Alkylated cyclodextrin composition, method of preparation thereof, and method of use thereof

Abstract

The present disclosure relates to a method for the efficient, large-scale preparation of alkylated cyclodextrins. The disclosed method improves efficiency, increases batch size, and reduces total process time while providing high-purity alkylated cyclodextrins with high purity and low chloride levels. TIFF2023544122000020.tif81170

Description

[Technical Field]

[0001] field This disclosure relates to a method for the efficient and large-scale preparation of high-purity alkylated cyclodextrins, a composition comprising alkylated cyclodextrins, and a method for using the same. [Background technology]

[0002] Explanation of related technologies Hydrophobic, hydrophilic, polymeric, ionized, non-ionized, and many other derivatives of cyclodextrins have been developed, and their use in various industries has been established. Generally, the derivatization of cyclodextrins proceeds via reactions in which the -OH groups at the 2nd, 3rd, and / or 6th positions of the amylose ring of the cyclodextrin are replaced with substituents. Substituents include neutral functional groups, anionic functional groups, and / or cationic functional groups.

[0003] Known cyclodextrin derivatives such as alkylated cyclodextrins include, but are not limited to, sulfoalkyl ether cyclodextrins, alkyl ether cyclodextrins (e.g., methyl, ethyl, and propyl ether cyclodextrins), hydroxyalkyl cyclodextrins, thioalkyl ether cyclodextrins, carboxylated cyclodextrins (e.g., succinyl-β-cyclodextrin), and sulfated cyclodextrins. Alkylated cyclodextrins having two or more functional groups, such as sulfoalkyl ether-alkyl ether-cyclodextrins, are also known (see, for example, International Publication No. 2005 / 042584 and U.S. Patent Application Publication No. 2009 / 0012042, both of which are incorporated herein in their entirety by reference). In particular, alkylated cyclodextrins having a 2-hydroxypropyl group and / or a sulfoalkyl ether group are used in pharmaceutical formulations.

[0004] A sulfobutyl ether derivative of β-cyclodextrin ("SBE-β-CD") is commercialized by CyDex Pharmaceuticals, Inc. as CAPTISOL®. The anionic sulfobutyl ether substituent improves the water solubility and safety of the parent β-cyclodextrin, enabling reversible complex formation with active pharmaceutical agents, thereby increasing the solubility of the active pharmaceutical agent and, in some cases, its stability in aqueous solution. CAPTISOL® is derived from formula X: It has the chemical structure of TIFF0007836804000001.tif63128, where R is -H or -(CH2)4-SO3 - Na + And -(CH2)4-SO3 - Na + The average degree of substitution is 6-7.1.

[0005] Sulfoalkyl ether derivatized cyclodextrins (such as CAPTISOL®) are prepared, for example, by batch methods described in U.S. Patents 5,134,127, 5,376,645 and 6,153,746, all of which are incorporated herein by reference in their entirety.

[0006] Sulfoalkyl ether cyclodextrins and other derivatized cyclodextrins are covered by the following patents and published patent applications: U.S. Patent No. 3,426,011; U.S. Patent No. 3,453,257; U.S. Patent No. 3,453,259; U.S. Patent No. 3,459,731; U.S. Patent No. 4,638,058; U.S. Patent No. 4,727,064; U.S. Patent No. 5,019,562; U.S. Patent No. 5,173,481; U.S. Patent No. 5,183,809; U.S. Patent No. 5,241,059; U.S. Patent No. 5,536,826; U.S. National Patent No. 5,594,125; U.S. Patent No. 5,658,894; U.S. Patent No. 5,710,268; U.S. Patent No. 5,756,484; U.S. Patent No. 5,760,015; U.S. Patent No. 5,846,954; U.S. Patent No. 6,407,079; U.S. Patent No. 7,625,878; U.S. Patent No. 7,629,331; U.S. Patent No. 7,635,773; U.S. Patent Application Publication No. 2009 / 0012042; JP-A-5-1102; and International Publication No. 01 / 40316; and the following non-patent publications: Lammers et al., Recl. Trav. Chim. Pays-Bas 91:733 (1972); Staerke 23:167 (1971);Adam et al., J. Med. Chem. 45:1806 (2002);Qu et al., J. Inclusion Phenom. Macrocyclic Chem. 43:213 (2002);Tarver et al., Bioorg. Med. Chem. 10:1819 (2002);Fromming et al., Cyclodextrins in Pharmacy (Kluwer Academic Publishing, Dordrecht, 1994);Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (CJ Easton et al. eds., Imperial College Press, London, UK, 1999);New Trends in Cyclodextrins and Derivatives (Dominique Duchene ed.It can be prepared according to the method described in *Comprehensive Supramolecular Chemistry 3* (Elsevier Science Inc., Tarrytown, NY), Editions de Sante, Paris, FR, 1991; these disclosures are incorporated herein by reference in their entirety.

[0007] Impurities present in alkylated cyclodextrin compositions may reduce the shelf life and potency of the activator composition. These impurities can be removed from the alkylated cyclodextrin composition by exposure to activated carbon (e.g., mixing with activated carbon). Methods for increasing the purity of alkylated cyclodextrins are described in U.S. Patents 7,635,773, 9,493,582, and 10,040,872, the disclosures of which are incorporated herein by reference in their entirety.

[0008] As the importance of alkylated cyclodextrins in pharmaceutical applications increases, there is a need for efficient and large-scale methods for producing alkylated cyclodextrins of a purity suitable for pharmaceutical use. [Overview of the project]

[0009] overview This disclosure provides a method for preparing an alkylated cyclodextrin composition, the method comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction environment containing the alkylated cyclodextrin; (b) performing a first one or more separations to form a first solution containing the alkylated cyclodextrin, wherein the one or more separations include dialysis filtration through an ultrafiltration membrane; (c) treating the first solution with activated carbon to produce a second alkylated cyclodextrin solution; and (d) performing a second one or more separations to form a third alkylated cyclodextrin solution, wherein the one or more separations include nanofiltration through a nanofiltration membrane.

[0010] In some embodiments, a solvent may be added to dilute the reaction environment formed in step (a) before performing the first one or more separations. In some specific embodiments, the solvent is water. In some embodiments, the concentration of the alkylated cyclodextrin in step (b) is less than 10% (w / w) before the first one or more separations. In some embodiments, the concentration of the alkylated cyclodextrin in step (b) is less than 8% (w / w) before the first one or more separations. In some embodiments, the concentration of the alkylated cyclodextrin in step (b) is less than 6% (w / w) before the first one or more separations. In some embodiments, the concentration of the alkylated cyclodextrin in step (b) is from about 3% (w / w) to about 8% (w / w) or from about 4% (w / w) to about 6% (w / w) before the first one or more separations.

[0011] In some embodiments, the ultrafiltration membrane in step (b) has a molecular weight cut-off (MWCO) of about 1000 Da or less. In some embodiments, the ultrafiltration membrane in step (b) has an MWCO of about 1000 Da. In another embodiment, the ultrafiltration membrane in step (b) has an MWCO of about 650 Da. In yet another embodiment, the ultrafiltration membrane in step (b) has an MWCO of about 500 Da. In some embodiments, the ultrafiltration membrane in step (b) has an MWCO from about 500 to about 1000 Da.

[0012] In some embodiments, the activated carbon is prepared by a method including subjecting the activated carbon to an initial carbon cleaning process including adding a portion of the first solution containing the alkylated cyclodextrin from step (b) to the carbon, immersing the carbon in the first solution, and eluting and discarding the solution.

[0013] ​In some embodiments, the activated carbon may be further subjected to a cleaning process that includes flowing water through the carbon after an initial carbon cleaning process and eluting the water. In some embodiments, the water is flowed through the carbon for at least 30 minutes. In some embodiments, the water is flowed through the carbon for at least 2 hours. In some embodiments, the eluted wash water has a residual conductivity of 10 μS / cm or less.

[0014] In some embodiments, the activated carbon does not contain phosphate. In some embodiments, the activated carbon is steam-activated. In another embodiment, the activated carbon is acid-activated with, for example, phosphoric acid. In yet another embodiment, the activated carbon is activated with zinc chloride. In some embodiments, the activated carbon is granular.

[0015] In some embodiments, the concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced into step (d) is from about 3% (w / w) to about 8% (w / w). In some embodiments, the concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced into step (d) is from about 4% (w / w) to about 7% (w / w). In some embodiments, the concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced into step (d) is about 5% (w / w).

[0016] In some embodiments, the nanofiltration membrane in step (d) has a MWCO of about 500 Da or less. In some embodiments, the nanofiltration membrane has a MWCO of about 500 Da. In another embodiment, the nanofiltration membrane has a MWCO of about 400 Da. In some embodiments, the nanofiltration membrane has a MWCO of about 300 Da. In some embodiments, the nanofiltration membrane has a MWCO of about 200 Da. In some embodiments, the nanofiltration membrane has a MWCO of about 150 Da. In some embodiments, the nanofiltration membrane has a MWCO of about 150 - 500 Da. In some embodiments, the nanofiltration membrane has a MWCO of about 300 - 500 Da.

[0017] In some embodiments, nanofiltration is performed over a period of 30 minutes to 12 hours. In some embodiments, nanofiltration is performed over a period of approximately 1 hour to approximately 3 hours. In some embodiments, nanofiltration is performed over a period of 2 hours. In some embodiments, nanofiltration is performed over a period of 3 hours.

[0018] In some embodiments, the concentration of alkylated cyclodextrin in the third alkylated cyclodextrin solution is approximately 10% (w / w) to approximately 25% (w / w). In some embodiments, the concentration of alkylated cyclodextrin in the third alkylated cyclodextrin solution is approximately 15% (w / w) to approximately 20% (w / w). In some embodiments, the concentration of alkylated cyclodextrin in the third alkylated cyclodextrin solution is approximately 18% (w / w) to approximately 20% (w / w).

[0019] In some embodiments, the third alkylated cyclodextrin solution (i.e., the solution formed after a second one or more separations including nanofiltration through a nanofiltration membrane) may be concentrated for a period of about 2 to 24 hours to form a fourth alkylated cyclodextrin solution. In some embodiments, the third alkylated cyclodextrin solution may be concentrated for a period of about 6 to 18 hours to form a fourth alkylated cyclodextrin solution. In some embodiments, the third alkylated cyclodextrin solution may be concentrated for a period of about 8 to 12 hours to form a fourth alkylated cyclodextrin solution. In some embodiments, the third alkylated cyclodextrin solution may be concentrated for a period of about 9 hours to form a fourth alkylated cyclodextrin solution. In some embodiments, the step of concentrating the third alkylated cyclodextrin solution is carried out by distillation.

[0020] In some embodiments, the concentration of alkylated cyclodextrin in the fourth alkylated cyclodextrin solution is approximately 30% (w / w) to approximately 70% (w / w). In some embodiments, the concentration of alkylated cyclodextrin in the fourth alkylated cyclodextrin solution is approximately 40% (w / w) to approximately 60% (w / w). In some embodiments, the concentration of alkylated cyclodextrin in the fourth alkylated cyclodextrin solution is approximately 50% (w / w).

[0021] In some embodiments, the methods disclosed herein further include the step of removing some or all of the solvent from the fourth alkylated cyclodextrin solution to form a solid alkylated cyclodextrin. In some embodiments, the solvent is removed by distillation, freeze-drying, or spray-drying.

[0022] In some embodiments, the solid alkylated cyclodextrin formed by the method described herein contains less than 500 ppm of phosphate. In some embodiments, the solid alkylated cyclodextrin contains less than 125 ppm of phosphate. In some embodiments, the solid alkylated cyclodextrin contains less than 0.05% (w / w) of chloride. In some embodiments, the solid alkylated cyclodextrin contains less than 0.01% (w / w) of chloride. In some embodiments, the solid alkylated cyclodextrin contains less than 0.002% (w / w) of chloride.

[0023] In some embodiments, the method described herein includes the step of preparing a single batch of alkylated cyclodextrin having a mass of more than 275 kg of starting cyclodextrin. In another embodiment, the method described herein includes the step of preparing a single batch of alkylated cyclodextrin having a mass of more than 300 kg of starting cyclodextrin. In yet another embodiment, the method described herein includes the step of preparing a single batch of alkylated cyclodextrin having a mass of more than 350 kg of starting cyclodextrin.

[0024] In some embodiments, the alkylated cyclodextrin has an average degree of substitution of 2 to 9. In some embodiments, the alkylated cyclodextrin has an average degree of substitution of 4.5 to 7.5. In some embodiments, the alkylated cyclodextrin has an average degree of substitution of 6 to 7.5.

[0025] In some embodiments, alkylated cyclodextrin prepared by the method disclosed herein is of formula (II): TIFF0007836804000002.tif66128 is a sulfoalkyl ether cyclodextrin, where p is 4, 5, or 6, and R1 is -OH or -O-(C2~C6 alkylene)-SO3 each time it appears. - -T is independently selected from the pharmaceutically acceptable cations each time it appears, wherein at least one R1 is -OH and at least one R1 is O-(C2~C6 alkylene)-SO3 - -T

[0026] In some embodiments, each time R1 appears, it is either -OH or -O-(C4 alkylene)-SO3 - -T is selected independently of Na each time it appears. + That is the case.

[0027] In some embodiments, the method described herein may further include the step of combining a solid alkylated cyclodextrin with one or more excipients. In some embodiments, the method described herein may further include the step of combining a solid alkylated cyclodextrin with an activator.

