Poly(oxazoline)- and poly(oxazine)-based lipids, process for the preparation thereof, and use thereof

Abstract

The invention relates to poly(oxazoline)- and poly(oxazine)-based lipids, a process for the preparation thereof, and the use thereof. Polymers of formulas lni-[N(COR1)-CR3H-CR4H]w-R2 (I), lni-[N(COR1)-CR3H-CR4H]w-R2 (II) are described, as well as biodegradable derivatives thereof obtained by hydrolysis and oxidation. Group R is selected from the group consisting of -OR11, -OCO-R11, -OCO-R14-CO-OR11, -OCO-R14-CO-NR12R13, - NR12- R14-CO-NR13R15, -O-R16-(O-OC-R18)m and -(cyclo-N3R17)-CH2-OCO- NR12R13, where R11, R13 and R18 correspond to a C6-C20 alkyl. The polymers are prepared by modifying the ω-end group of telechelic poly(2-n-alkyl-oxazolines) and poly(2-n-alkyloxazines), have amphiphilic properties, and are suitable as replacements for polyethylene glycols, in particular in active-ingredient formulations.

Description

[0001] Description

[0002] Poly(oxazoline)- and poly(oxazine)-based lipids, processes for their preparation and their use

[0003] The invention relates to novel polymeric lipids suitable as replacements for polyethylene glycols (hereinafter also referred to as "PEG"). Furthermore, the invention relates to the preparation of these polymers and their use in the production of pharmaceutical formulations.

[0004] Biocompatible polymers are highly attractive materials for biomedical applications such as drug delivery. PEGs are widely used in pharmaceutical products due to the advantages associated with their use. For example, SARS-CoV-2 mRNA vaccines use lipid nanoparticles containing PEG lipids as a crucial component for mRNA delivery. In these lipid nanoparticles, the PEG lipids not only influence the particle size during manufacturing but also prevent particle aggregation and contribute to their storage stability. Furthermore, PEG's stealth effect prolongs the circulation time of the particles in the blood, thus preventing rapid recognition and elimination by the immune system (see X. Hou, T. Zaks, R. Langer, Y. Dong, Nat. Rev. Mater. 2021, 6, 1078-1094).

[0005] However, so-called PEGylation also brings with it significant disadvantages, referred to as the "PEG dilemma." The stimulation of anti-PEG antibodies, which are widespread in humans due to the excessive use of PEG, including in cosmetics, leads to accelerated elimination in the blood, preventing PEGylated particles from efficiently reaching their desired site of action, resulting in reduced efficacy. In addition to lower transfection efficiency, e.g. with SARS CoV 2 mRNA vaccines, anti-PEG antibodies can also lead to hypersensitivity reactions that manifest as pseudoallergy in humans (cf. T. Ishida, M. Ichihara, X. Wang, K. Yamamoto, J. Kimura, E. Majima, H. Kiwada, J. Controlled Release 2006, 112, 15-25 and SS Nogueira, A. Schlegel, K. Maxeiner, B. Weber, M. Barz, MA Schroer, CE Blanchet, DI Svergun, S. Ramishetti, D. Peer, P. Langguth, U. Sahin, H. Haas, ACS Appl. Nano Mater.2020, 3, 10634-10645).

[0006] In addition to these disadvantages, another problem with the use of PEG is the formation of toxic byproducts such as 1,4-dioxane during synthesis and of PEG oligomers due to sequential oxidation when using PEG with lower molecular weights (cf. K. Knop, R. Hoogenboom, D. Fischer, US Schubert, Angew. Chem. Int. Ed. 2010, 49, 6288-6308). Therefore, it is important to develop PEG alternatives.

[0007] Poly(2-n-alkyl-2-oxazolines) (hereinafter also referred to as "PAOx") with short side chains exhibit similar hydrophilicity, biocompatibility, and "stealth effect" and therefore appear to be promising candidates for replacing PEG, which was further confirmed by a detailed comparison of their solubility behavior (cf. M. Grube, M.N. Leiske, U.S. Schubert, I. Nischang, Macromolecules 2018, 51, 1905-1916). In contrast to PEG, PAOx also exhibit greater structural versatility due to their side-chain modifiability.

[0008] PAOx with longer side chains are hydrophobic and can be used to prepare amphiphilic copolymers, low surface energy materials, or low adhesion coatings. Thermal and crystalline properties can also be tailored by variations in the PAOx side chains (cf. R. Hoogenboom, MWM Fijten, HML Thijs, BM van Lankvelt, US Schubert, Designed Monomers and Polymers 2005, 8, 659-671 ; EFJ Rettler, JM Kranenburg, HML Lambermont-Thijs, R. Hoogenboom, US Schubert, Macromolecular Chemistry and Physics 2010, 211, 2443-2448; K. Kempe, M. Lobert, R. Hoogenboom, US Schubert, Journal of Polymer Science Part A: Polymer Chemistry 2009, 47, 3829-3838; M. Beck, P. Birnbrich, U. Eicken, H. Fischer, WE Fristad, B. Hase, HJ Krause, Die Angewandte Makromolekulare Chemie 1994, 223, 217-233; JM Rodriguez-Parada, M. Kaku, DY Sogah, Macromolecules 1994, 27, 1571-1577; N. Oleszko-Torbus, A.Utrata-Wesolek, M. Bochenek, D. Lipowska-Kur, A. Dworak, W. Watach, Polymer Chemistry 2020, 11, 15-33; AL Demirel, P. Tatar Güner, B. Verbraeken, H. Schlaad, US Schubert, R. Hoogenboom, Journal of Polymer Science Part B: Polymer Physics 2016, 54, 721-729). Schubert and colleagues previously reported a decrease in the glass transition temperature (T. g ) with increasing side chain length for a series of poly(2-n-alkyl-2-oxazolines) to poly(2-pentyl-2-oxazolines). For PAOx with longer side chains, crystalline properties were observed with a melting temperature T independent of the side chain length. m observed.

[0009] Polyoxazolines (PAOx), with poly(2-ethyl-2-oxazoline) being of particular interest, therefore appear to represent an alternative to PEG, as they also exhibit a stealth effect like PEG. It is believed that PAOx lipids could represent an alternative to PEG lipids, for example, the PEG lipid ALC-0159 used in the BioNTech mRNA vaccine "Comirnaty®."

[0010] There are already studies in which PEG-lipid alternatives have been synthesized. S. Nogueira et al., in collaboration with BioNTech, produced lipids from polysarcosine (pSar). However, these pSar lipids showed lower transfection rates compared to a PEG-lipid reference, making them an unattractive alternative for vaccination (cf. S. S. Nogueira, A. Schlegel, K. Maxeiner, B. Weber, M. Barz, M. A. Schroer, C. E. Blanchet, D. I. Svergun, S. Ramishetti, D. Peer, P. Langguth, U. Sahin, H. Haas, ACS Appl. Nano Mater. 2020, 3, 10634-10645).

[0011] M. Bentley et al. synthesized lipids from polyoxazolines in which phospholipids were coupled to PAOx (see US Pat. Nos. 9,284,411 B2 and 8,883,211 B2). PAOx and PEG are not biodegradable, but for many biomedical applications, it is important to prevent long-term accumulation of polymers with higher molecular masses.

[0012] It would therefore be desirable to have lipids based on biodegradable polyoxazolines (hereinafter also referred to as "degPAOx") available to ensure biodegradability. The synthesis of degPAOx has already been reported (cf. NE Göppert, M. Kleinsteuber, C. Weber, US Schubert, Macromolecules 2020, 53, 10837-10846) and WO 2022 / 106049 A1.

[0013] Functionalized polyglycine-poly(alkyleneimine) copolymers are known from WO 2022 / 106049 A1. Polymers with long-chain alkyl groups or with long-chain alkyl ester groups as end groups are not disclosed in this document.

[0014] The use of PAOx lipids and degPAOx lipids is not limited to vaccine applications, but these lipids can be used generally as carrier materials for drug or gene delivery.

[0015] Using analytical ultracentrifugation, the hydrodynamic radii of PEG-lipid alternatives can be measured. This allows the molar mass of PAOx lipids and degPOx lipids to be precisely matched to the hydrodynamic volume of commercial PEG types, e.g., the commercial PEG-lipid ALC-0159, facilitating the potential replacement of PEG lipids with PAOx lipids and degPAOx lipids in existing biomedical applications.

[0016] The object of the present invention is therefore to provide new polymeric lipids which are suitable as replacements for PEG lipids.

