EP1606044B2 - Dispositif et procede de production continue d'emulsions ou de dispersions - Google Patents

Dispositif et procede de production continue d'emulsions ou de dispersions Download PDF

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Publication number
EP1606044B2
EP1606044B2 EP03816337A EP03816337A EP1606044B2 EP 1606044 B2 EP1606044 B2 EP 1606044B2 EP 03816337 A EP03816337 A EP 03816337A EP 03816337 A EP03816337 A EP 03816337A EP 1606044 B2 EP1606044 B2 EP 1606044B2
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EP
European Patent Office
Prior art keywords
mixing vessel
emulsion
emulsions
dispersion
mixing
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EP03816337A
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German (de)
English (en)
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EP1606044A1 (fr
EP1606044B1 (fr
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/fr
Priority to EP03816337A priority patent/EP1606044B2/fr
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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/41—Emulsifying
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/43—Mixing liquids with liquids; Emulsifying using driven stirrers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/50—Mixing liquids with solids
    • B01F23/53—Mixing liquids with solids using driven stirrers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/50—Pipe mixers, i.e. mixers wherein the materials to be mixed flow continuously through pipes, e.g. column mixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/80—Mixing plants; Combinations of mixers
    • B01F33/81—Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/80—Mixing plants; Combinations of mixers
    • B01F33/81—Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles
    • B01F33/811—Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles in two or more consecutive, i.e. successive, mixing receptacles or being consecutively arranged
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/21—Measuring
    • B01F35/213—Measuring of the properties of the mixtures, e.g. temperature, density or colour

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.
  • discontinuous mixing devices must be made 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. 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.
  • 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.
  • 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 .
  • US 5,250,576 relates to a process for the preparation of emulsions which can be polymerized to foam materials to be absorbed, in particular the production of superabsorbents for hygiene articles, which have a porous structure. Described is the preparation of a water-in-oil emulsion with a high proportion of internal phase.
  • the oil phase contains monomers which are polymerized to a foam after preparation of the emulsion.
  • the mixing vessel for the continuous production of the emulsion is shown in FIG.
  • the device consists of a combination of dynamic mixer with downstream static mixer.
  • the aqueous phase and the oil phase are metered separately from storage vessels into the dynamic mixer where they are converted into an emulsion under shear.
  • the weight ratio of water to oil is about 2: 1 to 10: 1.
  • the flow of oil phase and water phase is adjusted so that ultimately the weight ratio of water to oil is 12: 1 to 100: 1.
  • the low weight ratio is only used when starting up the mixer.
  • the shear entry is about 1,000 to 7,000 l / s, in particular 1,500 to 3,000 l / s.
  • the dynamic mixer is also on a proposed vent (reference numerals 12 and 13). It is stated that in operation a purely liquid environment is obtained. As can be seen from Figure 2, the entry of the starting materials (reference numerals 9 and 10) as well as the discharge from the dynamic mixer (reference numeral 17) parallel to the stirrer axis and in the longitudinal direction of the mixing vessel.
  • US 4,539,139 relates to a process for the preparation of oil-in-water emulsions.
  • the preparation is carried out discontinuously in a tank containing a high-speed agitator.
  • the tank which is shown in Figure 3, can be evacuated via a line 8 and a pump 7, so that you can work under exclusion of air.
  • a conductivity measuring probe 9 is provided.
  • an oil phase is charged and a water phase is added continuously until phase inversion occurs.
  • 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.
  • 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 device according to claim 1.
  • 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 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.
  • 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 arranged the inlet and outlet pipes substantially perpendicular to the cylinder axis in the upper and lower peripheral region of the cylinder from each other are.
  • 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, if appropriate, further entries in the further mixing vessel can be entered. 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.
  • 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, d. H. 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, a different phase volume ratio is obtained in the mixing vessel, which leads to an altered 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, 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 with an average diameter in the range of 5 to 1000 nm, preferably 15 to 300 nm.
  • a finely divided primary emulsion is generally prepared in the first mixture under high-viscosity conditions, which in the second mixing vessel with one of both phases is diluted 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, in the second mixing device, the main part of the external phase is diluted.
  • 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.
  • 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 with 12 to 30 carbon atoms, such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, Behenic acid, lignoceric acid, cerotic acid, melamine acid, and esters thereof 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).
  • Polysaccharides with or in individual cases without 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 .-%, 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 also 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 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.
  • suitable surfactants are Biobase® EP and Ceralution® H.
  • emulsifiers are also glycerol esters, polyglycerol esters, sorbitan esters, sorbitol esters, fatty alcohols, propylene glycol esters, alkylglucoside esters, sugar esters, lecithin, silicone copolymers, wool wax and mixtures thereof or derivatives thereof.
  • 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, lauric acid and capric acid.
  • succinates, amides or ethanolamides of the fatty acids may also be present.
  • fatty acid alkoxylates are in particular 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 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, Polyoxiethylenklarebetanester, pressureurebetanester 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, dichlorfenac, 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 which i.a. contain 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.
  • 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.
  • 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.
  • 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 can be constructed in the structure DE-A-43 41 113 correspond to described emulsions.
  • 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 preferably 1 to 80 wt .-%, particularly preferably 1 to 30 wt .-%, 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 may contain, for example, organically modified clay minerals, hydrophobically coated (micro) pigments, organic oil-soluble light protection filters, 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 are customary in cosmetics as sunscreen 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.
  • Phase A Protelan LS 9011 Sodium lauroyl sarcosinate 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 60.0% 60.0% triglycerides
  • Phase C demin.
  • 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 [ ⁇ m] 0.39 ⁇ 1 ⁇ m [%] 100.0 cm 2 / cm 3 17.2
  • 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 [ ⁇ m] 0.67 ⁇ 1 ⁇ m [%] 82.0 m 2 / cm 3 11.0
  • 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 [ ⁇ m] 0.39 ⁇ 1 ⁇ m [%] 100 m 2 / cm 3 17.3
  • 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 [ ⁇ m] 0.36 ⁇ 1 ⁇ m [%] 100.0 cm 2 / cm 3 16.8