[0028] [Invention 1001] A method for preparing an alkylated cyclodextrin composition, comprising the following steps: (a) A step of mixing the starting cyclodextrin with an alkylating agent to form a reaction environment containing alkylated cyclodextrin; (b) A step of performing a first one or more separations to form a first solution containing alkylated cyclodextrin, wherein the one or more separations include dialysis filtration through an ultrafiltration membrane; (c) The step of treating the first solution with activated carbon to produce a second alkylated cyclodextrin solution; and (d) A step of performing a second one or more separations to form a third alkylated cyclodextrin solution, wherein the one or more separations include nanofiltration through a nanofiltration membrane. [Invention 1002] The method of the present invention 1001, wherein a solvent is added to dilute the reaction environment formed in step (a) before the first one or more separations. [Invention 1003] The method of the present invention 1002, wherein the solvent is water. [Invention 1004] The method according to any one of the invention 1001 to 1003, wherein the concentration of alkylated cyclodextrin in step (b) is less than 10% (w / w) before the first one or more separations. [Invention 1005] A method according to any one of the present invention 1001 to 1004, wherein the concentration of alkylated cyclodextrin in step (b) is less than 8% (w / w) before the first one or more separations. [Invention 1006] Any method of the present invention 1001 to 1004, wherein the concentration of alkylated cyclodextrin in step (b) is less than 6% (w / w) before the first one or more separations. [Invention 1007] The method according to any of the 1001 to 1004 of the present invention, wherein the concentration of alkylated cyclodextrin in step (b) is approximately 3% (w / w) to approximately 8% (w / w) before the first one or more separations. [Invention 1008] The method according to any of the 1001 to 1004 of the present invention, wherein the concentration of alkylated cyclodextrin in step (b) is approximately 4% (w / w) to approximately 6% (w / w) before the first one or more separations. [Invention 1009] A method according to any one of the present invention 1001 to 1008, wherein the ultrafiltration membrane in step (b) has a molecular weight cutoff (MWCO) of approximately 1000 Da or less. [Invention 1010] A method according to any one of the present invention 1001 to 1008, wherein the ultrafiltration membrane in step (b) has an MWCO of approximately 1000 Da. [Invention 1011] A method according to any one of the present invention 1001 to 1008, wherein the ultrafiltration membrane in step (b) has an MWCO of approximately 650 Da. [Invention 1012] A method according to any one of the present invention 1001 to 1008, wherein the ultrafiltration membrane in step (b) has an MWCO of approximately 500 Da. [Invention 1013] A method according to any one of the present invention 1001 to 1008, wherein the ultrafiltration membrane in step (b) has an MWCO of about 500 to about 1000 Da. [Invention 1014] The activated carbon in process (c) An initial carbon washing process comprising adding a portion of the first solution containing alkylated cyclodextrin from step (b) to the carbon, immersing the carbon in the first solution, and eluting and discarding the solution. A method of any one of the present invention 1001 to 1013, which includes the step of providing activated carbon to a substance. [Invention 1015] The method of the present invention 1014, wherein the activated carbon of step (c) is further subjected to a washing process that includes passing water over the carbon and eluting the water after the initial carbon washing process. [Invention 1016] The method of the present invention 1015, wherein water is flowed over carbon for at least 30 minutes. [Invention 1017] The method of the present invention 1015, wherein water is flowed over carbon for at least two hours. [Invention 1018] A method according to any one of the present invention 1015 to 1017, wherein the eluted washing water has a residual conductivity of 10 μS / cm or less. [Invention 1019] The method according to any one of the present invention 1001 to 1018, wherein the activated carbon does not contain phosphate. [Invention 1020] The method according to any one of the present invention 1001 to 1019, wherein the activated carbon is activated by steam. [Invention 1021] The method according to any one of the present invention 1001 to 1020, wherein the activated carbon is in granular form. [Invention 1022] The method according to any one of the present invention 1001 to 1021, wherein the concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced in step (d) is approximately 3% (w / w) to approximately 8% (w / w). [Invention 1023] The method according to any one of the present invention 1001 to 1021, wherein the concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced in step (d) is approximately 4% (w / w) to approximately 7% (w / w). [Invention 1024] The method according to any one of the present invention 1001 to 1021, wherein the concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced in step (d) is approximately 5% (w / w). [Invention 1025] A method according to any one of the present invention 1001 to 1024, wherein the nanofiltration membrane in step (d) has an MWCO of approximately 500 Da or less. [Invention 1026] A method according to any one of the present invention 1001 to 1024, wherein the nanofiltration membrane in step (d) has an MWCO of approximately 500 Da. [Invention 1027] A method according to any one of the present invention 1001 to 1024, wherein the nanofiltration membrane in step (d) has an MWCO of approximately 400 Da. [Invention 1028] A method according to any one of the present invention 1001 to 1024, wherein the nanofiltration membrane in step (d) has an MWCO of approximately 300 Da. [Invention 1029] A method according to any one of the present invention 1001 to 1024, wherein the nanofiltration membrane in step (d) has an MWCO of approximately 200 Da. [Invention 1030] A method according to any one of the present invention 1001 to 1024, wherein the nanofiltration membrane in step (d) has an MWCO of approximately 150 Da. [Invention 1031] A method according to any one of the present invention 1001 to 1024, wherein the nanofiltration membrane in step (d) has an MWCO of approximately 150 to 500 Da. [Invention 1032] A method according to any one of the present invention 1001 to 1024, wherein the nanofiltration membrane in step (d) has an MWCO of approximately 300 to 500 Da. [Invention 1033] A method according to any of items 1001 to 1032 of the present invention, wherein the nanofiltration in step (d) is performed over a period of 30 minutes to 12 hours. [Invention 1034] A method according to any of the present invention 1001 to 1032, wherein the nanofiltration in step (d) is performed over a period of approximately 1 to 3 hours. [Invention 1035] A method according to any one of the present invention 1001 to 1032, wherein the nanofiltration in step (d) is performed over a period of 2 hours. [Invention 1036] A method according to any of the 1001 to 1032 of the present invention, wherein the nanofiltration in step (d) is performed over a period of 3 hours. [Invention 1037] The method according to any of the invention 1001 to 1036, wherein the concentration of alkylated cyclodextrin in the third alkylated cyclodextrin solution is approximately 10% (w / w) to approximately 25% (w / w). [Invention 1038] The method according to any of the invention 1001 to 1036, wherein the concentration of alkylated cyclodextrin in the third alkylated cyclodextrin solution is approximately 15% (w / w) to approximately 20% (w / w). [Invention 1039] The method according to any of the invention 1001 to 1036, wherein the concentration of alkylated cyclodextrin in the third alkylated cyclodextrin solution is approximately 18% (w / w) to approximately 20% (w / w). [Invention 1040] Any method of the present invention 1001 to 1040, further comprising the step of concentrating the third alkylated cyclodextrin solution over a period of about 2 hours to about 24 hours in order to form a fourth alkylated cyclodextrin solution. [Invention 1041] Any method of the present invention 1001 to 1040, further comprising the step of concentrating the third alkylated cyclodextrin solution over a period of about 6 hours to about 18 hours in order to form a fourth alkylated cyclodextrin solution. [Invention 1042] Any method of the present invention 1001 to 1041, further comprising the step of concentrating the third alkylated cyclodextrin solution over a period of about 8 to 12 hours in order to form a fourth alkylated cyclodextrin solution. [Invention 1043] Any method of the present invention 1001 to 1042, further comprising the step of concentrating the third alkylated cyclodextrin solution over a period of about 9 hours in order to form a fourth alkylated cyclodextrin solution. [Invention 1044] A method according to any one of the present invention 1040 to 1043, wherein the step of concentrating the third alkylated cyclodextrin solution is carried out by distillation. [Invention 1045] The method according to any of the invention 1040 to 1044, wherein the concentration of the fourth alkylated cyclodextrin solution is approximately 30% (w / w) to approximately 70% (w / w). [Invention 1046] The method according to any of the invention 1040 to 1044, wherein the concentration of alkylated cyclodextrin in the fourth alkylated cyclodextrin solution is approximately 40% (w / w) to approximately 60% (w / w). [Invention 1047] The method according to any of the invention 1040 to 1044, wherein the concentration of alkylated cyclodextrin in the fourth alkylated cyclodextrin solution is approximately 50% (w / w). [Invention 1048] A method according to any one of the present invention 1001 to 1047, further comprising the step of removing the solvent from a fourth alkylated cyclodextrin solution in order to form a solid alkylated cyclodextrin. [Invention 1049] The method of the present invention 1048, wherein the solvent is removed by distillation, freeze-drying, or spray-drying. [Invention 1050] Any method according to invention 1048 to 1049, comprising a phosphate containing less than 500 ppm of solid alkylated cyclodextrin. [Invention 1051] A method according to any one of the present invention 1048 to 1050, comprising a phosphate containing less than 125 ppm of solid alkylated cyclodextrin. [Invention 1052] A method according to any one of the present invention 1048 to 1051, comprising a chloride containing less than 0.05% (w / w) of solid alkylated cyclodextrin. [Invention 1053] Any method according to invention 1048 to 1052, comprising a chloride containing less than 0.01% (w / w) of solid alkylated cyclodextrin. [Invention 1054] A method according to any one of the present invention 1048 to 1053, wherein the solid alkylated cyclodextrin contains less than 0.002% (w / w) of chloride. [Invention 1055] A method according to any one of the present invention 1001 to 1054, comprising the step of preparing a single batch of alkylated cyclodextrin having an initial cyclodextrin mass of more than 275 kg. [Invention 1056] A method according to any one of the present invention 1001 to 1055, comprising the step of preparing a single batch of alkylated cyclodextrin having an initial cyclodextrin mass of more than 300 kg. [Invention 1057] A method according to any one of the present invention 1001 to 1056, comprising the step of preparing a single batch of alkylated cyclodextrin having an initial cyclodextrin mass of more than 350 kg. [Invention 1058] A method according to any of the present invention 1001 to 1057, wherein the alkylated cyclodextrin has an average degree of substitution of 2 to 9. [Invention 1059] A method according to any one of the present invention 1001 to 1058, wherein the alkylated cyclodextrin has an average degree of substitution of 4.5 to 7.5. [Invention 1060] A method according to any one of the present invention 1001 to 1059, wherein the alkylated cyclodextrin has an average degree of substitution of 6 to 7.5. [Invention 1061] Any method of the present invention 1001 to 1060, wherein the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of formula (II): TIFF0007836804000003.tif66128 In the formula, p is 4, 5, or 6, and R 1 Each time it appears, it is either -OH or -O-(C 2 ~C 6 Alkylene)-SO 3 - -T is independently selected from T, and T is independently selected from pharmaceutically acceptable cations each time it appears, provided that at least one R is selected. 1 is -OH and has at least one R 1 is O-(C 2 ~C 6 Alkylene)-SO 3 - -T [Invention 1062] R 1 However, each time it appears, -OH or -O-(C 4 Alkylene)-SO 3 - -T is selected independently of Na, and each time -T appears, Na + The method of the present invention 1061. [Invention 1063] Any method of the present invention 1048 to 1062, further comprising the step of combining a solid alkylated cyclodextrin with one or more excipients. [Invention 1064] Any method of the present invention 1048 to 1063, further comprising the step of combining a solid alkylated cyclodextrin with an activator. [Invention 1065] A product prepared by any of the methods described in invention 1001 to 1064. Further aspects, features, and advantages of the present disclosure, as well as the compositions, structures, and operations of the various aspects of the present disclosure, will be described in detail below with reference to the accompanying drawings.

Brief Description of the Drawings

[0029] [Figure 1] FIG. 1 shows a schematic diagram of a purification method for the preparation of alkylated cyclodextrin described herein.

Modes for Carrying Out the Invention

[0030] Detailed Description As used herein, percentages refer to "weight percent" and / or "w / w" (weight-specific concentration) unless otherwise specified.

[0031] Any spatial descriptions made herein (e.g., “above,” “below,” “up,” “down,” “upper,” “lower,” etc.) are for illustrative and illustrative purposes only and should not be construed as limiting to any process, apparatus, composition, and product of any method of this disclosure, which may be spatially arranged in any orientation or manner.

[0032] Alkylated cyclodextrin An alkylated cyclodextrin composition is a composition comprising alkylated cyclodextrin having a degree of substitution or average degree of substitution (ADS) for each specified substituent. The alkylated cyclodextrin composition has a distribution of alkylated cyclodextrin species with different degrees of substitution for each species-specific substituent, where the species-specific substituent is the same. As used herein, an alkylated cyclodextrin composition is a composition that does not contain another or a second substance as a pharmaceutically active agent. For example, a cyclodextrin composition may contain at least 90% (w / w) cyclodextrin, at least 95% (w / w) cyclodextrin, at least 97% (w / w) cyclodextrin, at least 99% (w / w) cyclodextrin, at least 99.9% (w / w) cyclodextrin, or at least 99.99% (w / w) cyclodextrin.

[0033] Alkylated cyclodextrins can be water-soluble alkylated cyclodextrins, which are any alkylated cyclodextrins that exhibit improved water solubility compared to their corresponding non-derivative parent cyclodextrins and have a molecular structure based on α-, β-, or γ-cyclodextrins. In some embodiments, the derivatized cyclodextrins prepared by the methods of the present disclosure have a water solubility of 100 mg / mL or more, or less than 100 mg / mL.

[0034] Cyclodextrins can be derivatized by neutral, anionic, or cationic substituents at the C2, C3, or C6 positions of the individual sugars forming the cyclodextrin ring. Suitable water-soluble alkylated cyclodextrins are described herein. Alkylated cyclodextrins may also be water-insoluble alkylated cyclodextrins or alkylated cyclodextrins that are less water-soluble than their corresponding non-derivative parent cyclodextrins.

[0035] As used herein, “substituent precursor” or “alkylating agent” refers to a compound, reagent, moiety, or substance that can react with the -OH group present on a cyclodextrin. In some embodiments, the derivatized cyclodextrin includes substituents such as sulfoalkyl ether groups, ether groups, alkyl ether groups, alkenyl ether groups, hydroxyalkyl ether groups, hydroxyalkenyl ether groups, thioalkyl ether groups, aminoalkyl ether groups, mercapto groups, amino groups, alkylamino groups, carboxyl groups, ester groups, nitro groups, halo groups, aldehyde groups, 2,3-epoxypropyl groups, and combinations thereof. In some embodiments, the alkylating agent includes alkylsultones (e.g., 1,4-butanesultone, 1,5-pentanesultone, 1,3-propanesultone, etc.). The alkylated cyclodextrin is a cyclodextrin in which one or more -OH groups are replaced by -OR groups, where R is the alkyl moiety. For example, the -OR group may be an alkyl ether or a sulfoalkyl ether.

[0036] After reaction, purification, and / or isolation, the alkylated cyclodextrins of the present disclosure may contain small amounts (e.g., less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, less than 0.001%, less than 0.0005%, or less than 0.0001% by weight) of cyclodextrin starting material (e.g., non-derivative cyclodextrins).

[0037] Alkylated cyclodextrins may exist in high-purity forms. See U.S. Patents 7,635,773, 9,493,582, and 10,040,872 (each disclosure is incorporated herein by reference in whole). In some embodiments, alkylated cyclodextrins are high-purity SAE-CD compositions with reduced levels of drug degradation products. Alkylated cyclodextrins may optionally have reduced levels of phosphate or be phosphate-free. Alkylated cyclodextrins may also optionally have reduced levels of chromogenic agents. SAE-CDs may also have reduced levels of 1,4-butanesultone and 4-hydroxybutane-1-sulfonic acid. SAE-CDs may also have reduced levels of chloride.

[0038] The alkylated cyclodextrins of this disclosure exhibit unexpected advantages compared to other structurally related alkylated cyclodextrins. “Structurally related” means, for example, that the substituents of the alkylated cyclodextrin in the composition are essentially the same as those of other alkylated cyclodextrins to which it is compared. Exemplary advantages include improved purity, reduced pyrogen content, reduced drug-degradable component content, reduced chromogenic agent content, reduced unreacted substituent precursor content, and / or reduced unreacted cyclodextrin starting material content. Reduced chloride ion content and / or phosphate content are also exemplary advantages.

[0039] Water-soluble alkylated cyclodextrin compositions may include sulfoalkyl ether cyclodextrin (SAE-CD) compounds of formula I or mixtures thereof: In formula TIFF0007836804000004.tif31128, n is 4, 5, or 6; R1, R2, R3, R4, R5, R6, R7, R8, and R9 are independently -H, linear or branched C1~C8-(alkylene)-SO3 -A C1-C8 group, or a linear or branched C1-C6 group which may be substituted; at least one of R1, R2, R3, R4, R5, R6, R7, R8, and R9 is a linear or branched C1-C8-(alkylene)-SO3 group. - It is the basis.

[0040] In some embodiments, SAE-CD is a water-soluble alkylated cyclodextrin of formula II: In formula TIFF0007836804000005.tif65128, p is 4, 5, or 6; Each time R1 appears, it is selected independently of -OH or -SAE-T; -SAE- is -O-(C2~C6 alkylene)-SO3 - The base is -O-(C2~C6 alkylene)-SO3, where at least one SAE is independently -O-(C2~C6 alkylene)-SO3 - -O-(CH2) group with 2-6 or 2-4 g groups g SO3 - Base (e.g., -OCH2CH2CH2SO3) - or -OCH2CH2CH2CH2SO3 - ) and -T is independently selected each time it appears from a group consisting of pharmaceutically acceptable cations, for example, H + Alkali metals (e.g., Li + kaNa + , K + ), alkaline earth metals (e.g., Ca +2 Mg +2 ), particularly containing ammonium ions, as well as amine cations such as (C1-C6)-alkylamines, piperidines, pyrazines, (C1-C6)-alkanolamines, ethylenediamines, and (C4-C8)-cycloalkanolamines; However, at least one R1 is a hydroxyl moiety, and at least one R1 is -SAE-T.

[0041] In some embodiments, T may be associated with an ion exchange resin, poly-L-lysine, polycationic chitosan, or a combination thereof.

[0042] If at least one R1 of a derivatized cyclodextrin molecule is -SAE-T, the degree of substitution with respect to the -SAE-T moiety is understood to be at least 1. When the term -SAE- is used to indicate a sulfoalkyl-(alkylsulfonic acid)-ether moiety, the -SAE- moiety is understood to contain a cation (-T) unless otherwise specified. Thus, the terms "SAE" and "-SAE-T" may be used interchangeably herein as appropriate.

[0043] Since SAE-CD is a polyanionic cyclodextrin, it can be obtained in different salt forms. Suitable counterions include cationic organic atoms or molecules, and cationic inorganic atoms or molecules. SAE-CD may contain a single type of counterion or a mixture of different counterions. The properties of SAE-CD can be modified by changing the uniqueness of the counterions present. For example, a first salt form of an SAE-CD composition may have a greater osmotic potential or a greater water activity reduction potential than a different second salt form of the same SAE-CD.

[0044] In some embodiments, the sulfoalkyl ether cyclodextrin is, for example, H + Alkali metals (e.g., Li + kaNa + , K + ), alkaline earth metals (e.g., Ca +2 Mg +2 It forms complexes with ammonium ions, as well as amine cations such as (C1-C6)-alkylamines, piperidines, pyrazines, (C1-C6)-alkanolamines, ethylenediamines, and (C4-C8)-cycloalkanolamines, and one or more pharmaceutically acceptable cations selected from combinations thereof.

[0045] Further exemplary sulfoalkyl ether (SAE-CD) derivatives include the following:

[0046] [Table 1] In the table, x represents the average degree of substitution. In some embodiments, alkylated cyclodextrins are formed as salts.

[0047] Various embodiments of sulfoalkyl ether cyclodextrin include eicosa-O-(methyl)-6G-O-(4-sulfobutyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, and heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(sulfomethyl)-β-cyclodextrin. Other known alkylated cyclodextrins containing a sulfoalkyl moiety include sulfoalkylthio and sulfoalkylthioalkyl ether derivatives such as octakis-(S-sulfopropyl)-octathio-γ-cyclodextrin, octakis-O-[3-[(2-sulfoethyl)thio]propyl]-β-cyclodextrin, and octakis-S-(2-sulfoethyl)-octathio-γ-cyclodextrin.

[0048] In some embodiments, the alkylated cyclodextrin composition is a sulfoalkyl ether-β-cyclodextrin composition having ADS of 2-9, 4-8, 4-7.5, 4-7, 4-6.5, 4.5-8, 4.5-7.5, 4.5-7, 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, 5.5-6.5, 6-8, 6-7.5, 6-7.1, 6.5-7.1, 6.2-6.9, or 6.5 per alkylated cyclodextrin, with the remaining substituent being -H.

[0049] In some embodiments, alkylated cyclodextrin is a compound of formula III: In formula TIFF0007836804000007.tif35128, n is 4, 5, or 6, and R1, R2, R3, R4, R5, R6, R7, R8, and R9 are independently -H, linear or branched C1~C8-(alkylene)-SO3 - A group is selected from linear or branched C1-C6 groups, which may be substituted.

[0050] Water-soluble alkylated cyclodextrin compositions may contain alkyl ether (AE)-cyclodextrin compounds of formula IV or mixtures of such compounds: In formula TIFF0007836804000008.tif36128, m is 4, 5, or 6; R is independently selected from the group consisting of -OH and AE each time it appears; AE is -O-(C1~C6 alkyl), where at least one R is -OH; and at least one AE exists.

[0051] Further exemplary AE-CD derivatives include the following:

[0052] [Table 2] In the table, ME represents methyl ether, EE represents ethyl ether, PE represents propyl ether, BE represents butyl ether, PtE represents pentyl ethyl ether, HE represents hexyl ether, and y represents the average degree of substitution.

[0053] The water-soluble alkylated cyclodextrin composition may contain a HAE-cyclodextrin compound of formula V or a mixture of such compounds: In formula TIFF0007836804000010.tif34128, "v" is 4, 5, or 6; "Q" is independently selected from the group consisting of -OH and -HAE each time it appears; and HAE is HO(C1~C6 alkyl)-O-, wherein at least one -HAE moiety is present.

[0054] Further exemplary hydroxyalkyl ether (HAE)-CD derivatives include the following:

[0055] [Table 3] In the table, HME represents hydroxymethyl ether, HEE represents hydroxyethyl ether, HPE represents hydroxypropyl ether, HBE represents hydroxybutyl ether, HPtE represents hydroxypentyl ether, HHE represents hydroxyhexyl ether, and z represents the average degree of substitution.

