Preparation of pharmaceutical or cosmetic dispersions.

0001The invention relates to a process for the production of finely divided, stable, pharmaceutical or cosmetic dispersions from an aqueous phase and an organic phase (oil phase) which is insoluble or not completely soluble in water, in which a pre-emulsion is first prepared from the two phases by known emulsification methods, which is then processed into the end product. The invention further relates to a device for performing the method.

0002Pharmaceutical or cosmetic emulsions are usually prepared in such a way that the melted organic phase (oil phase) and the entire aqueous phase brought to the same temperature are combined in a stirred kettle at a temperature of 60 to 80 ° C. and in an ointment reactor for ointments and creams cools to room temperature with stirring and homogenizing tools and homogenizes in the process. In the case of flowable emulsions, the crude emulsion thus obtained is pre-emulsified and cooled to 20 to 40 ° C. in a jacket or flow cooler and then finely dispersed using a high-pressure homogenizer. A disadvantage of this type of production of a flowable emulsion is that the entire batch must first be heated and then cooled again after the pre-emulsification in order then to bring the entire emulsion to the desired fineness using high-pressure homogenizers, often with only a small proportion of disperse oil phase . High-pressure homogenizers require a very high operating pressure in the order of 200 bar, which can only be generated with relatively complex, multi-stage high-pressure piston pumps with high drive power. In addition, a high energy consumption occurs due to the process-related temperature control described above.

0003Another disadvantage is that the high shear forces in the high-pressure homogenizer can destroy high-molecular organic compounds, so that product damage occurs.

0004Up to now, complex ointment reactors (heavy machine stands, vacuum devices, complicated shaft seals, etc.) have been used for the production of ointment and cream preparations, in which completely undefined manufacturing conditions prevail due to the simultaneous stirring, homogenization and cooling (e.g. each volume element of the product is only a statistical average pass through the shear gap of the homogenizer). In addition, long cooling times result from poor heat transfer.

0005The invention has for its object to improve the economy of the known methods. This is to be understood here as meaning that, with the least possible outlay on equipment, a favorable energy balance is also sought (reduction of investment and operating costs). As a boundary condition, it should be noted that no product damage occurs (excessive shear stress) and that the particle properties (average particle size and particle size distribution) are the same as in the known processes.

0006Starting from the process described at the outset, this object is achieved according to the invention in that the pre-emulsion produced by known emulsification methods is fed to a jet disperser in which the homogenization and fine dispersion which are characteristic of the end product take place. "Jet disperser" is understood here to mean a pressure release nozzle in which the available pressure energy is dissipated in a dispersion zone with the smallest possible volume and a high volume-based dispersion performance is achieved.

0007The method according to the invention is advantageously combined with a phase inversion method. In the phase reversal process, the oil phase is initially introduced as the outer phase to produce the pre-emulsion and in. this emulsifies the aqueous phase as the inner phase. In contrast to the end product, in the pre-emulsion the aqueous phase forms the inner (disperse) phase and the oil phase the outer (continuous) phase. The pre-emulsion thus produced is then pumped through the jet disperser in the subsequent process step, the temperature, the ratio of the two phases and the pressure on the jet disperser being adjusted such that the emulsion is reversed in phase with the homogenization and fine dispersion at the same time. When passing through the jet disperser, the aqueous phase is transferred to the outer phase and the oil phase to the inner phase. The phase reversal temperature belonging to a certain quantity ratio can be determined empirically without further ado.

0008The use of the phase inversion process in combination with the jet disperser leads to a very simple dispersion process. Would, for example a homogenization pressure of 200 bar when using a high-pressure homogenizer and 40 to 50 bar when using a jet disperser is required for homogenization according to standard technology, so an operating pressure in the range of 2 to 50 "bar, preferably 10 to 50 bar, which can be generated with relatively simple and cheap pumps.

