Method for producing nanoparticles or microparticles comprising a carrier polymer and one or more biologically active components - Patent Application 20070122997

Abstract

The present invention relates to a method for producing nanoparticles or microparticles containing a carrier polymer and a biologically active ingredient, said method being a solvent emulsion method comprising an organic phase (OP) and an aqueous phase (AP), wherein in the case of an oil-in-water emulsion (O / W), the organic phase (OP) contains the biologically active ingredient dissolved or dispersed therein, or in the case of a water-in-oil emulsion (W1 / O), the aqueous phase (AP) contains the biologically active ingredient dissolved or dispersed therein, and the organic phase (OP) is saturated with a salt-containing aqueous phase (AP) or vice versa.

Description

[Technical field]

[0001] The present invention is in the field of a method for producing nanoparticles or microparticles comprising a carrier polymer and a biologically active component, the method being a solvent emulsion method comprising an organic phase (OP) and an aqueous phase (AP). [Background technology]

[0002] US Patent No. 6,291,013 describes an emulsion-based method for producing microparticles. The method includes a first phase including a solution of an excipient dissolved in a first solvent and a second phase including a second solvent that is at least partially soluble in the first solvent. The extraction phase includes a third solvent that is a non-solvent for the excipient, a solvent for the second phase, and a solvent for the first solvent, the second solvent having a solubility in the extraction phase of about 0.1-25% by weight. The first and second phases are mixed to form an emulsion having microdroplets including the first phase. A portion of the extraction phase in the emulsion is mixed in an amount sufficient to initiate hardening of the microdroplets to form the microparticles, and substantially all of the remaining solvent is evaporated from the microparticles.

[0003] US Patent No. 8,916,196 describes a method for making emulsion-based microparticles. The method comprises passing an organic phase, containing a biologically active component and a polymer, and an aqueous phase through a packed bed apparatus under laminar flow conditions to form an emulsion. In some instances, a solvent from the organic phase is added to saturate the aqueous phase. Hardening of the microparticles is initiated after passing through the packed bed apparatus, and the hardened microparticles are collected.

[0004] WO 2015 / 082562 describes a method for producing nanoparticles and / or microparticles comprising one or more therapeutic agents dispersed in amorphous form in a matrix containing one or more polymers. The (organic) solution comprising one or more therapeutic agents and one or more polymers in dissolved form comprises a solvent mixture of solvent S1 and solvent S2. S1 is fully miscible with water and is a solvent for the one or more therapeutic agents and one or more polymers, and solvent S2 is fully miscible with solvent S1 and partially miscible with water. An aqueous surfactant solution having a volume at least twice the volume of the stirred organic solution is added. By adding a larger volume of the aqueous surfactant solution to a smaller volume of the organic solution, a phase inversion process occurs and nanoparticles and / or microparticles are formed by extracting the organic solvent into the aqueous surfactant solution. Some examples include nanoparticles and / or microparticles based on (meth)acrylate copolymers.

[0005] WO 9933558 and WO 0102087 describe methods for producing aqueous colloidal dispersions of nanoparticles. The methods are emulsion-based, where the organic phase comprises a partially water-soluble organic solvent and an aqueous phase that comprises water. In a preferred embodiment, the partially water-soluble organic solvent may be pre-saturated with water and / or vice versa. Some examples include nanoparticles based on (meth)acrylate copolymers.

[0006] Summary of the Invention Mutual solvent saturation of phases and addition of salt The present invention is based on a solvent emulsion method comprising an organic phase (OP) and an aqueous phase (AP), where these phases are mutually saturated with their solvents and contain pharma- ceutically acceptable salts.

[0007] The organic phase (OP) comprises a partially water-miscible organic solvent or solvent mixture (S1), the organic phase (OP) is saturated with the aqueous phase (AP), the organic phase (OP) further comprises a carrier polymer and, optionally, a biologically active ingredient dissolved or dispersed therein.

[0008] The aqueous phase (AP), in addition to saturation with the solvent or solvent mixture (S1), comprises water and an aqueous solvent or solvent mixture (S2) comprising a pharma- ceutically acceptable salt dissolved therein, an emulsion stabilizer and optionally a biologically active ingredient.

[0009] The background to these mutual saturations and salt additions can be explained, for example, as follows.

[0010] Ethyl acetate, a typical partially water-miscible organic phase (OP) solvent, and water, the (main) aqueous phase (AP) solvent, are mixed, for example, in a 1:1 ratio, and the two partially miscible solvents transfer to each other until they are saturated with each other. In this example, ethyl acetate will account for up to about 3.3% by weight of water (at 20° C.), and water will account for up to about 8.5% by weight of ethyl acetate (at 20° C.). After the saturation end point is reached, the two phases are in a stable state and no inter-exchange of solvents occurs. Such systems are described in WO 9933558 and WO 0102087.

[0011] However, before mixing, the water further contains salts, e.g., 25% by weight of NaCl, and less than about 3.3% by weight of water (20°C) dissolves in the ethyl acetate phase, and less than about 8.5% by weight of ethyl acetate (20°C) dissolves in the water phase due to the high ionic strength of the phases. Furthermore, a small amount of salt migrates from the water phase to the ethyl acetate phase. After mixing both phases, they form mutually saturated phases. In the presence of an emulsion stabilizer, a stable emulsion can be formed in which little exchange of solvent from one phase to the other occurs. This makes the process of emulsion formation more reliable and reproducible. Thus, ideal conditions are provided for the formation of nanoparticles or microparticles from the encapsulated carrier polymer and biologically active components.

[0012] This situation changes dramatically when excess water is added in the form of an extraction phase (EP). Salts migrate from the ethyl acetate phase to the aqueous phase, which in turn migrates more water from the aqueous phase to the ethyl acetate phase. The diluted aqueous phase can again take up more ethyl acetate. This migration of salts and solvents actively promotes the initial hardening of the nano- or microparticles.

[0013] The addition of salts to the aqueous phase (AP) and the mutual solvent saturation of the organic phase (OP) with the aqueous phase (AP) containing salts is particularly advantageous for biologically active components present in the organic phase (OP), preferably components selected from BCS-class II (and IV), since their solubility in the organic phase is significantly increased. Thus, overall, less organic phase (OP) and, as a result, less aqueous phase (AP) is required to form micro- or nanoparticles on an industrial production scale, less aqueous extraction phase (EP) and less liquid for washing. This reduces the amount of wastewater liquid, resulting in fewer environmental and recycling problems, thereby reducing the overall costs.

[0014] Detailed Description of the Invention 1. The present specification discloses a method for producing nanoparticles or microparticles comprising a carrier polymer and a biologically active ingredient, the method being a solvent emulsion method comprising an organic phase (OP) and an aqueous phase (AP), in the case of an oil-in-water emulsion (O / W), the organic phase (OP) containing the biologically active ingredient dissolved or dispersed therein, and in the case of a water-in-oil emulsion (W1 / O), the aqueous phase (AP) containing the biologically active ingredient dissolved or dispersed therein, the method comprising the steps of: a) providing an organic phase (OP) comprising a partially water-miscible organic solvent or solvent mixture (S1), said organic phase (OP) being saturated with an aqueous phase (AP), said organic phase (OP) comprising a carrier polymer and, optionally, a biologically active ingredient dissolved or dispersed therein, b) providing an aqueous phase (AP) comprising an aqueous solvent or solvent mixture (S2) containing water and a pharma- ceutically acceptable salt dissolved therein, said salt-containing aqueous phase being further saturated with the solvent or solvent mixture (S1) of said organic phase (OP) and containing an emulsion stabilizer and optionally a biologically active ingredient dissolved or dispersed therein; c) mixing said organic phase (OP) with said aqueous phase (AP) to obtain an oil-in-water emulsion (O / W) or a water-in-oil emulsion (W1 / O); d) in case of a water-in-oil emulsion (W1 / O), adding an excess of additional aqueous phase (AP) to obtain a water-in-oil-in-water emulsion (W1 / O / W2), e) removing the organic solvent or solvent mixture (S1) from the oil-in-water emulsion (O / W) or from the water-in-oil-in-water emulsion (W1 / O / W2) by evaporation and / or extraction to promote the formation of nanoparticles or microparticles comprising the carrier polymer and the biologically active ingredient in the remaining aqueous suspension; f) separating said nanoparticles or said microparticles from said aqueous suspension.

[0015] Step a) and step b): Providing an organic phase (OP) and an aqueous phase (AP) The organic phase (OP) and the aqueous phase (AP) can be provided as follows: The aqueous phase (AP) comprises, in addition to saturation with the organic solvent or solvent mixture (S1), an aqueous solvent or solvent mixture (S2) which comprises water and a pharma- ceutically acceptable salt dissolved therein. Usually, the aqueous solvent or solvent mixture (S2) of the aqueous phase (AP) comprises 98% by weight or more of water. However, small amounts, usually up to 2% by weight, of partially or completely water-miscible organic solvents can be present without impairing the advantageous effects of the invention. Usually, the aqueous phase comprises water as the only solvent (100%).

[0016] If an oil-in-water emulsion (O / W) is intended to be prepared in step c), the organic phase (OP) has dissolved or dispersed therein the biologically active ingredient. In this case, the biologically active ingredient present in the organic phase (OP) is preferably selected from BCS-classes II and IV (Biopharmaceutical Classification System according to Prof. Amidon; Amidon et al., Pharm. Res. 12, 413-420 (1995), class II: high permeability, low solubility, class IV: low permeability, low solubility).

[0017] The BCS-classes (Biopharmaceutical Classification System) are well known to those skilled in the art in the pharmaceutical field. The addition of salts to the aqueous phase (AP) and to the mutual solvent saturation of the organic phase (OP) with the aqueous phase (AP) containing salts is particularly advantageous for biologically active ingredients from BCS-classes II (and IV) due to increased solubility in the organic phase. Thus, less organic phase (OP) and, as a result, less aqueous phase (AP), less aqueous extraction phase (EP) and less liquid for washing are required to form micro- or nanoparticles on an industrial production scale. This leads to fewer environmental and recycling problems, thereby reducing the amount of wastewater liquids and thus reducing the overall costs.

[0018] If a water-in-oil emulsion (W1 / O) is intended to be prepared in step c), the aqueous phase (AP) comprises the biologically active ingredient dissolved or dispersed therein. In this case, the aqueous phase (AP) may preferably comprise the biologically active ingredient in an amount of 0.1-40% by weight, more preferably 0.5-25% by weight. The biologically active ingredient present in the aqueous phase (AP) is preferably selected from BCS-classes I and III (biopharmaceutical classification system according to Prof. Amidon; Amidon et al., Pharm. Res. 12, 413-420 (1995), class I: high permeability, high solubility, class III: low permeability, high solubility).

[0019] The aqueous phase (AP) and organic phase (OP) can be prepared as follows.

[0020] The pharma- ceutically acceptable salt is added to an aqueous solvent or solvent mixture (S2) containing water and mixed until the salt is completely dissolved. A partially water-miscible organic solvent or solvent mixture (S1) is then added to the aqueous solvent or solvent mixture (S2) containing the salt and mixed (stirred, shaken or otherwise vigorously mixed) for about 10 seconds to about 10 minutes. In this way, a cloudy emulsion is produced. Mixing is stopped and the cloudy emulsion separates into a stable two-phase system after a few minutes (usually 1-10 minutes).

[0021] The upper (light) phase of the two-phase system is usually a solvent or solvent mixture (S1), which is saturated with a salt-containing aqueous solvent or solvent mixture (S2). The lower (heavy) phase of the two-phase system is usually a salt-containing aqueous phase, which is saturated with a solvent or solvent mixture (S1). The two phases are then separated from each other.

[0022] The (organic) phase comprising a solvent or solvent mixture (S1) saturated with an aqueous solvent or solvent mixture (S2) containing a salt is separated from the two-phase system and the carrier polymer, and optionally the biologically active ingredient is dissolved or dispersed therein. Preferably, the carrier polymer and the biologically active ingredient are soluble therein. Thus, an organic phase (OP) is provided, comprising a partially water-miscible organic solvent or solvent mixture (S1), saturated with an aqueous solvent or solvent mixture containing a salt (S2), and further comprising a carrier polymer and optionally a biologically active ingredient.

[0023] The (aqueous) phase comprising an aqueous solvent or solvent mixture (S2) containing a salt saturated with a solvent or solvent mixture (S1) is separated from the two-phase system, and the emulsion stabilizer polymer and optionally the biologically active ingredient are dissolved or dispersed therein. Preferably, the emulsion stabilizer and the biologically active ingredient are soluble therein. Thus, an aqueous phase (AP) is provided, comprising an aqueous solvent or solvent mixture (S2) containing a salt, saturated with a solvent or solvent mixture (S1), and further comprising an emulsion stabilizer and optionally a biologically active ingredient.

[0024] Step c): Mixing of oil-in-water emulsion (O / W) or water-in-oil emulsion (W1 / O) Step c) can be carried out in two alternative ways: by mixing the organic phase (OP) and the aqueous phase (AP) to obtain an oil-in-water emulsion (O / W) or by obtaining a water-in-oil emulsion (W1 / O).

