Alkylated cyclodextrin composition and methods for producing and using the same

Abstract

The present disclosure also relates to low chloride alkylated cyclodextrin compositions, as well as methods for making the same. The methods of the present invention provide alkylated cyclodextrins with low chloride levels.

Description

[Technical Field]

[0001] This disclosure relates to compositions comprising low-chloride alkylated cyclodextrin compositions, and to methods for producing and using the same. [Background technology]

[0002] 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, cyclodextrin derivatization proceeds via reactions in which the -OH groups at the 2-, 3-, and / or 6-positions of the amylose ring of cyclodextrin are replaced by substituents. Substituents include neutral, anionic, 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 more than one type of functional group, such as sulfoalkyl ether-alkyl ether-cyclodextrins, are also known (see, for example, WO2005 / 042584 and US2009 / 0012042, each of which is incorporated herein by reference in whole). In particular, alkylated cyclodextrins having a 2-hydroxypropyl group and / or a sulfoalkyl ether group have been found to be used in pharmaceutical formulations.

[0004] The sulfobutyl ether derivative of β-cyclodextrin ("SBE-β-CD") is Captisol (登録商標)It is commercialized by CyDex Pharmaceuticals, Inc. The anionic sulfobutyl ether substituent improves the water solubility and safety of the β-cyclodextrin, and by reversibly forming a complex with the active agent, it can increase the solubility of the active agent and, in some cases, increase the stability of the active agent in aqueous solution. (Captisol) (登録商標) It has the chemical formula given by equation X: [ka] In the formula, 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 cyclodextrin (e.g., CAPTISOL) (登録商標) These are prepared using batch methods described in, for example, U.S. Patents No. 5,134,127, No. 5,376,645 and No. 6,153,746, which are each incorporated herein by reference in their entirety.

[0006] Sulfoalkyl ether cyclodextrins and other derivatized cyclodextrins are also included in the following patents and published patent applications, the full disclosure of which is incorporated herein by reference: US3,426,011, US3,453,257, US3,453,259, US3,459,731, US4,638,058, US4,727,06, US5,019,562, US5,173,481, US5,183,809, US5,241. ,059, US5,536,826, US5,594,125, US5,658,894, US5,710,268, US5,756,484, US5,760,015, US5,846,954, US6,407,079, US7,625,878, US7,629,331, US7,635,773, US2009 / 0012042, JP05001102, and WO01 / 40316, as well as 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. 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(CJEaston et al.eds.,Imperial College Press, London, UK, 1999), New Trends in Cyclodextrins and Derivatives (Dominique Duchene ed., Editions de Sante, Paris, FR, 1991), Comprehensive Supramolecular Chemistry 3 (Elsevier Science Inc.It can also be prepared according to the method described in (Tarrytown, NY).

[0007] Impurities present in alkylated cyclodextrin compositions can reduce the shelf life and efficacy of the activator composition. These impurities can be removed from alkylated cyclodextrin compositions by exposure to activated carbon (e.g., mixing with activated carbon). Treatment of cyclodextrin-containing aqueous solutions and suspensions with activated carbon is known; see, for example, U.S. Patents 4,738,923, 5,393,880, and 5,569,756. In addition, 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 entirety of which is incorporated herein by reference. However, there is a continuing need for alkylated cyclodextrin compositions of higher purity. [Overview of the Initiative]

[0008] The present invention provides a method for producing an alkylated cyclodextrin composition, comprising: (a) mixing cyclodextrin with an alkylating agent to form a reaction environment containing alkylated cyclodextrin; (b) performing one or more separations to form a partially purified solution containing alkylated cyclodextrin; (c) preparing activated carbon, which includes subjecting the activated carbon to a carbon washing process, wherein the carbon washing process includes adding a portion of the partially purified solution containing alkylated cyclodextrin to the activated carbon, immersing the activated carbon in the partially purified solution, and eluting and discarding the solution; and (d) treating the remaining partially purified solution with the activated carbon prepared in step (c) to produce a final purified alkylated cyclodextrin composition.

[0009] In some embodiments, one or more separation steps include ultrafiltration, dialysfiltration, centrifugation, extraction, solvent precipitation, or dialysis.

[0010] In some embodiments, the activated carbon of step (c) is first subjected to an initial washing process which includes adding water to the activated carbon and eluting the water, and the eluted washing water has a residual conductivity of 10 μS / cm or less. In some embodiments, the residual conductivity of the eluted washing water is 8 μS / cm or less. In some embodiments, the residual conductivity of the eluted washing water is 6 μS / cm or less.

[0011] In some embodiments, the initial carbon washing process is carried out for approximately 6 hours. In some embodiments, the initial carbon washing process is carried out for approximately 12 hours.

[0012] In some embodiments, the activated carbon of (c) is further subjected to a washing process which includes flowing water over the activated carbon after the initial carbon washing process. In some embodiments, the water is flowed over the activated carbon for at least 30 minutes. In some embodiments, the water is flowed over the activated carbon for at least 2 hours.

[0013] In some embodiments, the activated carbon of step (c) is subsequently subjected to a washing process which includes adding water to the activated carbon and eluting the water. In some embodiments, the eluted washing water from the subsequent washing process has a residual conductivity of 10 μS / cm or less. In some embodiments, the eluted washing water from the subsequent washing process has a residual conductivity of 8 μS / cm or less. In some embodiments, the eluted washing water from the subsequent washing process has a residual conductivity of 6 μS / cm or less.

[0014] In some embodiments, the activated carbon is phosphate-free. In some embodiments, the activated carbon is granular.

[0015] In some embodiments, the final purified alkylated cyclodextrin composition contains less than 500 ppm of phosphate. In some embodiments, the final purified alkylated cyclodextrin composition contains less than 125 ppm of phosphate.

[0016] In some embodiments, the final purified alkylated cyclodextrin composition contains less than 0.1% (w / w) of chloride. In some embodiments, the final purified alkylated cyclodextrin composition contains less than 0.05% (w / w) of chloride. In some embodiments, the final purified alkylated cyclodextrin composition contains less than 0.01% (w / w) of chloride. In some embodiments, the final purified alkylated cyclodextrin composition further contains less than 0.002% (w / w) of chloride.

[0017] In some embodiments, the final purified alkylated cyclodextrin composition has an average degree of substitution of 2 - 9. In some embodiments, the final purified alkylated cyclodextrin composition has an average degree of substitution of 4.5 - 7.5. In some embodiments, the final purified alkylated cyclodextrin composition has an average degree of substitution of 6 - 7.5.

[0018] In some embodiments, the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of formula (II):

Chemical formula

[0019] In some embodiments, the alkylated cyclodextrin is sulfoalkyl et al. In some embodiments, R1 is -OH or -O-(C4 alkylene)-SO3 - -T is independently selected in each occurrence, and -T is Na in each occurrence. + That is the case.