0009A preferred embodiment of the invention is that the phase reversal is carried out at a concentration of 50 to 70 wt .-% oil phase (corresponding to 50 to 30 wt .-% aqueous phase). This means that the jet dispersion produces a highly concentrated emulsion which is later diluted to the desired final concentration. The dilution is carried out by adding cold aqueous phase, so that cooling takes place at the same time. Since the process only has to be carried out with a fraction of the total amount of emulsion, a high space-time yield is achieved with a favorable energy balance. This means that either with a smaller kettle volume the same amount compared to the previously used processes or with a correspondingly increased diluent kettle capacity can be produced in one batch in a significantly larger amount.

0010Cosmetic and pharmaceutical dispersions are generally composed of the following basic components:<ul id="ul0001" list-style="none"><li>1. The aqueous phase consists of an aqueous solution of glycerin, glycol, cosmetic or pharmaceutical active ingredients, viscosity-increasing additives and preservatives.</li><li>2nd The organic oil phase which is insoluble or not completely soluble in water consists of glycerol or fatty acid esters and / or liquid or semi-solid hydrocarbons, higher-quality alcohols, nonionic emulsifiers and fat-soluble pharmaceutical or cosmetic active ingredients.</li></ul>

0011In the pre-emulsion, the aqueous phase forms the inner phase and the oil phase the outer phase, while in the finished end product the oil phase is dispersed as an inner phase in the aqueous phase.

0012The method according to the invention is carried out with two emulsifying devices connected in series. The second emulsifying device is a jet disperser that is optimized in terms of process technology. It consists of one or more nozzles which are designed as capillary bores with a diameter of 0.3 to 1 mm, preferably 0.5 to 0.8 mm, and a ratio of length to diameter of 1 to 4, preferably of 1.5 to 2. With this dimensioning, the volume of the dispersion zone is only 0.1 mm³ up to 1 mm³. It has been found that almost all of the pump energy is consumed in the dispersion zone and the dispersion leaves the dispersion zone as an undirected jet.

0013The nozzles are either arranged in such a way that the emerging emulsion jet hits a solid wall or the emulsion jets themselves collide. In the case of the last-mentioned embodiment, the flow energies still present after the outlet from the nozzles are consumed by the collision of the jets.

0014The essential and surprising advantage of the method according to the invention is that an improved space-time yield is achieved with a simplified apparatus. It is important here that the same particle fineness can be achieved with the jet disperser with a significantly lower pressure and consequently with less expensive pumps than with the high-pressure homogenizers previously used. The process is also gentle on the product, since the high-molecular components in the oil phase and water phase in the steel disperser are exposed to less shear stress.

0015In contrast to the past, the process conditions for the production of ointments and creams are strictly defined. In particular, a very narrow particle size distribution spectrum is generated in the jet disperser. Therefore, the model transfer from the laboratory to the production scale is completely unproblematic.

0016The invention is described in more detail below with the aid of exemplary embodiments and drawings. Show it<ul id="ul0002" list-style="none"><li>_Fig. 1 shows a flow diagram for the method according to the invention and</li><li>Fig. 2 to 4 different versions (cross section) of the jet disper^Gators.</li></ul>

00171, the aqueous phase is in a boiler 1 and the oil phase in a boiler 2. The boiler temperatures may have to be adjusted by heating so that the temperature of the two phases is above the solidification point of any fat components present. The two phases are then stirred together in the stirred tank 3 and pre-emulsified. The pre-emulsion thus produced is then pumped out of the stirred tank 3 through the jet disperser 4, in which the homogenization and fine dispersion characteristic of the end product takes place. Subsequently, the desired final concentration is adjusted from the highly concentrated emulsion by introducing the aqueous phase into the storage tank 5. (Dilution). The process, which is carried out discontinuously here, can also be operated in a continuous procedure. In this case, both phases are metered continuously from the tanks 1 and 2 into the stirred tank 3, pre-emulsified and then pumped through the jet disperser 4.