[0017] A further object of the present invention is to provide simple methods for producing these polymeric lipids. This object is achieved by providing a first group of polymers of formulas (I) or (II)

[0018] CO-R 1

[0019] I lni-[N-CR 3 H-CR 4 H] w -R 2 (I),

[0020] CO-R 1

[0021] I lni-[N-CR 3 H-CR 4 H-CR 5 H] w -R 2 (II), or by providing a second group of polymers containing, based on all structural units, 10 to 95 mol% of structural units of the formula (III), 5 to 90 mol% of structural units of the formula (IV) and 0 to 20 mol% of structural units of the formula (V)

[0022] CO-R 1

[0023] I

[0024] -N-CHR 3 -CHR 4 - (III), -NH-CO-CHR 5 - (IV), -NH-CHR 6 -CHR 7 - (V), or containing 10 to 95 mol% of structural units of formula (VI), 5 to 90 mol% of structural units of formula (VII) and 0 to 20 mol% of structural units of formula (VIII)

[0025] CO-R 1

[0026] I

[0027] -N-CHR 3 -CHR 4 -CHR 5 - (VI), -NH-CO-CHR 6 -CHR 7 - (VII),

[0028] -NH-CHR 8 -CHR 9 -CHR 10 - (VIII), wherein at least one of the structural units of formula (III), (IV) or (V) or of formula (VI), (VII) or (VIII) is provided with the group -CHR 4 -, -CHR 5 - or -CHR 7 - or with the group -CHR 5 -, -CHR 7 - or -CHR 10 - covalently with a radical R2 is connected, wherein

[0029] Ini is a residue derived from an initiator of cationic polymerization, R 1 is selected from the group consisting of hydrogen or C1-C4 alkyl,

[0030] R 2 is selected from the group consisting of -OR 11 , -OCO-R 11 , -OCO-R 14 - CO-OR 11 , -OCO-R 14 -CO-NR 12 R 13 , -NR 12 -R 14 -CO-NR 13 R 15 , -OR 16 -(O-OC-R 18 ) m and

[0031] N=N

[0032] II

[0033] -NR 17 -CH2-OCO-NR 12 R 13 ,

[0034] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 independently of one another represent hydrogen, methyl, ethyl, propyl or butyl,

[0035] R 11 C6-C 20-alkyl,

[0036] R 12 and R 15 are independently hydrogen or alkyl,

[0037] R 13 C6-C 20 -Alkyl means

[0038] R 14 alkylene, cycloalkylene, arylene or aralkylene,

[0039] R 16 an m+1 -valent aliphatic hydrocarbon radical, m is an integer from 1 to 5,

[0040] R 18 C6-C 20 -Alkyl means, with the proviso that several radicals R 18 a residue R 16 may be different within the given definitions, R 17 is a trivalent bicyclic radical, and w is an integer in the range from 1 to 5000.

[0041] For the purposes of this description, "polymers" refers to the above-mentioned organic compounds characterized by the repetition of certain units (monomer units or repeating units). Polymers can consist of one type or several types of different repeating units. Polymers are produced by the chemical reaction of monomers with the formation of covalent bonds (polymerization) and form the so-called polymer backbone by linking the polymerized units. This backbone can have side chains that may contain functional groups. If polymers have partially hydrophobic properties, they can form nanoscale structures (e.g., nanoparticles, micelles, vesicles) in an aqueous environment. Homopolymers consist of only one monomer unit.Copolymers, on the other hand, consist of at least two different monomer units, which can be arranged randomly, as a gradient, alternating or as a block.

[0042] The polymers of the invention are functionalized poly(oxazolines) or poly(oxazines). The former are derived from oxazolines, and the latter from oxazines. The following description focuses primarily on the preparation and use of poly(oxazolines). These statements also apply analogously to the homologous poly(oxazines).

[0043] For the purposes of this description, "lipids" are understood to mean substances that are completely or at least largely insoluble in water (hydrophobic) and that dissolve readily in hydrophobic (lipophilic) solvents. Lipids are amphiphilic and represent a subgroup of surfactants. In polar solvents such as water, lipids form micelles, vesicles, or membranes.

[0044] In the context of this description, “active ingredients” are understood to mean compounds or mixtures of compounds that exert a desired effect on a living organism. These can be, for example, pharmaceutical active ingredients or agrochemical active ingredients. Active ingredients can be low- or high-molecular-weight organic compounds. The active ingredients are preferably low-molecular-weight pharmaceutically active substances or high-molecular-weight pharmaceutically active substances, with particular reference to hydrophilic active ingredients made from potentially therapeutically useful nucleic acids (e.g. short interferin RNA, short hairpin RNA, micro RNA, messenger RNA, plasmid DNA) or from potentially useful proteins (e.g. antibodies, interferons, cytokines). Preferred examples of active ingredients are vaccines or nucleic acids.Active ingredients can be those that have only low or no bioavailability without inclusion in a nanoparticle or liposome, have low or no stability in vivo, or are only intended to act in certain cells of an organism.

[0045] For the purposes of this description, "auxiliaries and additives" are substances that are 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, or surfactants. In particular, "auxiliaries and additives" are understood to mean any pharmacologically acceptable 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, in particular improve, the qualitative properties of the pharmaceutical composition.Preferably, the excipients and / or additives have no pharmacological effect or, with regard to the intended treatment, no significant or at least no undesirable effect.

[0046] Ini is a residue derived from the initiator of the cationic polymerization that leads to the formation of the polyoxazoline. Ini can be an organic residue such as alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl. However, other residues are also possible. Examples of such residues can be found in US Pat. No. 8,883,211 B2.

[0047] residues R 12 ,R 15and Ini can denote alkyl. These are generally alkyl groups with one to twenty carbon atoms, which can be straight-chain or branched. Examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl. R residues 11, R 13 and R 18 can mean C6-C20 alkyl. These are alkyl groups with six to twenty carbon atoms, which can be straight-chain or branched. Examples include hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl.

[0048] Rest R 1 can mean C1-C4 alkyl. These are alkyl groups with one to four carbon atoms, which can be straight-chain or branched. Examples include methyl, ethyl, propyl, and butyl.

[0049] Preferably, R 1 methyl, ethyl or propyl, particularly preferably methyl or ethyl.

[0050] The residue Ini can be cycloalkyl. These are usually cycloalkyl groups with five to six ring carbon atoms. Cyclohexyl is particularly preferred.

[0051] The residue Ini can be aryl. These are usually aromatic hydrocarbon residues with five to ten ring carbon atoms. Phenyl is preferred.

[0052] The residue Ini can be aralkyl. These are usually aryl groups that are bonded to the rest of the molecule via an alkylene group. Benzyl is preferred.

[0053] The residue Ini can be heterocyclyl. These are typically aromatic or non-aromatic hydrocarbon residues with five to ten ring carbon atoms, which contain one or two heteroatoms, such as nitrogen and / or oxygen and / or sulfur, in the ring.

[0054] Rest R 14 can mean alkylene. These are generally alkylenyl groups with one to six carbon atoms, which can be straight-chain or branched. Examples of alkylene radicals are methylene, ethylene, propylene, butylene, pentylene, and hexylene. Ethylene, propylene, and butylene are preferred, and ethylene is especially preferred.

[0055] Rest R 14 can mean cycloalkylene. These are usually cycloalkylene groups with five to six ring carbon atoms. Cyclohexylene is particularly preferred.

[0056] Rest R 14can mean arylene. These are usually divalent aromatic hydrocarbon radicals with five to ten ring carbon atoms. Phenylene is preferred.

[0057] Rest R 14 can mean aralkylene. These are usually arylene groups containing an alkylene group, with the aralkylene radical being connected to the rest of the molecule via the arylene group and the alkylene group. Benzylene is preferred.

[0058] R 16is a di- to hexavalent (m+1 -valent) aliphatic hydrocarbon radical derived from an m+1 -valent aliphatic alcohol. One of the OH oxygen atoms of this alcohol is covalently bonded to the polyoxazoline. The remaining OH radicals of this alcohol are esterified with fatty acids. If multiple ester groups are present in the radical, these can each be derived from the same or different fatty acids. Examples of dihydric alcohols are ethylene glycol or propylene glycol; examples of trihydric alcohols are glycerol or trimethylolpropane; an example of a tetrahydric alcohol is pentaerythritol; and examples of hexahydric alcohols are sugar alcohols. R is preferably 16 a residue derived from glycerol.

