EP1942873A2

EP1942873A2 - Method and device for producing very fine particles and coating such particles

Info

Publication number: EP1942873A2
Application number: EP06828817A
Authority: EP
Inventors: Rainer Helmut MÜLLER; Jan Möschwitzer
Original assignee: Abbott GmbH and Co KG
Current assignee: AbbVie Deutschland GmbH and Co KG
Priority date: 2005-11-04
Filing date: 2006-10-13
Publication date: 2008-07-16
Also published as: DE102005053862A1; WO2007051520A3; JP2009514821A; WO2007051520A2; CN101360482A; CA2628562C; US20090297565A1; CA2628562A1; US9168498B2

Abstract

Disclosed are methods and devices for producing very fine particles which are then coated with protective polymers in another step of the process. The particles are produced using a method in which a liquid flow comprising a particle-free liquid 1 that contains the active substance in a dissolved form is combined with a second liquid flow comprising a liquid 2 in a high-energy zone or no sooner than two seconds before reaching the high-energy zone. Said two liquids can be mixed with each other while the active substance dissolved in liquid 1 is insoluble or more difficult to dissolve in liquid 2 than in liquid 1 and settles in the form of particles in the high-energy zone or within a maximum of 2 seconds before reaching the high-energy zone when the two liquids are mixed. The obtained particles are introduced into an aqueous outer phase which contains the coating materials in a dissolved form and are then subjected to a drying step such that said materials settle on the particles as a closed coating. The coated particles are protected from damaging influences and are provided with modified release kinetics compared to uncoated particles.

Description

Method and device for producing very fine particles and for coating such particles

Field of the invention

The invention describes a method and an apparatus for the production of suspensions of very fine particles as well as a method and an apparatus for coating or coating such superfine particles.

Processes and devices for the production of very fine particles are described, which are then coated in a further process step with protective polymers.

State of the art

Micronization is a process used to produce particles with a size in the range of a few microns, usually in the range from lμm to lOμm. Micronization is widely used in the pharmaceutical field to improve the delivery of drugs, eg through increased oral bioavailability. The reduction of the particle size leads to an enlargement of the surface, and according to the law of Noyes-Whitney, the increased surface leads to an accelerated dissolution rate of the particles. The oral bioavailability problems can be reduced by micronization if dissolution rate or solubility are the uptake limiting parameters (so-called class II drugs according to BCS (Biopharmaceutical Classification System)). Nevertheless, an increasing number of newly prepared compounds show even lower solubilities and, associated therewith, even lower dissolution rates than the abovementioned drugs. In many cases, therefore, the micronization is no longer sufficient to a sufficiently high dissolution rate and resulting in a sufficiently high bioavailability to achieve.

The next step was then the nanonization of drug powders, i. the conversion of drug microparts into drug nanoparticles with a mean particle diameter in the nanometer range (from about 2-3 nm to 1000 nm). Drug nanoparticles can be made using so-called "bottom-up" or alternatively "top-down" technologies. In the bottom-up technologies, you start with molecules and their association leads to particle formation. The classic bottom-up technique is precipitation, the drug is dissolved in a solvent, the solvent added to a non-solvent, resulting in precipitation of drug nanocrystals. This principle is exploited in the so-called "hydrosol" technology of Sucker and List (US-A-5 389 382, US-A-6 447 806) The resulting particles are crystalline in nature, especially if they have a particle size in the upper nanometer range The precipitation is also described in combination with specific polymers used to stabilize the precipitated drug nanoparticle dispersions (WO 00 2003/080034 A3) A precipitation method is also described which leads to the precipitation of amorphous particles with the trade name "Nanomorph ™ was originally developed by the company Knoll in Germany (EP 1 219 292 B1) Many problems are associated with the precipitation techniques:

1. After the onset of the crystallization process, it may be difficult to inhibit crystal growth, resulting in the formation of large crystals beyond the nanometer range, i. for the formation of drug microparts.

2. To maintain the physical stability of the prepared suspension, lyophilization is recommended (Sucker, H., Hydrosols - an alternative for the parenteral application of poorly water-soluble drugs, in: Müller, RH, Hildebrand, GE, (ed.), Pharmaceutical Technology: Modern Pharmaceutical Forms, 2nd Edition, 1998, WVG, Stuttgart).

3. Especially in precipitated particles in the amorphous state, it is difficult to obtain this amorphous state during the shelf-life, which is typically 3 years for pharmaceutical products. Especially when the amorphous particles have a size in the upper nanometer range (> 500 nm), they are more prone to recrystallization.

Continuation of crystal growth after precipitation is a major problem of the precipitation process. Sucker et al. solve this problem by using a further process step after the precipitation, i. by lyophilization of the drug nanocrystal suspension. In many cases, but no dry product, but an aqueous suspension is needed. One method of obtaining the particle size achieved by the precipitation is the combination of precipitation with annealing (US Pat. No. 6,607,784). After precipitation, the resulting drug suspension is subjected to a second energy-inputting step, e.g. by temperature increase, high-speed stirring or a Homogenisa- tion process exposed. This energy entry has two effects:

1. Transformation of the partially or fully amorphous particles in a completely crystalline state and

2. the maintenance of particle size and the prevention of particle growth.

The combination of the precipitation and the annealing process could solve or at least minimize the problem of particle growth. However, due to the "perfection" of the drug crystals, this combination is unable to overcome the limitation in particle size reduction. Therefore, although a preservation of the particle size obtained, but no further particle size reduction could be reported.

Based on these considerations, there was a clear need for improved technologies to produce drug nanocrystals.

The alternatives are the "top down" technologies, that is, one starts with a "coarse" powder, which is then minced into drug nanocrystals in various ways. A simple technique is the milling of drug microsuspensions in a ball mill. The drug powder is suspended in a surfactant solution and the resulting suspension is then filled into a mill containing beads as a milling material. The beads are agitated by stirrers and the drug microcrystals are ground between the grinding beads to drug nanocrystals. Alternatively, instead of a stirrer, the entire grinding vessel can be moved together with balls and suspension (US Pat. No. 5,145,684). Disadvantages are associated with the use of particle size reduction mills:

1. Depending on the hardness of the drug crystals, milling may take up to several days in the case of hard, crystalline drugs. This makes it not a production-friendly process.

2. During the milling process, the grinding balls wear out, which leads to contamination of the drug nanoparticle suspension. Contamination with glass microparticles has been reported using glass grinding beads

(Buchmann reference), as well as using zirconia grinding beads, contamination was found to be greater than 70 ppm, with the extent of contamination naturally being dependent on whether the drug is rather hard or soft.

3. Milling of aqueous suspensions over a period of several days may also result in bacterial growth and bacterial growth. lead to possible microbiological problems in the pharmaceutical product.

4. The scale-up process has some limitations due to the weight of the ball mills. Assuming a hexagonal packing of spherically equal size balls, these take 76% of the mill volume, whereas only 24% of the volume remain for the suspension to be ground. This results in the case of a mill with a capacity of 1000 L, that only about 240 L of suspension can be produced. Depending on the density of the grinding material (e.g., zirconia = 3.69 kg / L), such a mill would weigh between about 2.8 tons, a further increase in the chaff capacity of the mill is not possible due to the total weight.