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Colloid Chemistry (AREA)
  • Cosmetics (AREA)
  • Accessories For Mixers (AREA)
  • Mixers Of The Rotary Stirring Type (AREA)

Abstract

L'invention concerne un dispositif permettant la production continue d'émulsions ou de dispersions, sous exclusion d'air, qui comprend une cuve de mélange présentant des tuyaux d'amenée et d'évacuation, pour introduire et évacuer des substances ou des mélanges de substances coulant(e)s, ainsi qu'un outil agitateur, qui permet d'introduire un mouvement d'agitation dans l'émulsion ou la dispersion, sans produire de forces de cavitation et sans homogénéisation à haute pression.

Claims (8)

  1. Dispositif de préparation continue d'émulsions ou de dispersions à l'abri de l'air, comprenant un récipient mélangeur fermé de tous côtés, qui présente des tubes d'amenée et d'évacuation, pour introduire et faire sortir des substances ou des mélanges de substances fluides, ainsi qu'un outil agitateur, lequel permet de réaliser une agitation dans l'émulsion ou la dispersion sans produire de forces de cavitation, et sans homogénéisation sous haute pression, caractérisé en ce que le récipient mélangeur présente une forme pour l'essentiel cylindrique, l'axe de l'outil agitateur coïncide avec l'axe du cylindre, et les tubes d'amenée et d'évacuation sont disposés pour l'essentiel perpendiculairement à l'axe du cylindre, dans la zone supérieure et dans la zone inférieure du cylindre, à distance l'un de l'autre et le dispositif comprend au moins deux récipients mélangeurs montés en série l'un derrière l'autre, la sortie du premier récipient mélangeur étant introduite dans le deuxième récipient mélangeur, un autre tube d'amenée étant prévu dans le deuxième récipient mélangeur.
  2. Dispositif selon la revendication 1, caractérisé en ce qu'au moins un capteur, destiné à la mesure continue de la température, de la conductivité et/ou des propriétés optiques de l'émulsion ou de la dispersion, est disposé dans le tube d'évacuation.
  3. Dispositif selon l'une des revendications 1 ou 2, caractérisé en ce que les récipients mélangeurs peuvent être portés à l'équilibre de température indépendamment les uns des autres.
  4. Dispositif selon l'une des revendications 1 à 3, caractérise en ce que l'amenée des substances fluides, et la réalisation de l'agitation, et éventuellement la mise à l'équilibre de température des récipients mélangeurs, sont commandés par ordinateur.
  5. Procédé de préparation continue d'émulsions et de dispersions à l'abri de l'air, dans lequel au moins deux courants fluides, constitués d'au moins deux phases des émulsions ou des dispersions, sont dosés séparément et en continu dans un récipient mélangeur fermé de tous côtés, dans lequel ils sont, avec réalisation d'une agitation, convertis en une émulsion ou une dispersion, et l'émulsion/dispersion est évacuée en continu du récipient mélangeur, la réalisation de l'agitation s'effectuant sans produire de forces de cavitation et sans homogénéisation sous haute pression, et dans lequel le rapport entre les au moins