[0059] Rest R 17is a trivalent bicyclic residue. These are usually trivalent residues composed of two cycloalkyl groups, one of which has three ring carbon atoms and the other of which has five to eight ring carbon atoms. The larger of these rings contains a double bond. The bonds with the rest of the molecule are formed via one covalent bond originating from the residue with the three ring carbon atoms and two further covalent bonds originating from the residue with the five to eight ring carbon atoms.

[0060] The first group of polymers according to the invention are linear polymers.

[0061] The second group of polymers according to the invention can be linear or branched polymers. Linear polymers are preferred.

[0062] Linear polymers of this second group have structures of formula (IX) or (X)

[0063] CO-R1 lni-[N-CR 3 H-CR 4 H] x -[NH-CO-CR 5 H] y -[NH-CR 6 H-CR 7 H] z -R 2 (IX),

[0064] CO-R 1

[0065] I lni-[N-CR 3 H-CR 4 H-CR 5 H] X -[NH-CO-CR 6 H-CR 7 H] y -[NH-CR 8 H-CR 9 H-CR 10 H] z -R 2

[0066] (X), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the meaning defined above, x and y are independently integers in the range from 1 to 5000, z is an integer in the range from 0 to 1000, with the proviso that the molar proportion of the molar fraction ... x denoted structural units is 10 to 95 mol%, the molar fraction of the [] ydenoted structural units is 5 to 90 mol%, and the molar fraction of the [] z denoted structural units is 0 to 20 mol%, in each case based on the total amount of the [] x , [] y and [] z The solubility of the polymers 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.

[0067] The polymers according to the invention can cover a wide range of molecular weights. Typical molecular weights (M n ) range from 1,000 to 500,000 g / mol, especially from 1,000 to 50,000 g / mol. These molar masses can be 1 H NMR spectroscopy of the dissolved polymer can be used. In particular, an analytical ultracentrifuge or chromatographic methods such as size-exclusion chromatography can be used to determine the molecular weights.

[0068] Preferred polymers according to the invention have an average molecular weight (number average) in the range from 1,000 to 50,000 g / mol, in particular from 3,000 to 10,000 g / mol, determined by 1 H-NMR spectroscopy or by using an analytical ultracentrifuge.

[0069] R 1 is hydrogen or C1-C4 alkyl. R is preferably 1 Hydrogen or Ci-C3-alkyl, in particular Ci-C2-alkyl, and most preferably ethyl.

[0070] R 2 means-OR 11 , -OCO-R 11 , -OCO-R 14 -CO-OR 11 , -OCO-R 14 -CO-NR 12 R 13 , -NR 12 -R 14 -CO-NR 13 R 15 , -OR 16 -(O-OC-R 18 ) m and

[0071] N=N

[0072] II

[0073] -NR 17 -CH2-OCO-NR 12 R 13 .

[0074] Preferably, R 2 -OR 11, -OCO-R 11 , -OCO-R 14 -CO-OR 11 and -OCO-R 14 -CO- NR 12 R 13 .

[0075] Particularly preferably, R 2 -OCO-R 11 , -OCO-R 14 -CO-OR 11 and -OCO-R 14 -CO-NR 12 R 13 . Most preferably, R 2 -OCO-R 14 -CO-NR 12 R 13 .

[0076] At R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen, methyl, ethyl, propyl or butyl.

[0077] Preferably, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 independently of each other are hydrogen, methyl or ethyl and in particular only hydrogen.

[0078] R 11 and R 18 are C6-C20 -Alkyl. Preferably, R 11 and R 18 Cs-Ci8 alkyl and in particular C10-C14 alkyl.

[0079] R 12 and R 15 are independently hydrogen or alkyl. Preferably, R 12 and R 15 Cs-C14 alkyl and in particular C10-C14 alkyl.

[0080] R 13 means Ce-C2o-alkyl. Preferably, R 13 Cs-C alkyl and in particular C10-C14 alkyl.

[0081] R 14 means alkylene, cycloalkylene, arylene or aralkylene. Preferably, R 14 C1-C6 alkylene, in particular C2-C4 alkylene, in particular C2 alkylene. m is an integer from 1 to 5, preferably 2 or 3, and in particular 2.

[0082] R 16is a di- to hexavalent aliphatic hydrocarbon radical. It is derived from a di- to hexavalent aliphatic alcohol. Preferably, R 16 a trivalent aliphatic hydrocarbon radical. R is particularly preferably derived 16 from glycerin.

[0083] R 17 is a trivalent bicyclic radical. Preferred radicals are those of the formula w is an integer in the range from 1 to 5000. Preferably, w is an integer in the range from 5 to 500 and in particular in the range from 10 to 200. x and y are independently integers in the range from 1 to 5000. Preferably, x and y are independently integers in the range from 5 to 500 and in particular in the range from 10 to 200. z is an integer in the range from 0 to 1000. Preferably, z is an integer in the range from 0 to 100 and in particular in the range from 0 to 50.

[0084] The values ​​for x, y and z must be chosen in each individual case so that the molar fraction of the [] x denoted structural units is 10 to 95 mol%, the molar fraction of the [] y denoted structural units is 5 to 90 mol%, and the molar fraction of the [] z denoted structural units is 0 to 20 mol%. These percentages refer to the total amount of the [] x , [] y and [] z designated structural units.

[0085] The molar fraction of [] x in the copolymers according to the invention is preferably 20 to 90 mol% and in particular 30 to 70 mol%, based on the total amount of the structural units designated with [] x , [] y and [] z designated structural units.

[0086] The molar fraction of [] yin the copolymers according to the invention is preferably 10 to 80 mol% and in particular 30 to 70 mol%, based on the total amount of the structural units designated with [] x , [] y and [] z The molar fraction of the structural units designated with [] z in the copolymers according to the invention is preferably 0 to 10 mol% and in particular 0 to 5 mol%, based on the total amount of the structural units designated with [] x , [] y and [] z designated structural units.

[0087] Ini is a radical derived from a cationic polymerization initiator, preferably an organic radical. It can be alkyl, cycloalkyl, aryl, aralkyl, or heterocyclyl. Alkyl and aryl are preferred, particularly preferably C1-C8 alkyl, especially methyl.

[0088] Preferred are polymers of formulas (I) or (IX), in particular polymers of formula (I).

[0089] Preferred polymers are those having a radical Ini selected from the group consisting of alkyl, aralkyl or carboxyalkyl.

[0090] Also preferred are polymers in which R 1 Ci-Ca-alkyl means, in particular methyl or ethyl.

[0091] Also preferred are polymers in which R 2 is selected from the group consisting of -OCO-R 14 -CO-OR 11 , -OCO-R 14 -CO-NR 12 R 13 and

[0092] N=N

[0093] II

[0094] -N— R 17 -CH2-OCO-NR 12 R 13 , particularly preferred is R 2 a radical of the formula -OCO-R 14 -CO-NR 12 R 13 .

[0095] Also preferred are polymers in which R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10

[0096] hydrogen.

[0097] Polymers are also preferred in which R 11 or R 18 C8-Ci6-alkyl. Also preferred are polymers in which R 12 and R 15 C6-C20 alkyl, especially Cs-C alkyl.

[0098] In addition, polymers are preferred in which R 13 Cs-Cie-alkyl.

[0099] Polymers are also preferred in which R 14 C2-C4alkylene, especially ethylene.

[0100] In further preferred polymers, m is 2 or 3, in particular 2.

[0101] Other preferred polymers include those in which R 16 is an aliphatic hydrocarbon residue derived from glycerol.

[0102] Polymers are also preferred in which R 17 a remainder of the formula is.

[0103] Very particular preference is given to polymers in which w is an integer in the range from 5 to 500, x and y are independently integers in the range from 5 to 500, z is an integer in the range from 0 to 100, with the proviso that the molar proportion of the monomers substituted with [] x denoted structural units is 20 to 90 mol%, the molar fraction of the [] y denoted structural units is 10 to 80 mol%, and the molar fraction of the [] z denoted structural units is 0 to 20 mol%, in each case based on the total amount of the [] x , [] y and [] z designated structural units.

[0104] Most preferred are polymers of formula (I) in which R 1 Ethyl is, R 2 -OCO-R 14 -CO-NR 12 R 13 means R 3 and R 4 hydrogen, R 12 and R 13 independently of one another are Cs-Cs-alkyl, R14 C2-C4 alkylene, especially ethylene, and w is an integer in the range from 5 to 200. The polymers of the invention can be prepared using conventional polymerization processes. Examples include bulk polymerization, solution polymerization, or emulsion or suspension polymerization. These procedures are known to those skilled in the art. Solution polymerization is preferred.

