Non-immunogenic polysorbates

Abstract

The present invention refers to novel polyoxyalkylene based compounds and their manufacturing method as well as compositions comprising at least one novel polyoxyalkylene based compound. Furthermore, the present invention refers to pharmaceutical compositions for use in the treatment of an illness in mammals or humans.

Description

[0001] 202200147

[0002] 1

[0003] Non-immunogenic polysorbates

[0004] Technical Field

[0005] The present invention refers to novel polyoxyalkylene based compounds and their manufacturing method as well as compositions comprising at least one novel polyoxyalkylene based compound. Furthermore, the present invention refers to pharmaceutical compositions for use in the treatment of an illness in mammals or humans.

[0006] Background of the invention

[0007] Polysorbates (PS) are surfactants that are used in food, cosmetics, and pharmaceutical applications. Relevant PS in the pharmaceutical industry are polysorbate 80 (PS 80) and polysorbate 20 (PS 20). PS 80 is an important surfactant for parenteral pharmaceutical dosage forms that is monographed in US pharmacopeia. The chemical structures of PS 80 and PS 20 are composed of ethoxylated sorbitan esterified with oleic acid or lauric acid, respectively. Manufacture of PS 80 is carried out in three steps: 1) Dehydration and esterification of sorbitol to yield sorbitan, 2) Esterification of sorbitan with oleic acid to yield sorbitan monooleate (SMO), 3) Anionic ring opening polymerization (AROP) of EO using SMO as the initiator.

[0008] It is documented in literature (Zhang et al., Anal. Chem., 2015, 87(19), 9810) that because of the synthesis protocol for the manufacture of PS 80, the product is a complex mixture of compounds. The idealized reaction pathway leads to polyether sorbitan monooleate, which is commonly referred to as PS 80. Parallel reactions result in at least two additional compounds: polyether isosorbide monooleate and polyether monooleate. The three compounds possess similar spectroscopic and chromatographic properties, which makes it difficult to quantify, separate or purify them in the product mix.

[0009] A drawback of PS is presence of ethylene oxide (EO) repeating units in the molecular structures. The average degree of polymerization per PS 80 or PS 20 molecule is 20, and thus the average number of ethylene oxide (EO) repeating units per hydroxy group of sorbitan is 5. Thus, PS contains oligomeric chains of poly(ethylene oxide) (PEO). It is known that PEO can lead to the formation of anti-PEO antibodies (APAs), for example as disclosed in Zhan C. et al., Nano Today, Volume 55, 2024, 102163. For example, APAs can lead to side effects like pseudo-allergic reactions and rapid clearance of PEO and pegylated drug delivery systems from patient’s body.

[0010] Another known drawback of PS is the formation of particles that can jeopardize storage stability of parenteral dosage forms (injection vials), for example described in Engblom J. Journal of Colloid and Interface Science, Volume 592, 2021 , 468. 202200147

[0011] 2

[0012] Therefore, there is a need in the field of pharmaceutical applications for novel compound, which have similar physicochemical characteristics like PS but show less APA formation and / or improved storage stability.

[0013] It has surprisingly found by the present inventors that the compounds of the present invention can overcome one or more of the drawbacks of PS 80. In particular, the novel compounds show improved stability compared to PS 80. Not to be bound by theory, it is assumed that this is due to the different structure, i.e. PS 80 being crystalline, while the new compounds are amorphous. Furthermore, the novel compounds show an improved immunological profile compared to PS 80.

[0014] Summary of the invention

[0015] In a first aspect the present invention refers to a compound having following formula (I)

[0016] R1, R2and R3are independently selected from each other from -H and saturated branched or straightchain C1-C5 hydrocarbon groups;

[0017] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R1, R2and R3are bound to an oxygen atom of the polyoxyalkylene group A, respectively and the polyoxyalkylene group A is bound via a carbon atom to the remainder of the molecule opposite of R1, R2and R3, respectively;

[0018] A is a polyoxyalkylene group comprising unit 202200147

[0019] 3 and optionally at least one unit selected from the group of erein n is 2 to 8, preferably 4 to 6, more preferably 5; m is 2 to 8, preferably 4 to 6, more preferably 5; o is 2 to 8, preferably 4 to 6, more preferably 5; p is 2 to 8, preferably 4 to 6, more preferably 5; and the sum of n + m + o + p is 10 to 30, preferably 15 to 25, more preferably 20.