[0056] The water-soluble alkylated cyclodextrin composition may contain the SAE-AE-CD compound of formula VI or a mixture of the compound: In formula TIFF0007836804000012.tif36128, "v" is 4, 5, or 6; "A" is independently selected from the group consisting of -OH, -SAE-T, and -AE each time it appears; x is the degree of substitution of the SAE-T part, between 1 and 3v+5; y is the degree of substitution of the AE part, between 1 and 3v+5; and -SAE is -O-(C2~C6 alkylene)-SO3 - The set is such that; T is an independent cation each time it appears; AE is -O(C1~C3 alkyl), where there is at least one -SAE-T moiety and at least one -AE moiety; and the sum of x, y, and the total number of -OH groups in the alkylated cyclodextrin is 3v+6.

[0057] Specific embodiments of the derivatives of this disclosure include: (1) derivatives in which the alkylene portion of SAE has the same number of carbon atoms as the alkyl portion of AE; (2) derivatives in which the alkylene portion of SAE has a different number of carbon atoms than the alkyl portion of AE; (3) derivatives in which the alkyl portion and the alkylene portion are independently selected from the group consisting of a linear portion or a branched portion; (4) derivatives in which the alkyl portion and the alkylene portion are independently selected from the group consisting of a saturated portion or an unsaturated portion; (5) derivatives in which the ADS of the SAE group is greater than or close to the ADS of the AE group; or (6) derivatives in which the ADS of the SAE group is less than the ADS of the AE group.

[0058] The water-soluble alkylated cyclodextrin composition may contain the SAE-HAE-CD compound of formula VII or a mixture of the compound: In formula TIFF0007836804000013.tif33128, "v" is 4, 5, or 6; "X" is independently selected from the group consisting of -OH, SAE-T, and HAE each time it appears; x is the degree of substitution of the SAE-T moiety, between 1 and 3w+5; y is the degree of substitution of the HAE moiety, between 1 and 3w+5; and -SAE is -O-(C2~C6 alkylene)-SO3 - The set is such that; T is an independent cation each time it appears; HAE is HO-(C1~C6 alkyl)-O-, where there is at least one -SAE-T moiety and at least one -HAE moiety; and the sum of x, y, and the total number of -OH groups in the alkylated cyclodextrin is 3w+6.

[0059] Examples of alkylated cyclodextrins include SAE-CD, HAE-CD, SAE-HAE-CD, HANE-CD, HAE-AE-CD, HAE-SAE-CD, AE-CD, SAE-AE-CD, neutral cyclodextrin, anionic cyclodextrin, cationic cyclodextrin, halo-derivative cyclodextrin, amino-derivative cyclodextrin, nitrile-derivative cyclodextrin, aldehyde-derivative cyclodextrin, carboxylate-derivative cyclodextrin, sulfate-derivative cyclodextrin, sulfonate-derivative cyclodextrin, mercapto-derivative cyclodextrin, alkylamino-derivative cyclodextrin, or succinyl-derivative cyclodextrin.

[0060] In some embodiments, examples of alkylated cyclodextrins, such as mixed ether alkylated cyclodextrins, are those listed in Table 4 below.

[0061] [Table 4] TIFF0007836804000015.tif233168TIFF0007836804000016.tif139168

[0062] Further examples of alkylated cyclodextrins that can be prepared by the methods disclosed herein are described in U.S. Patents 5,438,133, 6,479,467, and 6,610,671, the respective disclosures of which are incorporated herein by reference in their entirety.

[0063] In a given alkylated cyclodextrin composition, the substituents of the alkylated cyclodextrin may be the same or different. For example, the SAE or HAE moiety may have the same or different types of alkylene (alkyl) radicals each time they appear in the alkylated cyclodextrin composition. In such embodiments, the alkylene radicals in the SAE or HAE moiety may be ethyl, propyl, butyl, pentyl, or hexyl each time they appear in the alkylated cyclodextrin composition.

[0064] Alkylated cyclodextrins may differ in their degree of substitution by functional groups, the number of carbon atoms in the functional groups, their molecular weight, the number of glucopyranose units in the original cyclodextrin used to form the derivatized cyclodextrin, and / or their substitution patterns. Furthermore, the derivatization of cyclodextrins by functional groups occurs in a controlled manner, though not strictly so. For this reason, the degree of substitution is actually a numerical value representing the average number of functional groups per cyclodextrin (for example, SBE7-β-CD has an average of 7 substituents per cyclodextrin). Thus, the average degree of substitution ("ADS") is 7. In some embodiments, ADS may be determined by techniques including capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) spectroscopy, or a combination thereof. Furthermore, the regiochemistry of hydroxyl group substitutions in cyclodextrins differs depending on the substitution of the specific hydroxyl group on the hexose ring. For this reason, substitutions of different hydroxyl groups are likely to occur during the production of derivatized cyclodextrins, and certain derivatized cyclodextrins will have a preferred substitution pattern, though not exclusively or specifically. Considering the above, the molecular weight of a particular derivatized cyclodextrin composition may vary from batch to batch.

[0065] A single parent cyclodextrin molecule has 3v+6 hydroxyl groups available for derivatization. For v=4 (α-cyclodextrin), the degree of substitution "y" can range from 1 to 18. For v=5 (β-cyclodextrin), the degree of substitution "y" can range from 1 to 21. For v=6 (γ-cyclodextrin), the degree of substitution "y" can range from 1 to 24. Generally, "y" is also in the range of 1 to 3v+g, where g is in the range of 0 to 5. In some embodiments, "y" is in the range of 1 to 2v+g, or 1 to 1v+g.

[0066] The degree of substitution ("DS") of a specific site (e.g., SAE, HAE, or AE) is a measure of the number of SAE (HAE, or AE) substituents attached to individual cyclodextrin molecules, in other words, the number of moles of substituents per mole of cyclodextrin. Thus, each substituent has its own DS for each individual alkylated cyclodextrin species. The average degree of substitution ("ADS") is a measure of the total number of substituents present per cyclodextrin molecule with respect to the distribution of alkylated cyclodextrins in the alkylated cyclodextrin composition of this disclosure. Thus, SAE4-CD has an ADS (per CD molecule) of 4.

[0067] Some aspects of the present disclosure include: (1) more than half of the hydroxyl moiety of the alkylated cyclodextrin is derivatized; (2) less than half of the hydroxyl moiety of the alkylated cyclodextrin is derivatized; (3) the substituents of the alkylated cyclodextrin are identical each time they appear; (4) the substituents of the alkylated cyclodextrin include at least two different substituents; or (5) the substituents of the alkylated cyclodextrin include one or more substituents selected from the group consisting of unsubstituted alkyl, substituted alkyl, halide (halo), haloalkyl, amine (amino), aminoalkyl, aldehyde, carbonylalkyl, nitrile, cyanoalkyl, sulfoalkyl, hydroxyalkyl, carboxyalkyl, thioalkyl, unsubstituted alkylene, substituted alkylene, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0068] Alkylated cyclodextrin compositions may contain multiple alkylated cyclodextrin molecules with different degrees of substitution. For example, an alkylated cyclodextrin molecule may have one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more hydroxyl groups of the parent cyclodextrin functionalized with substituents, such as sulfoalkyl ethers. In such compositions, the average degree of substitution (ADS) can be calculated based on the relative amounts of alkylated cyclodextrin molecules having a particular degree of substitution, as described herein. As a result, the ADS for SAE in an SAE-CD derivative composition represents a weighted average of the degrees of substitution of individual SAE-CD molecules in the composition. For example, SAE 5.2 -CD composition multiple SAE x -Includes the distribution of CD molecules, where "x" (DS of the SAE group) can be an integer range of 1 to 12 for each individual cyclodextrin molecule, however, the population of SAE-cyclodextrin molecules has an average value of 5.2 for "x" (ADS of the SAE group).

[0069] Alkylated cyclodextrin compositions may have high, moderate, or low ADS. Alkylated cyclodextrin compositions may also have a broad or narrow "span," which is the number of alkylated cyclodextrin molecules with different degrees of substitution within the alkylated cyclodextrin composition. For example, an alkylated cyclodextrin composition containing a single alkylated cyclodextrin species with a single degree of substitution is said to have a span of 1, in which case the degree of substitution of the alkylated cyclodextrin molecules will be equal to the ADS of that alkylated cyclodextrin composition. For example, the electrophoresis of an alkylated cyclodextrin with a span of 1 should show only one alkylated cyclodextrin species in relation to the degree of substitution. An alkylated cyclodextrin composition with a span of 2 contains two distinct alkylated cyclodextrin species with different degrees of substitution, and for example, its electrophoresis will show two different alkylated cyclodextrin species with different degrees of substitution. Similarly, the span of an alkylated cyclodextrin composition with a span of 3 includes three distinct alkylated cyclodextrin species with different degrees of substitution. The spans of alkylated cyclodextrin compositions are typically in the range of 5 to 15, or 7 to 12, or 8 to 11.

[0070] The parent cyclodextrin contains secondary hydroxyl groups at the C-2 and C-3 positions and a primary hydroxyl group at the C-6 position of the glucopyranose residue that forms the cyclodextrin. Each of these hydroxyl moieties is available for derivatization with substituent precursors. Depending on the synthetic method employed, the substituent moieties may be distributed randomly or in a somewhat ordered manner among the available hydroxyl positions. The positional isomerism of the substituent derivatization can also be varied as desired. The positional isomerism of each composition is independently selected. For example, many of the substituents present may be located on one or both of the primary or secondary hydroxyl groups of the parent cyclodextrin. In some embodiments, the primary distribution of substituents is C-3>C-2>C-6, while in other embodiments, the primary distribution of substituents is C-2>C-3>C-6. Some embodiments of this disclosure include alkylated cyclodextrin molecules in which some substituent moieties are located at the C-6 position and many substituent moieties are located at the C-2 and / or C-3 positions. A further aspect of the present disclosure includes an alkylated cyclodextrin molecule in which the substituents are substantially uniformly distributed among the C-2, C-3, and C-6 positions.

[0071] Alkylated cyclodextrin compositions have a distribution of multiple individual alkylated cyclodextrin species, each with a distinct degree of substitution ("IDS"). The content of each cyclodextrin species in a particular composition can be quantified using capillary electrophoresis. The analytical method (e.g., capillary electrophoresis for charged alkylated cyclodextrins) is sensitive enough to distinguish between a composition in which one alkylated cyclodextrin is present at only 5% and the other at 95% and a starting alkylated cyclodextrin composition containing a single alkylated cyclodextrin.

[0072] The above-mentioned variation among individual alkylated cyclodextrin species in the distribution is due to the complex formation equilibrium constant K 1:1This can lead to changes in the equilibrium constant, which affect the required molar ratio of derivatized cyclodextrin to the active agent. The equilibrium constant may also vary somewhat with temperature, and this ratio needs to have a tolerance to ensure that the active substance remains solubilized during temperature fluctuations that may occur during manufacturing, storage, transport, and use. The equilibrium constant may also vary with pH, ​​and this ratio may need to have a tolerance to ensure that the active substance remains solubilized during pH fluctuations that may occur during manufacturing, storage, transport, and use. The equilibrium constant may also vary in the presence of other excipients (e.g., buffers, preservatives, antioxidants). Therefore, to compensate for the above variables, the ratio of derivatized cyclodextrin to the active agent can be varied from the ratio disclosed herein.

[0073] Alkylated cyclodextrins produced according to the process of this disclosure are, for example, U.S. Patents No. 5,134,127, 5,376,645, 5,914,122, 5,874,418, 6,046,177, 6,133,248, 6,153,746, 6,407,079, 6,869,939, 7,034,013, 7,625,878, 7,629,331, 7,635,773, 9,493,582, and 10,040,872, which are incorporated herein by reference in their entirety; U.S. Patent Application Publications No. 2005 / 0164986, 2005 / 0186267, 2005 / 0250738, 2006 / 0258537, 2007 / 0020196, 2007 / 0020298, 2007 / 0020299, 2007 / 0175472, 2007 / 0202054, 2008 / 0194519, 2009 / 0011037, 2009 / 0012042, and 2009 / 0123540; It can be used in the compositions, formulations, methods, and systems disclosed in U.S. Patent Applications No. 12 / 404,174, No. 12 / 407,734, No. 61 / 050,918, No. 61 / 177,718, and No. 61 / 182,560; and PCT International Applications No. PCT / US06 / 62346, No. PCT / US07 / 71758, No. PCT / US07 / 71748, No. PCT / US07 / 72387, No. PCT / US07 / 72442, No. PCT / US07 / 78465, No. PCT / US08 / 61697, No. PCT / US08 / 61698, No. PCT / US08 / 70969, and No. PCT / US08 / 82730, etc. Alkylated cyclodextrins prepared according to the method of the present invention can also be used as suitable substitutes for other known grades of alkylated cyclodextrins having the same functional groups.

[0074] In some embodiments, alkylated cyclodextrins have greater water solubility than the corresponding cyclodextrins from which the alkylated cyclodextrin compositions of this disclosure are prepared. For example, in some embodiments, underivativeated cyclodextrins are used as starting materials, such as α-, β-, or γ-cyclodextrins, which are commercially available from sources such as WACKER BIOCHEM CORP. (Adrian, Michigan) and other sources. Underivativeated cyclodextrins have more limited water solubility compared to the alkylated cyclodextrin compositions of this disclosure. For example, underivativeated α-CD, β-CD, and γ-CD have water solubility of approximately 145 g / L, 18.5 g / L, and 232 g / L, respectively, when saturated.

[0075] The water-soluble alkylated cyclodextrin composition may be treated to remove the majority (e.g., more than 50%) of the non-derivativeated cyclodextrin or other impurities.

[0076] The terms "alkylene" and "alkyl" as used herein (e.g., -O-(C2~C6-alkylene)SO3) - The groups (or alkylamine cations) include linear, cyclic, and branched divalent alkylene groups and monovalent alkyl groups, respectively, that are saturated and unsaturated (i.e., containing one or more double bonds). For example, the SAE or HAE moiety may have the same or different types of alkylene (alkyl) groups each time they appear in the alkylated cyclodextrin composition. In such embodiments, the alkylene groups in the SAE or HAE moiety may be ethyl, propyl, butyl, pentyl, or hexyl each time they appear in the alkylated cyclodextrin composition.

[0077] Similarly, the term “alkanol” in this document includes linear, cyclic, and branched saturated and unsaturated alkyl components of an alkanol group, wherein the hydroxyl group may be located at any position on the alkyl moiety. The term “cycloalkanol” includes unsubstituted or substituted (e.g., methyl or ethyl) cyclic alcohols.

[0078] In some embodiments, the disclosure provides an alkyl ether cyclodextrin (AE-CD) composition comprising an alkyl ether cyclodextrin with an average degree of substitution of 2 to 9 and less than 0.1% (w / w) of chloride. In some embodiments, the disclosure provides an AE-CD composition comprising an alkyl ether cyclodextrin with an average degree of substitution of 2 to 9 and less than 0.05% (w / w) of chloride. In some embodiments, the disclosure provides an AE-CD composition comprising an alkyl ether cyclodextrin with an average degree of substitution of 2 to 9 and less than 0.01% (w / w) of chloride. In some embodiments, the disclosure provides an AE-CD composition comprising an alkyl ether cyclodextrin with an average degree of substitution of 2 to 9 and less than 0.002% (w / w) of chloride. In some embodiments, the alkyl ether cyclodextrin composition is not a sulfobutyl ether cyclodextrin composition. In some embodiments, the alkyl ether cyclodextrin is not a sulfobutyl ether β-cyclodextrin.

[0079] In some embodiments, the average degree of substitution of AE-CD is 4.5 to 7.5. In some embodiments, the average degree of substitution of AE-CD is 6 to 7.5. In some embodiments, the average degree of substitution of AE-CD is 6.2 to 6.9.

[0080] In some embodiments, the disclosure provides compositions comprising AE-CD and an activator.

[0081] In some embodiments, the Disclosure provides a sulfoalkyl ether cyclodextrin (SAE-CD) composition comprising a sulfoalkyl ether cyclodextrin with an average degree of substitution of 2 to 9 and less than 0.1% (w / w) of chloride. In some embodiments, the Disclosure provides an SAE-CD composition comprising a sulfoalkyl ether cyclodextrin with an average degree of substitution of 2 to 9 and less than 0.05% (w / w) of chloride. In some embodiments, the Disclosure provides an SAE-CD composition comprising a sulfoalkyl ether cyclodextrin with an average degree of substitution of 2 to 9 and less than 0.01% (w / w) of chloride. In some embodiments, the Disclosure provides an SAE-CD composition comprising a sulfoalkyl ether cyclodextrin with an average degree of substitution of 2 to 9 and less than 0.002% (w / w) of chloride.

[0082] In some embodiments, sulfoalkyl ether cyclodextrin is of formula (II): The compound is TIFF0007836804000017.tif66128, where p is 4, 5, or 6, and R1 is -OH or -O-(C2~C6 alkylene)-SO3 each time it appears. - -T is independently selected from the pharmaceutically acceptable cations each time it appears, wherein at least one R1 is -OH and at least one R1 is O-(C2~C6 alkylene)-SO3 - -T. In some embodiments, R1 is -OH or -O-(C4 alkylene)-SO3 each time it appears. - -T is selected independently of Na each time it appears. + That is the case.

[0083] In some embodiments, T may be associated with an ion exchange resin, poly-L-lysine, polycationic chitosan, or any combination thereof.

[0084] In some embodiments, the average substitution degree of SAE-CD is 4.5 to 7.5. In some embodiments, the average substitution degree of SAE-CD is 6 to 7.5. In some embodiments, the average substitution degree of SAE-CD is 6.2 to 6.9.

[0085] In some embodiments, the present disclosure provides compositions comprising SAE-CD and an activator.