[0020] In some embodiments, a method for producing an alkylated cyclodextrin composition (i) A first washing process comprising: (a) mixing cyclodextrin with an alkylating agent to form a reaction environment containing alkylated cyclodextrin; (b) performing one or more separations to form a partially purified solution containing alkylated cyclodextrin; (c) preparing activated carbon, wherein the first washing process comprises: (i) adding water to the activated carbon to eluate the water, and the eluted washing water having a residual conductivity of 10 μS / cm or less; (ii) further subjecting the activated carbon to a washing process, wherein the process comprises flowing water over the activated carbon after the first carbon washing process; and subjecting the activated carbon to a carbon washing process The present invention discloses a method comprising the following steps: (iii) adding a portion of a partially purified solution containing alkylated cyclodextrin to the activated carbon, immersing the activated carbon in the partially purified solution, and eluting and discarding the solution; (iv) subsequently subjecting the activated carbon from step (iii) to a washing process, wherein the process includes adding water to the activated carbon and eluting the water; and (d) treating the remaining partially purified solution with the activated carbon prepared in step (c) to produce a final purified alkylated cyclodextrin composition.

[0021] In some embodiments, the alkylated cyclodextrin composition is combined with one or more excipients.

[0022] In some embodiments, the alkylated cyclodextrin composition is combined with an activator.

[0023] This disclosure also covers the products prepared by the processes described herein.

[0024] Further embodiments, features, and advantages of the present disclosure, as well as compositions, structures, and operations of various embodiments of the present disclosure, will be described in detail below with reference to the accompanying figures.

[0025] The accompanying figures incorporated herein and forming part of this specification illustrate one or more embodiments of the invention and, together with the detailed description, further illustrate the principles of the invention and enable those skilled in the art to practice and use the invention. The following figures are given for illustrative purposes only and are therefore not intended to limit the scope of the invention. [Brief explanation of the drawing]

[0026] [Figure 1] Figure 1 provides a graphical representation of the chloride content for purified batches of SBE6.6-β-CD prepared using the carbon treatment method disclosed herein. [Modes for carrying out the invention]

[0027] This disclosure includes various aspects and combinations and subcombinations of embodiments disclosed herein. Furthermore, where specific features, structures, or characteristics are described in relation to an embodiment, it will be understood that such features, structures, or characteristics extend to other embodiments, whether expressly stated or not, within the knowledge of those skilled in the art. These and other aspects of this disclosure will become apparent with reference to the following detailed description, examples, claims, and accompanying drawings.

[0028] As used herein, percentages refer to "weight percent" and / or "w / w" (weight / weight concentration) unless otherwise indicated.

[0029] References to spatial descriptions made in this specification (e.g., "above", "below", "up") Terms such as “bottom,” “top,” and “bottom” are for illustrative purposes only and should be construed as not limiting to any process, apparatus, composition, and product of any method of this disclosure that may be spatially arranged in any orientation or manner.

[0030] Alkylated cyclodextrin An alkylated cyclodextrin composition is a composition comprising alkylated cyclodextrin having a degree of substitution or average degree of substitution (ADS) for a particular substituent. The alkylated cyclodextrin composition comprises a distribution of alkylated cyclodextrin species having the same specific substituents but different individual degrees of substitution for each specific substituent. As used herein, an alkylated cyclodextrin composition is a substantially pharmaceutically inert composition (i.e., a composition that does not contain 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.

[0031] Alkylated cyclodextrins can be water-soluble alkylated cyclodextrins, which are any alkylated cyclodextrins that exhibit improved water solubility than their corresponding non-derivative parenteral cyclodextrins and have a molecular structure based on α-, β-, or γ-cyclodextrins. In some embodiments, the derivatized cyclodextrins prepared by the processes of the present disclosure have a water solubility of 100 mg / mL or more, or less than 100 mg / mL.

[0032] Cyclodextrins can be derivatized by neutral, anionic, or cationic substituents at the C2, C3, or C6 position of the individual saccharides forming the cyclodextrin ring. Suitable water-soluble alkylated cyclodextrins are described herein. Alkylated cyclodextrins may also be alkylated cyclodextrins having lower water solubility than water-insoluble alkylated cyclodextrins or their corresponding non-derivative parent cyclodextrins.

[0033] As used herein, “substituent precursor” or “alkylating agent” refers to a compound, reagent, site, or substance that can react with the -OH groups present in cyclodextrin. In some embodiments, derivatized cyclodextrins include 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.). Alkylated cyclodextrins are cyclodextrins in which one or more -OH groups are replaced by -OR groups, where R contains an alkyl site. For example, the -OR group may be an alkyl ether or a sulfoalkyl ether.

[0034] In some embodiments, alkylated cyclodextrins, such as mixed ether alkylated cyclodextrins, include, for example, those listed in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3]

[0035] After reaction, purification, and / or isolation, the alkylated cyclodextrin composition of the present disclosure may contain a small amount (e.g., 1% or less, 0.5% or less, 0.1% or less, 0.05% or less, 0.001% or less, 0.0005% or less, or 0.0001% or less by weight) of cyclodextrin starting material (e.g., non-derivative cyclodextrin).

[0036] Alkylated cyclodextrins may exist in high-purity forms. See 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. In some embodiments, alkylated cyclodextrins are used in Captisol (登録商標) High-purity SAE-C with reduced amounts of drug decomposition agent compared to known commercial lots. This is composition D. (登録商標) It has a reduced amount of phosphate compared to known commercial lots, or contains no phosphate at all. The above composition is also Captisol (登録商標) The SAE-CD composition also optionally contains a lower amount of color-forming agent compared to known commercial lots. (登録商標) It may also have reduced amounts of 1,4-butanesultone and 4-hydroxy-butane-1-sulfonic acid compared to known commercial lots.

[0037] The alkylated cyclodextrin compositions of this disclosure offer unexpected advantages over other structurally related alkylated cyclodextrin compositions. “Structurally related” means, for example, that the substituents of the alkylated cyclodextrin in the composition are essentially the same as those of the substituents of other alkylated cyclodextrins being compared. Exemplary advantages may include improved purity, reduced pyrogen content, reduced drug degradation component content, reduced colorant content, reduced unreacted substituent precursor content, and / or reduced unreacted cyclodextrin starting material content. Exemplary advantages also include reduced chloride content.

[0038] A water-soluble alkylated cyclodextrin composition may contain a sulfoalkyl ether cyclodextrin (SAE-CD) compound of formula I, or a mixture of such compounds: [ka] In the formula, n is 4, 5, or 6; R1, R2, R3, R4, R5, R6, R7, R8, and R9 are independently -H, a straight-chain or branched-chain C1-C8-(alkylene)-SO3 - A C1-C6 group, or a linear or branched C1-C6 group that is optionally 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.

[0039] In some embodiments, the SAE-CD composition comprises a water-soluble alkylated cyclodextrin of formula II: [ka] In the formula, p is 4, 5, or 6; R1 is independently selected from -OH or -SAE-T in each occurrence; -SAE- is -O-(C2-C6 alkylene)-SO3 -It is a group, and at least one SAE independently forms -O-(C2-C6 alkylene)-SO3 - group, -O-(CH2) g SO3 - It is a group, and g is 2-6, or 2-4 (e.g., -OCH2CH2CH2SO3) - or -OCH2CH2CH2CH2SO3 - ) and -T is independently selected in each occurrence from the group consisting of pharmaceutically acceptable cations, such a group may include, for example, H + Alkali metals (for example, Li + na + , K + ), alkaline earth metals (e.g., Ca +2 Mg +2 ), and ammonium ions and amine cations, for example, (C1-C6)-alkylamines, piperidines, pyrazines, (C1-C6)-alkanolamines, ethylenediamines and (C4-C8)-cycloalkanolamine cations, in particular; provided that at least one R1 is a hydroxyl group and at least one R1 is -SAE-T.