[0020] In a second aspect the present invention pertains to a compound having following formula (II) wherein 202200147

[0021] 4

[0022] R1is selected from -H and saturated branched or straight-chain C1-C5 hydrocarbon groups, preferably is - H;

[0023] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R1is bound to an oxygen atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via a carbon atom to the remainder of the molecule opposite of R1;

[0024] A is a polyoxyalkylene group comprising unit and optionally at least one unit selected from the group of n is 2 to 8, preferably 4 to 6, more preferably 5; p is 2 to 8, preferably 4 to 6, more preferably 5; 202200147

[0025] 5 and the sum of n and p is 5 to 15, preferably 8 to 13, more preferably 10.

[0026] In a third aspect the present invention refers to a pharmaceutical composition comprising i) at least one compound of formula (I) according to the present invention; ii) optionally at least one compound of formula (II) according to the present invention; iii) optionally at least one compound of formula (III) wherein

[0027] R5is selected from -H and -OH;

[0028] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5;

[0029] A is a polyoxyalkylene group comprising unit and optionally at least one unit selected from the group of 202200147

[0030] 6 p is 2 to 8, preferably 4 to 6, more preferably 5; and iv) at least one active agent, which is preferably a biological drug or vaccine.

[0031] In a fourth aspect the present invention pertains to a cosmetic composition comprising i) at least one compound of formula (I) according to the present invention; ii) optionally at least one compound of formula (II) according to the present invention; iii) optionally at least one compound of formula (III) wherein

[0032] R5is selected from -H and -OH;

[0033] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5;

[0034] A is a polyoxyalkylene group comprising unit 202200147

[0035] 7 and optionally at least one unit selected from the group of p is 2 to 8, preferably 4 to 6, more preferably 5.

[0036] In a fifth aspect the present invention pertain to a food composition comprising i) at least one compound of formula (I) according to the present invention; ii) optionally at least one compound of formula (II) according to the present invention; iii) optionally at least one compound of formula (III) wherein

[0037] R5is selected from -H and -OH; 202200147

[0038] 8

[0039] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5; A is a polyoxyalkylene group comprising unit and optionally at least one unit selected from the group of p is 2 to 8, preferably 4 to 6, more preferably 5.

[0040] In a sixth aspect the present invention refers to the use of compound (I) or (II) according to the present invention as emulsifier, solubilizer, lubricant or stabilizer. 202200147

[0041] 9

[0042] In an seventh aspect the present invention pertains to a method of producing a compound of formula (I) to the present invention and / or formula (II) according to the present invention comprising or consisting of the steps: allowing sorbitol to react with oleic acid and glycidyl methyl ether and optionally at least one compound selected from ethylene oxide, ethyl glycidyl ether, propyl glycidyl ether, isopropyl glycidyl ether.

[0043] In an eighth aspect the present invention refers to a pharmaceutical composition according to the present invention for use in the treatment of an illness in humans.

[0044] In a ninth aspect the present invention pertain to a pharmaceutical composition according to the present invention for use in the treatment of an illness in mammals.

[0045] These and other aspects, embodiments, features, and advantages of the invention will become apparent to a person skilled in the art through the study of the following detailed description and claims. Any feature from one aspect of the invention can be used in any other aspect of the invention. Furthermore, it will readily be understood that the examples contained herein are intended to describe and illustrate the invention but not to limit the invention and that, in particular, the invention is not limited to these examples.

[0046] Description of the Figures

[0047] Fig. 1 : MALDI spectrum (linear Mode, m / z 600 - 6600) of pGME-PS 80 (sample b(2)). Three main compounds (polyether sorbitan monooleate, polyether isosorbide monooleate, polyether monooleate) were identified.

[0048] Fig. 2 : Determination of the CMC of PS 80 (sample a(2)) and pGME-PS 80 (sample b(2)) using dynamic light scattering (DLS). Results were comparable between 0.01 and 0.1 mg / mL.

[0049] Fig. 3 : Insulin aggregation assay: Both PS 80 (sample a(2)) and pGME-PS 80 (sample b(2)) prevent precipitation of insulin compared to the surfactant-free control.

[0050] Detailed description of the invention

[0051] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0052] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises", "comprising", “contain”, and “containing” are to be construed in an open and inclusive sense, that is, as "including, but not limited to". 202200147

[0053] 10

[0054] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art. As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0055] Numerical ranges that are indicated in the format “from x to y” also include the stated values. If several preferred numerical ranges are indicated in this format, it is self-evident that all ranges that result from the combination of the various endpoints are also included.

