METHOD FOR PRODUCING AN OIL-IN-WATER EMULSION, OIL-IN-WATER EMULSION, AND INSTALLATION FOR PRODUCING AN OIL-IN-WATER EMULSION

Abstract

A system and method for producing an oil-in-water (“O/W”) emulsion performs or includes the steps of: a) providing an oil phase and a water phase, b) premixing the oil phase and the water phase to form an O/W pre-emulsion, and c) homogenizing the O/W pre-emulsion to form an O/W emulsion by at least one counter-jet disperser.

Claims

1. A method for producing an O/W emulsion comprising the following steps: a) providing an oil phase and a water phase; b) premixing the oil phase and the water phase to form an O/W pre-emulsion; and c) homogenizing the O/W pre-emulsion to form an O/W emulsion by at least one counter-jet disperser.

2. The method according to claim 1, wherein step b) is carried out by at least one rotor-stator disperser.

3. The method according to claim 2, wherein the oil phase and the water phase are fed to the at least one rotor-stator disperser spatially separated from each other.

4. The method according to claim 2, wherein the oil phase and the water phase are fed to the at least one rotor-stator disperser by a tube-in-tube arrangement.

5. The method according to claim 2, wherein the oil phase and the water phase are passed through a droplet comminution zone of the at least one rotor-stator disperser.

6. The method according to claim 1, wherein step c) is carried out by a pump pressure of 1000 bar to 1900 bar.

7. The method according to claim 1, wherein step c) is carried out at a temperature of the O/W pre-emulsion of 30° C. to 80° C.

8. The method according to claim 1, wherein the O/W pre-emulsion is passed repeatedly through the at least one counter-jet disperser when carrying out step c).

9. The method according to claim 1, wherein step c) is carried out by a plurality of counter-jet dispersers.

10. The method according to claim 1, wherein step c) is carried out by a first counter-jet disperser and a second counter-jet disperser connected in series.

11. The method according to claim 10, wherein the first counter-jet disperser is operated at a higher pump pressure than the second counter-jet disperser.

12. The method according to claim 10, wherein the first counter-jet disperser is operated at a pump pressure of at most 1500 bar.

13. The method according to claim 1, wherein a pressure reducer is connected downstream of the at least one counter-jet disperser.

14. An O/W emulsion, produced or producible according to the method of claim 1 and/or having a PFAT5 value <0.04%.

15. A system for producing an O/W emulsion according to the method of claim 1, wherein the system has at least one disperser for premixing an oil phase and a water phase to form an O/W pre-emulsion and comprises the at least one counter-jet disperser for homogenizing the O/W pre-emulsion to an O/W emulsion.

Description

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0088] The following is shown schematically in the figures:

[0089] FIG. 1 is a schematic view of a microchannel structure of a counter-jet disperser which can be used according to the invention;

[0090] FIG. 2 is a flow diagram of a method according to the invention;

[0091] FIG. 3 is a further flow diagram of a method according to the invention; and

[0092] FIG. 4 is a further flow diagram of a method according to the invention.

DETAILED DESCRIPTION

[0093] FIG. 1 shows a channel structure 1 of a counter-jet disperser which can be used according to the invention. The channel structure 1 shown has a Y-shaped arrangement and can, for example, have an internal diameter d in the micrometer range. An O/W pre-emulsion can be passed through the channel structure 1 via the inlets 2 and 3 by means of a pressure generated by a pump (high-pressure pump) of the counter-jet disperser. Due to the oppositely arranged channels 4 and 6, jets of the O/W pre-emulsion encounter each other in a droplet comminution zone 5. Particularly under the influence of shear forces, there is a comminution of the droplets present in the O/W pre-emulsion. The resulting O/W emulsion can exit the channel structure 1 via an outlet 7.

[0094] FIG. 2 shows schematically a flow diagram of a method according to the invention according to the English method.

[0095] A pre-disperser 10 with a rotor-stator system 11 is used to provide a water phase. This enables an emulsifier, such as egg lecithin, to be dispersed in water, particularly in water for injection purposes (WFI). In addition to an emulsifier, the water can also be mixed with a stabilizer or isotonizing agent, such as glycerol, and with an emulsifying aid, such as sodium oleate. Subsequently, the mixture can be heated or temperature-controlled, for example to a temperature of 55° C. to 75° C., over a period of 60 minutes.