[0025] To obtain an oil-in-water emulsion (O / W), the aqueous phase (AP) should be mixed with the organic phase (OP) in excess volume. The excess volume of the aqueous phase (AP) may be, for example, 1.5 to 6 times higher than the volume of the organic phase (OP). In this case, the aqueous phase (AP) becomes the continuous phase containing dispersed droplets of the organic phase (OP). The emulsion stabilizer contained in the aqueous phase (AP) helps to form a stabilized emulsion.

[0026] To obtain a water-in-oil emulsion (W1 / O), the organic phase (OP) should be mixed with the aqueous phase (AP) in excess volume. The excess volume of the organic phase (OP) may be, for example, 1.5 to 6 times higher than the volume of the aqueous phase (AP). In this case, the organic phase (OP) becomes the continuous phase containing the dispersed droplets of the aqueous phase (AP). The emulsion stabilizer contained in the aqueous phase (AP) again serves to form a stabilized emulsion.

[0027] The mixing in step c) should preferably be carried out vigorously at high speed and / or high agitation. The mixing in step c) can be carried out using a static mixer, agitated or pulsed extraction column, a bead-packed column, a Pall-ring or Raschig-ring packed column, a rotor-stator mixing system, a baffled reactor, a vibrating baffle reactor, a continuous baffle reactor, a laminar jet-cutting device, a cross-flow membrane emulsifier, a premix-membrane emulsifier, a microfluidic device (working on co-flow, tangential cross-flow or flow-focusing principles), a swirling cross-flow membrane emulsifier or a microstructured membrane emulsifier, an ultrasonic device, a stirred vessel equipped with an agitator. During mixing, microdroplets are formed.

[0028] The mixing in step c) may be carried out under laminar flow conditions.

[0029] The mixing in step c) may be carried out under laminar flow conditions in a packed bed apparatus.

[0030] The mixing in step c) can be carried out as turbulent mixing.

[0031] Process d): Water-in-oil-in-water emulsion (W1 / O / W2) If in step c) a water-in-oil emulsion (W1 / 0) is formed, in step d) an excess of further aqueous phase (AP) is added and mixed with the water-in-oil emulsion (W1 / O). The further aqueous phase (W2) can have approximately the same or the same composition as above, except for any biologically active ingredients (present in W1 but usually not in W2). The emulsion stabilizers may be the same as those outlined above for the aqueous phase (AP). Mixing can be carried out in the same manner as in step c). In this way, a water-in-oil-in-water emulsion (W1 / O / W2) is obtained (step d).

[0032] Step e): Removal of the organic solvent or solvent mixture (S1) from the emulsion In step e), the organic solvent or solvent mixture (S1) is removed by evaporation and / or extraction from the oil-in-water emulsion (O / W) from step c) or from the water-in-oil-in-water (W1 / O / W2) emulsion from step d), promoting the formation of nanoparticles or microparticles comprising the carrier polymer and the biologically active component in the remaining aqueous suspension.

[0033] Evaporation of emulsifying solvent The nanoparticles can be obtained in step (e) from the emulsion of step c) or step d) by evaporating the emulsification solvent, for example by application of a vacuum.

[0034] The process of emulsification solvent evaporation is well known to those skilled in the art of pharmacy and herbal medicine. Most of the water or other solvent from the aqueous phase can be removed from the emulsion by evaporation. This results in the formation of nanoparticles or microparticles that contain the carrier polymer and the biologically active ingredient in the remaining aqueous suspension.

[0035] For further purification, the nanoparticles or microparticles containing the biologically active ingredient are obtained from the aqueous suspension remaining in step e) by further conventional filtration or centrifugation, washing, and / or evaporation and / or drying, etc.

[0036] Emulsified Solvent Extraction / Aqueous Extraction Phase (EP) The nanoparticles can be obtained in step e) from the emulsion of step c) or d) by emulsification solvent extraction.

[0037] For this purpose, an aqueous extraction phase (EP) can be used. The aqueous extraction phase can preferably contain 80% by weight or more (80-100% by weight) of water. Small amounts, usually 10% by weight or less, of partially or completely water-miscible organic solvents, such as ethanol, acetone, isopropanol or any mixtures thereof, can be present without impairing the advantageous effects of the present invention. Most preferably, the aqueous extraction phase (EP) contains water as the only solvent (100%). The extraction phase (EP) can further optionally contain 0-10% by weight, preferably 0.1-5% by weight, of an emulsion stabilizer, such as polyvinyl alcohol (PVA) or polysorbate. Usually, the extraction phase (EP) does not contain an emulsion stabilizer.

[0038] In step e), the emulsion from step c) or d) can be mixed with an excess of aqueous extraction phase (EP) to remove the solvent or solvent mixture (S1) from the emulsion and form a binding phase resulting in the formation of nanoparticles or microparticles of a mixture of biologically active pharmaceutical ingredient and carrier polymer. The excess of aqueous extraction phase (EP) can be 2 to 150 times, preferably 5 to 70 times, the volume of the emulsion. The addition of aqueous extraction phase (EP) transfers at least a portion, preferably 95% by weight or more, of the solvent or solvent mixture (S1) from the microdroplets formed in step c) or d) into the aqueous phase, thereby initiating the formation and hardening of nanoparticles or microparticles containing the biologically active ingredient contained therein. After removal of the solvent or solvent mixture (S1), for example by simple stirring and / or application of a vacuum, an aqueous suspension remains containing nanoparticles or microparticles with encapsulated biologically active ingredient.

[0039] Process f) For further purification, the nanoparticles or microparticles with contained biologically active components can be further obtained from the aqueous suspension of step e) by conventional filtration or centrifugation, washing and / or evaporation and / or drying, etc.

[0040] combination A combination of emulsification solvent extraction, preferably with a reduction in the excess amount of aqueous extraction phase (EP), and evaporation of the emulsification solvent can be advantageously used to reduce the amount of wastewater.

[0041] Nanoparticles or Microparticles The nanoparticles or microparticles can be obtained according to the methods disclosed herein.

[0042] Nanoparticles or microparticles can be obtained according to the methods disclosed herein for use in oral or parenteral dosage forms.

[0043] The nanoparticles or microparticles can have a particle size D50 in the range of about 500 nm to 1000 μm.

[0044] The nanoparticles or microparticles may be microparticles having a particle size D50 in the range of 50 to 500 μm.

[0045] The nanoparticles or microparticles may be microparticles with a particle size D50 in the range of 80-300 μm.

[0046] The method of determining particle size D50 is well known to those skilled in the art.Particle size D50 can be determined, for example, by laser diffraction method.Laser diffraction method is well known to those skilled in the art.Laser diffraction method is described in the United States Pharmacopoeia (USP), for example in USP36 (USP) Chapter 429, or the European Pharmacopoeia, for example in the European Pharmacopoeia 7.0 (EP) Chapter 2.9.31.

[0047] Also disclosed herein are nanoparticles or microparticles according to the invention in oral or parenteral dosage forms for use in methods of treatment of the human or animal body by therapy or diagnosis.

[0048] Particle size measurement The particle size determination can be carried out according to the United States Pharmacopoeia 36 (USP) Chapter 429 or as described in the European Pharmacopoeia 7.0 (EP) Chapter 2.9.31. The particle size distribution was determined using a laser scattering device (e.g., Malvern Analytical GmbH, Mastersizer 2000 model with MV Hydro medium volume automatic dispersion unit). The laser diffraction method is based on the phenomenon of scattering light in all directions with an intensity pattern that depends on the size of the particle. A representative sample dispersed at a suitable concentration in a suitable liquid or gas is passed through the beam of a monochromatic light source, usually a laser. The light scattered by the particles at various angles is measured by a multi-element detector and the numerical values ​​related to the scattering pattern are recorded for subsequent analysis. The numerical values ​​of scattering are then converted using appropriate optical models and mathematical procedures to obtain the percentage of the total volume of the discrete number of size classes that form the volumetric particle size distribution (e.g., D50 describes the particle size that corresponds to 50% of the cumulative undersize distribution).

[0049] Karl Fischer method / Coulometric titration The determination of water content can be carried out according to the United States Pharmacopoeia 36 (USP) Chapter 921, Method Ic, and the European Pharmacopoeia 7.0 (EP) Chapter 2.5.32. The Karl Fischer (KF) reaction is used for the coulometric determination of water. However, iodine is not added in the form of a volumetric solution, but is produced in an iodide-containing solution by anodic oxidation. In the KF oven method, the test substance is heated in an oven in a closed container. The water obtained from the sample is transported into the titration cell with the help of a flow of dry nitrogen gas and is usually determined by coulometric KF titration. As a reference, a standard lactose sample is utilized. Since the sample itself remains in the container and only water enters the titration cell, secondary reactions and matrix effects can be excluded. As a working medium, the reagent HYDRANAL (R) MEDIUM K and HYDRANAL (R) - Composite 5K can be used.

[0050] Oil-in-water emulsion (O / W) The emulsion of step c) may be an oil-in-water emulsion (O / W) in which an organic phase (OP) is dispersed in an aqueous phase (AP). In this case, the organic phase (OP) is the dispersed phase (internal oil phase) and the aqueous phase (AP) is the continuous phase. To produce an oil-in-water emulsion (O / W), the volume of the aqueous phase (AP) should be higher than the volume of the organic phase (OP), for example 1.5 to 5 times higher. The biologically active ingredient is present in the internal (dispersed) oil phase.

[0051] Water-in-oil emulsion (W1 / O) The emulsion of step c) may be a water-in-oil emulsion (W1 / O), in which the aqueous phase (AP) is the dispersed phase (internal aqueous phase) and the organic phase (OP) is the continuous phase. The water-in-oil emulsion (W1 / O) is usually further processed by mixing with an aqueous phase (W2) to obtain a water-in-oil-in-water emulsion (W1 / O / W2). To produce a water-in-oil emulsion (W1 / O), the volume of the organic phase (OP) should be higher than the volume of the aqueous phase (AP), for example 1.5-5 times higher. The biologically active ingredient is present in the internal (dispersed) aqueous phase (W1).

[0052] Carrier Polymer The carrier-polymer is contained in the organic phase (OP). The carrier polymer can be selected from (meth)acrylate copolymers, polyorthoesters, polylactides, polydioxanone, polycaprolactone, poly(trimethylene carbonate), polyglycolide, poly(lactide-co-glycolide) (PLGA), poly(lactide-co-caprolactone), poly(lactide-co-trimethylene carbonate), poly(lactide-co-polyethylene glycol), and any blends thereof.

[0053] The carrier polymer may be selected from cellulose ethers or cellulose esters, preferably ethyl cellulose, cellulose acetate phthalate (CAP), cellulose acetate, hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMC AS), and mixtures thereof.

[0054] The carrier polymer may be selected from collagen or collagen-like proteins.

[0055] Preferably, the carrier polymer is soluble in the organic phase (OP) but insoluble in the aqueous phase (AP) and, if applicable, insoluble in the aqueous extraction phase (EP).

[0056] The term "carrier polymer" is intended to include a single carrier polymer as well as mixtures or blends (in the sense of "at least one" or "one or more" carrier polymers) of carrier polymers.

[0057] A preferred carrier polymer may be a copolymer from polymerized units of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

[0058] The carrier polymer may be a copolymer of polymerized units of 40-60% by weight dimethylaminoethyl methacrylate, 20-30% by weight butyl methacrylate and 20-30% by weight methyl methacrylate, and the monomers may be added up to 100%.

[0059] Biologically Active Ingredients The term "biologically active ingredient" is intended to include a single biologically active ingredient as well as mixtures of biologically active ingredients (in the sense of "at least one" or "one or more" biologically active ingredients).

[0060] In the case of an oil-in-water emulsion (O / W), the organic phase (OP) contains the biologically active ingredient dissolved or dispersed therein. The organic phase (OP) may contain the biologically active ingredient in an amount preferably of 0.1 to 40% by weight, more preferably 0.5 to 25% by weight.

[0061] The biologically active ingredient is present in the organic phase (OP) and is preferably selected from BCS-classes II and IV (Biopharmaceutical Classification System according to Prof. Amidon; Amidon et al., Pharm. Res. 12, 413-420 (1995), class II: high permeability, low solubility, class IV: low permeability, low solubility). The BCS-classes (Biopharmaceutical Classification System) are well known to those skilled in the pharmaceutical field. The addition of salts to the aqueous phase (AP) and the mutual solvent saturation of the organic phase (OP) with the salt-containing aqueous phase (AP) is particularly advantageous for biologically active ingredients used in the organic phase (OP), preferably those selected from BCS-classes II and IV, due to their increased solubility in the organic phase. Thus, overall, less organic phase (OP) and, as a result, less aqueous phase (AP), less aqueous extract phase (EP) and less liquid for washing are required to form micro- or nanoparticles on an industrial production scale. This reduces the amount of wastewater liquid, thus creating fewer environmental and recycling issues, thereby reducing overall costs.

[0062] In the case of a water-in-oil emulsion (W1 / O), the aqueous phase (AP) contains the biologically active ingredient dissolved or dispersed therein. The aqueous phase (AP) may contain the biologically active ingredient in an amount of preferably 0.1-40% by weight, more preferably 0.5-25% by weight. The biologically active ingredient present in the aqueous phase (AP) is preferably selected from (Biopharmaceutical Classification System by Prof. Amidon; Amidon et al., Pharm. Res. 12, 413-420 (1995), Class I: Highly permeable, highly soluble, Class III: Lowly permeable, highly soluble).

