ORGANIC POLYMER PARTICLES CONTAINING POLY(OXAZOLINE) STABILIZERS AND USE OF POLY(OXAZOLINES) FOR THE STABILIZATION OF ORGANIC POLYMER PARTICLES

Description

[0001] The invention relates to the field of the production and processing of polymer dispersions, preferably polymer dispersions of nanoparticulate particles, as well as the polymer powders obtained by processing polymer dispersions. In particular, the invention relates to the production and processing of organic polymer particles stabilized with poly(oxazolines), which are preferably present dispersed in liquid water or in water-miscible liquids, or which are obtained from these liquids by liquid removal. This can preferably be carried out by freeze-drying (lyophilization).

[0002] It is known to stabilize polymer dispersions using surface-active agents such as surfactants or protective colloids. Polymer dispersions can be produced directly from monomers by selected polymerization processes, such as emulsion polymerization or suspension polymerization, or by dispersing a polymer in a dispersion medium, such as water and / or a water-miscible liquid. To produce these so-called secondary dispersions, polymer particles are obtained in a dispersion medium. This can be achieved, for example, by precipitating a polymer solution through the addition of water, by the progressive dispersion of water in a polymer until phase inversion occurs, or by dispersing a dissolved polymer through energy input, such as ultrasonic stimulation.

[0003] It is known from the prior art that various additives can be used to stabilize polymer particles during their production. The stabilization of these polymer particles can be divided into the following areas: i) Stabilization of polymer particles during the preparation and purification of polymer dispersions (stabilizing additives often referred to as "surfactants" or "surfactants"), ii) Stabilization of polymer particles during the lyophilization and storage of polymer dispersions (stabilizing additives often referred to as "cryoprotectants"), and iii) Stabilization of polymer particles during use in the dispersing medium, e.g., an aqueous system.

[0004] Regarding the stabilization of polymer particles during the preparation and purification of polymer dispersions, the following publications should be mentioned: C. Gomes et al. and H. Murakami et al.used poly(vinyl alcohol) (PVA) to synthesize poly(DL-lactide- co to stabilize poly(DL-lactide-co-glycolide) (PLGA) nanoparticles. Stabilizing the particles during production is therefore already known; however, poly(oxazolines) are not used for stabilization. Furthermore, PVA has hemolytic properties, and its proportion must be significantly reduced before biological application (J. Food Sci. 2011, 76, 16-24, Gomes, C., Moreira, RG, Castell-Perez, E. Poly(DL-lactide-co-glycolide) (PLGA) Nanoparticles with entrapped trans-cinnamaldehyde and eugenol for antimicrobial delivery applications and Int. J. Pharm. 1999, 187, 143-152, Murakami, H., Kobayashi, M., Takeuchi, H., Kawashima, Y. Preparation of poly(DL-lactide-co-glycolide) nanoparticles by modified spontaneous emulsification solvent diffusion method).

[0005] In WO 2015 / 28685 A1, poly(2-ethyl-2-oxazolines) are used as a stabilizer for indomethacin during its precipitation without the use of polymer particles. The use of poly(oxazoline) is intended to ensure that the resulting indomethacin particles have a size <500 nm, improved solubility in water or other media, and that these particles can be redispersed. Stabilization of polymer particles by poly(oxazoline)e is not described. C. Giardi et al.Lipid-poly(oxazoline) copolymers are used to form micelles. First, a lipid macroinitiator was synthesized, from which the cationic ring-opening polymerization of 2-methyl-2-oxazoline was initiated. A series of different copolymers were prepared, varying the chain length of the poly(2-oxazoline). The synthesized copolymers were then investigated with regard to surface stabilization of the resulting micelles. The prepared copolymers were proposed for use as polymeric surfactants. Here, a rather amphiphilic block copolymer with a water-insoluble block (lipid) was used. Stabilization of polymer particles by poly(oxazoline)e is not described. ( React. Func. Polym. 2009, 69, 643-649, Giardi, C., Lapinte, V., Charnay, C., Robin, J. Nonionic poly(oxazoline)e surfactants based on renewable source: Synthesis, surface and bulk properties). M. Miyamoto et al.Block copolymers consisting of poly(2-methyl-2-oxazoline) and poly(propylene oxide) were synthesized to test their suitability as potential nonionic surfactants. The surface tension of the polymers was measured and compared with that of Pluronic® < F68. The measured surface activity of the copolymers decreased with increasing hydrophilic polymer content. Stabilization of polymer particles by poly(oxazoline)e is not described. ( Polymer J., 1992, 24, 405-409, Miyamoto, M., Aoi, K., Yamanaka, H., Saegusa, T. Preparation of block copolymer consisting of poly(2-methyl-2-oxazoline) and poly(propylene oxide) blocks. A new nonionic surfactant). From this document, the person skilled in the art deduces that hydrophilic poly(oxazoline)s are not actually suitable as surfactants.

[0006] S. Kobayashi and H. Uyama used copolymers consisting of a hydrophobic (fatty acid) and a hydrophilic (poly(2-ethyl-2-oxazoline) or poly(2-methyl-2-oxazoline)) segment to synthesize nonionic surfactants. Surface tension measurements were performed to determine the surfactant properties. A rather amphiphilic block copolymer with a water-insoluble fatty acid block was used. Stabilization of finely divided polymers by poly(oxazoline)e is not described. ( Macromolecules 1991, 24, 5473-5475, Kobayashi, S., Uyama, H. Synthesis of a nonionic polymeric surfactant from 2-oxazoline having a carboxylate component as the hydrophobic group).

[0007] Z. Amjad & D. Morgan used poly(2-ethyl-2-oxazoline) as a surfactant to stabilize hydroxyapatite in aqueous solution. Stabilization of polymer particles is not disclosed. (Phosphorus Research Bulletin 2011, 25, 33-38. Amjad, Z.; Morgan, D. Efficacy of hydroxyapatite dispersants in the presence of surfactants.)

[0008] Regarding the stabilization of polymer particles during the lyophilization and storage of polymer dispersions, the following publications should be mentioned: US 2014 / 0158931 A1 describes poly(2-oxazoline) as a stabilizer for metal-based nanoparticles. The finished metal particles are suspended in aqueous solution and may be lyophilized. The poly(2-ethyl-2-oxazoline)e used has a reported molar mass (Mn) of 50,000 g mol-1. Stabilization of organic polymer particles is not disclosed.

[0009] CN 102552146 B describes the preparation and storage of liposomal doxorubicin and epirubizin. The liposomes are constructed from phospholipids and contain surfactants or cryoprotectants. Among the cryoprotectants mentioned is poly(2-ethyl-2-oxazoline) with a total content of up to 60%. Stabilization of organic polymer particles is not disclosed.

[0010] AT Press et al.Polyvinyl alcohol was used for particle stabilization during lyophilization by adding 1 µg of the polymer to the particles beforehand. The stabilization of particles during lyophilization is therefore already known; however, in this case, polyvinyl alcohol is used as a cryoprotectant (Nat. Commun. 2014, (5), 5565-5578. Press, AT, Traeger, A., Pietsch, C., Mosig, A., Wagner, M., Clemens, MG, Jbeily, N., Koch, N., Gottschaldt, M., Bézière, N., Ermolayev, V., Ntziachristos, V., Popp, J., Kessels, MM, Qualmann, B., Schubert, US, Bauer, M. Cell type-specific delivery of short interfering RNAs by dyefunctionalised theranostic nanoparticles).

[0011] P. Fonte et al.Trehalose, glucose, sucrose, fructose, or sorbitol at a concentration of 10 w / v% were used as additives to the PLGA nanoparticles for lyophilization. The stabilization of the particles during lyophilization is therefore already known; however, selected carbohydrates are used as cryoprotectants (Biomacromolecules, 2014, 15, 3753-3765, Fonte, P., Soared, S., Sousa, F., Costa, A., Seabra, V., Reis, S., Sarmento, B. Stability study perspective of the effect of freeze-drying using cryoprotectants on the structure of insulin loaded into PLGA nanoparticles).