[0040] When at least one R1 of a derivatized cyclodextrin molecule is -SAE-T, the degree of substitution is understood to be at least 1(1) with respect to the -SAE-T site. When the term -SAE- is used to represent a sulfoalkyl-(alkylsulfonic acid)-ether site, it is understood that the -SAE- site contains a cation (-T) unless otherwise specified. Thus, the terms "SAE" and "-SAE-T" may be used interchangeably herein as needed.

[0041] Since SAE-CD is a polyanionic cyclodextrin, it can be provided 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 altered by changing the identity of the counterions present. For example, a first salt form of an SAE-CD composition may have a higher osmotic potential or a higher water activity reduction potential than a different second salt form of the same SAE-CD.

[0042] In some embodiments, the sulfoalkyl ether cyclodextrin is, for example, H + Alkali metals (for example, Li + na + , K + ), alkaline earth metals (e.g., Ca +2 Mg +2 ), ammonium ions and amine cations, such as (C1-C6)-alkylamines, piperidines, pyrazines, (C1-C6)-alkanolamines, ethylenediamines and (C4-C8)-cycloalkanolamines, and These combinations are complexed with one or more pharmaceutically acceptable cations selected from these combinations.

[0043] Further exemplary sulfoalkyl ether (SAE)-CD derivatives include: [Table 2] In the formula, x represents the average degree of substitution. In some embodiments, alkylated cyclodextrins are formed as salts.

[0044] 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.

[0045] In some embodiments, the alkylated cyclodextrin composition of the present disclosure is a sulfoalkyl ether-β-cyclodextrin composition having 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 ADS per alkylated cyclodextrin, wherein the remaining substituent is -H.

[0046] In some embodiments, alkylated cyclodextrin is a compound of formula III: [ka] In the formula, n is 4, 5, or 6, and R1, R2, R3, R4, R5, R6, R7, R8, and R9 are -H, a straight-chain or branched-chain C1-C8-(alkylene)-SO3 - The group is independently selected from the C1-C6 groups of a linear or branched chain that are optionally substituted.

[0047] A water-soluble alkylated cyclodextrin composition may contain an alkyl ether (AE)-cyclodextrin compound of formula IV, or a mixture of such compounds: [ka] In the formula, m is 4, 5, or 6; R is independently selected in each occurrence from the group consisting of -OH and AE; AE is -O-(C1-C6 alkyl); however, at least one R is -OH; and at least one AE is present.

[0048] Further exemplary AE-CD derivatives include: [Table 3] In the formula, 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.

[0049] The water-soluble alkylated cyclodextrin composition may contain a HAE-cyclodextrin compound of formula V, or a mixture of such compounds: [ka] In the formula, "v" is 4, 5, or 6; "Q" is independently selected in each occurrence from the group consisting of -OH and -HAE; and HAE is HO(C1-C6 alkyl)-O-, provided that at least one -HAE moiety is present.

[0050] Further exemplary hydroxyalkyl ether (HAE)-CD derivatives include: [Table 4] In the formula, 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.

[0051] The water-soluble alkylated cyclodextrin composition may contain the SAE-AE-CD compound of formula VI, or a mixture of the compound: [ka] In the formula: "v" is 4, 5, or 6; "A" is independently selected in each occurrence from the group consisting of -OH, -SAET, and -AE; x is the degree of substitution for the SAET site, ranging from 1 to 3v+5; y is the degree of substitution for the AE site, ranging from 1 to 3v+5; and -SAE is -O-(C2-C6 alkylene)-SO3 - T is independently a cation in each occurrence; AE is -O(C1-C3 alkyl); provided that at least one -SAET site and at least one -AE site are present; In killed cyclodextrin, the sum of the total number of x, y, and -OH groups is 3v + 6.

[0052] Specific embodiments of the derivatives of this disclosure include: 1) the alkylene moiety of the SAE has the same number of carbon atoms as the alkyl moiety of the AE; 2) the alkylene moiety of the SAE has a different number of carbon atoms than the alkyl moiety of the AE; 3) the alkyl and alkylene moieties are independently selected from the group consisting of linear or branched moieties; 4) the alkyl and alkylene moieties are independently selected from the group consisting of saturated or unsaturated moieties; 5) the ADS for the SAE group is greater than or approximately equal to the ADS for the AE group; or 6) the ADS for the SAE group is less than the ADS for the AE group.

[0053] The water-soluble alkylated cyclodextrin composition may contain the SAE-HAE-CD compound of formula VII, or a mixture of the compound: [ka] In the formula: "v" is 4, 5, or 6; "X" is independently selected in each occurrence from the group consisting of -OH, SAET, and HAE; x is the degree of substitution for the SAET site, ranging from 1 to 3w+5; y is the degree of substitution for the HAE site, ranging from 1 to 3w+5; -SAE is -O-(C2-C6 alkylene)-SO3 - T is independently a cation in each occurrence; HAE is HO-(C1-C6 alkyl)-O-; provided that at least one -SAET site and at least one -HAE site are present; and the sum of the total number of x, y, and -OH groups in alkylated cyclodextrin is 3w+6.

[0054] Alkylated cyclodextrins may 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-derivativeated cyclodextrin, amino-derivativeated cyclodextrin, nitrile-derivativeated cyclodextrin, aldehyde-derivativeated cyclodextrin, carboxylate-derivativeated cyclodextrin, sulfate-derivativeated cyclodextrin, sulfonate-derivativeated cyclodextrin, mercapto-derivativeated cyclodextrin, alkylamino-derivativeated cyclodextrin, or succinyl-derivativeated cyclodextrin.

[0055] Within a given alkylated cyclodextrin composition, the substituent(s) 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 in each appearance in the alkylated cyclodextrin composition. In such embodiments, the alkylene radical at the SAE or HAE moiety may be ethyl, propyl, butyl, pentyl, or hexyl in each appearance in the alkylated cyclodextrin composition.

[0056] Alkylated cyclodextrins can have different degrees of substitution depending on the functional groups contained in the base cyclodextrin used to form the derivatized cyclodextrin and / or its substitution pattern, the number of carbon atoms in those functional groups, their molecular weights, and the number of glucopyranose units. Furthermore, the derivatization of cyclodextrins by functional groups occurs under controlled conditions, though not precisely. For this reason, the degree of substitution is, in practice, a number representing the average number of functional groups per cyclodextrin (for example, SBE7-β-CD has an average of 7 substitutions per cyclodextrin). Therefore, it has an average degree of substitution of 7 ("ADS"). Also, the regiochemistry of hydroxyl group substitutions in cyclodextrins is variable with respect to the substitution of specific hydroxyl groups on the hexose ring. For this reason, different hydroxyl group substitutions are likely to occur during the production of derivatized cyclodextrins, and certain derivatized cyclodextrins possess a preferred but not exclusive or specific substitution pattern. Considering the above, the molecular weight of a particular derivatized cyclodextrin composition may vary from batch to batch.

[0057] In a single parent cyclodextrin molecule, there is a 3v+6 hydroxyl moiety available for derivatization. When v=4 (α-cyclodextrin), the degree of substitution "y" for that moiety can range from 1 to 18. When v=5 (β-cyclodextrin), the degree of substitution "y" for that moiety can range from 1 to 21. When v=6 (γ-cyclodextrin), the degree of substitution "y" for that moiety can range from 1 to 24. Generally, "y" is also in the range of 1 to 3v+g when 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.