[0086] This disclosure describes several methods for preparing alkylated cyclodextrins. Generally, a non-derivativeated cyclodextrin starting material in a neutral to alkaline aqueous medium is exposed to a substituent precursor. The substituent precursor may be added gradually or as a bolus, and may be added before, during, or after exposure of the cyclodextrin starting material to an optionally alkaline aqueous medium. Additional alkaline substances or buffers may be added as needed to maintain the pH within the desired range. The derivatization reaction can be carried out at ambient temperature to high temperatures. Once the derivatization has progressed to the desired degree, the reaction is optionally quenched by the addition of an acid. The reaction environment is further treated (e.g., solvent precipitation, filtration, centrifugation, evaporation, concentration, drying, chromatography, dialysis, and / or ultrafiltration) to remove undesirable substances and form the target composition. After final processing, the composition may be in the form of a solid, liquid, semi-solid, gel, syrup, paste, powder, aggregate, granules, pellets, compresses, reconstituteable solid, suspension, glass, crystalline mass, amorphous mass, fine particles, beads, emulsion, or wet mass.

[0087] This disclosure provides a method for producing alkylated cyclodextrins having a predetermined degree of substitution, comprising the following steps: combining an unsubstituted cyclodextrin starting material with a sufficient amount of alkylating agent to achieve a predetermined degree of substitution in the presence of an alkali metal hydroxide; carrying out alkylation of the cyclodextrin in a pH range of 9 to 11 until the amount of residual unreacted cyclodextrin is less than 0.5% by weight or less than 0.1%; adding a sufficient amount of further hydroxide to achieve the degree of substitution and proceeding to the completion of the alkylation; and adding further hydroxide to destroy any residual alkylating agent.

[0088] The step of adding further hydroxide can be carried out by using a quantity of hydroxide such that the level of residual alkylating agent in the aqueous crude product is reduced to less than 20 ppm or less than 2 ppm, and under such conditions (i.e., the amount of further hydroxide added, the temperature, and the length of time for carrying out the alkylating agent hydrolysis).

[0089] The reaction environment or partially purified aqueous solution may contain unreacted alkylating agent. This alkylating agent can be decomposed in situ by adding further alkalizing agent or by heating the solution containing this agent. If an unacceptable amount of alkylating agent is present in the reaction environment after the mixing is complete, the excess alkylating agent will need to be decomposed. This alkylating agent can be decomposed in situ by adding further alkalizing agent or by heating the solution containing this agent.

[0090] Decomposition can be carried out by exposing the reaction environment to a high temperature of at least 60°C, at least 65°C, or 60°C to 85°C, 60°C to 80°C, or 60°C to 95°C for at least 6 hours, at least 8 hours, 8 hours to 12 hours, 6 hours to 72 hours, or 48 hours to 72 hours, thereby decomposing the alkylating agent in situ and reducing or eliminating the amount of alkylating agent in the aqueous liquid.

[0091] After carrying out the reaction as described herein, the aqueous medium containing alkylated cyclodextrin can be neutralized to pH 7 to stop the reaction. If further purification is required, in particular, this solution can then be diluted with water to reduce viscosity. Further purification can be used to purge the solution of reaction by-products, including but not limited to diafiltration on an ultrafiltration unit, to purge the solution of reaction by-products such as salts (e.g., NaCl if sodium hydroxide is used as the base) and other low molecular weight by-products. This product can be further concentrated by ultrafiltration. Next, the product solution can be treated with activated carbon to improve its color, reduce bioburden, and substantially remove one or more drug-degradable impurities. The product can be isolated by a suitable drying technique such as freeze-drying, spray-drying, or vacuum drum drying.

[0092] The reaction mixture can first be prepared by dissolving the unsubstituted α-, β-, or γ-cyclodextrin starting material in an aqueous solution of a base, usually a hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide. To achieve a predetermined or desired degree of substitution, the base may be present in a catalytic amount (i.e., a molar ratio of less than 1:1 to the cyclodextrin). That is, the base may be present in an amount of less than 1 molar equivalent for each hydroxyl group in the cyclodextrin molecule to be derivatized. As the temperature rises, the cyclodextrin becomes increasingly soluble in aqueous solution; therefore, to ensure complete dissolution, the aqueous reaction mixture containing the base and cyclodextrin can be raised to a temperature of 50°C. Stirring is generally used throughout the alkylation reaction.

[0093] After dissolution is complete, the alkylating agent is added to initiate the alkylation reaction. Since some of the alkylating agent is hydrolyzed and / or otherwise destroyed / decomposed during the reaction and becomes unavailable for the alkylation reaction, the total amount of alkylating agent added throughout the reaction generally exceeds the stoichiometric amount relative to the amount of cyclodextrin required to complete the reaction. The exact amount of alkylating agent to use for the desired degree of substitution can be determined by testing. The total amount of alkylating agent required to complete the reaction can be added before initiating the reaction. Because the system is aqueous, the reaction is generally carried out at temperatures of 50°C to 100°C. The reaction can be carried out at temperatures below 100°C to avoid the need for special pressure equipment. Generally, temperatures of 65°C to 95°C are preferred.

[0094] During the initial phase of the reaction (referred to herein as the pH control phase), care should be taken to monitor the pH and maintain it at least basic or between pH 8 and 11. pH monitoring can be conveniently achieved using a standard pH meter. pH adjustment can be achieved by adding an aqueous hydroxide solution, for example, a 10-15% solution. During the initial pH control phase, the unreacted cyclodextrin reacts to such an extent that less than 0.5% or 0.1% by weight of unreacted cyclodextrin remains in the solution. Thus, substantially the entire initial supply of cyclodextrin reacts by partial substitution, but less than the desired predetermined degree of substitution. The residual cyclodextrin can be monitored throughout this initial phase, for example by HPLC, as described below, until the desired endpoint of less than 0.5% or 0.1% of residual cyclodextrin starting material is achieved. The pH can be maintained and / or increased by adding concentrated hydroxide to the reaction medium in separate amounts, either continuously or in small incremental amounts. Addition in small incremental amounts is particularly preferred.

[0095] Standardizing or optimizing the alkylation procedure so that specific amounts of reactants can be combined to produce the desired degree of substitution with a small amount of residual cyclodextrin allows for ensuring that low levels of residual (unreacted) cyclodextrin starting material are achieved by simply checking this procedure at the end, rather than throughout or during the initial pH control. The table below discloses the relationship between the amount of butanesultone supplied to the reactor and the average degree of substitution obtained in SAE-CD. TIFF0007836804000018.tif61134

[0096] For example, after combining the initial supply of cyclodextrin starting material with a base, but before adding the alkylating agent, it should be noted that the initial pH of the reaction medium may exceed 11. However, after the alkylating agent is added and the reaction begins, the pH rapidly decreases, and therefore it becomes necessary to add a base to maintain a basic pH of approximately 8 to 11.

[0097] If the level of residual unreacted cyclodextrin reaches a desired level, e.g., less than 0.5% by weight, during the pH control step, the reaction can be completed by adding further base to raise the pH to above 11, e.g., above 12. The pH can be set to at least 12 so that the reaction proceeds at a considerable rate, but not so fast that the unreacted alkylating agent is hydrolyzed more rapidly than it reacts with the cyclodextrin. During this latter phase of the reaction, further substitution of the cyclodextrin molecule can be achieved until a predetermined degree of substitution is reached. Typically, the total amount of hydroxide added throughout the reaction is on the order of the stoichiometrically required amount plus a 10-20% molar excess relative to the amount of alkylating agent used. Additions exceeding a 10-20% excess are also feasible. The reaction endpoint described above can be detected by HPLC. The preferred temperature is 65°C to 95°C. The HPLC system typically employs an anion exchange analysis column with pulsed amperometric detection (PAD). Elution may occur, for example, by gradient using a two-solvent system in which solvent A is a 25 mM (millimoleous) aqueous solution of sodium hydroxide and solvent B is 1 M sodium nitrate in 250 mM sodium hydroxide.

[0098] Once the alkylation reaction is complete and a low residual cyclodextrin endpoint is reached, additional hydroxide can be added to destroy and / or decompose any remaining alkylating agent. The additional hydroxide is typically added in an amount of 0.5 to 3 molar equivalents relative to the cyclodextrin, and the reaction medium is heated at 65°C to 95°C for a period of typically 6 to 72 hours.

[0099] After the detoxification of residual alkylating agents, the resulting crude product can be further processed by dilution, dialyzing filtration to reduce or remove low molecular weight components such as salts from the product, concentration, carbon treatment, and drying to produce the final product.

[0100] The pH is initially monitored to ensure it is maintained between 8 and 11 as the alkyl derivatization reaction proceeds. In this initial stage, the addition of hydroxide to facilitate alkylation may be stepwise or incremental. Monitoring the reaction's pH ensures that the reaction is controlled so that the entire initial stock of cyclodextrin starting material reacts essentially to the extent that it results in at least one alkyl substitution on average per cyclodextrin molecule. Thus, since the entire cyclodextrin reactant is consumed at the start of the method, the level of residual (unreacted) cyclodextrin in the crude product is lower compared to the crude product produced by methods characterized by the step of first combining the entire stoichiometric or excess amount of base with the cyclodextrin and alkylating agent and then allowing the reaction to proceed without control. After the entire initial stock of cyclodextrin starting material has partially reacted, the reaction can be completed by adding the remaining hydroxide to finish the alkyl substitution to a predetermined desired degree. After the initial stock of cyclodextrin has been consumed in the first pH control phase, the rate of hydroxide addition is not critical. Therefore, hydroxides can be added sequentially or in separate stages (e.g., as a solution). Furthermore, the pH of the reaction medium should be maintained above approximately 12 so that the reaction rate is commercially useful. Further methods for producing alkylated cyclodextrins are described in U.S. Patent No. 9,751,957, the disclosure of which is incorporated herein by reference in its entirety.

[0101] Method for removing impurities from alkylated cyclodextrins This disclosure provides a method for preparing an alkylated cyclodextrin composition, the method comprising: (a) mixing a cyclodextrin with an alkylating agent to form a reaction environment containing the alkylated cyclodextrin; (b) performing a first one or more separation, including dialysis filtration through a first membrane, to form a first solution containing the alkylated cyclodextrin; (c) treating the first solution with activated carbon to produce a second alkylated cyclodextrin solution; and (d) performing a second one or more separation, including nanofiltration through a second membrane, to form a third alkylated cyclodextrin solution. In some embodiments, the first membrane is an ultrafiltration membrane. In some embodiments, the second membrane is a nanofiltration membrane.

[0102] Figure 1 provides a schematic diagram of the method of the present disclosure. In the first step (100), a reaction environment containing crude alkylated cyclodextrin is formed. In some embodiments, the reaction environment of step (a) containing crude alkylated cyclodextrin is purified by diafiltration and / or ultrafiltration (102), which is a process of contacting the crude product with a semipermeable membrane that allows low molecular weight impurities to pass through the membrane. The filtration membrane may include nylon, TEFLON®, PVDF, or another suitable material.

[0103] The molecular weight of impurities that pass through the membrane varies depending on the molecular weight cutoff (MWCO) of the membrane and may vary as needed depending on the particle size or molecular weight of the species separated from the alkylated cyclodextrin in the solution containing the alkylated cyclodextrin. For the purposes of this disclosure, membranes with a molecular weight cutoff of 1,000 daltons ("Da") are typically employed. Dialysis and / or ultrafiltration can be performed using filter membranes with molecular weight cutoffs of 500 Da to 2,000 Da, 500 Da to 1,500 Da, 750 Da to 1,250 Da, or 900 Da to 1,100 Da, or about 1,000 Da. For example, in some embodiments, the filter membrane may have an MWCO of approximately 500 Da, 550 Da, 600 Da, 650 Da, 700 Da, 750 Da, 800 Da, 850 Da, 900 Da, 950 Da, 1,000 Da, 1050 Da, 1100 Da, 1150 Da, 1200 Da, or 1250 Da.

[0104] In some embodiments, the reaction environment of step (a) is optionally diluted with a solvent before the first one or more separations by diafiltration (102). In some embodiments, the solvent is water. Before the one or more separations, the reaction environment is diluted to achieve the desired concentration of alkylated cyclodextrin in solution. For example, in some embodiments, the concentration of alkylated cyclodextrin in the reaction environment immediately before the first one or more separations by diafiltration may be less than 10% (w / w), less than 9% (w / w), less than 8% (w / w), less than 7% (w / w), less than 6% (w / w), less than 5% (w / w), or less than 4% (w / w). In some embodiments, the concentration of alkylated cyclodextrin in the reaction environment immediately before the first one or more separations by diafiltration may be approximately 1% (w / w), 2% (w / w), 3% (w / w), 4% (w / w), 5% (w / w), 6% (w / w), 7% (w / w), 8% (w / w), or 9% (w / w). In some embodiments, the concentration of alkylated cyclodextrin in the reaction environment immediately before the first one or more separations by diafiltration may be 2% (w / w) to 9% (w / w), 3% (w / w) to 8% (w / w), 5% (w / w) to 8% (w / w), or 4% (w / w) to 6% (w / w).

[0105] To substantially remove impurities, the solution obtained after diafiltration may be further treated with activated carbon (104). A wide variety of activated carbons are available. For example, Norit-Americas sells more than 150 different grades and types of activated carbon under trademarks such as DARCO®, HYDRODARCO®, NORIT®, BENTONORIT®, PETRODARCO®, and SORBONORIT®. These carbons differ in particle size, application, activation method, and usefulness. For example, some activated carbons are optimized for color and / or odor removal. Others are optimized for protein, mineral, and / or amino acid moieties removal, or for purifying solutions.

[0106] The activated carbon suitable for use in the methods of this disclosure does not have to be phosphate-free and may be in the form of a powder or granules, or a suspension or slurry derived therefrom. Generally, phosphate-free activated carbon is carbon that has not been activated using or otherwise exposed to phosphoric acid. In some embodiments, the activated carbon used in the methods described herein is phosphate-free. In some embodiments, the activated carbon used in the methods described herein is granular. In some embodiments, the activated carbon used in the methods described herein is steam-activated.

[0107] Suitable activated carbons for use relating to this disclosure include, but are not limited to, various steam-activated ColorSorb® granular activated carbons derived from minerals or coconut shells (Jacobi Carbons France SASU), including, but are not limited to, ColorSorb® 5000, ColorSorb® H150-LC, ColorSorb® H620, ColorSorb® HS, and ColorSorb® HS-D. In some embodiments, the activated carbon used in the methods described herein can be prepared for use using the carbon preparation methods described below.

[0108] The packing ratio of activated carbon ultimately depends on the amount or concentration of alkylated cyclodextrin and impurities in the solution, as well as the physical properties of the activated carbon used. Generally, the weight ratio of cyclodextrin to activated carbon per processing cycle is 5:1–10:1, 6:1–9:1, 7:1–9:1, 8:1–9:1, 8.3:1–8.5:1, 8.4:1–8.5:1, or 8.44:1 by weight.

[0109] As used herein, a “processing cycle” refers to contacting a predetermined amount of cyclodextrin composition with a predetermined amount of activated carbon. A processing cycle can be carried out as a single process or as multiple (recirculating) passes. In some embodiments, the alkylated cyclodextrin solution obtained after dialysfiltration can be subjected to a processing cycle in which the alkylated cyclodextrin solution is passed through (recirculated) the activated carbon for 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours or longer. In some embodiments, after the first processing cycle is completed, the alkylated cyclodextrin solution can be subjected to a second processing cycle in which the alkylated cyclodextrin solution is passed through (recirculated) the activated carbon for 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours or longer.

[0110] The alkylated cyclodextrin solution produced after carbon treatment may be further purified by nanofiltration through a nanofiltration membrane (106). The nanofiltration membrane generally has pore sizes ranging from 0.1 nm to 10 nm, which are smaller than those used in dialysis filtration and ultrafiltration. For example, nanofiltration films suitable for use in the methods of this disclosure have pore sizes of 0.1 nm, 0.2 nm, 0.3 nm, 0.4 nm, 0.5 nm, 0.6 nm, 0.7 nm, 0.8 nm, 0.9 nm, 1.0 nm, 1.5 nm, 2.0 nm, 2.5 nm, 3.0 nm, 3.5 nm, 4.0 nm, 4.5 nm, 5.0 nm, 5.5 nm, 6.0 nm, 6.5 nm, 7.0 nm, 7.5 nm, 8.0 nm, 8.5 nm, 9.0 nm, 9.5 nm, or 10 nm, or within the range defined by any of the aforementioned pore sizes, for example, 1.0 to 10 nm, 1.0 nm to 5 nm, 0.1 nm to 5 nm, 0.5 nm to 5 nm, or 0.5 nm to 2.0 nm. Nanofiltration membranes suitable for use in the methods of this disclosure generally have an MWCO of about 500 Da, for example, 150 Da to 500 Da, 200 Da to 500 Da, 300 Da to 500 Da, 300 Da to 600 Da, or 200 Da to 600 Da. In some embodiments, the nanofiltration membrane may have an MWCO of about 100 Da, 150 Da, 200 Da, 250 Da, 300 Da, 350 Da, 400 Da, 450 Da, 500 Da, 550 Da, or 600 Da.

[0111] The nanofiltration process may be carried out once or multiple times and over any period between 30 minutes and approximately 24 hours, 30 minutes and 12 hours, 1 hour and 10 hours, 1 hour and 4 hours, 1 hour and 3 hours, or any other suitable period. For example, in some embodiments, nanofiltration may be carried out over a period of 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or longer.