Therefore, there is definitely a limit to scaling up. For larger batches that exceed the fill volume of these bead mills, therefore, a bead mill operating in the circulation process is required. The suspension is pumped continuously through the bead mill. As a result, the situation is not significantly improved, since an increased batch size, of course, at the same time extends the required meal.

An alternative is the use of high-pressure homogenization technology. The powder is in this case dispersed in the surfactant solution and then the resulting suspension is subjected to a high-pressure homogenization process, for example by using a piston-gap homogenizer (US Pat. No. 5,858,410) or by utilizing the jet-stream principle (realized with the microfluidizer US-A-5 091 187). The comminution principle of the microfluidizer is the frontal collision of two streams that meet at high speed. A major disadvantage of this method is the required relatively large number of cycles to obtain drug nanoparticles. The 50-100 homogenization cycles required in the example (US Pat. No. 5,091,187) are not particularly easy to manufacture. In addition, the Microfluidizer Principle described as less effective compared to the piston-gap method, especially in the case of very hard crystals, it leads to an undesirable proportion of microparticles in the nanosuspension. The piston-gap homogenization of suspensions of a drug in water leads to drug nanocrystals having an average particle size in the range of about 200 nm to 1000 nm. The cavitation was described as the comminuting principle (US Pat. No. 5,858,410). In the meantime, effective particle size reduction in non-aqueous media or in mixtures of water and water-miscible liquids has also been described. Examples of nonaqueous media are liquid polyethylene glycols (PEG) (eg PEG 400 or PEG 600) or oils (eg medium chain triglycerides (MCT)). The advantage of these nanosuspensions is that they can be filled directly into hard or soft gelatin capsules. Homogenization in aqueous mixtures, such as water-ethanol mixtures leads to suspensions that can be easily spray-dried. Homogenization in water-glycerol mixtures leads directly to isotonic products for parenteral administration. The particle size achievable in high-pressure homogenization depends on the homogenizing pressure and the softness or hardness of the substance to be processed. For relatively soft drugs, diameters between 200 nm and 300 were published (eg paclitaxel (B. Bohm, Dissertation, FU Berlin, 1999)). In the case of relatively hard drugs, the diameters were more in the range of 700 nm to 1000 nm (eg, M.Grau, Dissertation, FU Berlin, 2000). More efficient crushing methods are particularly desirable for the latter group of drugs. The above-cited particle sizes were obtained by homogenization at a pressure of 1500 bar. From the literature it is known that smaller particle sizes can be obtained by increasing the homogenization pressure, for example from 500 bar to 1500 bar. As a result, hard crystalline substances were homogenized at pressures of up to 4000 bar. However, despite more than twice the homogenization pressure, the resulting particle sizes remained practically unchanged (Fichera, MA, Wissing, SA, Müller, RH, Effect of 4000 bar homogenization pressure on particle diminution on drug suspension, Int. Meeting on Pharm., Biopharm. and Pharm. Technology, Nuremberg, 679-680, 2004). One explanation for this is the increasing crystallinity of the particles during the homogenization process. At the beginning, the particles break at weak points, that is, especially at imperfections or in amorphous areas. As comminution progresses, however, the number of these defects or amorphous regions steadily decreases, and the smaller particles produced become increasingly perfect. At a certain point in the homogenization process, only almost perfect crystals remain. Further comminution, for example, by doubling the homogenization pressure is no longer possible because the force required for this increases in a non-linear manner with increasingly perfect crystals. It is an exponential increase. If you are already in the steepest part of the curve, even a doubling of the homogenisation pressure only has a small influence on the size. It is clear that in the high-pressure homogenization a maximum degree of dispersity can be achieved at pressures in the range of 1500 bar. In order to achieve further particle size reduction for a particular drug, one has to apply greatly improved comminution techniques.

In summary, the problems associated with the production of drug nanocrystals by precipitation, such as difficulties in maintaining particle size and the associated special methods required (eg, lyophilization), lead to the fact that little or no use has been made of these products can be found on the market. A potential problem, namely the subsequent particle growth occurring after the precipitation, could be solved or minimized by the use of the principle of the subsequent tempering, eg by introduction of energy which leads to a preservation of the particle size achieved by the precipitation (eg US Pat. A-6 607 784). Technologies that can be applied to drugs that are sparingly soluble in all media are the ball milling techniques and the high pressure homogenization technologies. Problems associated with the ball mills are the long meals and potential product contamination. These limitations have been overcome by the use of piston-gap homogenizers. However, there remains a need for improved homogenization technologies since the non-linear relationship between pressure and achievable crystal size as a function of crystallinity limits the minimum achievable particle size.

Therefore, there is a clear need for new production methods which:

1. Avoid limiting the particle size reduction due to the presence of perfect crystals and

2. lead to very small particles, which are usually smaller than 300 nm and preferably less than 200 nm and ideally less than 100 nm.

It is therefore an object of this invention to provide a method for producing coated particles, in particular nanoparticles, with rapid dissolution, which transport the drugs to the specific site of action and at the same time protect them against premature degradation by influences such as gastric acid, enzymes or other adverse factors. The process involves preparing the particles of minimum size and then coating these particles with protective polymers.

The inventive object of the preparation of the particles to be coated is achieved by a process for the preparation of suspensions of very fine particles, which is characterized in that a liquid stream of a particle-free, containing the drug dissolved liquid 1, with a second liquid stream of a liquid 2 in one high-energy zone or at the earliest 2 Seconds is merged before reaching the high-energy zone, the two liquids are miscible with each other and the active substance dissolved in the liquid 1 is not or less soluble in the liquid 2 and in or within a maximum of 2 seconds before reaching the high-energy zone when mixing the both liquids precipitates as particles.

The particles thus produced, for example, are then introduced into an aqueous outer phase containing the coating materials in dissolved form, and then subjected to a drying step, whereby these materials precipitate as a closed coating on the particles. The particles thus coated are protected against harmful influences and, in contrast to uncoated particles, have a modified release kinetics.

The size-reducing process involves dissolving the active ingredient in a solvent, mixing the solvent with a non-solvent, and carrying out precipitation in a high energy zone. Thereafter, the suspension obtained is subjected to a film coating process (coating process) with polymers or macromolecules. The film coating process is particularly applicable to nanoparticles, but of course to microparticles, without the need to use organic solvents. The process can be carried out in non-organic solvents, in particular in water or aqueous media.