[0096] An oil phase can be provided in a container 20, which can be configured as a pre-temperature control container, with a stirring element 21. For example, soybean oil and medium-chain triglycerides (MCT) as well as a-tocopherol can be used to provide the oil phase. The mixture produced in the container 20 can also be heated or temperature-controlled, for example to a temperature of 55° C. to 75° C.

[0097] The oil phase and water phase provided in this manner are then fed into a rotor-stator disperser 30. In this case, the oil phase and the water phase are preferably fed into the rotor-stator disperser 30 spatially separated from each other. This can be effected, for example, by means of a coaxial tube or a coaxial hose. This ensures that the oil droplets are exposed to a sufficient emulsifier concentration.

[0098] The oil phase and the water phase are preferably passed through a shear zone 32 of the rotor-stator disperser 30. As a result, an effective comminution of oil droplets with a diameter, in particular a mean diameter, ≥1 μm can already be achieved at this process stage. In the rotor-stator disperser 30, the oil phase and the water phase are premixed to form an O/W pre-emulsion.

[0099] Via an outlet 34 of the rotor-stator disperser, the O/W pre-emulsion can be fed to at least one counter-jet disperser 50 via an intermediate storage container 40. The intermediate storage device or container, with particular advantage, serves to maintain the process flow and therefore facilitates coordination between the rotor-stator disperser 30 and the at least one counter-jet disperser 50.

[0100] The counter-jet disperser 50 is operated by means of a high-pressure pump which, in particular, can generate a pressure in the range from 500 bar to 1900 bar. By means of the pump pressure generated within the counter-jet disperser 50, the O/W pre-emulsion is pumped through a microchannel structure with preferably opposing channels. In this case, jets of the O/W pre-emulsion meet each other in the droplet comminution zone, as a result of which droplets present in the O/W pre-emulsion are comminuted, in particular under the effect of shear forces. In this case, with particular advantage, droplets can be generated having a diameter, in particular a mean diameter (determined by photon correlation spectroscopy, PCS), of 180 nm to 340 nm, in particular 200 nm to 320 nm, preferably 240 nm to 280 nm.

[0101] The O/W emulsion generated in the counter-jet disperser 50 can then be transferred to a filling container 70 for further filling in suitable packaging sizes.

[0102] FIG. 3 shows schematically a further flow diagram of a method according to the invention which is operated according to the English method.

[0103] The method shown differs from the method shown in FIG. 1 in that it is operated with two counter-jet dispersers 50 and 60 connected in series.

[0104] In this case, droplets having a diameter, in particular a mean diameter (determined by photon correlation spectroscopy, PCS), of 180 nm to 340 nm, in particular 200 nm to 320 nm, preferably 200 nm to 300 nm, particularly preferably 240 nm to 280 nm, are preferably generated in the first counter-jet disperser 50, while in the second, i.e. downstream, counter-jet disperser 60, there is preferably a reduction in the proportion of droplets having a diameter, in particular a mean diameter, of ≥1 μm and therefore a reduction in the PFAT5 value. For this purpose, the first counter-jet disperser 50 can be operated, for example, at a pump pressure of 1500 bar, the O/W pre-emulsion within the counter-jet disperser 50 preferably having a temperature of 50° C. The second counter-jet disperser 60 is preferably operated at a pump pressure of 500 bar, the O/W emulsion within the counter-jet disperser 60 preferably having a temperature of 50° C.

[0105] Otherwise, the process sequence and the reference numbers correspond to the process sequence shown in FIG. 2 and to the reference numbers shown in FIG. 2.

[0106] FIG. 4 shows schematically a further flow diagram of a method according to the invention. In this case, however, the procedure is based on the continental method.

[0107] For this purpose, a water phase is provided by means of a container 15, which can be configured as a pre-temperature control container, and the oil phase is provided by means of a pre-disperser 25 with a rotor-stator system 23.

[0108] To provide the water phase, water, in particular water for injection purposes (WFI), can be admixed, for example, with aqueous sodium hydroxide solution and glycerol and the mixture thus obtained can be heated or temperature-controlled, for example, to a temperature of 55° C. to 75° C. with stirring by means of a stirrer element 13. To provide the oil phase, for example, oleic acid, soybean oil and medium-chain triglycerides can be admixed with an emulsifier, such as egg lecithin, and an antioxidant, such as a-tocopherol, and the mixture thus obtained can also be heated or temperature-controlled with stirring to a temperature of 55° C. to 75° C.