[0112] In some embodiments, nanofiltration yields an alkylated cyclodextrin solution that is more concentrated than the alkylated cyclodextrin solution obtained immediately after treatment with activated carbon. In some embodiments, the concentration of alkylated cyclodextrin in the solution obtained after nanofiltration may be about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 25% (w / w), about 15% (w / w) to about 30% (w / w), about 15% (w / w) to about 25% (w / w), about 15% (w / w) to about 20% (w / w), about 18% (w / w) to about 25% (w / w), or about 18% (w / w) to about 20% (w / w). For example, the concentration of alkylated cyclodextrin in the solution obtained after nanofiltration may be approximately 10% (w / w), 11% (w / w), 12% (w / w), 13% (w / w), 14% (w / w), 15% (w / w), 16% (w / w), 17% (w / w), 18% (w / w), 19% (w / w), 20% (w / w), 21% (w / w), 22% (w / w), 23% (w / w), 24% (w / w), 25% (w / w), 26% (w / w), 27% (w / w), 28% (w / w), 29% (w / w), or 30% (w / w).

[0113] To prepare for the recovery of solid alkylated cyclodextrin, the resulting alkylated cyclodextrin solution may be further concentrated after nanofiltration is complete (108). The alkylated cyclodextrin solution from nanofiltration may be further concentrated to produce an alkylated cyclodextrin solution with an alkylated cyclodextrin concentration of about 30% (w / w) to about 70% (w / w), about 40% (w / w) to about 60% (w / w), or about 50% (w / w). In some embodiments, the alkylated cyclodextrin solution obtained from the nanofiltration step is concentrated over a period of about 2 to about 24 hours, about 6 to about 18 hours, or about 8 to about 12 hours. In some embodiments, the alkylated cyclodextrin solution obtained from the nanofiltration step is concentrated over a period of approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some embodiments, the alkylated cyclodextrin solution obtained from the nanofiltration step is concentrated by removing the solvent via distillation. In some embodiments, the alkylated cyclodextrin solution obtained from the nanofiltration step is concentrated by removing the solvent via lyophilization. In some embodiments, the alkylated cyclodextrin solution obtained from the nanofiltration step is concentrated using standard methods known in the art.

[0114] The final solid alkylated cyclodextrin product can be isolated at this point by evaporation of the solvent (e.g., via distillation, spray drying, freeze-drying, etc.) (110). The final product produced by the present disclosure is advantageous in that the residual alkylating agent contained is at a very low level, e.g., less than 2 ppm, less than 1 ppm, less than 250 ppb relative to the dry weight of the final product (i.e., less than 10% by weight of water content), or there is essentially no residual alkylating agent. Thus, a final product containing less than 250 ppb of alkylating agent is provided as an additional feature of the present disclosure. The alkylating agent can be reduced after the completion of alkylation to the desired degree of substitution by the aforementioned alkaline hydrolysis treatment, i.e., by adding an additional hydroxide solution in an amount and under conditions sufficient to reduce the amount of unreacted alkylating agent in the dry product to the desired level of less than 2 ppm, less than 1 ppm, or less than 250 ppb.

[0115] In some embodiments, the phosphate level of the solid alkylated cyclodextrin is less than 500 ppm, less than 200, less than 150 ppm, less than 125 ppm, less than 100 ppm, less than 95 ppm, less than 90 ppm, less than 85 ppm, less than 80 ppm, less than 75 ppm, less than 70 ppm, less than 65 ppm, less than 60 ppm, less than 55 ppm, less than 50 ppm, less than 45 ppm, less than 40 ppm, less than 35 ppm, less than 30 ppm, less than 25 ppm, less than 20 ppm, less than 15 ppm, less than 10 ppm, or less than 5 ppm. In some embodiments, the phosphate level in the solid alkylated cyclodextrin composition is 200 ppm to 5 ppm, 150 ppm to 5 ppm, 125 ppm to 5 ppm, 100 ppm to 5 ppm, 75 ppm to 5 ppm, 50 ppm to 5 ppm, 150 ppm to 10 ppm, 125 ppm to 10 ppm, 100 ppm to 10 ppm, or 75 ppm to 10 ppm.

[0116] In some embodiments, the compositions of the present invention are substantially free of one or more UV-active impurities. In some embodiments, the UV-active impurities may be drug-degrading substances. The presence of one or more UV-active impurities can be determined, in particular, by UV / visible ("UV / vis") spectrophotometry. As used herein, "drug-degrading substance" or "drug-degrading impurity" refers to a species, part, etc., that degrades a particular active ingredient in aqueous solution. It will be understood that drug-degrading substances do not degrade all drugs that can be combined with alkylated cyclodextrin compositions, depending on the chemical structure of the drug and its degradation pathway. In some embodiments, the drug-degrading species have absorbance in the UV / visible spectrum, for example, an absorbance maximum at wavelengths of 245 nm to 270 nm.

[0117] Alkylated cyclodextrin compositions can be measured in absorbance units (AU) by UV / vis. In some embodiments, the alkylated cyclodextrin composition has an absorbance of less than 1 AU, less than 0.9 AU, less than 0.8 AU, less than 0.7 AU, less than 0.6 AU, less than 0.5 AU, less than 0.4 AU, less than 0.3 AU, less than 0.2 AU, or less than 0.1 AU. In some embodiments, the presence of a UV activator in the composition can be measured in absorbance units by UV / vis.

[0118] The absorbance of a solution is given by the formula: A = εlc According to this, it becomes linear with respect to concentration, During the ceremony, A = absorbance ε = extinction coefficient l = optical path length c = molar concentration That is the case.

[0119] Alkylated cyclodextrin compositions can be measured using UV / vis spectrophotometry at wavelengths of 245-270 nm with a cell having a path length of 1 cm. In some embodiments, the alkylated cyclodextrin composition is less than 1 A.U. at wavelengths of 245-270 nm in an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per 1 mL of solution, less than 1 A.U. at wavelengths of 245-270 nm in an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per 1 mL of solution, less than 1 A.U. at wavelengths of 245-270 nm in an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per 1 mL of solution, and per 1 mL of solution In an aqueous solution containing 500 mg of alkylated cyclodextrin composition, the emission level is less than 1 A.U. at wavelengths of 245 nm to 270 nm; in an aqueous solution containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, the emission level is 0.9 AU or less at wavelengths of 245 nm to 270 nm; in an aqueous solution containing 300 mg of alkylated cyclodextrin composition per 1 mL of solution, the emission level is 0.9 AU or less at wavelengths of 245 nm to 270 nm; and in an aqueous solution containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the emission level is 245 nm. For aqueous solutions containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU is 0.9 AU or less at wavelengths of 245 nm to 270 nm. For aqueous solutions containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU is 0.8 AU or less at wavelengths of 245 nm to 270 nm. For aqueous solutions containing 300 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU is 0.8 AU or less at wavelengths of 245 nm to 270 nm. In an aqueous solution containing 400 mg of the alkylated cyclodextrin composition, the AU level is 0.8 AU or less at wavelengths of 245 nm to 270 nm. In an aqueous solution containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU level is 0.8 AU or less at wavelengths of 245 nm to 270 nm. In an aqueous solution containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU level is 0.7 AU or less at wavelengths of 245 nm to 270 nm. In an aqueous solution containing 300 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU level is 0.7 AU at wavelengths of 245 nm to 270 nm.Below, for aqueous solutions containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at wavelengths of 245 nm to 270 nm is 0.7 AU or less; for aqueous solutions containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at wavelengths of 245 nm to 270 nm is 0.7 AU or less; for aqueous solutions containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at wavelengths of 245 nm to 270 nm is 0.6 AU or less; and for aqueous solutions containing 300 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at wavelengths of 245 nm to 270 nm is 0.6 AU or less. For aqueous solutions containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at wavelengths of 245 nm to 270 nm is 0.6 AU or less. For aqueous solutions containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at wavelengths of 245 nm to 270 nm is 0.6 AU or less. For aqueous solutions containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at wavelengths of 245 nm to 270 nm is 0.5 AU or less. In an aqueous solution containing 300 mg of the substance, the emission level is 0.5 AU or less at wavelengths of 245 nm to 270 nm; in an aqueous solution containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the emission level is 0.5 AU or less at wavelengths of 245 nm to 270 nm; in an aqueous solution containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the emission level is 0.5 AU or less at wavelengths of 245 nm to 270 nm; in an aqueous solution containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, the emission level is 0.4 AU or less at wavelengths of 245 nm to 270 nm; per 1 mL of solution In an aqueous solution containing 300 mg of alkylated cyclodextrin composition, the AU level is 0.4 AU or less at wavelengths of 245 nm to 270 nm; in an aqueous solution containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU level is 0.4 AU or less at wavelengths of 245 nm to 270 nm; in an aqueous solution containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU level is 0.4 AU or less at wavelengths of 245 nm to 270 nm; and in an aqueous solution containing 200 mg of alkylated cyclodextrin composition, the AU level is 0.3 AU at wavelengths of 245 nm to 270 nm.Below, for aqueous solutions containing 300 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU level is 0.3 AU or less at wavelengths of 245 nm to 270 nm; for aqueous solutions containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU level is 0.3 AU or less at wavelengths of 245 nm to 270 nm; for aqueous solutions containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU level is 0.3 AU or less at wavelengths of 245 nm to 270 nm; and for aqueous solutions containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution... In aqueous solutions, the absorbance is 0.2 AU or less at wavelengths of 245 nm to 270 nm. In aqueous solutions containing 300 mg of alkylated cyclodextrin composition per 1 mL, the absorbance is 0.2 AU or less at wavelengths of 245 nm to 270 nm. In aqueous solutions containing 400 mg of alkylated cyclodextrin composition per 1 mL, the absorbance is 0.2 AU or less at wavelengths of 245 nm to 270 nm. In some embodiments, the presence of impurities in the alkylated cyclodextrin composition can be measured in absorbance units by UV / vis.

[0120] The impurity components may include, but are not limited to, low molecular weight impurities (i.e., impurities with a molecular weight of about 500 Da or less), water-soluble and / or water-insoluble ions (i.e., salts), hydrolyzed sulfoalkylating agents, 5-(hydroxymethyl)-2-flualdehyde, unreacted cyclodextrin starting materials, decomposed cyclodextrin species (e.g., decomposed and / or ring-opened species formed from unreacted cyclodextrin, partially reacted cyclodextrin and / or SAE-CD), unreacted alkylating agents (e.g., 1,4-butanesultone), and combinations thereof.

[0121] While not bound by any particular theory, UV activators, species, or moieties may include one or more low molecular weight species (e.g., species with a molecular weight less than 1,000 Da), such as species that arise as by-products and / or decomposition products in the reaction mixture. Thus, UV activating species include, but are not limited to, glycoside moieties, ring-opened cyclodextrin species, reducing sugars, glucose decomposition products (e.g., 3,4-dideoxyglucosone-3-ene, carbonyl-containing decomposition products, e.g., 2-fluoraldehyde, 5-hydroxymethyl-2-fluoraldehyde, etc.), and combinations thereof.

[0122] In some embodiments, the solid alkylated cyclodextrin contains less than 1% by weight, less than 0.5% by weight, less than 0.2% by weight, less than 0.1% by weight, less than 0.09% by weight, less than 0.08% by weight, less than 0.07% by weight, less than 0.06% by weight, less than 0.05% by weight, less than 0.04% by weight, less than 0.03% by weight, less than 0.02% by weight, less than 0.01% by weight, less than 0.009% by weight, less than 0.008% by weight, less than 0.007% by weight, less than 0.005% by weight, or less than 0.002% by weight of an alkali metal halide salt.

[0123] In some embodiments, the solid alkylated cyclodextrin contains less than 1% by weight, less than 0.5% by weight, less than 0.2% by weight, less than 0.1% by weight, less than 0.09% by weight, less than 0.08% by weight, less than 0.07% by weight, less than 0.06% by weight, less than 0.05% by weight, less than 0.04% by weight, less than 0.03% by weight, less than 0.02% by weight, less than 0.01% by weight, less than 0.009% by weight, less than 0.008% by weight, less than 0.007% by weight, less than 0.005% by weight, or less than 0.002% by weight of chloride.

[0124] In some embodiments, the solid alkylated cyclodextrin contains less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, less than 0.1% by weight, less than 0.08% by weight, or less than 0.05% by weight of the hydrolyzed alkylating agent.

[0125] In some embodiments, the solid alkylated cyclodextrin contains an alkylating agent in an amount of less than 500 ppm, less than 100 ppm, less than 50 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, less than 2 ppm, less than 1 ppm, less than 500 ppb, or less than 250 ppb.

[0126] In some embodiments, the solid alkylated cyclodextrin comprises less than 0.5% by weight, less than 0.2% by weight, less than 0.1% by weight, or less than 0.08% by weight of non-derivativeated cyclodextrin.

[0127] The chloride level of alkylated cyclodextrins can be determined by any method commonly used by those skilled in the art. In some embodiments, the chloride level is measured using charged particle detection (CAD). In some embodiments, the chloride level is measured using ion chromatography.

[0128] In some embodiments, the chloride level, as measured by the weight ratio (w / w) of alkylated cyclodextrin, is ≤1%, ≤0.9%, ≤0.8%, ≤0.7%, ≤0.6%, ≤0.5%, ≤0.4%, ≤0.3%, ≤0.2%, ≤0.1%, ≤0.09%, ≤0.08%, ≤0.07%, ≤0.06%, ≤0.05%, ≤0.04%, ≤0.03%, ≤0.02%, ≤0.01%, ≤0.009%, ≤0.008%, ≤0.007%, ≤0.006%, ≤0.005%, ≤0.004%, ≤0.003%, or ≤0.002%. In some embodiments, the chloride levels in alkylated cyclodextrins are 1%~0.002%, 0.9%~0.002%, 0.8%~0.002%, 0.7%~0.002%, 0.6%~0.002%, 0.5%~0.002%, 0.4%~0.002%, 0.3%~0.002%, 0.2%~0.002%, 0.1%~0.002%, 0.09%~0.002%, 0.08%~0.002%, and 0.07%~0.0 These percentages are 0.2%, 0.06%~0.002%, 0.05%~0.002%, 0.04%~0.002%, 0.03%~0.002%, 0.02%~0.002%, 0.01%~0.002%, 0.009%~0.002%, 0.008%~0.002%, 0.007%~0.002%, 0.006%~0.002%, 0.005%~0.002%, 0.004%~0.002%, or 0.003%~0.002%.

[0129] The final yield of alkylated cyclodextrin (in isolated and / or purified or partially purified form) obtained at the completion of the method will vary. The final yield of alkylated cyclodextrin relative to the cyclodextrin starting material may range from 10% to 95%, 15% to 90%, 20% to 85%, 30% to 85%, 35% to 85%, 40% to 85%, 45% to 80%, 50% to 80%, 55% to 80%, 60% to 80%, 50% to 90%, 55% to 90%, 60% to 90%, 70% to 90%, 80% to 90%, 60% to 98%, 70% to 98%, 80% to 98%, or 90% to 98%. In some embodiments, the final yield of alkylated cyclodextrin relative to the cyclodextrin starting material is 80% or higher, 85% or higher, 90% or higher, or 95% or higher.

[0130] The method disclosed herein is suitable for the large-scale production and purification of alkylated cyclodextrins and represents a significant improvement over previously known methods. A single batch of alkylated cyclodextrin may be prepared using more than 275 kg of starting cyclodextrin (e.g., α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin) using the method described herein. In some embodiments, the starting cyclodextrin is β-cyclodextrin. In some embodiments, a single batch of alkylated cyclodextrin may be prepared using more than 300 kg, more than 325 kg, more than 350 kg, more than 375 kg, or more than 400 kg of starting cyclodextrin using the method described herein. In some embodiments, the amount of starting cyclodextrin is approximately 300 kg to 400 kg, approximately 325 kg to 375 kg, or approximately 325 kg to 400 kg. In some embodiments, the amount of starting cyclodextrin is approximately 350 kg.

[0131] Carbon preparation method As described above, to remove impurities generated during the synthesis of alkylated cyclodextrins, the purification of crude alkylated cyclodextrins disclosed herein may utilize a carbon purification step. For example, such a purification method is disclosed in U.S. Patent No. 6,153,746, the contents of which are incorporated herein by reference. An improvement to the carbon preparation method is described in U.S. Patent No. 7,635,773, in which activated carbon is washed until a certain conductivity is achieved before the purification of crude alkylated cyclodextrins. While the carbon preparation method described in U.S. Patent No. 7,635,773 removed some impurities, a large amount of chloride remained in the alkylated cyclodextrin product. Chloride impurities can react with activators, causing their decomposition.

[0132] Further improvements to carbon preparation methods are disclosed in U.S. Patent No. 9,493,582, which includes a step of washing the carbon until it reaches a conductivity level of 10 μS / cm. U.S. Patent No. 10,040,872 discloses a method of preparing carbon that includes an immersion step. The methods described in these applications reduce the amount of chloride impurities in the final alkylated cyclodextrin product, but it is desirable to further reduce the chloride level in the alkylated cyclodextrin product, especially when the activator is chloride-sensitive. The method disclosed herein further reduces the chloride level in the alkylated cyclodextrin product.

[0133] The conductivity of the aqueous wash eluent of activated carbon can be determined by any method commonly used by those skilled in the art. In some embodiments, conductivity is measured using a conductivity meter. In some embodiments, conductivity is measured using ion chromatography.