[0105] The oxazolines used to prepare the poly(oxazoline)s according to the invention are 2-oxazolines (4,5-dihydrooxazoles) with a C=N double bond between carbon atom 2 and the nitrogen atom. These can be substituted on the 2-, 4-, and / or 5-carbon atom and / or on the 3-nitrogen atom, preferably on the 2-carbon atom and / or on the 3-nitrogen atom.

[0106] Preference is given to using 2-oxazolines containing a substituent at the 2-position. Examples of such substituents are methyl or ethyl.

[0107] The polymers of the invention are derived from poly(oxazolines) or poly(oxazines) with selected end groups. These end groups are modified by functionalization. The necessary techniques are known to those skilled in the art.

[0108] Examples of end groups of the poly(oxazoline) or poly(oxazine) starting materials of the polymers according to the invention are halogen atoms, such as fluorine, chlorine, bromine or iodine; or azide groups -N3; ​​or fluoro(alkyl)sulfonic acid ester groups, such as the nonaflate group -OSO2C4F9, the trifluoromethanesulfonate group -OSO2CF3 or the fluorosulfonate group -OSO2F; or aryl or alkylsulfonic acid groups, such as the tosyl group CH3-CeH4-SO2- or the mesyl group CH3-SO2-; the unsubstituted, mono- or disubstituted amino group -NH2, -NHR or -NR2 (where R = monovalent organic radical), the hydroxyl group -OH, the thiol group -SH, or the ester group -OCOR, the thioester group -SCOR; the phthalimide group or the cyano group -CN, as well as other functional groups that can be obtained by modifying these end groups. The polymers according to the invention can be prepared analogously to known processes of organic chemistry.

[0109] The polymers according to the invention can be produced by different processes.

[0110] A common feature of the processes for preparing the polymers of formulas (I), (II), (IX) or (X) is that the preparation of poly(oxazolines) or poly(oxazines) is carried out by cationic ring-opening polymerization of oxazolines or oxazines. The polymerization is preferably carried out in solution and in the presence of an initiator. Examples of initiators are electrophiles, such as salts or esters of aromatic sulfonic acids or carboxylic acids, or salts or esters of aliphatic sulfonic acids or carboxylic acids, or aromatic halogen compounds. 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.

[0111] Polar aprotic solvents are usually used as solvents, for example acetonitrile, dimethylformamide, dimethylacetamide, ethylene carbonate or dimethyl sulfone.

[0112] The reaction temperature is generally between 20 and 180°C, especially in the range of 70 to 130°C.

[0113] The reaction time for polymerization is generally between 5 minutes and 24 hours.

[0114] The hydrolysis of poly(oxazolines) or poly(oxazines) is preferably carried out in solution, especially in aqueous or alcoholic-aqueous solution. Inorganic or organic acids can be used as acids. Mineral acids or carboxylic acids are preferred. Examples include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, or formic acid, preferably acetic acid. Suitable bases include alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide.

[0115] The reaction temperature during hydrolysis is generally between 20 and 120°C, especially in the range of 30 to 80°C.

[0116] The reaction time for hydrolysis is generally between 5 minutes and 24 hours.

[0117] The preparation of “degPAOx” as starting materials for the production of the second group of polymers according to the invention is described, for example, in WO 2022 / 106049 A1.

[0118] Preference is given to processes in which the poly(oxazoline) or poly(oxazine) used is obtained by hydrolysis, in particular by acid hydrolysis.

[0119] The end groups of the poly(oxazolines) or poly(oxazines) used as starting materials can be further modified before further processing.

[0120] For example, polymers with a carboxylate end group can be converted into polymers with a hydroxyl end group. This can be achieved by saponification in an aqueous or aqueous-alcoholic solution in the presence of a strong alkali, for example, an alkali metal alkoxide such as sodium methanolate.

[0121] The reaction temperature during saponification is generally between 10 and 120°C, especially in the range of 20 to 60°C.

[0122] The reaction time for saponification is generally between 1 and 24 hours. Polymers with a hydroxyl or amino end group can be further modified by reaction with dicarboxylic anhydrides. This results in polymers with carboxyl end groups. For example, polymers with a hydroxyl end group can be converted into polymers with an end group derived from dicarboxylic acids, for example, by reacting a hydroxyl-terminated polymer with the anhydride of an aliphatic dicarboxylic acid, such as succinic anhydride. The reaction can be carried out in an aprotic solvent, such as dimethylformamide, in the presence of tertiary amines, such as dimethylaminopyridine and triethylamine.

[0123] The reaction temperature in this reaction is generally between 10 and 120°C, especially in the range of 20 to 60°C.

[0124] The reaction time for this conversion is generally between 1 and 24 hours.

[0125] Finally, polymers with an end group derived from dicarboxylic acids can be further modified by reaction with a primary or secondary amine. This results in polymers with amide end groups. For example, the carboxyl end group of polymers with an end group derived from dicarboxylic acids can be converted into a corresponding carboxamide by reaction with a primary or secondary amine. The reaction can be carried out in a polar, aprotic solvent, such as chloroform, in the presence of tertiary amines, such as dimethylaminopyridine. The reaction also takes place in the presence of known coupling reagents, for example N-hydroxysuccinimide ester (NHS ester), N-hydroxysuccinimide (NHS), dicyclohexylcarbodiimide ester (DCC ester) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ester (EDC ester) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCL).

[0126] The reaction temperature for this reaction is generally between 10 and 120°C, particularly between 20 and 60°C. The reaction time for this reaction is generally between 1 and 24 hours.

[0127] In the preparation of the polymers according to the invention, depending on the nature of the radical R 2 Different processes are used. Further variations in the production processes can also be used in the production of the polymers according to the invention with degPAOx residues.

[0128] The polymers of formula (I) or (II) in which R 2 -OR 11 or — OCO— R 11 can be prepared by a process comprising the following measures: a) providing a polymer of formula (Ia)) or (Ia) by cationic polymerization of a 2-oxazoline or a 2-oxazine in the presence of an initiator of cationic polymerization

[0129] CO-R 1

[0130] I lni-[N-CR 3 H-CR 4 H] + w (An'')™ (la),

[0131] CO-R 1 lni-[ (lla), b) terminating the cationic polymerization by adding a compound of formula (XI) (XII) or (Xlla)

[0132] R 11 -OH (XI), R 11 -COOH (XII),

[0133] R 11 -CO-O-OC-R 11 (Xlla), where in these formulas Ini, R 1 , R 3 , R 4 , R 5 , R 11 and w have the meaning defined above, i is an integer from 1 to 4 and An is an i-valent anion.

[0134] The polymers of formula (I) or (II) in which R 2

[0135] N=N

[0136] II

[0137] -NR 17 -CH2-OCO-NR 12 R 13can be prepared by a process comprising the following measures: a) providing a polymer of formula (Ia)) or (Ia) by cationic polymerization of a 2-oxazoline or a 2-oxazine in the presence of an initiator of cationic polymerization

[0138] CO-R 1

[0139] I lni-[N-CR 3 H-CR 4 H] + w (To 1 ')™ (la),

[0140] CO-R 1

[0141] I lni-[N-CR 3 H-CR 4 H-CR 5 H] + w (An )i Zi (Ha), where Ini, R 1 , R 3 , R 4 , R 5 and w have the meaning defined above, i is an integer from 1 to 4 and An is an i-valent anion, c) terminating the cationic polymerization by adding an inorganic or organic azide, whereby an azide-terminated polymer of formula (Ib) or (IIb) is formed,

[0142] CO-R 1

[0143] I lni-[N-CR 3 H-CR 4 H] w -N3(Ib), CO-R 1

[0144] I lni-[N-CR 3 H-CR 4 H-CR 5 H] w -N3(llb), d) reacting the azide-terminated polymer of formula (Ib) or (llb) obtained from step c) with a cycloalkyne of formula (XIII) to give an ester-terminated polymer of formula (Ic) or (I Ic)

[0145] CO-R 1

[0146] I (Ic) lni-[N-CR 3 H-CR 4 H] w -R

[0147] CO-R 1 lni-[ with R = and e) reacting the ester-terminated polymer of formula (lc) or (lie) with an amine of formula (XIV)

[0148] R 12 R 13 NH (XV) to a polymer of formula (I) or (II) in which R 2 has the meaning defined above, wherein in these formulas Ini, R1 , R 3 , R 4 , R 5 , R 12 , R 13 and w have the meaning defined above, i is an integer from 1 to 4 and An is an i-valent anion.