[0058] The degree of substitution ("DS") for 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 individual alkylated cyclodextrin species. The average degree of substitution ("ADS") for a substituent is a measure of the total number of substitutions present per cyclodextrin molecule for the distribution of alkylated cyclodextrins within the range of alkylated cyclodextrin compositions of this disclosure. Thus, SAE4-CD has an ADS of 4 (per CD molecule).

[0059] Some embodiments 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 the same in each appearance; 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.

[0060] Alkylated cyclodextrin compositions may contain multiple individual alkylated cyclodextrin species with different degrees of substitution, and as a result, the average degree of substitution is calculated from the degrees of substitution of the individual species as described herein. More specifically, SAE-CD derivative compositions may contain multiple SAE-CD species, each having a specific degree of substitution with respect to the SAE substituent. As a result, the ADS for SAE in an SAE-CD derivative composition represents the average IDS value of the group of individual molecules in the composition. For example, SAE5.2 -CD composition, multiple SAE x -Includes the distribution of CD molecules, where "x" (DS for SAE group) is in the range of 1 to 10-11 for individual cyclodextrin molecules. It is possible; however, the population of SAE-cyclodextrin molecules has an average value of 5.2 for "x" (ADS for the SAE group).

[0061] 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 individual DS species within the alkylated cyclodextrin composition. For example, an alkylated cyclodextrin composition containing a single alkylated cyclodextrin species having a single specific individual DS is said to have a span of 1, where the individual DS of the alkylated cyclodextrin is equal to the ADS of that alkylated cyclodextrin composition. For example, the electrophoresis of an alkylated cyclodextrin having a span of 1 should have only 1 alkylated cyclodextrin species with respect to DS. An alkylated cyclodextrin composition having a span of 2 contains 2 individual alkylated cyclodextrin species with different individual DS, and its electrophoresis may, for example, show 2 different alkylated cyclodextrin species with different DS. Similarly, an alkylated cyclodextrin composition having a span of 3 contains 3 individual alkylated cyclodextrin species with different individual DS. The span of alkylated cyclodextrin compositions is typically in the range of 5 to 15, or 7 to 12, or 8 to 11.

[0062] The parent cyclodextrin contains secondary hydroxyl groups at the C-2 and C-3 positions of the glucopyranose residue that forms the cyclodextrin, and a primary hydroxyl group at the C-6 position of the glucopyranose residue. Each of these hydroxyl sites is available for derivatization with substituent precursors. Depending on the synthetic method used, the substituent sites may be distributed randomly or somewhat orderedly among the available hydroxyl positions. The positional isomerism of the substituent derivatization may be varied as desired. The positional isomerism of each composition is independently selected. For example, most of the substituents present may be located on either 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 the present disclosure include alkylated cyclodextrin molecules in which a small number of substituent sites are located at the C-6 position, and the majority of substituent sites are located at the C-2 and / or C-3 positions. Yet another embodiment of the present disclosure includes alkylated cyclodextrin molecules in which substituent sites are substantially equally distributed between the C-2, C-3, and C-6 positions.

[0063] Alkylated cyclodextrin compositions contain a distribution of multiple individual alkylated cyclodextrin species, each having an individual 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 sufficiently sensitive to distinguish between a composition containing only 5% of one alkylated cyclodextrin and a composition containing 95% of another alkylated cyclodextrin from the starting alkylated cyclodextrin composition containing it.

[0064] The above-mentioned variations among individual species of alkylated cyclodextrins in their distribution can affect the required molar ratio of derivatized cyclodextrin to activator, and the complexation equilibrium constant K1:1 This can lead to changes in the equilibrium constant. The equilibrium constant is also somewhat variable with temperature, and tolerances in the above ratio are necessary so that the drug remains solubilized during temperature fluctuations that may occur during manufacturing, storage, transport, and use. The equilibrium constant may also vary with pH, ​​and tolerances in the above ratio may be necessary so that the drug remains solubilized during fluctuations that may occur during manufacturing, storage, transport, and use. The equilibrium constant may also vary due to the presence of other excipients (e.g., buffers, preservatives, antioxidants). Therefore, the derivatized cyclodextrin to activator ratio may be varied from the ratio described herein to compensate for the above-mentioned variability.

[0065] Alkylated cyclodextrins produced by the methods disclosed herein are incorporated herein by reference in their compositions, formulations, methods and systems by 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, and 7, respectively. U.S. Patent Application Publications No. 034,013, No. 7,625,878, No. 7,629,331, No. 7,635,773, No. 9,493,582, and No. 10,040,872; U.S. Patent Application Publications No. 2005 / 0164986, No. 2005 / 0186267, No. 2005 / 0250738, No. 2006 / 0258537, No. 2007 / 0020196, No. 2007 / 0020298, and No. 2007 / 002029 Patent applications No. 9, 2007 / 0175472, 2007 / 0202054, 2008 / 0194519, 2009 / 0011037, 2009 / 0012042, 2009 / 0123540; US Patent applications No. 12 / 404,174, 12 / 407,734, 61 / 050,918, 61 / 177,718, and 61 / 182,560; and PCT international application PCT / US06 These can be used as described in PCT / US07 / 62346, PCT / US07 / 71758, PCT / US07 / 71748, PCT / US07 / 72387, PCT / US07 / 72442, PCT / US07 / 78465, PCT / US08 / 61697, PCT / US08 / 61698, PCT / US08 / 70969, and PCT / US08 / 82730. The alkylated cyclodextrins prepared by the processes described herein can also be used as suitable substituents for other known grades of alkylated cyclodextrins having the same functional groups.

[0066] 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, non-derivativeated cyclodextrins, such as α-, β-, or γ-cyclodextrins commercially available from Wacker Biochem Corp. (Adrian, MI) and other sources, are used as starting materials. Non-derivativeated cyclodextrins have limited water solubility compared to the alkylated cyclodextrin compositions of this disclosure. For example, non-derivativeated 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.

[0067] The water-soluble alkylated cyclodextrin composition is optionally treated to remove the main portion of the non-derivativeated cyclodextrin (e.g., >50%) or other contaminants.

[0068] The terms "alkylene" and "alkyl" are used herein when (for example, -O-(C2-C6-alkylene)SO3 - The groups (in the group or in the alkylamine cation) each contain a linear, cyclic, and branched, saturated, and unsaturated (i.e., containing one or more double bonds) divalent alkylene group and monovalent alkyl group, respectively. For example, the SAE or HAE moieties may have the same or different types of alkylene (alkyl) radicals in each appearance in the alkylated cyclodextrin composition. In such embodiments, the alkylene radical at the SAE or HAE moiety may be ethyl, propyl, butyl, pentyl, or hexyl in each appearance in the alkylated cyclodextrin composition.

[0069] In this text, the term "alkanol" refers to a linear, cyclic, and branched, saturated and It contains both unsaturated alkyl components, and the hydroxyl group may be located at any position within the alkyl group. The term "cycloalkanol" includes unsubstituted or substituted (e.g., by methyl or ethyl) cyclic alcohols.