deux courants fluides, l'un par rapport à l'autre, est ajusté de façon à définir dans le récipient mélangeur une zone de mélange viscoélastique, le procédé étant mis en oeuvre dans un dispositif comprenant un récipient mélangeur fermé de tous côtés, qui présente des tubes d'amenée et d'évacuation, pour introduire et faire sortir des substances ou des mélanges de substances fluides, ainsi qu'un outil agitateur, lequel permet de réaliser une agitation dans l'émulsion ou la dispersion sans produire de forces de cavitation, et sans homogénéisation sous haute pression, et le récipient mélangeur présente une forme pour l'essentiel cylindrique, l'axe de l'outil agitateur coïncide avec l'axe du cylindre, et les tubes d'amenée et d'évacuation sont disposés pour l'essentiel perpendiculairement à l'axe du cylindre, dans la zone supérieure et dans la zone inférieure du cylindre, à distance l'un de l'autre.
  6. Procédé selon la revendication 5, caractérisé en ce que le procédé étant mis en oeuvre dans un dispositif selon l'une des revendications 1 à 4.
  7. Procédé selon l'une des revendications 5 ou 6, caractérisé en ce que l'émulsion ou la dispersion évacuée du premier récipient mélangeur, ainsi qu'un courant fluide supplémentaire, sont dosés dans un deuxième récipient mélangeur fermé de tous côtés, récipient mélangeur duquel et évacuée l'émulsion ou la dispersion souhaitée.
  8. Procédé selon l'une des revendications 5 à 7, caractérisé en ce qu'il est utilisé pour préparer des nanoémulsions, des nanodispersions ou des dispersions SLN.
EP03816337A 2003-03-21 2003-03-21 Dispositif et procede de production continue d'emulsions ou de dispersions Expired - Lifetime EP1606044B2 (fr)

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EP06015110.7A EP1707256B1 (fr) 2003-03-21 2003-03-21 Appareil et procédé pour la production en continue d'émulsions ou de dispersions
EP03816337A EP1606044B2 (fr) 2003-03-21 2003-03-21 Dispositif et procede de production continue d'emulsions ou de dispersions

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EP03816337A EP1606044B2 (fr) 2003-03-21 2003-03-21 Dispositif et procede de production continue d'emulsions ou de dispersions
PCT/EP2003/002996 WO2004082817A1 (fr) 2003-03-21 2003-03-21 Dispositif et procede de production continue d'emulsions ou de dispersions

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EP06015110.7 Division-Into 2006-07-20

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EP (1) EP1606044B2 (fr)
JP (1) JP4782426B2 (fr)
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CA (1) CA2519591C (fr)
DE (2) DE50305216D1 (fr)
WO (1) WO2004082817A1 (fr)

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DE50305216D1 (de) 2006-11-09
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CA2519591C (fr) 2011-07-12
US20070025177A1 (en) 2007-02-01
JP2006520678A (ja) 2006-09-14
AU2003226694A1 (en) 2004-10-11
CA2519591A1 (fr) 2004-09-30
DE20321104U1 (de) 2006-01-05
US7775704B2 (en) 2010-08-17
EP1606044A1 (fr) 2005-12-21
EP1606044B1 (fr) 2006-09-27

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