[0149] The polymers of formula (I) or (II) in which R 2 -OCO-R 14 -CO-OR 11 or -OCO— R 14 — CO— NR 12 R 13 can be prepared by a process comprising the following measures: a) providing a polymer of formula (Ia)) or (Ha) by cationic polymerization of a 2-oxazoline or a 2-oxazine in the presence of an initiator of the cationic polymerization

[0150] CO-R 1

[0151] I lni-[N-CR 3 H-CR 4 H] + w (An'ji / i (la),

[0152] CO-R 1 lni-[ (Ha), f) terminating the cationic polymerization by adding a compound of formula (XII) or (Xlla) to a hydroxyl-terminated polymer of formula (Id) or (Hd)

[0153] R 11 -COOH (XII), R 11 -CO-O-OC-R 11 (Xlla), CO-R 1 I lni-[N-CR 3 H-CR 4 H] w -OH (Id),

[0154] CO-R 1 I lni-[N-CR 3 H-CR 4 H-CR 5 H] w -OH (lid), g) reacting the polymers of formula (Id) or (I Id) with an anhydride of formula (XVI) to give polymers of formula (le) or (Ile)

[0155] R 14 -CO (XVI),

[0156] II co-o

[0157] CO-R 1 I lni-[N-CR 3 H-CR 4 H] w -OOC-R 14 -COOH (le),

[0158] CO-R 1 I lni-[N-CR 3 H-CR 4 H-CR 5 H] w -OOC-R 14-COOH (Ile), and h) reacting the polymers of formula (le) or (Ile) from step g) with an alcohol of formula (XI) or with an amine of formula (XV) to give polymers of formula (I) or (II) in which R 2 has the meaning defined above,

[0159] R 11 -OH (XI), R 12 R 13 NH (XV) where in these formulas Ini, R 1 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 and w have the meaning defined above, i is an integer from 1 to 4 and An represents an i-valent anion.

[0160] The polymers of formula (I) or (II) in which R 2 -OR 16 -(O-OC-R 18 ) mcan be prepared by a process comprising the following measures: a) providing a polymer of formula (Ia) or (IIa) by cationic polymerization of a 2-oxazoline or a 2-oxazine in the presence of an initiator of the cationic polymerization

[0161] CO-R 1

[0162] I lni-[N-CR 3 H-CR 4 H] + w (To 1 ')™ (la),

[0163] CO-R 1

[0164] I lni-[N-CR 3 H-CR 4 H-CR 5 H] + w (To 1 ') (lla), i) terminating the cationic polymerization by adding a carboxylic acid, preferably acetic acid, to a carboxyl-terminated polymer of the formula (If) or (I If)

[0165] CO-R 1

[0166] I lni-[N-CR 3 H-CR 4 H] w -O-OC-R (If),

[0167] CO-R 1

[0168] I lni-[N-CR 3 H-CR 4 H-CR 5 H] w -O-OC-R (Hf), j) reacting the polymers of formula (If) or (Hf) from step i) with an alkali metal alkoxide, preferably with sodium methoxide, to give polymers of formula (Ig) or (Hg) CO-R 1

[0169] I lni-[N-CR 3 H-CR 4 H] w -OH (Ig),

[0170] CO-R 1

[0171] I lni-[N-CR 3 H-CR 4 H-CR 5 H] w -OH (IIg), k) reacting the polymers of formula (Ig) or (IIg) from step j) with a dicarboxylic anhydride of formula (XVI), preferably with succinic anhydride, to give polymers of formula (Ih) or (IIh)

[0172] CO-R 1 lni-[N-CR 3 H-CR 4 H] w -O-CO-R 14 -CO-OH (Ih),

[0173] CO-R 1

[0174] I lni-[N-CR 3 H-CR 4 H-CR 5 H] w-O-OC-R 14 -CO-OH (IIIh), and l) reacting the polymers of formula (Ih) or (IIh) from step k) with an alcohol of formula (XVII) to give polymers of formula (I) or (II) in which R 2 has the meaning defined above,

[0175] HOR 16 -(O-OC-R 18 ) m (XVII) where in these formulas Ini, R 1 , R 3 , R 4 , R 5 , R 14 , R 16 , R 18 , m and w have the meaning defined above, i is an integer from 1 to 4 and An represents an i-valent anion.

[0176] The polymers of formula (I) or (II) in which R 2 -NR 12 -R 14 -CO-NR 13 R 15can be prepared by a process comprising the following measures: a) providing a polymer of formula (Ia)) or (Ha) by cationic polymerization of a 2-oxazoline or a 2-oxazine in the presence of an initiator of the cationic polymerization

[0177] CO-R 1

[0178] I lni-[N-CR 3 H-CR 4 H] + w (la),

[0179] CO-R 1 lni-[ (Ha), m) terminating the cationic polymerization by adding an alkali metal phthalimide to an N-phthalimide-terminated polymer, n) reacting the polymers from step m) with hydrazine to give polymers of the formulas (li) or (Hi)

[0180] CO-R 1

[0181] I lni-[N-CR 3 H-CR 4 H] w -NH2(li),

[0182] CO-R 1

[0183] I lni-[N-CR 3 H-CR 4 H-CR 5 H]w -NH2(Hi), o) reacting the polymers of formula (Ii) or (Hi) from step n) with a dicarboxylic anhydride of formula (XVI), preferably with succinic anhydride, to give polymers of formula (Ij) or (Hj)

[0184] CO-R 1

[0185] I lni-[N-CR 3 H-CR 4 H] w -NH-CO-R 14 -CO-OH (Ij), CO-R 1

[0186] I lni-[N-CR 3 H-CR 4 H-CR 5 H] w -NH-OC-R 14 -CO-OH (llj), and p) reacting the polymers of formula (Ij) or (llj) from step o) with an amine of formula (XV) to give polymers of formula (I) or (II) in which R 2 has the meaning defined above,

[0187] R 12 R 13 NH (XV) where in these formulas Ini, R 1 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14and w have the meaning defined above, i is an integer from 1 to 4 and An represents an i-valent anion.

[0188] In the preparation of the copolymers of the second polymer group according to the invention, i.e. copolymers which contain degPAOx radicals, i.e. structural units of the formulas (III), (IV) and optionally (V) or of the formulas (VI), (VII) and optionally (VIII), different starting materials can be used.

[0189] These copolymers can be linear or branched.

[0190] The linear types are copolymers of formulas (IX) or (X). These can be prepared analogously to the linear polymers of the first group, i.e., the polymers of formulas (I) or (II). For this purpose, radicals R 2functionalized polyoxazolines or polyoxazines are completely or partially hydrolyzed. The resulting copolymers are then oxidized and, in the case of complete hydrolysis, reacylated, which leads directly to the inventive copolymers of the second polymer group. Details for the preparation of copolymers of the formulas (IX) and (X) are listed below. The branched types of the degPAOx-containing copolymers can be prepared by partial oxidation of radicals R 2The functionalized polyalkyleneimines can be partially oxidized, and the resulting product can be functionalized, for example, by reaction with an activated acyl derivative, such as an activated ester, or with an acyl halide, to form a copolymer of the second polymer group. Details on the preparation of these copolymers are listed below. Commercially available polyethyleneimines typically have a branched structure; therefore, the polymers derived from them are also branched.

[0191] These preparation processes of degPAOx copolymers are disclosed in WO 2022 / 106049 A1.

[0192] The linear polymers of formula (IX) or (X) in which R 2 -OR 11 or — OCO— R 11 can be prepared by a process comprising the following measures: q) providing a polymer of formula (I) or (II), wherein R 2 -OR 11 or — OCO— R 11means, r) partial hydrolysis of the polymer of formula (I) or (II) from step q) to a copolymer of formula (Ik) or formula (IIk)

[0193] CO-R 1

[0194] I lni-[N-CR 3 H-CR 4 H] x -[NH-CR 6 H-CR 7 H] za -R 2 (Ik),

[0195] CO-R 1

[0196] I lni-[N-CR 3 H-CR 4 H-CR 5 H] x -[NH-CR 8 H-CR 9 H-CR 10 H] za -R 2 (llk), s) reacting the copolymer of formula (Ik) or (llk) from step r) with an oxidizing agent to obtain a copolymer of formula (IX) or formula (X) in which R 2 has the meaning defined above, wherein in these formulas Ini, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12, R 13 , R 14 , R 15 , R 16 , w, x, y and z have the meaning defined above, and where za is an integer with the value wx,

[0197] The linear polymers of formula (IX) or (X) in which R 2

[0198] N=N

[0199] II

[0200] -NR 17 -CH2-OCO-NR 12 R 13 can be prepared by a process comprising the following measures: t) providing a polymer of formula (I) or (II), wherein R 2

[0201] N=N

[0202] II

[0203] -NR 17 - CH2-OCO-NR 12 R 13 means u) partial hydrolysis of the polymer of formula (I) or (II) from step t) to a copolymer of formula (II) or formula (III)

[0204] CO-R 1

[0205] I lni-[N-CR 3 H-CR 4 H] x -[NH-CR6 H-CR 7 H] za -R 2 (II),

[0206] CO-R 1

[0207] I lni-[N-CR 3 H-CR 4 H-CR 5 H] x -[NH-CR 8 H-CR 9 H-CR 10 H] za -R 2 (III), v) reacting the copolymer of formula (II) or (III) from step u) with an oxidizing agent to obtain a copolymer of formula (IX) or formula (X) in which R 2 has the meaning defined above, wherein in these formulas Ini, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 12 , R 13 , w, x, y and z have the meaning defined above, and where za is an integer with the value wx.

