Primary side modified sulfoalkyl ether- and hydroxypropyl-cyclodextrins, synthesis and use thereof

Abstract

The present invention relates to a cyclodextrin derivative of formula (I), wherein the cyclodextrin derivative has an average percentage of primary substitution (Rp) to total substitution with the substituted alkyl in the range of 15-99 %. The invention also relates to a composition comprising said cyclodextrin derivatives, a drug-cyclodextrin complex, use of a cyclodextrin derivative and a manufacturing method thereof.

Description

[0001] PRIMARY SIDE MODIFIED SULFOALKYL ETHER- AND HYDROXYPROPYLCYCLODEXTRINS, SYNTHESIS AND USE THEREOF

[0002] Technical field of the invention

[0003] The present invention relates to the field of cyclodextrins. In particular, the present invention relates to novel cyclodextrin derivatives with a substitution pattern with a preference for substitution of the primary alcohols. Thus, the cyclodextrin derivatives have an average percentage of primary substitution (Rp) to total substitution with a substituted alkyl in the range of 15-99 %. The altered substitution pattern of the novel cyclodextrin derivatives results in an altered structure and therefore different properties, such as in terms of drug solubilisation, compared with the commercially available cyclodextrins.

[0004] Background of the invention

[0005] Cyclodextrins (also abbreviated CDs) are a family of cyclic oligosaccharides consisting of glucopyranoside subunits organized in a toroidal shape. The interior of the toroids are less hydrophilic than the aqueous solvent environment and therefore able to host hydrophobic molecules. Cyclodextrins are therefore particularly suitable in drug delivery of hydrophobic molecules and are used in more than 30 different approved medicines. The three main types of cyclodextrins comprising 6, 7 and 8 glucose subunits are alpha-, beta- and gammacyclodextrins, respectively. Alpha-, beta-, and gamma-cyclodextrins are all generally recognized as safe by the U.S. FDA and have been applied for delivery of a variety of drugs.

[0006] In addition, substituted cyclodextrin derivatives have been developed to modify the properties of these compounds in e.g. solubilizing drugs and drug delivery. Particularly, cyclodextrins substituted with 2-hydroxypropyl (HPCD) or sulfoalkylether derivates, such as sulfobutylether (SBECD), has been commercialised.

[0007] Taking beta-cyclodextrins as an example, it has 7 primary alcohols (often designated the C6-hydroxy) on the narrow rim of the cavity of the toroid structure and 14 secondary alcohols on the other side (often designated C2- and C3- hydroxy). The secondary alcohols on cyclodextrins have a pKa between 12 and 13, whereas the pKa for the primary alcohols is between 16 and 18. Since the available syntheses of e.g. beta-cyclodextrins (e.g., WO 2013 / 123254 Al, WO 2015 / 008066 Al) are typically performed in water with sodium hydroxide as a base, it is not possible to achieve reaction conditions with a pH value above 14. In this way, less than 1% of the primary alcohols will be deprotonated, whereas more than 90% of the secondary alcohols would be deprotonated. Since the alkoxy anions formed are far more nucleophilic than the protonated ones, only a limited number of primary alcohols will be modified during the synthesis and the substituents will therefore primarily be placed on the secondary side of cyclodextrins of the prior art. Changing this substitution pattern so that more primary alcohols are substituted compared with secondary alcohols may affect the binding properties towards e.g. small molecule drugs and result in improved features of the cyclodextrins, such as improved solubilisation of drugs.

[0008] WO 2013 / 123254 Al and WO 2015 / 008066 Al disclose a synthesis of sulfobutyl- beta-cyclodextrins by reacting a beta-cyclodextrin with a base in a solvent and adding butane-sultone thereto. The examples all involve reactions in water using sodium hydroxide as base, and there is no indication that primary (C6) substitution is the purpose or is achieved during said synthesis processes.

[0009] Malanga, M. et al., J Chromatogr A. 2017 Sep 8; 1514: 127-133 discloses a complex multi-step synthesis towards primary (C6) substituted (6-O-sulfobytyl)- cyclodextrins, however, the synthesis process yields a single isomer with exclusive primary substitution and a DS of exactly 7. Said prior art document does not disclose any solubilizing data.

[0010] WO 2020 / 142716 Al relates to the synthesis of HPCD dimers with varying degrees of substitution and variations in secondary / primary substitution. Deprotonation of beta-cyclodextrin with sodium hydroxide is described on page 18, first full paragraph. However, it is with the aim of dimerising the cyclodextrin, with later hydroxypropylation using conventional methods. Thus, primary side substituted monomeric HPCD or the synthesis thereof is not disclosed. Hence, cyclodextrins with an alternative substitution pattern, wherein more primary alcohols are substituted as opposed to secondary alcohols, would be advantageous, and in particular cyclodextrins with a high degree of substitution would be advantageous. Furthermore, cyclodextrins with an altered solubilisation of drugs compared with the cyclodextrins of the prior art would be useful in drug delivery.

[0011] Summary of the invention

[0012] The commercially available cyclodextrins are mostly substituted on the secondary alcohols. The inventors have reversed the substitution pattern, providing isomers that have not previously been described in the prior art. The general concept of this invention is to reverse the reactivity of the hydroxyl groups of the cyclodextrin by a quantitative deprotonation prior to addition of side chain precursor in an aprotic solvent, whereby the primary side hydroxyl ions become the most nucleophilic.

[0013] Thus, an object of the present invention relates to providing cyclodextrins with an altered substitution pattern compared with the cyclodextrins of the prior art. In particular, it is an object of the present invention to provide a cyclodextrin derivative that has a high degree of primary (C6-hydroxy) substitution and an altered and improved solubilisation of some drugs compared with the commercially available cyclodextrins.

[0014] Thus, one aspect of the invention relates to a cyclodextrin derivative of formula (I):

[0015] wherein

[0016] Rp, RS1, and RS2are independently hydrogen (H) or a substituted alkyl, n is an integer selected from 6, 7, 8, wherein the substituted alkyl is selected from the group consisting of -(CH2)mSO3X and -CH2CH(O-Y)CH3, wherein m is an integer selected from 3 and 4,

[0017] X is selected from a cation and H,

[0018] Y is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3), and wherein the cyclodextrin derivative has an average percentage of primary substitution (Rp) to total substitution with the substituted alkyl in the range of 15- 99 %.

[0019] Another aspect of the present invention relates to a composition comprising cyclodextrin derivatives in accordance with the present invention.

[0020] Yet another aspect of the present invention relates to a drug-cyclodextrin complex, wherein the cyclodextrin is a cyclodextrin derivative in accordance with the present invention.

