geeignete Rührer wie Planetenrührer, Ankerrührer, Balkenrührer, Propeller, Blattrührer, Dissolverscheiben oder Intermig eingesetzt werden. Weitere geeignete Rührerkonfigurationen sind dem Fachmann bekannt.The stirrer allows mechanical stirring into the emulsion or dispersion without generating cavitation forces and without high pressure homogenization. In preferred stirring tools, suitable stirrer elements are arranged on a stirrer axis that is rotated. The stirrer tool may be so-called rotor / stator systems in which a rotor is moved by a motor. The stator is usually the housing, which may be provided with internals such as crushers. Suitable stirrers are, for example, paddle stirrers, which may optionally be provided with scrapers. In addition, kneaders and other suitable stirrers such as planetary stirrers, anchor stirrers, bar stirrers, propellers, blade stirrers, dissolver disks or Intermig can be used. Other suitable stirrer configurations are known to those skilled in the art.

Das Rührwerkzeug wird so betrieben, dass der Rühreintrag in die Emulsion oder Dispersion ohne Erzeugung von Kavitationskräften und ohne Hochdruckhomogenisierung erfolgt.The stirring tool is operated in such a way that stirring is effected in the emulsion or dispersion without generation of cavitation forces and without high-pressure homogenization.

Im Mischgefäß können zudem gegebenenfalls Mahlwerkzeuge wie Mahlperlen oder -kugeln vorliegen. Geeignete Mahlwerkzeuge sind dem Fachmann bekannt.In the mixing vessel may also be present optionally grinding tools such as grinding beads or balls. Suitable grinding tools are known in the art.

Das Mischgefäß kann jede geeignete Geometrie aufweisen, solange es eine geeignete Durchmischung der fließfähigen Stoffe oder Stoffgemische bzw. der Phasen der herzustellenden Emulsionen und Dispersionen erlaubt. Geeignete Geometrien sind dem Fachmann bekannt. Vorzugsweise weist das Mischgefäß eine im Wesentlichen zylindrische Form auf, wobei die Achse des Rührwerkzeugs in der Zylinderachse liegt und die Zu- und Abführrohre im Wesentlichen senkrecht zur Zylinderachse im oberen und unteren Umfangsbereich des Zylinders voneinander beabstandet angeordnet sind. Die Zu- und Abführrohre sind damit, entlang der Zylinderachse betrachtet, möglichst weit voneinander entfernt in Positionen entlang des Zylinderumfangs angeordnet. Sie sind im Wesentlichen senkrecht zur Zylinderachse angeordnet. Abweichungen von ± 10 °, vorzugsweise ± 5° hierzu sind möglich. Die Anordnung kann den praktischen Erfordernissen angepasst werden. Vorzugsweise werden die fließfähigen Stoffe oder Stoffgemische in das erste Mischgefäß getrennt eingetragen bzw. zugeführt. Die entsprechenden Zuführrohre ragen vorzugsweise etwas in das Mischgefäß hinein. Es ist auch möglich, eine Vormischstufe für die fließfähigen Stoffe oder Stoffgemische vorzusehen. Beim Herstellen einer Öl/Wasser-Emulsion oder Wasser/Öl-Emulsion können beispielsweise die einzelnen Komponenten der Ölphase und die einzelnen Komponenten der Wasserphase getrennt vorgemischt werden. Es ist auch möglich, dass die Ölphase und die Wasserphase in einer Vormischstufe zusammengeführt und gemeinsam in das Mischgefäß eingetragen werden. Üblicherweise werden die Ölphase und die Wasserphase oder entsprechende andere Phasen voneinander getrennt in das Mischgefäß geführt. Es können ein oder mehrere Zu- und Abführrohre vorgesehen werden. Üblicherweise werden zwei oder mehr, insbesondere zwei oder drei Zuführrohre und ein Abführrohr vorgesehen. Die Größe des Mischgefäßes kann nach den jeweiligen praktischen Erfordernissen gewählt werden. Im Labormaßstab beträgt das Innenvolumen (freie Volumen) des Mischgefäßes vorzugsweise 2 bis 70 ml, besonders bevorzugt 3 bis 50 ml, insbesondere 5 bis 15 ml. Im Technikumsmaßstab beträgt das Innenvolumen vorzugsweise 70 bis 500 ml, besonders bevorzugt 100 bis 400 ml. Im großtechnischen Maßstab beträgt das Volumen vorzugsweise mehr als 500 ml, beispielsweise 500 bis 50 000 ml.The mixing vessel may have any suitable geometry, as long as it allows a suitable mixing of the flowable substances or mixtures or the phases of the emulsions and dispersions to be prepared. Suitable geometries are known to the person skilled in the art. Preferably, the mixing vessel has a substantially cylindrical shape, wherein the axis of the stirring tool lies in the cylinder axis and the supply and discharge pipes are arranged substantially perpendicular to the cylinder axis in the upper and lower peripheral region of the cylinder spaced from each other. The supply and discharge pipes are thus, as far as possible from one another along the cylinder axis, arranged in positions along the cylinder circumference. They are arranged substantially perpendicular to the cylinder axis. Deviations of ± 10 °, preferably ± 5 ° are possible. The arrangement can be adapted to the practical requirements. Preferably, the flowable substances or mixtures are introduced or supplied separately in the first mixing vessel. The corresponding feed tubes preferably protrude somewhat into the mixing vessel. It is also possible to provide a premixing step for the flowable substances or mixtures of substances. When preparing an oil / water emulsion or water / oil emulsion, for example, the individual components of the oil phase and the individual components of the water phase can be premixed separately. It is also possible for the oil phase and the water phase to be combined in a premixing stage and introduced together into the mixing vessel. Usually, the oil phase and the water phase or similar other phases are fed separately from each other into the mixing vessel. One or more supply and discharge pipes can be provided. Usually, two or more, in particular two or three feed tubes and a discharge tube are provided. The size of the mixing vessel can be selected according to the respective practical requirements. On a laboratory scale, the internal volume (free volume) of the mixing vessel is preferably from 2 to 70 ml, particularly preferably from 3 to 50 ml, in particular from 5 to 15 ml. On a pilot plant scale, the internal volume is preferably from 70 to 500 ml, more preferably from 100 to 400 ml Scale is the volume preferably more than 500 ml, for example 500 to 50 000 ml.

Im Labormaßstab können beispielsweise Mischgefäße mit etwa 7 ml Volumen eingesetzt werden, die eine zylindrische Form aufweisen und einen Innendurchmesser von 20 mm und eine Innenhöhe von 25 mm aufweisen. Das Innenvolumen kann dabei auch durch die Dicke bzw. den Durchmesser der Rotorachse gesteuert werden. So ist es auch möglich, dass Konfigurationen entsprechend einem Ringkammerreaktor erhalten werden. Die Verweilzeiten im ersten Mischgefäß betragen vorzugsweise 2 bis 600 Sekunden, besonders bevorzugt 4 bis 100 Sekunden, insbesondere 8 bis 40 Sekunden.On a laboratory scale, for example, mixing vessels of about 7 ml volume can be used, which have a cylindrical shape and an inner diameter of 20 mm and an inner height of 25 mm. The internal volume can also be controlled by the thickness or the diameter of the rotor axis. So it is also possible that configurations are obtained according to an annular chamber reactor. The residence times in the first mixing vessel are preferably 2 to 600 seconds, more preferably 4 to 100 seconds, in particular 8 to 40 seconds.

Es ist erfindungsgemäß möglich, bereits mit einem Mischgefäß die gewünschten Emulsionen und Dispersionen kontinuierlich herzustellen. Vorzugsweise werden jedoch mindestens zwei Mischgefäße in Reihe hintereinander geschaltet, wobei der Austrag aus dem ersten Mischgefäß ins zweite Mischgefäß eingetragen wird und ein weiteres Zuführrohr in das zweite Mischgefäß vorgesehen ist. Auch das zweite (und folgende) Mischgefäß weist ein Rührwerk auf, wie beschrieben. Es ist entsprechend auch möglich, längere Kaskaden von Mischgefäßen vorzusehen, wobei der Austrag eines Mischgefäßes dem nächsten Mischgefäß zugeführt wird und gegebenenfalls jeweils weitere Einträge in das weitere Mischgefäß eingetragen werden können. Vorzugsweise wird mit zwei oder drei, insbesondere mit zwei hintereinander geschalteten Mischgefäßen gearbeitet.It is possible according to the invention to continuously produce the desired emulsions and dispersions with a mixing vessel. Preferably, however, at least two mixing vessels are connected in series one behind the other, wherein the discharge from the first mixing vessel is introduced into the second mixing vessel and a further feed pipe is provided in the second mixing vessel. Also, the second (and following) mixing vessel has an agitator as described. It is accordingly also possible to provide longer cascades of mixing vessels, wherein the discharge of a mixing vessel is supplied to the next mixing vessel and optionally further entries in the additional mixing vessel can be registered. Preferably, two or three, in particular two mixing vessels connected in series, are used.

Es ist erfindungsgemäß möglich, ein oder mehrere der Mischgefäße unabhängig voneinander zu temperieren. Eine Temperierung kann durch Kühl- oder Heiz-Mäntel oder durch Integrieren des Mischgefäßes in einen Ofen oder einen Kryostaten erreicht werden. Geeignete Vorrichtungen zum Heizen/Kühlen bzw. Temperieren der Mischgefäße sind dem Fachmann bekanntIt is possible according to the invention to temper one or more of the mixing vessels independently of each other. A tempering can be achieved by cooling or heating jackets or by integrating the mixing vessel in an oven or a cryostat. Suitable devices for heating / cooling or temperature control of the mixing vessels are known in the art

Sofern zwei hintereinander geschaltete Mischgefäße eingesetzt werden, wird im ersten Mischgefäß das Verhältnis der Zuströme so eingestellt, dass beim Mischen im ersten Mischgefäß im viskoelastischen bzw. hochviskoelastischen Bereich gearbeitet wird. Der viskoelastische Bereich bezeichnet den Bereich, in dem die viskoelastischen Flüssigkeiten nicht-newton'sches Flüssigkeitsverhalten zeigen. Für eine Beschreibung der Viskoelastizität kann auf Römpp, Chemielexikon, 9. Auflage, Stichwort "Viskoelastizität" verwiesen werden.If two mixing vessels connected in series are used, the ratio of the inflows in the first mixing vessel is set so that it is used in the first mixing vessel in the viscoelastic or highly viscoelastic region during mixing. The viscoelastic region indicates the region in which the viscoelastic fluids exhibit non-Newtonian fluid behavior. For a description of the viscoelasticity, reference may be made to Römpp, Chemielexikon, 9th edition, keyword "viscoelasticity".

Üblicherweise entspricht die Abhängigkeit der Viskosität einer Emulsion bzw. Dispersion vom Volumenanteil der dispersen Phase einer Exponentialfunktion. Der wichtige viskoelastische Bereich, in dem erfindungsgemäß vorzugsweise gearbeitet wird, ist der Bereich, in dem sich die Viskosität mit zunehmendem Volumenanteil der dispersen Phase sehr stark erhöht. Bei einer zweiphasigen Emulsion wird das Gewichtsverhältnis der Phasen vorzugsweise in einem Bereich von 1:15 bis 15:1, bevorzugt 1:5 bis 5:1, vorzugsweise 1:2 bis 2:1, insbesondere 1:1,5 bis 1,5:1 gewählt. Insbesondere bei Öl/Wasser-Emulsionen (O/W), Wasser/Öl-Emulsionen (W/O) und Polyol/Öl-Emulsionen (P/O) liegen die Gewichtsanteile der entsprechenden Phasen vorzugsweise in diesem Bereich.The dependence of the viscosity of an emulsion or dispersion on the volume fraction of the disperse phase usually corresponds to an exponential function. The important viscoelastic region in which work is preferably carried out according to the invention is the region in which the viscosity increases very greatly with increasing volume fraction of the disperse phase. In a biphasic emulsion, the weight ratio of the phases is preferably in a range of 1:15 to 15: 1, preferably 1: 5 to 5: 1, preferably 1: 2 to 2: 1, especially 1: 1.5 to 1.5 : 1 chosen. Particularly in the case of oil / water emulsions (O / W), water / oil emulsions (W / O) and polyol / oil emulsions (P / O), the weight fractions of the corresponding phases are preferably in this range.