[0012] Regarding the stabilization of polymer particles during use in the dispersing medium, the following publications should be mentioned as state of the art: D. Kedracki et al.Previously, modified hydrophobic poly(2-oxazoline)s were used for covalent DNA binding. For this purpose, the original double bonds of the monomer units were partially converted to amino groups via a thiol-ene reaction. The resulting copolymers were used to bind DNA directly to the polymer and to achieve surfactant properties via the hydrophobic side chains of the copolymer. The use of water-soluble poly(oxazoline)s and the stabilization of organic polymer particles are not disclosed. ( Adv.Func. Mater. 2013, 24, 1133-1139. Kedracki, D.; Maroni, P.; Schlaad, H. Vebert-Nardin, C. Polymer-aptamer hybrid emulsion templating yields bioresponsive nanocapsules).

[0013] WO 2016 / 087598 A1 discloses microcapsules with good storage stability. These consist of a core material, an inner shell layer of polyvinyl alcohol, and an outer shell layer of poly(oxazoline). The core materials are described as water-insoluble substances, including compounds known as polyesters. The description clarifies that these are esters of polycarboxylic acids with C4-C30 alcohols, and not organic polymers. This document therefore discloses storage-stable microcapsules made of water-insoluble core materials encased in layers of polyvinyl alcohol and poly(oxazoline).

[0014] The poly(oxazoline) surfactants described in the prior art consist largely of copolymers containing a hydrophilic structural unit, namely the unit derived from the polymerization of oxazoline, and a hydrophobic structural unit, namely the unit derived from the polymerization of hydrophobic monomers. The combination of these structural units in a single molecule ensures interactions with both the hydrophobic polymer particle and the hydrophilic dispersing medium. Additionally, the poly(oxazoline) surfactants can form their own nano- or microstructures in aqueous media. Only for the production of indomethacin particles, a low-molecular-weight substance, in aqueous solution has poly(2-ethyl-2-oxazoline) homopolymer been proposed as a stabilizer. Polymer-based particle systems, e.g.,PLGAs are typically stabilized by adding polyvinyl alcohol during preparation and purification. However, polyvinyl alcohol exhibits cytotoxicity, necessitating subsequent purification of the produced particles, e.g., by centrifugation. The stabilization of organic polymer particles, such as polymer-based nanoparticles or microparticles, using water-soluble poly(oxazoline)s, such as poly(2-ethyl-2-oxazoline) or poly(2-methyl-2-oxazoline), as surfactants has not yet been described. These poly(oxazoline)s are hydrophilic polymers.

[0015] Furthermore, the use of agents for surface stabilization and structural preservation after lyophilization (cryoprotectants) is generally known. Standard agents used are sugars (e.g., trehalose, glucose, or sucrose), which are added in relatively large quantities of approximately 5–10% by weight before lyophilization. The use of these sugars leads to very good resuspension of the particles. However, the uptake mechanisms of these particles can be influenced or altered by interaction with sugar transporters (GLUT transporters) on cell surfaces. In addition, sugars are hygroscopic and can cause problems during the storage of the generated particles. Furthermore, sugars are osmotically active, which is often an undesirable factor for biological systems. Stabilization of organic polymer particles, especially nanoparticles, during lyophilization using polyvinyl alcohol is also possible.However, this can lead to increased cytotoxicity.

[0016] The stabilization of organic polymer particles, especially nano- or microparticles, using poly(oxazolines), such as poly(2-ethyl-2-oxazoline) or poly(2-methyl-2-oxazoline) as cryoprotectants has not been described before.

[0017] One object of the present invention was to provide particles containing selected organic polymers that can be dispersed in hydrophilic liquids and whose dispersions are characterized by excellent stability.

[0018] Another object of the present invention was to provide particles of selected organic polymers, which can be in powder form and which are characterized by excellent stability.

[0019] Another object of the present invention was to provide dispersions of selected organic polymer particles in hydrophilic liquids that can be easily purified and / or processed without significant change in particle size, for example by freeze-drying, centrifugation or filtration.

[0020] Another object of the present invention was to provide cryoprotectants for selected organic polymer particles dispersed in hydrophilic liquids.

[0021] The present invention relates to compositions containing water-soluble poly(oxazoline) and organic polymer particles selected from the group of polymers according to claim 1 or from a mixture of two or more of these polymers.

[0022] For the purposes of this description, "hydrophilic liquids" are understood to mean water and / or water-miscible liquids, such as alcohols with one to four carbon atoms or ketones with two to six carbon atoms. For the purposes of this description, "polymer particles" are understood to mean polymers of the aforementioned groups of substances in particle form. The particles may be dispersed in a hydrophilic liquid or, preferably, in solid form, either dispersed in a hydrophilic liquid or in powder form. The particle size can be determined using visual methods, for example, microscopy; for particle sizes in the nanoscale range, light scattering or electron microscopy can be used. The shape of the polymer particles can be arbitrary, for example, spherical, ellipsoidal, or irregular.The polymer particles can also form aggregates of several primary particles. Preferably, the organic polymer particles are in the form of nanoparticles. In addition to the organic polymers, the particles can contain other components, such as active ingredients or excipients.

[0023] The terms "particle" or "particle" are used synonymously in this description.

[0024] For the purposes of this description, "nanoparticles" are defined as particles with a diameter of less than 1 µm, which may be composed of one or more molecules. They are generally characterized by a very high surface-to-volume ratio and thus exhibit very high chemical reactivity. Nanoparticles can consist of polymers or contain other components besides polymers, such as active ingredients or excipients.

[0025] For the purposes of this description, "polymers" refers to the organic compounds mentioned above, characterized by the repetition of certain units (monomer units or repeating units). Polymers can consist of one type or several different types of repeating units. Polymers are produced by the chemical reaction of monomers, forming covalent bonds (polymerization), and the polymerized units link together to form the so-called polymer backbone. This backbone may have side chains, which can contain functional groups. If polymers possess partially hydrophobic properties, they can form nanoscale structures (e.g., nanoparticles, micelles, vesicles) in aqueous environments. Homopolymers consist of only one monomer unit.Copolymers, on the other hand, consist of at least two different monomer units, which can be arranged statistically, as a gradient, alternating or as a block.

[0026] For the purposes of this description, "cryoprotectants" are understood to be water-soluble substances or mixtures of substances that serve to stabilize a particle during lyophilization (freeze-drying). They can be added to the particles dispersed in the dispersion medium, e.g., the particle suspension, either during production or subsequently (but before lyophilization). Furthermore, these substances or mixtures are not covalently bound to the particles.

[0027] For the purposes of this description, "surfactants" are understood to be water-soluble substances or mixtures of substances that serve to stabilize particles during their manufacture and storage in aqueous media. They are usually added to the dispersing medium, e.g., the aqueous phase, during particle production, but can also be added after production to stabilize the resulting dispersion.

[0028] For the purposes of this description, "water-soluble compounds" or "water-soluble poly(oxazolin)s" are understood to be compounds or poly(oxazolin)s that dissolve in at least 50 g / L of water at 25 °C.

[0029] For the purposes of this description, "active ingredients" are understood to be compounds or mixtures of compounds that exert a desired effect on a living organism. These can be, for example, pharmaceutical agents or agrochemical agents. Active ingredients can be low- or high-molecular-weight organic compounds. Preferably, the active ingredients are low-molecular-weight pharmaceutical substances or high-molecular-weight pharmaceutical substances, whereby hydrophilic active ingredients derived from potentially therapeutically useful nucleic acids (e.g., short interferin RNA, short hairpin RNA, microRNA, plasmid DNA) or from potentially useful proteins (e.g., antibodies, interferons, cytokines) can be used.

