DE102005053462A1 - Gentle method for preparing ultrafine particle suspensions, useful for formulating e.g. pharmaceuticals, cosmetics, foods or pesticides, comprises freezing non-aqueous solution then dispersion of the frozen product - Google Patents

Abstract

Gentle preparation of ultrafine particle suspensions comprises e.g.: (a) dissolving a solid (A) which is insoluble or sparingly soluble in water in a solvent; (b) freezing the solution to a solid matrix; (c) optionally removing solvent by drying, especially freeze drying; (d) dispersing the frozen solid matrix, optionally dried, in a dispersion medium; and (e) subjecting the dispersion to a medium to high force. Gentle preparation of ultrafine particle suspensions comprises: (a) dissolving a solid (A) which is insoluble or sparingly soluble in water in a solvent; (b) freezing the solution to a solid matrix; (c) optionally removing solvent by drying, especially freeze drying; (d) dispersing the frozen solid matrix, optionally dried, in a dispersion medium; and (e) subjecting the dispersion to a medium to high force, before the frozen, dispersed matrix has melted, and forming a particulate suspension of mean particle size (measured by photon correlation spectrometry) below 1000 (preferably 50-200, particularly below 100) nm. ACTIVITY : None given. MECHANISM OF ACTION : None given.

Description

Summary the invention

The The present invention describes a multi-stage process for Production of surface-modified Active substance nanoparticles or nanosuspensions by means of high-pressure homogenization of modified drug material in the presence of various Protective colloids to the exclusion of the use of surfactants and / or Emulsifiers. The modified drug nanoparticles have a mean Particle size of 10 nm to 1000 nm. As a nanosuspension present, the modified Wirkstoffananopartikel exclusively by the applied polyelectrolyte multilayer or polyelectrolyte multilayers stabilized and can either directly applied as nanosuspension or too dry Powders are further processed.

1. Field of the invention

The Invention describes a process for particularly effective, surfactant-free Production of surface-modified Active substance nanoparticles by means of high-pressure homogenization.

2. Stand the technology

The Production of drug nanoparticles has increasing economic Meaning, especially when it comes to the drug nanoparticles (general name for Active substance particles with an average particle size of <1000 nm) around drug nanocrystals is.

When Nanocrystals (generally drug nanocrystals, especially drug nanocrystals) refers to crystalline, solid particles having an average particle size of 1 to 1000 nm. Depending on the manufacturing method, it can also be Nanoparticles with partially amorphous areas act. The following will be the terms drug nanoparticles and drug nanocrystal used synonymously.

dispersions, contain the Wirkstoffananopartikel dispersed in a liquid phase, are referred to below as nanosuspensions.

The surface These drug nanocrystals / drug nanocrystals can be charged with opposite Polyelektrolytschichten coated are then the drug nanoparticles or drug nanocrystals as a template particle.

The production of drug nanoparticles by means of high-pressure homogenization is a recognized method and has been used for many years for the production of nanoparticles, in particular for the production of drug nanocrystals. The cavitation forces, collision forces, and occurring shear forces that occur during high-pressure homogenization lead to particle size reduction. In high-pressure homogenization, a distinction is made between homogenizers which operate according to the jet-stream principle (microfluidizer technology, Microfluidics Inc.), colloid mills and piston-gap homogenizers. The principle of the microfluidizer is the frontal collision of two liquid streams with very high velocity, whereby the collision of the particles leads to their comminution. Disadvantages of this method are the required high number of cycles (often more than 50 cycles) and a potential contamination of the resulting nanosuspension with residual microparticles ( US 5,091,187 ; US 5,922,355 ; US 6,018,080 ).