Bei einer Abfolge von zwei Mischgefäßen wird damit in der ersten Stufe hochviskos und in der nachfolgenden zweiten Stufe niederviskos gearbeitet. Die Einstellung einer feinteiligen Emulsion bzw. Dispersion wird dabei im ersten Reaktor erreicht, während die Verdünnung auf die endgültige Konzentration des Produktes im zweiten Mischgefäß erfolgt. Da in diesem Fall ins zweite Mischgefäß eine ergänzende Menge mindestens einer der Phasen oder eine weitere Phase eingetragen wird, ist die Verweilzeit im zweiten Mischgefäß entsprechend kürzer, sofern beide Mischgefäße das gleiche Innenvolumen aufweisen.In the case of a sequence of two mixing vessels, this work is highly viscous in the first stage and low-viscosity in the subsequent second stage. The setting of a finely divided emulsion or dispersion is achieved in the first reactor, while the dilution is carried out to the final concentration of the product in the second mixing vessel. Since in this case a supplementary amount of at least one of the phases or a further phase is introduced into the second mixing vessel, the residence time in the second mixing vessel is correspondingly shorter, if both mixing vessels have the same internal volume.

Durch Einhalten des Mengenverhältnisses der beiden Phasen im ersten Mischgefäß kann selbst mit dem Eintrag geringer Scherenergien eine sehr starke Mischwirkung erreicht werden. Ohne an eine Theorie gebunden zu sein, kann die beim Vermischen der Phasen erhaltene Mikroemulsion als ein System zweier interpenetrierender Netzwerke verstanden werden, so dass die Mikroemulsion einphasiges Verhalten zeigt.By maintaining the quantitative ratio of the two phases in the first mixing vessel, a very strong mixing effect can be achieved even with the entry of low shear energies. Without wishing to be bound by theory, the microemulsion obtained when mixing the phases can be understood as a system of two interpenetrating networks, so that the microemulsion exhibits single-phase behavior.

Erfindungsgemäß ist in den Abführrohren der Mischgefäße bzw. mindestens einem Abführrohr eines Mischgefäßes mindestens ein Sensor zur kontinuierlichen Messung der Temperatur, Leitfähigkeit und/oder optischen Eigenschaften der Emulsion oder Dispersion angeordnet. Ein entsprechender Sensor ist dabei in der Regel in der Nähe des Mischgefäßes im Abführrohr vorgesehen. Geeignete Sensoren zur Bestimmung der elektrischen Leitfähigkeit, der Temperatur oder optischer Eigenschaften wie Trübungen sind dem Fachmann bekannt. Bei der Beurteilung der optischen Eigenschaften kann auch ein Schauglas vorgesehen sein, durch das eine optische bzw. visuelle Kontrolle der Klarheit oder Trübung der Emulsion/Dispersion möglich ist. Maschinengestützte optische Verfahren schließen die Laserlichtstreuung und Extinktionsmessungen ein.According to the invention, at least one sensor for continuously measuring the temperature, conductivity and / or optical properties of the emulsion or dispersion is arranged in the discharge tubes of the mixing vessels or at least one discharge tube of a mixing vessel. A corresponding sensor is usually provided in the vicinity of the mixing vessel in the discharge pipe. Suitable sensors for determining the electrical conductivity, the temperature or optical properties such as turbidity are known in the art. In the evaluation of the optical properties, a sight glass can also be provided, by means of which an optical or visual control of the clarity or turbidity of the emulsion / dispersion is possible. Machine-aided optical techniques include laser light scattering and absorbance measurements.

Optische Verfahren zur Bestimmung der Teilchengröße in den Emulsionen oder Dispersionen können ebenfalls zur Prozesskontrolle eingesetzt werden. Weiterhin ist es möglich, Viskositätsmessungen, beispielsweise nach Brookfield, zum Beispiel in line durchzuführen. Die visuelle/optische Kontrolle kann durch geeignetes und geschultes Personal vorgenommen werden. Ferner ist es möglich, die eingetragene Energiemenge durch den Rührer zu bestimmen. Auch hier kann bei Abweichungen der eingetragenen Energie schnell reagiert werden, da dies auf eine geänderte Zusammensetzung der Emulsion/Dispersion hindeuten kann. Insgesamt erlaubt die kontinuierliche Bestimmung eines oder mehrerer der genannten Parameter eine kontinuierliche Prozesskontrolle und eine kontinuierliche Kontrolle der Zusammensetzung der Emulsion bzw. Dispersion. Die Qualitätssicherung bei der Herstellung wird damit erheblich verbessert bzw. vereinfacht. Dies ist insbesondere bei pharmazeutischen Produkten von hoher Wichtigkeit.Optical methods for determining the particle size in the emulsions or dispersions can also be used for process control. Furthermore, it is possible to carry out viscosity measurements, for example according to Brookfield, for example in line. The visual / visual control can be carried out by suitable and trained personnel. Furthermore, it is possible to determine the amount of energy input by the stirrer. Here, too, can be reacted quickly in deviations of the energy input, as this may indicate a change in the composition of the emulsion / dispersion. Overall, the continuous determination of one or more of the mentioned parameters allows a continuous process control and a continuous control of the composition of the emulsion or dispersion. The quality assurance in the production is thus considerably improved or simplified. This is particularly important in pharmaceutical products of high importance.

Über die Leitfähigkeit sind Aussagen über das Phasenvolumenverhältnis möglich. Durch Messung der Leitfähigkeit lassen sich deshalb Veränderungen in der Emuslionszusammensetzung bzw. in den Phasenvolumina leicht bestimmen. Die Prozesskontrolle wird vorzugsweise online durchgeführt, d. h. kontinuierlich während des Herstellungsverfahrens. Dies erlaubt es, auf Abweichungen der Zusammensetzungen der Emulsionen oder Dispersionen sofort zu reagieren. Ändern sich beispielsweise die Volumenströme der eingesetzten Phasen, so wird im Mischgefäß ein anderes Phasenvolumenverhältnis erhalten, was zu einer veränderten Leitfähigkeit führt. Durch die Bestimmung der Leitfähigkeit kann beispielsweise auch die Einstellung der Volumenströme wiederum gesteuert werden, um konstante Volumenströme sicher zu stellen.About the conductivity statements about the phase volume ratio are possible. By measuring the conductivity, it is therefore easy to determine changes in the emulsion composition or in the phase volumes. The process control is preferably carried out online, ie continuously during the manufacturing process. This makes it possible to react immediately to deviations of the compositions of the emulsions or dispersions. If, for example, the volume flows of the phases used change, the mixing vessel becomes different Phase volume ratio obtained, resulting in a changed conductivity. By determining the conductivity, for example, the adjustment of the volume flows can in turn also be controlled in order to ensure constant volume flows.

Gemäß einer Ausführungsform der Erfindung sind die Zufuhr der fließfähigen Stoffe und der Rühreintrag und gegebenenfalls die Temperierung der Mischgefäße rechnergesteuert. Über einen zentralen Rechner (Computer) können damit alle Prozessparameter gesteuert und kontrolliert werden. Die von den Sensoren gelieferten Messwerte können ebenfalls dem Rechner zugeführt und rechnergestützt ausgewertet werden.According to one embodiment of the invention, the supply of the flowable substances and the stirring and optionally the temperature of the mixing vessels are computer controlled. A central computer (computer) can be used to control and control all process parameters. The measured values supplied by the sensors can also be fed to the computer and evaluated computer-aided.

Die Dosierung der unterschiedlichen fließfähigen Stoffe erfolgt beispielsweise durch geeignete Pumpen. Derartige Pumpen sind dem Fachmann bekannt Sie sind vorzugsweise unabhängig vom Gegendruck und können in feiner Abstufung angesteuert werden. Beispiele geeigneter Pumpen sind Zahnradpumpen, Peristaltik/Schlauchpumpen und andere geeignete Pumpen. Die Kombination dieser Pumpen mit den erfindungsgemäß eingesetzten Mischgefäßen erlaubt das blasen- und luftfreie Herstellen von Emulsionen. Im gesamten Weg der fließfähigen Stoffe ist der Zutritt von Luft erschwert bzw. unmöglich gemacht, da alle Verfahrensschritte in einem geschlossenen System durchgeführt werden. Dies ist ein weiterer Vorteil des erfindungsgemäßen Verfahrens, wobei auf aufwendige Verfahrensschritte wie ein Evakuieren der Emulsionen verzichtet werden kann.The dosage of the different flowable substances, for example, by suitable pumps. Such pumps are known in the art. They are preferably independent of the back pressure and can be controlled in fine gradation. Examples of suitable pumps are gear pumps, peristaltic / peristaltic pumps and other suitable pumps. The combination of these pumps with the mixing vessels used according to the invention allows the bubbles and air-free production of emulsions. In the entire path of the flowable substances, the access of air is made difficult or impossible, since all process steps are carried out in a closed system. This is a further advantage of the process according to the invention, wherein expensive process steps such as evacuation of the emulsions can be dispensed with.

Die erfindungsgemäße Vorrichtung kann bei Niederdruck, insbesondere bei einem Druck im Bereich von 1 bis 10 bar, besonders bevorzugt 1 bis 1,5 bar betrieben werden. Das Verfahren wird entsprechend bei einem Druck in diesem Bereich durchgeführt.The device according to the invention can be operated at low pressure, in particular at a pressure in the range of 1 to 10 bar, more preferably 1 to 1.5 bar. The process is accordingly carried out at a pressure in this range.

Die Mischgefäße und Leitungen können aus beliebigen geeigneten Materialien aufgebaut sein. Beispiele geeigneter inerter Materialien sind Kunststoffe, Stähle wie V2A- oder V4A-Stahl oder Kupfer. Geeignete Materialien oder Werkstoffe sind dem Fachmann bekannt.The mixing vessels and lines can be constructed of any suitable materials. Examples of suitable inert materials are plastics, steels such as V2A or V4A steel or copper. Suitable materials or materials are known in the art.

Es ist erfindungsgemäß möglich, die Vorrichtung in modularer Bauweise auszuführen. Dies bedeutet, dass mehrere Mischgefäße in einfacher Weise hintereinander oder auch parallel geschaltet werden können. Die Vorrichtung kann nach einem Baukastenprinzip aus Einzelkomponenten aufgebaut sein. Diese Einzelkomponenten können beispielsweise Pumpen, Mischgefäße, Sensorelemente, Rührmotoren, Temperiereinheiten und Verbindungselemente sein. Sämtliche Pumpen und Rührmotoren können dabei über einen zentralen Rechner angesteuert werden.It is possible according to the invention to carry out the device in a modular design. This means that several mixing vessels can be connected in a simple manner one behind the other or in parallel. The device can be constructed according to a modular principle of individual components. These individual components can be, for example, pumps, mixing vessels, sensor elements, stirring motors, tempering units and connecting elements. All pumps and stirring motors can be controlled via a central computer.

Die Auswahl der Rührer, der Größe der Mischgefäße und der Eintragsströme erfolgt nach den praktischen Erfordernissen und ist durch einfache Vorversuche zu ermitteln. Insbesondere bei der zweistufigen Vorgehensweise kann in der ersten Stufe hochviskos und in der zweiten Stufe niederviskos gearbeitet werden, wodurch eine Vielzahl unterschiedlicher Emulsionen oder Dispersionen in einfacher Weise zugänglich wird.The choice of stirrer, the size of the mixing vessels and the feed streams is based on the practical requirements and is to be determined by simple preliminary tests. Particularly in the two-stage procedure, low viscosity can be used in the first stage and low viscosity in the second stage, whereby a large number of different emulsions or dispersions can be obtained in a simple manner.