0018In many cases, a water-in-oil emulsion with high particle fineness is easier to produce than an oil-in-water emulsion. In such cases, the method described above is modified in such a way that a phase reversal occurs in the jet disperser 4. The procedure is such that the oil phase is first introduced from the boiler 2 into the stirred tank 3 and then the aqueous phase is slowly mixed in. This creates a pre-emulsion in which the oil phase forms the outer and the aqueous phase the inner phase (W / O emulsion). During the subsequent dispersion and homogenization in the jet disperser 4, a phase reversal then takes place in such a way that the outer phase becomes the inner phase and the inner phase becomes the outer phase. An oil-in-water emulsion (0 / W emulsion) is formed. Decisive for the phase reversal point are the concentrations of the two phases (quantitative ratio), the temperature and the mechanical stress in the jet disperser 4. For a given product, the phase reversal point can easily be determined empirically as a function of the process parameters mentioned above. To determine the phase reversal point, physical measurement methods such as the measurement of the electrical conductivity or the ultrasound absorption can be used, since these quantities change suddenly at the phase reversal point.

0019Various technical designs of the jet disperser 4 are described below. The simplest version of a jet disperser is shown in Fig. 2. It consists of an inlet pipe 6, which is closed at its end except for a capillary bore 7 and is connected to an outlet tube 8 through this capillary bore. The outlet pipe 8 is tightly connected to the inlet pipe 6. The diameter d of the capillary bore is, for example, 0.6 mm, its length 1 is 1 mm. Systematic series of tests have shown that optimum results with regard to particle properties and energy dissipation can be obtained if the following dimensions are observed:<maths id="math0001" num=""><img file="EP0101007A2_D0001.tif" /></maths><maths id="math0002" num=""><img file="EP0101007A2_D0002.tif" /></maths>

0020An alternative embodiment of the jet disperser is shown schematically in FIGS. 3 and 4. In this embodiment, a pipe section 9 with a smaller diameter that is open on one side is inserted into a pipe 10 with a larger diameter that is also open on one side. An annular space 11 remains between the inner wall of the outer tube 10 and the outer wall of the tubular piece 9. In the area of ​​this annular space, the tubular piece 9 is provided with opposing capillary bores 7. Similar to the embodiment according to FIG. 2, these capillary bores form the only connection between the tubes 10 and 9. According to FIG. 3 the flows_'Pre-emulsion through the tube 10 into the annular space 11 and from there through the capillary bores into the tube piece 9. Since the nozzles 7 face each other, the emerging emulsion jets collide in the tube 9. Particularly good dispersion is achieved in this way. The homogenized emulsion emerges from the jet disperser through outlet 12.

0021The apparatus of the jet disperser according to FIG. 4 is identical to the disperser according to FIG. 3. However, it is operated in the opposite direction in terms of flow. The pre-emulsion is fed here through the opening 12 of the inner tube 9 and then flows through the opposing nozzles 7 into the annular space 11 between the inner tube 9 and the outer tube 10. The emulsion jets emerging from the nozzles 7 strike the inner wall of the tube 10 and flow from there to the drain opening 13. The inner wall of the tube 10 thus represents a baffle for the emulsion jets. In the embodiment according to FIG. 4, the tube 9 forms the inlet tube and the tube 10 the outlet tube of the jet disperser. Conversely, in the embodiment according to FIG. 3, the tube 10 is to be regarded as an inlet tube and the tube 9 as an outlet tube. The nozzles or Capillary bores 7 are arranged, evenly distributed over the circumference, in such a way that their axes intersect at a point on the longitudinal axis of the jet disperser. With regard to their dimensioning, the regulation given above applies.

0022The jet dispersers described here are very simple and compact in terms of equipment and can therefore be manufactured inexpensively in any workshop. A pressure of the order of 10 to 50 bar is required for their operation. This pressure is significantly lower than the pressure required to operate a high-pressure homogenizer. For this reason, simple feed pumps, such as gear pumps or single or multi-stage eccentric screw pumps, completely sufficient. Instead of generating the operating pressure with the aid of pumps, the storage boilers can also be pressurized with compressed gas. For pressures up to 15 bar the throughput per single nozzle is approx. 500 liters per hour, at 60 bar approx. 1000 liters per hour. A further increase in throughput can be achieved by increasing the number of nozzles and / or by connecting several jet dispersers in parallel.