[0208] The linear polymers of formula (IX) or (X) in which R 2 -OCO-R 14 -CO-OR 11 or -OCO— R 14— CO— NR 12 R 13 can be prepared by a process comprising the following measures: w) providing a polymer of formula (I) or (II), wherein R 2 -OCO- R 14 -CO-OR 11 or -OCO-R 14 -CO-NR 12 R 13 means, x) partial hydrolysis of the polymer of formula (I) or (II) from step wo) to a copolymer of formula (Im) or formula (IIm)

[0209] CO-R 1 lni-[N-CR 3 H-CR 4 H] x -[NH-CR 6 H-CR 7 H] za -R 2 (In the),

[0210] CO-R 1

[0211] I lni-[N-CR 3 H-CR 4 H-CR 5 H] x -[NH-CR 8 H-CR 9 H-CR 10 H] za -R 2(Ilm), y) reacting the copolymer of formula (Im) or (Ilm) from step x) with an oxidizing agent to obtain a copolymer of formula (IX) or formula (X) in which R 2 has the meaning defined above, wherein in these formulas Ini, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , w, x, y and z have the meaning defined above, and where za is an integer with the value wx,

[0212] The branched copolymers of the second polymer group, in which R 2 -OR 11 , -OCO-R 11 , -OCO-R 14 -CO-OR 11 , -OCO-R 14 -CO-NR 12 R 13 , -NR 12 -R 14 -CO-NR 13 R 15 , -OR 16 -(O-OC-R 18 ) m or N=N

[0213] II

[0214] -N— R 17 -CH2-OCO-NR 12 R 13 can be prepared by a process comprising the following measures: z) providing a branched polyethyleneimine or polypropyleneimine, at least one end group of which is linked to a radical R 2 is functionalized, aa)partial oxidation of the functionalized polymer from step z), and bb)introduction of -CO-R 1 Groups into the polymer from step aa) by reaction with an acyl halide R 1 -CO-Hal to form a branched copolymer containing the structural units of formulas (III), (IV) and optionally (V) or containing the structural units of formulas (VI), (VII) and optionally (VIII). wherein in these formulas R 1 , R 2 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and m have the meaning defined above.

[0215] The oxidation in steps s), v), y), and aa) is preferably carried out in solution, especially in an aqueous or alcoholic-aqueous solution. Known oxidants can be used as oxidizing agents. Examples include peroxide compounds, hypochlorites, chlorine, or oxygen, especially hydrogen peroxide.

[0216] Per compounds are preferred. Examples include hydrogen peroxide, peracids, organic peroxides, or organic hydroperoxides, especially hydrogen peroxide.

[0217] Preferred processes are those in which the oxidizing agent used is hydrogen peroxide.

[0218] The amount of oxidizing agent is selected to achieve the desired proportion of oxidized structural units in the polymer backbone. The reaction temperature for this conversion is generally between 10 and 80°C, particularly between 20 and 40°C.

[0219] The reaction time for oxidation is generally between 5 minutes and 5 days.

[0220] The polymers according to the invention can be used to produce formulations containing pharmaceutical or agrochemical active ingredients.

[0221] The polymers according to the invention are preferably used to produce formulations containing pharmaceutical or agrochemical active ingredients. These are, in particular, formulations containing vaccines or nucleic acids, such as ribonucleic acids or deoxynucleic acids.

[0222] Due to their good surfactant activity, biocompatibility, and stealth effect, the polymers of the invention are outstandingly suitable for applications in the field of drug delivery. These uses are also the subject of the present invention.

[0223] In particular, the polymers of the second group are particularly suitable for the production of formulations containing pharmaceutical or agrochemical active ingredients due to their biodegradability.

[0224] Due to their amphiphilic nature, the polymers of the invention can be used as lipids. They can be dispersed in hydrophilic liquids, for example, as emulsions or suspensions.

[0225] The polymers according to the invention are preferably present in hydrophilic liquids, such as water or water-alcohol mixtures, in the form of particles, in particular in the form of nanoparticles. The invention therefore also relates to particles, in particular nanoparticles, containing the polymers described above.

[0226] Preference is given to nanoparticles whose average diameter D5o is less than 1 pm, preferably 20 to 500 nm.

[0227] Particles containing one or more pharmaceutical or agrochemical active ingredients are particularly preferred.

[0228] Particularly preferred particles contain, in addition to the polymer according to the invention, at least one pharmaceutical active ingredient as well as suitable auxiliaries and additives.

[0229] Preferably, the particles form a disperse phase in a liquid containing water and / or water-miscible compounds.

[0230] The proportion of particles in a dispersion can vary widely. Typically, the proportion of particles in the dispersion medium is 0.5 to 20 wt.%, preferably 1 to 5 wt.%.

[0231] The particles can be produced by precipitation, preferably by nanoprecipitation. For this purpose, the polymers of the invention, which are only slightly hydrophilic or not hydrophilic due to the presence of hydrophobic groups, are dissolved in a water-miscible solvent such as acetone. This solution is added dropwise to a hydrophilic dispersing medium. This is preferably done with vigorous stirring. This can promote the production of smaller particles. The polymer is deposited in the dispersing medium in finely divided form.

[0232] Alternatively, the particles can also be produced by emulsification, preferably by nanoemulsion. For this purpose, the polymers of the invention, which are only slightly hydrophilic or not hydrophilic due to the presence of hydrophobic groups, are dissolved in a water-immiscible solvent, such as dichloromethane or ethyl acetate. This solution is combined with a hydrophilic dispersing medium, preferably forming two liquid phases. This mixture is then emulsified by applying energy, preferably by ultrasonic irradiation.

[0233] In addition to the polymer according to the invention, one or more active ingredients and / or one or more auxiliaries and additives may be present during its dispersion in the dispersing medium. Alternatively, these active ingredients and / or auxiliaries and additives can be added after the polymer has been dispersed in the hydrophilic liquid.

[0234] Microfluidics is particularly suitable as a formulation method for the production of lipid nanoparticles (“LNPs”).

[0235] For example, LNPs can be produced using the ethanol dilution method using a microfluidic device. A lipid solution is prepared in ethanol, and a drug, e.g., RNA, is dissolved in suitable buffer solutions. To encapsulate the drug in LNPs, a cationic lipid or a pH-sensitive cationic lipid is used for the lipid components. The lipid solutions and the buffered drug solutions are introduced into the microfluidic device, where, for example, positively charged lipids and negatively charged RNAs form complexes via electrostatic interactions. The cationic RNA-lipid complexes are then combined with other lipids to form LNPs. Examples of other lipids include cholesterol, phospholipid, PEG-lipid, or PAOx-lipid.

[0236] The separation of polymer particles from hydrophilic liquids can be achieved in various ways. Examples include centrifugation, ultrafiltration, or dialysis. The polymer dispersion can be further purified after production.

[0237] Common methods include purification by dialysis, ultrafiltration, filtration or centrifugation.

[0238] The following examples illustrate the invention without limiting it.

[0239] The synthesis of poly(2-ethyl-2-oxazoline) lipids is described below.

[0240] Figure 1 shows a schematic representation of the synthesis of PEtOx lipids.