Um im ersten Mischgefäß im viskoelastischen, vorzugsweise hochviskoelastischen Bereich arbeiten zu können, können den einzelnen Phasen oder fließfähigen Stoffen oder Stoffgemischen gegebenenfalls Verdicker zugesetzt werden. Hierdurch ist es in einfacher Weise möglich, in einen geeigneten Viskositätsbereich zu gelangen, der die Herstellung feinteiliger Emulsionen und Dispersionen unter geringem Rühreintrag erlaubt.In order to be able to work in the first mixing vessel in the viscoelastic, preferably highly viscoelastic region, thickeners may optionally be added to the individual phases or flowable substances or mixtures of substances. This makes it possible in a simple manner to get into a suitable viscosity range, which allows the production of finely divided emulsions and dispersions with little stirring.

Die Vorteile des erfindungsgemäßen kontinuierlichen gegenüber diskontinuierlichen Verfahren sind vielfältig: Die Herstellung der Emulsionen oder Dispersionen wird wesentlich beschleunigt. Beispielweise dauert die Herstellung von 1 Liter einer Emulsion im kontinuierlichen Batch-Verfahren mit Heizen, Abkühlen und Homogenisieren mindestens etwa 1,5 Stunden. Hierbei sind noch keine Aussagen über die Qualität der Emulsionen oder Dispersionen möglich. Das erfindungsgemäße Verfahren erlaubt eine . entsprechende Herstellung in maximal etwa 15 Minuten, wobei die Emulsionen oder Dispersionen im Verfahren analysiert und kontrolliert werden können (In-Process-Produktkontrolle). Eine Variation der Produktmengen ist in einfacher Weise über die Länge der Produktionsdauer möglich. Damit sind sehr unterschiedliche Ansatzgrößen in einfacher Weise realisierbar. Durch Veränderung der Zuführströme in die Mischgefäße ist eine Variation der Zusammensetzung der Emulsionen oder Dispersionen in einfacher Weise möglich.The advantages of the continuous versus discontinuous processes according to the invention are manifold: The preparation of the emulsions or dispersions is substantially accelerated. For example, the production of 1 liter of an emulsion in a continuous batch process with heating, cooling and homogenizing takes at least about 1.5 hours. Here, no statements about the quality of the emulsions or dispersions are possible. The inventive method allows a. corresponding production in a maximum of about 15 minutes, whereby the emulsions or dispersions can be analyzed and controlled in the process (in-process product control). A variation of the product quantities is possible in a simple manner over the length of the production period. Thus, very different approach sizes can be realized in a simple manner. By varying the feed streams into the mixing vessels, a variation of the composition of the emulsions or dispersions is possible in a simple manner.

Da in geschlossenen Rohrleitungssystemen und geschlossenen Mischgefäßen gearbeitet wird, ist eine sterile Verarbeitung möglich. Kontaminationen von außen werden ausgeschlossen. Die Auslegung der Vorrichtung bzw. Anlage kann kleiner und leichter als bei einer Chargenanlage sein, so dass erhebliche Einsparungen an Investitionskosten möglich sind. Auf den Einsatz von Kühlmitteln kann in der Regel verzichtet werden, da zum Beispiel die Temperatur über die in das zweite Mischgefäß eingebrachte Phase gesteuert werden kann. Auch der Raumbedarf ist wesentlich geringer. Durch die kontinuierliche Verfahrensweise sind auch Energieeinsparungen möglich, wie sie vorstehend bereits beschrieben sind. Durch die Genauigkeit der verfügbaren Dosierpumpen sind sehr hohe Genauigkeiten bei der Zusammensetzung der Emulsionen oder Dispersionen möglich. Übliche Dosierpumpen erlauben Genauigkeiten im Bereich von ± 0,5 % bis zu ± 0,15%.Since work is done in closed piping systems and closed mixing vessels, sterile processing is possible. External contamination is excluded. The design of the device or system can be smaller and lighter than in a batch system, so that significant savings in investment costs are possible. As a rule, the use of coolants can be dispensed with since, for example, the temperature can be controlled via the phase introduced into the second mixing vessel. The space requirement is much lower. The continuous procedure also energy savings are possible, as already described above. Due to the accuracy of the available dosing pumps are very high accuracy in the composition of the emulsions or Dispersions possible. Conventional dosing pumps allow accuracies in the range of ± 0.5% to ± 0.15%.

Die Herstellung von Nanoemulsionen mit Teilchen- oder Tröpfchengrößen im Bereich von 15 bis 300 nm, maximal 1000 nm ist in einfacher Weise möglich.The preparation of nanoemulsions with particle or droplet sizes in the range of 15 to 300 nm, at most 1000 nm is possible in a simple manner.

Im Vergleich zu bekannten Verfahren ist die Herstellung wesentlich feinteiligerer Emulsionen mit wesentlich geringerem Aufwand möglich.In comparison to known methods, the production of substantially finely divided emulsions with much less effort is possible.

Gegenüber der diskontinuierlichen chargenweisen Herstellung kann die eingesetzte Emulgatormenge deutlich vermindert werden. Häufig kann mit weniger als der Hälfte der üblichen Emulgatormenge gearbeitet werden.Compared to the batchwise batchwise preparation, the amount of emulsifier used can be significantly reduced. Often you can work with less than half of the usual amount of emulsifier.

Die erfindungsgemäße Vorrichtung kann durch Auswahl geeigneter Rührwerkzeuge an eine Vielzahl von Anwendungen in unaufwendiger Weise angepasst werden.The device according to the invention can be inexpensively adapted to a variety of applications by selecting suitable stirring tools.

Eine Reinigung der erfindungsgemäßen Vorrichtung ist aufgrund der geringen Größe in einfacher und schneller Weise möglich. Bei einem Wechsel der herzustellenden Emulsionen oder Dispersionen kann auch auf eine Reinigung verzichtet werden. In diesem Fall werden die eingesetzten Stoffe oder Ströme gemäß der neuen Produktzusammensetzung variiert, und die erste Austragmenge aus den Mischgefäßen wird verworfen. Die Veränderung der Emulsion bis zum Erhalt der konstanten gewünschten Produktzusammensetzung kann wiederum über die Online-Prozeßkontrolle verfolgt werden.A cleaning of the device according to the invention is possible because of the small size in a simple and fast manner. When changing the emulsions or dispersions to be produced can also be dispensed with a cleaning. In this case, the materials or streams used are varied according to the new product composition, and the first output from the mixing vessels is discarded. The change in the emulsion until the constant desired product composition is obtained can in turn be monitored via the online process control.

Die erfindungsgemäße Vorrichtung und das erfindungsgemäße Verfahren sind auf eine Vielzahl von Emulsionen oder Dispersionen anwendbar. Insbesondere werden erfindungsgemäß Emulsionen oder multiple Emulsionen hergestellt. Beispiele sind OW-Emulsionen, WO-Emulsionen, PO-Emulsionen, multiple Emulsionen, LC-Gele, Liposome oder Perlglanzkonzentrate. Da luftfrei gearbeitet wird, können oxidationsempfindliche Wirkstoffe in vorteilhafter Weise in die Emulsionen eingebracht werden.The apparatus and method of the present invention are applicable to a variety of emulsions or dispersions. In particular, emulsions or multiple emulsions are prepared according to the invention. Examples are OW emulsions, WO emulsions, PO emulsions, multiple emulsions, LC gels, liposomes or pearlescent concentrates. Since working air-free, oxidation-sensitive active ingredients can be introduced into the emulsions in an advantageous manner.

Das erfindungsgemäße Verfahren erlaubt die Herstellung hochviskoser Systeme wie Gele. Liposome können ebenfalls bei Niederdruck hergestellt werden. So ist die Herstellung von Emulsionen, Salben, Gelen für alle üblichen pharmazeutischen, kosmetischen, lebensmitteltechnologischen oder waschmitteltechnologischen Bereiche möglich. Auch andere Anwendungsgebiete sind erfindungsgemäß zugänglich.The inventive method allows the production of highly viscous systems such as gels. Liposomes can also be made at low pressure. Thus, the production of emulsions, ointments, gels for all customary pharmaceutical, cosmetic, food technology or detergent technology areas is possible. Other fields of application are accessible according to the invention.

Nanoemulsionen weisen Emulsionströpfchen mit einem mittleren Durchmesser im Bereich von 5 bis 1000 um, vorzugsweise 15 bis 300 nm, auf. Bei der Herstellung von zweiphasigen Emulsionen wird in der Regel im ersten Gemisch unter hochviskosen Bedingungen eine feinteilige Primäremulsion hergestellt, die im zweiten Mischgefäß mit einer der beiden Phasen auf die gewünschte Endkonzentration verdünnt wird. Beispielsweise kann eine OW-Emulsion im ersten Mischgefäß mit hohen Ölanteilen hergestellt werden, wobei die so erhaltene Primäremulsion im zweiten Mischgefäß unter Wasserzusatz auf die gewünschte Endkonzentration verdünnt wird. Bei dieser Vorgehensweise wird in der zweiten Mischvorrichtung mit dem Hauptteil der externen Phase verdünnt Bei der Herstellung multipler Emulsionen ist es beispielsweise möglich, in dem ersten Mischgefäß eine PO-Emulsion herzustellen, die im zweiten Mischgefäß zusammen mit Wasser in eine POW-Emulsion überführt wird. Es können jeweils systemangepasste Drehzahlen und Rührwerkzeuge verwendet werden.Nanoemulsions have emulsion droplets having an average diameter in the range of 5 to 1000 μm, preferably 15 to 300 nm. In the preparation of biphasic emulsions, a finely divided primary emulsion is generally prepared in the first mixture under high-viscosity conditions, which is diluted in the second mixing vessel with one of the two phases to the desired final concentration. For example, an OW emulsion can be prepared in the first mixing vessel with high oil contents, wherein the primary emulsion thus obtained is diluted in the second mixing vessel with the addition of water to the desired final concentration. In this procedure, the main part of the external phase is diluted in the second mixing device. In the production of multiple emulsions, it is possible, for example, to produce in the first mixing vessel a PO emulsion which is converted into a POW emulsion together with water in the second mixing vessel. In each case system-adapted speeds and stirring tools can be used.

Zur Herstellung einer wässrigen Wirkstoffträger-Nanodispersion, die mindestens einen pharmazeutischen, kosmetischen und/oder lebensmitteltechnologischen Wirkstoff enthält, können zunächst der Wirkstoff und der Wirkstoffträger auf Lipidbasis und mindestens ein Emulgator, der Lamellarstrukturen ausbildet, bei einer Temperatur oberhalb des Schmelz- oder Erweichungspunktes des Wirkstoffträgers vermischt werden. Hierbei wird eine Phase B ausgebildet. Sodann kann diese Phase B mit einer wässrigen Phase A bei einer Temperatur oberhalb des Schmelz- oder Erweichungspunktes des Wirkstoffträgers vermischt werden.. Diese Mischung wird beispielsweise im ersten Mischgefäß durchgeführt. Sodann kann die Mischphase mit einer wässrigen Phase auf die gewünschte Endkonzentration verdünnt werden. Diese Verdünnung kann im zweiten Mischgefäß durchgeführt werden.For the preparation of an aqueous active substance carrier nanodispersion which contains at least one pharmaceutical, cosmetic and / or food-technological active ingredient, the active substance and the lipid-based active substance carrier and at least one emulsifier which forms lamellar structures can first be at a temperature above the melting or softening point of the active ingredient carrier be mixed. In this case, a phase B is formed. Then this phase B can be mixed with an aqueous phase A at a temperature above the melting or softening point of the active ingredient carrier. This mixture is carried out, for example, in the first mixing vessel. The mixed phase can then be diluted with an aqueous phase to the desired final concentration. This dilution can be carried out in the second mixing vessel.