[0030] For the purposes of this description, the term "pharmaceutical active ingredient" refers to any inorganic or organic molecule, substance, or compound that has a pharmacological effect. The term "pharmaceutical active ingredient" is used synonymously with the term "medicinal product" here.

[0031] Active ingredients can be those that, without being encapsulated in a nanoparticle or liposome, have only low or no bioavailability, or low or no stability. in vivo exhibit or are intended to act only in certain cells of an organism.

[0032] For the purposes of this description, "excipients and additives" are defined as substances added to a formulation to impart certain additional properties and / or to facilitate its processing. Examples of excipients and additives include tracers, contrast agents, carriers, fillers, pigments, dyes, perfumes, lubricants, UV stabilizers, antioxidants, and surfactants. Specifically, "excipients and additives" encompass any pharmacologically compatible and therapeutically useful substance that is not a pharmaceutical active ingredient but can be formulated together with a pharmaceutical active ingredient in a pharmaceutical composition to influence, and in particular improve, the qualitative properties of the pharmaceutical composition.Preferably, the excipients and / or additives have no effect, or no significant effect with regard to the intended treatment, or at least no undesirable effect.

[0033] Preferred compositions according to the invention relate to a pharmaceutical composition comprising a nanostructured carrier system according to the invention, at least one pharmaceutical active ingredient, and suitable excipients and additives.

[0034] Preferred compositions according to the invention contain particles of selected organic polymers with a mean diameter D50 of less than 10 µm, in particular less than 1 µm. Here, D50 means that 50 volume percent of the particles are smaller than the specified value for D50. The D50 value can be determined for the purposes of this description by light scattering or by microscopy, e.g., by transmission electron microscopy or scanning electron microscopy.

[0035] Particularly preferred compositions according to the invention are those with particles of selected organic polymers with particle diameters in the range of 50 to 999 nm. The particle diameters relate to the primary particles and can be determined for the purposes of this description by (dynamic) light scattering ((D)LS), by nanosize tracking analysis (NTA), or by electron microscopy, e.g. by transmission electron microscopy or by scanning electron microscopy.

[0036] The particles of selected organic polymers can be present in the compositions according to the invention as a powder in solid form or they can be dispersed in hydrophilic solvents, wherein the particles are present in the dispersing medium in liquid form or, in particular, in solid form.

[0037] In preferred compositions according to the invention, the particles of selected organic polymers form a dispersed phase in a liquid containing water and / or water-miscible compounds. In particularly preferred compositions according to the invention, the particles of selected organic polymers are dispersed in the hydrophilic liquid.

[0038] In a further preferred embodiment of the compositions according to the invention, the particles of the finely divided, selected organic polymer are in solid form and the particles are coated by the poly(oxazoline).

[0039] The selected organic polymer used according to the invention is a selected polymer according to the definition given above or a mixture of such polymers.

[0040] Classes of materials which can form the backbone of the polymer used according to the invention are polyesters derived from organic dicarboxylic acids and organic diols and / or from organic hydroxycarboxylic acids, polycarbonates, polymers derived from esters of ethylene unsaturated carboxylic acids, such as polyacrylate or polymethacrylate.

[0041] The polymers used according to the invention can be linear polymers or they can be graft, comb and star polymers, dendrimers, ladder polymers, ring-shaped polymers, polycatenanes and polyrotaxanes.

[0042] The solubility of the polymers used according to the invention can be influenced by copolymerization with suitable monomers and / or by functionalization. Such techniques are known to those skilled in the art.

[0043] The organic polymers used according to the invention can encompass a wide molar mass range. Typical molar masses (Mn) range from 2,000 to 500,000 g / mol, particularly from 5,000 to 49,900 g / mol. These molar masses can be determined by 1H NMR spectroscopy of the dissolved polymer. In particular, an analytical ultracentrifuge or chromatographic methods, such as size exclusion chromatography, can be used to determine the molar masses.

[0044] Preferred organic polymers have a number-average molar mass in the range of 5,000 to 20,000 g / mol, determined by 1< H-NMR spectroscopy or by using an analytical ultracentrifuge.

[0045] The proportion of the organic polymer in the composition according to the invention can cover a wide range. If the organic polymer is dispersed in a dispersion medium, its proportion of the total composition is generally 0.5 to 20 wt.%, preferably 1 to 5 wt.%. If the organic polymer is present in particle form together with the poly(oxazoline), for example as a powdered solid, its proportion of the total composition is generally 0.1 to 30 wt.%, preferably 0.5 to 10 wt.%.

[0046] The organic polymer used according to the invention can be produced using conventional polymerization methods. Examples include polymerization in bulk, polymerization in solution, or emulsion or suspension polymerization. These methods are known to those skilled in the art.

[0047] Among the most frequently used organic polymers is the group of polyesters. These are generally polycondensates derived from aliphatic or cycloaliphatic diols and from aliphatic, cycloaliphatic, and / or aromatic dicarboxylic acids or their polyester-forming derivatives, such as their dialkyl esters. They can also be polycondensates derived from aliphatic or cycloaliphatic hydroxymonocarboxylic acids or their polyester-forming derivatives, such as hydroxymonocarboxylic acid alkyl esters.

[0048] Preferred polyesters include those derived from aliphatic diols and from aliphatic dicarboxylic acids or from aliphatic dicarboxylic acid alkyl esters, and those derived from aliphatic hydroxymonocarboxylic acids or from aliphatic hydroxymonocarboxylic acid alkyl esters.

[0049] Polyhydroxyalkanoates are particularly preferred, and of these, lactic acid homopolymers (PLA) or copolymers are especially preferred. A particularly preferred polyester is the lactic acid-glycolic acid copolymer (PLGA).

[0050] Other highly preferred organic polymers are polymers derived from esters of ethylene unsaturated carboxylic acids, in particular from polyacrylic acid esters and / or from polymethacrylic acid esters, most preferably alkyl acrylate-methyl alkyl acrylate copolymers.

[0051] The compositions according to the invention contain one or more water-soluble poly(oxazoline)s. The amount of poly(oxazoline)s, based on the total amount of the composition according to the invention, is generally 0.1 to 30% by weight.

[0052] Poly(oxazoline)s are well-known compounds. They are typically prepared by cationic ring-opening polymerization of oxazolines, preferably 2-oxazolines, in solution and in the presence of an initiator. Examples of initiators include electrophiles such as salts or esters of aromatic sulfonic or carboxylic acids, salts or esters of aliphatic sulfonic or carboxylic acids, or aromatic halogen compounds. Multifunctional electrophiles can also be used as initiators. In addition to linear poly(oxazoline)s, branched or star-shaped molecules can also be formed. Examples of preferred initiators are esters of arylsulfonic acids, such as methyl tosylate, esters of alkanesulfonic acids, such as trifluoromethanesulfonic acid, or mono- or dibromobenzene. The polymerization is usually carried out in a polar aprotic solvent, for example, acetonitrile.

[0053] The oxazolines used to produce the poly(oxazoline)e according to the invention are 2-oxazolines (4,5-dihydrooxazoles) with a C=N double bond between the carbon atom 2 and the nitrogen atom. These can be substituted at the 2-, 4- and / or 5-carbon atom and / or at the 3-nitrogen atom, preferably at the 2-carbon atom and / or at the 3-nitrogen atom.

[0054] 2-Oxazolines containing a substituent at the 2-position are preferred. Examples of such substituents are methyl or ethyl.

[0055] In addition to the 2-oxazolines, small amounts of other monomers copolymerizable with 2-oxazolines can be used in the production of the water-soluble poly(oxazoline)e used according to the invention.