[0056] "One or more", as used herein, relates to at least one and comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9 or more of the referenced species. Similarly, "at least one" means one or more, i.e., 1 , 2, 3, 4, 5, 6, 7, 8, 9 or more. "At least one", as used herein in relation to any component, refers to the number of chemically different molecules, i.e. to the number of different types of the referenced species, but not to the total number of molecules. For example, "at least one therapeutic agent" means that at least one type of molecule falling within the definition for a therapeutic agent is used but that also two or more different types of therapeutic agents falling within this definition can be present, but does not mean that only one or more molecules of one type of therapeutic agents are present.

[0057] All percentages given herein in relation to the compositions relate to wt.-% relative to the total weight of the respective composition, if not explicitly stated otherwise.

[0058] “Essentially free of’ according to the present invention with regard to compounds means that the compound can only be present in an amount, which does not influence the characteristics of the composition, in particular the respective compound is present in less than 3 wt.-%, preferably 1 wt.-%, more preferably 0.01 wt.-%, based on the total weight of the composition or is not present at all.

[0059] An "effective amount" or "therapeutically effective amount" of an active agent such as a nucleic acid is an amount sufficient to produce the desired effect, e.g., an increase or inhibition of expression of a target sequence in comparison to the normal expression level detected in the absence of the nucleic acid. An increase in expression of a target sequence is achieved when any measurable level is detected in the case of an expression product that is not present in the absence of the nucleic acid. In the case where the expression product is present at some level prior to contact with the nucleic acid, an in increase in expression is achieved when the fold increase in value obtained with a nucleic acid such as mRNA relative to control is about 1 .05, 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 250, 500, 750, 1000, 5000, 10000, or greater. Inhibition of expression of a target gene or target sequence is achieved when the value obtained with a nucleic acid such as antisense oligonucleotide relative to the control is about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 0%. Suitable assays for measuring expression of a target gene or target sequence include, e.g., examination of protein or RNA levels using techniques known to those of skill in the art such as dot blots, northern blots, in situ hybridization, ELISA, immunoprecipitation, enzyme function, fluorescence, or luminescence of suitable reporter proteins, as well as phenotypic assays known to those of skill in the art. 202200147

[0060] 11

[0061] The disclosure disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of the compound of formulae (I), (II) and (III) being their pharmaceutically acceptable salt and / or being isotopically labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine.

[0062] The compounds of the present invention including their pharmaceutically acceptable salts may contain one or more stereocenters and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0063] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0064] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any said compounds.

[0065] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0066] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, 202200147

[0067] 12 galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, / toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0068] In particular, the present invention refers to a compound having following formula (I)

[0069] R1, R2and R3are independently selected from each other from -H and saturated branched or straightchain C1-C5 hydrocarbon groups;

[0070] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R1, R2and R3are bound to an oxygen atom of the polyoxyalkylene group A, respectively and the polyoxyalkylene group A is bound via a carbon atom to the remainder of the molecule opposite of R1, R2and R3, respectively;

[0071] A is a polyoxyalkylene group comprising unit and optionally at least one unit selected from the group of 202200147

[0072] 13 n is 2 to 8, preferably 4 to 6, more preferably 5; m is 2 to 8, preferably 4 to 6, more preferably 5;

[0073] 0 is 2 to 8, preferably 4 to 6, more preferably 5; p is 2 to 8, preferably 4 to 6, more preferably 5; and the sum of n + m + 0 + p is 10 to 30, preferably 15 to 25, more preferably 20. In general the polyoxyalkylene group -(A)P- is bound via a oxygen atom to the carbonyl group and via a carbon atom to the remainder of compound (I).

[0074] In one embodiment R4is selected from i) saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C6-C20 hydrocarbon groups; or ii) saturated or unsaturated with up to two -C=C- bonds, straight-chain Ca-C hydrocarbon groups; or iii) saturated or unsaturated with one -C=C- bond, branched or straight-chain C6-C20 hydrocarbon groups; or iv) saturated or unsaturated with one -C=C- bond, straight-chain C15-C17 hydrocarbon groups; or 202200147

[0075] 14 v) -C7Hi4-CH=CH-C8Hi7, preferably cis -C7Hi4-CH=CH-C8Hi7.

[0076] In one embodiment the dispersity of compound (I) is 1 .3 or less.

[0077] In one embodiment of the compound of formula (I) A consists of units (a).