Alternatively, the preparation of nanosuspensions can also be carried out with the aid of piston-gap homogenizers. When using piston-gap homogenizers, a previously prepared macrosuspension is forced through a very narrow gap which, depending on the applied pressure and on the viscosity of the dispersion medium, has a size of 5-20 μm (Rainer H. Müller, Jan Möschwitzer and Faris Nadiem Bushrab, Manufacturing of nanoparticles by milling and homogenization techniques, Eds. Gupta, Kompella, Publisher: Marcel Dekker, submitted for printing). patent US 5,858,410 describes, for example, the use of piston-gap homogenizers for the comminution of particle dispersions with pure water / surfactant mixtures as dispersion medium. In contrast, the patent application WO 002001003670C2 (RH Muller et al.) Describes the use of this technology to particulate, which are dispersed in non-aqueous media or in mixtures of water with water-miscible liquids, in a particularly gentle manner, for example at reduced temperatures, to homogenize. Using micronized starting material, particles having an average particle size of approximately 200-1000 nm can be produced by means of high-pressure homogenization (Muller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy: Rational for development and what we can expect for the future Advanced Drug Delivery Reviews 2001; 47 (1): 3-19).

In an earlier one The inventors were able to show that the effectiveness of particle size reduction significantly improved by a modification of the starting material can be (German Patent Application 10 2005 017 777.8). For this Reason is expressly referred to in the present invention taken on this method and again this method of particle production used.

In general, it needs stabilization the colloidal systems prepared in this way an addition of surfactants, emulsifiers or polymeric stabilizers. The surfactants are used in the ratio often in the ratio 1: 1 to 1:10 (surfactant to drug). The surfactants used can cause undesirable effects, such as allergic reactions.

aim However, the present invention has been the production of nanosuspensions excluding surfactants by preparation of surface-modified (polymer coated) drug nanoparticles.

According to the state of the art, a coating of, for example, micro- and nanocrystals (template particles) is achieved by mixing a dispersion of template particles (crystals to be coated) or solid template particles in a salt-containing liquid phase containing the components required for coating (capsule formation) in dissolved form contains dispersed and a capsule shell is formed by precipitation of the components ( EP 1305109 B1 ).

So far has always been concerned with coating material when coating template particles in dissolved Form (polyelolyte solutions) went out. The in dissolved Form present polyelectrolyte chains can, however, via so-called Bridge formation that Occurrence of a strong, partially irreversible aggregation of the Cause template particles, especially if the template particle dispersion not with the help of surfactants, stabilizers or other surfactants Substances is stabilized.

The coating of the template particles with polyelectrolyte multilayers takes place stepwise, ie the template particles are coated with several (at least two) alternating layers of oppositely charged polyelectrolytes. After each individual coating step, the template particles are generally to be separated from the excess polymers by filtration, centrifugation or dialysis (as described in US Pat US 6,833,192 or WO 2004/047977 A1) before the next polyelectrolyte layer can be applied. As a result, filter residues on the one hand and irreversible aggregation and agglomeration during centrifugation on the other hand lead to relatively large losses of freely movable template particles.

3. Detailed Description of the invention

The The present invention is a combined process for production of drug nanoparticles with simultaneous surface modification for the purpose of reducing aggregation and agglomeration tendency the produced particles.