The present invention opens up the possibility of using ultrafine or ultrafine drug particles or polymer particles having a mean diameter of less than 1000 nm, preferably less than 300 nm, more preferably less than 200 nm and especially less than 100 nm to approximately 5 to 10 nm, to obtain. To date, various methods have been described for preparing suspensions via precipitation, the achievable size being dependent exclusively on the precipitation conditions (eg, mixing rate, type of stabilizer) (see US-A-5,389,382 and US-A-2005 0 139 144). It was too described that treating the precipitated product after completion of precipitation in a second, subsequent step. The precipitated product is treated with high energy to obtain the particle size achieved and to prevent further growth of the suspension, as occurs when storing the suspensions over days (see US-A-2002 0 127 278). The same process can also be used to alter the crystalline character of the material, ie to convert amorphous or semi-crystalline regions into completely crystalline material. In contrast to merely maintaining the particle size achieved by precipitation, this invention prevents growth of the crystals during the precipitation process by the application of energy. The method is not applied after the complete precipitation process as described in US-A-2002 0 127 278, but already during the precipitation. Surprisingly, it has additionally been found that prevention of crystal growth leads to crystals which can be relatively easily further comminuted by further application of energy (Example 1).

Performing the precipitation in a high energy zone requires a special design of the apparatus. This design can also be achieved by altering existing equipment by adding various modified parts to feed the liquid phase processed in the high energy zone.

The film coating process can be performed in various ways. Either you dissolve the desired polymers before particle production in the outer phase or you first make particles of the desired size to then disperse them in a polymer solution and then to achieve film formation by removal of the solvent or change the properties of the solvent. The removal of the solvent or the film formation can be effected by spray drying, evaporation methods, solvent diffusion methods, lyophilization or in the course of the application of further methods, such as, for example, fluidized bed granulation. tion or suspension spraying (suspension layering).

The aim of this invention was to develop a process for producing coated particles, in particular nanoparticles, with rapid dissolution in order to transport these drugs to the intestinal tract and at the same time to protect them against the acidic pH of the stomach. The process involves, for example, the production of nanoparticles of a minimum size and then coating these particles with protective polymers.

The present invention opens up the possibility of using ultrafine or ultrafine drug particles or polymer particles having a mean diameter of less than 1000 nm, preferably less than 300 nm, more preferably less than 200 nm and especially less than 100 nm to approximately 5 to 10 nm, to obtain.

To date, various methods have been described for preparing suspensions by precipitation, the achievable size being dependent exclusively on the precipitation conditions (eg mixing rate, nature of the stabilizer) (see US Pat. No. 5,389,382, US Pat. No. 2005,0 139 144). It has also been described that the precipitated product is treated after completion of precipitation in a second, subsequent step. The precipitated product is treated with high energy to obtain the particle size achieved and further growth the suspension as it occurs when storing the suspensions for days to prevent (US-A-2002 0 127 278). The same process can also be used to alter the crystalline character of the material, ie to convert amorphous or semi-crystalline regions into completely crystalline material. In contrast to merely maintaining the particle size achieved by precipitation, this invention prevents growth of the crystals during the precipitation process by the application of energy. The method is not applied after the complete precipitation process as described in (US-A-2002 0 127 278), but already during the precipitation. Surprisingly, it has additionally been found that prevention of crystal growth leads to crystals which can be relatively easily further comminuted by further application of energy (Example 1).

The film coating process can be performed in various ways. Either you dissolve the desired polymers before particle production in the outer phase or you first make particles of the desired size to then disperse them in a polymer solution and then to achieve film formation by removal of the solvent or change the properties of the solvent. The removal of the solvent or the film formation can be carried out by spray drying, evaporation methods, solvent diffusion methods, lyophilization or in the course of the application of other methods, such as fluidized bed granulation or suspension spraying (suspension layering). Detailed description of the invention

A conventional precipitation step results in a product having an average particle diameter in the size range of about 500 nm to a few microns within 1 to 10 seconds; typically, crystal growth rapidly results in a micron-sized precipitate. The processing of this material by means of high-pressure homogenization can preserve the precipitated particle size and prevent further crystal growth, but does not significantly reduce the particle size (US Pat. No. 2002 0 127 278). Therefore, it is particularly important that in the present invention the comminution process begin immediately or within milliseconds to seconds after the crystallization process. At this stage, the particles are still in the lower nanometer range (e.g., below 500 nm). In addition, it can be assumed that the orientation process of the molecules forming the crystal is not yet completely completed, since crystallization has just begun.

As with lipids, arranging the molecules takes time for an optimized alignment within the crystal structure. In the case of lipids such as Adeps solidus (hard fat) it takes about 6 seconds to move from the alpha modification to the more ordered beta modification. Apart from highly purified fats, fats are chemically inhomogeneous, meaning they are composed of very different molecules. These spatially differently constructed molecules require more time to orient themselves compared to chemically unified compounds. This can be compared to the construction of a wall of uniform bricks, which, in contrast to a wall of very different stones, can be set up relatively quickly. In conclusion, from this theoretical consideration, the crystal formation process of a chemically unified drug should proceed very rapidly. Surprisingly, it has been found that precipitation in the high energy range or followed by the immediate application of high energy (eg, above the power density of 10 ⁵ W / m ³ ) to medium level prednisolone nanocrystals Diameter of 133.6 ntn (as determined by Photon Correlation Spectroscopy (PCS)) (Example 2). The achievement of such a size has not yet been reported when using the high pressure homogenization technique.

The resulting suspension was further processed under the action of further energy. Circulation of the suspension to a total of 5 minutes in the homogenizer resulted in a PCS diameter of 26.6 nm. Surprisingly, the structure of the particles precipitated under the influence of high energy appears to reform into a more fragile form. The particle diameter decreased to a size (Example 3) that has never been reported for a high pressure homogenization process, according to US-A-5,091,187 or US-A-5,858,410.

According to the Kelvin equation, the vapor pressure of liquid droplets in a gas phase increases with increasing curvature of the droplets, ie as the droplet size decreases. Equivalent to this, the solution pressure of solid particles in a liquid increases with decreasing particle size, ie the saturation solubility increases (K.Peters, Dissertation, FU Berlin, 1999). Model calculations were carried out for the increase of the vapor / solution pressure as a function of the size of the spherical droplets / particles (S. Anger, Dissertation, FU Berlin, 2004). An exponential relationship was obtained. The calculations showed no or only a very small increase for sizes around 1 μm. However, a remarkable increase was noted in the reduction in size from 1 μm (1000 nm) to 100 nm. Due to the exponential nature of the relationship between size and solution pressure, a significant increase in solution pressure was noted for particle sizes below 100 nm, especially emphasized below 50 nm and an extremely high increase in particle sizes below 25 nm. Based on this, the saturation solubility will have a particularly pronounced increase as the size moves below 50 nm. In Example 4, the prednisolone particles were homogenized in a continuous process for 10 minutes. After 6 minutes, the PCS diameter was 22.1 nm, after 7 minutes 21.4 nm, after 8 minutes the nanocrystals were dissolved and a clear solution was obtained. This supersaturated solution was stable for about 1 hour before precipitation occurred with the formation of large crystals.