[0063] The biologically active ingredients are 17-β-estradiol, actretin, albendazole, albuterol, alendronate, alprostadil, amidoline, aminoglutemide, amiodarone, amphotericin, amprenavir, aripiprazole, asenapine, atazavir, atorvastatin, atovaquone, baclofen, beclomethasone, benezepril, benzocaine, benzonatate, betacarotene, betamethasone, bexarotene, bicaltanide, biperiden, bisacodyl, bleomycin, bosentan, buprenorphine, budesonide, bupropion, busulfan, butenafine, carphydione, calciprotiene, calcitriol, calcitrol, camptothecan, candesartan, capsaicin, carbamazepine, carmustine, candesartan, Capsaicin, carbamazepine, carmustine, carvedilol, cefuroxime, celecoxib, ceribistatin, chloramphenicol, chlordiazepoxide, chlorpheniramine, chlorpropamide, chlorthiazide, cholecalciferol, cilazapril, cilostazol, cimetidine, cinaridin, ciprofloxacin, cisapride, cytolysine, clarithromycin, clemastine, clioquinol, clodronic acid, clofazimine, clomipramine, clopidrogel, clotrimazole, codeine, cortisol, curcurmin, cyclosporine, cytarabine, danazol, dantrolene, darunavir, dasatinib, diferasirox, dexamethasone, dexlopheniramine, dexlansoprazole, diazepam, diclofenac, dicumarol, digoxin. Dihydroepiandrosterone, dihydroergotamine, dihydrotachysterol, diltiazem, dimethindene, dipyridamole, dirithromycin, disulfiram, docetaxel, donepezil, doxerciferol, doxorubicin, dronabinol, droperidol, droxetine, durastride, efavirenz, elbasvir, elinogrel, eprosartan, ergocalciferol, ergotamine, erlotinib, essential fatty acids, estradiol, etidronic acid, etodolac, etoposide, etravirine, everolimus, exemestane, ezetimibe, famotidine, felodipine, fenofibrate, fenoldopamine,Fentanyl, fexofenadine, finasteride, floctafenine, fluconazole, fluogracil. Flurbiprofen, flutamide, fluvastatin, frovatriptan, fulvestrant, furazolidone, furosemide, gabapentin, gemfibrozil, glafenine, glibenclamide, glimepiride, glipizide, grizoprevir, griseofulvin, halofantrine, haloperidol, hydrocortin, ibuprofen, imatinib, indomethacin, irbesartan ... Ibuprofen, ibuprofarin, ibuprofamine, ibuprofamine, ibuprofamine, ibuprofamine, ibupropamine, indomethacin, irbesartan, irinotecan, isotretinoin, itraconazole, ivacaftor, ivermectin, ketoconazole, ketoprofen, ketorolac, lamotrigine, lansoprazole, ledipasvir, leflunomide, lidocaine, linezolid, lisinopril, lonidamine, loperamide, lopinavir, rotagene, rotadyne, losartan , l-thritol, lumacaftor, lumefantrine, medroxyprogesterone, mefenamic acid, mefepristone, mefloquine, megestrol acetate, melphalan, mesalazine, methadone, mesocarbamyl, methotrexate, methoxsalen, mesoprolol, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxanthone, modafinil, moexipril, montelukast, morphine, mycophenolate, nabilone, nabumetone, nalbuphine, naloxone, naproxen, narcolepsy putan, nelfinavir, nifedipine, nilotinib, nilsolidipine, nirutanic acid, nirvadapine, nimodipine, nimotiv, nitlendipine, nitrofurantoin, nizatidine, oestradiol, olanzapine, olmesartan, ombitasvir, omeprazole, ondansetron, oplevuquin, oridonin, oxaprozin, oxytetracycline, paclitaxel, pamidronic acid, paracetamol, paricalcitol, paritaprevir, paroxetine, pemethotrexed, penazosin, perindopril,Phenytoin, pioglitazone, piroxicam, pizotifen, posaconazole, prasugrel, pravastatin, prednisolone, prednisone, probucol, progesterone, propafenone, profol, pyridostigmine, quetiapine, rabeprazole, raloxifene, raltegravir, ramipril, ribamipide, rifocoxib, repaglinide, riboflavin, rifabutin. Rifapentine, rimexion, risedronate, risperidone, ritanovir, rivarxaban, rivastigmine, rizatriptan, rosiglitazone, rosuvastatin, saquinavir, selegiline, sertraline, sevelamer, sibutramine, sibutramine base, sildenafil, simvastatin, sirolimus, sitagliptin, sofosbuvir. sorafenib, spirapril, spironolactone, sulfathiazole, sumatriptan, sunitinib, tacrine, tacrolimus, tadalafil, tamoxifen, tamsulosin, targretin, tazarotene, telapirevir, telmisartan, teniposide, tenokilicam, terazosin, terbinafine, terbutaline, tetracycline, tetrahydrocannabinol Theophylline, tiagabine, ticagrelor, ticlidpine, tiludronic acid, tirofibran, tizanidine, tocopherol acetate, tolbutamide, tolvaptan, topiramat, topotecan, torcetrabib, trebifen, tramadol, trandolapir, tretinoin, troglitazone, trovafloxacin, valproic acid, valrubicin, valsartan, velpatasvir, vemurafenib, venlafaxine, verapamil, veltorphine, viadol, vigabatrin, vildagliptin, vitamin A, vitamin D, vitamin K, vitamin Q10, vorapaxar, voriconazole, zafelkast, zileiton, ziprazidone, zithromycin, zoledronic acid, zolmitriptan, zolpidem, zopiclone, or, where applicable, a pharma- ceutically acceptable salt form thereof.

[0064] Preferably, the biologically active ingredient is soluble or dispersible in the organic phase (OP) and insoluble in the aqueous phase (AP) and, if applicable, insoluble in the aqueous extract phase (EP).

[0065] Pharmaceutically acceptable salts The pharma- ceutically acceptable salt may be an organic salt or an inorganic salt. The solubility in water is preferably about 1-50% by weight at 25°C. The pharma- ceutically acceptable salt preferably has essentially no surfactant properties. Inorganic salts are preferred.

[0066] The aqueous phase (AP) may contain about 1 to 50% by weight of a pharma- ceutically acceptable salt.

[0067] The aqueous phase (AP) preferably contains about 2 to 40% by weight of a pharma- ceutically acceptable salt.

[0068] The aqueous phase (AP) preferably contains about 4 to 30% by weight of a pharma- ceutically acceptable salt.

[0069] The pharma- ceutically acceptable salt is preferably selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, magnesium chloride, magnesium sulfate, calcium chloride, sodium acetate, potassium acetate, magnesium acetate, ammonium acetate, ammonium sulfate and ammonium chloride, and mixtures thereof.

[0070] The term "pharmaceutically acceptable salt" is intended to include a single pharmaceutically acceptable salt, but also encompasses mixtures of pharmaceutically acceptable salts (one or more pharmaceutically acceptable salts). Pharmaceutically acceptable means that the salt is approved by an authority for use in medicinal applications.

[0071] Emulsion Stabilizers Since emulsions are thermodynamically unstable systems, the addition of emulsion stabilizers in the aqueous phase (AP) is advantageous.

[0072] The emulsion stabilizer may be an emulsifier or a surfactant. The aqueous phase (AP) may contain about 0.001 to 5% by weight, preferably about 0.1 to 2.5% by weight, of the emulsion stabilizer. The aqueous phase (AP) may contain glyceryl monooleate, medium chain monoglyceride, diglyceride, caprylic acid, caprate, glyceryl monocaprylate, propylene glycol monocaprylate, oleyl polyoxyl-6-glyceride, lineoyl polyoxyl-6-glyceride, lauroyl polyoxyl-6-glyceride, propylene glycol monolaurate, diacetylated monoglyceride, polyoxyl-23-lauryl ether ... oleyl-2 oleyl ether, polyoxy-35 hydrogenated castor oil, polyoxy-40 hydrogenated castor oil, lauroyl polyoxyl-32 glyceride, stearoyl polyoxyl-32 glyceride, polyoxyl-15 hydroxystearate, poloxamer 124, poloxamer 188 (triblock copolymer), poloxamer 407, polyoxyethylene, polyoxypropylene, caprylocaproyl polyoxyl-8 glyceride, polyoxyl- The emulsion stabilizer may be selected from the group consisting of polyoxyethylene-(20)-sorbitan monolaurate, polyoxyethylene-(40)-sorbitan monopalmitate, polyoxyethylene-(80)-sorbitan monooleate, polyvinyl alcohol, polysorbates and / or polyoxyethylene fatty acid alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycol, polypropylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene polyoxypropylene copolymers (poloxamers), polaxamine, glyceryl esters and polyvinylpyrrolidone, or combinations thereof. Polyvinyl alcohol and polysorbates are preferred.

[0073] Organic solvent or solvent mixture (S1) The organic phase (OP) comprises a partially water-miscible organic solvent or solvent mixture (S1), a carrier polymer and any biologically active ingredients dissolved or dispersed therein, the organic phase (OP) being saturated with the aqueous phase (AP).

[0074] The organic solvent or solvent mixture (S1) preferably has a miscibility in water at 25°C of 0.1 to 35% by weight.

[0075] The solvent or solvent mixture (S1) may be 1-butanol, 1-methoxy-2-propanyl acetate, 1-pentanol, 2,2,5-tetramethyltetrahydrofuran, 2,2-dimethyltetrahydrofuran, 2,5-dimethylfuran, 2-ethyl-1-butanol, 2-methylbutan-2-ol, 2-methylpentan-1-ol, 2-methylpentan-2-ol, 2-methylpropan-1-ol, 3-methoxypropyl acetate, 3-hexanol, 3-methoxypropyl acetate, 3-methyl ... Acetate, 3-methoxy-1-butanol, 3-methoxy-3-methyl-1-butanol, 3-methylbutan-1-ol, 3-methylbutan-2-ol, 3-methyl-2-pentanol, 4-methyl-1,3-dioxolan-2-one, 4-methyl-2-pentanol, 4-methylcyclohexanone, 5-methyldihydro-2(3H)-furanone, acetaldehyde diethyl acetal, acetaldehyde dimethyl acetal, benzoic acid methyl ester, benzyl alcohol, butadiene non, butyl 2-hydroxy-2-methylpropanoate, butyl acetate, butyl formate, chloroform, cyclohexanol, cyclopentanol, cyclopentanone, dichloromethane, diethyl carbonate, diethyl ether, diethyl ketone, di-isopropyl ether, dimethyl carbonate, ethyl acetate, ethyl butyrate, ethyl formate, ethyl-3-oxobutanoate, gamma-valerolactone, hexane-2-ol, iso-butyl acetate, iso-butyl formate, iso-propyl acetate, isopropyl butyrate, isopropyl methyl ketone, isopropyl methyl ketone, malonic acid diethyl ester, malonic acid dimethyl ester, methyl acetate, methyl butyrate, methyl formate, methyl propyl ketone, methyl-tetrahydrofuran, methyl-iso-butyl ketone, methyl propyl ketone, pentan-2-ol, pentan-3-ol, propyl acetate, t-butyl methyl ether, toluene, or a mixture of two or more thereof.

[0076] Aqueous solvent or solvent mixture (S2) The aqueous solvent or solvent mixture (S2) comprises 98% by weight or more of water. However, small amounts, usually up to 2% by weight, of partially or completely water-miscible organic solvents can be present without impairing the advantageous effects of the invention. Usually, the aqueous phase (AP) comprises water as the only solvent (100%).

[0077] Mutual solvent and salt saturation of each phase The mutual solvent and salt saturation process is illustrated as an example. For example, when ethyl acetate, a typical partially water-miscible organic phase (OP) solvent, and water, the (major or only) aqueous phase (AP) solvent, are mixed, the partially miscible solvents will transfer between each other until they are saturated with each other. In this example, ethyl acetate will contain about 3.3% water (20° C.) by weight, and water will contain about 8.5% ethyl acetate (20° C.) by weight. After saturation has been reached to the end point, the two phases are in a stable state and no further inter-exchange of solvents will occur.

[0078] Before mixing, the water further contains salts, and less than about 3.3% by weight of water (at 20° C.) dissolves in the ethyl acetate phase, and less than about 8.5% by weight of ethyl acetate (at 20° C.) dissolves in the water phase due to the high ionic strength of the phases. In addition, a small amount of salt migrates from the water phase to the ethyl acetate phase. After mixing, both phases may again form mutually saturated phases, and in the presence of an emulsion stabilizer, a stable emulsion may be formed in which little exchange of solvent from one to the other occurs. Thus, certain conditions are provided for the formation of nanoparticles or microparticles from the encapsulated carrier polymer and biologically active ingredient. This allows the formation of nanoparticles or microparticles to be performed more reliably and reproducibly.

[0079] When excess water is added in the form of an extraction phase (EP), the situation changes dramatically. Salts migrate from the ethyl acetate to the aqueous phase, which allows more water to migrate to the ethyl acetate phase. The diluted aqueous phase can pick up the ethyl acetate again. This migration of salts and solvents promotes the initial formation and hardening of nano- or microparticles.