The invention is characterized in that the active substance nanoparticles to be coated are produced in the first process step by means of high-pressure homogenization. For this purpose, the sparingly water-soluble or water-insoluble active ingredient ( 1 ., Item 1) dissolved in a suitable solvent and the resulting solution is then frozen ( 1 , Item 2), creating a solid, frozen matrix. Subsequently, either the solvent is completely removed from the frozen matrix by means of lyophyllization or the mixture is further worked with the frozen matrix. The modified active substance ( 1 , Item 3) is used together with the powdery polymer 1 or protective colloid 1 ( 1 , Item 4) in an outer phase with the aid of suitable mixers (eg Ultra-Turrax) dispersed ( 1 , Point 5). It is important that only the polymer 1 or protective colloid 1 is soluble in the outer phase. Subsequently, the dispersion of water-soluble or water-insoluble active ingredient ( 1 ., Item 1) and solid polymer 1 or protective colloid 1 ( 1 , Item 4) several high-pressure homogenization cycles ( 1 , Item 4) ( 1 , Item 6), so that a metastable nanosuspension is formed, the surface of the active substance nanoparticles being filled with polymer 1 or protective colloid 1 ( 1 , Point 7). To this metastable nanosuspension is then added to the polymer 1 or protective colloid 1 oppositely charged polymer 2 or protective colloid 2 ( 1 , Point 8). This mixture is then homogenized again ( 1 , Item 9), where the pressure compared to the first Homogenisationszyklen (( 1 , Item 6) can be reduced because the homogenization no longer serves the particle size reduction. The nanoparticles ( 1 , Item 10) have an oppositely directed surface charge compared to the particles of the metastable nanosuspension ( 1 , Point 7). In addition, the resulting nanosuspension is no longer metastable, but has excellent physical stability with no tendency for particle aggregation or agglomeration. These nanosuspensions prepared in this way can be used as a product or further processed. By conventional drying methods ( 1 , Item 11), such as spray drying, lyophilization or simple filtration with subsequent drying of the filter cake arise nanocrystalline active ingredient powder ( 1 , Item 12), which are filled eg in hard gelatin capsules or can be compressed into tablets.

The surface modified by the inventive method Particles have an average particle size of 10 nm to 2000 nm, preferably from 100 nm to 1000 nm, most preferably from 200 nm to 500 nm.

The active ingredients can be processed originate from various fields, ie it can be processed pharmaceutical active ingredients, cosmetic active ingredients, but also additives for the food industry and materials for other technical areas, which are preferably present as nanocrystalline material, such as dyes and dye pigments for paints and coatings or for cosmetic applications.

Pharmaceutical agents may be derived from the therapeutic areas listed below (optionally in the form of their sparingly water-soluble form, eg as the base instead of the hydrochloride):
Examples of drug groups to be processed in the form of a nanosuspension are:

1. analgesics / anti-inflammatory drugs

• z. Morphine, codeine, piritramide, fentanyl, levomethadone, Tramadol, diclofenac, ibuprofen, dexibuprofen, ketoprofen, dexketoprofen, Meloxicam, indomethacin, naproxen, piroxicam, rofecoxib, celecoxib,

2. Antiallergic drugs

• z. Pheniramine, dimetinden, terfenadine, astemizole, loratidine, Desloratadine, Doxylamine, Meclozin, Fexofenadine, Mizolastine

3. Antibiotics / chemotherapeutics

• z. B. rifamoicin, ethambutol, thiazetazone, buparvaquone, Atovaqone, tarezepide

4. Antiepileptic drugs

• z. Carbamazepine, clonazepam, mesuximide, phenytoin, valproic acid

5. Antifungals

• a) internal: z. Natamycin, amphotericin B, miconazole, itraconazole
• b) externally: z. Clotrimazole, econazole, fenticonazole, Bifonazole, ketoconazole, tolnaftate

6. Corticoids (internals)

• z. Aldosterone, fludrocortisone, betametasone, dexametasone, Triamcinolone, triamcinolone acetonide, fluocortolone, hydrocortisone, Hydrocortisone acetate, prednisolone, prednylidene, cloprednol, budesonide, methylprednisolone

7. Dermatics

• a) Antibiotics: z. Tetracycline, erythromycin, Framycetin, tyrothricin, fusidic acid
• b) antivirals as above, in addition: z. Vidarabine
• c) Corticoids as above, in addition: z. B. amcinonide, Flupredniden, Alclometasone, clobetasol, halcinonide, fluocinolone, clocortolone, flumetasone, Diflucortolone, Fludroxycortide, Halometasone, Desoximetasone, Fluocinolide, Fluocortinbutyl, flupredniden, prednicarbate, desonide