[0134] In some embodiments, the conductivity of the activated carbon water wash eluent is measured before the addition of the alkylated cyclodextrin solution, which has been partially purified beforehand by diafiltration. In some embodiments, the conductivity of the activated carbon water wash eluent is measured after washing the activated carbon with water. In some embodiments, the conductivity of the activated carbon water wash eluent is measured after passing water over the carbon. In some embodiments, the conductivity of the activated carbon water wash eluent before treating the partially purified alkylated cyclodextrin solution with activated carbon to produce the final purified alkylated cyclodextrin composition is 35 μS / cm or less, 34 μS / cm or less, 33 μS / cm or less, 32 μS / cm or less, 31 μS / cm or less, 30 μS / cm or less, 29 μS / cm or less, 28 μS / cm or less, 27 μS / cm or less, 26 μS / cm or less, 25 μS / cm or less, 24 μS / cm, 23 μS / cm or less. Below 22 μS / cm or less, 21 μS / cm or less, 20 μS / cm or less, 19 μS / cm or less, 18 μS / cm or less, 17 μS / cm or less, 16 μS / cm or less, 15 μS / cm or less, 14 μS / cm or less, 13 μS / cm or less, 12 μS / cm or less, 11 μS / cm or less, 10 μS / cm or less, 9 μS / cm or less, 8 μS / cm or less, 7 μS / cm or less, 6 μS / cm or less, 5 μS / cm or less, 4 μS / cm or less, 3 μS / cm or less, 2 μS / cm or less, or 1 μS / cm or less. In some embodiments, the conductivity of the water wash eluent of activated carbon before the addition of the partially purified alkylated cyclodextrin solution is 10 μS / cm to 15 μS / cm, 5 μS / cm to 15 μS / cm, 5 μS / cm to 10 μS / cm, 4 μS / cm to 10 μS / cm, 3 μS / cm to 10 μS / cm, or 4 μS / cm to 8 μS / cm.

[0135] In some embodiments, the activated carbon is washed 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times before treating the partially purified alkylated cyclodextrin solution with the activated carbon. In some embodiments, the activated carbon is washed 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more times before treating the partially purified alkylated cyclodextrin solution with the activated carbon.

[0136] Even after washing the activated carbon with water in the column, the wetting of the activated carbon may be insufficient. Channeling through the carbon bed cannot be controlled during the washing procedure. It is thought that more thorough washing of the carbon before circulating the alkylated cyclodextrin solution reduces or removes all further addition of residual chloride from the alkylated cyclodextrin composition product.

[0137] In some embodiments, activated carbon is added to a dedicated tank system equipped with a stirrer and a screen system. After charging the activated carbon, an initial carbon wash is performed with water in several stages over a predetermined time at a predetermined stirring speed. After washing, the aqueous layer is removed from the dedicated tank and an additional wash is performed. After the additional wash, the conductivity of the activated carbon is measured, and if the conductivity falls below a predetermined level, the carbon is suspended in water, and the carbon / water slurry is pumped into a column for further processing. Thus, the activated carbon will be ready for further processing, including the steps of passing water over the carbon or adding a portion of a partially purified solution containing alkylated cyclodextrin to the carbon, immersing the carbon in the partially purified solution, and eluting and discarding the solution. A predetermined level of conductivity refers to, for example, 35 μS / cm or less, 34 μS / cm or less, 33 μS / cm or less, 32 μS / cm or less, 31 μS / cm or less, 30 μS / cm or less, 29 μS / cm or less, 28 μS / cm or less, 27 μS / cm or less, 26 μS / cm or less, 25 μS / cm or less, 24 μS / cm, 23 μS / cm or less, 22 μS / cm or less, 21 μS / cm or less, 20 μS / cm or less, and 19 μS / cm. The following are possible: 18 μS / cm or less, 17 μS / cm or less, 16 μS / cm or less, 15 μS / cm or less, 14 μS / cm or less, 13 μS / cm or less, 12 μS / cm or less, 11 μS / cm or less, 10 μS / cm or less, 9 μS / cm or less, 8 μS / cm or less, 7 μS / cm or less, 6 μS / cm or less, 5 μS / cm or less, 4 μS / cm or less, 3 μS / cm or less, 2 μS / cm or less, or 1 μS / cm or less. In some embodiments, the desired conductivity level may be achieved after washing with water for about 6 to 12 hours.

[0138] Stirring can be measured in revolutions per minute (rpm). In some embodiments, the stirring speed may be in the range of, for example, 5 rpm to 300 rpm. For example, the stirring speed may be 5 rpm, 10 rpm, 20 rpm, 30 rpm, 40 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, 90 rpm, or 100 rpm. The stirring time may be in the range of 1 minute to 5 days. For example, the stirring time may be 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 2 days, 3 days, or 4 days. In some embodiments, the stirring time is 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 3 hours, 5 minutes to 4 hours, 5 minutes to 5 hours, 10 minutes to 1 hour, 10 minutes to 2 hours, 10 minutes to 3 hours, 10 minutes to 4 hours, 20 minutes to 1 hour, 20 minutes to 2 hours, 20 minutes to 3 hours, 20 minutes to 4 hours, 30 minutes to 1 hour, 30 minutes to 2 hours, 30 minutes to 3 hours, or 30 minutes to 4 hours.

[0139] In some embodiments, the tank system is maintained at room temperature (25°C) during the water washing process. In some embodiments, the tank system can be heated during the water washing process. In some embodiments, the temperature may be in the range of, for example, 30°C to 100°C. For example, the cooling temperature may be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C. The heating time may be in the range of 1 minute to 5 days. For example, the heating time may be 5 minutes to 4 days, 5 minutes to 60 minutes, 10 minutes to 50 minutes, 20 minutes to 40 minutes, 30 minutes to 60 minutes, 2 hours to 24 hours, 3 hours to 12 hours, 4 hours to 10 hours, 5 hours to 9 hours, 6 hours to 8 hours, 2 days to 4 days, or 3 days to 4 days. In some embodiments, the heating time is 5 minutes to 1 hour, 5 minutes to 2 hours, 5 minutes to 3 hours, 5 minutes to 4 hours, 5 minutes to 5 hours, 10 minutes to 1 hour, 10 minutes to 2 hours, 10 minutes to 3 hours, 10 minutes to 4 hours, 20 minutes to 1 hour, 20 minutes to 2 hours, 20 minutes to 3 hours, 20 minutes to 4 hours, 30 minutes to 1 hour, 30 minutes to 2 hours, 30 minutes to 3 hours, or 30 minutes to 4 hours.

[0140] In some embodiments, the carbon transferred to the column may be subjected to a further washing process. The further washing process may include flowing water through activated carbon. In some embodiments, purified water may be filled into the column from top to bottom or bottom to top and held in the column for a certain period of time. In some embodiments, the water is held in the column for at least 30 minutes. In some embodiments, the water is held in the column for 30 to 45 minutes. The purified water is then flowed through activated carbon and discharged. In some embodiments, the purified water is flowed in the same direction as the water was filled in the first carbon washing process. In other embodiments, the water is flowed through activated carbon in a different direction than the water was filled in the first carbon washing process. For example, in some embodiments, the water may be filled from top to bottom in the first carbon washing process and flowed through activated carbon from top to bottom in the second carbon washing process. In some embodiments, the water may be filled from top to bottom in the first carbon washing process and flowed through activated carbon from bottom to top in the second carbon washing process. In some embodiments, water may be filled from bottom to top during the first carbon washing process, and water may be flowed from top to bottom through the activated carbon during the second carbon washing process.

[0141] Water may be passed through the activated carbon for a set period of time. For example, water may be passed through the activated carbon for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, 390 minutes, 420 minutes, 450 minutes, 480 minutes or longer. For example, water may be passed through the activated carbon for about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours. Water may be flowed through the activated carbon at a flow rate of at least 50 liters per hour, 100 liters per hour, 150 liters per hour, 200 liters per hour, 250 liters per hour, 300 liters per hour, 350 liters per hour, 400 liters per hour, 450 liters per hour, 500 liters per hour, or more. For example, water may be flowed through the activated carbon at a flow rate of approximately 100 liters per hour, approximately 200 liters per hour, approximately 300 liters per hour, approximately 400 liters per hour, approximately 500 liters per hour, approximately 600 liters per hour, approximately 700 liters per hour, approximately 800 liters per hour, approximately 900 liters per hour, or approximately 1,000 liters per hour. After flowing water through the carbon, the column may be flushed from the top with purified water for 30 minutes and then discharged from the column.

[0142] In some embodiments, the activated carbon is subjected to a further carbon washing process which includes adding a portion of a partially purified alkylated cyclodextrin solution to the activated carbon, immersing the activated carbon in the partially purified alkylated cyclodextrin solution, and eluting and discarding the partially purified alkylated cyclodextrin solution. The alkylated cyclodextrin solution may be packed in a top-down or bottom-up direction. In one embodiment, the activated carbon is immersed for a set time before the partially purified alkylated cyclodextrin solution is eluted. For example, the activated carbon may be immersed for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, 390 minutes, 420 minutes, 450 minutes, 480 minutes, or longer. In one embodiment, the activated carbon is immersed for at least 120 minutes.

[0143] In some embodiments, the carbon may be stirred during the immersion process at a speed of, for example, 5 rpm to 300 rpm. For example, the stirring speed may be 5 rpm, 10 rpm, 20 rpm, 30 rpm, 40 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, 90 rpm, or 100 rpm. In some embodiments, the stirring speed may be approximately 40 to 50 rpm.

[0144] In some embodiments, the temperature for immersing carbon in the alkylated cyclodextrin solution may be in the range of 5°C to 100°C. For example, the immersion temperature may be 10°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C. In some embodiments, the immersion temperature is room temperature.

[0145] In some embodiments, the activated carbon may be subjected to a further carbon washing process after the immersion process. This further washing process includes the steps of filling the column with purified water and allowing the water to stand for a certain period of time. In some embodiments, the water is added from top to bottom. In other embodiments, the water is added from bottom to top. In some embodiments, the water may be allowed to stand for about 30 minutes. The purified water is then drained from the bottom of the column. This process may be continued for at least 1 hour, and the conductivity of the activated carbon is measured. If the conductivity is below a desired predetermined level, the column may be filled with water and used for the purification of alkylated cyclodextrin. If the conductivity is above a desired predetermined level, this further washing method may be repeated. The predetermined conductivity levels are, for example, 35μS / cm or less, 34μS / cm or less, 33μS / cm or less, 32μS / cm or less, 31μS / cm or less, 30μS / cm or less, 29μS / cm or less, 28μS / cm or less. cm or less, 27μS / cm or less, 26μS / cm or less, 25μS / cm or less, 24μS / cm, 23μS / cm or less, 22μS / cm or less, 21μS / cm or less, 20μS / cm or less, 19μS / cm or less The conductivity levels may be 18 μS / cm or less, 17 μS / cm or less, 16 μS / cm or less, 15 μS / cm or less, 14 μS / cm or less, 13 μS / cm or less, 12 μS / cm or less, 11 μS / cm or less, 10 μS / cm or less, 9 μS / cm or less, 8 μS / cm or less, 7 μS / cm or less, 6 μS / cm or less, 5 μS / cm or less, 4 μS / cm or less, 3 μS / cm or less, 2 μS / cm or less, or 1 μS / cm or less. In some embodiments, the predetermined conductivity level is 10 μS / cm or less.

[0146] Use of alkylated cyclodextrin composition Among its many applications, the alkylated cyclodextrins of this disclosure can be used to solubilize and / or stabilize a variety of different materials and to prepare formulations for specific applications. The alkylated cyclodextrins described herein can improve the solubility of other components in a composition and / or improve their chemical, thermochemical, hydrolytic and / or photochemical stability. For example, alkylated cyclodextrins can be used to stabilize activators in aqueous media. Alkylated cyclodextrins can also be used to increase the solubility of activators in aqueous media.

[0147] The alkylated cyclodextrin compositions of this disclosure comprise one or more activators. The one or more activators contained in the compositions of this disclosure may have a broad range of water solubility, bioavailability, and hydrophilicity. Activators particularly suited to this disclosure include water-insoluble, poorly water-soluble, slightly water-soluble, moderately water-soluble, water-soluble, very water-soluble, hydrophobic, and / or hydrophilic therapeutic agents. Those skilled in the art will understand that the one or more activators present in the compositions of this disclosure are selected independently of any known activators and those disclosed herein, each time they appear. It is not necessary for the one or more activators to form a complex with the alkylated cyclodextrin or to form an ionic association with the alkylated cyclodextrin.

[0148] Generally, active agents include physiologically active or pharmacologically active substances that produce one or more systemic or local effects on animals and humans. Active agents include pesticides, herbicides, insecticides, antioxidants, plant growth promoters, sterilizers, catalysts, chemical reagents, foods, nutrients, cosmetics, vitamins, infertility inhibitors, pregnancy promoters, microorganisms, seasonings, sweeteners, cleaning agents, pharmaceutically effective active agents, as well as other such compounds for pharmaceutical, veterinary, horticultural, household, food, cooking, agricultural, cosmetic, industrial, cleaning, confectionery, and seasoning applications. Active agents may exist in their neutral form, ionic form, salt form, basic form, acid form, natural form, synthetic form, diastereomer form, isomer form, enantiomerically pure form, racemic form, hydrate form, chelate form, derivative form, analog form, or other common forms.

[0149] Representative pharmaceutically effective active agents include nutrients and nutritional supplements, hematological agents, endocrine and metabolic agents, cardiovascular agents, nephrotic and urogenital agents, respiratory agents, central nervous system agents, gastrointestinal agents, antifungal agents, anti-infective agents, biological and immunological agents, dermatological agents, ophthalmic agents, anti-cancer agents, and diagnostic agents. Exemplary nutrients and nutritional supplements include minerals, trace elements, amino acids, lipid agents, enzymes, and chelating agents. Exemplary hematological agents include hematopoietic agents, antiplatelet agents, anticoagulants, coumarin and indanedione derivatives, blood coagulation agents, thrombolytic agents, antisickle agents, hemodynamic agents, antihemophilic agents, hemostatic agents, plasma replenishing solutions, and hemins. Examples of endocrine and metabolic agents include sex hormones, uterine agents, bisphosphonates, antidiabetic agents, glucose-raising agents, corticosteroids, adrenocortical steroids, parathyroid hormones, thyroid drugs, growth hormones, posterior pituitary hormones, octreotide acetate, imiglucerase, salmon calcitonin, sodium phenylbutyrate, anhydrous betaine, cysteamine bitartrate, sodium benzoate and sodium phenylacetate, bromocriptine mesylate, cabergoline, gout agents, and antidotes. Suitable antifungal agents for use in the alkylated cyclodextrin compositions of this disclosure include, but are not limited to, posaconazole, voriconazole, clotrimazole, ketoconazole, oxiconazole, sertaconazole, tetconazole, fluconazole, itraconazole, and miconazole. Suitable antischizophrenia agents for use in the alkylated cyclodextrin compositions of this disclosure include, but are not limited to, clozapine, prochlorperazine, haloperidol, thioridazine, thiothixene, risperidone, trifloperazine hydrochloride, chlorpromazine, aripiprazole, roxapine, loxitan, olanzapine, quetiapine fumarate, risperidone, and ziprasidone.

[0150] Examples of cardiovascular agents include nootropics, antiarrhythmics, calcium channel blockers, vasodilators, anti-adrenergic / sympathetic blockers, renin-angiotensin system antagonists, antihypertensive combinations, agents for pheochromocytoma, agents for hypertensive emergencies, antihyperlipidemic agents, antihyperlipidemic combination products, vasopressors for use in shock, potassium-removing resins, disodium edetate, cardiac arrest solutions, agents for patent ductus arteriosus, and sclerosing agents. Examples of nephrotic and urogenital agents include interstitial cystitis agents, sodium cellulose phosphate, anti-sexual dysfunction agents, acetohydroxamic acid (AHA), urogenital lavage agents, cystine depletion agents, urine alkalinizers, urine acidifiers, anticholinergics, urinary cholinergics, polymer phosphate binders, vaginal preparations, and diuretics. Examples of respiratory agents include bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, respiratory inhalation products, nasal decongestants, respiratory enzymes, pulmonary surfactants, antihistamines, non-narcotic antitussives, and expectorants. Examples of central nervous system agonists include CNS stimulants, narcotic agonist analgesics, narcotic agonist-antagonist analgesics, central analgesics, acetaminophen, salicylates, non-narcotic analgesics, nonsteroidal anti-inflammatory drugs, migraine medications, antiemetics / antivertigo agents, anxiolytics, antidepressants, schizophrenia treatments, cholinesterase inhibitors, non-barbiturate sedatives and hypnotics, non-prescription hypnotics, barbiturate sedatives and hypnotics, general anesthetics, injectable local anesthetics, anticonvulsants, muscle relaxants, antiparkinson's disease agents, adenosine phosphate, cholinergic muscle stimulants, disulfiram, smoking deterrents, riluzole, hyaluronic acid derivatives, and botulinum toxin. Examples of gastrointestinal agents include H. pylori drugs, histamine H2 antagonists, proton pump inhibitors, sucralfate, prostaglandins, antacids, gastrointestinal anticholinergics / antispasmodics, mesalamine, orsalazine sodium, valsalazide disodium, sulfasalazine, celecoxib, infliximab, tegaserod maleate, laxatives, antidiarrheals, anti-bloating agents, lipase inhibitors, GI stimulants, digestive enzymes, gastric acidifiers, cholagogues, gallstone solubilizers, oral and throat products, systemic deodorants, and anal and rectal preparations.Exemplary anti-infective agents include penicillin, cephalosporins and related antibiotics, carbapenems, monobactams, chloramphenicol, quinolones, fluoroquinolones, tetracyclines, macrolides, spectinomycin, streptogramin, vancomycin, oxalodinones, lincosamides, oral and parenteral aminoglycosides, colistimethate sodium, polymyxin B sulfate, bacitracin, metronidazole, sulfonamides, nitrofurans, methenamine, folic acid antagonists, antifungal agents, antimalarial agents, antituberculosis agents, anti-amebic agents, antiviral agents, antiretroviral agents, leprosy treatments, antiparasitic agents, anthelmintics, and CDC anti-infective agents. Exemplary biological and immunological agents include immunoglobulins, monoclonal antibodies, antibenins, active immunizers, allergenic extracts, immunological agents, and antirheumatic agents. Examples of dermatological agents include topical antihistamines, topical anti-infectives, anti-inflammatory agents, antipsoriasis agents, anti-seborrheic products, arnica, astringents, cleansers, capsaicin, detoxifying agents, drying agents, enzyme preparations, topical immunomodulators, keratolytic agents, liver derivative complexes, topical anesthetics, minoxidil, eflornithine hydrochloride, photochemotherapeutic agents, pigments, topical poison ivy products, topical pyrimidine antagonists, zinc pyrithione, retinoids, rexinoids, scabies insecticides / lice killers, wound healers, emollients, protectants, sunscreens, ointment bases and lotion bases, rubs and liniments, bandages and granules, and physiological cleansing solutions. Examples of ophthalmic agents include glaucoma agents, mast cell stabilizers, ophthalmic disinfectants, ophthalmic phototherapy agents, ocular lubricants, artificial tears, ophthalmic hyperosmolar preparations, and contact lens products.Exemplary anti-cancer agents include alkylating agents, antimetabolites, mitotic inhibitors, epipodophyllotoxins, antibiotics, hormones, enzymes, radiopharmaceuticals, platinum coordination complexes, anthracendions, substituted ureas, methylhydrazine derivatives, imidazotetrazine derivatives, cytoprotective agents, DNA topoisomerase inhibitors, bioresponse modifiers, retinoids, lexinoids, monoclonal antibodies, protein-tyrosine kinase inhibitors, porfimer sodium, mitotane (o,p'-ddd), and arsenic trioxide. Exemplary diagnostic agents include in vivo diagnostic aids, in vivo diagnostic biologics, and radiopaque agents.