[0078] In one embodiment of the compound of formula (I) A consists of units (a) and R4is selected from saturated or unsaturated with one -C=C- bond, straight-chain C15-C17 hydrocarbon groups or is -C7H14- CH=CH-CsHi7, preferably cis -C7Hi4-CH=CH-CsHi7.

[0079] In one embodiment of the compound of formula (I) A consists of units (a) and (b).

[0080] In one embodiment of the compound of formula (I) A consists of units (a) and (b) and R4is selected from saturated or unsaturated with one -C=C- bond, straight-chain C15-C17 hydrocarbon groups or is -C7H14- CH=CH-CsHi7, preferably cis -C7Hi4-CH=CH-CsHi7.

[0081] Furthermore, the present invention refers to a compound having following formula (II) wherein

[0082] R1is selected from -H and saturated branched or straight-chain C1-C5 hydrocarbon groups, preferably is - H;

[0083] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R1is bound to an oxygen atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via a carbon atom to the remainder of the molecule opposite of R1;

[0084] A is a polyoxyalkylene group comprising unit and optionally at least one unit selected from the group of 202200147

[0085] 15 n is 2 to 8, preferably 4 to 6, more preferably 5; p is 2 to 8, preferably 4 to 6, more preferably 5; and the sum of n and p is 5 to 15, preferably 8 to 13, more preferably 10.

[0086] In one embodiment of compound (II) R4is selected from i) saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C6-C20 hydrocarbon groups; or ii) saturated or unsaturated with up to two -C=C- bonds, straight-chain Ca-C hydrocarbon groups; or iii) saturated or unsaturated with one -C=C- bond, branched or straight-chain C6-C20 hydrocarbon groups; or iv) saturated or unsaturated with one -C=C- bond, straight-chain C15-C17 hydrocarbon groups; or v) -C7Hi4-CH=CH-C8Hi7, preferably cis -C7Hi4-CH=CH-C8Hi7. 202200147

[0087] 16

[0088] In one embodiment the dispersity of compound (II) is 1 .3 or less.

[0089] In one embodiment of the compound of formula (II) A consists of units (a).

[0090] In one embodiment of the compound of formula (II) A consists of units (a) and (b).

[0091] In one embodiment of the compound of formula (II) A consists of units (a) and (b) and R4is selected from saturated or unsaturated with one -C=C- bond, straight-chain C15-C17 hydrocarbon groups or is -C7H14- CH=CH-CaHi7, preferably cis -C7Hi4-CH=CH-CaHi7.

[0092] In a further aspect the invention refers to a pharmaceutical composition comprising i) at least one compound of formula (I) according to the present invention; ii) optionally at least one compound of formula (II) according to the present invention; iii) optionally at least one compound of formula (III) wherein

[0093] R5is selected from -H and -OH;

[0094] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5;

[0095] A is a polyoxyalkylene group comprising unit and optionally at least one unit selected from the group of 202200147

[0096] 17 p is 2 to 8, preferably 4 to 6, more preferably 5; and iv) at least one active agent, which is preferably pharmaceutically active agent, more preferably a biological drug or vaccine.

[0097] In one embodiment of the pharmaceutical composition the at least one active agent is selected from the group consisting of proteins, peptides, carbohydrates, nucleic acids and nucleic acid analogues, organic molecules having a molecular weight up to 1000 g / mol and combinations thereof.

[0098] In one embodiment the pharmaceutical composition contains:

[0099] 15 to 40 wt.-% of at least one compound of formula (I) according to the present invention; and / or

[0100] 5 to 30 wt.-% of at least one compound of formula (II) according to the present invention; and / or 30 to 75 wt.-% of at least one compound of formula (III) according to the present invention; and / or

[0101] 0.1 to 5 wt.-% of at least one active agent, wherein the total amount of the components of the pharmaceutical composition is 100 wt.-%. 202200147

[0102] 18

[0103] The pharmaceutical compositions according to the present invention can be used in the treatment of an illness in humans.

[0104] The pharmaceutical compositions according to the present invention can be used in the treatment of an illness in mammals.

[0105] In a further aspect the invention refers to a cosmetic composition comprising i) at least one compound of formula (I) according to the present invention; ii) optionally at least one compound of formula (II) according to the present invention; iii) optionally at least one compound of formula (III) wherein

[0106] R5is selected from -H and -OH;

[0107] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5;

[0108] A is a polyoxyalkylene group comprising unit and optionally at least one unit selected from the group of 202200147

[0109] 19 erein p is 2 to 8, preferably 4 to 6, more preferably 5.