8. Hypnotics, sedatives

• z. Cyclobarbital, pentobarbital, methaqualone, benzodiazepines (Flurazepam, Midazolam, Nitrazepam, Lormetazepam, Flunitrazepam, Triazolam, Brotizolam, temazepam, loprazolam)

9. Immunotherapeutics and cytokines

• z. Azathioprine, cyclosporin

10. Local anesthetics

• a) internal: z. Butanilica, mepivacaine, Bupivacaine, etidocaine, lidocaine, articaine
• b) externally: z. B. oxybuprocaine, tetracaine, benzocaine

11. Migraine remedies

• z. Lisuride, methysergide, dihydroergotamine, ergotamine, Triptans (such as zolmitriptan, sumatriptan, rizatriptan)

12. Anesthetic

• z. Methohexital, propofol, etomidate, ketamine, thiopental, Droperidol, fentanyl

13. parathyroid hormones, Calcium metabolism regulators

• z. B. dihydrotachysterol

14. Ophthalmics

• z. Cyclodrin, cyclopentolate, homatropin, tropicamide, Pholedrine, edoxudine, acyclovir, acetazolamide, diclofenamide, carteolol, Timolol, metipranolol, betaxolol, pindolol, bupranolol, levobununol, carbachol

15. Psychotropic drugs

• z. Benzodiazepines (lorazepam, diazepam), clomethiazole

16. Sexual hormones and their inhibitors

• z. Anabolic steroids, androgens, antiandrogens, gesta genes, estrogens, antiestrogens

17. cytostatics and metastasis inhibitors

• a) alkylating agents such as melphalan, carmustine, lomustine, cyclophosphamide, Ifosfamide, trofosfamide, chlorambucil, busulfan, prednimustin, thiotepa
• b) antimetabolites such as fluorouracil, methotrexate, mercaptopurine, thioguanine
• c) alkaloids such as vinblastine, vincristine, vindesine
• d) Antibiotics such as dactinomycin
• e) Taxol and related or analogous compounds
• f) dacarbazine, estramustine, etoposide

pharmaceutical Active substances of particular interest are amphotericin B, cyclosporin A, acyclovir, ritonavir, paclitaxel, taxanes, ketoconazole, itraconazole, Ibuprofen, naproxen, omeprazole, pantoprazole, loratadine, desloratadine, Loperamide, daglutril, testosterone, ketoprofen, hydrocortisone acetate.

A peculiarity of the inventive method is that the drug nanoparticles to be modified in their surface property by means of polymer adsorption are prepared directly by means of high pressure homogenization with simultaneous polymer coating in the process. Moreover, the process of particle size reduction due to the use of specially modified starting material is particularly effective, that is, to achieve nanometer-scale drug particle sizes (as described in point 6). 1 ) often only up to a maximum of 5 Homogenisationszyklen must be performed, in special cases only 3 Homogenisationszyklen, especially only 1 Homogenisationszyklus.

at the method of particle coating with polyelectrolyte multilayers According to the prior art, the adsorption of polyelectrolytes occurs due of opposite Charge of the polyelectrolytes used, wherein to achieve a so-called charge overcompensation (More polyelectrolytes are bound to the particle surface, as necessary for charge balance) an excess of polyelectrolytes and a certain salt content are required. In contrast this requires the inventive method no salt addition, since the Particle coating due to the applied high pressures rather takes active, that is, the polyelectrolytes are under pressure on the drug particle surface deposited. It is known that the addition of salts to colloidal Systems whose physical stability due to the reduction weaken the zeta potential can. Due to the avoidance of salt addition is the achievable physical stability the suspensions prepared by the inventive method clearly improved.

When Polyelectrolyte are suitable both low molecular weight polyelectrolytes or polyions as well as macromolecular polyelectrolytes, for example Polyelectrolytes of biological origin.