[0080] Pharmaceutical or Nutraceutical Dosage Forms The present invention also discloses pharmaceutical or nutraceutical dosage forms comprising the nanoparticles or microparticles. 1. A method for producing nanoparticles or microparticles containing a carrier polymer and a biologically active ingredient, said method being a solvent emulsion method comprising an organic phase (OP) and an aqueous phase (AP), in the case of an oil-in-water emulsion (O / W), said organic phase (OP) containing said biologically active ingredient dissolved or dispersed therein, and in the case of a water-in-oil emulsion (W1 / O), said aqueous phase (AP) containing said biologically active ingredient dissolved or dispersed therein, said method comprising the steps of: a) providing an organic phase (OP) comprising a partially water-miscible organic solvent or solvent mixture (S1), said organic phase (OP) being saturated with an aqueous phase (AP), said organic phase (OP) comprising a carrier polymer and, optionally, a biologically active ingredient dissolved or dispersed therein, b) providing an aqueous phase (AP) comprising an aqueous solvent or solvent mixture (S2) containing water and a pharma- ceutically acceptable salt dissolved therein, said salt-containing aqueous phase being further saturated with the solvent or solvent mixture (S1) of said organic phase (OP) and containing an emulsion stabilizer and optionally a biologically active ingredient dissolved or dispersed therein; c) mixing said organic phase (OP) with said aqueous phase (AP) to obtain an oil-in-water emulsion (O / W) or a water-in-oil emulsion (W1 / O); d) in case of a water-in-oil emulsion (W1 / O), adding an excess of additional aqueous phase (AP) to obtain a water-in-oil-in-water emulsion (W1 / O / W2), e) removing the organic solvent or solvent mixture (S1) from the oil-in-water emulsion (O / W) or from the water-in-oil-in-water emulsion (W1 / O / W2) by evaporation and / or extraction to promote the formation of nanoparticles or microparticles comprising the carrier polymer and the biologically active ingredient in the remaining aqueous suspension; f) separating said nanoparticles or said microparticles from said aqueous suspension. 2. The method according to item 1, wherein the nanoparticles or microparticles are separated from the aqueous suspension in step f) by filtration or centrifugation, washing and / or evaporation and / or drying. 3. The method according to item 1 or 2, wherein the nanoparticles or microparticles have a particle size D50 in the range of about 500 nm to 1000 μm. 4. The method according to any one of items 1 to 3, wherein the nanoparticles or microparticles have a particle size D50 in the range of 50 to 500 μm. 5. The method according to any one of items 1 to 4, wherein the nanoparticles or microparticles have a particle size D50 in the range of 80 to 300 μm. 6. The method according to any one of items 1 to 5, wherein the emulsion in step c) is an oil-in-water emulsion (O / W). 7. The method according to any one of items 1 to 5, wherein the emulsion in step c) is a water-in-oil emulsion (W1 / O). 8. The method of any one of items 1 to 7, wherein the carrier polymer is selected from (meth)acrylate copolymers, polylactides, polyorthoesters, polylactides, polydioxanone, polycaprolactone, poly(trimethylene carbonate), polyglycolide, poly(lactide-co-glycolide) (PLGA), poly(lactide-co-caprolactone), poly(lactide-co-trimethylene carbonate), poly(lactide-co-polyethylene glycol), and any blends thereof. 9. The method according to any one of items 1 to 8, wherein the carrier polymer is selected from cellulose ethers or cellulose esters, preferably selected from ethyl cellulose, cellulose acetate phthalate (CAP), cellulose acetate, hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMC AS), and mixtures thereof. 10. The method according to any one of items 1 to 9, wherein the carrier polymer is selected from collagen or collagen-like proteins. 11. The method according to any one of items 1 to 10, wherein the organic phase (OP) comprises the biologically active ingredient in an amount of 0.1 to 40% by weight. 12. The method according to any one of items 1 to 11, wherein the biologically active ingredient is selected from BCS-classes II and IV (Biopharmaceutical Classification System according to Prof. Amidon; Amidon et al., Pharm. Res. 12, 413-420 (1995)). 13. The method according to any one of items 1 to 11, wherein the biologically active ingredient is selected from BCS-classes I and III (Biopharmaceutical Classification System according to Prof. Amidon; Amidon et al., Pharm. Res. 12, 413-420 (1995)). 14. The biologically active ingredient is 17-β-estradiol, actretin, albendazole, albuterol, alendronate, alprostadil, amidoline, aminoglutemide, amiodarone, amphotericin, amprenavir, aripiprazole, asenapine, atazavir, atorvastatin, atovaquone, baclofen, beclomethasone, benezepril, benzocaine, benzonatate, betacarotene, betamethasone, bexarotene, bicaltanide, biperiden, bisacodyl, bleomycin, bosentan, buprenorphine, budesonide, bupropion, busulfan, butenafine, carphydione, calciprotiene, calcitriol, calcitrol, camptothecan, candesartan, capsaicin, carbamazepine, carmustine, candesartan , capsaicin, carbamazepine, carmustine, carvedilol, cefuroxime, celecoxib, ceribistatin, chloramphenicol, chlordiazepoxide, chlorpheniramine, chlorpropamide, chlorthiazide, cholecalciferol, cilazapril, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, cytolysine, clarithromycin, clemastine, clioquinol, clodronic acid, clofazimine, clomipramine, clopidrogel, clotrimazole, codeine, cortisol, curcurmin, cyclosporine, cytarabine, danazol, dantrolene, darunavir, dasatinib, diferasirox, dexamethasone, dexlopheniramine, dexlansoprazole, diazepam, diclofenac, dicumarol, digoxin. Dihydroepiandrosterone, dihydroergotamine, dihydrotachysterol, diltiazem, dimethindene, dipyridamole, dirithromycin, disulfiram, docetaxel, donepezil, doxerciferol, doxorubicin, dronabinol, droperidol, droxetine, durastride, efavirenz, elbasvir, elinogrel, eprosartan, ergocalciferol, ergotamine, erlotinib, essential fatty acids, estradiol, etidronic acid, etodolac, etoposide, etravirine, everolimus, exemestane, ezetimibe, famotidine, felodipine, fenofibrate, fenoldopamine,Fentanyl, fexofenadine, finasteride, floctafenine, fluconazole, fluogracil. Flurbiprofen, flutamide, fluvastatin, frovatriptan, fulvestrant, furazolidone, furosemide, gabapentin, gemfibrozil, glafenine, glibenclamide, glimepiride, glipizide, grizoprevir, griseofulvin, halofantrine, haloperidol, hydrocortin, ibuprofen, imatinib, indomethacin, irbesartan ... Ibuprofen, ibuprofarin, ibuprofamine, ibuprofamine, ibuprofamine, ibuprofamine, ibupropamine, indomethacin, irbesartan, irinotecan, isotretinoin, itraconazole, ivacaftor, ivermectin, ketoconazole, ketoprofen, ketorolac, lamotrigine, lansoprazole, ledipasvir, leflunomide, lidocaine, linezolid, lisinopril, lonidamine, loperamide, lopinavir, rotagene, rotadyne, losartan , l-thritol, lumacaftor, lumefantrine, medroxyprogesterone, mefenamic acid, mefepristone, mefloquine, megestrol acetate, melphalan, mesalazine, methadone, mesocarbamyl, methotrexate, methoxsalen, mesoprolol, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxanthone, modafinil, moexipril, montelukast, morphine, mycophenolate, nabilone, nabumetone, nalbuphine, naloxone, naproxen, narcolepsy putan, nelfinavir, nifedipine, nilotinib, nilsolidipine, nirutanic acid, nirvadapine, nimodipine, nimotiv, nitlendipine, nitrofurantoin, nizatidine, oestradiol, olanzapine, olmesartan, ombitasvir, omeprazole, ondansetron, oplevuquin, oridonin, oxaprozin, oxytetracycline, paclitaxel, pamidronic acid, paracetamol, paricalcitol, paritaprevir, paroxetine, pemethotrexed, penazosin, perindopril,Phenytoin, pioglitazone, piroxicam, pizotifen, posaconazole, prasugrel, pravastatin, prednisolone, prednisone, probucol, progesterone, propafenone, profol, pyridostigmine, quetiapine, rabeprazole, raloxifene, raltegravir, ramipril, ribamipide, rifocoxib, repaglinide, riboflavin, rifabutin. Rifapentine, rimexion, risedronate, risperidone, ritanovir, rivarxaban, rivastigmine, rizatriptan, rosiglitazone, rosuvastatin, saquinavir, selegiline, sertraline, sevelamer, sibutramine, sibutramine base, sildenafil, simvastatin, sirolimus, sitagliptin, sofosbuvir. sorafenib, spirapril, spironolactone, sulfathiazole, sumatriptan, sunitinib, tacrine, tacrolimus, tadalafil, tamoxifen, tamsulosin, targretin, tazarotene, telapirevir, telmisartan, teniposide, tenokilicam, terazosin, terbinafine, terbutaline, tetracycline, tetrahydrocannabinol Theophylline, tiagabine, ticagrelor, ticlidpine, tiludronic acid, tirofibran, tizanidine, tocopherol acetate, tolbutamide, tolvaptan, topiramat, topotecan, torcetrabib, trebifen, tramadol, trandolapir, tretinoin, troglitazone, trovafloxacin, valproic acid, valrubicin, valsartan, velpatasvir, vemurafenib, venlafaxine, verapamil, velpatasvir 14. The method according to any one of items 1 to 13, wherein the medicament is selected from torphin, viadol, vigabatrin, vildagliptin, vitamin A, vitamin D, vitamin K, vitamin Q10, vorapaxar, voriconazole, zafelkast, zileiton, ziprazidone, zithromycin, zoledronic acid, zolmitriptan, zolpidem, zopiclone, or, where applicable, a pharma- ceutically acceptable salt form thereof. 15. The method according to any one of items 1 to 14, wherein the aqueous phase (AP) comprises about 1 to 50% by weight of the pharma- ceutically acceptable salt. 16. The method according to any one of items 1 to 15, wherein the aqueous phase (AP) comprises about 2 to 40% by weight of the pharma- ceutically acceptable salt. 17. The method according to any one of items 1 to 16, wherein the aqueous phase (AP) comprises about 4 to 30% by weight of the pharma- ceutically acceptable salt. 18. The method according to any one of items 1 to 17, wherein the pharma- ceutically acceptable salt is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, magnesium chloride, magnesium sulfate, calcium chloride, sodium acetate, potassium acetate, magnesium acetate, ammonium acetate, ammonium sulfate, and ammonium chloride. 19. The method according to any one of items 1 to 18, wherein the solvent or solvent mixture (S1) has a water miscibility of 0.1 to 35% by weight at 25°C. 20. The solvent or solvent mixture (S1) is 1-butanol, 1-methoxy-2-propanyl acetate, 1-pentanol, 2,2,5-tetramethyltetrahydrofuran, 2,2-dimethyltetrahydrofuran, 2,5-dimethylfuran, 2-ethyl-1-butanol, 2-methylbutan-2-ol, 2-methylpentan-1-ol, 2-methylpentan-2-ol, 2-methylpropan-1-ol, 3-methoxypropyl acetate, 3-hexanol, 3-methoxypropyl acetate, 3-methyl ... tate, 3-methoxy-1-butanol, 3-methoxy-3-methyl-1-butanol, 3-methylbutan-1-ol, 3-methylbutan-2-ol, 3-methyl-2-pentanol, 4-methyl-1,3-dioxolan-2-one, 4-methyl-2-pentanol, 4-methylcyclohexanone, 5-methyldihydro-2(3H)-furanone, acetaldehyde diethyl acetal, acetaldehyde dimethyl acetal, benzoic acid methyl ester, benzyl alcohol, butanone, butyl 2- Hydroxy-2-methylpropanoate, butyl acetate, butyl formate, chloroform, cyclohexanol, cyclopentanol, cyclopentanone, dichloromethane, diethyl carbonate, diethyl ether, diethyl ketone, diisopropyl ether, dimethyl carbonate, ethyl acetate, ethyl butyrate, ethyl formate, ethyl-3-oxobutanoate, gamma-valerolactone, hexane-2-ol, iso-butyl acetate, iso-butyl formate, iso-propyl acetate, isopropyl 20. The method according to any one of items 1 to 19, wherein the methyl ethyl ketone, methyl propyl butyrate, isopropyl methyl ketone, isopropyl methyl ketone, malonic acid diethyl ester, malonic acid dimethyl ester, methyl acetate, methyl butyrate, methyl formate, methyl propyl ketone, methyl-tetrahydrofuran, methyl-iso-butyl ketone, methyl propyl ketone, pentan-2-ol, pentan-3-ol, propyl acetate, t-butyl methyl ether, toluene, or a mixture of two or more thereof. 21. The method according to any one of items 1 to 20, wherein the mixing in step c) is carried out by means of a stirred vessel or reactor, a static mixer, a stirred or pulsed extraction column, a bead-packed column, a Pall-ring or Raschig-ring packed column, a Sulzer packed column or a Raschig metal packed column, a rotor-stator mixing system, a baffled reactor, a vibrating baffled reactor, a continuous baffled reactor, a laminar jet break-up device, a cross-flow membrane emulsifier, a premixed membrane emulsifier, a swirling-flow membrane emulsifier, a microfluidic device (co-flow, tangential cross-flow, flow focusing principle) or a microstructured membrane emulsifier, an ultrasonic device and a stirred vessel with a stirrer. 22. The method according to any one of items 1 to 21, wherein the mixing in step c) is carried out under laminar flow conditions. 23. The method according to any one of items 1 to 21, wherein the mixing in step c) is carried out under laminar flow conditions in a packed bed. 24. The method according to any one of items 1 to 21, wherein the mixing in step c) is carried out under turbulent mixing conditions. 25. The method according to any one of items 1 to 24, wherein the aqueous phase (AP) comprises about 0.001 to 5% by weight of an emulsion stabilizer. 26. The aqueous phase (AP) is selected from the group consisting of glyceryl monooleate, medium chain monoglycerides, diglycerides, caprylic acid, caprate, glyceryl monocaprylate, propylene glycol monocaprylate, oleyl polyoxyl-6-glyceride, lineoyl polyoxyl-6-glyceride, lauroyl polyoxyl-6-glyceride, propylene glycol monolaurate, diacetylated monoglyceride, polyoxyl-23-lauryl ether, polyoxyl -2 oleyl ether, polyoxy-35 hydrogenated castor oil, polyoxy-40 hydrogenated castor oil, lauroyl polyoxyl-32 glyceride, stearoyl polyoxyl-32 glyceride, polyoxyl-15 hydroxystearate, poloxamer 124, poloxamer 188 (triblock copolymer), poloxamer 407, polyoxyethylene, polyoxypropylene, caprylocaproyl polyoxy-8 glyceride, polyoxyl-40 stearate 26. The method according to any one of items 1 to 25, comprising an emulsion stabilizer selected from the group consisting of glycerol, tocopherol, polyoxyethylene-(20)-sorbitan monolaurate, polyoxyethylene-(40)-sorbitan monopalmitate, polyoxyethylene-(80)-sorbitan monooleate, polyvinyl alcohol, polysorbates and / or polyoxyethylene fatty acid alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycol, polypropylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene polyoxypropylene copolymers (poloxamers), poloxamine, glyceryl esters, and polyvinylpyrrolidone, or combinations thereof. 27. The method according to any one of items 1 to 26, wherein the aqueous phase (AP) comprises an emulsion stabilizer selected from polyvinyl alcohol and polysorbate. 28. The method according to any one of items 1 to 27, wherein in step d) a combination of solvent evaporation and solvent extraction is applied. 29. Nanoparticles or microparticles obtainable by the method according to any one of items 1 to 28. 30. Nanoparticles or microparticles according to item 29, in oral or parenteral dosage forms for use in a method of treatment of the human or animal body by therapy or diagnosis. 31. A pharmaceutical or nutraceutical formulation comprising nanoparticles or microparticles according to item 30. 32. The method of any one of items 1 to 31, wherein the carrier polymer is a (meth)acrylate copolymer selected from: a copolymer comprising polymerized units of methacrylic acid and ethyl acrylate, a copolymer comprising polymerized units of methacrylic acid and methyl methacrylate, a copolymer comprising polymerized units of ethyl acrylate and methyl methacrylate or methacrylic acid, a copolymer comprising polymerized units of methyl acrylate and methyl methacrylate, a mixture of a copolymer comprising polymerized units of methacrylic acid and ethyl acrylate and a copolymer comprising polymerized units of methyl methacrylate and ethyl acrylate, and a mixture of a copolymer comprising polymerized units of methacrylic acid, methyl acrylate, and methyl methacrylate and a copolymer comprising polymerized units of methyl methacrylate and ethyl acrylate, dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, and a core-shell copolymer having a core comprising polymerized units of methyl methacrylate and ethyl acrylate and a shell comprising polymerized units of methacrylic acid and ethyl acrylate. 33. The method of any one of items 1 to 32, wherein the carrier polymer is a copolymer from polymerized units of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. 34. The method according to any one of items 1 to 33, wherein the carrier polymer is a copolymer of polymerized units of 40 to 60% by weight of dimethylaminoethyl methacrylate, 20 to 30% by weight of butyl methacrylate, and 20 to 30% by weight of methyl methacrylate. 35. The method according to any one of items 1 to 34, wherein the carrier polymer is a copolymer of 40 to 60% by weight of polymerized units of methacrylic acid and 60 to 40% by weight of ethyl acrylate. 36. The method according to any one of items 1 to 35, wherein the carrier polymer is a copolymer of polymerized units of 60 to 80% by weight of ethyl acrylate and 40 to 20% by weight of methyl methacrylate. 37. The method according to any one of items 1 to 36, wherein the carrier polymer is a copolymer of polymerized units of 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methyl acrylate, and 20 to 30% by weight of methyl methacrylate. 38. The method according to any one of items 1 to 37, wherein the carrier polymer is a copolymer comprising a copolymer of 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of polymerized units of ethyl acrylate, and a (meth)acrylate copolymer comprising 60 to 80% by mass of ethyl acrylate and 40 to 20% by mass of polymerized units of methyl methacrylate, in a ratio of 10:1 to 1:10. 39. The method according to any one of items 1 to 37, wherein the carrier polymer is a copolymer comprising a copolymer of 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of polymerized units of ethyl acrylate, and a (meth)acrylate copolymer comprising 60 to 80% by mass of ethyl acrylate and 40 to 20% by mass of polymerized units of methyl methacrylate, in a ratio of 10:1 to 1:10. 40. The method according to any one of items 1 to 39, wherein the carrier polymer is a copolymer of polymerized units of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate, and 7 to 15% by weight of 2-trimethylammonium methyl methacrylate chloride. 41. The method according to any one of items 1 to 40, wherein the carrier polymer is a core-shell copolymer comprising 50 to 90% by mass, preferably 70 to 80% by mass, of a core comprising 60 to 80% by mass, preferably 65 to 75% by mass, of polymerized units of ethyl acrylate and 40 to 20% by mass, preferably 35 to 25% by mass, of methyl methacrylate, and 50 to 10% by mass, preferably 30 to 20% by mass, of a shell comprising 40 to 60% by mass, preferably 45 to 55% by mass, of ethyl acrylate and 60 to 40% by mass, preferably 55 to 45% by mass, of methacrylic acid. 42. The method according to any one of items 1 to 41, wherein the organic phase (OP) comprises n-butanol as a partially water-miscible organic solvent and comprises celecoxib, valsartan or efabinin as a biologically active ingredient, and the aqueous phase (AP) comprises sodium chloride as a pharma- ceutically acceptable salt. [Brief description of the drawings]