Als Wirkstoffträgerteilchen werden Teilchen auf Lipidbasis eingesetzt. Hierzu gehören Lipide und lipidähnliche Strukturen. Beispiele geeigneter Lipide sind die Mono-, Di- und Triglyceride der gesättigten geradkettigen Fettsäuren mit 12 bis 30 Kohlenstoffatomen, wie Laurinsäure, Myristinsäure, Palmitinsäure, Stearinsäure, Arachinsäure, Behensäure, Lignocerinsäure, Cerotinsäure, Melesinsäure, sowie deren Ester mit anderen mehrwertigen Alkoholen wie Ethylenglykol, Propylenglykol, Mannit, Sorbit, gesättigten Fettalkoholen mit 12 bis 22 Kohlenstoffatomen wie Laurylalkohol, Myrestylalkohol, Cetylalkohol, Stearylalkohol, Arachidylalkohol, Behenylalkohol, gesättigten Wachsalkoholen mit 24 bis 30 Kohlenstoffatomen wie Lignocerylalkohol, Cerylalkohol, Cerotylalkohol, Myrizylalkohol. Bevorzugt sind Mono-, Di-, Triglyceride, Fettalkohole, deren Ester oder Ether, Wachse, Lipidpeptide oder Mischungen davon. Insbesondere werden synthetische Mono-, Di- und Triglyceride als Einzelsubstanzen oder in Form einer Mischung, zum Beispiel in Form eines Hartfettes, eingesetzt. Glycerintrifettsäureester sind beispielsweise Glycerintrilaurat, Glycerintrimyristat, Glycerinpalmitat, Glycerintristearat oder Glycerintribehenat. Geeignete Wachse sind beispielsweise Cetylpalmitat und Cera alba (gebleichtes Wachs, DAB 9). Als Lipide können auch Polysaccharide mit oder in Einzelfällen oder Polyalkylacrylate, Polyallcylcyanoacrylate, Polyalkylvinylpyrrolidone, Acrylpolymere, Polymilchsäuren oder Polylactide eingesetzt werden.The active ingredient carrier particles used are lipid-based particles. These include lipids and lipid-like structures. Examples of suitable lipids are the mono-, di- and triglycerides of the saturated straight-chain fatty acids having 12 to 30 carbon atoms, such as lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, cerotic, meleinic, as well as their esters with other polyhydric alcohols such as ethylene glycol , Propylene glycol, mannitol, sorbitol, saturated fatty alcohols having 12 to 22 carbon atoms, such as lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, saturated wax alcohols having 24 to 30 carbon atoms, such as lignoceryl alcohol, ceryl alcohol, cerotyl alcohol, myrizyl alcohol. Preference is given to mono-, di-, triglycerides, fatty alcohols, their esters or Ethers, waxes, lipid peptides or mixtures thereof. In particular, synthetic mono-, di- and triglycerides are used as individual substances or in the form of a mixture, for example in the form of a hard fat. Glycerol trifatty acid esters are, for example, glycerol trilaurate, glycerol trimyristate, glycerol palmitate, glycerol tristearate or glycerol tribehenate. Suitable waxes are, for example, cetyl palmitate and Cera Alba (bleached wax, DAB 9). As lipids it is also possible to use polysaccharides with or in individual cases or polyalkyl acrylates, polyalkyl cyanoacrylates, polyalkylvinylpyrrolidones, acrylic polymers, polylactic acids or polylactides.

Die Menge der Wirkstoffträgerteilchen, bezogen auf die gesamte wässrige Wirkstoffträger-Dispersion, beträgt vorzugsweise 0,1 bis 30 Gew.-%, besonders bevorzugt 1 bis 10 Gew.-%. Zusätzlich zu den Lipiden können Dispersionsstabilisatoren eingesetzt werden. Sie können beispielsweise in Mengen von 0,01 bis 10 Gew.-%, vorzugsweise 0,05 bis 5 Gew.-% eingesetzt werden. Beispiele geeigneter Substanzen sind Tenside, insbesondere ethoxylierte Sorbitanfettsäureester, Blockpolymere und Blockcopolymere (wie zum Beispiel Poloxamere und Poloxamine), Polyglycerinether und -ester, Lecithine verschiedenen Ursprungs (zum Beispiel Ei- oder Sojalecithin), chemisch modifizierte Lecithine (zum Beispiel hydriertes Lecithin) als auch Phospholipide und Sphingolipide, Mischungen von Lecithinen mit Phospholipiden, Sterine (zum Beispiel Cholesterin und Cholesterinderivate sowie Stigmasterin), Ester und Ether von Zuckern oder Zuckeralkoholen mit Fettsäuren oder Fettalkoholen (zum Beispiel Saccharosemonostearat), sterisch stabilsierende Substanzen wie Poloxamere und Poloxamine (Polyoxyethylen-Polyoxypropylen-Blockpolymere), ethoxylierte Sorbitanfettsäureester, ethoxylierte Mono- und Diglyceride, ethoxylierte Lipide und Lipoide, ethoxylierte Fettalkohole oder Fettsäuren und Ladungsstabilisatoren bzw. Ladungsträger wie zum Beispiel Dicetylphosphat, Phosphatidylglycerin sowie gesättigte und ungesättigte Fettsäuren, Natriumcholat, Natriumglykolcholat, Natriumtaurocholat oder deren Mischungen, Aminosäuren oder Peptisatoren wie Natriumcitrat (siehe J. S. Lucks, B. W. Müller, R. H. Müller, Int. J. Pharmaceutics 63, Seiten 183 bis 189 (1990 )), viskositätserhöhende Stoffe wie Celluloseether und -ester (zum Beispiel Methylcellulose, Hydroxyethylcellulose, Hydroxypropylcellulose, Natriumcarboxymethylcellulose), Polyvinylderivate wie Polyvinylallcohol, Polyvinylpyrrolidon, Polyvinylacetat, Alginate, Polyacrylate (zum Beispiel Carbopol), Xanthane und Pektine.The amount of active ingredient carrier particles, based on the total aqueous active ingredient carrier dispersion, is preferably 0.1 to 30 wt .-%, particularly preferably 1 to 10 wt .-%. In addition to the lipids, dispersion stabilizers can be used. They can be used, for example, in amounts of from 0.01 to 10% by weight, preferably from 0.05 to 5% by weight. Examples of suitable substances are surfactants, in particular ethoxylated sorbitan fatty acid esters, block polymers and block copolymers (such as poloxamers and poloxamines), polyglycerol ethers and esters, lecithins of various origins (for example egg or soya lecithin), chemically modified lecithins (for example hydrogenated lecithin) as well Phospholipids and sphingolipids, mixtures of lecithins with phospholipids, sterols (for example cholesterol and cholesterol derivatives and stigmasterol), esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols (for example sucrose monostearate), sterically stabilizing substances such as poloxamers and poloxamines (polyoxyethylene-polyoxypropylene) Block polymers), ethoxylated sorbitan fatty acid esters, ethoxylated mono- and diglycerides, ethoxylated lipids and lipids, ethoxylated fatty alcohols or fatty acids and charge stabilizers or charge carriers such as dicetyl phosphate, phosphatidylglycerol s as well as saturated and unsaturated fatty acids, sodium cholate, sodium glycol cholate, sodium taurocholate or their mixtures, amino acids or peptizers such as sodium citrate (see JS Lucks, BW Müller, RH Müller, Int. J. Pharmaceutics 63, pages 183 to 189 (1990 )), viscosity-increasing substances such as cellulose ethers and esters (for example methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose), polyvinyl derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetate, alginates, polyacrylates (for example carbopol), xanthans and pectins.

Als wässrige Phase A können Wasser, wässrige Lösungen oder Mischungen von Wasser mit wassermischbaren Flüssigkeiten wie Glycerin oder Polyethylenglycol eingesetzt werden. Weitere zusätzliche Komponenten für die wässrige Phase sind beispielsweise Mannose, Glucose, Fructose, Xylose, Trehalose, Mannit, Sorbit, Xylit oder andere Polyole wie Polyethylenglykol sowie Elektrolyte wie Natriumchlorid. Diese zusätzlichen Komponenten können in einer Menge von 0,5 bis 60, zum Beispiel 1 bis 30 Gew.-%, bezogen auf die wässrige Phase A, eingesetzt werden.As aqueous phase A, water, aqueous solutions or mixtures of water with water-miscible liquids such as glycerol or polyethylene glycol can be used. Further additional components for the aqueous phase are, for example Mannose, glucose, fructose, xylose, trehalose, mannitol, sorbitol, xylitol or other polyols such as polyethylene glycol and electrolytes such as sodium chloride. These additional components can be used in an amount of 0.5 to 60, for example 1 to 30 wt .-%, based on the aqueous phase A.

Falls gewünscht, können ferner viskositätserhöhende Stoffe oder Ladungsträger eingesetzt werden, wie Sie in EP-B-0 605 497 beschrieben sind.If desired, viscosity increasing agents or charge carriers can also be used, as described in US Pat EP-B-0 605 497 are described.

Als Emulgatoren, die Lamellarstrukturen ausbilden, können natürliche oder synthetische Produkte eingesetzt werden. Auch der Einsatz von Tensidgemischen ist möglich. Beispiele geeigneter Emulgatoren sind die physiologischen Gallensalze wie Natriumcholat, Natriumdehydrocholat, Natriumdeoxycholat, Natriumglykocholat, Natriumtaurocholat. Tierische und pflanzliche Phospholipide wie Lecithine mit ihren hydrierten Formen sowie Polypeptide wie Gelatine mit ihrem modifizierten Formen können ebenso verwendet werden.As emulsifiers forming lamellar structures, natural or synthetic products can be used. The use of surfactant mixtures is possible. Examples of suitable emulsifiers are the physiological bile salts such as sodium cholate, sodium dehydrocholate, sodium deoxycholate, sodium glycocholate, sodium taurocholate. Animal and plant phospholipids such as lecithins with their hydrogenated forms as well as polypeptides such as gelatin with their modified forms can also be used.

Als synthetische grenzflächenaktive Substanzen eignen sich die Salze der Sulfobernsteinsäureester, Polyoxyethylensäurebetanester, Säurebetanester und Sorbitanether, Polyoxyethylenfettalkoholether, Polyoxyethylenstearinsäureester sowie entsprechende Mischungkondensate von Polyoxyethylen-Methpolyoxypropylenethem, ethoxylierte gesättigte Glyceride, partielle Fettsäure-Glyceride und Polyglycide. Beispiele geeigneter Tenside sind Biobase® EP und Ceralution® H.Suitable synthetic surface-active substances are the salts of sulfosuccinic acid esters, polyoxyethylene acid betanesters, acid betanesters and sorbitan ethers, polyoxyethylene fatty alcohol ethers, polyoxyethylene stearates and corresponding mixed condensates of polyoxyethylene-methopolyoxypropylene ethers, ethoxylated saturated glycerides, partial fatty acid glycerides and polyglycides. Examples of suitable surfactants are Biobase® EP and Ceralution® H.

Beispiele geeigneter Emulgatoren sind ferner Glycerinester, Polyglycerinester, Sorbitanester, Sorbitolester, Fettalkohole, Propylenglykolester, Alkylglucositester, Zuckerester, Lecithin, Silikoncopolymere, Wollwachs und deren Mischungen oder Derivate. Glycerinester, Polyglycerinester, Alkoxylate und Fettalkohole sowie Isoalkohole können sich beispielsweise ableiten von Rizinusfettsäure, 12-Hydroxystearinsäure, Isostearinsäure, Ölsäure, Linolsäure, Linolensäure, Stearinsäure, Myristinsäure, Laurinsäure und Caprinsäure. Neben den genannten Estern können auch Succinate, Amide oder Ethanolamide der Fettsäuren vorliegen. Als Fettsäurealkoxylate kommen insbesondere die Ethoxylate, Propoxylate oder gemischten Ethoxylate/Propoxylate in Betracht.Examples of suitable emulsifiers are also glycerol esters, polyglycerol esters, sorbitan esters, sorbitol esters, fatty alcohols, propylene glycol esters, alkylglucositesters, sugar esters, lecithin, silicone copolymers, wool wax and mixtures thereof or derivatives. Glycerol esters, polyglycerol esters, alkoxylates and fatty alcohols and isoalcohols can be derived, for example, from castor fatty acid, 12-hydroxystearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, myristic acid, lauric acid and capric acid. In addition to the stated esters, succinates, amides or ethanolamides of the fatty acids may also be present. Particularly suitable fatty acid alkoxylates are the ethoxylates, propoxylates or mixed ethoxylates / propoxylates.

