EP1707256A1 - Device and method for continuously producing emulsions or dispersions - Google Patents

Abstract

Apparatus for continuous production of emulsions or dispersions with exclusion of air comprising a closed mixing vessel with an inlet and outlet and a stirrer that permits agitation without cavitation or high-pressure homogenization, is new. An independent claim is also included for production of emulsions or dispersions with exclusion of air by continuously feeding separate fluid streams of the emulsion or dispersion components in metered amounts into an apparatus as above and continuously discharging the emulsion or dispersion.

Description

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. 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.

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.

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.

In addition, discontinuous mixing devices must be made 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.

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. A high pressure homogenization of this preemulsion is then carried out, which is then transferred to 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.

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.

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 production of solid lipid nanoparticles with a low average particle diameter according to the prior art is expensive, since high-pressure homogenizers generally have to be used. By merely stirring at high speed only relatively large average particle diameter of about 3 microns can be achieved.

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 control. 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.

The object is achieved by a device for the continuous production of emulsions or dispersions with exclusion of air, comprising a well-closed mixing vessel, the inlet and outlet pipes for the input and output of flowable substances or mixtures and a stirring tool having a stirring entry into the emulsion or dispersion without generation of cavitation forces and without high pressure homogenization allowed.

In addition, the object is achieved according to the invention by a process for the continuous preparation of emulsions and dispersions in the absence of air, in which at least two flowable streams of at least two phases of the emulsions or dispersions are continuously metered separately into a mixing vessel closed on all sides, in which they are mixed with stirring in an emulsion or dispersion, and the emulsion / dispersion is continuously discharged from the mixing vessel, wherein the stirring entry takes place without generation of cavitation forces and without high-pressure homogenization.

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".

The stirrer allows mechanical stirring into the emulsion or dispersion without generating cavitation forces and without high pressure homogenization. In preferred stirring tools, suitable stirring elements are arranged on a stirrer axis which is rotated. The stirring tool may be so-called rotor / stator systems in which a rotor is moved by motor-driven operation. 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.

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.

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.

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 inlet and outlet 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.

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.

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.

It 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.

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".

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.

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.

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.

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.

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.

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.

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.

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.

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. 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.

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.

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.

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.

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, 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.

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%.

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.

In comparison to known methods, the production of substantially finely divided emulsions with much less effort is possible.

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.

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. 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.

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.

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 with an average diameter in the range of 5 to 1000 nm, 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, in the second mixing device, the main part of the external phase is diluted. In the production of multiple emulsions, it is possible, for example, to produce a PO emulsion in the first mixing vessel, which is converted into a POW emulsion in the second mixing vessel together with water. In each case system-adapted speeds and stirring tools can be used.

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 initially 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.

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). Polysaccharides with or in individual cases or polyalkyl acrylates, polyalkyl cyanoacrylates, polyalkyl vinyl pyrrolidones, acrylic polymers, polylactic acids or polylactides can also be used as lipids.

The amount of active ingredient carrier particles, based on the total aqueous active ingredient carrier dispersion, is preferably 0.1 to 30 wt .-%, more 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 for example dicetyl phosphate, phosphatidylglycerol and saturated and unsaturated fatty acids, sodium cholate, sodium glycol cholate, sodium taurocholate or mixtures thereof, 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 agents such as cellulose ethers and esters (for example, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose), polyvinyl derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, alginates, polyacrylates (for example Carbopol), xanthans and pectins.

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.

If desired, viscosity increasing agents or charge carriers can also be used, as described in US Pat EP-B-0 605 497 are described.

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.

Suitable synthetic surfactants are the salts of sulfosuccinic acid esters, polyoxyethylene acid betanesters, acid betanesters and sorbitan ethers, polyoxyethylene fatty alcohol ethers, polyoxyethylene stearate esters and corresponding blend condensates of polyoxyethylene-methopolyoxypropylene ethers, ethoxylated saturated glycerides, partial fatty acid glycerides and polyglycides. Examples of suitable surfactants are Biobase® EP and Ceralution® H.

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.

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.

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.

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 .-%.

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, asternizole, 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, foscamet, 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, In111 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, procarbazine, 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 ,

Suitable active ingredients are, for example, also dichlorphenac, ibuprofen, acetylsalicylic acid, salicylic acid, erythromycin, ketoprofen, cortisone, glucocorticoids.

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.

Suitable are vitamins such as retinol, tocopherol, ascorbic acid, riboflavin, pyridoxine.
Also suitable are whole extracts from plants which contain, inter alia, 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 (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.

Other organic sunscreen filters are octyltriazone, avobenzone, octylmethoxycinnamates, octylsalicylates, benzotriazoles and triazines.

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.

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, riboflavin and pyridoxine.

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.

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 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.

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 can be constructed in the structure DE-A-43 41 113 correspond to described emulsions.

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.

When introducing the P / O emulsion according to the invention into an O / W emulsion, the proportion of the P / O emulsion is preferably from 0.01 to 60% by weight, particularly preferably from 0.1 to 40% by weight, in particular 1 to 30 wt .-%, based on the final 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.

The water phase may further contain glycerin, polyethylene glycol, propylene glycol, ethylene glycol and the like, as well as derivatives thereof.

The use of customary auxiliaries and additives in the emulsions is known to the person skilled in the art.

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.

The invention is further illustrated by the following examples.

Examples

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).