[0110] In one embodiment the cosmetic composition contains:

[0111] 15 to 40 wt.-% of at least one compound of formula (I) according to the present invention; and / or

[0112] 5 to 30 wt.-% of at least one compound of formula (II) according to the present invention; and / or

[0113] 30 to 75 wt.-% of at least one compound of formula (III) according to the present invention; and / or

[0114] 0.1 to 5 wt.-% of at least one active agent, wherein the total amount of the components of the pharmaceutical composition is 100 wt.-%.

[0115] In a further aspect the present invention refers to a food composition comprising i) at least one compound of formula (I) according to the present invention; ii) optionally at least one compound of formula (II) according to the present invention; iii) optionally at least one compound of formula (III) 202200147

[0116] 20 wherein

[0117] R5is selected from -H and -OH;

[0118] R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C3- C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5;

[0119] A is a polyoxyalkylene group comprising unit and optionally at least one unit selected from the group of 202200147

[0120] 21 p is 2 to 8, preferably 4 to 6, more preferably 5.

[0121] In one embodiment the food composition contains:

[0122] 15 to 40 wt.-% of at least one compound of formula (I) according to the present invention; and / or

[0123] 5 to 30 wt.-% of at least one compound of formula (II) according to the present invention; and / or

[0124] 30 to 75 wt.-% of at least one compound of formula (III) according to the present invention; and / or

[0125] 0.1 to 5 wt.-% of at least one active agent, wherein the total amount of the components of the pharmaceutical composition is 100 wt.-%.

[0126] The compounds according to formula (I) and (II) of the present invention can be used as emulsifier, solubilizer, lubricant or stabilizer.

[0127] The compounds according to formula (I) and (II) of the present invention can be obtained by a method comprising or consisting of the steps: allowing sorbitol to react with oleic acid and glycidyl methyl ether and optionally at least one compound selected from ethylene oxide, ethyl glycidyl ether, propyl glycidyl ether, isopropyl glycidyl ether.

[0128] In one embodiment the method is a two step process, wherein sorbitol is reacted with oleic acid and the resulting compounds are reacted with glycidyl methyl ether and optionally at least one compound selected from ethylene oxide, ethyl glycidyl ether, propyl glycidyl ether, isopropyl glycidyl ether.

[0129] In one embodiment the method is a one step process, wherein sorbitol, oleic acid and glycidyl methyl ether and optionally at least one compound selected from ethylene oxide, ethyl glycidyl ether, propyl glycidyl ether, isopropyl glycidyl ether are allowed to react. 202200147

[0130] 22

[0131] In one embodiment the reaction takes place at reaction temperatures above 200 °C.

[0132] In one embodiment the glycidyl methyl ether and optionally at least one compound selected from ethylene oxide, ethyl glycidyl ether, propyl glycidyl ether, isopropyl glycidyl ether are provided via liquid dosing.

[0133] In one embodiment the method is a bulk reaction.

[0134] Examples

[0135] Preparation Example 1 : SMO synthesis

[0136] Scheme 1 : Idealized reaction pathway for the synthesis of SMO from Sorbitol

[0137] To a reaction vessel equipped with Teflon stopcock and stirrer, 1 eq of sorbitol, 0.04 eq sodium hydroxide (NaOH, 32% aqueous solution), 0.03 eq of hypophosphoric acid (H2PO2, 50% aqueous solution), and 1 .30 eq of oleic acid were added. Subsequently, dehydration and esterification were carried out at 230 °C under reduced pressure. Reaction mixture was allowed to cool to 80 °C. Phase separation occurred. The lower phase was discarded. The upper phase was purified by filtration. SMO was obtained as a viscous liquid. SMO was characterized by1H NMR spectroscopy (Bruker 400 MHz device at 300 K).