Auch zur Herstellung der erfindungsgemäßen kosmetischen Emulsionen werden in der Regel Emulgatoren verwendet. Beispiele geeigneter Emulgatoren sind Glycerinester, Polyglycerinester, Sorbitanester, Sorbitolester, Fettalkohole, Propylenglykolester, Alkylglucosidester, Zuckerester, Lecithin, Silikoncopolymere, Wollwachs und ihre Mischungen und Derivate. Glycerinester, Polyglycerinester, Alkoxylate und Fettalkohole sowie Isoalkohole können sich beispielsweise ableiten von Rhizinusfettsäure, 12-Hydroxystearinsäure, Isostearinsäure, Ölsäure, Linolsäure, Linolensäure, Stearinsäure, Myrestinsäure, Maurinsäure und Caprinsäure. Neben den genannten Estern können auch Succinate, Amide oder Ethanolamide der Fettsäuren vorliegen. Als Fettsäurealkoxylate kommen insbesondere die Ethoxylate, Propoxylate oder gemischten Ethoxylate/Propoxylate in Betracht. Ferner können Emulgatoren eingesetzt werden, die Lamelarstrukturen ausbilden. Beispiele derartiger Emulgatoren sind die physiologischen Gallensalze wie Natriumcheolat, Natriumdehydrocheolat, Natriumdeoxycheolat, Natriumglycochealat, Natriumtaurochealat. Tierische und pflanzliche Phospholipide wie Lecithine mit Ihren hydrierten Formen sowie Polypeptide wie Gelatine mit ihren modifizierten Formen können ebenso verwendet werden.Emulsifiers are also generally used to prepare the cosmetic emulsions according to the invention. Examples of suitable emulsifiers are glycerol esters, polyglycerol esters, sorbitan esters, sorbitol esters, fatty alcohols, propylene glycol esters, Alkylglucoside esters, sugar esters, lecithin, silicone copolymers, wool wax and their mixtures and derivatives. Glycerol esters, polyglycerol esters, alkoxylates and fatty alcohols and isoalcohols can be derived, for example, from castor fatty acid, 12-hydroxystearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, myristic acid, mauric acid and capric acid. In addition to the stated esters, succinates, amides or ethanolamides of the fatty acids may also be present. Particularly suitable fatty acid alkoxylates are the ethoxylates, propoxylates or mixed ethoxylates / propoxylates. It is also possible to use emulsifiers which form lamellar structures. Examples of such emulsifiers are the physiological bile salts such as sodium cheolate, sodium dehydrocheolate, sodium deoxycheolate, sodium glycochelate, sodium taurochalate. Animal and plant phospholipids such as lecithins with their hydrogenated forms as well as polypeptides such as gelatin with their modified forms can also be used.

Als synthetische grenzflächenaktive Substanzen eignen sich die Salze der Sulfobernsteinsäureester, Polyoxiethylensäurebethanester, Säurebethanester und Sorbitanether, Polyoxiethylenfettalkoholether, Polyoxiethylenstearinsäureester sowie entsprechende Mischungskondensate von Polyoxiethylen-methpolyoxipropylenethern, ethoxylierte gesättigte Glyceride, partielle Fettsäure-Glyceride und Polyglycide. Beispiele geeigneter Tenside sind Biobase® EP und Ceralution® H.Suitable synthetic surfactants are the salts of sulfosuccinic, Polyoxiethylensäurebethanester, Säurebethanester and sorbitan, Polyoxiethylenfettalkoholether, Polyoxiethylenstearinsäureester and corresponding mixture condensates of Polyoxiethylen-methpolyoxipropylenethern, ethoxylated saturated glycerides, partial fatty acid glycerides and polyglycides. Examples of suitable surfactants are Biobase ® EP and Ceralution ® H.

Lipide und Emulgatoren werden vorzugsweise in einem Gewichtsverhältnis von 50: 1 bis 2: 1, vorzugsweise 15:1 bis 30:1 eingesetzt.Lipids and emulsifiers are preferably used in a weight ratio of 50: 1 to 2: 1, preferably 15: 1 to 30: 1.

Die pharmazeutischen, kosmetischen und/oder lebensmitteltechnologischen Wirkstoffe werden, bezogen auf die Phase B, vorzugsweise in einer Menge von 0,1 bis 80 Gew.-%, besonders bevorzugt 1 bis 10 Gew.-% eingesetzt.The pharmaceutical, cosmetic and / or food-technological active ingredients are, based on the phase B, preferably used in an amount of 0.1 to 80 wt .-%, particularly preferably 1 to 10 wt .-%.

Nachfolgend werden beispielhaft pharmazeutische Wirkstoffe aufgeführt, die beispielsweise in freier Form, als Salz, Ester oder Ether eingesetzt werden können:

  • Analgetika/Antirheumatika, wie Morphin, Copdein, Piritamid, Fentanyl und Fentanylderivate, Leyomethadon, Tramadol, Diclofenac, Ibuprofen, Indometacin, Naproxen, Piroxicam, Penicillamin; Antiallergika, wie Pheniramin, Dimetinden, Terfenadin, Astemizol, Loratidin, Doxylamin, Meclozin, Bamipin, Clemastin; Antibiotika / Chemotherapeutika, wie Polypetidantibiotika wie Colistin, Polymyxin B, Teicplanin, Vancomycin; Malariamittel wie Chinin, Halofantrin, Mefloquin, Chloroquin, Virustatika wie Ganciclovir, Foscarnet, Zidovudin, Aciclovir und andere wie Dapson, Fosfomycin, Fusafungin, Trimetoprim; Antiepileptika, wie Phenytoin, Mesuximid, Ethosuximid, Primidon, Phenobarbital, Valproinsäure, Carbamazepin, Clonazepam; Antimykotika, wie intern: Nystatin, Natarrycin, Amphotericin B, Flucytoan, Miconazol, Fluconazol, Itraconazol; extern außerdem: Clotrimazol, Econazol, Tioconazol, Fenticonazol, Bifonazol, Oxiconazol, Ketoconazol, isoconazol, Tlnattat; Corticoide (Interna), wie Aldosteron Fludrocortison, Betametason, Dexametason, Triamcinolon, Fluocortolon, Hydroxycortison, Prednisolon, Prednyliden, Cloprednol, Methylprednisolon; Dermatika, wie Antibiotika: Tetracyclin, Erythromycin, Neomycin, Gentamycin, Clindamiycin, Framycetin, Tyrothricin, Chlortetracyclin Mipirocin, Fusidnsäure; Virustatika wie oben, außerdem: Podohyllotoxin, Vidarabin, Tromantadin; Corticoide wie oben, außerdem: Amcinonid, Flupredniden, Alclometason, Clobetasol, Diflorason, Halcinonid, Fluocinolon, Clocortolon, Flumetason, Difluocortolon, Fludroxycortid, Halometason, Desoximtason, Fluocinolid, Fluocortinbutyl, Flupredniden, Prednicarbat, Desonid; Diagnostika, wie radioaktive Isotope wie Te99m, Inlll oder I131, kovalent gebunden an Lipide oder Lipoide oder andere Moleküle oder in Komplexen, hochsubstituierte iodhaltige Verbindungen wie zum Beispiel Lipide; Hämostyptika, wie Blutungsgerinnungsfaktoren VIII, IX; Hypnotika, Sedativa, wie Cyclobarbital, Pentobarbital, Phenobarbital, Methaqualon, Benzodiazepine (Flurazepam, Midazolam, Netrazepam, Lormetazepam, Flunitrazepam, Trazolam, Brotizolam, Temazepam, Loprazolam); Hypophysen-, Hypothalamushormone, regulatorische Peptide und ihre Hemmstoffe, wie Corticotrophin, Tetracosactid, Choriongonadotropin, Urofollitropin, Urogonadotropin, Somatropin, Metergolin, Bromocriptin, Terlipressin, Desmopressin, Oxrtocin, Argipressin, Ornipressin, Leuprorelin, Triptorelin, Gonadorelin, Buserelin, Nafarelin, Goselerin, Somatostatin; Immuntherapeutika und Zytokine, wie Dimepranol-4-acetatamidobenzoat, Thymopentin, α-Interferon, β-Interferon, Filgrastim, Interleukine, Azathioprin, Ciclosporin; Lokalanaesthetika, wie intern: Butanilicain, Mepivacain, Bupivacain, Etidocain, Lidocain, Articain, Prilocain; extern außerdem: Propipocain, Oxybuprocain, Etracain, Benzocain; Migränemittel, wie Proxibarbal, Lisurid, Methysergid, Dihydroergotamin, Clonidin, Ergotamin, Pizotifen; Narkosemittel, wie Methohexital, Propofol, Etomidat, Ketamin, Alfentanil, Thiopental, Droperidol, Fentanyl; Nebenschilddrüsenhormone, Calciumstoffwechselregulatoren, wie Dihydrotachysterol, Calcitonin, Clodronsäure, Etidronsäure; Opthalmika, wie Atropin, Cyclodrin, Cyclopentolat, Homatropin, Tronicamid, Scopolamin, Pholedrin, Edoxudin, Idouridin, Tromantadin, Aciclovir, Acetazolamid, Diclofenamid, Carteolol, Timolol, Metipranolol, Betaxolol, Pindolol, Befunolol, Bupranolol, Levobununol, Carbachol, Pilocarpin, Clonidin, Neostigmin; Psychopharmaka, wie Benzodiazepne (Lorazepam, Diazepam), Clomethiazol; Schilddrüsentherapeutika, wie 1-Thyroxin, Carbirnazol, Thiamazol, Propylthiouracil; Sera, Immunglobuline, Impfstoffe, wie Immunglobuline allgemein und spezifisch wie Hepatitis-Typen, Röteln, Cytomegalie, Tollwut; FSME, VaricellaZoster, Tetanus, Rhesusfaktoren, Immunsera wie Botulismus-Antitoxin, Diphterie, Gasbrand, Schlangengift, Skorpiongift, Impfstoffe wie Influenza, Tuberkulose Cholera, Diphterie, Hepatitis-Typen, FSME, Röteln, Hämophilus influenzae, Masern, Neisseria, Mumps, Poliomyelitis, Tetanus, Tollwut, Typhus; Sexualhormone und ihre Hemmstoffe, wie Anabolika, Androgene, Antiandrogene, Gestagene, Estrogene, Antiestrogene (Tamoxifen etc.); Zystostatika und Metastasenhemmer, wie Alkylantien wie Nimustin, Melphalan, Carmustin, Lomustin, Cyclophosphamid, Ifosfamid, Trofosfamid, Chlorambucil, Busulfan, Treosulfan, Predninmustin, Thiotepa,
  • Antimetabolite wie Cytarabin, Fluorouracil, Methotrexat, Mercaptopurin, Tioguanin, Alkaloide wie Vinblastin, Vincristin, Vindesin; Antibiotika wie Aclarubicin, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin, Mitomycin, Plicamycin,
  • Komplexe von Nebengruppenelementen (zum Beispiel Ti, Zr, V, Nb, Ta, Mo, W, Pt) wie Carboplatin, Cisplatin und Metallocenverbindungen wie Titanocendichlorid
  • Amsacrin, Dacarbazin, Estramustin, Etoposid, Hydroxycarbamid, Mitoxynthron, Procazbazin, Temiposid
  • Alkylamidophospholipide (beschrieben in J. M. Zeidler, F. Emling, W. Zimmermann und H. J. Roth, Archiv der Pharmazie, 324 (1991), 687 )
  • Etherlipide wie Hexadecylphosphocholin, Ilmofosin und Analoga, beschrieben in R. Zeisig, D. Arndt und H. Brachwitz, Pharmazie 45 (1990), 809 bis 818 .
The following are exemplary pharmaceutical active ingredients listed, which can be used for example in free form, as a salt, ester or ether:
  • Analgesics / antirheumatics such as morphine, copdein, piritamide, fentanyl and fentanyl derivatives, leyomethadone, tramadol, diclofenac, ibuprofen, indomethacin, naproxen, piroxicam, penicillamine; Antiallergic agents such as pheniramine, dimetinden, terfenadine, astemizole, loratidine, doxylamine, meclozin, bamipin, clemastine; Antibiotics / chemotherapeutics such as polypetid antibiotics such as colistin, polymyxin B, teicplanin, vancomycin; Antimalarials such as quinine, halofantrine, mefloquine, chloroquine, antivirals such as ganciclovir, foscarnet, zidovudine, acyclovir and others such as dapsone, fosfomycin, fusafungine, trimetoprim; Anticonvulsants such as phenytoin, mesuximide, ethosuximide, primidone, phenobarbital, valproic acid, carbamazepine, clonazepam; Antifungals such as internally: nystatin, natarrycin, amphotericin B, flucytoan, miconazole, fluconazole, itraconazole; external also: clotrimazole, econazole, tioconazole, fenticonazole, bifonazole, oxiconazole, ketoconazole, isoconazole, tlnattate; Corticoids (internals), such as aldosterone fludrocortisone, betametasone, dexametasone, triamcinolone, fluocortolone, hydroxycortisone, prednisolone, prednylidene, cloprednol, methylprednisolone; Dermatics, such as antibiotics: tetracycline, erythromycin, neomycin, gentamycin, clindamiycin, framycetin, tyrothricin, chlortetracycline mipirocin, fusidic acid; Antivirals as above, also: podohyllotoxin, vidarabine, tromantadine; Corticoids as above, also: amcinonide, flupredniden, alclometasone, clobetasol, diflorasone, halcinonide, fluocinolone, clocortolone, flumetasone, difluocortolone, fludroxycortide, halometasone, desoximtasone, fluocinolide, fluocortinbutyl, flupredniden, prednicarbate, desonide; Diagnostics such as radioactive isotopes such as Te99m, InIII or I131 covalently linked to lipids or lipids or other molecules or in complexes, highly substituted iodine-containing compounds such as lipids; Hemostatic agents, such as bleeding factors VIII, IX; Hypnotics, sedatives such as cyclobarbital, pentobarbital, phenobarbital, methaqualone, benzodiazepines (flurazepam, midazolam, netrazepam, lormetazepam, flunitrazepam, trazolam, Brotizolam, temazepam, loprazolam); Pituitary and hypothalamic hormones, regulatory peptides and their inhibitors such as corticotrophin, tetracosactide, chorionic gonadotropin, urofollitropin, urothonototropin, somatropin, metergoline, bromocriptine, terlipressin, desmopressin, oxrtocin, argipressin, ornipressin, leuprorelin, triptorelin, gonadorelin, buserelin, nafarelin, goselerin, somatostatin; Immunotherapeutics and cytokines, such as dimepranol 4-acetatamidobenzoate, thymopentin, α-interferon, β-interferon, filgrastim, interleukins, azathioprine, ciclosporin; Local anesthetics, such as internally: butanilicain, mepivacaine, bupivacaine, etidocaine, lidocaine, articaine, prilocaine; external also: propipocaine, oxybuprocaine, etracaine, benzocaine; Migraine agents such as proxibarbal, lisuride, methysergide, dihydroergotamine, clonidine, ergotamine, pizotifen; Anesthetics such as methohexital, propofol, etomidate, ketamine, alfentanil, thiopental, droperidol, fentanyl; Parathyroid hormones, calcium metabolism regulators such as dihydrotachysterol, calcitonin, clodronic acid, etidronic acid; Opthalmics such as atropine, cyclodrin, cyclopentolate, homatropin, tronicamide, scopolamine, pholedrine, edoxudine, idouridin, tromantadine, acyclovir, acetazolamide, diclofenamide, carteolol, timolol, metipranolol, betaxolol, pindolol, befunolol, bupranolol, levobununol, carbachol, pilocarpine, clonidine , Neostigmine; Psychotropic drugs, such as benzodiazepines (lorazepam, diazepam), clomethiazole; Thyroid therapeutics such as 1-thyroxine, carbirnazole, thiamazole, propylthiouracil; Sera, immunoglobulins, vaccines, such as immunoglobulins in general and specific such as hepatitis types, rubella, cytomegalovirus, rabies; TBE, varicella zoster, tetanus, Rhesus factors, immune serums such as botulism antitoxin, diphtheria, gas gangrene, snake venom, scorpion venom, vaccines such as influenza, tuberculosis cholera, diphtheria, hepatitis types, TBE, rubella, hemophilus influenzae, measles, neisseria, mumps, poliomyelitis, Tetanus, rabies, typhus; Sex hormones and their inhibitors, such as anabolic steroids, androgens, antiandrogens, progestogens, estrogens, antiestrogens (tamoxifen etc.); Cystostats and metastasis inhibitors such as alkylating agents such as nimustine, melphalan, carmustine, lomustine, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, busulfan, treosulfan, predninmustine, thiotepa,
  • Antimetabolites such as cytarabine, fluorouracil, methotrexate, mercaptopurine, tioguanine, alkaloids such as vinblastine, vincristine, vindesine; Antibiotics such as aclarubicin, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitomycin, plicamycin,
  • Complexes of subgroup elements (for example, Ti, Zr, V, Nb, Ta, Mo, W, Pt) such as carboplatin, cisplatin and metallocene compounds such as titanocene dichloride
  • Amsacrine, dacarbazine, estramustine, etoposide, hydroxycarbamide, mitoxynthrone, procazabazine, temiposide
  • Alkylamidophospholipids (described in JM Zeidler, F. Emling, W. Zimmermann and HJ Roth, Archiv der Pharmazie, 324 (1991), 687 )
  • Etherlipids such as hexadecylphosphocholine, ilmofosine and analogs described in R. Zeisig, D. Arndt and H. Brachwitz, Pharmacy 45 (1990), 809-818 ,