Example formulations for continuous emulsion production

example 1

Emulsification of a triglyceride 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. water 2.25% 2.10% Phase B: Miglyol 812 N Caprylic / capric triglycerides 60.0% 60.0% Phase C: 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 PSA Median [μm] 0.39 0.44 <1 μm [%] 100.0 98.3 cm ² / cm ³ 16.5 15.3

Example 2

Emulsification of an alkyd resin sample Phase A: 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% Phase B: Woleekyd L3 alkyd resin 58.0% Phase C: 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 PSA Median [μm] 0.39 <1 μm [%] 100.0 cm ² / cm ³ 17.2

Example 3

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% Phase B: WorléeCryl product acrylate 63.0% Phase C: 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 PSA Median [μm] 0.67 <1 μm [%] 82.0 m ² / cm ³ 11.0

Example 4

Preparation of a W / O emulsion Formulation No .: trade name Wt .-% Phase A Arlacel 1690 Sorbitan oleate, 7.00 polyglyceryl ricinoleate Isopar L. C10-13 isoparaffin 3.50 Phase B demin. water 40,00 NaCl Sodium chloride 1.00 Phase C Isopar L. C10-13 isoparaffin 48,50 Total: 100.00 Speed level 1 [min-1] 3750 Speed level 2 [min-1] 3000 Dwell time level 1 [s] 25 Dwell time level 2 [s] 13 PSA (Volume) Median [μm] 0.39 <1 μm [%] 100 m ² / cm ³ 17.3

Example 5

Preparation of a P / O emulsion Recipe No. Production Day: Empty-PO trade name [Wt .-%] Phase A Dow Corning DC DC 5225 C Cyclomethicone, PEG / PPG 13.80 18/18 dimethicone Abil EM 97 Cetyl PEG / PPG-10/1 dimethicone 5.20 Wacker Belsil CM 040 Cyclomethicone Phase B Propylene glycol (0.5% NaCl) Propylene glycol 71.00 Phase C Wacker Belsil CM 040 Cyclomethicone 10.00 total 100.00 Speed level 1 [min-1] 3000 Speed level 2 [min-1] 2400 Dwell time level 1 [s] 20 Dwell time level 2 [s] 18 PSA (Volume) Median [μm] 0.71 <1 μm [%] 83 m ² / cm ³ 9.97

Example 6

Production of a basic OW Formulation No .: trade name [Wt .-%] Phase A Biobase RS Glycerol stearate, cetyl alcohol, sodium stearoyl lactylate, tocopherol 2.50 Vara AB petrolatum 5.00 Cosmacol EBI C12-15 alkyl benzoate 5.00 Cetiol J 600 Oleyl erucate 3.70 Abil 350 Dimethicone 1.30 Vitamin E acetate Tocopheryl acatate 1.00 Phase B demin. water 3.70 Brij 700 Stearath-100 0.50 Keltrol Xanthan gum 0.30 Phase C demin. water 77.0 total 100.00 Speed level 1 [min-1] 4000 Speed level 2 [min-1] 3200 Dwell time level 1 [s] 20 Dwell time level 2 [s] 5

Example 7

Preparation of a SLN emulsion 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. PSA (area) Median [μm] 0.36 <1 μm [%] 100.0 cm ² / cm ³ 16.8

Claims (13)

Apparatus for the continuous production of emulsions or dispersions in the absence of air, comprising a mixing vessel which is closed on all sides and has inlet and outlet pipes for the introduction and discharge of flowable substances or mixtures of substances, and a stirring tool which effects stirring in the emulsion or dispersion without generation of cavitation forces and allowed without high-pressure homogenization. Apparatus according to claim 1, characterized in that the mixing vessel has a substantially cylindrical shape, the axis of the stirrer is in the cylinder axis and the inlet and outlet pipes are arranged substantially perpendicular to the cylinder axis in the upper and lower peripheral portion of the cylinder spaced from each other. Apparatus according to claim 1 or 2, characterized in that in the discharge tube at least one sensor for continuously measuring the temperature, conductivity and / or optical properties of the emulsion or dispersion is arranged. Device according to one of claims 1 to 3, characterized in that it comprises at least two series-connected in series mixing vessels, wherein the discharge from the first mixing vessel is introduced into the second mixing vessel and another feed pipe is provided in the second mixing vessel. Device according to one of claims 1 to 4, characterized in that the mixing vessels can be tempered independently. Device according to one of claims 1 to 5, characterized in that the supply of the flowable substances and the Rühreintrag and optionally the temperature of the mixing vessels are computer controlled. Device according to one of claims 1 to 6, characterized in that the device can be operated at low pressure, in particular at a pressure in the range of 1 to 10 bar, more preferably at 1 to 1.5 bar. Process for the continuous preparation of emulsions and dispersions in the absence of air, in which at least two flowable streams of at least two phases of the emulsions or dispersions are metered separately into a mixing vessel closed on all sides, in which they are transferred with stirring into an emulsion or dispersion, and the emulsion / Dispersion is discharged continuously from the mixing vessel, wherein the stirring entry takes place without the generation of cavitation forces and without high-pressure homogenization. A method according to claim 8, characterized in that the ratio of the at least two flowable streams to each other is adjusted so that in the mixing vessel einviskoelastischer range of the mixture is adjusted. A method according to claim 8 or 9, characterized in that the discharged from the first mixing vessel emulsion or dispersion and a further flow stream are metered into a second mixing vessel closed on all sides, from which the desired emulsion or dispersion is discharged. Method according to one of claims 8 to 10, characterized in that it is carried out in a device according to one of claims 1 to 6. Method according to one of claims 7 to 11, characterized in that it is used for the preparation of nanoemulsions, nanodispersions or SLN dispersions. Method according to one of claims 7 to 11, characterized in that the method at low pressure, in particular at a pressure in the range of 1 to 10 bar, more preferably at 1 to 1.5 bar is performed.