The Active substance nanoparticles are coated with at least two polyelectrolyte layers, this means with at least one positive and one negative polyelectrolyte layer (Protective colloid layer) coated. Under Polyelectrolytes are generally polymers with ionically dissociable Groups which are part or substituent of the polymer chain can. The number of dissociable groups in polyelectrolytes is so great that the polymers in the dissociated form (also polyions called) in the liquid Phase of the nanosuspension are soluble. Depending on the type of dissociable groups, a distinction is made with polyelectrolytes polyacids and polybases.

Polyacids split in the dissociation to form polyanions protons from. examples for polyacids are polymethacrylates, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyacrylic acid, alginic acid, carboxymethylcellulose, Dextran sulfate, lignin sulfonic acid, polyvinyl, polyvinyl Chondroitinsulfonsäure and their salts.

usable Biopolymers are, for example, gelatin A and gelatin B, chitosan and its salts, protmainsulfate, hyaluronic acid, polylysic acid, polylactic acid, carrageenans, Pectins, gum arabic, nucleic acids.

Polybases contain protinizable groups capable of generating protons, e.g. B. by reaction with acids to form salt. Examples of polybases with chain or pendant dissociable groups are polyethyleneimine, polyvinylamine and polyvinylpyridine. Polybases are present after their protonation as polycations. A particular advantage of the inventive method is that no separation of excess polyelectrolytes by means of separation processes, such as centrifugation, filtration or dialysis, must take place between the individual coating steps. On the one hand, the required amounts of polymer can be determined in preliminary experiments or calculated accordingly, so that exactly the required amount can be added without requiring a large polymer excess. On the other hand, excess polymers do not disturb the production process. It can then come only to the formation of drug-free complexes from the oppositely charged polymers or protective colloids, but have no negative impact on the Pro have product properties. Since it is possible to dispense with separation steps during the coating of the active substance nanoparticles, the inventive method is particularly suitable for use as a continuous process on a large industrial scale.

Due to the high energy that is introduced into the system during the high-pressure homogenization and the simultaneous particle coating, possibly occurring aggregates of active substance nanoparticles are destroyed immediately. By forming a stable, very high zeta potential by applying the second oppositely charged polymer ( 1 , Item 8), the Wirkstoffanosuspension is very well stabilized and then has a very good physical stability. The zeta potential (in this case only the amount, and not the sign of the charge) of the nanosuspension prepared by the inventive method, measured in water with a conductivity in the range of 50 .mu.S at pH values between 4 to 7, is in the range of 5 mV to 100 mV, preferably in the range from 20 mV to 80 mV, particularly preferably in the range from 30 mV to 60 mV.

by virtue of the high surface charge and the stable adhesion of the polyelectrolyte layer to the drug nanocrystals have both the nanosuspensions themselves and those obtained by drying Powder excellent physical stability Electrolyte influence.

One Another advantage of the inventive method is the possibility of the complete Exclusion of surfactants during of the manufacturing process. In contrast to the prior art could be shown that colloidal drug suspensions, too under complete Exclusion of surfactants produced by high-pressure homogenization are (Examples 1 to 5). This is particularly advantageous if the nanosuspensions prepared by the inventive method be used as medicines or as medicines should be further processed. The exclusion of surfactants is especially for the production of Wirkstoffananosuspensionen for parenteral administration really important.

Example 1:

4.0 micronized ibuprofen were dissolved in 36.0 mL of acidified water (pH 2.5) with the addition of 36.0 mg solid powdered Eudragit E (cationic Protective colloid 1) using an Ultra-Turrax (Jahnke & Kunkel, Germany) 5 seconds at 9500 revolutions per minute dispersed. The resulting dispersion was used in a high pressure homogenizer Micron Lab 40 (APV Systems, Germany) homogenized at 1500 bar at room temperature. To 5 cycles of homogenization were obtained from the obtained metastable crude suspension determines the zeta potential. The value for the zeta potential (measured in water with a pH adjusted to 3.8 and a conductivity set to 50 μS) was: 75.2 mV. After addition of 400 mg of solid, powdery polyacrylic acid (anionic Protective colloid 2) (pH measurement / adjustment to pH 3.8) became the metastable Raw suspension again for 5 cycles in a Micron Lab 40 high pressure homogenizer (APV Systems, Germany) homogenized at 1500 bar at room temperature.