[0021] Still another aspect of the present invention relates to the use of a cyclodextrin derivative according to the present invention for forming a drug-cyclodextrin complex. An aspect of the present invention relates to a method for manufacturing a cyclodextrin derivative, said method comprising : contacting a cyclodextrin of formula (II) wherein n is an integer selected from 6, 7, 8 with a base with a pKa of at least 14, and subsequently adding a compound selected from the group consisting of 1,3- propanesultone, 1,4-butanesultone and propylene oxide, to obtain the cyclodextrin derivative of formula (I), wherein

[0022] Rp, RS1, and RS2are independently hydrogen (H) or a substituted alkyl, n is an integer selected from 6, 7, 8, wherein the substituted alkyl is selected from the group consisting of -(CH2)mSO3X and -CH2CH(O-Y)CH3, wherein m is an integer selected from 3 and 4, X is selected from a monovalent cation and H, and

[0023] Y is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3).

[0024] Brief description of the figures

[0025] Figure 1A shows a generalised structure of sulfobutylether cyclodextrins (SBECDs) of the present invention (right) and the commercially available SBECDs (left).

[0026] Figure IB shows a generalised structure of hydroxypropyl cyclodextrins (HPCDs) of the present invention (right) and the commercially available HPCDs (left).

[0027] Figure 2A shows aXH NMR spectrum of the SBECDs of the present invention as compared to commercially available SBECDs (Dexolve from Cyclolab and Captisol from Ligand).

[0028] Figure 2B shows a13C NMR spectrum of the SBECDs of the present invention as compared to commercially available SBECDs (Dexolve from Cyclolab and Captisol ligand).

[0029] Figure 2C shows a 2D HSQC NMR spectrum withXH and13C NMR of the SBECD of the present invention.

[0030] Figure 2D shows a 2D HSQC NMR spectrum withXH and13C NMR of a commercially available SBECD (Captisol from Ligand).

[0031] Figure 3A shows aXH NMR spectrum of the HPCDs of the present invention (at a DS of 7.4) as compared to commercially available HPCDs (Trappsol THPB-EC from CTD, Kleptose HP from Roquette, 2HPBCD 1380 from Sigma and 2HPBCD from Cyclolab).

[0032] Figure 3B shows a13C NMR spectrum of the HPCDs of the present invention (at a DS of 7.4) as compared to commercially available HPCDs (Trappsol THPB-EC from CTD, Kleptose HP from Roquette, 2HPBCD 1380 from Aldrich and 2HPBCD from Cyclolab).

[0033] Figure 4A shows aXH NMR spectrum of the HPCDs of the present invention (at a DS of 4.6) as compared to commercially available HPCDs (Cavasol HP Pharma from Wacker, Emprove Expert from Merck, Kleptose HPB from Roquette and 2HPBCD 1460 from Aldrich).

[0034] Figure 4B shows a13C NMR spectrum of the HPCDs of the present invention (at a DS of 4.6) as compared to commercially available HPCDs (Cavasol HP Pharma from Wacker, Emprove Expert from Merck, Kleptose HPB from Roquette and 2HPBCD 1460 from Aldrich).

[0035] Figure 5A shows a 2D HSQC NMR spectrum withXH and13C NMR of the HPCD of the present invention (at a DS of 4.6) (THPB-EC).

[0036] Figure 5B shows a 2D HSQC NMR spectrum withXH and13C NMR of a commercially available HPCD (Wacker Cavasol HP Pharma).

[0037] Figure 6A shows the solubilisation efficacy of different drugs for SBECD of the present invention relative to commercially available SBECD (Captisol).

[0038] Figure 6B shows the solubilisation efficacy of different drugs for HPCD of the present invention (at a DS of 4.6 and 7.4) relative to commercially available HPCD (Kleptose at a DS of 4.3 and THPB-EC at a DS of 7.2).

[0039] Figure 7 Shows HPLC elution profiles of SBECD of the present invention as compared to commercially available SBECD (Captisol) when analayzed on a polar C18 column (Phenomenex, Kinetex Polar C18).

[0040] Figure 8 Shows HPLC elution profiles of SBECD of the present invention as compared to commercially available SBECD (Captisol) when analysed on a CD Screen IEC column (Cyclolab, CD Screen IEC).

[0041] Figure 9 Shows HPLC elution profiles of HPCD of the present invention (at a DS of 4.6 and 7.4) as compared to commercially available HPCD (Kleptose at a DS of 4.3 and THPB-EC at a DS of 7.2) when analysed on a polar C18 column (Phenomenex, Kinetex Polar C18).

[0042] Figure 1OA shows aXH NMR spectrum of the primary side enriched HPCDs of the present invention (at a DS of 4.0).

[0043] Figure 1OB shows a13C NMR spectrum of the primary side enriched HPCDs of the present invention (at a DS of 4.0).

[0044] Figure IOC shows a 2D HSQC NMR spectrum withXH and13C NMR of the primary side enriched HPCDs of the present invention (at a DS of 4.0).

[0045] Figure 11 shows HPLC elution profiles of primary side enriched HPCD of the present invention (at a DS of 4.0 when analysed on a polar C18 column (Phenomenex, Kinetex Polar C18).

[0046] The present invention will now be described in more detail in the following. Detailed description of the invention

[0047] Definitions

[0048] Prior to discussing the present invention in further details, the following terms and conventions will first be defined:

[0049] Cvclodextrin

[0050] Cyclodextrins, abbreviated CDs, are a family of cyclic oligosaccharides consisting of glucopyranoside subunits linked by a-1,4 glycosidic bonds. Cyclodextrins are composed of 5 or more, typically 6-8, glucose monomers organized in a toroidal shape. The three main types of cyclodextrins comprising 6, 7 and 8 glucose subunits are alpha- (o-CD), beta- (0-CD) and gamma-cyclodextrins (y-CD), respectively. The main types of cyclodextrins may be represented by formula (II) above, where n is selected from 6, 7 or 8 or alternatively formula (Ila) below, where n is selected from 0, 1 or 2:

[0051] Due to this arrangement, the interior of the toroids is less hydrophilic than the aqueous solvent environment and thereby able to host other hydrophobic molecules, thus making cyclodextrins and derivatives suitable for solubilisation and drug delivery of hydrophobic molecules. Cvclodextrin derivative

[0052] In the present context, a "cyclodextrin derivative" relates to a cyclodextrin compound with substitutions on primary and / or secondary alcohols. Some alcohols in the cyclodextrin derivative may not be substituted. The cyclodextrin derivatives of the present inventions as provided by the method of the present invention are to be understood to represent an average in terms of the individual CD derivatives having some variations in their substitution patterns, but having an average degree of substitution and an average degree of primary vs total substitution. These average values and ratios can be measured using e.g. nuclear magnetic resonance (XH and13C NMR). The derivatives are represented by formula (I) below:

[0053] Where n is 6, 7 or 8 and the substituents Rp, RS1and RS2are independently selected from either a proton (H) or a substituted alkyl as defined in the claims. It is to be understood that formula (I) represents an average as explained above, which includes an average over the n glucose sub-units in the ring. That is, each Rp, RS1and RS2in the entire cyclodextrin may be independently selected across each glucose sub-unit. Formula I may alternatively be represented by formula (la), having the same meaning, wherein n is selected from 0, 1 or 2, preferably 0 or 1:

[0054]

[0055] Further, formula I may alternatively be represented by formula (I-o), (1-3), (I-y), having the same meaning:

[0056] Substitution

[0057] Substitution relates to a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. In the present context, substitution relates to the replacement of hydrogen in an alcohol (-OH) with a substituted alkyl as defined in claim 1. The substituted alkyl in this context is selected from the group consisting of -(CH2)mSO3X and -CH2CH(O-Y)CH3, wherein m is an integer selected from 3 and 4, X is selected from a cation and H, and Y is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3). When referring to -OH groups herein, the terms alcohol or alcohol group and hydroxy may be used interchangeably.

[0058] In the present context, "primary substitution" relates to the combined substitution on the primary alcohols in a cyclodextrin compound. In a glucose monomer of a cyclodextrin compound, the primary alcohols are located on C6. Thus, in formula (I) above, the primary substitution can occur at position Rp. The substituent Rpcan therefore be either H or, if substitution on the primary alcohol has occurred, a substituted alkyl as defined in claim 1. Thus, in a beta-cyclodextrin (n = 7 in formula (II) herein) compound, the maximum number of substitutions on primary alcohols is 7.

[0059] Secondary substitution

[0060] In the present context, "secondary substitution" relates to the combined substitution on the secondary alcohols in a cyclodextrin derivative. In a glucose monomer of a cyclodextrin compound, the secondary alcohols are located on C2 and C3. Thus, in formula (I) above, the secondary substitution can occur at position RS1and RS2. The substituents RS1and RS2can therefore be either H or, if substitution on the secondary alcohols have occurred, a substituted alkyl as defined in claim 1. Thus, in a beta-cyclodextrin compound (n=7 in formula (II) herein), the maximum number of substitutions on secondary alcohols is 14.

[0061] Total substitution

[0062] In the present context, "total substitution" refers to the combined substitution with a substituted alkyl on the primary alcohols (Rp) and the secondary alcohols (RS1and RS2) of the cyclodextrin compound. The maximum total substitution for beta-cyclodextrin (n=7 in formula (II) herein) is 21, however, commonly, some primary or secondary alcohols may not be substituted.

[0063] Degree of substitution

[0064] Degree of substitution, abbreviated DS, is herein defined as the average number of hydroxyl groups capable of being chemically modified that were replaced by a given substituent. All 3n hydroxy groups on a given cyclodextrin of formula (II) herein may potentially be substituted. Thus, the maximum DS for e.g. a beta- cyclodextrin (n=7 in formula (II) herein) is 21 (7 primary alcohols and 14 secondary alcohols). The DS of the cyclodextrin derivatives as defined herein may be varied by modifying the reaction conditions during their synthesis.

[0065] Degree of substitution and average degree of substitution is used interchangeable herein.

[0066] Solubility is the ability of a substance, the solute, to form a solution with a solvent. In the present context of drug solubility, the solute is a drug. Drug solubility is defined as the maximum concentration of a substance that can be completely dissolved in a given solvent at a certain temperature and pressure level. In general, cyclodextrins increase the solubility of hydrophobic drugs. The cyclodextrin derivatives of the present invention alter the drug solubility of some drugs and give rise to alternative or improved drug solubilities compared with some of the commercially available cyclodextrins. To compare solubility, relative solubility is used, where a test solubility is divided with a reference solubility. Thus a relative solubility above 1 means that the test CD derivative solubilises the drug better than the reference CD derivative.

[0067] Solvent

[0068] In the present context, the term "solvent" relates to any industrially applicable solvent, e.g., suitable for use in drug delivery formulations. A solvent or a cosolvent may be added to improve solubility of reactants or products. In an embodiment, the solvent is an aqueous solution. Said aqueous solution may comprise e.g. buffers to manage pH and / or NaCI to render the solvent iso-osmolar to the physiological osmolality wherein the drug is delivered into. Solvents are preferably pharmaceutically acceptable solvents. In the present context, the term polar aprotic solvent is also used. Said polar aprotic solvent may be different from the solvent described in relation to drug delivery formulations.

[0069] Deprotonation in its broadest sense, is the removal or transfer of a proton (or hydrogen cation, H+) from a Bronsted-Lowry acid in an acid-base reaction. In the present context, the term "deprotonation" is used to describe the removal of a proton from the primary or secondary alcohol groups in the cyclodextrin compound, thereby generating alkoxide anions.

[0070] Cyclodextrin derivatives

[0071] Cyclodextrins are often substituted on secondary alcohols, however, the present inventors have generated cyclodextrin derivatives with a substitution pattern with a preference for the primary alcohols.

[0072] Thus, a first aspect of the present invention relates to a cyclodextrin derivative of formula (I): wherein

[0073] Rp, RS1, and RS2are independently hydrogen (H) or a substituted alkyl, n is an integer selected from 6, 7, 8, wherein the substituted alkyl is selected from the group consisting of -(CH2)mSO3X and -CH2CH(O-Y)CH3, wherein m is an integer selected from 3 and 4,

[0074] X is selected from a cation and H,

[0075] Y is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3), and wherein the cyclodextrin derivative has an average percentage of primary substitution (Rp) to total substitution with the substituted alkyl in the range of 15- 99 %. Y may in some cases be -CH2CH(OH)CH3 because additional hydroxypropyl may be added during the process of the present invention to make HPCD cyclodextrin derivatives (branching). The amount of branching may depend on the reaction conditions. In accordance with the present invention yet further (double or triple) branching may be possible, but in trace amounts, which may generally be considered as minor impurities. In a preferred embodiment Y is H.

[0076] Cyclodextrins comprises several primary alcohols ranging from six to eight in alpha (6), beta- (7) and gamma-cyclodextrins (8). In an embodiment, the average percentage of primary substitution (Rp) to total substitution with the substituted alkyl is in the range of 15-98%, such as 15-95%, such as 20-95 %, such as 25-95%, such as 30-90%, such as 35-85%, such as preferably 40-80%. The term primary substitution relates to the combined substitution on the primary alcohols in a cyclodextrin compound, whereas total substitution relates to the combined substitution on the primary alcohols and the secondary alcohols of a cyclodextrin compound. Some alcohols may not be substituted and would therefore not be included in the total substitution.