Geeignete Wirkstoffe sind beispielsweise auch Dichlorphenac, Ibuprofen, Acetylsalicylsäure, Salicylsäure, Erythromycin, Ketoprofen, Cortison, Glucocorticoide.Suitable active ingredients are, for example, also dichlorphenac, ibuprofen, acetylsalicylic acid, salicylic acid, erythromycin, ketoprofen, cortisone, glucocorticoids.

Weiterhin geeignet sind kosmetische Wirkstoffe, die insbesondere oxidations- oder hydrolyseempfindlich sind wie beispielsweise Polyphenole. Hier seien genannt Catechine (wie Epicatechin, Epicatechin-3-gallat, Epigallocatechin, Epigallocatechin-3-gallat), Flavonoide (wie Luteolin, Apigenin, Rutin, Quercitin, Fisetin, Kaempherol, Rhametin), Isoflavone (wie Genistein, Daidzein, Glycitein, Prunetin), Cumarine (wie Daphnetin, Umbelliferon), Emodin, Resveratrol, Oregonin.Also suitable are cosmetic active ingredients which are particularly susceptible to oxidation or hydrolysis, for example polyphenols. Catechins (such as epicatechin, epicatechin-3-gallate, epigallocatechin, epigallocatechin-3-gallate), flavonoids (such as luteolin, apigenin, rutin, quercitin, fisetin, kaempherol, rhametin), isoflavones (such as genistein, daidzein, glycitein, Prunetin), coumarins (such as daphnetin, umbelliferone), emodin, resveratrol, oregonin.

Geeignet sind Vitamine wie Retinol, Tocopherol, Ascorbinsäure, Riboflavin, Pyridoxin. Geeignet sind ferner Gesamtextrakte aus Pflanzen, die. u.a. obige Moleküle oder Molekülklassen enthalten.Suitable are vitamins such as retinol, tocopherol, ascorbic acid, riboflavin, pyridoxine. Also suitable are whole extracts from plants that. including the above molecules or classes of molecules.

Bei den Wirkstoffen handelt es sich gemäß einer Ausführungsform der Erfindung um Lichtschutzfilter. Diese können als organische Lichtschutzfilter bei Raumtemperatur (25°C) in flüssiger oder fester Form vorliegen. Geeignete Lichtschutzfilter (UV-Filter) sind beispielsweise Verbindungen auf Basis von Benzophenon, Diphenylcyanacrylat oder p-Aminobenzoesäure. Konkrete Beispiele sind (INCI- oder CTFA-Bezeichnungen) Benzophenone-3, Benzophenone-4, Benzophenone-2, Benzophenone-6, Benzophenone-9, Benzophenone-1, Benzophenone-11, Etocrylene, Octocrylene, PEG-25 PABA, Phenylbenzimidazole Sulfonic Acid, Ethylhexyl Methoxycinnamate, Ethylhexyl Dimethyl PABA, 4-Methylbenzylidene Camphor, Butyl Methoxydibenzoylmethane, Ethylhexyl Salicylate, Homosalate sowie Methylene-Bis-Benzotriazolyl Tetramethylbutylphenol (2,2'-Methylen-bis-{6-(2H-benzoetriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)-phenol}, 2-Hydroxy-4-methoxybenzophenon-5-sulfonsäure und 2,4,6-Trianilino-p-(carbo-2'-ethylhexyl-1'-oxi)-1,3,5-triazin.The active substances are, according to one embodiment of the invention, light protection filters. These can be present as organic sunscreen at room temperature (25 ° C) in liquid or solid form. Suitable light protection filters (UV filters) are, for example, compounds based on benzophenone, diphenylcyanoacrylate or p-aminobenzoic acid. Specific examples are (INCI or CTFA designations) Benzophenone-3, Benzophenone-4, Benzophenone-2, Benzophenone-6, Benzophenone-9, Benzophenone-1, Benzophenone-11, Etocrylene, Octocrylene, PEG-25 PABA, Phenylbenzimidazole Sulfonic Acid, ethylhexyl methoxycinnamate, ethylhexyl dimethyl PABA, 4-methylbenzylidene camphor, butyl methoxydibenzoylmethane, ethylhexyl salicylates, homosalates and methylene-bis-benzotriazolyl tetramethylbutylphenol (2,2'-methylene-bis- {6- (2H-benzoetriazol-2-yl) -4- (1,1,3,3-tetramethylbutyl) phenol}, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and 2,4,6-trianilino-p- (carbo-2'-ethylhexyl-1 ' -oxi) -1,3,5-triazine.

Weitere organische Lichtschutzfilter sind Octyltriazone, Avobenzone, Octylmethoxycinnamate, Octylsalicylate, Benzotriazole und Triazine.Other organic sunscreen filters are octyltriazone, avobenzone, octylmethoxycinnamates, octylsalicylates, benzotriazoles and triazines.

Gemäß einer weiteren Ausführungsform der Erfindung werden als Wirkstoffe Antischuppen-Wirkstoffe eingesetzt, wie sie üblicherweise in kosmetischen oder pharmazeutischen Formulierungen vorliegen. Ein Beispiel hierfür ist Piroctone Olamine (1-Hydroxy-4-methyl-6-(2,4,4-dimethylpentyl)-2(1H)-pyridone; vorzugsweise in Kombination mit 2-Aminoethanol (1:1)). Weitere geeignete Mittel zur Behandlung von Hautschuppen sind dem Fachmann bekannt.According to a further embodiment of the invention, anti-dandruff agents are used as active ingredients, as they are usually present in cosmetic or pharmaceutical formulations. An example of this is Piroctone Olamine (1-hydroxy-4-methyl-6- (2,4,4-dimethylpentyl) -2 (1H) -pyridone, preferably in combination with 2-aminoethanol (1: 1)). Other suitable agents for the treatment of dander are known in the art.