[0081] [Figure 1] FIG. 1 is an electron micrograph of the 125-500 μm microparticle fraction. [Diagram 2] FIG. 2 shows the particle size distribution of the microparticle fraction of 125 to 500 μm measured by SEM. [Diagram 3] FIG. 3 shows the release profile of telmisartan in acetate buffer pH 4.0 using USP II method. [Figure 4] FIG. 4 shows X-ray powder diffraction analyses of telmisartan-EUDRAGIT® EPO microparticles and telmisartan+EUDRAGIT® EPO powder mixtures. [Diagram 5] FIG. 5 is an SEM photograph of the 125-500 μm microparticle fraction. [Figure 6] FIG. 6 shows the particle size distribution of the microparticle fraction of 125 to 500 μm measured by SEM. EXAMPLES

[0082] Example 1 35.01 g of ethyl acetate (Merck KGaA, Darmstadt, Germany) was weighed into a 100 mL screw-top glass bottle and 35.0 g of water was added. The mixture was then vigorously stirred at 1100-1200 rpm for 10 min using an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. The stirrer was stopped and the temporarily formed emulsion was left for about 10 min, which resulted in separation into an upper organic phase (OP) containing ethyl acetate and a lower aqueous phase (AP) saturated with ethyl acetate. After 10 min of stirring, the organic ethyl acetate phase (OP) saturated with water was filled into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and the solution was 21-22 °C. The samples were then analyzed by the Karl Fischer method (KF Titrado, Deutsche METROHM GmbH & Co. KG, Filderstadt, Germany). 0.3-1.1 g of ethyl acetate was used to determine the water content in the solvent. As the working medium, the reagent HYDRANAL (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0083] Example 2 180.0 g of MgSO4 (Merck KGaA, Darmstadt, Germany) was dissolved in 420.0 g of water with stirring using a magnetic stirrer to give a 30.0% (w / w) solution. 35.0 g of ethyl acetate (Merck KGaA, Darmstadt, Germany) was weighed into a 100 ml screw-top glass bottle and 35.0 g of MgSO4 solution was added. The mixture was then vigorously stirred for 10 min at 1100-1200 rpm with an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. When the stirrer was stopped and the temporarily formed emulsion was allowed to stand for about 10 min, it separated into an upper organic phase (OP) containing ethyl acetate and a lower aqueous phase (AP) containing brine. After stirring for 10 min, the aqueous MgSO4 saturated organic ethyl acetate phase (OP) was filled into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and solution was 21-22 °C. The samples were then analyzed by Karl Fischer method (KF Titrado, Deutsche METROHM GmbH&Co.KG, Filderstadt, Germany). The water content in the solvent was measured using 0.3-1.1 g of ethyl acetate. (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0084] Example 3 150.0 g of NaCl (Merck KGaA, Darmstadt, Germany) was dissolved in 420.0 g of water with stirring using a magnetic stirrer to give a 25.0% (w / w) solution. 35.0 g of ethyl acetate (Merck KGaA, Darmstadt, Germany) was weighed into a 100 ml screw-top glass bottle and 35.0 g of 25% NaCl solution was added. The mixture was then vigorously stirred for 10 min at 1100-1200 rpm in an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. The stirrer was stopped and the temporarily formed emulsion was allowed to stand for about 10 min, whereupon it separated into an upper organic phase (OP) containing ethyl acetate and a lower NaCl-containing aqueous phase (AP) saturated with ethyl acetate. After 10 min of stirring, the aqueous NaCl-saturated organic ethyl acetate phase (OP) was filled into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and solution was 21-22 °C. The samples were then analyzed by Karl Fischer method (KF Titrado, Deutsche METROHM GmbH&Co.KG, Filderstadt, Germany). The water content in the solvent was measured using 0.3-1.1 g of ethyl acetate. (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0085] Example 4 35.0 g of n-butanol (Merck KGaA, Darmstadt, Germany) was weighed into a 100 ml screw-top glass bottle and 35.0 g of water was added. The mixture was then vigorously stirred for 10 min at 1100-1200 rpm with an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. When the stirrer was stopped and the temporarily formed emulsion was allowed to stand for about 10 min, it separated into a saturated organic phase (OP) containing n-butanol and a lower aqueous phase (AP) saturated with n-butanol. After stirring for 10 min, the organic n-butanol phase (OP) saturated with water was filled into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and the solution was 21-22 °C. The samples were then analyzed by Karl Fischer method (KF Titrado, Deutsche METROHM GmbH&Co.KG, Filderstadt, Germany). The water content in the solvent was measured using 0.3-1.1 g of n-butanol. (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0086] Example 5 35.0 g of n-butanol (Merck KGaA, Darmstadt, Germany) was weighed into a 100 ml screw-top glass bottle and 35.0 g of 30% MgSO4 solution (obtained in Example 2) was added. The mixture was then vigorously stirred for 10 min at 1100-1200 rpm with an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. The stirrer was stopped and the temporarily formed emulsion was allowed to stand for about 10 min, whereupon it separated into an upper organic phase (OP) containing n-butanol and a lower aqueous phase (AP) saturated with n-butanol. After stirring for 10 min, the aqueous MgSO4 saturated organic n-butanol phase (OP) was filled into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and solution was 21-22 °C. The samples were then analyzed by the Karl Fischer method (KF Titrado, Deutsche METROHM GmbH&Co.KG, Filderstadt, Germany). The water content in the solvent was determined using 0.3–1.1 g of n-butanol. As the working medium, the reagent HYDRANAL (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0087] Example 6 35.0 g of n-butanol (Merck KGaA, Darmstadt, Germany) was weighed into a 100 ml screw-top glass bottle and 35.0 g of 25% NaCl solution (obtained in Example 3) was added. The mixture was then vigorously stirred for 10 min at 1100-1200 rpm using an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. The stirrer was stopped and the temporarily formed emulsion was allowed to stand for about 10 min, whereupon it separated into an upper organic phase (OP) containing n-butanol and an aqueous phase (AP) containing NaCl solution saturated with n-butanol. After stirring for 10 min, the aqueous NaCl saturated organic n-butanol phase (OP) was filled into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and solution was 21-22 °C. The samples were then analyzed by the Karl Fischer method (KF Titrado, Deutsche METROHM GmbH&Co.KG, Filderstadt, Germany). The water content in the solvent was determined using 0.3–1.1 g of n-butanol. As the working medium, the reagent HYDRANAL (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0088] Example 7 35.0 g of methyl ethyl ketone (Merck KGaA, Darmstadt, Germany) was weighed into a 100 ml screw-top glass bottle and 35.0 g of water was added. The mixture was then vigorously stirred for 10 min at 1100-1200 rpm with an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. When the stirrer was stopped and the temporarily formed emulsion was allowed to stand for about 10 min, it separated into an upper methyl ethyl ketone-containing organic phase (OP) saturated with water and a lower aqueous phase (AP) saturated with methyl ethyl ketone. After stirring for 10 min, the water-saturated organic methyl ethyl ketone phase (OP) was filled into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and solution was 21-22 °C. The samples were then analyzed by Karl Fischer method (KF Titrado, Deutsche METROHM GmbH&Co.KG, Filderstadt, Germany). The water content in the solvent was measured using 0.3-1.1 g of methyl ethyl ketone. (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0089] Example 8 35.0 g of methyl ethyl ketone (Merck KGaA, Darmstadt, Germany) was weighed into a 100 ml screw-top glass bottle and 35.0 g of 30% MgSO4 solution (obtained in Example 2) was added. The mixture was then vigorously stirred for 10 min at 1100-1200 rpm with an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. The stirrer was stopped and the temporarily formed emulsion was allowed to stand for about 10 min, whereupon it separated into an upper organic phase (OP) containing methyl ethyl ketone and a lower aqueous phase (AP) containing the MgSO4 solution saturated with methyl ethyl ketone. After stirring for 10 min, the aqueous MgSO4 saturated organic methyl ethyl ketone phase (OP) was charged into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and solution was 21-22 °C. The samples were then analyzed by the Karl Fischer method (KF Titrado, Deutsche METROHM GmbH&Co.KG, Filderstadt, Germany). The water content in the solvent was determined using 0.3–1.1 g of methyl ethyl ketone. As the working medium, the reagent HYDRANAL (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0090] Example 9 35.0 g of methyl ethyl ketone (Merck KGaA, Darmstadt, Germany) was weighed into a 100 ml screw-top glass bottle and 35.0 g of 25% NaCl solution (obtained in Example 3) was added. The mixture was then vigorously stirred for 10 min at 1100-1200 rpm with an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. The stirrer was stopped and the temporarily formed emulsion was allowed to stand for about 10 min, whereupon it separated into a saturated upper organic phase (OP) containing methyl ethyl ketone and a lower aqueous phase (AP) containing NaCl solution saturated with methyl ethyl ketone. After stirring for 10 min, the NaCl saturated organic methyl ethyl ketone phase (OP) was filled into a 50 ml screw-top glass bottle using a 5 ml glass Pasteur pipette. The temperature of the solvent and solution was 21-22°C. The samples were then analyzed by the Karl Fischer method (KF Titrado, Deutsche METROHM GmbH&Co.KG, Filderstadt, Germany). The water content in the solvent was determined using 0.3–1.1 g of methyl ethyl ketone. As the working medium, the reagent HYDRANAL (R) -MEDIUM K and HYDRANAL (R) - Composite 5K was used.