[0077] The preferred average percentage of primary substitution (Rp) to total substitution with the substituted alkyl may depend on the type of substituted alkyl, e.g., whether the substituted alkyl is -CH2CH(O-Y)CH3 (HPCD) or -(CH2)4SO3Na+(SBE- CD) as demonstrated in Example 2. Thus, in an embodiment, the average percentage of primary substitution (Rp) to total substitution with the substituted alkyl is in the range of 15-98%, such as 15-95%, such as 20-90%, such as 25- 85%, 30-75%, 35-65%, such as preferably 40-50% when the substituted alkyl is -CH2CH(O-Y)CH3, and in the range of 15-98%, such as 15-95%, such as 20-95%, such as 30-95%, 40-90%, 50-85%, such as preferably 65-85% when the substituted alkyl is -(CH2)mSO3X.

[0078] In Example 2, the substitution and the degree of substitution were measured usingXH NMR and13C NMR. Thus, in an embodiment the average percentage of primary substitution (Rp) to total substitution with the substituted alkyl, is as measured byXH or13C Nuclear Magnetic Resonance (NMR) spectroscopy, or a combination thereof. The three main types of cyclodextrins comprising 6, 7 and 8 glucose subunits are alpha- (n=6), beta- (n=7) and gamma-cyclodextrins (n=8), respectively. Said cyclodextrins are all generally recognized as safe by the U.S. FDA and have been applied for delivery of a variety of drugs also as substituted variants. In a preferred embodiment, n is 6 or 7, preferably 7. Thus, in said embodiment, the cyclodextrin derivative is beta-cyclodextrin.

[0079] The average degree of substitution (DS) of the cyclodextrin derivatives is the average number of hydroxyl groups where the proton has been replaced by a substituted alkyl. Since the average number of hydroxyl groups is dependent on the number of glucose monomers in the cyclodextrin derivative, the DS is dependent on the type of cyclodextrin, e.g., the maximum DS for alfa-cyclodextrin is 18 (6 primary alcohols, 12 secondary alcohols), the maximum DS for beta- cyclodextrin is 21 (7 primary alcohols, 14 secondary alcohols), and the maximum DS for gamma-cyclodextrin is 24 (8 primary alcohols, 16 secondary alcohols). Thus, in an embodiment, the average degree of substitution (DS) of the cyclodextrin derivatives is within the following ranges: 2-18, such as 2-14, such as 3-10, such as 4-8, for n = 6;

[0080] 2-21, such as 2-15, such as 3-12, such as 4-8, for n = 7;

[0081] 2-24, such as 2-16, such as 3-14, such as 4-8, for n = 8.

[0082] The substituted alkyl may be either -CH2CH(O-Y)CH3 or -(CH2)mSO3X, wherein m is an integer selected from 3 and 4, X is selected from a cation and H, and Y is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3). In an embodiment, X is a cation, preferably a monovalent cation. In another embodiment, the monovalent cation is selected from the group consisting of Na+and K+, preferably Na+. In the substituted alkyl -(CH2)mSO3X, m is an integer selected from 3 and 4. In a preferred embodiment, m is 4. In a preferred embodiment, the substituted alkyl is -CH2CH(O-Y)CH3, wherein Y is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3). Thus, in said embodiment, the substituted alkyl (hydroxy propyl, -CH2CH(O-Y)CH3) may itself be substituted with -CH2CH(OH)CH3or -CH2CH(O[CH2CH(OH)CH3]CH3) and thereby being branched. In a preferred embodiment, the substituted alkyl is - CH2CH(OH)CH3. Hence, in said embodiment, the substituted alkyl is hydroxypropyl. It is clear for a person skilled in the art that a composition comprising several different cyclodextrin molecules with different substitution patterns may arise when generating cyclodextrin derivatives. Thus, an aspect relates to a composition comprising cyclodextrin derivatives in accordance with the present invention. As explained for the cyclodextrins as such, the substitution patterns of the present invention describe average substitution patterns for such compositions.

[0083] Drug-cyclodextrin complex

[0084] Cyclodextrins comprises glucopyranoside subunits organized in a toroidal shape. The interior of the toroidal shape is less hydrophilic than the aqueous solvent environment and cyclodextrins are therefore able to host hydrophobic molecules, which makes them particularly suitable in drug delivery of hydrophobic drugs. Thus, an aspect of the present invention relates to a drug-cyclodextrin complex, wherein the cyclodextrin is a cyclodextrin derivative in accordance with the present invention.

[0085] In an embodiment, the drug in the drug-cyclodextrin complex is a small molecule drug having a molecular weight in the range 80-2000 g / mol, such as 100-1500 g / mol, such as 150-1000 g / mol, such as preferably 200-800 g / mol.

[0086] In another embodiment, the drug in the drug-cyclodextrin complex is selected from the group consisting of cinnarizine, itraconazole, aripiprazole, ziprasidone mesylate, voriconazole, delafloxacin meglumine, posaconazole, budesonide, dexamethasone, prednisolone, cholesterol, 7-ketocholesterol, ibuprofen, paclitaxel, and hydrocortisone.

[0087] Use of a cyclodextrin derivative

[0088] Cyclodextrins are used in drug delivery of hydrophobic molecules and are ingredients in more than 30 different approved medicines. Thus, an aspect of the present invention relates to the use of a cyclodextrin derivative according to the present invention for forming a drug-cyclodextrin complex. An alternative aspect of the present invention relates to the use of a cyclodextrin derivative according to the present invention for forming a drug-cyclodextrin admixture. The drug may have altered solubility in said admixture, as for complexes.

[0089] The cyclodextrin derivatives of the present invention have been used to solubilise drugs in Example 3. Hence, in an embodiment, the solubility of the drug in a solvent is altered.

[0090] In yet another embodiment, the solvent is an aqueous solution. The aqueous solution may contain other hydrophilic substances, such as NaCI. It may also comprise buffers. Preferably, the solvent is a pharmaceutically acceptable solvent, such as a solvent suitable for liquid drug formulations.

[0091] A Method for manufacturing cyclodextrin derivatives

[0092] The general concept of method of the invention is to reverse the usual reactivity of the hydroxyl groups of the cyclodextrin by a quantitative deprotonation prior to addition of side chain precursor in an aprotic solvent, whereby the primary side hydroxyl ions become the most nucleophilic compared with the secondary hydroxyl ions. Thus, an aspect of the present invention relates to a method for manufacturing a cyclodextrin derivative, said method comprising:

[0093] Contacting a cyclodextrin of formula (II) wherein n is an integer selected from 6, 7, 8 with a base with a pKa of at least 14, and subsequently adding a compound selected from the group consisting of 1,3- propanesultone, 1,4-butanesultone and propylene oxide, to obtain the cyclodextrin derivative of formula (I), wherein

[0094] Rp, RS1, and RS2are independently hydrogen (H) or a substituted alkyl, n is an integer selected from 6, 7, 8, wherein the substituted alkyl is selected from the group consisting of -(CH2)mSO3X and -CH2CH(O-Y)CH3, wherein m is an integer selected from 3 and 4,

[0095] X is selected from a monovalent cation and H, and

[0096] Y is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3).