[0109] Otherwise, the process sequence and the reference numbers correspond to the process sequence shown in FIG. 2 and to the reference numbers shown in FIG. 2.

EXAMPLE SECTION

[0110] 1. Preparation of a Parenteral Fat Emulsion (Lipofundin MCT/LCT 20%)

[0111] The preparation process was divided into the following three process steps.

[0112] In a first step, the oil phase and water phase were prepared. The water phase was prepared in a stirred tank reactor for comminuting and dissolving the emulsifier. The oil phase was produced by simply controlling the temperature of the oil phase on a magnetic stirrer.

[0113] In a second step, an O/W pre-emulsion was prepared by means of a rotor-stator disperser commercially available under the registered trademark Inline ULTRA-TURRAX® (Ytron-Z). In contrast to conventional processes, the oil phase and the water phase were passed through the shear zone of the rotor-stator disperser by means of a forced passage. This ensured that every part of the oil phase also passed through the homogenization zone. In classical stirred tank reactors, the introduction of the oil phase into the rotor-stator stirrer can only be considered statistically and experience has shown that it leads to an undesirably broad particle distribution which can only be controlled to a limited extent.

[0114] In a third step, the final fine emulsion was produced using a high pressure homogenizer of the PSI-40 type configured as a counter-jet disperser. In contrast to the piston-gap homogenizers used in conventional processes, which use a dynamic valve to break up the droplets, the counter-jet disperser has a static microchannel structure for breaking up the droplets.

[0115] 1.1 Rotor-Stator Disperser (Inline Rotor-Stator, Ytron-Z)

[0116] The rotor-stator disperser (Ytron-Z) used consisted of eleven main components. The raw materials (oil phase and water phase) could be fed for metered addition to the system via two feed funnels, which could each be closed or opened via a disk valve. From there, the raw materials ran directly into the inlet of two diaphragm motor-driven metering pumps (Sigma/i Control Type S1Cb available under the registered trademark ProMinent®). These two pumps worked on the principle of an oscillating displacement pump, which was driven by an electric motor. This transmitted a stroke movement to a metering diaphragm by means of a push rod. The stroke movement of the displacer was continuously recorded and regulated, so that the stroke could be carried out according to a predefined metering profile and thus could be adapted accordingly to the properties of the raw materials (viscosity and/or outgassing property). So that each oil droplet was exposed to a direct emulsifier concentration, the metered addition was conducted via a metering head having a tube-in-tube structure. While the oil phase was fed through the center of the inner tube, the water phase was fed into a surrounding outer tube. The raw materials were pumped directly into a reactor head by means of the two metering pumps and there ran through a forced passage directly into a rotating rotor/stator set. This was driven by a three-phase motor (ATB Motorenwerke GmbH, IM B3; 1.5 kW).

[0117] The product passed the rotor/stator and left the reactor head via a product outlet which was narrowed by a compressed air-driven pinch valve (KVT GmbH).

[0118] The pinch valve served on the one hand as a technically obligatory counter pressure valve for the correct functionality of the two diaphragm metering pumps, on the other hand as a reduction unit for the product outlet to guarantee that the reactor head reached its working volume and could not run empty during the process. The system was controlled via a switch cabinet using a programmable logic controller (PLC, SIMATIC, Siemens AG). The ratios of the two metering pumps and the speed of the rotor-stator disperser could be entered and started simultaneously via a touch panel mounted on the switch cabinet door. The shaft of the rotor-stator disperser was sealed by means of a product-lubricated mechanical ring seal.

[0119] The rotor disk was clamped onto the rotary shaft of the three-phase motor by means of a feather key and was firmly fixed to it by means of a rotor screw with an O-ring seal. The stator was firmly screwed onto the reactor cover and was moved without contact against the rotor disk when the reactor head was closed. The reactor head was closed using a clamp connection with an O-ring seal.