[0091] [Table 1] Table 1 : Summary of water content in different solvents saturated with water, 30% MgSO4 aqueous solution and 25% NaCl aqueous solution.

[0092] Results: By adding pharma- ceutically acceptable salt solutions to partially water-miscible organic solvents such as those described in Examples 1-9, the solubility of the aqueous phase (AP) is significantly reduced depending on the solvent and salt selected. It is clear that the NaCl solutions containing the organic phase (shown in Examples 3, 6 and 9) have the lowest water uptake. Advantageously, the solubility of active ingredients of BCS class II or IV (BCS: Biopharmaceutical Classification System according to Prof. Amidon; Amicon et al., Pharm. Res. 12, 413-420 (1995). Class II: high permeability, low solubility; Class IV: low permeability, low solubility) in salt-water saturated organic solutions will be improved compared to the active ingredient solutions in water-saturated organic solutions only. Therefore, solubility studies of valsartan, efavirenz and celecoxib in a water-saturated organic phase containing n-butanol (capable of uptake of approximately 20% water at room temperature) were performed in comparison to the solubility of the saturated n-butanol (capable of uptake of approximately 7.2% of an aqueous solution containing 25% NaCl after saturation).

[0093] Examples 10-18 demonstrate the solubility of the three active ingredients in pure n-butanol, n-butanol saturated with water, and n-butanol saturated with 25% NaCl solution.

[0094] Example 10 (Comparative) 29.73 mg of valsartan (Finetech Industry Limited, Hubei, China) was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 100 μl of n-butanol was added and the dispersion was stirred at 300-500 rpm by a magnetic stirrer at 21-23°C. 10 μl of n-butanol was added in aliquots. After adding 250 μl of n-butanol, all of the valsartan was dissolved and a clear solution was obtained.

[0095] Example 11 (Comparative) 28.88 mg of valsartan was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 100 μl of n-butanol (obtained in Example 4) was added and the dispersion was stirred at 300-500 rpm with a magnetic stirrer at 21-23°C. 10 μl of n-butanol was added in increments. After 400 μl of n-butanol was added, all of the valsartan was dissolved and a clear solution was obtained.

[0096] Example 12 (present invention) 29.72 mg of valsartan was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 100 μl of n-butanol saturated with 25% aqueous NaCl (obtained in Example 6) was added and the dispersion was stirred at 300-500 rpm with a magnetic stirrer at 21-23° C. 10 μl of n-butanol was added in aliquots. After adding 250 μl of n-butanol, all of the valsartan was dissolved and a clear solution was obtained.

[0097] Example 13 (Comparative) 31.35 mg of efavirenz (Anguene International Limited, China) was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 50 μl of water-saturated n-butanol was added and the dispersion was stirred at 300-500 rpm by magnetic stirrer at 21-23 °C. n-butanol was added in 10 μl increments. After adding 70 μl of n-butanol, all of the efavirenz was dissolved and a clear solution was obtained.

[0098] Example 14 (Comparative) 30.57 mg of efavirenz was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 50 μl of water-saturated n-butanol (obtained in Example 4) was added and the dispersion was stirred at 300-500 rpm with a magnetic stirrer at 21-23° C. n-butanol was added in 10 μl increments up to 250 μl, followed by 25 μl increments. After 325 μl of water-saturated n-butanol was added, all of the efavirenz was dissolved and a clear solution was obtained.

[0099] Example 15 (Invention) 31.35 mg of efavirenz was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 50 μl of n-butanol saturated with 25% aqueous NaCl (obtained in Example 6) was added and the dispersion was stirred at 300-500 rpm by magnetic stirrer at 21-23° C. 10 μl of n-butanol saturated with 25% aqueous NaCl was added in portions. After adding 60 μl of n-butanol saturated with 25% aqueous NaCl, all of the efavirenz was dissolved and a clear solution was obtained.

[0100] Example 16 (Comparative) 32.72 mg of celecoxib (Anguene International Limited, China) was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 100 μl of n-butanol was added and the dispersion was stirred at 300-500 rpm by a magnetic stirrer at 21-23 °C. 100 μl of n-butanol was added in increments. After adding 1500 μl of n-butanol, all of the celecoxib was dissolved and a clear solution was obtained.

[0101] Example 17 (Comparative) 31.93 mg of celecoxib was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 100 μl of water-saturated n-butanol (obtained in Example 4) was added and the dispersion was stirred at 300-500 rpm with a magnetic stirrer at 21-23° C. 100 μl of water-saturated n-butanol was added in aliquots. After adding 2000 μl of water-saturated n-butanol, all of the celecoxib was dissolved and a clear solution was obtained.

[0102] Example 18 (Invention) 32.32 mg of celecoxib was weighed into a 10 ml glass vial with a 1 cm magnetic stir bar. 100 μl of n-butanol saturated with 25% aqueous NaCl (obtained in Example 6) was added and the dispersion was stirred at 300-500 rpm with a magnetic stirrer at 21-23° C. 100 μl of n-butanol saturated with 25% aqueous NaCl was added in increments. After adding 1600 μl of n-butanol saturated with 25% aqueous NaCl, all of the celecoxib was dissolved and a clear solution was obtained.

[0103] [Table 2] Table 2

[0104] Results (see Table 2) Pure n-butanol (Examples 10, 13 and 16) can dissolve a similar amount of active ingredient as n-butanol saturated with 25% NaCl salt solution (Examples 12, 15 and 18), but n-butanol saturated with water (Examples 11, 14 and 17) dissolves a significantly lower amount of active ingredient compared to n-butanol saturated with 25% NaCl salt solution (or pure butanol, individually). Pure n-butanol as a solvent is as good as n-butanol saturated with 25% NaCl salt solution. Nevertheless, the water uptake of about 20.4% for pure butanol (Example 4) during the emulsification process can cause precipitation of active ingredient that is difficult to control over time. Physicochemical properties such as interfacial tension (prerequisite for process scaling of emulsification process) can change. Saturation of the solvent with water or with a 25% NaCl salt solution, in combination with the aqueous phase saturated with the solvent and the saturation of the salt water containing the surfactant (AP), reduces or prevents the uptake of water into the organic phase containing the active ingredient and the polymer (OP), thus stabilizing the emulsification process over time. Examples 19 and 20 show the water uptake over time in a pure butanol phase that is not saturated (Example 19) and the effect of n-butanol saturated with a 25% NaCl solution (Example 20).

[0105] Example 19 (Comparative) Pure unsaturated n-butanol (n-butanol (Merck KGaA, Darmstadt, Germany) was measured against n-butanol saturated aqueous solution (from Example 4). The water saturated solution was filled into a cuvette of a pendant drop analyzer (Dataphysics Instruments GmbH, Filderstadt, Germany). A drop of unsaturated pure n-butanol was then slowly pumped through the needle and the size of the drop was analyzed over time. This method is usually used to measure the interfacial tension between two partially miscible or immiscible liquids. This value is calculated after a stable equilibrium state is reached resulting in a stable droplet morphology and size and thus the interfacial tension. In this example, only the size was observed. The droplets increase their size by more than 33% relative to the initial size within about 600 seconds, resulting in process conditions that change and become undefined. This affects both the formation of the emulsion and the subsequent particle formation in an unpredictable way. Therefore, controlled process reproducibility is not given.

[0106] Example 20 (Invention) n-butanol saturated with 25% aqueous NaCl was measured against 25% aqueous NaCl saturated with n-butanol (from Example 6). Up to 5 ml of 25% aqueous NaCl saturated with n-butanol was filled into a cuvette of a pendant drop analyzer (Dataphysics Instruments GmbH, Filderstadt, Germany). A drop of unsaturated pure n-butanol was then slowly pumped through the needle and the size of the drop was analyzed over time. This method is usually used to measure the interfacial tension between two partially miscible or immiscible liquids. This value is calculated after a stable equilibrium state is reached, resulting in a stable droplet morphology and size, and therefore the interfacial tension. In this example, only the size was observed over a time period of 600 seconds. The droplets increase their size by about 1.7% relative to their initial size within about 600 seconds, resulting in a constant and defined process condition. This allows both the formation of the emulsion and the subsequent particle formation to be controlled in a more predictable way. Thus, controlled process repeatability is provided.

[0107] Results: Saturation of partially water-miscible n-butanol with 25% aqueous NaCl solution significantly reduces the water uptake over time. Thus, the resulting interfacial tension (here about 7 mN / m) changes little over time.

[0108] Example 21 (Invention) 200 g of NaCl (Merck KGaA, Darmstadt, Germany) are dissolved in 800 g of water at 25° C. with stirring at 500-1000 revolutions / min in a 1 liter screw bottle for 30 minutes using a magnetic stirrer.

[0109] Then, 300 g of n-butanol (Merck KGaA, Darmstadt, Germany) is added to 500 g of 20% (w / w) sodium chloride solution with vigorous mixing for 15 min at 1500-2000 rpm using an overhead stirrer equipped with a 3 cm diameter stainless steel dissolver stirring rotor. The stirrer is stopped and the temporarily formed emulsion is left to stand for about 10 min, whereupon it separates into saturated organic and aqueous phases (n-butanol upper phase, brine lower phase). 85 g of saturated n-butanol from the upper phase is charged into a 250 ml screw-top glass bottle using a graduated glass pipette. 15 g of Eudragit (R) EPO (Evonik Nutrition & Care GmbH, Darmstadt, Germany) was dissolved in 85 g of saturated n-butanol by stirring at 500-1000 rpm with a 3 cm diameter stainless steel dissolver stirring rotor. After a clear, slightly viscous yellow polymer solution was obtained, 4.5 g of valsartan (Finetech Industry Limited, Hubei, China) was dissolved in 100 g of the 15% (w / w) polymer solution under stirring at 500-1000 rpm for 30 min, resulting in a total of 18.66% (w / w) valsartan-EUDRAGIT with an active ingredient:polymer ratio of 30:100% (w / w, 30% based on polymer). (R) 104.5 g of organic phase (OP) containing EPO solids was obtained.

[0110] 399.2 g of a saturated aqueous solution of n-butanol (solvent for the aqueous phase AP) is weighed into a 500 ml screw-top glass bottle. Then, 0.8 g of polyvinyl alcohol (Mowiol (R) 4-88, Mw 31,000 or less, Sigma Aldrich, Germany) was weighed into a saturated aqueous solution of n-butanol. The mixture was stirred at 400-600 rpm and heated to 80 °C in a sealed screw-top glass bottle using a magnetic stirrer equipped with a heating plate. After a clear solution was obtained, the solution was cooled again to 24-26 °C to obtain the aqueous phase (AP).