[0097] The deprotonation with a base with a pKa of at least 14 is preferably performed in the presence of a solvent, such as an anhydrous solvent. Preferred solvents are dialkylsulfoxides. In a preferred embodiment, the cyclodextrin of formula II is dissolved in a polar aprotic solvent comprising dimethylsulfoxide (DMSO) prior to contacting said cyclodextrin with a base with a pKa of at least 14. The DMSO may preferably be present in catalytic amounts. In an embodiment, the polar aprotic solvent optionally comprising DMSO is selected from the group comprising DMF, HMPA , and dialkylsulfoxides such as DMSO. For example, NaH and DMSO form a base in situ (sodium methylsulfinylmethylide) that catalyses the deprotonation of the cyclodextrin of formula II. The use of sodium methylsulfinylmethylide in the deprotonation of the cyclodextrin (II) results in the deprotonation occurring in less than 0.5 hours, whereas the deprotonation with other commonly used solvents occurs in up to 1 day. Thus, in an embodiment, the deprotonation of the cyclodextrin (II) with a base with a pKa of at least 14 is performed in less than 5 hours, such as less than 2 hours, such as less than 1.5 hours, such as less than 1 hour, preferably less than 30 minutes. In another embodiment, the deprotonation of the cyclodextrin (II) with a base with a pKa of at least 14 is performed at a temperature in the range of 40 °C to 90 °C, such as 50 °C to 80 °C, preferably 60 °C to 70 °C.

[0098] In another embodiment, the base with a pKa of at least 14 is selected from the group consisting of NaH, LiH, KH, LDA, tBuONa, BuLi , and Grignard reagents. In a preferred embodiment, the base with a pKa of at least 14 is NaH.

[0099] In yet another embodiment, the propylene oxide is racemic propylene oxide.

[0100] It is preferred that the method is performed under anhydrous conditions so that the compounds 1,3-propanesultone, 1,4-butanesultone or propylene oxide are the only compounds capable of donating a functional group to the alkoxy ions. Thus, in an embodiment, said method is performed under anhydrous conditions. Thus, in one embodiment, the amount of water present with the cyclodextrin prior to contacting the cyclodextrin with a base with a pKa of at least 14 is less than 1%, such as less than 0.1%, preferably less than 0.01%.

[0101] In another embodiment, the method is performed under an inert atmosphere, such as an argon atmosphere or a nitrogen atmosphere.

[0102] In yet another embodiment, the reaction mixture is allowed to cool prior to adding the compound selected from the group consisting of 1,3-propanesultone, 1,4- butanesultone and propylene oxide, to a temperature in the range of 0-35 °C, such as 10-30 °C, preferably 15-25 °C.

[0103] The inventors of the present invention can control the degree of substitution by controlling the amount of the compound selected from the group consisting of 1,3-propanesultone, 1,4-butanesultone and propylene oxide added compared with the cyclodextrin of formula II. Thus, in an embodiment, the compound selected from the group consisting of 1,3-propanesultone, 1,4-butanesultone and propylene oxide is added in a molar excess of 2-50, such as 3-24, such as 4-18, preferably 5-10, as compared to the cyclodextrin of formula (II). In another embodiment, the method is quenched by the addition of an acid, preferably hydrochloric acid.

[0104] In a preferred embodiment the cyclodextrin derivative obtained is a cyclodextrin derivative according to the first aspect of the present invention

[0105] In an embodiment, the cyclodextrin derivative of formula (I) is precipitated by adding a polar solvent, preferably a polar aprotic solvent. As demonstrated in example 1, acetonitrile can be used to precipitate the cyclodextrin derivative. Thus, in another embodiment, the polar solvent is selected from the group consisting of acetonitrile, acetone, ethyl acetate, methanol, and ethanol, preferable acetonitrile.

[0106] The present inventors demonstrated in example 4 that the HPCDs with primary side modifications can be enriched by applying a simple toluene precipitation step. Thus, in an embodiment, the method further comprises hydrating the precipitated cyclodextrin derivative of formula (I) and subsequently adding a solvent selected from the group consisting of toluene, xylene, benzene, trichloroethylene, and tetrachloroethylene, preferably toluene.

[0107] Another aspect of the present invention is a cyclodextrin derivative obtainable by the above method, such as a cyclodextrin derivative obtained by the above method.

[0108] Therapeutic uses of the cyclodextrin derivative

[0109] The inventors have demonstrated in Example 3 that the cyclodextrin derivatives of the present invention can solubilise several different drugs, among which cholesterol and 7- ketocholesterol (7KC). Cyclodextrins have recently progressed beyond the role as excipients to function as therapeutics with HPCD being granted an orphan drug status for the treatment of Niemann-Pick type C in which it is used to deplete cholesterol from cellular membranes. Thus, an aspect relates to the cyclodextrin derivative according to the present invention for use as a medicament. The cyclodextrin derivatives of the present invention are more efficient at solubilising cholesterol and 7KC compared with their commercial counterparts. Said cyclodextrin derivates therefore have the potential to be better therapeutics than the commercial counterparts when treating diseases associated with an elevated cholesterol or 7KC level. Thus, another aspect relates to the cyclodextrin derivative of the present invention for use in the treatment and / or prevention of diseases or disorders associated with an elevated level of cholesterol and / or 7- ketocholesterol.

[0110] In an embodiment, the level of cholesterol is above 5.0 mmol / L, such as above 6.0 mmol / L, such as above 6.4 mmol / L, such as above 7.0 mmol / L, such as above 7.5 mmol / L, such as above 7.9 mmol / L, preferably in the range of 6.5 mmol / L to 7.9 mmol / L.

[0111] In another embodiment, the disease or disorder are selected from the group consisting of cardiovascular disease, type 2 diabetes, cancer, Parkinson's disease, Alzheimer's disease, and Niemann-Pick disease type C, or a mixture thereof.

[0112] In yet another embodiment, the cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer, melanoma, liver cancer, pancreatic cancer, kidney cancer and lung cancer.

[0113] In a further embodiment, the cardiovascular disease is selected from the group consisting of atherosclerosis, coronary artery disease (CAD), arrhythmia, heart failure, valvular heart disease, peripheral artery disease (PAD), cerebrovascular disease, congenital heart disease, hypertensive heart disease, and cardiomyopathy.