[0070] In some embodiments, the present invention provides an alkyl ether cyclodextrin (AE-CD) composition comprising an alkyl ether cyclodextrin having an average substitution degree of 2 to 9 and less than 0.05% (w / w) of chloride, wherein the AE-CD composition has an absorption of less than 1 A.U., as determined by UV / Vis spectrophotometric analysis at wavelengths of 245 nm to 270 nm, for an aqueous solution containing 300 mg of the AE-CD composition per 1 mL of solution in a cell with a path length of 1 cm. In some embodiments, the absorption of less than 1 A.U. is due to impurities. 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. In some embodiments, the AE-CD composition has an absorption of 0.5 AU or less, as determined by UV / Vis spectrophotometric analysis at wavelengths of 245 nm to 270 nm, for an aqueous solution containing 300 mg of the AE-CD composition per 1 mL of solution in a cell with a path length of 1 cm. In some embodiments, the above-mentioned absorption of 0.5 AU or less is due to impurities. In some embodiments, the AE-CD composition has an absorption of 0.2 AU or less, as determined by UV / Vis spectrophotometric analysis at wavelengths of 245 nm to 270 nm for an aqueous solution containing 300 mg of the AE-CD composition per 1 mL of solution in a cell with a path length of 1 cm. In some embodiments, the above-mentioned absorption of 0.2 AU or less is due to impurities. In some embodiments, the absorption of the AE-CD composition is determined by UV / Vis spectrophotometric analysis at wavelengths of 245 nm to 270 nm for an aqueous solution containing 500 mg of the AE-CD composition per 1 mL of solution in a cell with a path length of 1 cm.

[0071] In some embodiments, the present invention provides a sulfoalkyl ether cyclodextrin (SAE-CD) composition comprising a sulfoalkyl ether cyclodextrin having an average substitution degree of 2 to 9 and less than 0.05% (w / w) of chloride, wherein an aqueous solution containing 300 mg of the SAE-CD composition per 1 mL of solution in a cell with a path length of 1 cm has an absorption of less than 1 A.U. as determined by UV / Vis spectrophotometric analysis at wavelengths of 245 nm to 270 nm. In some embodiments, the above absorption of less than 1 A.U. is due to impurities. In some embodiments, the sulfoalkyl ether cyclodextrin composition is a sulfobutyl ether cyclodextrin composition. In some embodiments, the sulfoalkyl ether cyclodextrin is a sulfobutyl ether β-cyclodextrin. In some embodiments, the sulfoalkyl ether cyclodextrin composition is not a sulfobutyl ether cyclodextrin composition. In some embodiments, the sulfoalkyl ether cyclodextrin is not a sulfobutyl ether β-cyclodextrin. In some embodiments, the SAE-CD composition has an absorption of 0.5 AU or less, as determined by UV / Vis spectrophotometric analysis at wavelengths of 245 nm to 270 nm, for an aqueous solution containing 300 mg of the SAE-CD composition per 1 mL of solution in a cell with a path length of 1 cm. In some embodiments, the above absorption of 0.5 AU or less is due to impurities. In some embodiments, the SAE-CD composition has an absorption of 0.2 AU or less, as determined by UV / Vis spectrophotometric analysis at wavelengths of 245 nm to 270 nm, for an aqueous solution containing 300 mg of the SAE-CD composition per 1 mL of solution in a cell with a path length of 1 cm. In some embodiments, the above absorption of 0.2 AU or less is due to impurities. In some embodiments, the absorption of the SAE-CD composition is determined by UV / Vis spectrophotometric analysis at wavelengths of 245 nm to 270 nm for an aqueous solution containing 500 mg of the SAE-CD composition per 1 mL of solution in a cell with a path length of 1 cm.

[0072] In some embodiments, the disclosure provides an alkyl ether cyclodextrin (AE-CD) composition comprising an alkyl ether cyclodextrin having an average substitution degree 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 having an average substitution degree 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 having an average substitution degree 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 having an average substitution degree 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.

[0073] 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.

[0074] In some embodiments, the present disclosure provides compositions comprising AE-CD and an activator.

[0075] In some embodiments, the Disclosure provides a sulfoalkyl ether cyclodextrin (SAE-CD) composition comprising a sulfoalkyl ether cyclodextrin having an average substitution degree 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 having an average substitution degree 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 having an average substitution degree 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 having an average substitution degree of 2 to 9 and less than 0.002% (w / w) of chloride.

[0076] In some embodiments, the sulfoalkyl ether cyclodextrin is a compound of formula (II): [ka] In the formula, p is 4, 5, or 6, and R1 is -OH or -O-(C2-C6 alkylene)-SO3 - -T is independently selected in each occurrence, and T is independently selected in each occurrence from pharmaceutically acceptable cations, wherein at least one R1 is -OH and at least one R1 is O-(C2-C6 alkylene)-SO3 - Let it be -T. In some embodiments, R1 is -OH or -O-(C4 alkylene)-SO3 - -T is independently selected in each occurrence, and -T is Na in each occurrence. + That is the case.

[0077] In some embodiments, the average degree of substitution of SAE-CD is 4.5 to 7.5. In some embodiments, the average degree of substitution of SAE-CD is 6 to 7.5. In some embodiments, the average degree of substitution of SAE-CD is 6.2 to 6.9.

[0078] In some embodiments, the present disclosure provides compositions comprising SAE-CD and an activator.

[0079] The present invention also relates to a method for stabilizing an activator, comprising imparting an alkylated cyclodextrin composition containing alkylated cyclodextrin and less than 0.05% chloride, wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV / Vis spectrophotometric analysis 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 having a path length of 1 cm; and the method comprising combining the alkylated cyclodextrin composition with an activator. In some embodiments, the absorption of less than 1 A.U. is due to impurities.

[0080] This disclosure provides a method for producing an alkylated cyclodextrin composition, comprising: (a) mixing cyclodextrin with an alkylating agent to form a reaction environment containing alkylated cyclodextrin; (b) performing one or more separations to form a partially purified solution containing alkylated cyclodextrin; (c) preparing activated carbon, which includes subjecting the activated carbon to a carbon washing process, wherein the carbon washing process includes adding a portion of the partially purified solution containing alkylated cyclodextrin to the activated carbon, immersing the activated carbon in the partially purified solution, and eluting and discarding the solution; and (d) treating the remaining partially purified solution with the activated carbon prepared in step (c) to produce a final purified alkylated cyclodextrin composition.

[0081] In some embodiments, one or more separation steps include ultrafiltration, dialysfiltration, centrifugation, extraction, solvent precipitation, or dialysis.

[0082] In some embodiments, the activated carbon of step (c) is first subjected to an initial washing process which includes adding water to the activated carbon and eluting the water, wherein the eluted washing water has a residual conductivity of 10 μS / cm or less.

[0083] In some embodiments, the activated carbon of step (c) is subjected to a further washing process, which includes running water over the activated carbon after the initial carbon washing process.

[0084] In some embodiments, the activated carbon of step (c) is subsequently subjected to a washing process which includes adding water to the activated carbon and eluting the water.

[0085] In some embodiments, a method for producing an alkylated cyclodextrin composition, comprising: (a) mixing cyclodextrin with an alkylating agent to form a reaction environment containing alkylated cyclodextrin; (b) performing one or more separations to form a partially purified solution containing alkylated cyclodextrin; (c) preparing activated carbon, comprising: (i) an initial washing process comprising adding water to the activated carbon to eluate the water, wherein the eluted wash water has a residual conductivity of 10 μS / cm or less; (ii) further subjecting the activated carbon to a washing process, wherein the process comprises flowing water over the activated carbon after the initial carbon washing process; and carbonizing the activated carbon. The present invention discloses a method for preparing activated carbon, comprising: (iii) a process in which the activated carbon is subjected to a partial purification process, the process comprising adding a portion of a partially purified solution containing alkylated cyclodextrin to the activated carbon, immersing the activated carbon in the partially purified solution, and eluting and discarding the solution; and (iv) a process in which the activated carbon from step (iii) is subsequently subjected to a washing process, the process comprising adding water to the activated carbon and eluting the water; and (d) a method for preparing a final purified alkylated cyclodextrin composition, the process comprising treating the remaining partially purified solution with the activated carbon prepared in step (c).