[0056] The water-soluble poly(oxazoline)s used according to the invention generally contain at least 80 wt.%, in particular at least 90 wt.% and most preferably at least 95 wt.%, based on their total mass, of recurring structural units of formula I and / or formula II -NR 1< -CR 3< H-CR 4< H- (I), -NR 1< -CR 3< H-CR 4< H-CR 5< H- (II), wherein R1< means a residue of the formula -CO-R2<, R3<, R4< and R5< independently mean hydrogen, methyl, ethyl, propyl or butyl, R2< is selected from the group consisting of hydrogen, methyl, ethyl, -CmH2m-X or -(CnH2n-O)o-(CpH2p-O)q, -R6<, R6< is hydrogen or C1-C6-alkyl, in particular methyl or, most preferably, hydrogen, m is an integer from 1 to 6, X is selected from the group consisting of hydroxyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, carboxyl, carboxylic ester, sulfonyl, sulfonic ester or carbamate, n and p are independently integers from 2 to 4, where n is not equal to p, n is preferably 2 and p is preferably 3, and o and q are independently integers from 0 to 60, in particular 1 to 20 and most preferably 2 to 10, wherein at least one of the o or q is not equal to 0.

[0057] Preferred water-soluble poly(oxazoline)s used according to the invention are those in which R 2< is hydrogen, methyl or ethyl and R 3< to R 5< is hydrogen, or in which R 2< is hydrogen, methyl or ethyl and two of the residues R 3< to R 5< are hydrogen and one of the residues R 3< to R 5< is methyl or ethyl.

[0058] The molar mass of the poly(oxazoline)e used according to the invention is typically 5,000 to 500,000 g / mol, in particular 5,000 to 20,000 g / mol. For the purposes of this description, the molar mass is determined by 1H NMR analysis.

[0059] Particularly preferred compositions according to the invention contain a water-soluble poly(oxazoline) which has at least 90 wt.%, in particular at least 95 wt.%, based on its total mass, of recurring structural units of formula I, wherein R 2< means methyl or ethyl.

[0060] Other preferred compositions according to the invention contain, in addition to the finely divided organic polymer, one or more pharmaceutical active ingredients.

[0061] The compositions according to the invention can be prepared by precipitation, preferably by nanoprecipitation. For this purpose, the organic polymers used according to the invention, which are hydrophilic due to the presence of polar groups, are dissolved in a water-immiscible solvent, such as dichloromethane, or in a water-miscible solvent, such as acetone or ethyl acetate. This solution is added dropwise to a hydrophilic dispersing medium containing a water-soluble poly(oxazoline), preferably water containing water containing poly(2-oxazoline) or a water-soluble mixture of water and methanol or ethanol containing poly(2-oxazoline). This is preferably carried out with vigorous stirring. This promotes the production of smaller particles. The organic polymer is deposited in the dispersing medium in finely divided form.

[0062] Alternatively, the compositions according to the invention can also be produced by emulsification, preferably by nanoemulsion. For this purpose, the organic polymers used according to the invention, which are hydrophilic due to the presence of polar groups, are dissolved in a water-immiscible solvent, such as dichloromethane, or in a water-miscible solvent, such as acetone or ethyl acetate. This solution is combined with a hydrophilic dispersing medium containing a water-soluble poly(oxazoline), preferably water containing water-soluble poly(2-oxazoline) or a water-soluble mixture of water and methanol or ethanol containing poly(2-oxazoline), preferably forming two liquid phases. This mixture is then emulsified by the input of energy, preferably by sonication with ultrasound.

[0063] In addition to the organic polymer, one or more active ingredients and / or one or more excipients and additives may be present when it is dispersed in the dispersing medium. Alternatively, these active ingredients and / or excipients and additives may be added after the organic polymer has been dispersed in the hydrophilic liquid.

[0064] In the production of organic polymers dispersed in hydrophilic liquids, polyvinyl alcohol or polyethylene polypropylene block copolymers, such as Pluronic® < F127 or Pluronic® < F68, or polyoxyethylene sorbitan monooleate, such as Tween® < 80, have typically been used. The compositions according to the invention are characterized by increased stability compared to these known compositions.

[0065] The separation of the polymer particles and the poly(oxazoline) stabilizer from the hydrophilic liquid can be achieved in various ways. Examples include centrifugation, ultrafiltration, or dialysis.

[0066] Particularly preferably, the polymer particles, which may optionally contain an active ingredient and / or excipients and additives, and the poly(oxazoline) stabilizer are extracted from the hydrophilic liquid by freeze-drying. Surprisingly, it has been found that the poly(oxazoline) acts as a cryoprotectant. Compared to previously used sugar-based cryoprotectants, such as Hepes Buffered Glucose, glucose, or sucrose, no further processing step is necessary after freeze-drying for the poly(oxazoline)-stabilized dispersions, for example, by centrifugation, since the finely divided polymers obtained according to the invention do not trigger cytotoxicity, hemolysis, or other known immune reactions.

[0067] The polymer dispersion produced according to the invention can be further purified after production. Common methods include purification by dialysis, ultrafiltration, filtration, or centrifugation.

[0068] Purification by filtration can separate particles, such as aggregates, but also endotoxins, unencapsulated active ingredients or excipients, or bacterial contaminants from the dispersion. This process can change the particle concentration.

[0069] Purification via dialysis can separate solvents or dissolved molecules from the dispersion. The process is largely independent of particle size with respect to the dispersed particles. However, the concentration of the dispersed particles decreases during dialysis, and the process is relatively time-consuming.

[0070] Purification by centrifugation can also separate solvents or dissolved molecules from the dispersion. However, this method also reduces the concentration of the dispersed particles. Furthermore, only dispersions with larger diameter nanoparticles, e.g., more than 150 nm, can be treated, and the particles may be damaged in the process. Additionally, redispersing the particles obtained in this way can be difficult.

[0071] Surprisingly, when using poly(oxazolin)e according to the invention for the purification of polymer dispersions, it has been shown that the previously known disadvantages in dialysis, centrifugation and purification using filters only occur to a significantly reduced extent or have even disappeared completely.

[0072] The invention also relates to the use of water-soluble poly(oxazoline) for stabilizing organic polymer particles selected from the group of polymers according to claim 15 or from a mixture of two or more of these polymers in a liquid containing water and / or water-miscible compounds.

[0073] Furthermore, the invention relates to the use of water-soluble poly(oxazoline) for stabilizing organic polymer particles selected from the group of polymers according to claim 16 or from a mixture of two or more of these polymers during freeze-drying.

[0074] Suspensions of the finely divided organic polymer in a hydrophilic liquid are particularly preferred.

[0075] Furthermore, the invention relates to the use of water-soluble poly(oxazoline) as stabilizers in the production or processing of organic polymer particles selected from the group of polymers according to claim 17 or from a mixture of two or more of these polymers in a hydrophilic liquid.

[0076] The preferred processing methods are dialysis, centrifugation or filtration.

[0077] Finally, the invention relates to the use of water-soluble poly(oxazoline) for stabilizing powdered organic polymer particles selected from the group of polymers according to claim 18 or from a mixture of two or more of these polymers.

[0078] The following examples illustrate the invention without limiting it. Example 1: Production of poly(2-oxazoline)ene (PO x )

[0079] The synthesis of poly(2-oxazoline)ene has already been described in the literature (see, e.g., Wiesbrock, F. et al. Macromolecular Rapid Communications 2004, 25, 1895-1899). The procedure is therefore described using poly(2-ethyl-2-oxazoline) with a degree of polymerization (DP) of 61 (P(EtOx) 61 ).

[0080] In a microwave reaction vessel, 2-ethyl-2-oxazoline (6.06 mL, 60.0 mmol), methyl tosylate (0.15 mL, 0.1 mmol), and acetonitrile (8.79 mL) were mixed under inert conditions. The reaction vessel was then heated to 140 °C in a synthesis microwave oven for 14 min. The reaction was then terminated by adding 0.5 mL of deionized water and stirred overnight at room temperature. The resulting solution was purified by diluting it with dichloromethane and then precipitating it in an excess of ice-cold diethyl ether. The precipitated polymer was then filtered off and dissolved in dichloromethane. The solvent was subsequently removed by rotary evaporation, and the polymer was dried under high vacuum until completely solvent-free. The final product was a crystalline, white solid.