[0241] The following abbreviations were used in the examples: MeOH: Methanol

[0242] EtOH: Ethanol

[0243] NaOMe: sodium methoxide

[0244] DMAP: Dimethylaminopyridine

[0245] DMF: Dimethylformamid

[0246] NHS: N-Hydroxysuccinimid

[0247] EDC-HCI: 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimid-hydrochlorid

[0248] Materialien

[0249] All chemicals and solvents were purchased from commercial suppliers and used without further purification unless otherwise stated. 2-Ethyl-2-oxazoline (EtOx, 99+%), triethylamine (NEts, 99.7%), and EtOx were purchased from Sigma Aldrich. 2-Ethyl-2-oxazoline was dried over calcium hydride and distilled under an argon atmosphere. Methyl tosylate (MeOTs, 98%) was dried over barium oxide and distilled under an argon atmosphere. Hydrochloric acid (37%) was purchased from Fisher Chemicals. Aqueous hydrogen peroxide solution (30% w / w) was obtained from Carl Roth. Acetyl chloride (approximately 90%) was purchased from Merck Schuchardt. Amberlite IRA-67 was obtained from Merck and was washed several times with deionized water before use. N,N-Dimethylformamide (DMF) and acetonitrile were dried in a solvent purification system (MB-SPS-800 from M Braun). Phosphate-buffered saline (PBS) was obtained from Biowest.Succinic anhydride (>99%), N-hydroxysuccinimide (NHS, >99%), sodium methoxide (0.5 M in methanol), and BCN-NHS were obtained from Sigma-Aldrich. Ditetradecylamine (95%) was purchased from AmBeed. N-(3-Dimethylaminopropyl)-N'-Ethylcarbodiimide Hydrochloride (EDC-HCL) was purchased from Apollo Scientific. Triethylamine (>99%) and 4-Dimethylaminopyridine (DMAP, >99%) were purchased from TCI.

[0250] Carrying out measurements

[0251] Proton ( 1H) Nuclear magnetic resonance (NMR) spectra were measured on a Bruker AC 300 MHz and a Bruker AC 400 MHz spectrometer. Correlation spectroscopic (COSY) NMR, heteronuclear single quantum correlation (HSQC) NMR, heteronuclear multiple bond correlation (HMBC) NMR spectra, and DOSY NMR spectra were recorded on a Bruker AC 400 MHz spectrometer. Measurements were performed at room temperature using either D2O, d4-methanol, or deuterated chloroform as solvent. Chemical shifts (δ) are given in parts per million (ppm) relative to the remaining non-deuterated solvent resonance signal. Infrared (IR) spectroscopy was performed on a Shimadzu I RAffinity-1 CE system equipped with a Quest ATR diamond crystal single-reflecting ATR cuvette for extended-range measurement.

[0252] Size exclusion chromatography (SEC) was performed using two different setups. Measurements in N,N-dimethylacetamide (DMAc) were performed using an Agilent 1200 Series system equipped with a PSS degasser, a G1310A pump, a G1329A autosampler, a Techlab oven, a G1362A refractive index detector (RID), and a PSS GRAM-guard / 30 / 1000 Å column (10 pm particle size). DMAc with 0.21 wt% LiCl was used as the eluent. The flow rate was 1 mL min. -1 and the oven temperature was 40 °C. For the calculation of molar masses, polystyrene (PS) or polymethyl methacrylate (PMMA) standards from 400 to 1,000,000 g mol' 1The measurements in chloroform were performed using a Shimadzu system (Shimadzu Corp., Kyoto, Japan) equipped with an SCL-10A VP system controller, a SIL-10AD VP autosampler, an LC-10AD VP pump, an RID-10A RI detector, a CTO-10A VP oven, and a PSS SDV guard / lin S column (5 mm particle size). A mixture of chloroform / isopropanol / triethylamine (94 / 2 / 4 vol%) was used as the eluent. The flow rate was 1 mL min. 1 and the oven temperature was 40 °C. PS standards from 400 to 100,000 g mol' 1 were used to calibrate the system.

[0253] Characterization of the polymers by 1 H-NMR spectroscopy

[0254] The first step in the preparation of PEtOx lipids consisted of the synthesis of PEtOx with different repeat units (20, 40, 50, 60 & 100) via CROP (see synthesis of PEtOx-OAc). CROP was terminated by the addition of acetic acid. The degree of polymerization was determined by 1 H-NMR spectroscopy was used to determine the conversion of monomer to polymer. The hydrolysis was carried out under basic conditions (see synthesis of POx-OH). To achieve complete hydrolysis, the reaction was carried out overnight with NaOMe. The successful synthesis was confirmed by the 1 H-NMR confirmed this, which clearly showed the disappearance of the signals assigned to the CH3 groups of the OAc-w end group of PEtOx-OAc. To extend the linker unit, PEtOx-OH was reacted with succinic anhydride (see synthesis of succinylated PEtOx). The product was also analyzed by 1H-NMR spectroscopy. To introduce the lipid group, the end group of the succinylated PEtOx was activated by EDC coupling and NHS and reacted with ditetradecylamine. The product was 1 Characterized by H-NMR. Cationic ring-opening polymerization of ethyloxazoline (PEtOx-OAc)

[0255] The synthesis was carried out according to M. Dirauf, A. Erlebach, C. Weber, S. Hoeppener, JR Buchheim, M. Sierka, US Schubert, Macromolecules 2020, 53, 3580-3590.

[0256] Methyl tosylate (1 eq.) and ethyl oxazoline (20, 40, 50, 60, 100 eq., depending on the desired chain length) were dissolved in anhydrous acetonitrile and heated to reflux. The mixture was cooled, acetic acid (1.5 eq.) and triethylamine (2 eq.) were added sequentially and stirred overnight at 50 °C. The reaction mixture was diluted with CHCl3 (100 mL), washed with saturated NaHCO3 solution (3 x 200 mL) and brine (200 mL). The combined organic phases were dried over Na2SO4, the volatiles were removed under reduced pressure, and the mixture was dried overnight at 40 °C under vacuum.

[0257] PEtOx 50 -OAc: 1 H NMR (300 MHz, CDCI3): <50.99 - 1.23 (br, 150H, CH2-CH3); 2.01 - 2.13 (br, 3H, CO-CH3); 2.18 - 2.56 (m, 100H, CH2-CH3); 2.98 - 3.13 (br, 3H, CH3-N), 3.30 - 3.66 (br, 200H, N-CH2-CH 2) backbone) ppm.

[0258] SEC (DMAc + 0.21 wt% LiCl): M n = 8820 g mol' 1 , £> = 1 .06.

[0259] Synthesis of PEtOx-OH

[0260] The synthesis was also carried out according to M. Dirauf, A. Erlebach, C. Weber, S. Hoeppener, JR Buchheim, M. Sierka, US Schubert, Macromolecules 2020, 53, 3580-3590.

[0261] PEtOx-OAc (1 eq.) was dissolved in anhydrous MeOH (0.15 g mL' 1 ) and NaOMe (0.1 eq., 0.5 M in MeOH) was added with vigorous stirring. The reaction mixture was stirred overnight at room temperature, and then the solvent was removed under reduced pressure. The residue was taken up in CHCl3 and washed with saturated NaHCO3 (3 x 200 mL) and brine (200 mL). The combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure. The product was then dissolved in CH2Cl2 and precipitated in ice-cold diethyl ether. The polymer was dried overnight at 40 °C under vacuum.

[0262] PEtOx 50 -OH: 1H NMR (300 MHz, CDCI3): ö 0.99 - 1.25 (br, 150H, CH2-CH3); 2.19- 2.59 (m, 100H, CH2-CH3); 3.00 - 3.12 (br, 3H, CH3-N), 3.31 - 3.69 (br, 200H, N- CH2-CH2, backbone) ppm.

[0263] SEC (DMAc + 0.21 wt% LiCI): M n = 9240 g mol' 1 , £> = 1 .05.

[0264] Synthese von succinyliertem PEtOx

[0265] PEtOx-OH (1 eq.) and DMAP (1.05 eq.) were dissolved in anhydrous DMF (c = 0.145 M). Triethylamine (0.1 eq.) and succinic anhydride (3 eq.) were added to the mixture, which was stirred overnight at room temperature. The reaction mixture was then precipitated in ice-cold diethyl ether and subsequently dissolved in dichloromethane. The mixture was subsequently washed with saturated NH4Cl solution, and the combined organic phases were dried over MgSO4. The volatiles were removed under reduced pressure, redissolved in dichloromethane, and precipitated in ice-cold diethyl ether. The resulting solid was dried overnight in vacuo.

[0266] PEtOx 50 -COOH: 1 H NMR (300 MHz, CDCI3): ö 0.96 - 1.13 (br, 150H, CH2-CH3); 2.13- 2.43 (m, 100H, CH2-CH3); 2.44 - 2.67 (br, 4H, CO-CH2-CH2-CO); 2.95 - 3.01 (br, 3H, CH3-N), 3.28 - 3.58 (br, 200H, N-CH2-CH2, backbone) ppm.