[0086] In some embodiments, the final purified alkylated cyclodextrin composition contains less than 500 ppm of phosphate. In some embodiments, the final purified alkylated cyclodextrin composition contains less than 125 ppm of phosphate.

[0087] In some embodiments, the final purified alkylated cyclodextrin composition contains less than 0.1% (w / w) of chloride. In some embodiments, the final purified alkylated cyclodextrin composition contains less than 0.05% (w / w) of chloride. In some embodiments, the final purified alkylated cyclodextrin composition contains less than 0.01% (w / w) of chloride. In some embodiments, the final purified alkylated cyclodextrin composition further contains less than 0.002% (w / w) of chloride.

[0088] In some embodiments, the final purified alkylated cyclodextrin composition has an average degree of substitution of 2 to 9. In some embodiments, the final purified alkylated cyclodextrin composition has an average degree of substitution of 4.5 to 7.5. In some embodiments, the final purified alkylated cyclodextrin composition has an average degree of substitution of 6 to 7.5.

[0089] In some embodiments, the alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of formula (II): [ka] In the formula, p is 4, 5, or 6, and R1 is -OH or -O-(C2-C6 alkylene)-SO3 - -T is independently selected in each occurrence, and T is independently selected in each occurrence from pharmaceutically acceptable cations, wherein at least one R1 is -OH and at least one R1 is O-(C2-C6 alkylene)-SO3 - Let's assume it's -T.

[0090] In some embodiments, the alkylated cyclodextrin is sulfoalkyl et al. In some embodiments, R1 is -OH or -O-(C4 alkylene)-SO3 - -T is independently selected in each occurrence, and -T is Na in each occurrence. + That is the case.

[0091] In some embodiments, the alkylated cyclodextrin composition is combined with one or more excipients.

[0092] In some embodiments, the alkylated cyclodextrin composition is combined with an activator.

[0093] Further embodiments, features, and advantages of the present disclosure, as well as compositions, structures, and operations of various embodiments of the present disclosure, will be described in detail below with reference to the accompanying figures.

[0094] Preparation of alkylated cyclodextrin compositions This disclosure describes several methods for preparing alkylated cyclodextrin compositions. 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 in a bolus dose, and may be added before, during, or after the cyclodextrin starting material is optionally exposed to the alkaline aqueous medium. Further alkaline or buffering agents may be added as needed to maintain a pH within a desired range. The derivatization reaction may be carried out at ambient temperature to high temperatures. Once derivatization has progressed to the desired degree, the reaction is optionally quenched by the addition of an acid. The reaction environment is further processed (e.g., solvent precipitation, filtration, centrifugation, evaporation, concentration, drying, chromatography, dialysis, and / or ultrafiltration) to remove undesirable materials 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, compressed material, reconfigurable solid, suspension, glass, crystalline mass, amorphous mass, particulate matter, beads, emulsion, or wet mass.

[0095] This disclosure provides a process for producing an alkylated cyclodextrin composition comprising an alkylated cyclodextrin having a predetermined degree of substitution in an optional manner, comprising: combining an alkylating agent and an unsubstituted cyclodextrin starting material in an amount sufficient to achieve a predetermined degree of substitution in the presence of an alkali metal hydroxide; alkylating the cyclodextrin at a pH of 9 to 11 until the amount of residual unreacted cyclodextrin is less than 0.5% by weight or less than 0.1% by weight; adding a further hydroxide in an amount sufficient to achieve the degree of substitution and proceeding with the alkylation to complete the process; and adding further hydroxide to destroy any residual alkylating agent.

[0096] Further addition of hydroxide may be carried out using a certain amount of hydroxide under conditions (i.e., the amount of further hydroxide added, the temperature, and the length of time for the hydrolysis of the alkylating agent) 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.

[0097] The reaction environment or partially purified aqueous solution may contain unreacted alkylating agent. The alkylating agent can be decomposed in situ by adding a further alkalizing agent or by heating the solution containing the agent. If an unacceptable amount of alkylating agent is present in the reaction environment after the mixing is complete, it is necessary to decompose the excess alkylating agent. The alkylating agent can be decomposed in situ by adding a further alkalizing agent or by heating the solution containing the agent.

[0098] Decomposition may 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 a period of 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 to reduce the amount of alkylating agent in the aqueous liquid or removing the alkylating agent;

[0099] After the reaction is carried out as described herein, the aqueous medium containing alkylated cyclodextrin may be neutralized to pH 7 to quench the reaction. The solution may then be diluted with water to reduce its viscosity, especially when further purification is to be performed. Further purification may be employed, including dialysis in an ultrafiltration unit, to remove solutions of reaction by-products, e.g., salts (e.g., NaCl when sodium hydroxide is used as a base) and other low molecular weight by-products, but not limited to these. The product may be further concentrated by ultrafiltration. The product solution may then be treated with activated carbon to improve its color, reduce bioburden, and substantially remove one or more drug-degrading impurities. The product may be isolated by a preferred drying technique, e.g., freeze-drying, spray-drying, or vacuum drum-drying.

[0100] The reaction can first be prepared by dissolving an unsubstituted α-, β-, or γ-cyclodextrin starting material in an aqueous solution of a base, usually a hydroxide, such as lithium hydroxide, sodium, or potassium hydroxide. The base may be present in a catalytic amount (i.e., a molar ratio of less than 1:1 to the cyclodextrin) to achieve a predetermined or desired degree of substitution. That is, the base may be present in an amount of less than 1 molar equivalent with respect to each hydroxyl group to be derivatized in the cyclodextrin molecule. Since cyclodextrin becomes increasingly soluble in aqueous solution as the temperature rises, the aqueous reaction containing the base and cyclodextrin... The mixture is raised to a temperature of 50°C to ensure complete dissolution. Stirring is generally used throughout the alkylation reaction.

[0101] After dissolution is complete, the alkylating agent is added to initiate the alkylation reaction. The total amount of alkylating agent added throughout the reaction generally exceeds the stoichiometric amount required to complete the reaction relative to the amount of cyclodextrin, because some of the alkylating agent is hydrolyzed and / or otherwise destroyed / decomposed during the reaction, and as a result becomes unavailable for use in the alkylation reaction. The exact amount of alkylating agent to use for the desired degree of substitution can be determined through trial use. The total amount of alkylating agent required to complete the reaction can be added before initiating the reaction. Since the system is aqueous, the reaction generally takes place at temperatures between 50°C and 100°C. The reaction can also take place at temperatures below 100°C, thus eliminating the need for specialized pressure equipment. Generally, temperatures between 65°C and 95°C are preferred.