[0081] 1< H-NMR (CDCl 3 , 300 MHz): δ = 4.34 (0.1H, s, backbone-OH), 3.44 (4.0H, s, backbone), 3.02 (0.3H, s, CH 3 -backbone), 2.4 (1.7H, m, CH 2 (EtOx)), 1.11 (2.5H, s, CH 3 (EtOx)) ppm.

[0082] SEC (Eluent: DMAc 1)< , 0.21% LiCl, PS 2)< -Standard): M n = 11,200 g mol -1< ,

[0083] M w = 12,200 g mol -1< , D = 1.09.

[0084] Figure 1 zeigt das 1< H-NMR (300 MHz, CDCl 3 ) Diagramm des P(EtOx) 61 .

[0085] Figure 2 zeigt das Größenausschlusschromatographie-Diagramm (DMAc 1)< , 0.21% LiCl, PS 2)< -Calibration) des P(EtOx) 61 . 1) DMAc = Dimethylacetamid 2) PS = Polystyrol Example 2: Freeze-drying experiments

[0086] PLGA 3)< Nanoparticles were prepared by nanoprecipitation (see Example 3) and characterized by dynamic light scattering with respect to size (particle diameter, z-mean) and size distribution (PDI). After this characterization, a specific amount of cryoprotectant was added to the nanoparticle suspension at various concentrations. The suspensions were frozen in a -80 °C freezer and subsequently freeze-dried (24 h, -56 °C, 0.01 mbar). Approximately 2 mg of the resulting powder was resuspended in 1 mL of ultrapure water and then again characterized by dynamic light scattering with respect to particle diameter (z-mean) and PDI. The ratios were determined by dividing the values ​​obtained after lyophilization by those determined immediately after preparation. Table 1: Results of the lyophilization experiments of PLGA 3)< nanoparticles with different concentrations of P(EtOx) 61 as cryoprotectant. Concentration of cryoprotectant [%] 0 0,05 0,10 0,50 1,00 2,50 5,00 Size after preparation [nm] 88,9 ± 0,8 Size after lyophilization [nm] 2131,2 ± 1090,4 171,2 ± 12,7 130,5 ± 19,1 123,5 ± 24,3 133,4 ± 28,6 129,8 ± 20,1 138,5 ± 31,6 Size ratio 23,9 1,9 1,5 1,4 1,5 1,5 1,6 PDI after preparation 0,095 ± 0,007 PDI after lyophilization 0,669 ± 0,131 0,387 ± 0,050 0,272 ± 0,046 0,190 ± 0,065 0,217 ± 0,049 0,230 ± 0,064 0,240 ± 0,064 PDI ratio 7,0 4,1 2,9 2 2,3 2,4 2,5 Zeta potential after preparation [mV] -29,6 ± 0,2 Zeta potential after lyophilization [mV] -29,7 ± 4,4 -29,2 ± 2,5 -30,9 ± 9,4 -21,1 ± 6,7 -19,7 ± 12,1 -23,1 ± 10,7 -23,9 ± 7,9 Zeta Potential Ratio 1,0 1,0 1,0 0,7 0,7 0,8 0,8 3) < PLGA = Lactic acid-glycolic acid copolymer Example 3a: Production of nanoparticle suspensions by nanoprecipitation

[0087] 5 mg of PLGA 3)< were dissolved in 2.5 mL of acetone and then transferred by syringe pump at a defined rate with continuous stirring into a vessel containing 4.5 mL of an aqueous P(EtOx) 61 solution. The organic solvent was then evaporated overnight with continuous stirring, and the nanoparticles were characterized with respect to their particle diameter and PDI. Table 2: Results of the production of PLGA 3)< nanoparticles by nanoprecipitation with different concentrations of P(EtOx) n as surfactant. Surfactant concentration [mg mL -1< ] 0 0,3 0,5 1 Size [nm] 98,0 ± 9,9 118,0 ± 0,7 122,2 ± 5,9 116,6 ± 5,2 PDI 0,103 ± 0,020 0,093 ± 0,007 0,153 ± 0,043 0,086 ± 0,017 3) < PLGA = Lactic acid-glycolic acid copolymer Example 3b: Production of nanoparticle suspensions by nanoemulsion

[0088] A defined amount of P(EtOx) 61 was dissolved in 1 mL of ultrapure water. 10 mg of PLGA 3)< was dissolved in 0.5 mL of ethyl acetate, carefully pipetted onto the surfactant solution, and then treated with an ultrasonic finger (Power: 40 W, Cycle: 100%, Amplitude: 100%, Time: 10 sec). The particle suspension was then diluted tenfold with ultrapure water and stirred overnight at room temperature to evaporate the organic solvent. The nanoparticles were then characterized with respect to their particle diameter and PDI. Table 3: Results of the production of PLGA 3)< nanoparticles using nanoemulsion with different concentrations of P(EtOx) 61 as surfactant. Surfactant concentration [%] 0 0,3 0,5 1 Size [nm] 231,5 ± 15,3 448,9 ± 21,2 460,5 ± 48,5 217,4 ± 6,1 PDI 0,353 ± 0,010 0,383 ± 0,039 0,463 ± 0,061 0,164 ± 0,015 3) < PLGA = Lactic acid-glycolic acid copolymer Example 4a: Influence of the DP of poly(2-oxazoline) on the size of polymer nanoparticles after preparation by nanoprecipitation

[0089] 5 mg of PLGA 3)< were dissolved in 2.5 mL of acetone and then transferred by syringe pump at a defined rate with continuous stirring into a vessel containing 4.5 mL of an aqueous P(EtOx) n or P(MeOx) n solution. The organic solvent was then evaporated overnight with continuous stirring, and the nanoparticles were characterized with respect to their particle diameter and PDI by dynamic light scattering. A portion of the suspension was frozen in a -80 °C freezer and subsequently lyophilized overnight. Approximately 2 mg of the resulting powder was then resuspended in 1 mL of ultrapure water and characterized again. The ratio of the values ​​was calculated by dividing the corresponding measurements after lyophilization by those after preparation. Table 4: Results of the production of PLGA 3)< nanoparticles by nanoprecipitation with P(EtOx) n as surfactant at a concentration of 1% (w / v). DP P(EtOx) n 25 61 107 184 Size after preparation [nm] 157,5 ± 7,2 118,0 ± 0,7 164,4 ± 11,5 172,5 ± 10,8 Size after lyophilization [nm] 272,1 ± 167,8 134,5 ± 4,7 167,1 ± 15,7 173,4 ± 13,8 Size ratio 1,7 1,4 1,02 1,0 PDI after preparation 0,071 ± 0,009 0,093 ± 0,007 0,076 ± 0,007 0,074 ± 0,010 PDI after lyophilization 0,261 ± 0,054 0,147 ± 0,052 0,114 ± 0,007 0,112 ± 0,002 PDI ratio 3,7 1,6 1,5 1,5 Table 5: Results of the production of PLGA 3)< nanoparticles by nanoprecipitation with P(MeOx) n as surfactant at a concentration of 1% (w / v). DP P(MeOx) n 25 57 100 211 Size after preparation [nm] 169,8 ± 9,7 195,8 ± 6,0 172,9 ± 18,8 181,8 ± 5,9 Size after lyophilization [nm] 299,4 ± 114,1 223,0 ± 36,6 181,6 ± 27,0 173,4 ± 15,9 Size ratio 1,8 1,1 1,1 1,0 PDI after preparation 0,059 ± 0,006 0,069 ± 0,009 0,069 ± 0,015 0,124 ± 0,092 PDI after lyophilization 0,343 ± 0,069 0,125 ± 0,065 0,137 ± 0,023 0,108 ± 0,026 PDI ratio 5,8 1,8 2,0 0,9 3) < PLGA = Lactic acid-glycolic acid copolymer Example 4b:Influence of the DP of poly(2-oxazoline) on the particle size of polymer nanoparticles after preparation using nanoemulsion