[0120] 1.2 Formulation of a Model Emulsion (Lipofundin MCT/LCT 20%; Parenteral Fat Emulsion)

[0121] To prepare an example of an O/W emulsion, the formulation given in Table 1 below was used:

TABLE-US-00001 TABLE 1 Formulation of a model emulsion (parenteral fat emulsion) Material Amount [g] Egg lecithin 120 Sodium oleate 3 Glycerol 250 Soybean oil 1000 Medium chain triglycerides (MCT) 1000 alpha-tocopherol 2 Water for injection purposes filled up to 10 l

[0122] 1.3 Procedure:

[0123] The water phase was produced in a 10 l stirred tank, which was heated to a process temperature of 65° C. by means of a temperature control unit via a double jacket.

[0124] This process step essentially served to comminute and hydrate the emulsifier in the water phase. For this process step, egg lecithin (emulsifier), glycerol and sodium oleate were placed in a stirred tank and made up to a volume of 10 l with temperature-controlled (65° C.) water for injection purposes (WfI).

[0125] For the dispersion, a rotor-stator stirrer, obtainable under the registered trademark IKA T 50 ULTRA-TURRAX®, was used at maximum speed (10,000 rev/min). The dispersion was effected for 1 h in the stirred tank on the rotor-stator stirrer with simultaneous temperature control at 65° C. by means of the jacket temperature control of the stirred tank.

[0126] Subsequently, the water phase was further temperature-controlled at a process temperature of 75° C. on a magnetic stirrer, in preparation for use in the disperser, and transferred to a first storage container of the inline rotor-stator reactor. This also had a jacket temperature control which brought the water phase to the process temperature during the emulsification. The preparation of the water phase was completed with this step.

[0127] To produce the oil phase, soybean oil, MCT and alpha-tocopherol were placed in a glass beaker and then temperature-controlled at a process temperature of 75° C. on a magnetic stirrer, in preparation for use in the disperser, and transferred to a second storage container of the inline rotor-stator reactor. This storage container also had a jacket temperature control which brought the oil phase to the process temperature during the emulsification. The preparation of the oil phase was completed with this step.

[0128] A rotor with a slot width of 1 mm and a stirrer circumference of 33 mm for an innermost toothed ring, a stirrer circumference of 44 mm for a central toothed ring and a stirrer circumference of 55 mm for an outer toothed ring was used.

[0129] The tooth spacing of the stator was 0.5 mm. The circumference of the three toothed rings was 38 mm for an inner toothed ring, 49 mm for a middle toothed ring and 60 mm for an outer toothed ring.

[0130] Prior to the start of the emulsification, the process parameters for the metered addition and for the rotor-stator speed were set on the PLC of the control unit of the inline rotor-stator according to the following Table 2:

TABLE-US-00002 TABLE 2 Process parameters of the inline rotor-stator Process parameters Setting Speed 5860 rpm Metered addition 75 L/h Counter pressure 2 bar Temperature 75° C.

[0131] After starting the system, the pressure at the product outlet was set to a counter pressure of 2 bar. The O/W pre-emulsion was collected at the product outlet in a glass beaker and continuously maintained under stirring.

[0132] The O/W emulsion was then finely emulsified by three passes in a high-pressure homogenizer of the PSI-40 type configured as a counter-jet disperser. Instead of a conventional dynamic valve, this high-pressure homogenizer used a static micrometer-sized channel structure in which the droplet breakup took place. Due to the much narrower and invariant channel dimensions, there was more intensive shear and a lower and reproducible flow distribution with resulting narrow droplet distributions. In addition, due to their static chamber geometry, such high pressure homogenizers can be scaled more easily. The droplet break-up took place in an interaction chamber (shear chamber), consisting of a diamond core which was sunk into a 316L stainless steel casing. The diamond core was provided with the microstructured channels mentioned above, in which the droplets were accelerated and broken up at a high process pressure. So-called Y-chambers were used for the emulsification. The microchannels in such chambers were formed into a Y-shape. In this case, process pressures of 500 bar to 2000 bar were possible.

[0133] In order to protect the interaction chamber from damage caused by cavitation at high process pressures, an APM (auxiliary processing module) was connected downstream of the interaction chamber (secondary chamber). This secondary chamber functioned as a pressure reducer and generated a low counter pressure on the outlet side (outlet) of the primary chamber. Depressurization of the interaction chamber against the direct atmospheric pressure with induced cavitation was thus prevented. In practice, the APM module was a stainless steel core provided with a specially dimensioned hole in a stainless steel casing.