When The final product became a physically stable, homogeneous suspension which have neither a tendency for particle aggregation nor to agglomerate, what with the help of a light microscope approved could be. Subsequently the zeta potential of the suspension (measured in water with a pH adjusted to 3.8 and a conductivity set to 50μS) determined, whose value: -22,7 mV was.

Example 2:

4.0 g of ibuprofen were dissolved in 10.0 mL of ethanol. Liquid nitrogen was added to this solution, resulting in immediate freezing of the drug solution. After the liquid nitrogen had evaporated, the resulting porous matrix consisting of frozen ethanol and ibuprofen with the aid of an Ultra-Turrax (Jahnke & Kunkel, Germany) for 5 seconds at 9500 revolutions per minute in 36.0 mL of acidified water (pH 2, 5) with the addition of 36.0 mg of solid powdered Eudragit E (cationic protective colloid 1) and immediately homogenized in a high-pressure homogenizer Micron Lab 40 (APV Systems, Germany) at 1500 bar at room temperature. After 5 Homogenisationszyklen the zeta potential was determined by the obtained metastable crude suspension. The value for the zeta potential (measured in water with a pH adjusted to 3.8 and a conductivity set to 50 μS) was: 41.6 mV. After addition of 400 mg of solid, powdery polyacrylic acid (Carbopol 980) (anionic protective colloid 2) (pH measurement / adjustment to pH 3.8), the metastable crude suspension was re-run for 5 cycles in a Micron Lab 40 high pressure homogenizer (APV Systems, Germany) at 1500 bar homogenized at room temperature. The end product was a physically stable, homogeneous suspension which had neither a tendency to particle aggregation nor to agglomeration, which in turn could be confirmed by means of a light microscope. Subsequently, the zeta potential of the suspension was again determined (measured in water with a pH adjusted to 3.8 and a conductivity set to 50 μS), the value of which was: -31.3 mV.

Example 3:

4.0 Ibuprofen was dissolved in 10.0 mL of acetone. On this solution was liquid Nitrogen, resulting in immediate freezing of the drug solution. After this the liquid Nitrogen was evaporated, the thereby obtained porous matrix consisting of frozen acetone and ibuprofen with the help of an Ultra-Turrax (Jahnke & Kunkel, Germany) 5 seconds at 9500 revolutions per minute in 36.0 mL of acidified water (pH 2.5) with the addition of 36 mg solid, powdered Eudragit E (cationic Protective colloid 1) and immediately in a high pressure homogenizer Micron Lab 40 (APV Systems, Germany) at 1500 bar at room temperature homogenized. After 5 Homogenisationszyklen was from the obtained metastable crude suspension determines the zeta potential. The value for the Zeta potential (measured in water with a pH adjusted to 3.8 and a conductivity set to 50μS) was: 6.2 mV. After addition of 400 mg of solid, powdery polyacrylic acid (Carbopol 980) (anionic protective colloid 2) (pH measurement / adjustment to pH 3.8), the metastable crude suspension was re-cycled for 5 cycles in a high-pressure homogenizer Micron Lab 40 (APV Systems, Germany) Homogenized at 1500 bar at room temperature. As the final product was obtained a physically stable, homogeneous suspension, which neither a tendency to particle aggregation nor agglomeration showed what again be confirmed with the help of a light microscope could. Subsequently Again, the zeta potential of the suspension was measured in water with a pH adjusted to 3.8 and a conductivity set to 50 μS), its value: -31.9 mV was.