[0090] A defined amount of P(EtOx)n or P(MeOx)n was dissolved in 1 mL of ultrapure water. 10 mg of PLGA 3)< were dissolved in 0.5 mL of ethyl acetate, carefully pipetted onto the surfactant solution, and then treated with an ultrasonic finger (power: 40 W, cycle: 100%, amplitude: 100%, time: 10 sec). The particle suspension was then diluted tenfold with ultrapure water and stirred overnight at room temperature to evaporate the organic solvent. The nanoparticles were characterized with respect to their particle diameter and PDI. A portion of the suspension was frozen in a -80 °C freezer and then lyophilized overnight. Approximately 2 mg of the particles were then resuspended in 1 mL of ultrapure water and characterized again. The ratio of the values ​​was calculated by dividing the corresponding measurements after lyophilization by those after preparation. Table 6: Results of the production of PLGA 3)< nanoparticles using a nanoemulsion with P(EtOx) n as a surfactant at a concentration of 1% (w / v). nd: not determined. DP P(EtOx) n 25 61 107 184 Size after preparation [nm] 808,1 ± 362,7 217,4 ± 6,1 230,2 ± 18,5 194,2 ± 10,3 Size after lyophilization [nm] and 204,4 ± 4,3 213,1 ± 12,8 179,2 ± 13,1 Size ratio and 0,9 0,9 0,9 PDI after preparation 0,754 ± 0,426 0,164 ± 0,015 0,146 ± 0,047 0,086 ± 0,011 PDI after lyophilization and 0,100 ± 0,017 0,113 ± 0,010 0,102 ± 0,008 PDI ratio and 0,6 0,8 1,2 Table 7: Results of the production of PLGA 3)< nanoparticles using a nanoemulsion with P(MeOx) n as a surfactant at a concentration of 1% (w / v). nd: not determined. DP P(MeOx) n 25 57 100 211 Size after preparation [nm] 803,7 ± 231,8 159,7 ± 4,0 273,2 ± 20,7 200,5 ± 5,3 Size after lyophilization [nm] and 164,4 ± 6,7 269,9 ± 32,5 191,8 ± 7,2 Size ratio and 1,0 1,0 1,0 PDI after preparation 0,289 0,086 ± 0,003 0,165 ± 0,007 0,080 ± 0,004 PDI after lyophilization and 0,108 ± 0,019 0,185 ± 0,083 0,100 ± 0,013 PDI ratio and 1,3 1,1 1,3 3) < PLGA = Lactic acid-glycolic acid copolymer Example 5: Nanoparticles made of different coating polymers

[0091] 100 mg of P(EtOx)n or P(MeOx)n were dissolved in 1 mL of ultrapure water. 10 mg of coating polymer were dissolved in 0.5 mL of ethyl acetate, carefully pipetted onto the surfactant solution, and then treated with an ultrasonic finger (power: 40 W, cycle: 100%, amplitude: 100%, time: 10 sec). The particle suspension was then diluted tenfold with ultrapure water and stirred overnight at room temperature to evaporate the organic solvent. The nanoparticles were characterized with respect to their particle diameter and PDI. The nanoparticles were purified differently as described in the table. All resulting particle suspensions were then frozen in a -80 °C freezer and subsequently lyophilized overnight. Approximately 2 mg of the powder were then resuspended in 1 mL of ultrapure water and characterized again.The ratio of the values ​​was calculated by dividing the corresponding measurements after lyophilization by those after preparation. Table 8: Properties of nanoparticles of different coating polymers using P(EtOx) 61 or P(MeOx) 57 as surfactant after preparation by nanoemulsion. na: not available (not available because the nanoparticles aggregated too strongly). Coating polymer surfactant Size [d, nm] PDI Zeta potential [mV] PLGA 3)< P(EtOx) 61 214,9 ± 1,5 0,147 ± 0,030 -33,0 ± 0,9 P(MeOx) 57 155,8 ± 0,9 0,087 ± 0,023 -37,9 ± 0,5 None n / a n / a n / a Eudragit ®< RS 100 4)< P(EtOx) 61 214,0 ± 0,7 0,063 ± 0,018 35,7 ± 0,4 P(MeOx) 57 244,3 ± 2,5 0,081 ± 0,012 42,1 ± 1,7 None 101,6 ± 0,5 0,246 ± 0,020 58,6 ± 0,4 P(MMA 97 - co -FIGURE 32 ) 5)< P(EtOx) 61 155,2 ± 2,8 0,165 ± 0,012 32,3 ± 0,1 P(MeOx) 57 162,9 ± 1,3 0,138 ± 0,028 33,6 ± 1,4 None 176,2 ± 2,4 0,191 ± 0,012 49,1 ± 0,4 Table 9: Properties of nanoparticles of different coating polymers using P(EtOx) 61 or P(MeOx) 57 as surfactant after purification and lyophilization. P(MeOx) 57 is a poly(2-methyl-2-oxazoline) with a degree of polymerization (DP) of 57. na: not available (not available because the nanoparticles aggregated too strongly). P(MMA 97 - co -FIGURE 32 ) 5)< surfactant P(EtOx) 61 P(MeOx) 57 None Purification method Size [d, nm] PDI Size [d, nm] PDI Size [d, nm] PDI After preparation 155,2 ± 2,8 0,165 ± 0,012 162,9 ± 1,3 0,138 ± 0,028 176,2 ± 2,4 0,191 ± 0,012 Lyophilization without purification 172,2 ± 2,7 0,215 ± 0,021 157,5 ± 1,9 0,109 ± 0,026 n / a n / a Centrifugation and resuspension in 1 mL of ultrapure water 229,2 ± 14,9 0,330 ± 0,019 294,7 ± 67,1 0,375 ± 0,033 325,8 ± 88,1 0,362 ± 0,034 Centrifugation and resuspension in 1 mL of 0.5% POx solution 175,4 ± 2,3 0,258 ± 0,035 179,7 ± 3,8 0,128 ± 0,083 253,4 ± 4,1* 0,278 ± 0,042* Syringe filtration n / a n / a 211,6 ± 3,1 0,269 ± 0,032 n / a n / a Eudragit ®< RS100 4)< surfactant P(EtOx) 61 P(MeOx) 57 None Purification method Size [d, nm] PDI Size [d, nm] PDI Size [d, nm] PDI After preparation 214,0 ± 0,7 0,063 ± 0,018 244,3 ± 2,5 0,081 ± 0,012 101,6 ± 0,5 0,246 ± 0,020 Lyophilization without purification 217,2 ± 2,2 0,080 ± 0,024 247,3 ± 4,3 0,086 ± 0,038 n / a n / a Centrifugation and resuspension in 1 mL of ultrapure water 239,3 ± 1,7 0,105 ± 0,037 315,9 ± 8,3 0,220 ± 0,044 n / a n / a Centrifugation and resuspension in 1 mL of 0.5% POx solution 223,3 ± 1,5 0,069 ± 0,026 252,0 ± 3,4 0,105 ± 0,039 n / a n / a Syringe filtration 220,4 ± 4,4 0,062 ± 0,042 257,5 ± 3,7 0,068 ± 0,033 n / a n / a Table 10: Properties of nanoparticles with different coating polymers using P(EtOx) 61 or P(MeOx) 57 as surfactant after purification and lyophilization. P(MeOx) 57 is a poly(2-methyl-2-oxazoline) with a degree of polymerization (DP) of 57. na: not available (not available because the nanoparticles aggregated too strongly). P(MMA 97 - co -FIGURE 32 ) 5)< surfactant P(EtOx) 61 P(MeOx) 57 None Purification method Size ratio PDI ratio Size ratio PDI ratio Size ratio PDI ratio Lyophilization without purification 1,11 1,30 0,97 0,79 n / a n / a Centrifugation and resuspension in 1 mL of ultrapure water 1,48 2,00 1,01 1,06 1.85 1.90 Centrifugation and resuspension in 1 mL of 0.5% POx solution 1,13 1,56 1,10 0,93 1,44* 1,46* Syringe filtration n / a n / a 1,30 1,95 n / a n / a Eudragit ®< RS100 4)< surfactant P(EtOx) 61 P(MeOx) 57 None Purification method Size ratio PDI ratio Size ratio PDI ratio Size ratio PDI ratio Lyophilization without purification 1,01 1,27 1,01 1,06 n / a n / a Centrifugation and resuspension in 1 mL of ultrapure water 1,12 1,67 1,29 2,71 n / a n / a Centrifugation and resuspension in 1 mL of 0.5% POx solution 1,04 1,10 1,03 1,30 n / a n / a Syringe filtration 1,03 0,98 1,05 0,84 n / a n / a 3)< PLGA = Lactic acid-glycolic acid copolymer 4)< Eudragit ®< RS 100 = Methyl methacrylate-(2-(N,N,N-trimethylammonium ethyl))methacrylate-ethyl acrylate copolymer 5)< P(MMA 97 - co -MAEMA 32 ) = 2-(N-methylamineethyl)methacrylate-methylacrylate copolymer Example 6: Influence of purification on the size of nanoparticles