[0102] During the initial stage of the reaction (referred to herein as the pH control stage), care should be taken to maintain the reaction at least basic, or at a pH of 8–11. pH monitoring can be done conventionally by using a standard pH meter. pH adjustment can be done by adding an aqueous solution of hydroxide, e.g., a 10–15% solution. During the first pH control stage, the unreacted cyclodextrin reacts to such an extent that less than 0.5% by weight or less than 0.1% by weight of unreacted cyclodextrin remains in the solution. Substantially, the entire initial input of cyclodextrin reacts to a degree below the desired predetermined substitution, due to partial substitution as a result. The residual cyclodextrin can be monitored throughout this initial stage, for example by HPLC as described below, until less than 0.5% or less than 0.1% by weight of the desired endpoint of the residual cyclodextrin starting material is achieved. pH can be maintained and / or increased by adding concentrated hydroxide to the reaction medium in separate amounts, either continuously or gradually increasing. It is particularly preferable to add it in small increments.

[0103] Once the alkylation procedure is standardized or optimized so that a specific amount of reactant can be combined in a procedure that produces the desired degree of substitution with a low residual cyclodextrin, the procedure can then be easily checked at the end, either through or in contrast to initial pH control, to ensure that a low residual level of (unreacted) cyclodextrin starting material is obtained. The table below shows the relationship between the amount of butanesultone added to the reactor and the average degree of substitution obtained in SAE-CD. [Table 5]

[0104] Note that the initial pH of the reaction medium, after combining the cyclodextrin starting material and the initial base additions, can exceed 11 before the addition of the alkylating agent. However, after the alkylating agent is added and the reaction begins, the pH drops rapidly, and the addition of bases becomes necessary to maintain a basic pH of approximately 8 to 11.

[0105] 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 pH can be raised to a level greater than 11, e.g., greater than 12, by adding further base to drive and complete the reaction. The pH can be at least greater than 12, but not so high, so that the unreacted alkylating agent is hydrolyzed more rapidly than it reacts with the cyclodextrin, allowing the reaction to proceed at a reasonable rate. During this later stage of the reaction, further substitution of the cyclodextrin molecule is made until a predetermined degree of substitution is achieved. The total amount of hydroxide added throughout the reaction is typically on the order of the stoichiometrically required amount, plus a 10-20% molar excess compared to the amount of alkylating agent used. Additions exceeding a 10-20% excess are also feasible. The reaction endpoint can be detected by HPLC as described above. The preferred temperature is 65°C to 95°C. In the HPLC system, an anion exchange analysis column with pulsed amperometric detection (PAD) is typically used. Elution may be achieved by a gradient using a two-solvent system, for example, solvent A being 25 mM (millimoleous) aqueous sodium hydroxide and solvent B being 1 M sodium nitrate in 250 mM sodium hydroxide.

[0106] Once the alkylation reaction is complete and the endpoint of low residual cyclodextrin is achieved, further hydroxides can be added to destroy and / or decompose any residual alkylating agent. The further hydroxides are typically added in amounts of 0.5 to 3 molar equivalents relative to the cyclodextrin, and heating is continued in the reaction medium at 65°C to 95°C for typically 6 to 72 hours.

[0107] After the breakdown of residual alkylating agents, the resulting crude product may be further processed by dilution, dialyzing filtration to reduce or remove low molecular weight components, such as salts, concentration, carbon treatment, and drying to produce the final product. The pH is initially monitored to ensure it remains between 8 and 11 as the alkyl derivatization reaction progresses. In this initial stage, the addition of hydroxides to facilitate alkylation may be carried out systematically or stepwise. By monitoring the reaction's pH, the reaction can be controlled to ensure it reacts essentially to the extent that the entire initial stock of cyclodextrin starting materials makes at least one alkyl substitution on average per cyclodextrin molecule. All cyclodextrin reactants are thus consumed at the beginning of the process, resulting in a lower level of residual (unreacted) cyclodextrin in the crude product compared to a crude product produced by a process characterized by initially combining the total stoichiometric or excess amount of base with the cyclodextrin and alkylating agent without controlling the reaction. After the entire input of cyclodextrin starting materials has partially reacted, the remaining hydroxides can be added to drive and complete the reaction by finishing the alkyl substitution to a predetermined, desired degree. After the initial input of cyclodextrin is consumed in the first pH control step, the rate of hydroxide addition is not critical. Therefore, hydroxides can be added (for example, as a solution) continuously or in separate stages. Furthermore, the pH of the reaction medium should be maintained above approximately 12 so that the reaction rate is commercially viable. Further methods for producing alkylated cyclodextrins are described in U.S. Patent No. 9,751,957, which is incorporated herein by reference in its entirety.

[0108] Reduction and removal of impurities in cyclodextrin compositions Initial pH control provides a means to reduce certain byproducts from the reaction mixture. For example, acids are produced as a result of alkylation, and the pH of the reaction mixture tends to decrease (i.e., become more acidic) as the reaction proceeds. On the other hand, the reaction is kept basic because if the reaction medium becomes acidic, the reaction will slow down considerably or stop. Therefore, the pH of the reaction medium should be maintained at a level of at least 8 by adding aqueous hydroxide as needed. On the other hand, if the pH is allowed to exceed a certain level, for example, above 12, the reaction may produce high levels of byproducts, such as 4-hydroxyalkyl sulfonates and bis-sulfoalkyl ethers, thereby consuming the alkylating agent starting material. By monitoring the pH of the reaction solution and maintaining the pH between 8 and 12, or between 8 and 11, the reaction proceeds producing relatively low levels of byproducts, resulting in a relatively clear reaction mixture containing relatively low levels of the above byproducts.

[0109] The above references to reactants that are "stoichiometrically sufficient" refer to the amount of reactant required to completely derivatize the cyclodextrin of interest to the desired degree of substitution. As used herein, "alkali metal hydroxide" refers to LiOH, NaOH, KOH, etc. NaOH may be used when it is desired to produce a product suitable for parenteral administration.

[0110] The degree of substitution can be controlled by using a correspondingly lower or higher amount of alkylating agent, depending on whether a lower or higher degree of substitution is desired. Generally, the achievable degrees of substitution are, on average, 4.5–7.5, 5.5–7.5, or 6–7.1.

[0111] The crude products of the processes described herein, i.e., the products obtained after the breakdown of residual alkylating agents, contain lower levels of residual cyclodextrin than those produced by processes in which a base is initially added as a single input, and are provided as a further feature of the disclosure. The crude products produced by the processes of the disclosure typically contain less than 0.5% by weight or less than 0.1% by weight of residual cyclodextrin. As described below, the crude products also have the advantage of containing very low levels of residual alkylating agents.

[0112] Typically, the aqueous solution of the crude cyclodextrin product obtained after the decomposition of residual alkylating agents is purified by ultrafiltration, a process in which the crude product is brought into contact with a semipermeable membrane through which low molecular weight impurities pass. The molecular weight of the impurities that pass through the membrane depends on the molecular weight cutoff of the membrane. In the present disclosure, membranes with a molecular weight cutoff of 1,000 daltons ("Da") are typically used. Diafiltration and / or ultrafiltration may be carried out by filtration membranes with molecular weight cutoffs of 500 Da–2,000 Da, 500 Da–1,500 Da, 750 Da–1,250 Da, or 900 Da–1,100 Da, or about 1,000 Da. The desired product in the residue is then further treated with activated carbon to substantially remove impurities. The crude cyclodextrin product aqueous solution (i.e., obtained after the decomposition of residual alkylating agents but before purification) is advantageous in that it contains less than 2 ppm, less than 1 ppm, or less than 250 ppb of residual alkylating agent, based on the weight of the solution. The crude solution also does not need to contain any residual alkylating agent in its essence.