A similar effect was observed in the precipitation of budesonide, resulting in the formation of crystals with a diameter of LD 50% of 7.339 μm (volume distribution as determined by laser diffractometry, LD) (Example 5). The precipitation according to the invention using the jet-stream principle (corresponding to the structure of Figure 2) resulted in an LD 50% of 1.858 μm (Example 6). When using the Jet Stream setup (Figure 2), the time between the onset of precipitation and the energy expenditure on the crystals is extremely short. To study the effect of the time delay between the onset of crystallization and the energy input, an experiment was performed in a piston-gap homogenizer. The use of the piston-gap homogenizer resulted in a size LD50% of 2.651 μm. In this case, the delay between the start of precipitation and the energy expenditure was 2 seconds. From this one can conclude: To obtain very small particles, the time between the beginning of crystal formation and the expenditure of energy should be much less than 2 seconds.

In order to be able to immediately subject the crystallizing particles to comminution, it is necessary that the precipitation be carried out directly in the dissipation zone of the energy supplying device, eg ultrasonic rod (Figure 1), homogenizer (Figures 2-4) or rotor blade. Stator colloid mill takes place. Alternatively, the particles may be brought to the dissipation zone (eg gap in the piston-gap homogenizer) within 1 to 100 milliseconds, 100 to 500 milliseconds, or 1 to 2 seconds, but no later than 1 minute. If a "mature" precipitate is subjected to a homogenization process, in contrast to the use of the inventive method, no such fine product is obtained (Example 7) Time delay between the beginning of the precipitation and the energy input should not be too long.

Depending on the rate of in situ particle formation during the precipitation process, it may either be more advantageous to precipitate the particles directly in the homogenization zone or to bring the particles into the homogenization zone with a small delay so that at least core formation is complete. Otherwise, further precipitation and crystal growth could occur if the particles have already left the homogenization zone. In order to be able to control the delay time between the onset of crystallization and homogenization, a device has been developed which uses the pumping speed and a variable distance between the "mixing point" and "the power input zone" to provide the required Delay can be adjusted to obtain the desired target size of the crystals. Not always, it is desirable to produce the smallest possible crystals.

To achieve this, special homogenization chambers were designed for this process (Figure 1 and Figure 3, Figure 2 shows the principle), alternatively, the arrangement of a commercially available homogenization unit was modified. (Figure 4 to 6).

Figure 1: Solvent (S, solvent) and non-solvent (NS) tubes are arranged in parallel so that the liquid streams of solvent and non-solvent flow parallel to each other and the first and second streams are mixed is minimized. The two beams reach the dissipation zone below the rod of the ultrasonic apparatus. There is a mixing of both liquids below the vibrating rod, whereby the precipitation takes place directly in the zone of the energy input (Figure IA). In a second variant of the device, the two liquids come into contact with each other at a certain distance x from the dissipation zone, whereby First crystallization nuclei are formed at the interface between the little or no mixing liquid streams (Figure IB). The currents are characterized in that both flow in the same direction. Optionally, static mixers (various types) can be installed, whereby within the mixers the flow direction of both flows is again only possible in one direction.

Figure 2 shows the basic process arrangement with respect to the invention using piston-gap homogenizers based on the Bernoulli principle. The liquid flow of the solvent is aligned parallel to the liquid stream of the non-solvent within a low flow velocity region. The two parallel liquid streams then reach a zone with a narrower diameter. The occurring cavitation leads to a mixing of the liquids, which leads to a precipitation. The resulting particles are comminuted by cavitation forces still in their formation state. A second or repeated passage of these crystals can be used for further comminution of the crystals. By varying the tube with the solvent (S - solvent), the time between the start of particle formation and energy input can be varied (analogous to Figure IB).

Figure 3 shows the basic structure of a double-piston arrangement for a piston-gap homogenizer, two pistons are located in a cylinder and move towards each other during the homogenization process. In the first step, the pistons move apart, sucking in the solvent and the non-solvent. The tubes of the liquid streams are positioned so that a parallel movement of the liquid streams in one direction is ensured and mixing is minimized (Figure 3A). After filling the cylinders, the pistons are furthest apart (Figure 3B). During the Homogenisationsschrittes the two pistons move towards each other while pressing the solvent flow (S) and the non-solvent stream (NS) in parallel flow through the ring homogenization gap Figure 3C).

Figure 4: The existing piston-gap homogenizers can be used after minor modifications to apply the method of the invention (e.g., the continuous version of Micron LAB 40, APV Homogenizer Systems, Unna, Germany). The inlet of the one-piston homogenizer is modified so that the two parallel tubes of solvent (S) and non-solvent stream (NS) flow parallel into the cylinder during the filling process as the piston moves down (Figure 4A). A ball valve closes the two inlet tubes as the piston moves up during the homogenization process to force the two fluids through the homogenization gap. The supply of S and NS can alternatively be done as shown in Figure 4B (see Figure 2).

Figure 5 shows the basic structure when using Jet Stream Homogenizers. Prior to the homogenization chamber (e.g., y-type or z-type chamber in the Microfluidizer, Microfluidics Inc. USA), a unit is switched to allow the parallel flow of the solvent stream (S) and the non-solvent stream (NS). After both fluid streams have met, they flow in a parallel direction through a variable-length tube x. This length x can be varied to time the entry of the liquid streams into the dissipation zone. If necessary, static mixers of different types can be used. The constriction of the tubes in the homogenization chamber results in an extremely high flow rate before the crystals meet in the collision zone.

Figure 6: Liquid streams of solvent (S) and non-solvent (NS) are fed to a rotor-stator assembly of a wet-grinding colloid mill. The arrangement of the tubes allows a parallel entry of the two fluid streams. If desired - as in Figure 1 - the distance x can be modified or static Mixers are installed. Mixing of the two liquid streams occurs between the two plates of the rotor and the stator.

In order to avoid that energy "impinges" on the precipitate-forming particles at too early a stage, a delay may be incorporated by mixing the solvent and non-solvent with a delay of one millisecond to a maximum of two minutes The time of retardation of arrival in the homogenization zone may be achieved by changing the flow rate of the liquid streams and varying the distance X (eg, Figure IB, 5, 6) The calculations are based on the Hagen-Poiseuilleschen law and the Bernoulli equation.

The Lab-Scale Microfluidizer HC-2000 (Microfluidics Inc., USA) was adapted for this process in which a 0.45 g cannula tube was placed in the inflow reservoir to control the solvent-liquid flow. The pumping rate was 10 mL / min. The non-solvent was added to the influent reservoir (as shown in Figure 5, left).

The pumping speed of the liquids through the homogenizer was about 200mL / min. On the suction side of the pump, the flow rate of the product is up to 0.1 m / s for low-viscosity liquids (Müller, RH, Böhm, B. (Eds.), Dispersion Techniques for Laboratory and Industrial Scale Processing, Scientific Publishing Company Stuttgart, 113 p. , 2001, p.77). Considering the low viscosity of water and ethanol, as well as the small distance between the reservoir and the pump, the fluids reach the pump approximately after less than 200 ms. According to the device manufacturer, the diameter of the inlet tube is relatively large, to the lowest possible To allow flow resistance (Müller, RH, Böhm, B. (Eds.), Dispersion Techniques for Laboratory and Industrial Scale Processing, Scientific Publishing Company Stuttgart, 113 p., 2001, p.77). By modifying the device as shown in Figure 5, the diameter can be reduced, in addition, the length of the inlet tube can also be reduced (the reservoir is placed closer to the pump), reducing the inflow time to 20 ms or less. Alternatively, the reservoir may also be located directly at the inlet of the pump, whereby only a few milliseconds would be needed. Once the fluids have left the pump, stainless steel tubing will accelerate up to 10 m / s. The fluids reach the dissipation zone within milliseconds.