Weitere mögliche Inhaltstoffe der Emulsionen sind hydrophil beschichtete Mikropigmente, Elektrolyte, Glycerin, Polyethylenglykol, Propylenglykol, Bariumsulfat, Alkohole, Wachse, Metallseifen, Magnesiumstearat, Vaseline oder andere Inhaltsstoffe. Beispielsweise können weiterhin Parfums, Parfumöle oder Parfumaromen zugesetzt werden. Geeignete kosmetische Wirkstoffe beispielsweise Polyphenole und davon abgeleitete Verbindungen. Geeignete Vitamine sind Retinol, Tocopherol, Ascorbinsäure, Riboffavin und Pyridoxin.Other possible ingredients of the emulsions are hydrophilic coated micropigments, electrolytes, glycerol, polyethylene glycol, propylene glycol, barium sulfate, alcohols, waxes, metal soaps, magnesium stearate, vaseline or other ingredients. For example, it is also possible to add perfumes, perfume oils or perfume flavors. Suitable cosmetic agents, for example polyphenols and compounds derived therefrom. Suitable vitamins are retinol, tocopherol, ascorbic acid, ribovavin and pyridoxine.

Als Wirkstoffe kommen zudem beispielsweise alle oxidationssensiblen Wirkstoffe wie Tocopherol in Betracht.
Gemäß einer weiteren Ausführungsform der Erfindung werden organische Farbstoffe als Wirkstoffe bzw. an Stelle von Wirkstoffen eingesetzt.
As active ingredients, for example, all oxidation-sensitive active ingredients such as tocopherol come into consideration.
According to a further embodiment of the invention, organic dyes are used as active ingredients or instead of active substances.

Mit dem erfindungsgemäßen Verfahren können alle bekannten und geeigneten Wasser-in-Öl-Emulsionen oder Öl-in-Wasser-Emulsionen hergestellt werden. Dazu können die nach den beschriebenen Emulgatoren und weiteren Inhaltsstoffe eingesetzt werden. Ferner ist die Herstellung von Polyol-in-Öl-Emulsionen möglich. Hierbei können beliebige geeignete Polyole eingesetzt werden.All known and suitable water-in-oil emulsions or oil-in-water emulsions can be prepared by the process according to the invention. These can be used after the emulsifiers described and other ingredients. Furthermore, the preparation of polyol-in-oil emulsions is possible. Any suitable polyols can be used here.

In den Emulsionen können die Anteile der zwei Hauptphasen in weiten Bereichen variiert werden. Beispielsweise liegen 5 bis 95 Gew.-%, vorzugsweise 10 bis 90 Gew.-%, insbesondere 20 bis 80 Gew.-% der jeweiligen Phasen vor, wobei die Gesamtmenge 100 Gew.-% ergibt.In the emulsions, the proportions of the two main phases can be varied within wide limits. For example, from 5 to 95% by weight, preferably from 10 to 90% by weight, in particular from 20 to 80% by weight, of the respective phases are present, the total amount being 100% by weight.

Die. beschriebene P/O-Emulsion kann auch in Wasser oder eine Wasser-in-Öl-Emulsion emulgiert werden. Dabei resultiert eine Polyol-in-Öl-inWasser-Emulsion (P/O/W-Emulsion), die mindestens eine beschriebene Emulsion und zusätzlich mindestens eine wässrige Phase enthält. Derartige multiple Emulsionen können im Aufbau den in DE-A-43 41 113 beschriebenen Emulsionen entsprechen.The. described P / O emulsion can also be emulsified in water or a water-in-oil emulsion. This results in a polyol-in-oil-in-water emulsion (P / O / W emulsion) containing at least one described emulsion and additionally at least one aqueous phase. Such multiple emulsions may correspond in structure to the emulsions described in DE-A-43 41 113.

Beim Einbringen der erfindungsgemäßen P/O-Emulsion in Wasser oder wässrige Systeme kann das Gewichtsverhältnis der einzelnen Phasen in weiten Bereichen variiert werden. Vorzugsweise beträgt in der letztendlich erhaltenen P/O/W-Emulsion der Gewichtsanteil der P/O-Emulsion 0,01 bis 80 Gew.-%, besonders bevorzugt 0,1 bis 70 Gew.-%, insbesondere 1 bis 30 Gew.-%, bezogen auf die gesamte P/O/W-Emulsion.When introducing the P / O emulsion according to the invention into water or aqueous systems, the weight ratio of the individual phases can be varied within wide limits. In the finally obtained P / O / W emulsion, the weight fraction of the P / O emulsion is preferably from 0.01 to 80% by weight, particularly preferably from 0.1 to 70% by weight, in particular from 1 to 30% by weight. %, based on the total P / O / W emulsion.

Beim Einbringen der erfindungsgemäßen P/O-Emulsion in eine O/W-Emulsion beträgt der Anteil der P/O-Emulsion vorzugsweise 0,01 bis 60 Gew.-%, besonders bevorzugt 0,1 bis 40 Gew.-%, insbesondere 1 bis 30 Gew.-%, bezogen auf die letztendlich erhaltene P/O/W-Emulsion. In der O/W-Emulsion, die hierzu verwendet wird, beträgt der Ölanteil vorzugsweise 1 bis 80 Gew.-%, besonders bevorzugt 1 bis 30 Gew.-%, bezogen auf die eingesetzte O/W-Emulsion. Anstelle einer P/O-Emulsion kann auch eine W/O-Emulsion eingebracht werden, was zu einer W/O/W-Emulsion führt. Die einzelnen Phasen der Emulsionen können noch übliche für die einzelnen Phasen bekannte Inhaltsstoffe aufweisen. Beispielsweise können die einzelnen Phasen weitere in diesen Phasen lösliche pharmazeutische oder kosmetische Wirkstoffe enthalten. Die wässrige Phase kann beispielsweise organische lösliche Lichtschutzfilter, hydrophil gecoatetes Micropigment, Elektrolyte, Alkohole usw. enthalten. Einzelne oder alle der Phasen können zudem Feststoffe enthalten, die vorzugsweise ausgewählt sind aus Pigmenten oder Micropigmenten, Mikrosphären, Silikagel und ähnlichen Stoffen. Die Ölphase kann beispielsweise organisch modifizierte Tonmineralien, hydrophob gecoatete (Micro)Pigmente, organische öllösliche Lichtschutzfilter, öllösliche kosmetische Wirkstoffe, Wachse, Metallseifen wie Magnesiumstearat, Vaseline oder Gemische davon enthalten. Als (Micro)Pigmente können Titandioxid, Zinkoxid und Bariumsulfat sowie Wollastonit, Kaolin, Talk, Al2O3, Bismutoxidchlorid, micronisiertes Polyethylen, Glimmer, Ultramarin, Eosinfarben, Azofarbstoffe, genannt werden. Insbesondere Titandioxid oder Zinkoxid sind in der Kosmetik als Lichtschutzfilter gebräuchlich und lassen sich mittels der erfindungsgemäßen Emulsionen besonders glatt und gleichmäßig auf die Haut auftragen. Mikrosphären oder Silicagel können als Träger für Wirkstoffe eingesetzt werden, und Wachse können beispielsweise als Grundlage für Polituren verwendet werden.When introducing the P / O emulsion according to the invention into an O / W emulsion, the proportion of the P / O emulsion is preferably 0.01 to 60% by weight, particularly preferably 0.1 to 40% by weight, in particular 1 to 30 wt .-%, based on the finally obtained P / O / W emulsion. In the O / W emulsion used for this purpose, the oil content is preferably 1 to 80% by weight, particularly preferably 1 to 30% by weight, based on the O / W emulsion used. Instead of a P / O emulsion, a W / O emulsion can also be introduced, which leads to a W / O / W emulsion. The individual phases of the emulsions may still have conventional ingredients known for the individual phases. For example, the individual phases may contain further pharmaceutical or cosmetic active substances which are soluble in these phases. The aqueous phase may contain, for example, organic soluble sunscreen, hydrophilically coated micropigment, electrolytes, alcohols, etc. Also, any or all of the phases may contain solids which are preferably selected from pigments or micropigments, microspheres, silica gel, and the like. The oil phase can For example, organically modified clay minerals, hydrophobic coated (micro) pigments, organic oil-soluble sunscreen, oil-soluble cosmetic agents, waxes, metal soaps such as magnesium stearate, Vaseline or mixtures thereof. Titanium dioxide, zinc oxide and barium sulfate, as well as wollastonite, kaolin, talc, Al 2 O 3 , bismuth oxychloride, micronized polyethylene, mica, ultramarine, eosin dyes, azo dyes, may be mentioned as (micro) pigments. Titanium dioxide or zinc oxide, in particular, are customary in cosmetics as light protection filters and can be applied particularly smoothly and evenly to the skin by means of the emulsions according to the invention. Microspheres or silica gel can be used as carriers for drugs, and waxes can be used, for example, as a base for polishes.

Die Wasserphase kann darüber hinaus Glycerin, Polyethylenglykol, Propylenglykol, Ethylenglykol und ähnliche Verbindungen sowie Derivate davon enthalten.The water phase may further contain glycerin, polyethylene glycol, propylene glycol, ethylene glycol and the like, as well as derivatives thereof.

Die Verwendung von üblichen Hilfs- und Zusatzstoffen in den Emulsionen ist dem Fachmann bekannt.The use of customary auxiliaries and additives in the emulsions is known to the person skilled in the art.

Als wässrige Phase können Wasser, wässrige Lösungen oder Mischungen von Wasser mit wassermischbaren Flüssigkeiten wie Glycerin oder Polyethylenglykol eingesetzt werden. Ferner können in der wässrigen Phase Elektrolyte wie Natriumchlorid enthalten sein. Falls gewünscht, können ferner viskositätserhöhende Stoffe oder Ladungsträger eingesetzt werden, wie sie in der EP-B-0605 497 beschrieben sind.As the aqueous phase, water, aqueous solutions or mixtures of water with water-miscible liquids such as glycerol or polyethylene glycol can be used. Further, electrolytes such as sodium chloride may be contained in the aqueous phase. If desired, it is also possible to use viscosity-increasing substances or charge carriers, as described in US Pat EP-B-0605497 are described.

Die Erfindung wird durch die nachstehenden Beispiele näher erläutert.The invention is further illustrated by the following examples.

BeispieleExamples

Alle Versuche wurden in einer zweistufigen Vorrichtung durchgeführt, wobei Phase A und Phase B getrennt in das erste Mischgefäß geführt wurden, der Austrag und Phase C sodann getrennt in das zweite Mischgefäß geführt wurden. Die angegebenen Prozentangaben beziehen sich auf das Gewicht. Es wurden Teilchengrößen und innere Oberflächen mit einem Particle Size Analyzer (PSA) bestimmt.All experiments were carried out in a two-stage apparatus, wherein phase A and phase B were fed separately into the first mixing vessel, the discharge and phase C were then fed separately into the second mixing vessel. The percentages given are by weight. Particle sizes and internal surfaces were determined with a Particle Size Analyzer (PSA).