[0138] 1H NMR (CDCI3, 400 MHz) 5 [ppm]: 0.9 (3H, t, -CH3oleate), 1 .3 (20H, m,-CH2- oleate), 1 .7 (2H, m, B- CH2), 2.0 (4H, m, CH2-C=C-CH2), 2.3 (2H, t, ester a-CH2), 3.5-4.5 (8H, m, CH2 / CH sorbitan), 5.3 (2H, - CH=CH-). 202200147

[0139] 23

[0140] Example 2: PS 80 and pGME-PS 80 synthesis from SMO

[0141] Scheme 2: Idealized reaction pathway for the synthesis of PS 80 compounds from SMO

[0142] To a reaction vessel equipped with Teflon stopcock, stirrer and septum 1 eq of SMO from Example 1 was added. An aqueous solution containing 0.0058 eq of NaOH was added. Water was removed under reduced pressure. The residue was dried at 120 °C for 30 min. Vessel was flushed with argon and 20 eq of oxirane monomer were added to the flask via a syringe. Reaction mixture was heated to 125 °C and bulk polymerization was carried out under argon atmosphere for 24 h. Reaction mixture was allowed to cool to 100 °C and residual GME was removed under reduced pressure. The vacuum was broken, the vessel was flushed with argon, and the reaction mixture was allowed to further cool down to 80 °C. Aqueous L-Lactic acid and aqueous NaOH solution were used to adjust the pH to 5.5-7. Crude product was discharged from the vessel, dissolved in diethyl ether, purified by micro-filtration, and dried overnight in vacuo.

[0143] Table 1 : Characterization of PS 80 compounds by size exclusion chromatography (SEC) and1H-NMR spectroscopy.

[0144] Entry Sample DPNMR Mn,NMR Mn,sEc [kDa] PDISEC

[0145] (Example) [kDa] a (2) PS 80 20 1.31 1.42 1.14 b (2) pGME-PS 80 21 2.23 1.37 1.22

[0146] Mw, Mnand dispersity (Mw / Mn= PDI) of all samples were determined by a size exclusion chromatography (SEC) apparatus equipped with a refractive index (Rl) detector. SEC measurements were performed using dimethylformamide (DMF) containing 1 g / L lithium bromide (LiBr) as the mobile phase at a flow rate of 1 mL / min on poly(2-hydroxyethylmethacrylate) (PHEMA) 300 / 100 / 40 columns at 50 °C. Polymer concentrations were 1 mg / mL. Calibration was carried out using PEO standards from Polymer Standard Service (PSS, Mainz, Germany). Product was characterized by1H-NMR spectroscopy (Bruker, Billerica, MA, USA 400 MHz device at 300 K). 202200147

[0147] 24

[0148] 1H NMR (CDCI3, 400 MHz) 5 [ppm]: 0.9 (3H, t, -CH3oleate), 1 .3 (20H, m,-CH2- oleate), 1 .7 (2H, m, B- CH2), 2.0 (4H, m, CH2-C=C-CH2), 2.3 (2H, t, a-CH2), 3.3 (60H, s, -OCH3), 3.3-3.7 (97H, m, pGME -CH2- and -CH-), 3.9 (3H, m, HO-CH-(CH2O)2-), 5.2 (1 H, C17H33-OOC-CH-), 5.3 (2H, -CH=CH-).

[0149] Example 3: Identification of main compounds in the product mixture of pGME-PS 80 by MALDI- ToF MS

[0150] As a result of the synthesis protocol for the manufacture of PS 80, the product is a complex mixture of compounds. The idealized reaction pathway that leads to polyether sorbitan monooleate, which is typically referred to as PS 80, is described in scheme 1 and 2 of Example 1 and 2. In reality, the reaction pathway is more complex as depicted in scheme 3. Parallel reactions result in at least two additional components: First, an additional dehydration step of sorbitan results in isosorbide that reacts with oleic acid and oxirane monomer to yield polyether isosorbide monooleate. Second, direct esterification of oleic acid with oligomeric polyethers yields polyether monooleate.

[0151] Compounds in the product mixture were identified by matrix-assisted laser-desorption-ionization time of flight mass spectroscopy (MALDI-ToF MS). Measurements were carried out at a Bruker autoflex maX MALDI-TOF / TOF. The potassium salt of trifluoroacetic acid and trans-2-[3-(4-tert-butylphenyl)-2-methyl-2- propenylidene]malononitrile (DCTB) was used as ionization salt and matrix, respectively. In the MALDI- TOF mass spectrum, the main polysorbate product and the two different components (polyether isosorbide monooleate and polyether monooleate) were identified (see Figure 1). The maxima of the molar mass distributions were approximately at 2670 Da, 1420 Da, and 1380 Da, respectively. The mass distance AM within the molar mass distributions of all three compounds is 88 Da which corresponds to the molecular weight of the GME repeating unit.

[0152] 202200147

[0153] 25

[0154] Scheme 3: Reaction pathway yielding the main compounds of PS 80.