[0134] The following process parameters and chamber configurations were established for the high pressure homogenizer:

TABLE-US-00003 TABLE 3 Process parameters and chamber configurations of the high pressure homogenizer Process parameters Setting Pressure 1000 bar Temperature 60° C. Passes 3 Primary chamber E101D (interaction chamber) Secondary chamber (APM) APM

[0135] The E101D chamber was a single-slot Y-chamber and provided flow rates of up to 20 L/h.

[0136] The APM module provided a counter pressure of ca. 50 bar for the primary chamber E101D.

[0137] By further optimization of the chamber configuration, an additionally improved emulsion quality could be achieved with the PSI-40 high pressure homogenizer. This configuration was set with the following process parameters:

TABLE-US-00004 TABLE 4 further optimized process parameters and chamber configurations of the high pressure homogenizer Process parameters Setting Pressure 1000 bar Temperature 60° C. Passes 3 Primary chamber E101D (interaction chamber) Secondary chamber (APM) APM (reduced counter pressure)

[0138] The E101D chamber was a single-slot Y-chamber and provided flow rates of up to 20 L/h.

[0139] The APM module (reduced counter pressure) provided a counter pressure for the primary chamber E101D, but with a reduced counter pressure close to 50 bar.

[0140] Information regarding the counter pressures generated was based on the manufacturer's data.

[0141] The following particle analysis was used to characterize the O/W emulsions produced.

[0142] a) Photon Correlation Spectroscopy (PCS):

[0143] Using this method, Brownian molecular motion is quantified with the aid of an autocorrelation function of the scattered light signal of dispersed particles. For the measurement, a light beam of a defined wavelength is passed through a sample by means of a laser, whereby the laser light is scattered. The scattered light intensity is subject to time-dependent fluctuations due to the undirected diffusion of molecules which surround the particles. These time-dependent interference phenomena are dependent on the size of the scattering particles.

[0144] The mean particle or droplet diameter in nanometers [nm] is used as the output parameter.

[0145] b) Microscopic Image Recording (Micrograph):

[0146] For the microscopic image recording, one droplet (ca. 10 l sample) in each case was viewed on a slide under a light microscope with a ×100 immersion oil lens. A sample image was taken from this sample at five points (top left, bottom left, bottom right, top right, center) on the slide, which was then evaluated using software by counting droplets over a size of 2 μm.

[0147] The micrograph with the unit [droplet] was used as output parameter. The micrograph corresponded to the number of droplets from five sample images of one observed sample volume.

[0148] 2. Preparation of O/W Emulsions at Different Homogenization Temperatures and Pressures

[0149] The fat emulsion prepared according to 1. was prepared using different homogenization temperatures and pressures. A type PSI-40 counter-jet disperser was used. From a description by Microfluidics (Chamber User Guide, Dec. 30, 2014), it is known how the process temperature changes with pressure during the homogenization (2.5° C. per 100 bar). This temperature is to be added to the respective test temperature T.sub.H of the O/W pre-emulsion, i.e. the temperature of the O/W pre-emulsion before it enters the at least one counter-jet disperser, and gives the homogenization temperature in the context of the present invention. For example, for an O/W pre-emulsion having a temperature of 20° C. before it enters the at least one counter-jet disperser, a temperature of the O/W pre-emulsion within the counter-jet disperser of 45° C. is calculated in the case of a counter-jet disperser which is operated at a homogenizing pressure (pump pressure) of 1000 bar.

[0150] Measured were the percentage of emulsion droplets larger than 5 micrometers (PFAT5), the mean particle or droplet diameter (MDS=mean droplet size), measured using photon correlation spectroscopy (PCS), the number of droplets using microscopic counting, and the pH value.