[0111] EUDRAGIT (R)A saturated organic phase (OP) containing EPO and valsartan, and Mowiol (R) After the aqueous phase (AP) containing 4-88 was obtained, the aqueous phase (AP) and the organic phase (OP) were mixed in a ratio of 2 to 1 (m / m) using a stainless steel (Swagelok, Maintal, Germany) packed column with 1.0-1.2 mm ceramic beads (VMA-Getzmann, Reichshof, Germany) having a length of 152.4 cm, an outer diameter of about 12.7 mm, and an inner diameter of about 10 mm. To this end, the beads were flushed with the aqueous phase (AP) at a flow rate of 4 g / min for 5 min using an ISCO syringe pump, D-series (Teledyne ISCO, Lincoln, USA), which was previously filled with the aqueous phase (AP) and air and was bubble-free. Then, using a second ISCO pump, the organic phase (OP) was pumped through the column containing the bead packing at a flow rate of 2 g / min through a t-connector installed below the upright column. The extraction phase (EP) for dilution of the resulting emulsion consisted of 12 g of polyvinyl alcohol (Mowiol (R) 4-88, Mw ≦31,000, Sigma Aldrich, Germany) was heated to 80°C in 5988 g of water, and the solution was cooled again to 24-26°C to obtain the extract phase (EP). One liter of 0.2% (w / w) Mowiol containing non-saturated aqueous extraction phase (EP) is loaded into a 10 liter screw-top glass bottle equipped with a magnetic stirrer. The resulting emulsion is poured into the top of the column (at the end of the dispersion unit) connected to another T-connector, and then into 5000 g of 0.2% Mowiol. (R)The extraction phase (EP) is diluted by adding 4-88 solution at a flow rate of 100 g / min over 50 min. The emulsion is collected in a glass bottle while stirring the dispersion generated by the solidifying microparticles. After emulsifying 100 g of the organic phase (OP) by adding the aqueous phase (AP), the ISCO pump is stopped and the aqueous dispersion is stirred for another 5 h at 200 rpm. After 5 h, the material is separated from the resulting solid dispersion by sieving through 500 μm and 125 μm metal sieves. The microparticle fraction is then washed 5 times with 1 liter of cold water. The 125-500 μm sieved fraction is then filled into a flat stainless steel bowl and freeze-dried using a freeze-dryer system, type Epsilon 2-6 from Martin Christ (Martin Christ, Osterode, Germany). The resulting white material is then filled into 250 ml screw-top glass bottles and freeze-dried with 0.5% Aerosil based on solids. (R) 200 (EVONIK Nutrition&Care GmbH, Kirschenallee, Darmstadt) and blended for 5 min at 49 rpm in a Mini Turbula Blender T2F (Williy A., Bachhofen, Muttenz, Switzerland). The active ingredient in the resulting microparticles is amorphous. The flow properties are similar to those of cellet 200-355 μm (HARKE Pharma GmbH, Mülheim an der Ruhr, Germany). The example material is suitable for oral immediate release in the stomach.

[0112] Example 22 (Invention) 430.01 g of cyclopentanol (Merck KGaA, Darmstadt, Germany) was charged into a 500 ml screw-top glass bottle. A 10% aqueous solution of sodium chloride was added while stirring the cyclopentanol with magnetic stirring at 800 rpm. The mixture was stirred for about 30 min. The partially precipitated sodium chloride was removed by vacuum membrane filtration using a 10 cm diameter suction filter to obtain 426.8 g of an organic phase saturated with 10% sodium chloride. 22.5 g of AQOAT AS-LG was dissolved in the saturated cyclopentanol solution while stirring at 600-800 rpm. 200 g of 5% AQUOAT AS-LG in cyclopentanol was added to 200 g of 10% saturated sodium chloride in cyclopentanol, and the resulting viscous solution (5% by weight AQUOAT AS-LG) was diluted 1:1 to give a 2.5% by weight slightly hazy yellow polymer solution. This organic solution was used as the dispersed phase (DP). 2.00 g of polyvinyl alcohol-10000 Da (Merck KGaA, Darmstadt, Germany) was dissolved in 98 g of Milli-Q water at room temperature while stirring at 400-800 rpm using a magnetic stirrer to obtain a 0.2% polyvinyl alcohol solution. Then, 200 g of sodium chloride was dissolved in 800 g of Milli-Q water to obtain a 20% by weight sodium chloride solution. Then, 500 g of both solutions were mixed to obtain a solution containing 10% by weight sodium chloride and 0.1% polyvinyl alcohol. Then, 23.9 g of cyclopentanol was added dropwise to the solution by magnetic stirring at 800 rpm for 10 min until a slightly turbid solution was obtained. This aqueous solution was used as the continuous phase (CP). The CP was first flushed for 3 min with HPLC pumps (Shimadzu LC-9A and LC-8A, Shimadzu Deutschland GmbH, Duisburg, Germany) through an emulsification device consisting of two 3 / 16" Kenics static mixers (Kenics Chemineer, Ohio, USA) with diameter mm and length 38 cm (each) mounted in series in a vertically oriented position with Swagelok stainless steel fittings, 3 / 16" to 3 / 16" and 3 / 16" to 1 / 8". The CP flowed through the static mixers into two different liquid streams controlled by Swagelok 3 / 2-way valves combined in a T-connector 1 / 8" (Swagelok, Dörnigheim, Maintal, Germany) into a 1 liter glass bottle for collecting the liquid waste. The two solutions were then pumped together using a flow rate of 2.3-2.4 ml / min for DP and 10 ml / min for CP forming the emulsion by switching the 3 / 2-way valve from CP to DP phase. The resulting emulsion droplets were poured into a 5 liter glass beaker equipped with an overhead stirrer and anchor blade (stirrer speed 100-150 rpm) containing 4 liters of deionized water to which 40 ml of 1 molar HCl solution (Merck KGaA, Darmstadt, Germany) was added to obtain a pH of 2.25. The acidic aqueous phase was used as the extraction phase (EP). After emulsification of 80 g of organic phase (DP) by addition of aqueous phase (CP), the HPLC pump was stopped and the aqueous dispersion was then stirred overnight at 115 rpm at room temperature. After stirring overnight, the material was separated from the resulting solid dispersion by sieving through 800 μm, 500 μm, 125 μm and 100 μm metal woven sieves. The resulting microparticle fraction was washed five times with 1 liter of cold water. The fraction was filled into Petri dishes and freeze-dried using a Martin Christ, Epsilon 2-6 type (Martin Christ, Osterode, Germany) freeze-dryer system. The resulting dry white placebo microparticles were then filled into glass vials and the mass of each was measured (see Table 3).

[0113] [Table 3] Table 3

[0114] Example 23 32.73g of Eudragit (R) EPO (Evonik Industries AG, Darmstadt, Germany) was dissolved in 144 g of dichloromethane (JT Baker by Fisher Scientific, Schwerte, Germany) under stirring with magnetic stirring at 400 rpm and 22.5 °C for 2 h. After a clear solution was obtained, 3.27 g of telmisartan (MedChemExpress, Hoelzel Diagnostika Handles GmbH, Cologne, Germany) was dissolved in the organic dichloromethane with stirring at 400-600 rpm. The organic telmisartan solution was saturated with the solvent by mixing the organic solution with 0.5 g of 5 wt.% sodium chloride solution with magnetic stirring for 15 min. The sodium chloride solution was obtained by dissolving 5 g of sodium chloride (Merck KGaA, Darmstadt, Germany) in 95 g of deionized water at 500 rpm and room temperature. The resulting solution was used as the dispersed phase (DP). 8 g of polyvinyl alcohol (PVA, 10000 Da, Merck KGaA, Darmstadt, Germany) was dissolved at room temperature with stirring at 530 rpm using a magnetic stirrer for 1 h to obtain a 0.4 wt % polyvinyl alcohol solution. 200 g of sodium chloride was dissolved in deionized water to a total of 2000 g while stirring magnetically at 500-550 rpm. 500 g of 0.4 wt. % PVA solution and 500 g of 10 wt. % salt solution were mixed to obtain 0.2 wt. % PVA and 5 wt. % sodium chloride solution. The aqueous salt solution was mixed with 9 g of dichloromethane to saturate the aqueous salt solution with the organic solvent. The mixture was stirred at 500 rpm for 15 min. The resulting slightly cloudy solution was used as the continuous phase (CP). The pH of the CP was 8.22 at room temperature. The CP was then flushed through both the DP and CP liquid connectors of Example 22, first through the same static mixer apparatus as above, at a flow rate of 10 ml / min for 3 min into a liquid waste collection bottle. After switching from CP liquid to DP liquid through the DP connector, the liquid was formed into droplets in the static mixer apparatus at a flow rate of 5 ml / min and transferred into 18 liters of a deionized water solution (pH 8.2) buffered with disodium hydrogen phosphate (Merck KGaA, Darmstadt, Germany). The disodium hydrogen phosphate buffer was previously prepared by adding 360 g of 0.5 molar disodium hydrogen phosphate to 18 liters of deionized water, resulting in a 0.01 M disodium hydrogen phosphate solution. The pH was 8.1-8.2. After dispensing 180 g of DP phase containing 24.0 g of solids, the pump was stopped. After stirring overnight, material was separated from the resulting solid dispersion by sieving through 500 μm and 125 μm metal sieves. The resulting microparticle fraction was washed five times with 1 liter of deionized water (22-24° C.). The fraction was filled into Petri dishes and freeze-dried using a Martin Christ, Epsilon 2-6 type (Martin Christ, Osterode, Germany) freeze-drier system. The slightly beige to white dried microparticles were then filled into glass vials and weighed. Samples of the resulting 125-500 pm fraction were analyzed by SEM (Scanning Electron Microscopy Analysis) (shown in FIG. 1), particle size distribution by SEM particle analysis (shown in FIG. 2), and telmisartan release profile was analyzed by USP II dissolution tester (ERWEKA GmbH, Langen, Germany) in acetate buffer (shown in FIG. 3 and Table 4) at pH 4.0 over 2 hours, and telmisartan-EUDRAGIT® was analyzed by HPLC. (R) X-ray powder diffraction analyses of the EPO microparticles and the telmisartan + EUDRAGIT® EPO powder mixture were performed (shown in FIG. 4).

[0115] The yields are shown in Table 5. [Table 4] Table 5: Obtained Telmisartan-EUDRAGIT (R) Yield of EPO microparticle fraction

[0116] The microparticle material obtained from this example can be used for oral application of telmisartan.

[0117] [Table 5] Table 4: Release profile of Telmisartan in acetate buffer at pH 4.0 using USP II method

[0118] Example 24 (Invention) 45.45g EUDRAGIT (R) EPO (Evonik Industries AG, Darmstadt, Germany) was dissolved in 328.75 g dichloromethane (JT Baker, Fischer Scientific, Schwerte, Germany) in a 1000 ml screw-cap laboratory storage bottle under stirring by magnetic stirring at 400 rpm and 24.3 °C for 2 h. After obtaining a clear solution, 4.54 g itraconazole (Alfa Aesar GmbH&Co KG, Landau, Germany) was dissolved in the organic dichloromethane under stirring at 400-600 rpm. The organic itraconazole solution was saturated with the solvent by mixing this organic solution with 0.65 g of 5 wt.% sodium chloride solution under stirring by magnetic stirring for 15 min. The sodium chloride solution was obtained by dissolving 5 g of sodium chloride (Merck KGaA, Darmstadt, Germany) in 95 g of deionized water at 500 rpm and room temperature. The resulting solution was used as the dispersed phase (DP). 8 g of polyvinyl alcohol (PVA, 10,000 Da, Merck KGaA, Darmstadt, Germany) was dissolved in deionized water at room temperature with magnetic stirring at 530 rpm for 1 h to a total of 2,000 g, resulting in a 0.4 wt % polyvinyl alcohol solution. 200 g of sodium chloride was dissolved in deionized water to a total volume of 2000 g with magnetic stirring at 500-550 rpm. 500 g of 0.4 wt% PVA solution and 500 g of 10 wt% salt solution were mixed to obtain a solution of 0.2 wt% PVA and 5 wt% sodium chloride. This aqueous salt solution was mixed with 9 g of dichloromethane to saturate the aqueous salt solution with the organic solvent. This mixture was stirred at 500 rpm for 15 min. The resulting slightly cloudy solution was used as the continuous phase (CP). The pH of the CP was 7.25 at room temperature. The CP was then flushed through the same static mixer device as above through both the DP and CP liquid connectors of Example 22 at a flow rate of 10 ml / min for 3 minutes into a liquid waste collection bottle. After switching from CP liquid to DP liquid through the DP connector, the liquid was formed into droplets in the static mixer device at a flow rate of 5 ml / min and transferred into 18 liters of a deionized water solution (pH 7.2) buffered with disodium hydrogen phosphate (Merck KGaA, Darmstadt, Germany). The disodium hydrogen phosphate buffer was prepared by adding 360 g of 0.5 molar disodium hydrogen phosphate to 18 liters of deionized water, resulting in a 0.01 M disodium hydrogen phosphate solution. The pH was 7.2. After dispensing 180 g of DP phase containing 24.0 g of solids, the pump was stopped. After stirring overnight, materials were separated from the resulting solid dispersion by sieving through 500 μm, 125 μm and 100 μm metal sieves. The resulting microparticle fraction was washed five times with 1 liter of deionized water (22-25 °C). The fraction was filled into a Petri dish and freeze-dried using a Martin Christ, type Epsilon 2-6 (Martin Christ, Osterode, Germany) freeze-dryer system. The resulting dry white microparticles were then filled into glass vials and weighed. A sample of the resulting 125-500 pm microparticle fraction was analyzed by SEM (scanning electron microscope) (shown in Figure 5) and the particle size distribution was performed by SEM particle analysis (shown in Figure 6).