[0155] Example 4: Differential scanning calorimetry (DSC)

[0156] Thermoanalytical characterization of PS 80 (compound a(2)) and pGME-PS 80 (compound b(2)) was carried out by differential scanning calorimetry (DSC) using a TA Instruments (Waters Corp., New Castle, DE, US) DSC 250 according to ASTM D 3418. The thermal history of the samples was excluded via three cooling and three heating cycles:

[0157] 1. Cooling: Ramp 10 K / min to -80 °C

[0158] 2. Isothermal for 1 min

[0159] 3. Heating: Ramp 10 K / min to 200 °C

[0160] 4. Isothermal for 1 min

[0161] 5. Cooling: Ramp 5 K / min to -80 °C

[0162] 6. Isothermal for 1 min

[0163] 7. Heating: Ramp 5 K / min to 200 °C

[0164] 8. Isothermal for 1 min

[0165] 9. Cooling: Ramp 5 K / min to -80 °C

[0166] 10. Isothermal for 1 min

[0167] 11 . Heating: Ramp 10 K / min to 200 °C

[0168] Thermal transition temperatures were obtained from the third heating curve. 202200147

[0169] 26

[0170] PS 80: Glass transition temperature Tgas determined by half step height method was observed at -66 °C. Exothermal crystallization and endothermal melting peak maxima were observed at -45 °C and -10 °C, respectively. The obtained melting enthalpy AHmwas 43.5 J / g. pGME-PS 80: Tgas determined by half step height method was observed at -66 °C. No crystallization or melting transitions were detected.

[0171] Besides differences quantified via thermoanalysis, there were differences in visual appearance between the materials. At room temperature pGME-PS 80 appeared more viscous than PS 80. Further, in agreement with thermoanalysis, differences between PS 80 and pGME-PS 80 during thawing from the frozen state (- 80 °C) to room temperature were observed: PS 80 was going through an opaque solid phase indicating crystallinity. pGME-PS 80 was directly transitioning from the solidified glassy state to the liquid state. The fully amorphous nature of pGME-PS 80 excludes crystallization during cold storage that can jeopardize storage stability.

[0172] Example 5: Critical Micelle Concentration (CMC)

[0173] CMC was determined by dynamic light scattering (DLS) using a DynaPro™ 3 Plate Reader (Wyatt Technology, Santa Barbara, CA, US) operating at a wavelength of 830 nm. The scattered light was detected at an angle of 158° at constant temperature of 20 °C. Measurements were carried out in 96 well plate format. A series of solutions ranging from 100 mg / mL to 24 ng / mL were prepared from aqueous stock solutions of PS 80 and pGME-PS 80 (compounds a(2) and b(2)). The CMC was determined as the concentration marking the onset of the sharply increasing scattering intensity. Results for PS 80 and pGME-PS 80 were comparable between 0.01 and 0.1 mg / mL.

[0174] Example 6: Use-test of PS 80 and pGME-PS 80

[0175] To evaluate the performance of pGME-PS 80 as a surfactant, an insulin aggregation assay was performed. Prior to the experiment, the following stock solutions were prepared: 25 mg / mL human recombinant insulin (Merck, cat. number: 91077c) stock solution in 0.1 M HCI; 10 mg / mL stock solution of PS 80 (compound a(2)) in 1 *PBS (Gibco, cat. number: 15326239) and 10 mg / mL stock solution of pGME-PS 80 (compound b(2)) in 1 *PBS. PS 80 and pGME-PS 80 were tested with a concentration of 0.25 mg / mL and 0.50 mg / mL. The concentration of insulin was held constant at 20 mg / mL. As a control, the 20 mg / mL insulin solution was incubated without surfactant. Mixtures were prepared and tested in 2 mL Eppendorf tubes that were incubated in a Thermomixer at 1500 rpm at 37 °C over six hours. The absorbance of samples was analyzed every hour (100 pL each) in a transparent 96 well plate using a Tecan (Mannedorf, Switzerland) multiplate reader (Infinite® 200 PRO) at a wavelength of 600 nm. After measurement, samples were transferred back into the Eppendorf tube and continued to stir. The first sample was taken prior to stirring. Both PS 80 and pGME-PS 80 prevent precipitation for at least six 202200147

[0176] 27 hours, whereas the control (insulin without surfactant) showed precipitation after 3 h, as indicated by an increase in the absorbance.