[0151] Exemplary active agents also include compounds sensitive to compound chlorine levels. Exemplary chlorine-sensitive compounds include proteasome inhibitors, such as bortezomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, and carfilzomib.

[0152] The active agents listed above should not be considered exhaustive, but merely illustrative of the many embodiments considered within the scope of this disclosure. Many other active agents can be administered by formulations of this disclosure.

[0153] The formulations of this disclosure can be used to deliver two or more different active agents. Special combinations of active agents can be given in the formulations of this disclosure. Some combinations of active agents include: 1) a first drug from a first therapeutic class and a different second drug from the same therapeutic class; 2) a first drug from a first therapeutic class and a different second drug from a different therapeutic class; 3) a first drug having a first type of biological activity and a different second drug having substantially the same biological activity; and 4) a first drug having a first type of biological activity and a different second drug having a different second type of biological activity. Exemplary combinations of active agents are described herein.

[0154] The active agents contained in the formulations of this disclosure may exist as pharmaceutically acceptable salts thereof. As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound in which the active agent has been modified by reacting the active agent with an acid and / or base as necessary to form an ionic bond pair. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of a compound, for example, formed from a non-toxic inorganic or organic acid. Preferred non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, nitric acid, and other acids known to those skilled in the art. This salt can also be prepared from organic acids such as amino acids, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and other acids known to those skilled in the art. pharmaceutically acceptable salts suitable for use in this disclosure can be prepared by conventional chemical methods using an active agent containing a basic or acidic group. Suitable addition salts can be found in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing Co., Easton, PA, 1985), the relevant disclosures of which are incorporated herein by reference in their entirety.

[0155] This disclosure also aims to provide a method for stabilizing an activator, comprising the steps of preparing an alkylated cyclodextrin composition containing the alkylated cyclodextrin described herein, and combining the alkylated cyclodextrin composition with an activator.

[0156] A method for stabilizing an activator can be carried out, wherein the composition comprising one or more activators and an alkylated cyclodextrin composition containing alkylated cyclodextrin exists as a dry solution, a wet solution, an inhalable composition, a parenteral composition, a solid solution, a solid mixture, granules, a gel, and other activator compositions known to those skilled in the art.

[0157] In some embodiments, the method for stabilizing an activator provides an activator assay in which a composition comprising one or more activators and alkylated cyclodextrin is maintained at a temperature of 80°C for 120 minutes, after which the activator content is 98% or more, 98.5% or more, 99% or more, or 99.5% or more.

[0158] In some embodiments, the stabilization method provides alkylated cyclodextrins comprising alkylated cyclodextrins having a phosphate level of less than 400 ppm, less than 300 ppm, less than 200 ppm, less than 125 ppm, less than 100 ppm, less than 75 ppm, or less than 50 ppm.

[0159] In some embodiments, the stabilization method provides an alkylated cyclodextrin composition comprising an alkylated cyclodextrin, wherein the alkylated cyclodextrin composition has an absorbance of 0.5 AU or less, as determined by UV / vis spectrophotometry at wavelengths of 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per 1 mL of solution in a cell with a path length of 1 cm. In some embodiments, the absorbance of 0.5 AU or less is due to drug degradation products.

[0160] Generally, alkylated cyclodextrins are present in sufficient quantities to stabilize the activator. Sufficient quantities can be in molar ratios (alkylated cyclodextrin:activator) of 0.1:1 to 10:1, 0.5:1 to 10:1, 0.8:1 to 10:1, or 1:1 to 5:1.

[0161] Cyclodextrins in a combination composition do not need to bind to other raw materials, such as active agents, present in the formulation containing them. However, if cyclodextrins do bind to other raw materials, such binding may be formed as a result of inclusion complexation, ion pairing, hydrogen bonding, and / or van der Waals interactions.

[0162] Anionic derivatized cyclodextrins can be complexed with or otherwise bound to acid-ionizable agents. As used herein, the term acid-ionizable agent is adopted to mean any compound that is ionized or is ionized in the presence of an acid. An acid-ionizable agent comprises at least one acid-ionizable functional group that ionizes when exposed to an acid or when placed in an acidic medium. Exemplary acid-ionizable functional groups include primary amines, secondary amines, tertiary amines, quaternary amines, aromatic amines, unsaturated amines, primary thiols, secondary thiols, sulfonium, hydroxyl, enol, and other functional groups known to those skilled in the art of chemistry.

[0163] The degree to which an acid-ionizable agent binds by inclusion complex formation is different from the degree to which an acid-ionizable agent binds by non-covalent ionic bonding. 1 H-NMR, 13 The phase solubility of acid-ionizable agents and anionic derivatized cyclodextrins can be determined spectroscopically by analyzing phase solubility data, for example, using methods such as 1C-NMR or circular dichroism. Those skilled in the art can determine whether the bonding between chemical species is primarily due to non-covalent ionic bonding or inclusion complex formation by estimating the amount of each type of bond formed in solution using these conventional methods. Under conditions where non-covalent ionic bonding is dominant over inclusion complex formation, the amount of inclusion complex formation measured by NMR or circular dichroism decreases, even though the phase solubility data indicates significant bonding between chemical species under those conditions. Furthermore, the intrinsic solubility of acid-ionizable agents determined from the phase solubility data is generally higher than predicted under those conditions.

[0164] As used herein, the term “non-covalent ionic bond” refers to a bond formed between an anionic species and a cationic species. Because the bond is non-covalent, these two species combine to form a salt or ion pair. Anionic derivatized cyclodextrins give the anionic species of the ion pair, and agents that are ionizable with acids give the cationic species of the ion pair. Because anionic derivatized cyclodextrins are polyvalent, alkylated cyclodextrins can form ion pairs with agents that are ionizable with one or more acids or otherwise cationic.

[0165] The liquid formulations of this disclosure can be converted into solid formulations for reconstitution. The reconstituteable solid compositions of this disclosure comprise an active agent, a derivatized cyclodextrin, and optionally at least one other pharmaceutically acceptable excipient. By reconstituting the reconstituteable composition with an aqueous liquid, a liquid formulation for storage can be formed. The composition may comprise a mixture of a solid derivatized cyclodextrin and a solid containing the active agent (the presence of the inclusion complex ranges from minimal to absent), and optionally at least one solid pharmaceutically acceptable excipient, wherein the majority of the active agent does not complex with the derivatized cyclodextrin before reconstitution. Alternatively, the composition may comprise a solid mixture of the derivatized cyclodextrin and the active agent, wherein the majority of the active agent is complexed with the derivatized cyclodextrin before reconstitution. Furthermore, the reconstituteable solid composition may comprise a derivatized cyclodextrin and an active agent, wherein substantially all or at least the majority of the active agent is complexed with the derivatized cyclodextrin.

[0166] The reconstituteable solid composition may be prepared according to any of the following processes: First, prepare the liquid formulation of the present disclosure, and then form a solid by lyophilization (freeze-drying), spray drying, spray lyophilization, poor solvent precipitation, sterile spray drying, various processes utilizing supercritical or near-supercritical fluids, or other methods known to those skilled in the art for producing solids for reconstitution.

[0167] The liquid medium contained in the formulations of the present disclosure may include an aqueous liquid carrier (such as water), a hydroalcohol, an aqueous organic solvent, a non-aqueous liquid carrier, and combinations thereof.

[0168] The formulations of the present disclosure may include one or more pharmaceutical excipients, such as conventional preservatives, defoaming agents, antioxidants, buffers, acidifying agents, alkalizing agents, bulking agents, coloring agents, complexing agents, cryoprotective substances, electrolytes, glucose, emulsifiers, oils, plasticizers, solubilizing agents, stabilizers, osmotic pressure regulators, fragrances, sweeteners, adsorbents, anti-adhesive agents, binders, diluents, direct compression excipients, disintegrants, flow promoters, lubricants, opaquants, abrasives, complexing agents, aromatics, and other excipients known to those skilled in the art for use in formulations, and combinations thereof.

[0169] As used herein, the term "adsorbent" is intended to mean an agent capable of retaining other molecules on its surface by physical or chemical (chemisorption) means. Examples of such compounds include, but are not limited to, powdered activated carbon and other materials known to those skilled in the art.

[0170] As used herein, the term "alkalizing agent" is intended to mean a compound used to provide an alkaline medium for product stability. Examples of such compounds include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organic amine bases, basic amino acids, and trolamine, and other compounds known to those skilled in the art.

[0171] As used herein, the term “acidifying agent” is intended to mean a compound used to provide an acidic medium for product stability. Examples of such compounds include, but are not limited to, acetic acid, acidic amino acids, citric acid, fumaric acid and other α-hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid, as well as other compounds known to those skilled in the art.

[0172] As used herein, the term “anti-sticking agent” is intended to mean an agent that prevents solid dosage formulation components from adhering to punches and dies in a tablet press during manufacturing. Examples of such compounds include, but are not limited to, magnesium stearate, talc, calcium stearate, glyceryl behenate, polyethylene glycol, hydrogenated vegetable oil, mineral oil, stearic acid, and other materials known to those skilled in the art.

[0173] As used herein, the term “binder” is intended to mean a substance used to cause adhesion between powder particles in a solid dosage formulation. Examples of such compounds include, but are not limited to, gum arabic, alginate, sodium carboxymethylcellulose, poly(vinylpyrrolidone), compressible sugars, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone, and pregelatinized starch, as well as other materials known to those skilled in the art.

[0174] If necessary, binders may be included in the dosage form. Examples of binders include gum arabic, tragacanth, gelatin, starch, cellulose materials such as methylcellulose and sodium carboxymethylcellulose, alginic acid and its salts, polyethylene glycol, guar gum, polysaccharides, bentonite, sugars, invert sugar, poloxamer (Pluronic® F68, Pluronic® F127), collagen, albumin, gelatin, cellulosinic materials in non-aqueous solvents, combinations thereof, and other binders known to those skilled in the art. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymers, polyethylene esters, polyethylene sorbitan esters, polyethylene oxides, combinations thereof, and other materials known to those skilled in the art.

[0175] The conventional preservatives used herein are compounds used to at least reduce the rate at which bioburden increases, but which maintain bioburden at a constant level or reduce bioburden after contamination. Examples of such compounds include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercury nitrate, phenylmercury acetate, thimerosal, metacresol, myristyl-γ-picolinium chloride, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, and methylparaben, ethylparaben, propylparaben, or butylparaben, as well as other compounds known to those skilled in the art. It is understood that some preservatives may interact with alkylated cyclodextrins to reduce the effectiveness of the preservative. Nevertheless, by selecting the preservative and adjusting the concentrations of the preservative and alkylated cyclodextrin, well-preserved formulations can be found.

[0176] As used herein, the terms “diluent” or “filler” are intended to mean an inert substance used as a filler in a liquid or solid formulation to produce desired bulk properties, flow properties, and compressibility characteristics. Examples of such compounds include, but are not limited to, liquid media (e.g., water, alcohol, solvents), calcium hydrogen phosphate, kaolin, lactose, glucose, magnesium carbonate, sucrose, mannitol, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, and other materials known to those skilled in the art.

[0177] As used herein, the term “direct compression excipient” is intended to mean a compound used in a compression solid formulation. Examples of such compounds include, but are not limited to, calcium hydrogen phosphate and other materials known to those skilled in the art.

[0178] As used herein, the term “antioxidant” is intended to mean an agent used to inhibit oxidation and thus prevent the deterioration of a formulation by the oxidation process. Examples of such compounds include, but are not limited to, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, EDTA, pentetate, and sodium metabisulfite, as well as other compounds known to those skilled in the art.

[0179] As used herein, the term “buffer” is intended to mean a compound used to resist changes in pH during dilution or the addition of an acid or alkali. Examples of such compounds include, but are not limited to, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, sodium dihydrogen phosphate, sodium hydrogen phosphate, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, sodium dihydrogen acetate, sodium bicarbonate, Tris, sodium tartrate, and anhydrous sodium citrate and sodium citrate dihydrate, and other compounds known to those skilled in the art.

[0180] Complexation promoters may be added to the formulations of this disclosure. If such agents are present, the cyclodextrin / active agent ratio may be varied. The complexation promoter is one or more compounds that promote the complexation of the active agent with cyclodextrin. Suitable complexation promoters include one or more pharmacologically inert water-soluble polymers, hydroxy acids, and other organic compounds that are typically used in storage solutions to promote the complexation of a particular agent with cyclodextrin.

[0181] To improve the performance of formulations containing CD-based preservatives, hydrophilic polymers can be used as complexing promoters, solubility enhancers, and / or water activity reducers. Loftsson has disclosed several polymers suitable for use in combination with cyclodextrins (non-derivativeized or derivatized) to improve the performance and / or properties of said cyclodextrins. Suitable polymers are found in Pharmazie 56:746 (2001); Int. J. Pharm. 212:29 (2001); Cyclodextrin: From Basic Research to Market, 10th Int'l Cyclodextrin Symposium, Ann Arbor, MI, US, May 21-24, p. 10-15 (2000); PCT International Publication No. WO99 / 42111; Pharmazie 53:733 (1998); Pharm. Technol. Eur. 9:26 (1997); J. Pharm. Sci. 85:1017 (1996); European Patent Application No. 0579435; Proc. of the 9th Int'l Symposium on Cyclodextrins, Santiago de Comostela, ES, May 31-June 3, 1998, pp. 261-264 (1999); STP Pharma Sciences 9:237 (1999); Amer. Chem. Soc. Symposium Series 737 (Polysaccharide Applications):24-45 (1999); Pharma. Res. 15:1696 (1998); Drug Dev. Ind. Pharm. 24:365 (1998); Int. J. Pharm. 163:115 (1998); Book of Abstracts, 216th Amer. Chem. Soc. Nat'l Meeting, Boston, Aug. 23-27 CELL-016 (1998); J. Controlled Release 44:95 (1997); Pharm. Res.Ophthalmol. Vis. Sci. 37:1199 (1996); Proc. of the 23rd Int'l Symposium on Controlled Release of Bioactive Materials 453-454 (1996); Drug Dev. Ind. Pharm. 22:401 (1996); Proc. of the 8th Int'l Symposium on Cyclodextrins, Budapest, HU, Mar. 31-Apr. 2, 1996, pp. 373-376 (1996); Pharma. Sci. 2:277 (1996); Eur. J. Pharm. Sci. 4S:S144 (1996); 3rd Eur. Congress of Pharma. Sci. Edinburgh, Scotland, UK September 15-17, 1996; Pharmazie 51:39 (1996); Disclosures are made in Eur. J. Pharm. Sci. 4S:S143 (1996); U.S. Patents No. 5,472,954 and 5,324,718; Int. J. Pharm. 126:73 (1995); Abstracts of Papers of the Amer. Chem. Soc. 209:33-CELL (1995); Eur. J. Pharm. Sci. 2:297 (1994); Pharm. Res. 11:S225 (1994); Int. J. Pharm. 104:181 (1994); and Int. J. Pharm. 110:169 (1994), all of which are incorporated herein by reference.

[0182] Other suitable polymers are well-known excipients commonly used in the field of pharmaceutical formulations, as seen in: Remington's Pharmaceutical Sciences, 18th ed., pp. 291-294, AR Gennaro (editor), Mack Publishing Co., Easton, PA (1990); A. Martin et al., Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3d ed., pp. 592-638 (Lea & Febinger, Philadelphia, PA (1983); AT Florence et al., Physicochemical Principles of Pharmacy, 2d ed., pp. 281-334, MacMillan Press, London, UK). For example, these disclosures are included in (1988), and the whole of these disclosures is incorporated herein by reference. Further suitable polymers include water-soluble natural polymers, water-soluble semi-synthetic polymers (such as water-soluble derivatives of cellulose), and water-soluble synthetic polymers. Natural polymers include polysaccharides such as inulin, pectin, algin derivatives (e.g., sodium alginate), and agar, as well as polypeptides such as casein and gelatin. Semi-synthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose, hydroxypropyl methylcellulose, and its mixed ethers such as hydroxyethyl-ethylcellulose and hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose phthalate, and carboxymethylcellulose and its salts, in particular sodium carboxymethylcellulose. Synthetic polymers include polyoxyethylene derivatives (polyethylene glycol), polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone, and polystyrene sulfonic acid), and various copolymers of acrylic acid (e.g., carbomers).Other natural, semi-synthetic, and synthetic polymers not named herein that meet the criteria of water solubility, pharmaceutically acceptable, and pharmaceutically inert are also considered to be within the scope of this disclosure.

[0183] As used herein, "aroma" refers to a relatively volatile substance or combination of substances that produces a detectable scent, odor, or fragrance. Examples of aromas include those generally accepted as safe by the U.S. Food and Drug Administration.