Example 1: Sun protection milk

0023The organic phase (oil phase), consisting of:<tables id="tabl0001" num="0001"><img file="EP0101007A2_D0003.tif" /></tables>

0024submitted and the cold aqueous phase, consisting of:<tables id="tabl0002" num="0002"><img file="EP0101007A2_D0004.tif" /></tables>admitted. By briefly stirring, an emulsion concentrate of the type W / 0 of approx. 40 ° C. is formed. This is homogenized at 10 bar pressure by the jet disperser 4 in the storage tank 5, where<tables id="tabl0003" num="0003"><img file="EP0101007A2_D0005.tif" /></tables>are located. The phase reversal takes place in the beam disperser 4. The mixture is stirred during the introduction. This results in 10,000 kg of finished, liquid sun protection emulsion type O / W with a very high degree of dispersity.

Example 2: Day cream type 0 / w

0025In a normal boiler 2, the organic phase (oil phase) consisting of:<tables id="tabl0004" num="0004"><img file="EP0101007A2_D0006.tif" /></tables>melted at 70 ° C and adjusted to 40 ° C.

0026Then the oil-soluble active ingredients and<ul id="ul0003" list-style="none"><li>20th - 40 kg of perfume oil added.</li></ul>

0027In another boiler 1 are in<ul id="ul0004" list-style="none"><li>6000-8000 kg water at 45 ° C,</li><li>20th - 40 kg of carboxyl vinyl polymer</li></ul>dispersed and<ul id="ul0005" list-style="none"><li>300 - 600 kg of 1,2-propylene glycol</li></ul>admitted. After adjustment to 40 ° C, the water-soluble active ingredients are added.

0028The water phase is then added to the oil phase in the agitator tank 3 and<ul id="ul0006" list-style="none"><li>100 - 150 kg sodium hydroxide solution 10%</li></ul>added for neutralization.

0029After briefly stirring, the still liquid emulsion becomes homo through the jet disperser 4 at 10-15 bar pressure^Genaised. After homogenization, the cream solidifies in storage container 5. This creates 10,000 kg of day cream O / W with a very high degree of dispersity.

Example 3: Night cream type W / 0

0030In a normal boiler 2, the oil phase becomes:<tables id="tabl0005" num="0005"><img file="EP0101007A2_D0007.tif" /></tables><tables id="tabl0006" num="0006"><img file="EP0101007A2_D0008.tif" /></tables>melted at 80 ° C and adjusted to 75 ° C.

0031In another boiler 1, the water phase, consisting of:<tables id="tabl0007" num="0007"><img file="EP0101007A2_D0009.tif" /></tables>prepared and set to 45 ° C.

0032. The water-soluble active ingredients are added to the water phase.

0033The water phase is then added to the oil phase in the agitator kettle with stirring. After the raw emulsion has cooled to 45-50 ° C., the oil-soluble active ingredients and

40 - 80 kg of perfume oil

0034admitted. This creates a water-in-oil emulsion (W / 0 emulsion). After incorporating the perfume oil, the still liquid W / O emulsion is homogenized in the jet disperser 4 at a pressure of 10-15 bar and filled into the storage container 5, where it solidifies into the finished cream. The W / O emulsion is retained, which means that there is no phase reversal.

Example 4: Ointment preparation

0035The organic phase (oil phase), consisting of:<tables id="tabl0008" num="0008"><img file="EP0101007A2_D0010.tif" /></tables>melted at 50 - 75 ° C and then cooled again to 35 - 45 ° C. The aqueous phase then becomes:<ul id="ul0007" list-style="none"><li>550 - 750 kg of sterilized water with a temperature of 38 - 45 ° C,</li></ul>emulsified in the oil phase (W / O emulsion). In addition, pharmaceutical active ingredients, emulsifiers and thickeners can be added to the aqueous phase. The pre-emulsion thus produced is then pumped through the jet disperser 4 at a pre-pressure of 10-15 bar and with a material flow of 1000-2000 kg per hour and thereby homogenized: the initial W / 0 emulsion inverts into the desired O / W Emulsion (oil-in-water emulsion). The finished ointment can either be filled directly into tubes or left to cool in a storage tank 5 beforehand. Alternatively, the cooling can also take place “in line” by means of a heat exchanger connected between the jet disperser 4 and the storage tank 5.