[0114] It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention. All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

[0115] The invention will now be described in further details in the following non-limiting examples. Examples

[0116] Example 1 - Synthesis of cyclodextrin derivatives

[0117] Aim of study

[0118] The industrial syntheses of SBECDs and HPCDs are typically performed in water with sodium hydroxide as base and 1,4-butanesultone or (±)-propylene oxide as the source of side chains. Due to the basicity of the hydroxide and the similar acidity of the secondary hydroxyls of the cyclodextrins, regioselectivity arises with respect to the substitution pattern yielding a product primarily substituted on the secondary alcohols. The aim of this study was therefore to reverse this pattern and provide cyclodextrin derivatives, particularly sulfobutylether beta-cyclodextrin and hydroxypropyl beta-cyclodextrin, with substitution patterns with a preference for the primary side.

[0119] Materials and methods

[0120] Cyclodextrins were of pharmaceutical quality and purchased from Wacker. Other reagents were purchased from Merck.

[0121] Synthesis of invention HPCD with DS 4.6:

[0122] Beta-cyclodextrin (5 g, 4.40 mmol) was dissolved in 200 mL anhydrous dimethyl sulfoxide (DMSO) under argon atmosphere. Sodium hydride (92.5 mmol) was added and the solution was heated to 65 °C and maintained at this temperature until seizure of development of hydrogen (approx. 25 minutes). The solution was cooled to ambient temperature and (±)-propylene oxide (1.54 g, 26.4 mmol) was added and the mixture was vigorously stirred for 16 hours. The reaction was quenched by the addition of hydrochloric acid (18.2 mL, 185 mmol). The product was isolated by precipitation in 1 L acetonitrile, filtered, purified by ultrafiltration for 48 hours and finally lyophilized. The employed ratio of propylene oxide to beta-cyclodextrin in this example is 6 resulting in a DS of 4.6. To obtain products with different DS the ratio should be varied accordingly, for instance employing a ratio of 4 and 8 of propylene oxide to beta-cyclodextrin yields HPCD with a DS of 3.4 and 7.2, respectively.

[0123] Synthesis of SBECD of the invention with DS 6.4:

[0124] Beta-cyclodextrin (5 g, 4.40 mmol) was dissolved in 200 mL anhydrous dimethyl sulfoxide (DMSO) under argon atmosphere. Sodium hydride (92.5 mmol) was added and the solution was heated to 65 °C and maintained at this temperature until seizure of development of hydrogen (approx. 25 minutes). The solution was cooled to ambient temperature and 1,4-butanesultone (4.79 g, 35.2 mmol) was added and the mixture was vigorously stirred for 16 hours. The reaction was quenched by the addition of hydrochloric acid (18.2 ml_, 185 mmol). The product was purified by ultrafiltration and clarified using active carbon before being lyophilized. The employed ratio of butanesultone to beta-cyclodextrin in this example is 8 resulting in a DS of 6.4. To obtain products with different DS the ratio should be varied accordingly, for instance employing a ratio of 4 and 6 of butanesultone to beta-cyclodextrin yields SBECD with a DS of 3.5 and 5.5, respectively.

[0125] Results

[0126] The inventors have tested more than fifty combinations of bases, solvents, additives e.g., crown ethers), temperatures etc., and have achieved the best results with sodium hydride (NaH) as base and DMSO as solvent / reagent and with no additional additives. NaH and DMSO form in situ a base (sodium methylsulfinylmethylide) that catalysis the deprotonation of the beta-cyclodextrin in less than 30 minutes, whereas this step usually takes up to 1 day for other traditional solvents.

[0127] After the deprotonation, the primary alkoxy ions will be significantly more reactive than the secondary alcohols, and the substitution pattern of the cyclodextrins of the present invention will thus change dramatically compared to the commercially available beta-cyclodextrins, since the substitution pattern will have a preference for the primary side (Figure 1A-B). The 3D structure of the cyclodextrin derivatives of the present invention would therefore also be markedly different from the commercially available beta-cyclodextrins, since more primary alcohols located on the narrow rim of the cavity of the toroid structure would be substituted compared with the secondary alcohols located on the other side of the toroid structure. Due to the substitution pattern differences, the cyclodextrin products of the present invention would most likely have different properties than the commercially available beta-cyclodextrins.

[0128] These syntheses have been scaled up to about 400g yield using same conditions. Conclusion

[0129] The inventors successfully generated new cyclodextrin derivatives with a substitution pattern with a preference for the primary side.

[0130] Example 2 - Testing the substitution pattern of cyclodextrin derivatives Aim of study

[0131] The aim of this study was to test the substitution patterns of the cyclodextrin derivatives generated in Example 1.

[0132] Materials and methods

[0133] The substitution patterns were tested usingXH NMR and13C NMR.

[0134] NMR spectra were recorded on a BRUKER AVIII-600 MHz (Bruker) spectrometer equipped with a cryogenically cooled CPP-TCI 5 mm probe. Structure elucidation was made from [H^CJ-HSQC, [1H,13C]-1,1-ADEQUATE and [H^CJ-HMBC measurements and quantitativeXH and13C NMR were used to determine the DS. All NMR spectra were processed using Bruker Topspin 3.6.4.

[0135] DMSO was added as chemical shift standard (2.722 ppm forXH and 41.39 ppm for13C.

[0136] The substitution patterns were further analysed using High-Performance Liquid Chromatography (HPLC) coupled with charged aerosol detection.

[0137] Results

[0138] Where commercial SBECD (Captisol and Dexolve) has a substitution pattern of 40: 50: 10 for C2, C3 and C6, respectively, the SBECD of the present invention has a substitution pattern in the ranges of 15-20: 5-10:70-80 (with a DS of approx. 6) (See Figure 2A-B). For HPCD, the substitution pattern for the commercially available is in the range 52-58:33-40:8-10 for C2, C3 and C6, respectively, whereas the HPCD of the present invention has altered pattern in the ranges of 11-16:0-4:83-89. (Table 1, Figure 3A-B and 4A-B).

[0139] Based on the NMR spectra of the substitution patterns, the distribution of hydroxypropyl side chains was measured and the HPCD according to the invention was significantly different from the commercially available hydroxypropyl beta- cyclodextrins (Table 1). DS was determined by dividing the integrals of the SBE or HP side chains with the integral of the anomeric region.