[0151] 2.1 20° C. Study

TABLE-US-00005 TABLE 5 Investigation of emulsion parameters after preparation of a fat emulsion at 20° C. (test temperature) and different homogenization pressures T.sub.H = 20° C. Mean Micro- Theoretical particle graph Pressure temperature diameter [Number P increase Passes pFat5 (PCS) of [bar] [° C.] PSI-40 [%] [nm] droplets] pH 1900 47.5 1 0.030 280 46 8.27 1900 47.5 2 0.011 237 18 8.19 1900 47.5 3 0.004 222 13 8.16 1900 47.5 4 0.009 209 14 8.12 1900 47.5 5 0.003 205 7 8.08 1500 37.5 1 0.027 307 38 8.24 1500 37.5 2 0.005 260 17 8.17 1500 37.5 3 0.003 242 12 8.14 1500 37.5 4 0.002 234 9 8.10 1500 37.5 5 0.002 223 5 8.07 1000 25.0 1 0.030 348 28 8.24 1000 25.0 2 0.010 296 14 8.09 1000 25.0 3 0.002 269 12 8.13 1000 25.0 4 0.001 260 9 8.10 1000 25.0 5 0.001 263 6 8.07 500 12.5 1 0.039 434 26 8.29 500 12.5 2 0.004 354 14 8.20 500 12.5 3 0.007 347 5 8.15 500 12.5 4 0.002 327 7 8.14 500 12.5 5 0.002 321 5 8.11

[0152] 2.2 30° C. Study

TABLE-US-00006 TABLE 6 Investigation of emulsion parameters after preparation of a fat emulsion at 30° C. (test temperature) and different homogenization pressures T.sub.H = 30° C. Mean Micro- Theoretical particle graph temperature diameter [Number Pressure increase Passes pFat5 (PCS) of [bar] [° C.] PSI-40 [%] [nm] droplets] pH 1900 47.5 1 0.033 273 39 7.88 1900 47.5 2 0.011 233 19 7.78 1900 47.5 3 0.006 219 20 7.74 1900 47.5 4 0.003 209 17 7.72 1900 47.5 5 0.004 202 16 7.70 1500 37.5 1 0.021 295 33 7.84 1500 37.5 2 0.004 252 16 7.69 1500 37.5 3 0.002 235 15 7.69 1500 37.5 4 0.001 226 14 7.85 1500 37.5 5 0.001 217 8 7.63 1000 25.0 1 0.029 360 21 7.85 1000 25.0 2 0.003 286 12 7.79 1000 25.0 3 0.004 258 17 7.75 1000 25.0 4 0.001 252 7 7.72 1000 25.0 5 0.001 246 8 7.70 500 12.5 1 0.042 430 26 7.87 500 12.5 2 0.006 353 8 7.81 500 12.5 3 0.009 336 7 7.78 500 12.5 4 0.005 324 3 7.75 500 12.5 5 0.007 307 6 7.69

[0153] 2.3 40° C. Study

TABLE-US-00007 TABLE 7 Investigation of emulsion parameters after preparation of an emulsion at 40° C. (test temperature) and different homogenization pressures T.sub.H = 40° C. Mean Micro- Theoretical particle graph temperature diameter [number Pressure increase Passes pFat5 (PCS) of [bar] [° C.] PSI-40 [%] [nm] droplets] pH 1900 47.5 1 0.099 257 43 8.31 1900 47.5 2 0.022 221 26 8.23 1900 47.5 3 0.013 209 19 8.17 1900 47.5 4 0.008 204 12 8.15 1900 47.5 5 0.006 200 12 8.15 1500 37.5 1 0.045 278 58 8.29 1500 37.5 2 0.013 239 19 8.20 1500 37.5 3 0.005 227 12 8.18 1500 37.5 4 0.003 211 7 8.12 1500 37.5 5 0.002 209 13 8.12 1000 25.0 1 0.028 315 35 8.29 1000 25.0 2 0.004 265 17 8.19 1000 25.0 3 0.004 241 7 8.12 1000 25.0 4 0.001 231 9 8.09 1000 25.0 5 0.002 227 5 8.09 500 12.5 1 0.043 381 21 8.33 500 12.5 2 0.003 339 7 8.24 500 12.5 3 0.003 309 4 8.20 500 12.5 4 0.002 294 6 8.17 500 12.5 5 0.001 278 2 8.13