Claims

20220014728Claims1 . A compound having following formula (I)R1, R2and R3are independently selected from each other from -H and saturated branched or straight-chain C1-C5 hydrocarbon groups;R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straightchain C3-C25 hydrocarbon groups; and wherein R1, R2and R3are bound to an oxygen atom of the polyoxyalkylene group A, respectively and the polyoxyalkylene group A is bound via a carbon atom to the remainder of the molecule opposite of R1, R2and R3, respectively;A is a polyoxyalkylene group comprising unitand optionally at least one unit selected from the group of20220014729n is 2 to 8; m is 2 to 8; o is 2 to 8; p is 2 to 8; and the sum of n + m + o + p is 10 to 30.

2. Compound according to claim 1 , wherein R1,R2, and R3are the same.

3. A compound having following formula (II)whereinR1is selected from -H and saturated branched or straight-chain C1-C5 hydrocarbon groups;R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straight- chain C3-C25 hydrocarbon groups; and wherein R1is bound to an oxygen atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via a carbon atom to the remainder of the molecule opposite of R1;A is a polyoxyalkylene group comprising unit20220014730and optionally at least one unit selected from the group ofn is 2 to 8; p is 2 to 8; and the sum of n and p is 5 to 15.

4. Compound according to any of the preceding claims, wherein R4is selected from i) saturated or unsaturated with up to two -C=C- bonds, branched or straight-chain C6-C20 hydrocarbon groups; or ii) saturated or unsaturated with up to two -C=C- bonds, straight-chain Ca-C hydrocarbon groups; or20220014731 iii) saturated or unsaturated with one -C=C- bond, branched or straight-chain C6-C20 hydrocarbon groups; or iv) saturated or unsaturated with one -C=C- bond, straight-chain C15-C17 hydrocarbon groups; or v) -C7Hi4-CH=CH-C8Hi7.

5. Compound according to any one of the preceding claims, wherein the dispersity is 1 .3 or less.

6. Compound according to any of the preceding claims, wherein A consists of units (a).

7. Compound according to any of claims 1 to 5, wherein A consists of units (a) and (b).

8. A pharmaceutical composition comprising i) at least one compound of formula (I) according to any one of claims 1 , 2 and 4 to 7; ii) optionally at least one compound of formula (II) according to any one of claims 3 to 7; iii) optionally at least one compound of formula (III)whereinR5is selected from -H and -OH;R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straightchain C3-C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5;A is a polyoxyalkylene group comprising unit20220014732 and optionally at least one unit selected from the group ofp is 2 to 8; and iv) at least one active agent.

9. The composition of claim 8, wherein the at least one active agent is selected from the group consisting of proteins, peptides, carbohydrates, nucleic acids and nucleic acid analogues, organic molecules having a molecular weight up to 1000 g / mol and combinations thereof.

10. A cosmetic composition comprising i) at least one compound of formula (I) according to any one of claims 1 , 2 and 4 to 7; ii) optionally at least one compound of formula (II) according to any one of claims 3 to 7; iii) optionally at least one compound of formula (III)20220014733whereinR5is selected from -H and -OH;R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straightchain C3-C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5;A is a polyoxyalkylene group comprising unitand optionally at least one unit selected from the group of20220014734wherein p is 2 to 8.

11. A food composition comprising i) at least one compound of formula (I) according to any one of claims 1 , 2 and 4 to 7; ii) optionally at least one compound of formula (II) according to any one of claims 3 to 7; iii) optionally at least one compound of formula (III)whereinR5is selected from -H and -OH; R4is selected from saturated or unsaturated with up to two -C=C- bonds, branched or straightchain C3-C25 hydrocarbon groups; and wherein R5is bound to a carbon atom of the polyoxyalkylene group A, and the polyoxyalkylene group A is bound via an oxygen atom to the remainder of the molecule opposite of R5; A is a polyoxyalkylene group comprising unitand optionally at least one unit selected from the group of2022001473512. Use of the compound of any of claims 1 to 7 as emulsifier, solubilizer, lubricant or stabilizer.

13. Method of producing a compound of formula (I) to any one of claims 1 , 2 and 4 to 7 and / or formula (II) according to any one of claims 3 to 7 comprising or consisting of the steps: allowing sorbitol to react with oleic acid and glycidyl methyl ether and optionally at least one compound selected from ethylene oxide, ethyl glycidyl ether, propyl glycidyl ether, isopropyl glycidyl ether.

14. Composition of claim 8 or 9 for use in the treatment of an illness in humans.

15. Composition of claim 8 or 9 for use in the treatment of an illness in mammals.

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