Example 4:

0.4 g of hydrocortisone acetate were dissolved in 10mL dimethylsulfoxide. On this solution then became more fluid Nitrogen, resulting in immediate freezing of the drug solution. The frozen one solution was subsequently in a lyophilization apparatus Christ alpha I-5 (Christ-Apparatebau, Osterode, Germany) Lyophilized for 48 hours. The resulting porous matrix was mixed with 200 mg of solid, powdered Chitosan hydrochloride (cationic protective colloid 1) and added with the help of an Ultra-Turrax (Janke & Kunkel, Germany) 5 seconds 9500 revolutions per minute in 39.2 g of water and instantly dispersed in a high-pressure homogenizer Micron Lab 40 (APV Systems, Germany) Homogenized at 1500 bar at room temperature The after 5 Homogenisationszyklen obtained metastable crude suspension was considered microscopic and microscopic images were taken. The value for the zeta potential (measured in water with a pH adjusted to 6.5 and one conductivity set to 50μS) was: 47.8 mV. After addition of 400 mg of solid, powdered gelatin B (anionic protective colloid 2) (pH measurement / adjustment to pH 7.0) The metastable crude suspension was re-run for 5 cycles in a high pressure homogenizer Micron Lab 40 (APV Systems, Germany) at 1500 bar at room temperature homogenized.

When The final product became a physically stable, homogeneous suspension which have neither a tendency for particle aggregation nor to agglomerate, what with the help of a light microscope approved could be. Subsequently the zeta potential of the suspension was again determined (measured in water with a pH adjusted to 6.5 and a conductivity set to 50 μS), whose Value: -16.9 mV was.

Example 5:

0.4 g of hydrocortisone acetate were dissolved in 10 mL of dimethylsulfoxide. On this solution then became more fluid Nitrogen, resulting in immediate freezing of the drug solution. The frozen one solution was subsequently in a lyophilization apparatus Christ alpha I-5 (Christ-Apparatebau, Osterode, Germany) Lyophilized for 48 hours. The resulting porous matrix was mixed with 200 mg of solid, powdered Chitosan hydrochloride (cationic protective colloid 1) and added with the help of an Ultra-Turrax (Janke & Kunkel, Germany) 5 seconds 9500 revolutions per minute in 39.2 g of water and instantly dispersed in a high-pressure homogenizer Micron Lab 40 (APV Systems, Germany) Homogenized at 1500 bar at room temperature. The after 5 Homogenisationszyklen obtained metastable crude suspension was considered microscopic and microscopic images were taken. The value for the zeta potential (measured in water with a pH adjusted to 6.5 and one conductivity set to 50 μS) was: 47.8 mV. After addition of 400 mg of solid, powdery polyacrylic acid (Carbopol 980) (anionic protective colloid 2) became the metastable crude suspension again for 5 cycles in a Micron Lab 40 high pressure homogenizer (APV Systems, Germany) homogenized at 1500 bar at room temperature. When The final product became a physically stable, homogeneous suspension which have neither a tendency for particle aggregation nor to agglomeration had. Subsequently, the zeta potential was again the suspension is determined (measured in water with a pH adjusted set to 6.5 and a conductivity to 50 μS), its value: -34.2 mV was.

The mean particle diameter, measured by photon correlation spectroscopy (PCS) was 1025.4 nm at a polydispersity index (PI) of 0.294. The volume distributions determined by laser diffractometry (LD) were LD50% 414 nm, LD90% 1977 nm and LD95% 2926 nm.