[0092] 5 mg of PLGA 3)< were dissolved in 2.5 mL of acetone and then transferred by syringe pump at a defined rate with continuous stirring into a vessel containing 4.5 mL of an aqueous P(EtOx) 61 solution. The organic solvent was then evaporated overnight with continuous stirring, and the nanoparticles were characterized with respect to their particle diameter and PDI. The nanoparticles were purified differently as described in the table. All resulting particle suspensions were then frozen in a -80 °C freezer and subsequently lyophilized overnight. Approximately 2 mg of the powder were then resuspended in 1 mL of ultrapure water and characterized again. The ratio of the values ​​was calculated by dividing the corresponding measurements after lyophilization by those after preparation. Table 11: Properties of the PLGA 3)< nanoparticles using P(EtOx) 61 or P(MeOx) 57 as surfactant after purification and lyophilization. surfactant P(EtOx) 61 P(MeOx) 57 Purification method prior to lyophilization Size [d, nm] PDI Size [d, nm] PDI After preparation 157,7 ± 1,3 0,102 ± 0,017 201,7 ± 4,2 0,062 ± 0,029 Lyophilization without purification 1262 ± 1182 0,714 ± 0,201 213,5 ± 3,1 0,067 ± 0,010 Centrifugation and resuspension in 1 mL of ultrapure water 898 ± 1062 0,549 ± 0,305 206,7 ± 3,1 0,111 ± 0,034 Syringe filtration and addition of 1 mL of 0.5% POx solution 165,1 ± 1,0 0,172 ± 0,044 189,6 ± 1,2 0,068 ± 0,018 Syringe filtration 1075 ± 111,6 0,948 ± 0,100 190,6 ± 1,5 0,101 ± 0,019 Table 12: Properties of PLGA 3)< nanoparticles using P(EtOx) 61 or P(MeOx) 57 as surfactant after purification and lyophilization. na: not available (not available because the nanoparticles aggregated too strongly). Additive P(EtOx) 61 P(MeOx) 57 Purification method Size ratio PDI ratio Size ratio PDI ratio Lyophilization without purification 8,00 7,00 1,06 1,08 Centrifugation and resuspension in 1 mL of ultrapure water 5,69 5,38 1,02 1,79 Syringe filtration and addition of 1 mL of 0.5% POx solution 1,05 1,69 0,94 1,10 Syringe filtration 6,82 9,29 0,94 1,63 3) < PLGA = Lactic acid-glycolic acid copolymer Example 7: Encapsulation of Nile red

[0093] Nanoparticles were prepared from 10 mg of PLGA 3)< and 0.1 mg of Nile Red from a 1 mg mL stock solution in acetone, as in Example 3, by nanoprecipitation or nanoemulsion. A final surfactant concentration of 1% for the nanoemulsion and 0.3% for the nanoprecipitation was targeted (if present in the aqueous solution).

[0094] The nanoparticles were purified differently as described in the table. All resulting particle suspensions were then frozen in a -80 °C freezer and subsequently lyophilized overnight. Approximately 2 mg of the powder was then resuspended in 1 mL of ultrapure water and characterized again. The ratio of the values ​​was calculated by dividing the corresponding measurements after lyophilization by those after preparation. A portion of the resulting nanoparticles was dissolved in DMF 6)< and the encapsulation efficiency of the active ingredient was determined by UV / VIS spectroscopy via its absorbance. Table 13: Properties of PLGA 3)< -Nil red nanoparticles using P(EtOx) 61 or P(MeOx) 57 as surfactant after preparation by nanoemulsion and nanoprecipitation. na = not available. Active ingredient surfactant Preparation method Size [d, nm] PDI Nile red P(EtOx) 61 Nanoprecipitation 160,8 ± 1,5 0,053 ± 0,028 Nile red P(EtOx) 61 Nanoemulsion 190,7 ± 1,9 0,124 ± 0,013 Nile red P(MeOx) 57 Nanoprecipitation 151,2 ± 0,8 0,065 ± 0,021 Nile red P(MeOx) 57 Nanoemulsion 180,0 ± 0,8 0,099 ± 0,014 Nile red None Nanoprecipitation 145,2 ± 2,5 0,075 ± 0,018 Nile red None Nanoemulsion n / a n / a Table 14: Properties of PLGA 3)< -Nil Red nanoparticles using P(EtOx) 61 or P(MeOx) 57 as surfactant after purification and lyophilization. na: not available (because the nanoparticles aggregated too strongly). nr: not resuspended. Additive P(EtOx) 61 P(MeOx) 57 None Purification method Size [d, nm] PDI Size [d, nm] PDI Size [d, nm] PDI After the preparation 160,8 ± 1,5 0,053 ± 0,028 169,0 ± 2,5 0,069 ± 0,021 145,2 ± 2,5 0,075 ± 0,018 Lyophilization without purification 168,0 ± 1,6 0,087 ± 0,031 n / a n / a n / a n / a Centrifugation and resuspension in 1 mL of 0.5% PO₄²⁻ solution 184,3 ± 1,6 0,145 ± 0,028 187,4 ± 3,2 0,123 ± 0,052 n.r. n.r. Syringe filtration and addition of 1 mL of 0.5% PO x solution 167,7 ± 3,2 0,148 ± 0,045 233,1 ± 8,4 0,314 ± 0,022 180,5 ± 1,6 0,169 ± 0,020 Syringe filtration 161,7 ± 3,4 0,157 ± 0,011 n / a n / a n / a n / a Table 15: Property ratios of PLGA 3)< -Nil red nanoparticles using P(EtOx) 61 or P(MeOx) 57 as surfactant after purification and lyophilization. EE: Encapsulation efficiency. Additive P(EtOx) 61 P(MeOx) 57 None Purification method size ratio PDI ratio EE [µg mg -1< ] Size ratio PDI ratio EE [µg mg -1< ] Size ratio PDI ratio EE [µg mg -1< ] Lyophilization without purification 1,04 1,64 0,52 n / a n / a n / a 28,21 12,23 1,53 Centrifugation and resuspension in 1 mL of 0.5% POx solution 1,14 2,74 0,28 1,15 1,71 0,32 n / a n / a n / a Syringe filtration and addition of 1 mL of 0.5% POx solution 1,04 2,79 0,21 n / a n / a n / a 1,24 2,25 0,28 Syringe filtration 1,01 2,96 0,51 n / a n / a n / a n / a n / a n / a 3)< PLGA = Lactic acid-glycolic acid copolymer 6)< DMF = Dimethylformamide Example 8: Encapsulation of PKC 412 7)<

[0095] 10 mg of PLGA 3)< were dissolved in 1 mL of acetone. 0.3 mg of PKC 412 7)< were dissolved in 30 µL of DMSO 8)< and added to the PLGA 3)< solution. The polymer-drug solution was then transferred by syringe pump at a defined rate with continuous stirring into a vessel containing 10 mL of an aqueous solution, optionally containing a surfactant. The organic solvent was then evaporated overnight with continuous stirring, and the nanoparticles were characterized with respect to their particle diameter and PDI. Subsequently, all resulting particle suspensions were frozen in a -80 °C freezer and then lyophilized overnight. Approximately 2 mg of the particles were then resuspended in 1 mL of ultrapure water or a 0.5% solution of the corresponding poly(2-oxazoline) and characterized again.