[0140] The presence of a SBE or an HP chain at 02 splits the peak of the anomeric proton Hl into two peaks denoted Hl and Hl'. Substitution at 06 shifts the C6 peak downfield in the13C spectra demoted C6'. Using an inverse gated ^-decoupling pulse program, the substitution on 02 and 06 can be directly determined by integration of the respective regions. For the invention, a very limited 03 substitution is observed and is in the range of 0-5% depending on DS for both HP and SBE. In the case of HP in the invention, approximately 25% of the side chains are oligomerized, denoted Ho' in the HSQC spectrum (Figure 4A).

[0141] Table 1: Distribution of hydroxyl propyl side chains on the HPCD derivatives of the present invention and commercially available HPCDs. 1) CTD, Inc Lot 1612A0189. 2) Wacker, Batch A1602A0048. 3) Roquette, Batch E0317. 4) Roquette, Batch E0010 5) Sigma, Lot MKCF6059. 6) Cyclolab, CYL- 4259. 7) Merck, Lot K52026220 021. Hence, the chemical sum formula of the present invention is close to identical to the commercially available beta-cyclodextrins, but the structure is significantly different as demonstrated in Figures 2-5 and Table 1. Therefore, the properties of these novel modified cyclodextrins will be completely different compared to the commercially available products.

[0142] The altered substitution pattern and properties of the HPCD and SBECD of the present invention as compared to their commercially available counterparts are further evident from their chromatographic behaviour when analysed by HPLC (See Example 2: Figures 7-9).

[0143] Conclusion

[0144] The cyclodextrin derivatives of the present invention are mainly substituted on the primary alcohols as opposed to the commercially available cyclodextrins, which are mainly substituted on the secondary alcohols. The altered substitution pattern will most likely result in different properties of the cyclodextrins of the present invention as compared to the commercially available cyclodextrins.

[0145] Example 3 - Solubilisation of drugs in the cyclodextrin derivatives

[0146] Aim of study

[0147] The aim of this study was the investigate whether the different substitution pattern of the cyclodextrin derivatives of the present invention has an effect on the solubilisation of drugs.

[0148] Materials and methods

[0149] The relative drug solubilisation efficacy of the cyclodextrins of the present invention as compared to the currently available commercial CD counterparts was evaluated using reverse-phase HPLC coupled with Ultraviolet (UV) detection. The efficacy of drug solubilisation by the novel CD derivatives is quantified by calculating the ratio of the absorbance value (represented as the area under the curve) of the drug solubilized by cyclodextrins of the present invention relative to that of the drug solubilized by the commercial counterparts. This approach provides a quantitative measure of the solubilisation capacity of the cyclodextrins of the present invention vis-a-vis the standard commercial variants. A list of the drugs used for solubilisation in the cyclodextrin derivatives is shown in Table 2. Table 2: List of tested drug actives

[0150] In the preparation of cyclodextrin (CD) standard solutions and inclusion complexes, the following steps are meticulously followed. Initially, cyclodextrins are dried under vacuum at a temperature of 105°C for a minimum of 1 hour to ensure complete dehydration. Immediately after drying, the CDs are precisely weighed and used to prepare standard solutions.

[0151] For the formation of inclusion complexes, a specified amount of drug, approximately three times the molar amount of CDs, is weighed into a Biosphere® SafeSeal 2 mL Eppendorf tube. To this, 1.5 mL of the prepared CD standard solution is added. The mixture in the tube is then vortexed until the drug is fully suspended. This suspension is left to shake continuously for 48 hours at ambient temperature. An additional sample is introduced and removed after 24 hours to confirm that equilibrium is reached.

[0152] The final stage involves preparing the samples for analysis. After the 48-hour incubation, the suspensions are centrifuged at 14.000 rpm for 15 minutes. The supernatant is then collected using a syringe and needle and filtered through a 0.45 pm syringe filter. 1 mL of this filtered supernatant is transferred to a new tube and diluted with 250 pL of the respective CD standard solution to prevent any drug precipitation. Finally, the solution is transferred to a HPLC vial, making it ready for the determination of drug concentration.

[0153] Results

[0154] The relative drug solubilisation efficacy of the novel CD derivatives as compared to the currently available commercial CD counterparts was evaluated using reverse-phase HPLC coupled with Ultraviolet (UV) detection. The efficacy of drug solubilisation by the novel CD derivatives is quantified by calculating the ratio of the absorbance value (represented as the area under the curve) for the new CD derivatives relative to that of the commercial CD counterparts.

[0155] The solubilisation efficacy of different drugs in the SBECD of the present invention relative to the solubilisation efficacy of the same drugs in Captisol is shown in Table 3 and depicted in Figure 6A. A performance of 1 indicates that the drug solubilisation is the same in the HPCD of the present invention compared with the drug solubilisation in Captisol. Changing the pH (3.5 as opposed to 5) affects the solubilisation of the drugs, and said effect is dependent on the drug used.

[0156] The same experiment has been performed with HPCD of the present invention (at a DS of 4.6 or 7.4) relative to either Roquette Kleptose HPB with a DS of 4.3 or CTD Trappsol THPB-EC with a DS of 7.2 at a pH of 5 (Table 4 and Figure 6B). It is evident that the drug solubilisation efficacy of HPCD of the present invention is different compared with the respective drug solubilisation in the commercially available HPCDs (Roquette Kleptose HPB and CTD Trappsol THPB-EC). The HPCDs of the present invention could therefore be an alternative or an improvement to commercially available CDs.

[0157] The significant enhancement of drug solubilisation efficacy observed for cholesterol and 7-Ketocholesterol (7KC) in HPCD and SBECD of the present invention is highly interesting as cyclodextrins recently have progressed beyond the role as excipients to function as therapeutics. Specifically, attention has been given to HPCD as therapeutic for cholesterol and 7KC related disease, with HPCD being granted an orphan drug status for the treatment of Niemann-Pick type C in which it is used to deplete cholesterol from cellular membranes. Cholesterol and 7KC are highly relevant targets as both are implicated in many age-related diseases including cancer, atherosclerosis, Parkinson's and Alzheimer's disease.

[0158] Conclusion

[0159] The cyclodextrin derivatives of the present invention with an altered substitution pattern result in a different solubilisation of some drugs compared with commercially available cyclodextrins. Whether it is beneficial to have a higher or lower solubilisation of the drugs depend on the effect of the drug in the human body, the indication for administering said drug and the patient in question. Increased binding strength is generally advantageous as it enhances the dissolution of the drug per CD unit. Thus, the cyclodextrins of the present invention could be used as an alternative to the commercially available cyclodextrins. The present example further demonstrates that the HPCD and SBECD of the present invention could be used as a therapeutic. Specifically, the example demonstrates that said cyclodextrins can solubilise cholesterol and 7KC and the CDs can therefore be used in the treatment of diseases where cholesterol and 7KC are implicated, such as cancer, atherosclerosis, Parkinson's and Alzheimer's disease.