[0154] 2.4 50° C. Study

TABLE-US-00008 TABLE 8 Investigation of emulsion parameters after preparation of an emulsion at 50° C. (test temperature) and different homogenization pressures T.sub.H = 50° C. Mean Micro- Theoretical particle graph temperature diameter [Number Pressure increase Passes pFat5 (PCS) of [bar] [° C.] PSI-40 [%] [nm] droplets] pH 1900 47.5 1 0.102 257 66 8.31 1900 47.5 2 0.039 221 29 8.24 1900 47.5 3 0.020 201 35 8.22 1900 47.5 4 0.021 291 34 8.18 1900 47.5 5 0.021 197 35 8.18 1500 37.5 1 0.072 266 41 8.30 1500 37.5 2 0.016 231 26 8.20 1500 37.5 3 0.009 216 21 8.15 1500 37.5 4 0.005 205 13 8.16 1500 37.5 5 0.006 199 9 8.13 1000 25.0 1 0.036 293 22 8.35 1000 25.0 2 0.005 253 15 8.25 1000 25.0 3 0.002 238 8 8.21 1000 25.0 4 0.001 228 7 8.21 1000 25.0 5 0.001 223 12 8.18 500 12.5 1 0.031 383 13 8.34 500 12.5 2 0.005 314 9 8.21 500 12.5 3 0.001 287 5 8.13 500 12.5 4 0.001 278 4 8.15 500 12.5 5 0.002 257 3 8.15

[0155] 2.5 60° C. Study

TABLE-US-00009 TABLE 9 Investigation of emulsion parameters after preparation of an emulsion at 60° C. (test temperature) and different homogenization pressures T.sub.H = 60° C. Mean Micro- Theoretical particle graph temperature diameter [Number Pressure increase Passes pFat5 (PCS) of [bar] [° C.] PSI-40 [%] [nm] droplets] pH 1900 47.5 1 0.227 254 52 8.21 1900 47.5 2 0.069 219 50 8.15 1900 47.5 3 0.057 202 45 8.08 1900 47.5 4 0.048 199 30 8.08 1900 47.5 5 0.035 195 25 8.06 1500 37.5 1 0.124 265 27 8.17 1500 37.5 2 0.045 226 36 8.03 1500 37.5 3 0.029 208 20 8.05 1500 37.5 4 0.024 202 22 8.04 1500 37.5 5 0.023 201 25 7.97 1000 25.0 1 0.058 297 20 8.16 1000 25.0 2 0.011 253 13 8.10 1000 25.0 3 0.006 237 8 8.02 1000 25.0 4 0.004 225 6 8.01 1000 25.0 5 0.002 215 4 7.99 500 12.5 1 0.044 398 13 8.21 500 12.5 2 0.003 299 7 8.09 500 12.5 3 0.002 274 4 8.06 500 12.5 4 0.002 229 3 8.02 500 12.5 5 0.001 251 3 8.01

[0156] 2.6 70° C. Study

TABLE-US-00010 TABLE 10 Investigation of emulsion parameters after preparation of an emulsion at 70° C. (test temperature) and different homogenization pressures T.sub.H = 70° C. Mean Micro- Theoretical particle graph temperature diameter [Number Pressure increase Passes pFat5 (PCS) of [bar] [° C.] PSI-40 [%] [nm] droplets] pH 1900 47.5 1 0.190 252 72 8.14 1900 47.5 2 0.055 212 50 8.06 1900 47.5 3 0.033 207 36 8.01 1900 47.5 4 0.029 204 31 8.02 1900 47.5 5 0.020 203 50 8.03 1500 37.5 1 0.150 264 50 8.10 1500 37.5 2 0.118 222 55 8.01 1500 37.5 3 0.054 210 49 7.99 1500 37.5 4 0.053 202 54 7.98 1500 37.5 5 0.035 199 26 7.99 1000 25.0 1 0.145 293 53 8.11 1000 25.0 2 0.041 249 23 8.00 1000 25.0 3 0.012 229 13 7.92 1000 25.0 4 0.006 216 14 7.93 1000 25.0 5 0.009 206 16 7.95 500 12.5 1 0.981 378 68 8.20 500 12.5 2 0.008 291 4 8.10 500 12.5 3 0.004 268 4 8.02 500 12.5 4 0.001 248 2 8.00 500 12.5 5 0.002 242 3 7.97

[0157] The test results shown in Tables 5 to 10 show that the minimum medical standard required for parenteral administration of O/W emulsions, according to which the mean droplet diameter of the O/W emulsions should not exceed a value of 500 nm, is met by all the O/W emulsions produced. Furthermore, the results shown in tabular form in Tables 5 to 10 show that the mean droplet diameter can be reduced with increasing pressure and/or with increasing number of homogenization cycles.