Claims (10)

Process for the preparation of high-purity active substance particles, characterized in that the active substance comminution by means of high-pressure homogenization and the surface modification of the resulting active substance particles take place simultaneously. The method comprises the following successive steps: a frozen active substance solution or a powder modified by lyophilization of an active substance is processed to a metastable nanosuspension in the presence of a permanently present protective colloid 1 (polyelectrolyte 1) and an outer dispersion phase by means of high pressure homogenization - after reaching the desired Particle size of the active ingredient particles by applying the required number of Homogenisationszyklen, this metastable nanosuspension is added a second, protective colloid 1 (polyelectrolyte 1) oppositely charged, solid protective colloid 2 (polyelectrolyte 2) and homogenized the resulting suspension under again until a finely divided, homogeneous nanosuspension is obtained. Method according to claim 1, characterized in that that, too surface-modified Active ingredient particles, the active substance to be processed is a pharmaceutical Active substance, a cosmetic active substance, an additive for food, a dye or a pigment. Process according to claims 1 to 2, characterized that produced by means of high-pressure homogenization and with at least two oppositely charged polyelectrolyte layers coated and thereby surface-modified Active ingredient particles have a mean particle size below 1000 nm, preferably below 800 nm, and in particular below 400, especially below 100 nm, determined by photon correlation spectroscopy (PCS). Process according to claims 1 to 3, characterized that the energy consumed by a high-pressure homogenizer is used, in particular homogenizers of the piston-gap type (e.g., APV Gaulin, Niro Soavi, Avestin), of the jet-stream type (e.g. Microfluidizer) or a type of French Press (SLM Instruments, Urbana, USA). Process according to claims 1 to 4, characterized that it is produced by means of high-pressure homogenization Active substance nanoparticles used for the purpose of surface modification and stabilization with at least two, at a certain pH of the dispersion medium coated oppositely charged polyelectrolyte layers are, especially about drug nanocrystals. Process according to claims 1 to 5, characterized that the modification of the surface of the drug nanoparticles through a coating consisting of at least one, at a certain pH of the Dispersion medium as polycation polyelectrolytes present and, at a certain pH of the dispersion medium as Polyanion present polyelectrolyte is achieved. Process according to claims 1 to 6, characterized that the polyelectrolytes used are polymethacrylates, Cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid, alginic acid, carboxymethylcellulose, Dextran sulfate, lignin sulfonic acid, polyvinyl, polyvinyl Chondroitinsulfonsäure, Gelatin A, gelatin B, chitosan, protmainsulfate, hyaluronic acid, polylysic acid, polylactic acid, carrageenans, Pectins, gum arabic, nucleic acids, polyethylenimine, polyvinylamine and polyvinylpyridine, and in each case their different salts, free Bases or free acids is. Method according to claim 1, characterized that for the resolution the solvent used Mixtures of water and water completely or partially miscible liquids or hydrophilic liquids, in particular alcohols, preferably methanol, ethanol or isopropanol or other organic solvents, or water immiscible liquids in particular chloroform or dichloromethane, with preferred solvent Water, N-methyl-2-pyrrolidinone, 2-pyrrolidone, dimethylacetamide, ethanol, acetone, chloroform, dichloromethane, Dimethyl sulfoxide, n-propanol, Glycerol, ethylene glycol, dimethylformamide, dimethylacetamide or acids and bases, in particular hydrochloric acid, sulfuric acid, acetic acid, formic acid, triethanolamine, pyridine, Ammonia, optionally with a mixture of two or more of the same is used. A method according to claim 1, characterized in that the resulting surface-modified Wirkstoffananopartikel a Zetapotential, measured in water with a conductivity in the range of 50μS, at pH values between 4 to 7, in the range of 5 mV to 100 mV, preferably in the range of 20 mV to 80 mV, particularly preferably in the range of 30 mV to 60 mV, possess, wherein only the amount of the zeta potential and not its sign is relevant. Process according to claims 1-8, characterized that the obtained nanosuspensions either directly or after separation the Wirkstoffananopartikel, for the purpose of surface modification and stabilization with at least two, at a certain pH of the dispersion medium coated oppositely charged polyelectrolyte layers were, in different forms to the pharmaceutical and cosmetic Application, e.g. in the form of tablets and capsules, creams, ointments or as powders for reconstitution before use become.