[0096] The ratio of the values ​​was calculated by dividing the corresponding measurements after lyophilization by those after preparation. A portion of the resulting nanoparticles was dissolved in DMSO 8)< and the encapsulation efficiency of the active ingredient was determined by UV / VIS spectroscopy via its absorbance. Table 16: Properties of PLGA-PKC 412 3.7)< nanoparticles using P(EtOx) 61 or P(MeOx) 57 as surfactant after purification and lyophilization. na: not available (because the nanoparticles aggregated too strongly). EE: encapsulation efficiency. surfactant After preparation After lyophilization Relationship Size [d, nm] PDI Size [d, nm] PDI Size PDI EE [µg mg -1< ] P(EtOx) 61 168,6 ± 2,4 0,061 ± 0,019 178,9 ± 2,0 0,058 ± 0,025 1,06 0,95 0 P(MeOx) 57 184,6 ± 1,1 0,063 ± 0,034 190,4 ± 2,4 0,086 ± 0,022 1,03 1,36 0,92 ± 0,08 None 156,1 ± 0,9 0,077 ± 0,024 7272 ± 2494 0,740 ± 0,383 n / a n / a 0,98 ± 0,31 3)< PLGA = Milchsäure-Glycolsäure-Copolymer 7)< PKC 412 = [9 S -(9α,10β,11β,13α)]- N -(2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1 H ,9 H -diindolo[1,2,3- gh :3',2',1'- lm ]pyrrolo[3,4- j ][1,7]benzodiazonin-11-yl)- N -methylbenzamid 8)< DMSO = Dimethylsulfoxid

Claims

1. Compositions comprising water-soluble poly(oxazoline) and organic polymer particles selected from the group of polyesters derived from organic dicarboxylic acids and organic diols and / or from organic hydroxycarboxylic acids, polycarbonates, polymers derived from esters of ethylenically unsaturated carboxylic acids or of a mixture of two or more of these polymers.

2. Compositions according to claim 1, whrein the polymer particles are selected from the group consisting of polyesters derived from aliphatic, cycloaliphatic and / or aromatic dicarboxylic acids or their polyester-forming derivatives and aliphatic or cycloaliphatic diols and / or from aliphatic or cycloaliphatic hydroxymonocarboxylic acids or their polyester-forming derivatives or from polymers derived from esters of ethylenically unsaturated carboxylic acids.

3. Compositions according to at least one of claims 1 or 2, wherein the mean diameter D50 of the organic polymer particles is less than 10 µm, preferably less than 1 µm.

4. Compositions according to at least one of claims 1 to 3, wherein the organic polymer particles have diameters in the range between 50 and 999 nm.

5. Compositions according to at least one of claims 1 to 4, wherein the organic polymer particles form a dispersed phase in a hydrophilic liquid.

6. Compositions according to claim 5, wherein the organic polymer particles are suspended in the hydrophilic liquid.

7. Compositions according to at least one of claims 1 to 6, wherein the organic polymer particles are in solid form and are coated by the poly(oxazoline).

8. Compositions according to at least one of claims 1 to 7, wherein the organic polymer particle contains a polyester derived from organic dicarboxylic acids and organic diols and / or from organic hydroxycarboxylic acids.

9. Compositions according to claim 8, wherein the polyester is a polyhydroxy-alkanoate, in particular a lactic acid homopolymer or copolymer.

10. Compositions according to at least one of claims 1 to 7, wherein the organic polymer particle comprises a polymer derived from esters of ethylenically unsaturated carboxylic acids, in particular a homopolymer or copolymer derived from acrylic acid esters and / or methacrylic acid esters, most preferably an alkyl acrylate-alkyl methacrylate copolymer.

11. Compositions according to at least one of claims 1 to 10, wherein the water-soluble poly(oxazoline) comprises at least 80% by weight, based on its total mass, of recurring structural units of formula I and / or formula II         -NR1-CR3H-CR4H-     (I),         -NR1-CR3H-CR4H-CR5H-     (II), wherein R1 represents a residue of the formula -CO-R2, R3, R4 and R5 independently represent hydrogen, methyl, ethyl, propyl, or butyl, R2 is selected from the group consisting of hydrogen, methyl, ethyl, -CmH2m-X or -(CnH2n-O)o-(CpH2p-O)q-R6, R6 is hydrogen or C1-C6 alkyl, m is an integer from 1 to 6, X is selected from the group consisting of hydroxyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, carboxyl, carboxylic ester, sulfonyl, sulfonic ester, or carbamate, n and p are independently integers from 2 to 4, where n is not equal to p, and o and q are independently integers from 0 to 60, where at least one of o or q is not equal to 0.

12. Compositions according to claim 11, wherein R2 is hydrogen, methyl, or ethyl, and R3 to R5 are hydrogen, or in which R2 is hydrogen, methyl, or ethyl, and two of the residues R3 to R5 are hydrogen, and one of the residues R3 to R5 is methyl or ethyl.

13. Compositions according to at least one of claims 11 or 12, wherein the water-soluble poly(oxazoline) comprises at least 90% by weight, based on its total mass, of repeating structural units of formula I, wherein R2 is methyl or ethyl.

14. Compositions according to at least one of claims 1 to 13, wherein the organic polymer particles comprise one or more pharmaceutical active ingredients.

15. Use of water-soluble poly(oxazoline)s for stabilizing organic polymer particles selected from the group of polyesters derived from organic dicarboxylic acids and organic diols and / or from organic hydroxycarboxylic acids, polycarbonates, polymers derived from esters of ethylenically unsaturated carboxylic acids, or of a mixture of two or more of these polymers in a hydrophilic liquid.

16. Use of water-soluble poly(oxazoline)s for stabilizing organic polymer particles selected from the group of polyesters derived from organic dicarboxylic acids and organic diols and / or from organic hydroxycarboxylic acids, polycarbonates, polymers derived from esters of ethylenically unsaturated carboxylic acids, or of a mixture of two or more of these polymers in freeze-drying.

17. Use of water-soluble poly(oxazoline)s as stabilizers in the manufacture or processing of organic polymer particles selected from the group of polyesters derived from organic dicarboxylic acids and organic diols and / or from organic hydroxycarboxylic acids, polycarbonates, polymers derived from esters of ethylenically unsaturated carboxylic acids, or of a mixture of two or more of these polymers in a hydrophilic liquid.

18. Use of water-soluble poly(oxazoline)s for stabilizing powdered organic polymer particles selected from the group of polyesters derived from organic dicarboxylic acids and organic diols and / or from organic hydroxycarboxylic acids, polycarbonates, polymers derived from esters of ethylenically unsaturated carboxylic acids, or of a mixture of two or more of these polymers.