[0158] In addition, the test results obtained show that droplets having a diameter, in particular a mean diameter, above 1 μm, in particular between 1 μm and 5 μm, preferably at a homogenizing pressure below 1000 bar, in particular at a homogenizing pressure of 500 bar, are comminuted. This makes it possible, particularly in the case of two counter-jet dispersers connected in series, to control the mean droplet diameter of the O/W emulsions to be produced via the first counter-jet disperser and the PFAT5 value of the O/W emulsions to be produced by the second, i.e. downstream, counter-jet disperser. In this manner, both the existing minimum standard with respect to the mean droplet diameter and the minimum standard required with respect to the PFAT5 value can be met in a targeted manner and the process quality can therefore be significantly increased.

[0159] 3. Preparation of O/W Emulsions by Means of Homogenization at Different Pressure Levels

[0160] The fat emulsion prepared according to 1. was produced using two counter-jet dispersers (each of the PSI-40 type) connected in series. The results obtained here are shown in Tables 11 to 13 below.

[0161] 2.7 First Pressure Stage 1900 Bar

TABLE-US-00011 TABLE 11 Investigation of the emulsion droplet diameter after preparation of an emulsion using two different microfluidizer pressures 1st pass, mean 2nd pass, mean Temperature 1st Pass PSI-40 2nd Pass PSI-40 particle diameter particle diameter [° C.] pressure [bar] pressure [bar] (PCS) [nm] (PCS) [nm] 20 1900 1500 279 234 30 1900 1500 277 241 40 1900 1500 266 234 50 1900 1500 259 227 60 1900 1500 251 223 70 1900 1500 251 223 20 1900 1000 279 254 30 1900 1000 277 250 40 1900 1000 266 242 50 1900 1000 259 238 60 1900 1000 251 227 70 1900 1000 251 228 20 1900 500 279 274 30 1900 500 277 265 40 1900 500 266 266 50 1900 500 259 255 60 1900 500 251 220 70 1900 500 251 238

[0162] 2.8 First Pressure Stage 1500 Bar

TABLE-US-00012 TABLE 12 Investigation of the emulsion droplet diameter after preparation of an emulsion using two different microfluidizer pressures 1st pass, mean 2nd pass, mean Temperature 1st Pass PSI-40 2nd Pass PSI-40 particle diameter particle diameter [° C.] pressure [bar] pressure [bar] (PCS) [nm] (PCS) [nm] 20 1500 1000 298 239 30 1500 1000 298 259 40 1500 1000 280 257 50 1500 1000 271 246 60 1500 1000 267 238 70 1500 1000 268 233 20 1500 500 298 276 30 1500 500 298 270 40 1500 500 280 269 50 1500 500 271 254 60 1500 500 267 256 70 1500 500 268 251

[0163] 2.9 First Pressure Stage 1000 Bar

TABLE-US-00013 TABLE 13 Investigation of the emulsion droplet diameter after preparation of an emulsion using two different microfluidizer pressures 1st pass, mean 2nd pass, mean Temperature 1st Pass PSI-40 2nd Pass PSI-40 particle diameter particle diameter [° C.] pressure [bar] pressure [bar] (PCS) [nm] (PCS) [nm] 20 1000 500 367 333 30 1000 500 329 304 40 1000 500 317 306 50 1000 500 318 282 60 1000 500 295 267 70 1000 500 287 265

[0164] The results presented in tabular form show that the medical minimum standard required for parenterally administered O/W emulsions with respect to the mean droplet diameter is met by all the O/W emulsions produced. The results also show that the mean droplet diameter can be further reduced by using a second counter-jet disperser connected in series. If the second counter-jet disperser is also operated at a homogenizing pressure (pump pressure)<1000 bar, in particular at a homogenizing pressure of 500 bar, the PFAT5 value applicable to parenterally administered O/W emulsions can be significantly undercut. Overall, therefore, a significant increase in the process quality can be achieved, particularly with regard to the mean droplet diameter and the PFAT5 value of the O/W emulsions to be produced.