This setup can also be used to precipitate particles directly in the collision zone (Figure 5). In this case, the solvent-liquid stream with the dissolved compound or the compound and the non-solvent stream are passed in parallel into the Z-chamber of the microfluidizer, where the distance x is zero (Figure 5, right, distance x = zero). Alternatively, the two fluid streams may be routed to meet directly in a modified Y chamber. The liquid flow is not split before arriving in the collision zone, but two liquid streams are led separately to the collision zone. The solvent stream strikes the non-solvent stream and mixes with it in the collision zone, where the two liquid streams can both meet one another frontally or in an angular position, e.g. 90 ° or less, e.g. 45 ° (Figure 5C).

For oral administration, the drug nanocrystals often require a polymer coating, especially if they are acid labile drugs that could be destroyed in the unprotected gastric passageway. Other reasons for polymer coatings are a drug targeting or a desirable control. controlled release. In order not to have to forego the above-mentioned advantageous properties of individual drug nanocrystals, the possibility of coating individual nanocrystals, as implemented in this patent, particularly desirable.

The use of organic solvents for each process is undesirable, be it for toxicological, ecological or economic reasons. For this reason, a process has been developed in which the produced (nano) crystals are preferably coated with polymers without the use of organic solvents.

Acid polymers which are present in protonated form at the acidic pH of the stomach and are insoluble are frequently used for the production of enteric-coated dosage forms. If the pH then increases during the transition to the intestine, salts of these polymers form.

The deprotonated polymers are more soluble and release the entrapped drug.

In order to apply these polymers to the drug forms, they are usually dissolved in organic solvents or applied in the form of aqueous dispersions (O / W emulsions). In general, the use of organic solvents is not advantageous and not applicable in the specific case, since many water-insoluble active ingredients in organic solvents are sometimes even very soluble. Aqueous dispersions can likewise not be used for coating nanocrystals, since on the one hand they have too large a particle size / drop size in comparison with the drug nanocrystals and on the other hand they often react very unstably during mixing.

For these reasons, in the present invention, aqueous polymer solutions have been used as the coating material, taking advantage of the pH-dependent solubility of polymers. Aqueous solutions of enteric film formers have been known for some time (Bianchini, R., Resciniti, M., Vecchio, C. Technology evaluation of aqueous enteric coating systems with and without insoluble additives, Drug Dev Ind Pharm 17, 1779-1794, 1991; Company Information Röhm, Pharmapolymere, Gastro-resistant coatings, 2003). However, to date, these polymer solutions have only been used to coat conventional dosage forms, such as tablets and pellets, with an enteric-coated film former. When using conventional bases, such as sodium hydroxide or potassium hydroxide, however, gastroresist resistance can only be achieved with large application quantities. This is technically not feasible for nanoparticles / nanocrystals (eg excessive dilution of the nanosuspension, which is difficult to re-concentrate, reduction of the zeta potential by addition of electrolyte with subsequent crystal aggregation). One approach, namely the use of volatile bases, such as ammonium bicarbonate, is described by Hasan Rafati in patent GB2353215. However, this patent only includes the solution-layering technique (especially in the coating pan method) and also only gives examples of enteric-coated acetylsalicylic acid tablets.

In contrast, the present invention describes the use of aqueous polymer solutions both as a dispersion medium during nanocrystal preparation and for coating nanoparticles, more particularly drug nanocrystals.

In principle, two embodiments can be distinguished when coating the drug nanocrystals. In the first embodiment, the particles to be coated are prepared directly in the polymer solution. One can either use the methods given above or produce the drug nanocrystals in other ways. Possible methods are described, for example, in the patent of RH Müller et al. (WO0103670), but without reference to a Coat coating process (coating) of individual nanocrystals.

In a further embodiment variant of the patent, the drug nanocrystals are prepared prior to addition to the polymer solution and only subsequently dispersed in the form of a nanosuspension or a powder in the polymer solution with the aid of low power density mixers (for example toothed disk mixers, paddle stirrers).

Depending on the method and starting size used, the coated nanoparticles subsequently have a particle size in the range of a few 100 nm to 100 μm, preferably less than 50 μm, ideally less than 5 μm, the drug crystals having a particle size in the nanometer range.

In the case of acidic polymers (for example, polymethacrylates, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, HPMCAS), an aqueous polymer solution is obtained, for example, by adding sufficient amounts of volatile bases, e.g. Ammonium bicarbonate. The pH is shifted by adding this base to a region where the polymer is soluble (Figure 7a). When ammonium bicarbonate is used as the base component, the ammonium salts of the acidic polymers and carbonic acid are formed, which immediately decomposes into carbon dioxide and water (Figure 7b). Another advantage of the inventive method is that by the dissolution of the acidic polymers in aqueous basic solutions acid-sensitive drugs (such as omeprazole) are protected from chemical decomposition. In order to improve the film properties of the finished formulations, plasticizers (such as triethyl citrate, acetyltributyl citrate, dibutyl sebacate, propylene glycol, etc.) may additionally be added to this polymer solution. In addition, the outer phase may also contain surfactants, stabilizers and other auxiliaries.

Typical surfactants or stabilizing substances that can be added to the solvent are, for example, compounds the series of polyoxyethylene-polyoxypropylene block copolymers (poloxamers), ethylene diamine-polyethylene oxide-polypropylene oxide block polymers, poloxamines (poloxamines), ethoxylated mono- and diglycerides, ethoxylated lipids and lipids, ethoxylated fatty alcohols and alkylphenols, ethoxylated fatty acid esters, polyglycerol ethers and esters, Lecithins, esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols, such as ethoxylated sorbitan fatty acid esters, especially polysorbates (eg polysorbate 80 or Tween80), polyglycerol methyl glucose distearate (Tego Care 450, sorbitan fatty acid ester (eg Span 85), Phospholipids and sphingolipids, sterols, their esters or ethers and their mixtures of these compounds, as well as egg lecithin, soya lecithin or hydrogenated lecithins, their mixtures or mixtures of one or both lecithins with one or more phospholipid components, cholesterol, cholesterol palmitate, stigmasterol or other sterols in Question to be added to the solution.

It may be necessary to add further substances to the solution in order to influence the properties of the solution itself or the properties of the dry powder prepared from the solution. These include: diacetyl phosphate, phosphatidylglycerol, saturated or unsaturated fatty acids, sodium cholate, peptizers or amino acids, and cellulose ethers and esters, polyvinyl derivatives, alginates, xanthans, pectins, polyacrylates, poloxamers and poloxamines, polyvinyl alcohol, polyvinylpyrrolidone or Glucose, mannose, trehalose, mannitol and sorbitol, fructose, sodium citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, potassium chloride, glycerin. If necessary, dyes may also be added to the solvent, either in dissolved form or in insoluble form as pigments.