[0267] SEC (DMAc + 0.21 wt% LiCl): M n= 8900 g mol' 1 , D = 1 .07.

[0268] Synthesis of succinylated PEtOx with ditetradecylamine

[0269] Succinylated PEtOx (1 eq.) was dissolved in anhydrous CHCl3, and DMAP (0.1 eq.), NHS (2.5 eq.), and EDC-HCl (3 eq.) were added and stirred at room temperature for 3 h. Ditetradecylamine (4 equivalents) was added, and the mixture was stirred overnight at 45 °C. The mixture was then precipitated in ice-cold diethyl ether, redissolved in CH2Cl2, and cooled to -20 °C for 3 to 5 h. The precipitate was filtered (0.25 pm PTFE filter), precipitated in ice-cold diethyl ether, and dialyzed against EtOH:water (1:1, 1000 Da MWCO dialysis membrane) for 3 days, dialyzed against water for 2 days, and then freeze-dried.

[0270] PEtOx 50 -Lipids: 1 H NMR (300 MHz, CDCI3): ö 0.81 (t, 6H, lipids CH2-CH3); 0.97 -

[0271] 1.12 (br, 150H, CH2-CH3); 1.13 - 1.27 (br, 36H, lipid alkyl chain); 1.38 - 1.45 (br, 2H, N-CH2-CH2); 1.45 - 1.57 (br, 2H, N-CH2-CH2); 2.14- 2.42 (m, 100H, CH2-CH3);

[0272] 2.51 - 2.61 (m, 4H, CO-CH2-CH2-CO); 2.94 - 3.02 (br, 3H, CH3-N), 3.15 (t, 2H, N-CH2); 3.17 - 3.23 (m, 2H, N-CH2); 3.28 - 3.58 (br, 200H, N-CH2-CH2, backbone) ppm.

[0273] SEC (DMAc + 0.21 wt% LiCl): M n = 9300 g mol' 1 , £> = 1.06.

[0274] Figure 2 shows a schematic representation of the synthesis of a degPOx lipid. The linker is activated by strain-promoted azide-alkyl cycloaddition (SPAAC), and the lipid is then coupled to the linker.

Claims

Patent claims 1. Polymers of formulas (I) or (II) CO-R 1 I lni-[N-CR 3 H-CR 4 H] w -R 2 (I), CO-R 1 I lni-[N-CR 3 H-CR 4 H-CR 5 H] w -R 2 (II), or containing polymers, based on all structural units, 10 to 95 mol % of structural units of formula (III), 5 to 90 mol % of structural units of formula (IV) and 0 to 20 mol % of structural units of formula (V) CO-R 1 I -N-CHR 3 -CHR 4 - (III), -NH-CO-CHR 5 - (IV), -NH-CHR 6 -CHR 7 - (V), or containing 10 to 95 mol % of structural units of formula (VI), 5 to 90 mol % of structural units of formula (VII) and 0 to 20 mol % of structural units of formula (VIII) CO-R 1 I -N-CHR 3 -CHR 4 -CHR5 - (VI), -NH-CO-CHR 6 -CHR 7 - (VII), -NH-CHR 8 -CHR 9 -CHR 10 - (VIII), wherein at least one of the structural units of formula (III), (IV) or (V) or of formula (VI), (VII) or (VIII) is grouped with the -CHR 4 -, -CHR 5 - or -CHR 7 - or with the grouping -CHR 5 -, -CHR 7 - or -ear 10 - covalent with a residue R 2 is connected in which Ini is a residue derived from an initiator of cationic polymerization, R 1 The selection is made from the group consisting of hydrogen or C1-C4 alkyl, R 2 The selection is made from the group consisting of -OR 11 , -OCO-R 11 , -OCO-R 14 -CO-OR 11 , -OCO-R 14 -CO-NR 12 R 13 , -NR 12 -R 14 -CO-NR 13 R 15 , -OR 16 -(O-OC-R 18 )m and N=N II -NR 17 -CH2-OCO-NR 12 R 13 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 independent of each other, hydrogen, methyl, ethyl, propyl or butyl mean, R 11 C6-C 20 -Alkyl is R 12 and R 15 independent of each other are hydrogen or alkyl, R 13 C6-C2o-alkyl means, R 14 Alkylene, cycloalkylene, arylene or aralkylene means, R 16 an m+1 aliphatic hydrocarbon residue is, R 18 Ce-C2o-alkyl means, with the proviso that several R groups 18 of a remainder R 16 within the framework of the given definitions, m is an integer from 1 to 5, R 17a trivalent bicyclic residue, and w is an integer in the range of 1 to 5000. Polymers according to claim 1, characterized in that these have structures of formula (IX) or (X). CO-R 1 I lni-[N-CR 3 H-CR 4 H] x -[NH-CO-CR 5 H] y -[NH-CR 6 H-CR 7 H] z -R 2 (IX), CO-R 1 I lni-[N-CR 3 H-CR 4 H-CR 5 H] X -[NH-CO-CR 6 H-CR 7 H] y -[NH-CR 8 H-CR 9 H-CR 10 H] z -R 2 (X), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10which have the meaning defined in claim 1, x and y independently represent integers in the range from 1 to 5000, z is an integer in the range from 0 to 1000, with the proviso that the molar part of the number with [] x the structural units designated as 10 to 95 mol%, the molar fraction of which is denoted by [] y the structural units designated as 5 to 90 mol%, and the molar fraction of those labelled with [] z The structural units designated as 0 to 20 mol% are based on the total amount of the elements marked with [] x , [] y and [] zDesignated structural units. Polymers according to claim 1 or 2, characterized in that they have formulas (I) or (IX). Polymers according to claim 1, characterized in that they have formula (I). Polymers according to at least one of claims 1 to 4, characterized in that Ini is selected from the group consisting of alkyl, aralkyl, or carboxyalkyl. Polymers according to at least one of claims 1 to 5, characterized in that R 1 Ci-C3-Alkyl means, in particular, methyl or ethyl.

7. Polymers according to at least one of claims 1 to 6, characterized in that R 2 The selection will be made from the group consisting of -OCO-R 14 - CO-OR 11 , -OCO-R 14 -CO-NR 12 R 13 and N=N II -N— R 17 -CH2-OCO-NR 12 R 13 , in particular a remainder of the formula -OCO-R 14 -CO-NR 12 R 13 is.

8. Polymers according to at least one of claims 1 to 7, characterized in that R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 hydrogen.

9. Polymers according to at least one of claims 1 to 8, characterized in that R 11 It is C8-Ci6-alkyl.

10. Polymers according to at least one of claims 1 to 9, characterized in that R 12 and R 15 C6-C20 alkyls are, in particular Cs-C-13 alkyls.

11. Polymers according to at least one of claims 1 to 10, characterized in that R 13 Co-Cis alkyl is.

12. Polymers according to at least one of claims 1 to 11, characterized in that R 14 C2-C4 alkylene means, in particular, ethylene.

13. Polymers according to at least one of claims 1 to 12, characterized in that m means 2 or 3, in particular 2.

14. Polymers according to at least one of claims 1 to 13, characterized in that R 16 is an aliphatic hydrocarbon residue derived from glycerol.

15. Polymers according to at least one of claims 1 to 14, characterized in that R 17 a remainder of the formula 6. Polymers according to at least one of claims 1 to 15, characterized in that w represents an integer in the range of 5 to 500, x and y independently represent integers in the range of 5 to 500, z is an integer in the range of 0 to 100, with the proviso that the molar component of the [] x the structural units designated as 20 to 90 mol%, the molar fraction of which is denoted by [] y the structural units designated as 10 to 80 mol%, and the molar fraction of those labelled with [] z The structural units designated as 0 to 20 mol% are based on the total amount of the elements marked with [] x , [] yand [] z designated structural units.

7. Polymers according to claim 4, characterized in that R 1 Ethyl is, R 2 -OCO-R 14 -CO-NR 12 R 13 means, R 3 and R 4 hydrogen means, R 12 and R 13 independently of each other Cs-Cis alkyl, R 14 C2-C4 means alkylene, especially ethylene, and w means an integer in the range of 5 to 200.

18. Use of the polymers according to at least one of claims 1 to 17 for the manufacture of formulations containing pharmaceutical or agrochemical active ingredients.

19. Use according to claim 18, characterized in that the active ingredient is a pharmaceutical or agrochemical active ingredient, in particular a vaccine or a nucleic acid.

20. Particles, in particular nanoparticles, containing the polymers according to at least one of claims 1 to 17.

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