[0184] As used herein, the term “flow enhancer” is intended to mean an agent used in a solid-dosage formulation to improve the flowability of a solid mass. Examples of such compounds include, but are not limited to, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, colloidal silicon, tricalcium phosphate, silicon hydrogel, and other materials known to those skilled in the art.

[0185] As used herein, the term “lubricant” is intended to mean a substance used in a solid dosage formulation to reduce friction during compression. Examples of such compounds include, but are not limited to, calcium stearate, magnesium stearate, polyethylene glycol, talc, mineral oil, stearic acid, zinc stearate, and other materials known to those skilled in the art.

[0186] As used herein, the term “opacifier” is intended to mean a compound used to make a coating opaque. Opacifiers can be used alone or in combination with colorants. Examples of such compounds include, but are not limited to, titanium dioxide, talc, and other materials known to those skilled in the art.

[0187] As used herein, the term “abrasive” is intended to mean a compound used to impart an attractive gloss to a solid formulation. Examples of such compounds include, but are not limited to, carnauba wax, white wax, and other materials known to those skilled in the art.

[0188] As used herein, the term “disintegrant” is intended to mean a compound used in a solid dosage form to facilitate the splitting of a solid mass into smaller particles that disperse or dissolve more easily. Examples of disintegrants include, but are not limited to, starches such as corn starch, potato starch, its pregelatinized and modified starches, sweeteners, clay, bentonite, crystalline cellulose (e.g., Avicel®), carboxymethylcellulose calcium, croscarmellose sodium, alginic acid, sodium alginate, cellulose polacrilin potassium (e.g., Amberlite®), alginates, sodium starch glycolate, gum, agar, guar, locust bean, karaya, pectin, tragacanth, crospovidone, and other materials known to those skilled in the art.

[0189] As used herein, the term “stabilizer” is intended to mean a compound used to stabilize a therapeutic agent against physical, chemical, or biochemical processes that may reduce the therapeutic agent’s therapeutic activity. Suitable stabilizers include, but are not limited to, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophanate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerin, polyethylene glycol, sodium caprylate, and sodium saccharin, as well as other stabilizers known to those skilled in the art.

[0190] As used herein, the term "osmotic pressure regulator" is intended to mean one or more compounds that can be used to adjust the osmotic pressure of a liquid formulation. Suitable osmotic pressure regulators include glycerin, lactose, mannitol, glucose, sodium chloride, sodium sulfate, sorbitol, trehalose, and other osmotic pressure regulators known to those skilled in the art. In some embodiments, the osmotic pressure of the liquid formulation is substantially the same as the osmotic pressure of blood or plasma.

[0191] As used herein, the term "antifoaming agent" is intended to mean one or more compounds that prevent or reduce the amount of foaming formed on the surface of a liquid formulation. Suitable antifoaming agents include dimethicone, simethicone, octoxynol, and other antifoaming agents known to those skilled in the art.

[0192] As used herein, the term "bulking agent" is intended to mean a compound that is used to add bulk to a solid product and / or assist in controlling the properties of the formulation during lyophilization. Such compounds include, but are not limited to, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethyl sulfoxide, glycerin, albumin, calcium lactobionate, and other compounds known to those skilled in the art.

[0193] As used herein, the term "cryoprotectant" is intended to mean a compound that is used to protect an active therapeutic agent from physical or chemical degradation during lyophilization. Such compounds include, but are not limited to, dimethyl sulfoxide, glycerin, trehalose, propylene glycol, polyethylene glycol, and other compounds known to those skilled in the art.

[0194] As used herein, the terms “emulsifier” or “emulsifying agent” are intended to mean a compound added to one or more phase components of an emulsion to stabilize droplets of the inner phase within the outer phase. Examples of such compounds include, but are not limited to, lecithin, polyoxyethylene-polyoxypropylene ether, polyoxyethylene-sorbitan monolaurate, polysorbate, sorbitan ester, stearyl alcohol, tyroxapol, tragacanth, xanthan gum, acacia gum, agar, alginic acid, sodium alginate, bentonite, carbomer, sodium carboxymethylcellulose, cholesterol, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, octoxynol, oleyl alcohol, polyvinyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, and other compounds known to those skilled in the art.

[0195] A solubility enhancer may be added to the formulations of this disclosure. The solubility enhancer is one or more compounds that improve the solubility of an active agent when it is in a liquid formulation. When such an agent is present, the cyclodextrin / active agent ratio can be changed. Suitable solubility enhancers include one or more organic solvents, detergents, soaps, surfactants, and other organic compounds that are typically used in parenteral solutions to improve the solubility of special agents.

[0196] Suitable organic solvents include, for example, ethanol, glycerin, polyethylene glycol, propylene glycol, poloxamer, and other organic solvents known to those skilled in the art.

[0197] Preparations comprising alkylated cyclodextrins of this disclosure may include oils (e.g., fixed oils, peanut oil, sesame oil, cottonseed oil, corn oil, olive oil, etc.), fatty acids (e.g., oleic acid, stearic acid, isostearic acid, etc.), fatty acid esters (e.g., ethyl oleate, isopropyl myristate, etc.), fatty acid glycers, acetylated fatty acid glycers, and combinations thereof. Preparations comprising alkylated cyclodextrins of this disclosure may also include alcohols (e.g., ethanol, isopropanol, hexadecyl alcohol, glycerin, propylene glycol, etc.), glycerin ketals (e.g., 2,2-dimethyl-1,3-dioxolane-4-methanol, etc.), ethers (e.g., poly(ethylene glycol) 450, etc.), petroleum hydrocarbons (e.g., mineral oil, petrolatum, etc.), water, surfactants, suspending agents, emulsifiers, and combinations thereof.

[0198] It should be understood that compounds used in the field of pharmaceutical formulations generally serve a variety of functions or purposes. Therefore, if a compound named herein is mentioned only once or used to define two or more terms herein, its purpose or function should not be construed as being limited solely to the purpose or function named herein.

[0199] The preparations comprising alkylated cyclodextrins of this disclosure may also include biological salts, sodium chloride, potassium chloride, and other electrolytes.

[0200] Since some active agents are subjected to oxidative degradation, the liquid formulations of this disclosure may be substantially oxygen-free. For example, the headspace of a container containing a liquid formulation may be made oxygen-free, substantially oxygen-free, or oxygen-depleted by purging the headspace with an inert gas (e.g., nitrogen, argon, carbon dioxide, etc.) or by blowing an inert gas into the liquid formulation. For long-term storage, liquid formulations containing active agents subjected to oxidative degradation can be stored in an oxygen-free or oxygen-depleted environment. Removing oxygen from the formulation improves its preservation against aerobic microorganisms, while adding oxygen to the formulation improves its preservation against anaerobic microorganisms.

[0201] The term "pharmaceutically acceptable" is used herein to mean a compound, raw material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues, within the bounds of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, and that is in proportion to a reasonable profit-benefit ratio.

[0202] As used herein, the terms “patient” or “subject” are adopted to mean warm-blooded animals such as mammals, for example, cats, dogs, mice, guinea pigs, horses, cattle, cows, sheep, non-humans, and humans.

[0203] The formulations of this disclosure include an active agent present in an effective amount. The term "effective amount" means an amount or quantity of the active agent sufficient to elicit a required or desired response, in other words, a sufficient amount to elicit a substantial biological response when administered to a subject.

[0204] The compositions of this disclosure may be present in formulations for dosage forms such as reconstituteable solids, tablets, capsules, pills, lozenges, patches, osmotic devices, sticks, suppositories, implantable tablets, gums, effervescent compositions, injectable solutions, eye drops or nasal drops, or inhalable powders or solutions.

[0205] The disclosure also provides methods for preparing liquid formulations comprising one or more active agents and alkylated cyclodextrins, including alkylated cyclodextrin. A first method comprises the steps of: forming a first aqueous solution comprising an alkylated cyclodextrin composition; forming a second solution or suspension comprising one or more active agents; and mixing the first solution and the second solution to form a liquid formulation. A similar second method comprises the step of directly adding one or more active agents to the first solution without forming a second solution. A third method comprises the step of directly adding alkylated cyclodextrins to a solution / suspension containing one or more active agents. A fourth method comprises the step of adding a solution containing one or more active agents to a powdered or particulate alkylated cyclodextrin composition. A fifth method comprises the steps of directly adding one or more active agents to a powdered or particulate alkylated cyclodextrin composition and adding the resulting mixture to a second solution. A sixth method comprises the steps of producing a liquid formulation by any of the above methods, and then isolating a solid raw material by freeze-drying, spray-drying, sterile spray-drying, spray freeze-drying, poor solvent precipitation, a process utilizing a supercritical or near-supercritical fluid, or another method known to those skilled in the art for producing a powder for reconstitution.

[0206] Specific embodiments of a method for preparing a liquid formulation include: (1) an embodiment comprising a step of sterile filtering the formulation using a filter medium having a pore size of 0.1 μm or larger; (2) an embodiment comprising sterilizing the liquid formulation by irradiation or autoclaving; (3) an embodiment comprising a step of isolating a solid from a solution; (4) an embodiment comprising purging the solution with nitrogen, argon, or other inert pharmaceutically acceptable gas so that a substantial portion of the oxygen dissolved in and / or surface-contacting the solution is removed.

[0207] This disclosure also provides a reconstituted solid pharmaceutical composition comprising one or more active agents, an alkylated cyclodextrin composition, and optionally at least one other pharmaceutical excipient. When this composition is reconstituted with an aqueous liquid to form a storage liquid formulation, it can be administered to a subject by injection, intravenous infusion, topical administration, inhalation, or orally.

[0208] Some embodiments of a reconstituteable solid pharmaceutical composition include: (1) a mixture of an alkylated cyclodextrin composition and a solid containing one or more active agents, and optionally at least one solid pharmaceutical excipient, wherein the majority of the active agents do not complex with the alkylated cyclodextrin before reconstitution; and / or (2) a mixture of an alkylated cyclodextrin composition and one or more active agents, wherein the majority of the one or more active agents complex with the alkylated cyclodextrin before reconstitution.

[0209] The compositions of this disclosure can be used in pharmaceutical dosage forms, pharmaceutical compositions, or combinations of other such raw materials. These fractionated alkylated cyclodextrin compositions are also useful as analytical reagents, food and cosmetic auxiliaries and / or additives, and environmental decontamination agents, but are not limited to these.

[0210] Conclusion While various aspects of this disclosure have been described above, it should be understood that these are presented only as examples and not as limitations. It will be apparent to those skilled in the art that various variations can be made in form and detail without departing from the spirit and scope of this disclosure. Therefore, the breadth and scope of this disclosure should not be limited by any of the exemplary aspects described above, but should be defined solely by the following claims and their equivalents.

[0211] All aspects, embodiments, and options described herein can be combined in any and all variations.

[0212] All documents cited herein, including journal articles or abstracts, published or corresponding U.S. or foreign patent applications, granted or foreign patents, or any other documents, are fully incorporated herein by reference, each containing all data, tables, drawings, and text.

Claims

1. A method for preparing an alkylated cyclodextrin composition, comprising the following steps: (a) A step of mixing the starting cyclodextrin with an alkylating agent to form a reaction environment containing alkylated cyclodextrin; (b) A step of performing one or more first separations to form a first solution containing alkylated cyclodextrin, wherein the one or more separations include dialysis filtration through an ultrafiltration membrane; (c) A step of treating the first solution with activated carbon to produce a second alkylated cyclodextrin solution; and (d) A step of performing a second one or more separations to form a third alkylated cyclodextrin solution, wherein the one or more separations include nanofiltration through a nanofiltration membrane. Here, the nanofiltration membrane in step (d) has an MWCO of 500 Da or less.

2. The method according to claim 1, wherein a solvent is added and the reaction environment formed in step (a) is diluted before the first one or more separations.

3. The method according to claim 2, wherein the solvent is water.

4. The concentration of alkylated cyclodextrin in step (b) is less than 10% (w / w) before the first one or more separations; or, The concentration of alkylated cyclodextrin in step (b) is less than 8% (w / w) before the first one or more separations; or, The concentration of alkylated cyclodextrin in step (b) is less than 6% (w / w) before the first one or more separations; or, The concentration of alkylated cyclodextrin in step (b) is 3% (w / w) to 8% (w / w) before the first one or more separations; or, The concentration of alkylated cyclodextrin in step (b) is 4% (w / w) to 6% (w / w) before the first one or more separations. The method according to any one of claims 1 to 3.

5. The method according to any one of claims 1 to 4, wherein the ultrafiltration membrane in step (b) has an MWCO of 500 Da.

6. The activated carbon in process (c) An initial carbon washing process comprising adding a portion of the first solution containing alkylated cyclodextrin from step (b) to the carbon, immersing the carbon in the first solution, and eluting and discarding the solution. The method according to any one of claims 1 to 5, which is prepared by a method comprising the step of providing activated carbon to the method.

7. The method according to claim 6, wherein the activated carbon of step (c) is further subjected to a washing process comprising running water over the carbon and eluting the water after the initial carbon washing process.

8. Water is flowed over the carbon for at least 30 minutes; or, Water is flowed over the carbon for at least two hours. The method according to claim 7.

9. The method according to claim 7 or 8, wherein the eluted washing water has a residual conductivity of 10 μS / cm or less.

10. The method according to any one of claims 1 to 9, wherein the activated carbon does not contain phosphate.

11. The method according to any one of claims 1 to 10, wherein the activated carbon is steam-activated.

12. The method according to any one of claims 1 to 11, wherein the activated carbon is in the form of granules.

13. The concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced in step (d) is 3% (w / w) to 8% (w / w); or The concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced in step (d) is 4% (w / w) to 7% (w / w); or The concentration of alkylated cyclodextrin in the second alkylated cyclodextrin solution introduced in step (d) is 5% (w / w). The method according to any one of claims 1 to 12.

14. The nanofiltration membrane in step (d) has an MWCO of 400 Da; or, The nanofiltration membrane in step (d) has an MWCO of 300 Da; or, The nanofiltration membrane in step (d) has an MWCO of 200 Da; or, The nanofiltration membrane in step (d) has an MWCO of 150 Da; or, The nanofiltration membrane in step (d) has an MWCO of 150 to 500 Da; or, The nanofiltration membrane in step (d) has an MWCO of 300 to 500 Da. The method according to any one of claims 1 to 13.

15. The nanofiltration in step (d) is performed over a period of 30 minutes to 12 hours; or, The nanofiltration in step (d) is performed over a period of 1 to 3 hours; or, The nanofiltration in step (d) is performed over a period of 2 hours; or, The nanofiltration in step (d) is performed over a period of 3 hours. The method according to any one of claims 1 to 14.

16. The method according to any one of claims 1 to 15, wherein the concentration of alkylated cyclodextrin in the third alkylated cyclodextrin solution is 10% (w / w) to 25% (w / w).

17. The method according to any one of claims 1 to 16, further comprising the step of concentrating a third alkylated cyclodextrin solution over a period of 2 to 24 hours to form a fourth alkylated cyclodextrin solution.

18. The method according to any one of claims 1 to 17, further comprising the step of concentrating a third alkylated cyclodextrin solution over a period of 9 hours to form a fourth alkylated cyclodextrin solution.

19. The method according to claim 17 or 18, wherein the step of concentrating the third alkylated cyclodextrin solution is carried out by distillation.

20. The method according to any one of claims 17 to 19, wherein the concentration of the fourth alkylated cyclodextrin solution is 30% (w / w) to 70% (w / w).

21. The method according to any one of claims 17 to 20, wherein the concentration of alkylated cyclodextrin in the fourth alkylated cyclodextrin solution is 50% (w / w).

22. The method according to any one of claims 17 to 21, further comprising the step of removing the solvent from a fourth alkylated cyclodextrin solution to form a solid alkylated cyclodextrin.

23. The method according to claim 22, wherein the solvent is removed by distillation, freeze-drying, or spray-drying.

24. Solid alkylated cyclodextrin containing less than 500 ppm of phosphate; or, A phosphate containing less than 125 ppm of solid alkylated cyclodextrin, The method according to claim 22 or 23.

25. Solid alkylated cyclodextrin contains less than 0.05% (w / w) chloride; or Solid alkylated cyclodextrin contains less than 0.01% (w / w) of chloride; or Solid alkylated cyclodextrin containing less than 0.002% (w / w) of chloride, The method according to any one of claims 22 to 24.

26. The process includes a step of preparing a single batch of alkylated cyclodextrin having an initial mass of more than 275 kg; or, The process includes a step of preparing a single batch of alkylated cyclodextrin having an initial cyclodextrin mass of more than 300 kg; or, The process includes a step of preparing a single batch of alkylated cyclodextrin having an initial cyclodextrin mass of more than 350 kg, The method according to any one of claims 1 to 25.

27. Alkylated cyclodextrins have an average degree of substitution of 2 to 9; or, Alkylated cyclodextrins have an average degree of substitution of 4.5 to 7.5; or, Alkylated cyclodextrins have an average degree of substitution of 6 to 7.

5. The method according to any one of claims 1 to 26.

28. The method according to any one of claims 1 to 27, wherein the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of formula (II): where p is 4, 5, or 6, and R 1 is independently selected each time it appears from -OH or -O-(C 2 ~C 6 alkylene)-SO 3 - -T, and T is independently selected each time it appears from pharmaceutically acceptable cations, provided that at least one R 1 is -OH, and at least one R 1 is O-(C 2 ~C 6 alkylene)-SO 3 - -T.

29. R 1 However, each time it appears, -OH or -O-(C 4 Alkylene)-SO 3 - -T is selected independently of Na, and each time -T appears, Na + The method according to claim 28.

30. The method according to any one of claims 22 to 29, further comprising the step of combining a solid alkylated cyclodextrin with one or more excipients.

31. The method according to any one of claims 22 to 30, further comprising the step of combining a solid alkylated cyclodextrin with an activator.

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