After the particles to be coated have been completely prepared or dispersed in the polymer solution, film formation can be achieved by increasing the temperature of the system or by various drying methods Initiate particles. The film-forming process can be realized in different ways.

One possible method is spray-drying, wherein the process temperature is to be selected as a function of the temperature sensitivity of the drug and the properties of the polymer. In the case of the thermolabile drug omeprazole, a product temperature of 50 to 60 ⁰ C should not be exceeded.

During the spray-drying process, the ammonium salt of the enteric polymer / macromolecule formed upon dissolution of the polymer decomposes into the free acid and ammonia and water, with the ammonia formed evaporating immediately (Figure 7c). The polymer precipitates in the phase separation process and surrounds the nanoparticles with a polymer layer which has enteric properties without further heat treatment. Improved film properties can be achieved by adding suitable plasticizers.

Examples of spray dryers which can be used are devices from Niro, Nubilosa, Caldyn, Büchi, APV, Trema, etc.

For non-temperature-sensitive active ingredients, the base dispersion formed can be heated with stirring, whereby generally preferred temperatures above 60 ⁰ C. Ammniak, carbon dioxide and water are produced, with ammonia and CO2 escaping and the polymer, because of the reduced pH, separating out on the surface of the nanocrystals via phase separation. With appropriate process control, individual, encapsulated nanocrystals are formed. By addition of electrolytes, the process can also be controlled via zeta potential reduction in such a way that encapsulated nanocrystals aggregate into large aggregates. The latter may be advantageous in further processing (eg, these particle aggregates are easier to separate).

Another approach to film formation is to add acids to nanosuspensions if the active ingredients to be encapsulated Substances are sufficiently acid stable for the process time and the polymers are used, for example, only for improved "drug targeting" to coat the drug nanocrystals.

Another approach to film formation is the use of drying methods via emulsion techniques. The base dispersion is dispersed as an inner phase in a nonaqueous phase by conventional dispersion techniques (e.g., paddle stirrers, rotor-stator systems, toothed disks, high pressure homogenization, with the aid of ultrasound). The result is a w / o system, where the water droplets contain the nanoparticles and dissolved polymer. In the next step, water is removed, which can be done in different ways, e.g. :

1. By direct use of a non-aqueous dispersion medium having relatively good solubility for water

(e.g., castor oil, 4% water solubility)

2. Evaporation under vacuum or by heating or combination of both

3. by solvent displacement, i. Admixing a liquid to the outer phase after preparation of the emulsion, wherein the admixed liquid has good solubility for water (e.g., acetone).

When dehydrated Polmer settles on the surface of the nanoparticles, the viscosity increases, with temperature increase it comes back to the evaporation of ammonia and carbon dioxide and it produces an enteric coating. The resulting polymer particles are characterized in the preferred embodiment in that they have typically included more than one nanoparticle.

The prepared base dispersion can also be further processed directly in a granulation process. In principle, the same process takes place as with the evaporation methods, but with the difference that even more indifferent auxiliaries from a conventional granulation process are present (eg Lactosekristalle). Parallel deposition on nanoparticles and lactose crystals, so that a mixture of encapsulated nanoparticles and encapsulated excipients is prepared.

The resulting granules can either be filled in capsules, alternatively tablets can be pressed. Another possibility is bottling in sachets, e.g. for redispersing in drinks for application. Furthermore, extrusion of the granules to matrix pellets is possible.

In a further embodiment variant, the suspension obtained after the homogenization with polymer / macromolecule still dissolved after addition of plasticizer is sprayed directly onto eg sugar pellets (non pareilles). The drying process produces a solid polymer shell containing nanoparticles firmly enclosed. The drying process is carried out at temperatures above 60 ⁰ C, so that escape again ammonia and carbon dioxide.

The film formation of the polymer on the surface of the drug particles significantly alters the properties of the coated drug nanocrystal. Depending on the polymer used, e.g. achieve sustained release, increased mucoadhesiveness or protection of sensitive drugs from the influence of gastric juice. For gastroresist resistance, however, it is necessary that the base used to adjust the pH be volatile under the process conditions, i. not present in dry form in the final product.

When using non-volatile bases, such as sodium hydroxide, it comes only by acid contact to a precipitation of the acidic polymers, thereby initially acid can penetrate and damage the sensitive drug. The use of volatile bases, such as ammonium bicarbonate, occurs during the drying process a complete escape of the base portion, since the ammonium salts of the acidic polymers release ammonia and then again in protonated, ie acid-insoluble form. The resulting polymer films are therefore solid and acid-resistant even before the action of an acid (Figure 7b).

Examples

Example 1:

Prednisolone was precipitated in the classical manner, that is, by adding a solvent to a non-solvent. 275 mg Prednisolone were dissolved in 10 mL ethanol 90% (v / v), this solution was poured with stirring with magnetic stirring in 9OmL of distilled water. The particle size determination directly after the precipitation gave a diameter LD 50% of 2.185 μm, LD 95% of 5.108 μm, LD 99% of 6.414 μm and a diameter of LD 100% of 8.944 μm (volume distribution, laser diffractometry, Coulter LS 230, Beckman Coulter, USA).

Example 2:

Prednisolone was dissolved in 10 mL ethanol 90% (v / v) analogously to Example 1. Then, 10 mL of this prednisolone solution was pumped into a device described in Figure 2 using an infuser (Braun Melsungen, Germany). The pumping speed was 1.5 mL / min. The volume of the aqueous phase was exactly as in Example 90 mL, to compare the classical precipitation with the inventive method. After one minute infusion time, a sample of the precipitated product was drawn and analyzed by photon correlation spectroscopy (Zetasizer 4, Malvern, United Kingdom). The mean particle diameter (z-average) was 113 nm, the polydispersity index (PI) was 0.678.

Example 3

A precipitation was carried out analogously to Example 2, after 5 minutes a sample of the precipitated product was taken and examined by photon correlation spectroscopy. The mean particle diameter (z-average) was 27 nm with a polydispersity index (PI) of 0.460.

Example 4:

A precipitation was carried out analogously to Example 2, the homogenization time was 10 min. After 6 minutes, a sample of the precipitate was taken and examined by photon correlation spectroscopy. The mean particle diameter (z-average) was 22 nm with a polydispersity index (PI) of 0.854. A sample taken after 7 minutes had a PCS diameter of 22 nm at a PI of 0.441. After 8 minutes, the prednisolone crystals dissolved due to the increased solution pressure at this small size. The milky suspension turned into a clear solution. After one hour, the highly supersaturated solution began to crystallize in the form of long, macroscopically visible needles.

Example 5:

Budesonide was conventionally precipitated by addition of a solvent to a non-solvent. To this end, 275 mg of budesonide were dissolved in 10 mL of 90% (v / v) ethanol, and this solution was poured into 90 mL of distilled water while stirring with a magnetic stirrer. The particle size determination directly after the precipitation gave a diameter LD 50% of 7.339 μm and LD 90% of 10.920 μm (volume distribution, laser diffractometry, Coulter LS 230, Beckman-Coulter, USA).