[0119] Itraconazole - EUDRAGIT (R)The yield of EPO microparticles is shown in Table 6.

[0120] [Table 6] Table 6: Itraconazole-EUDRAGIT obtained (R) Yield of EPO microparticle fraction

Claims

1. A method for producing nanoparticles or microparticles containing a carrier polymer and a biologically active ingredient, said method being a solvent emulsion method comprising an organic phase (OP) and an aqueous phase (AP), in the case of an oil-in-water emulsion (O / W), said organic phase (OP) containing said biologically active ingredient dissolved or dispersed therein, and in the case of a water-in-oil emulsion (W1 / O), said aqueous phase (AP) containing said biologically active ingredient dissolved or dispersed therein, said method comprising the steps of: a) providing an organic phase (OP) comprising a partially water-miscible organic solvent or solvent mixture (S1), said organic phase (OP) being saturated with an aqueous phase (AP), said organic phase (OP) comprising a carrier polymer and, optionally, a biologically active ingredient dissolved or dispersed therein, b) providing an aqueous phase (AP) comprising an aqueous solvent or solvent mixture (S2) containing water and a pharma- ceutically acceptable salt dissolved therein, said salt-containing aqueous phase being further saturated with the solvent or solvent mixture (S1) of said organic phase (OP) and comprising an emulsion stabilizer and optionally a biologically active ingredient dissolved or dispersed therein; c) mixing said organic phase (OP) with said aqueous phase (AP) to obtain an oil-in-water emulsion (O / W) or a water-in-oil emulsion (W1 / O); d) in case of a water-in-oil emulsion (W1 / O), adding an excess of additional aqueous phase (AP) to obtain a water-in-oil-in-water emulsion (W1 / O / W2), e) removing said organic solvent or solvent mixture (S1) from said oil-in-water emulsion (O / W) or from said water-in-oil-in-water emulsion (W1 / O / W2) by evaporation and / or extraction to promote the formation of nanoparticles or microparticles comprising the carrier polymer and the biologically active ingredient in the remaining aqueous suspension; f) Separating the nanoparticles or microparticles from the aqueous suspension.

2. 2. The method according to claim 1, wherein the nanoparticles or microparticles are separated from the aqueous suspension in step f) by filtration or centrifugation, washing and / or evaporation and / or drying.

3. The method according to claim 1 or 2, wherein the nanoparticles or microparticles have a particle size D50 in the range of 500 nm to 1000 μm.

4. 4. The method of any one of claims 1 to 3, wherein the carrier polymer is selected from (meth)acrylate copolymers, polylactides, polyorthoesters, polydioxanone, polycaprolactone, poly(trimethylene carbonate), polyglycolide, poly(lactide-co-glycolide) (PLGA), poly(lactide-co-caprolactone), poly(lactide-co-trimethylene carbonate), poly(lactide-co-polyethylene glycol), cellulose ethers or cellulose esters, collagen or collagen-like proteins, and any blends or mixtures thereof.

5. The carrier polymer is i) a copolymer of polymerized units of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, or ii) A copolymer consisting of polymerized units of 40 to 60% by weight of dimethylaminoethyl methacrylate, 20 to 30% by weight of butyl methacrylate, and 20 to 30% by weight of methyl methacrylate. The method according to any one of claims 1 to 4, wherein

6. The method according to any one of claims 1 to 5, wherein the biologically active component is selected from BCS-classes II and IV.

7. The biologically active ingredient is 17-β-estradiol, actretin, albendazole, albuterol, alendronic acid, alprostadil, amidoline, aminoglutemide, amiodarone, amphotericin, amprenavir, aripiprazole, asenapine, atazavir, atorvastatin, atovaquone, baclofen, beclomethasone, benezepril, benzocaine, benzonatate, betacarotene, betamethasone, bexarotene, bicaltanide, biperiden, bisacodyl, bleomycin, bosentan, buprenorphine, budesonide, , bupropion, busulfan, butenafine, carphydione, calciprotiene, calcitriol, calcitrol, camptothecan, candesartan, capsaicin, carbamazepine, carmustine, carvedilol, cefuroxime, celecoxib, ceribistatin, chloramphenicol, chlordiazepoxide, chlorpheniramine, chlorpropamide, chlorthiazide, cholecalciferol, cilazapril, cilostazol, cimetidine, cinaridine, ciprofloxacin Sasin, cisapride, cytolidine, clarithromycin, clemastine, clioquinol, clodronic acid, clofazimine, clomipramine, clopidrogel, clotrimazole, codeine, cortisol, curcurmin, cyclosporine, cytarabine, danazol, dantrolene, darunavir, dasatinib, diferasirox, dexamethasone, dexlopheniramine, dexlansoprazole, diazepam, diclofenac, dicumarol, digoxin, dihydroepiandrosterone, dihydroergotamine, dihydrotachysterol, dilthiazolinone ... Zem, dimethindene, dipyridamole, dirithromycin, disulfiram, docetaxel, donepezil, doxerciferol, doxorubicin, dronabinol, droperidol, droxetine, durastride, efavirenz, elbasvir, elinogrel, eprosartan, ergocalciferol, ergotamine, erlotinib, essential fatty acids, estradiol, etidronic acid, etodolac, etoposide, etravirine, everolimus, exemestane, ezetimibe, famotidine, felodipine, fenofibrate, fenoldopamine,Fentanyl, fexofenadine, finasteride, floctafenine, fluconazole, fluogracil, flurbiprofen, flutamide, fluvastatin, frovatriptan, fulvestrant, furazolidone, furosemide, gabapentin, gemfibrozil, glafenine, glibenclamide, glimepiride, glipizide, grizoprevir, griseofulvin, halofantrine, haloperidol, hydrocortin, ibuprofen, imatinib, indomethacin, irbesartan, irbesartan, irbesartan , irbesartan, irbasartan, ibuprofen, ibuprofarin, ibuprofamine, ibuprofamine, ibuprofamine, ibuprofamine, ibupropamine, indomethacin, irbesartan, irinotecan, isotretinoin, itraconazole, ivacaftor, ivermectin, ketoconazole, ketoprofen, ketorolac, lamotrigine, lansoprazole, ledipasvir, leflunomide, lidocaine, linezolid, lisinopril, lonidamine, loperamide, lo Pinavir, Rotagene, Rotadyne, Losartan, l-Thriroxine, Lumacaftor, Lumefantrine, Medroxyprogesterone, Mefenamic acid, Mefepristone, Mefloquine, Megesterol acetate, Melphalan, Mesalazine, Methadone, Mesocarbamyl, Methotrexate, Methoxsalen, Mesoprolol, Metronidazole, Miconazole, Midazolam, Miglitre, Minoxidil, Mitoxanthone, Modafinil, Moexipril, Montelukast, Morphine, Mycophenolate, Nabilone, Nabumetone, Nalbuphine, Naloxone , naproxen, naratiptan, nelfinavir, nifedipine, nilotinib, nisolizine, nirutanic acid, nirvadapine, nimodipine, nimotiv, nitlendipine, nitrofurantoin, nizatidine, oestradiol, olanzapine, olmesartan, ombitasvir, omeprazole, ondansetron, oplevuquin, oridonin, oxaprozin, oxytetracycline, paclitaxel, pamidronate, paracetamol, paricalcitol, paritaprevir, paroxetine, pemethotrexed, penazosin, perindopril,Phenytoin, pioglitazone, piroxicam, pizotifen, posaconazole, prasugrel, pravastatin, prednisolone, prednisone, probucol, progesterone, propafenone, profol, pyridostigmine, quetiapine, rabeprazole, raloxifene, raltegravir, ramipril, ribamipide, rifocoxib, repaglinide, riboflavin, rifabutin, rifapentine, rimexion, risedronate, risperidone, ritanovir, rivaroxaban, rivastigmine, rizatriptan, rosiglitazone, rosvastatin Statins, Saquinavir, Selegiline, Sertraline, Sevelamer, Sibutramine, Sibutramine Base, Sildenafil, Simvastatin, Sirolimus, Sitagliptin, Sofosbuvir, Sorafenib, Spirapril, Spironolactone, Sulfathiazole, Sumatriptan, Sunitinib, Tacrine, Tacrolimus, Tadalafil, Tamoxifen, Tamsulosin, Targretin, Tazarotene, Telapirevir, Telmisartan, Teniposide, Tenokiricam, Terazosin, Terbinafine, Terbutaline, Tetracycline, Tetrahydrocannabinol Theophylline, tiagabine, ticagrelor, ticlidpine, tiludronic acid, tirofibran, tizanidine, tocopherol acetate, tolbutamide, tolvaptan, topiramat, topotecan, torcetrabib, trebifen, tramadol, trandolapir, tretinoin, troglitazone, trovafloxacin, valproic acid, valrubicin, valsartan, velpatasvir, vemurafenib, venlafaxine, verapamil, velpatasvir 7. The method according to any one of claims 1 to 6, wherein the medicament is selected from torphin, viadol, vigabatrin, vildagliptin, vitamin A, vitamin D, vitamin K, vitamin Q10, vorapaxar, voriconazole, zafelkast, zileiton, ziprazidone, zithromycin, zoledronic acid, zolmitriptan, zolpidem, zopiclone, or, where applicable, a pharma- ceutically acceptable salt form thereof.

8. The method according to any one of claims 1 to 7, wherein the aqueous phase (AP) comprises 1 to 50% by weight of the pharma- ceutically acceptable salt.

9. 9. The method of any one of claims 1 to 8, wherein the pharma- ceutically acceptable salt is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, magnesium chloride, magnesium sulfate, calcium chloride, sodium acetate, potassium acetate, magnesium acetate, ammonium acetate, ammonium sulfate, and ammonium chloride, or mixtures thereof.

10. 10. The process according to claim 1, wherein the solvent or solvent mixture (S1) has a water miscibility of 0.1 to 35% by weight at 25° C.

11. The solvent or solvent mixture (S1) is 1-butanol, 1-methoxy-2-propanyl acetate, 1-pentanol, 2,2,5-tetramethyltetrahydrofuran, 2,2-dimethyltetrahydrofuran, 2,5-dimethylfuran, 2-ethyl-1-butanol, 2-methylbutan-2-ol, 2-methylpentan-1-ol, 2-methylpentan-2-ol, 2-methylpropan-1-ol, 3-hexanol, 3-methoxypropyl acetate, 3-methoxy-1-butanol, 3-Methoxy-3-methyl-1-butanol, 3-Methylbutan-1-ol, 3-Methylbutan-2-ol, 3-Methyl-2-pentanol, 4-Methyl-1,3-dioxolan-2-one, 4-Methyl-2-pentanol, 4-Methylcyclohexanone, 5-Methyldihydro-2(3H)-furanone, acetaldehyde diethyl acetal, acetaldehyde dimethyl acetal, benzoic acid methyl ester, benzyl alcohol, butanone, butyl 2-hydroxy-2-methyl 11. The method of any one of claims 1 to 10, wherein the carboxylic acid ester is selected from the group consisting of butyl propanoate, butyl acetate, butyl formate, chloroform, cyclohexanol, cyclopentanol, cyclopentanone, dichloromethane, diethyl carbonate, diethyl ether, diethyl ketone, di-isopropyl ether, dimethyl carbonate, ethyl acetate, ethyl butyrate, ethyl formate, ethyl-3-oxobutanoate, gamma valerolactone, hexane-2-ol, iso-butyl acetate, iso-butyl formate, iso-propyl acetate, isopropyl butyrate, isopropyl methyl ketone, isopropyl methyl ketone, malonic acid diethyl ester, malonic acid dimethyl ester, methyl acetate, methyl butyrate, methyl formate, methyl propyl ketone, methyl-tetrahydrofuran, methyl-iso-butyl ketone, methyl propyl ketone, pentan-2-ol, pentan-3-ol, propyl acetate, t-butyl methyl ether, toluene, or a mixture of two or more thereof.

12. 12. The method according to any one of claims 1 to 11, wherein the mixing in step c) is carried out by means of a stirred vessel or reactor, a static mixer, a stirred or pulsed extraction column, a bead-packed column, a Pall-ring or Raschig-ring packed column, a packed column according to Sulzer or a packed column with Raschig metal, a rotor-stator mixing system, a baffled reactor, a vibrating baffled reactor, a continuous baffled reactor, a laminar jet break-up device, a cross-flow membrane emulsifier, a premixed membrane emulsifier, a swirl-flow membrane emulsifier, a microfluidic device (co-flow, tangential cross-flow, flow focus principle) or a microstructured membrane emulsifier, an ultrasonic device and a stirred vessel with a stirrer.

13. 13. The method according to any one of claims 1 to 12, wherein the aqueous phase (AP) comprises 0.001 to 5% by weight of an emulsion stabilizer.

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