[0160] Example 4 - Enrichment of primary side modification of HPCD

[0161] Aim of study

[0162] The aim of this study was to test whether HPCD of the present invention could be enriched with respect to primary side modification by applying a simple toluene precipitation step.

[0163] Materials and methods

[0164] The synthesis procedure was identical to that described in 'Synthesis of invention HPCD with DS 4.6' in Example 1, except that the product, isolated after precipitation in acetonitrile, was dissolved in 50 mL water, to which 5 mL toluene was added. After 24 hours the precipitate was filtered off, dried in vacuo, purified by ultrafiltration for 48 hours and lyophilized.

[0165] The substitution patterns were characterized usingXH NMR,13C NMR and HPLC coupled with charged aerosol detection.

[0166] Results

[0167] The primary side enriched HPCD of the present invention has a substitution pattern of 2:0:98 and as a result thereof there is almost no splitting of the anomeric region (Figures 10A-C). The decrease in isomers due to the removal of isomers with modification on C2 and C3 was further evident from the HPLC analysis (Figure 11).

[0168] Conclusion

[0169] This example demonstrates that the HPCDs with primary side modifications can be enriched by applying a simple toluene precipitation step. The substitution pattern obtained by said precipitation step is 2:0:98. Due to the substitution pattern differences, the cyclodextrin products of the present invention would have different properties than the commercially available HPCDs.

[0170] References WO 2013 / 123254 Al

[0171] WO 2015 / 008066 Al

[0172] Malanga M., et al. "Synthesis, analytical characterization and capillary electrophoretic use of the single-isomer heptakis-(6-O-sulfobutyl)-beta- cyclodextrin", J Chromatogr A. 2017 Sep 8; 1514: 127-133 WO 2020 / 142716 Al

Claims

Claims1. A cyclodextrin derivative of formula (I):whereinRp, RS1, and RS2are independently hydrogen (H) or a substituted alkyl, n is an integer selected from 6, 7, 8, wherein the substituted alkyl is selected from the group consisting of -(CH2)mSO3X and -CH2CH(O-Y)CH3, wherein m is an integer selected from 3 and 4,X is selected from a cation and H,Y is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3), and wherein the cyclodextrin derivative has an average percentage of primary substitution (Rp) to total substitution with the substituted alkyl in the range of 15- 99 %.

2. The cyclodextrin derivative according to claim 1, wherein the average percentage of primary substitution (Rp) to total substitution with the substituted alkyl is in the range of 15-98%, such as 15-95%, such as 20-95 %, such as 25- 95%, such as 30-90%, such as 35-85%, such as preferably 40-80%.

3. The cyclodextrin derivative according to any one of the preceding claims, wherein the average degree of substitution (DS) of the cyclodextrin derivatives is within the following ranges:2-18, such as 2-14, such as 3-10, such as 4-8, for n = 6;2-21, such as 2-15, such as 3-12, such as 4-8, for n = 7;2-24, such as 2-16, such as 3-14, such as 4-8, for n = 8.

4. The cyclodextrin derivative according to any one of the preceding claims, wherein X is a cation, preferably a monovalent cation.

5. The cyclodextrin derivative according claim 4, wherein the monovalent cation is selected from the group consisting of Na+and K+, preferably Na+.

6. The cyclodextrin derivative according to any one of the preceding claims, wherein n is 7.

7. The cyclodextrin derivative according to any one of the preceding claims, wherein m is 4.

8. The cyclodextrin derivative according to any one of the preceding claims, wherein the substituted alkyl is -CH2CH(O-Y)CH3, preferably -CH2CH(OH)CH3.

9. A drug-cyclodextrin complex, wherein the cyclodextrin is a cyclodextrin derivative in accordance any one of claims 1-8.

10. The drug-cyclodextrin complex according to claim 9, wherein the drug in the drug-cyclodextrin complex is a small molecule drug having a molecular weight in the range 80-2000 g / mol, such as 100-1500 g / mol, such as 150-1000 g / mol, such as preferably 200-800 g / mol.

11. Use of a cyclodextrin derivative according to any one of claims 1-8 for forming a drug-cyclodextrin complex.

12. A method for manufacturing a cyclodextrin derivative, said method comprising: contacting a cyclodextrin of formula (II)wherein n is an integer selected from 6, 7, 8 with a base with a pKa of at least 14, and subsequently adding a compound selected from the group consisting of 1,3- propanesultone, 1,4-butanesultone and propylene oxide, to obtain the cyclodextrin derivative of formula (I),whereinRp, RS1, and RS2are independently hydrogen (H) or a substituted alkyl, n is an integer selected from 6, 7, 8, wherein the substituted alkyl is selected from the group consisting of -(CH2)mSO3X and -CH2CH(O-Y)CH3, wherein m is an integer selected from 3 and 4,X is selected from a monovalent cation and H, andY is selected from H, -CH2CH(OH)CH3, and -CH2CH(O[CH2CH(OH)CH3]CH3).

13. The method according to claim 12, wherein the cyclodextrin of formula (II) is dissolved in a polar aprotic solvent optionally comprising dimethylsulfoxide (DMSO) prior to contacting said cyclodextrin with a base with a pKa of at least 14.

14. The method according to any one of claims 12 or 13, wherein the base with a pKa of at least 14 is selected from the group consisting of NaH, LiH, KH, LDA, tBuONa, BuLi and Grignard reagents, preferably NaH.

15. The method according to any one of claims 12-14, wherein the propylene oxide is racemic propylene oxide.

16. The method according to any one of claims 12-15, wherein the cyclodextrin derivative has an average percentage of primary substitution (Rp) to total substitution with the substituted alkyl in the range of 15-99 %17. The method according to any one of claim 12-16, wherein the cyclodextrin derivative of formula (I) is precipitated by adding a polar solvent, preferably a polar aprotic solvent.

18. The method according to claim 17, wherein the method further comprises hydrating the precipitated cyclodextrin derivative of formula (I) and subsequently adding a solvent selected from the group consisting of toluene, xylene, benzene, trichloroethylene, and tetrachloroethylene, preferably toluene.

19. The method according to any one of claims 12-18, wherein the cyclodextrin derivative is a cyclodextrin derivative according to any one of claims 1-8.

20. A cyclodextrin derivative obtainable by the method according to any one of claims 12-18.

21. The cyclodextrin derivative according to any one of claims 1-8 or the cyclodextrin derivative according to claim 20 for use as a medicament.

22. The cyclodextrin derivative according to any one of claims 1-8 or the cyclodextrin derivative according to claim 20 for use in the treatment and / orprevention of diseases or disorders associated with an elevated level of cholesterol and / or 7- ketocholesterol.

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