Example 6:

Budesonide was dissolved analogously to Example 1 in 10 mL ethanol 90% (v / v). Then, 10 mL of this prednisolone solution was pumped into a device described in Figure 2 using an infuser (Braun Melsungen, Germany). The volume of the aqueous phase was exactly as in Example 90 mL, to the classical precipitation with the inventive method to compare. After 10 minutes circulation time, a sample of the precipitated product was taken and examined by laser diffractometry. The particle size determination gave a diameter LD 50% of 1.858 μm and LD 90% of 3.486 μm (volume distribution, laser diffractometry, Coulter LS 230, Beckman-Coulter, USA).

Example 7:

An ethanolic budesonide solution was prepared according to Example 6, a portion of this solution was added to distilled water, which was located directly in the reservoir of a Micron LAB 40 (APV Homogenizer Systems, Unna, Germany). The budesonide precipitated and energy was applied to the precipitate 2 seconds after precipitation in the form of a homogenization step to investigate the effect of delayed energy application. A homogenization cycle was carried out at 1500 bar. The diameter determined by laser diffractometry was LD 50% 2.651 μm and LD 90% 5.693 μm (volume distribution, laser diffractometry, Coulter LS 230, Beckman-Coulter, USA).

Example 8:

The precipitate, prepared for Example 5, was subjected to a jet-stream process, the homogenization taking place as described in Example 6. As the particle size, LD 50% of 2.157 μm was measured. Applying the inventive method, as described in Example 6, gives 1.858 microns.

Example 9:

The pharmaceutical active ingredient hydrocortisone acetate was comminuted according to the invention in an aqueous polymer solution by high-pressure homogenization. To this, 1.0 g of ammonium hydrogencarbonate was added to 92.0 g of water, and 5.0 g of hydroxypropylmethylcellulose phthalate 55 (HPMCP 55) was dissolved in this solution. This resulted in a loss of carbon dioxide. Subsequently, the pH became the resulting polymer solution adjusted to 7.5 by further addition of ammonium bicarbonate. In this solution, 1 g of poloxamer 188 was dissolved and 1.0 g of micronized hydrocortisone acetate was dispersed with an Ultra-Turrax (Janke & Kunkel, Germany) at 9,500 revolutions per minute. The mixture was then homogenized using a Micron LAB 40 high pressure homogenizer (APV Homogenisers, Unna, Germany). At the beginning of 2 cycles were carried out at 150 bar, then 2 cycles at 500 bar, then further homogenized at 1500 bar. After 20 homogenization cycles at room temperature (RT) and a pressure of 1500 bar, a mean particle diameter of 951 nm and a polydispersity index (PI) of 0.216 were obtained with the aid of photon correlation spectroscopy (PCS).

Example 10:

The pharmaceutical active ingredient hydrocortisone acetate was comminuted according to the invention in an aqueous polymer solution by high-pressure homogenization. For this purpose, initially 2.5 g of ammonium bicarbonate were added to 91.5 g of water, and 4.0 g of Eudragit S 100 (in powder form) were dissolved in this solution. This resulted in a loss of carbon dioxide. Subsequently, the pH of the resulting polymer solution was adjusted to 7.5 by further addition of ammonium bicarbonate. In this solution, 1.0 g poloxamer 188 was dissolved and 1.0 g micronized hydrocortisone acetate was dispersed with an Ultra-Turrax (Janke & Kunkel, Germany) at 9,500 revolutions per minute. The mixture was then homogenized using a Micron LAB 40 high pressure homogenizer (APV Homogenisers, Unna, Germany). At the beginning of 2 cycles were carried out at 150 bar, then 2 cycles at 500 bar, then further homogenized at 1500 bar. After 20 homogenization cycles at room temperature (RT) and a pressure of 1500 bar, a mean particle diameter of 787 nm and a polydispersity index (PI) of 0.273 were obtained by means of photon correlation spectroscopy (PCS). Example 11:

The pharmaceutical active ingredient omeprazole was likewise comminuted according to the invention in an aqueous polymer solution by high-pressure homogenization. To this, 1.0 g of ammonium hydrogencarbonate was added to 92.0 g of water, and 5.0 g of hydroxypropylmethylcellulose phthalate 55 (HPMCP 55) was dissolved in this solution. This resulted in a loss of carbon dioxide. Subsequently, the pH of the resulting polymer solution was adjusted to 7.5 by further addition of ammonium bicarbonate. In this solution, 1.0 g poloxamer 188 was dissolved and 1.0 g micronized omeprazole was dispersed with an Ultra-Turrax (Janke & Kunkel, Germany) at 9,500 revolutions per minute. The mixture was then homogenized using a high-pressure homogenizer Micron LAB 40 (APV Homogenizers, Unna, Germany). At the beginning of 2 cycles were carried out at 150 bar, then 2 cycles at 500 bar, then further homogenized at 1500 bar. After 20 Homogenisationszyklen at 5 ⁰ C and a pressure of 1500 bar were obtained by means of photon correlation spectroscopy (PCS) a mean particle diameter of 945 nm and a polydispersity index (PI) of 0.289.

Example 12:

The pharmaceutical active ingredient omeprazole was likewise comminuted according to the invention in an aqueous polymer solution by high-pressure homogenization. For this purpose, 2.5 g of ammonium bicarbonate were initially added to 91.5 g of water, and 4.0 g of Eudragit S 100 (in powder form) were dissolved in this solution. This resulted in a loss of carbon dioxide. Subsequently, the pH of the resulting polymer solution was adjusted to 7.5 by further addition of ammonium bicarbonate. In this solution, 1.0 g poloxamer 188 was dissolved and 1.0 g micronized omeprazole was dispersed with an Ultra-Turrax (Janke & Kunkel, Germany) at 9,500 revolutions per minute. The mixture was then homogenized using a Micron LAB 40 high pressure homogenizer (APV Homogenizers, Unna, Germany). At the beginning, 2 cycles were carried out at 150 bar. led, then 2 cycles at 500 bar, then further homogenized at 1500 bar. After 20 homogenization cycles at 5 ^° C. and a pressure of 1500 bar, a mean particle diameter of 921 nm and a polydispersity index (PI) of 0.370 were obtained by means of photon correlation spectroscopy (PCS).

Example 13:

The suspension prepared for Example 9 was then spray-dried with a Mini Spray Dryer spray dryer, model 190 (Büchi, Switzerland). The spray drying conditions were: flow rate 700 L / min, pump setting 5, aspiration 8, heating rate: 5, Inlet Temperature: 120 ⁰ C, outlet temperature: 55 to 6O ⁰ C. The powder thus obtained was then examined by light microscopy. It showed a uniform round appearance at 1000x magnification, only a few aggregates and a particle size in the range of 1 to 5 microns. Macroscopically, it is a white, loose powder with good flowability.