Beispielrezepturen für kontinuierliche EmulsionsherstellungExample formulations for continuous emulsion production

Beispiel 1example 1

Emulgierung eines Triglycerides Phase A: Protelan LS 9011 Sodium Sarcosinate Lauroyl 0,54 % 0,54 % Brij 35 P Nena Laureth-23 1,40 % 1,40 % Pricerine 9091 Glycerin 6,32 % 1,40 % demin. Wasser 2,25 % 2,10 % Phase B: Miglyol 812 N Caprylic/capric triglyceride 60,0 % 60,0% Phase C: demin. Wasser 29,5 % 34,3% 100,0 % 99,7% Drehzahl Stufe 1 [min-1] 4000 4000 Drehzahl Stufe 2 [min-1] 3200 3200 Verweilzeit Stufe 1 [s] 10 10 Verweilzeit Stufe 2 [s] 5 5 PSA Median [µm] 0,39 0,44 < 1 µm [%] 100,0 98,3 cm2/cm3 16,5 15,3 Emulsification of a triglyceride <b> Phase A: </ b> Protelan LS 9011 Sodium sarcosinate Lauroyl 0.54% 0.54% Brij 35 P Nena Laureth-23 1.40% 1.40% Pricerine 9091 glycerin 6.32% 1.40% demin. water 2.25% 2.10% Miglyol 812 N Caprylic / capric triglycerides 60.0% 60.0% demin. water 29.5% 34.3% 100.0% 99.7% Speed level 1 [min-1] 4000 4000 Speed level 2 [min-1] 3200 3200 Dwell time level 1 [s] 10 10 Dwell time level 2 [s] 5 5 Median [μm] 0.39 0.44 <1 μm [%] 100.0 98.3 cm 2 / cm 3 16.5 15.3

Beispiel 2Example 2

Emulgierung eines Alkydharzes
Probe Phase A: Protelan LS 9011 Sodium Lauroyl Sarcosinate 0,40 % Brij 35 P Nena Laureth-23 1,05 % Hexylenglykol Hexylene Glycol 1,50 % demin. Wasser 4,50 % Phase B: Woleekyd L3 Alkydharz 58,0 % Phase C: demin. Wasser 34,5% 100,0 % Drehzahl Stufe 1 [min-1] 3000 Drehzahl Stufe 2 [min-1] 2400 Verweilzeit Stufe 1 [s] 25 Verweilzeit Stufe 2 [s] 16 PSA Median [µm] 0,39 < 1 µm [%] 100,0 cm2/cm3 17,2
Emulsification of an alkyd resin
sample <b> Phase A: </ b> Protelan LS 9011 Sodium lauroyl sarcosinate 0.40% Brij 35 P Nena Laureth-23 1.05% hexylene Hexylene glycol 1.50% demin. water 4.50% Woleekyd L3 alkyd resin 58.0% demin. water 34.5% 100.0% Speed level 1 [min-1] 3000 Speed level 2 [min-1] 2400 Dwell time level 1 [s] 25 Dwell time level 2 [s] 16 Median [μm] 0.39 <1 μm [%] 100.0 cm 2 / cm 3 17.2

Beispiel 3Example 3

Emulgierung eines Acrylatharzes
(80 % in EEP)
Probe Phase A: Protelan LS 9011 Sodium Lauroyl Sarcosinate 0,38 % Brij 35 P Nena Laureth-23 0,41 % Brij 700 Steareth-100 0,41 % demin. Wasser 6,00% Phase B: WorleeCryl-Produkt Acrylatharz 63,0 % Phase C: demin. Wasser 29,8 % 100,0 % Drehzahl Stufe 1 [min-1] 3000 Drehzahl Stufe 2 [min-1] 2400 Verweilzeit Stufe 1 [s] 25 Verweilzeit Stufe 2 [s] 16 PSA Median [µm] 0,67 < 1 µm [%] 82,0 m2/cm3 11,0
Emulsification of an acrylate resin
(80% in EEP)
sample Phase A: Protelan LS 9011 Sodium lauroyl sarcosinate 0.38% Brij 35 P Nena Laureth-23 0.41% Brij 700 Steareth-100 0.41% demin. water 6.00% WorléeCryl product acrylate 63.0% demin. water 29.8% 100.0% Speed level 1 [min-1] 3000 Speed level 2 [min-1] 2400 Dwell time level 1 [s] 25 Dwell time level 2 [s] 16 Median [μm] 0.67 <1 μm [%] 82.0 m 2 / cm 3 11.0

Beispiel 4Example 4

Herstellung einer W/O EmulsionPreparation of a W / O emulsion Rezeptur-Nr.:Formulation No .: Handelsnametrade name Gew.-%Wt .-% Phase APhase A Arlacel 1690Arlacel 1690 Sorbitan oleate, polyglyceryl ricinoleateSorbitan oleate, polyglyceryl ricinoleate 7,007.00 Isopar LIsopar L. C10-13 isoparaffinC10-13 isoparaffin 3,503.50 Phase BPhase B demin. Wasserdemin. water 40,0040,00 NaClNaCl Sodium chlorideSodium chloride 1,001.00 Phase CPhase C Isopar LIsopar L. C10-13 isoparaffinC10-13 isoparaffin 48,5048,50 Summe:Total: 100,00100.00 Drehzahl Stufe 1 [min-1]Speed level 1 [min-1] 37503750 Drehzahl Stufe 2 [min-1]Speed level 2 [min-1] 30003000 Verweilzeit Stufe 1 [s]Dwell time level 1 [s] 2525 Verweilzeit Stufe 2 [s]Dwell time level 2 [s] 1313 PSA (Volume)PSA (Volume) Median [µm]Median [μm] 0,390.39 < 1 µm [%]<1 μm [%] 100100 m2/cm3 m 2 / cm 3 17,317.3

Beispiel 5Example 5

Herstellung einer P/O EmulsionPreparation of a P / O emulsion Rezeptur-NrReceipt No. Leer-POEmpty-PO Produktionstag:production day: Handelsnametrade name [Gew.-%][Wt .-%] Phase APhase A Dow Coming DC DC 5225Dow coming DC DC 5225 Cyclomethicone, PEG/PPG-Cyclomethicone, PEG / PPG 13,8013.80 CC 18/18 dimethicone18/18 dimethicone Abil EM 97Abil EM 97 Cetyl PEG/PPG-10/1 dimethiconeCetyl PEG / PPG-10/1 dimethicone 5,205.20 Wacker Belsil CM 040Wacker Belsil CM 040 CyclomethiconeCyclomethicone Phase BPhase B Propylene glycol (0,5 %Propylene glycol (0.5%) Propylene GlycolPropylene glycol 71,0071.00 NaCl)NaCl) Phase CPhase C Wacker Belsil CM 040Wacker Belsil CM 040 CyclomethiconeCyclomethicone 10,0010.00 Summetotal 100,00100.00 Drehzahl Stufe 1 [min-1]Speed level 1 [min-1] 30003000 Drehzahl Stufe 2 [min-1]Speed level 2 [min-1] 24002400 Verweilzeit Stufe 1 [s]Dwell time level 1 [s] 2020 Verweilzeit Stufe 2 [s]Dwell time level 2 [s] 1818 PSA (Volume)PSA (Volume) Median [µm]Median [μm] 0,710.71 < 1 µm [%]<1 μm [%] 8383 m2/cm3 m 2 / cm 3 9,979.97

Beispiel 6Example 6

Herstellung einer Basis-OWProduction of a basic OW Rezeptur-Nr.:Formulation No .: Handelsnametrade name [Gew.-%][Wt .-%] Phase APhase A Biobase RSBiobase RS Glycerin stearate, cetyl alcohol, sodium stearoyl lactylate, tocopherol Glycerol stearate, cetyl alcohol, sodium stearoyl lactylate, tocopherol 2,502.50 Vara ABVara AB Petrolatumpetrolatum 5,005.00 Cosmacol EBICosmacol EBI C12 - 15 Alkyl benzoateC12-15 alkyl benzoate 5,005.00 Cetiol J 600Cetiol J 600 Oleyl-erucateOleyl erucate 3,703.70 Abil 350Abil 350 DimethiconeDimethicone 1,301.30 Vitamin E AcetatVitamin E acetate Tocopheryl acatateTocopheryl acatate 1,001.00 Phase BPhase B demin. Wasserdemin. water 3,703.70 Brij 700Brij 700 Stearath-100Stearath-100 0,500.50 KeltrolKeltrol Xanthan-GumXanthan gum 0,300.30 Phase CPhase C demin. Wasserdemin. water 77,077.0 Summetotal 100,00100.00 Drehzahl Stufe 1 [min-1]Speed level 1 [min-1] 40004000 Drehzahl Stufe 2 [min-1]Speed level 2 [min-1] 32003200 Verweilzeit Stufe 1 [s]Dwell time level 1 [s] 2020 Verweilzeit Stufe 2 [s]Dwell time level 2 [s] 55

Beispiel 7Example 7

Herstellung einer SLN EmulsionPreparation of a SLN emulsion Phase A:Phase A: Protelan LS 9011Protelan LS 9011 Sodium Lauroyl SarcosinateSodium lauroyl sarcosinate 0,75 %0.75% Brij 35 P NenaBrij 35 P Nena Laureth-23Laureth-23 1,30 %1.30% Pricerine 9091Pricerine 9091 Glyceringlycerin 2,25 %2.25% demin. Wasserdemin. water 2,25%2.25% Phase B:Phase B: Cutina CPCutina CP Cetyl palmitateCetyl palmitate 44,8%44.8% a-Tocopherola-tocopherol Tocopheroltocopherol 11,2%11.2% Phase C:Phase C: demin. Wasserdemin. water 37,5 %37.5% 100,0 %100.0% Drehzahl Stufe 1 [min-1]Speed level 1 [min-1] 40004000 Drehzahl Stufe 2 [min-1]Speed level 2 [min-1] 32003200 Verweilzeit Stufe 1 [s]Dwell time level 1 [s] 1212 Verweilzeit Stufe 2 [s]Dwell time level 2 [s] 8.8th. PSA (Area)PSA (area) Median [µm]Median [μm] 0,360.36 < 1 µm [%]<1 μm [%] 100,0100.0 cm2/cm3 cm 2 / cm 3 16,816.8

Claims (9)

  1. A method for the continuous production of gels or primary emulsions with air excluded, in which at least two flowable streams of at least two phases for the production of the gels or primary emulsions are dosed separately and continuously into a mixing vessel that is closed on all sides, in which they are converted, by agitated introduction, into the gel or the primary emulsion, and the gel or the primary emulsion is discharged continuously from the mixing vessel, the agitated introduction taking place without the formation of cavitation forces and without high-pressure homogenisation, and wherein the ratio between the at least two flowable streams is set in such a way that a viscoelastic range of the mixture is established in the mixing vessel.
  2. The method according to claim 1, characterized in that the method is carried out at low pressure, in particular at a pressure within the range of from 1 to 10 bar, particularly preferred at 1 to 1.5 bar.
  3. A method for the continuous production of nanoemulsions, nanodispersions or SLN dispersions with air excluded, wherein a gel or a primary emulsion according to claim 1 or 2 is produced, and wherein the gel or primary emulsion discharged from the first mixing vessel and another flowable stream are dosed into a second mixing vessel that is closed on all sides, from which vessel the desired emulsion or dispersion is discharged.
  4. A device for the continuous production of nanoemulsions, nanodispersions or SLN dispersions with air excluded, comprising a first mixing vessel closed on all sides which has inlet and outlet pipes for the supply and discharge of flowable materials or mixtures of materials, and an agitator which permits agitated introduction into the emulsion or dispersion without the formation of cavitation forces and without high-pressure homogenisation, wherein, in the agitator, stirrer elements are arranged on an axis of the agitator, said axis being rotated, and there being at least another second mixing vessel connected in series one after the other, the output of the first mixing vessel being fed into the second mixing vessel, and there being another supply pipe into the second mixing vessel.
  5. The device according to claim 4, characterized in that the first mixing vessel is essentially cylindrical in shape, the axis of the agitator lies along the axis of the cylinder, and the inlet and outlet pipes are positioned at a distance from each other essentially perpendicular to the axis of the cylinder in the top and bottom areas of the periphery of the cylinder.
  6. The device according to claim 4 or 5, characterized in that there is at least one sensor located in the outlet pipe for the continuous measurement of the temperature, conductivity and/or optical properties of the emulsion or dispersion.
  7. The device according to one of claims 4 to 6, characterized in that the mixing vessels can be brought to temperature independently of each other.
  8. The device according to one of claims 4 to 7, characterized in that the supply of the flowable materials and the agitated introduction, and, if required, the bringing to temperature of the mixing vessels are controlled by a computer.
  9. The device according to one of claims 4 to 8, characterized in that the device can be operated at low pressure, in particular at a pressure within the range of from 1 to 10 bar, particularly preferred at 1 to 1.5 bar.
EP06015110.7A 2003-03-21 2003-03-21 Device and method for continuously producing emulsions or dispersions Expired - Fee Related EP1707256B1 (en)

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