Example 14:

The powder prepared in Example 13 was subjected to a release test to detect the reduced release in the acidic medium. For this purpose, the powder was first stirred for one hour at 37 ° C in 750 mL of 0.1 N HCl at 50 revolutions per minute and taken at appropriate intervals samples using a 0.2 micron filter syringe. The drug content was then determined using an HPLC system. Within the first hour, only 20% of the total drug content was released. Subsequently, a further 250 ml of phosphate buffer were added to the release medium and the pH was thus increased to pH 6.8. This pH increase resulted in the intended dissolution of the enteric polymer. Within 30 minutes of adding the phosphate buffer, all residual drug content was released.

Claims

Patentanspüche

1. A process for the preparation of suspensions of very fine particles, characterized in that a liquid stream from a particle-free, an active ingredient dissolved liquid 1 combined with a second liquid stream of a liquid 2 in a high-energy zone or at least 2 seconds before reaching the high-energy zone is, wherein the two liquids are miscible with each other and the active substance dissolved in the liquid 1 is not or less soluble in the liquid 2 and fails in the or within maximmal 2 seconds before reaching the high energy zone when mixing the two liquids as particles.

2. The method according to claim 1, characterized in that the high-energy zone of the gap in a rotor-stator colloid mill, the sonication zone in front of an ultrasonic rod, the gap of a piston-gap high-pressure homogenizer or the collision zone of a Hochdruckhomogenisa- sector, in particular the Y Chamber or the Z-chamber of a jet stream homogenizer.

3. The method according to claim 1 or 2, characterized in that the two liquid streams are arranged parallel to each other and do not mix with each other before reaching the high-energy zone.

4. The method according to claim 1 or 2, characterized in that the two liquid streams are initially arranged parallel to each other and flow before reaching the high-energy zone in contact with and parallel to each other over a distance x.

5. The method according to claim 4, characterized in that the two liquid streams initially parallel to each other are arranged to flow in contact with and parallel to each other over a distance x before reaching the high-energy zone and mixed before reaching the high-energy zone, in particular with a static mixer.

6. The method according to claim 4 or 5, characterized in that the delay time before reaching the high-energy zone by the two liquid streams by varying the distance x in the range of 1 to 100 ms, 100 to 500 ms or up to 1 s or even 2 s can be extended.

7. The method according to any one of claims 1 to 6, characterized in that average particle sizes (Laserdiffrak- tometrie, diameter 50%) are obtained, which is less than 10 microns, preferably less than 4 microns, more preferably less than 1 micron and in particular less than 0.2μm (200nm).

8. The method according to any one of claims 1 to 6, characterized in that average particle sizes (photon correlation spectroscopy (PCS), z-average) are obtained, which is smaller than 3000 nm, preferably less than 500 nm, in particular less than 200 nm, preferably smaller than 120 nm and in particular less than 50 to 80 nm.

9. Apparatus for producing a particle suspension according to one of claims 1 to 8, characterized by pipes through which two liquids are supplied in parallel flow of a high-energy zone, in particular the gap of a colloid mill or the sonication zone of an ultrasonic rod.

10. Apparatus according to claim 9, characterized by pipes through which two liquids are supplied in parallel flow of the sonication zone of an ultrasonic rod, wherein a) the delay time to reach the sonication zone and b) the contact time of the two currents via a change in the contact distance x variable is.

11. The device according to claim 9 or 10, characterized in that it is a high-pressure homogenizer, wherein the merging of the two liquids at the earliest 2 seconds before reaching the high-energy zone or directly in the high-energy zone.

12. Device according to one of claims 9 to 11, characterized by two tubes through which the two liquids in an upper region S (liquid 1) or in a lower region NS (liquid 2) of a piston-gap homogenizer are performed, which has two movable pistons in a cylinder, wherein the two liquids are sucked by the piston movements in the cylinder, the pistons move towards each other after reaching the dead center of the piston and press the liquids through the homogenization gap.

13. Device according to one of claims 9 to 11, characterized by two tubes through which the two liquids are passed without prior mixing in a piston-gap homogenizer having a piston, or the two liquids flowing in parallel before reaching the homogenizer cylinder with each other get in touch.

14. The apparatus of claim 12 or 13, characterized in that the gap of the piston-gap homogenizer is replaced by the collision zone of a jet stream homogenizer, the liquid 1 is introduced centrally into a tube that the liquid 2 leads, and the two Liquids are then fed via the pipe system of the homogenization chamber of the collision zone.

15. A process for coating particles, characterized in that the particles to be coated, in particular those which have been prepared by a process according to one of the statements 1 to 8, in a dispersion medium dium containing a coating material in dissolved form, wherein the coating material is brought into solution by a pH shift by means of a volatile component, or complex formation, in particular salt formation, with a volatile component, and the particle suspension thus produced subsequently elevated temperature is subjected to a drying process.

16. The method according to claim 15, characterized in that the coating material comprises or consists of polymers which are suitable for influencing the release properties of the particles in the desired manner.

17. The method according to any one of claims 15 or 16, characterized in that the drying of the particle suspensions by spraying the particle suspension in a spray dryer, fluidized bed dryer, fluidized bed granulator, high shear mixer, drum coater, rotor granulator takes place.

18. The method according to claim 17, characterized in that the spray-drying with a Mini Spray-Dryer B-190 (Büchi, Switzerland), preferably at temperatures of the inlet air stream between 20 ⁰ C and 200 ⁰ C, preferably between 50 ⁰ C and 150 ⁰ C, more preferably between 80 ⁰ C and 120 ⁰ C takes place.

19. The method according to claim 15 or 16, characterized in that the drying is carried out with a dry roller dryer, thin-layer vacuum dryer or dryers or drying methods, which lead to a rapid withdrawal of the dispersant of the particle suspension.

20. The method according to claim 15 or 16, characterized in that the drying by means of emulsion process, in particular by means of solvent evaporation process (Solvent evaporation), optionally also at reduced pressures or under vacuum.

21. The method according to any one of claims 15 to 20, characterized in that the volatile component is ammonium bicarbonate or ammonia.

22. The method according to any one of claims 15 to 21, characterized in that a powder with agglomerated particles or a powder with separate particles is formed, which has modified release properties depending on the coating material used.

23. The method according to any one of claims 15 to 22, characterized in that it leads to coated particles which are enteric-coated and dissolve depending on pH-dependent application.

24. The method according to any one of claims 1 to 9 or 15 to 23, characterized in that the resulting particle suspension is used either directly or after separation of the particles from the dispersion medium, in particular in different forms for pharmaceutical and cosmetic application, preferably in the form of tablets and capsules, creams, ointments or powders for reconstitution before use.

25. The method according to any one of claims 1 to 9 or 15 to 23, characterized in that the coated particles are used parenterally directly in the form of suspensions or after reconstitution from Lyophillisaten.

26. The method according to any one of claims 1 to 9 or 15 to 23, characterized in that the coated particles are processed into divided powders, filled into hard or soft gelatin capsules, pressed into tablets, effervescent tablets or orodispersible tablets or processed into pellets.