[0113] The final commercial product can be isolated at this point, for example, by filtration to remove activated carbon, followed by evaporation of water (e.g., via distillation, spray drying, freeze-drying, etc.). The final product produced by the present disclosure is advantageous in that it contains a very low residual level of alkylating agent, for example, less than 2 ppm, less than 1 ppm, or less than 250 ppb of residual alkylating agent based on the weight of the dry (i.e., less than 10% by weight) final product, or is essentially free of residual alkylating agent. A final product containing less than 250 ppb of alkylating agent is therefore provided as a further feature of the present disclosure. The alkylating agent is reduced after the completion of alkylation to the desired degree of substitution by hydrolysis of the alkali described above, 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.

[0114] Suitable activated carbon for use in the processes of this disclosure may be phosphate-free, in powder or granular form, or in the form of a suspension or slurry produced therefrom. Generally, phosphate-free activated carbon is carbon that has not been activated with or otherwise exposed to phosphoric acid.

[0115] A wide range of activated carbon is available. For example, Norit-Americas offers over 150 different grades and types of activated carbon, under trade names such as DARCO. (登録商標) , HYDRODARCO (登録商標) NORIT (登録商標) BENTONORIT (登録商標) PETRODARCO (登録商標) , and SORBONORIT (登録商標) These activated carbons are commercially available. Such activated 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 the removal of proteins, minerals, and / or amino acid moieties, or for purifying solutions.

[0116] Suitable activated carbon for use according to the present invention, but not limited to: DARCO (登録商標) 4x12, 12x20, or 20x40, granular lignite-derived material, activated by steam (Norit Americas, Inc., Amersfoort, NE); Darco (登録商標) S51HF (derived from lignite, activated by steam, powder); and Shirasagi, which is derived from wood and activated with zinc chloride. (登録商標) Examples include DC-32 powdered or granular carbon (Takeda Chemical Industries, Ltd., Osaka, JP).

[0117] As a phosphate-activated carbon that may be used in some embodiments: DARCO (登録商標) KB-G, DARCO (登録商標) KB-B and DARCO (登録商標) KB-WJ, and NORIT (登録商標) CASP and NORIT (登録商標) CN1 is one example.

[0118] In some embodiments, the phosphate level in the alkylated cyclodextrin composition 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, 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, 25 ppm, less than 20 ppm, less than 15 ppm, 10 ppm, or less than 5 ppm. In some embodiments, the phosphate level in the 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.

[0119] The optimal activated carbon charge ratio ultimately depends on the amount or concentration of alkylated cyclodextrin and impurities in the solution, as well as the 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.

[0120] As used herein, “processing cycle” refers to contacting a predetermined amount of cyclodextrin composition with a predetermined amount of activated carbon. A processing cycle may be carried out as a single process or as multiple (recirculating) passes.

[0121] The examples provided herein detail procedures used to evaluate and compare the efficiency of different grades, lots, sources, and types of activated carbon in removing impurities present in the process environment or solution of SAE-CD. Generally, the process environment or solution is treated with activated carbon and stirred for 120 minutes. When activated carbon is used in loose, particulate, or powder form, it can be removed by filtration of the liquid containing the activated carbon through a filtration medium to provide a purified solution.

[0122] The filtration membrane is made of nylon, TEFLON (登録商標) It may include PVDF or another comparable material. The pore size of the filtration membrane may be varied as needed depending on the particle size or molecular weight of the species separated from the SAE-CD in the solution containing SAE-CD.

[0123] The examples provided herein detail procedures for performing one or more separations and / or purifications in the aqueous reaction environment of the present invention. The reaction solution is diluted with an aqueous solution and subjected to dialysfiltration, during which the volume of the residue is kept substantially constant. Dialysis filtration may be performed on a 1,000 Da filter, resulting in one or more impurities passing through the filter, but the majority of the sulfoalkyl ethers present in the alkylated cyclodextrin composition being retained in the residue rather than passing through with the filtrate. Ultrafiltration is then performed by concentrating the residue by reducing its volume. A filter having a molecular weight cutoff of about 1,000 Da may also be used for ultrafiltration. The residue contains alkylated cyclodextrin and can be treated with activated carbon as described herein.

[0124] In some embodiments, the compositions of the present invention are substantially free of one or more impurities. In some embodiments, the impurities may be UV-active impurities. In some embodiments, the UV-active impurities may be drug degrading agents. The presence of one or more UV-active impurities can be determined, in particular, by UV / vis ("UV / vis") spectrophotometry. As used herein, "drug degrading agent" or "drug degrading impurity" refers to a species, site, etc., that degrades a certain active ingredient in an aqueous solution. It will be understood that the drug degrading agent may not be able to degrade all drugs to which the alkylated cyclodextrin composition may be combined, according to the drug's chemical formula and its degradation pathway. In some embodiments, the drug degrading species has an absorption in the UV / vis region of the spectrum, for example, an absorption maximum at wavelengths of 245 nm to 270 nm.

[0125] Alkylated cyclodextrin compositions can be measured in absorbance units by (AU) UV / vis. In some embodiments, alkylated cyclodextrin compositions have an absorption of less than 1 A.U., 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.

[0126] The absorbance of a solution is given by the formula: A = εlc The relationship with concentration becomes linear accordingly. During the ceremony A=absorbance ε = absorption coefficient l = path length c=molar concentration

[0127] Alkylated cyclodextrin compositions can be measured using UV / Vis spectrophotometric methods at wavelengths of 245 nm to 270 nm with a cell having a path length of 1 cm. In some embodiments, the alkylated cyclodextrin composition has a diametrically opposed emission of less than 1 A.U. at wavelengths of 245 nm to 270 nm for 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 nm to 270 nm for 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 nm to 270 nm for an aqueous solution containing 400 mg of the alkylated cyclodextrin composition per 1 mL of solution, less than 1 A.U. at wavelengths of 245 nm to 270 nm for an aqueous solution containing 500 mg of the alkylated cyclodextrin composition per 1 mL of solution, 0.9 AU or less at wavelengths of 245 nm to 270 nm for an aqueous solution containing 200 mg of the alkylated cyclodextrin composition per 1 mL of solution, and 245 nm to 270 nm for an aqueous solution containing 300 mg of the alkylated cyclodextrin composition per 1 mL of solution. For aqueous solutions containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at 0 nm is 0.9 AU or less; for aqueous solutions containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at 245 nm to 270 nm is 0.9 AU or less; for aqueous solutions containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at 245 nm to 270 nm is 0.8 AU or less; for aqueous solutions containing 300 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at 245 nm to 270 nm is 0.8 AU or less; for aqueous solutions containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at 245 nm to 270 nm is 0.8 AU or less; and for aqueous solutions containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU at 245 nm to 270 nm is 0.8 AUBelow are the results for aqueous solutions containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, with a AU of 0.7 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, with a AU of 0.7 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, with a AU of 0.7 AU or less at wavelengths of 245 nm to 270 nm; and for aqueous solutions containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution. For aqueous solutions containing [the specified substance], the AU emission is 0.7 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 emission is 0.6 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 emission is 0.6 AU or less at wavelengths of 245 nm to 270 nm; and for aqueous solutions containing 400 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU emission is 0.6 AU at wavelengths of 245 nm to 270 nm. Below are the values ​​for aqueous solutions containing 500 mg of alkylated cyclodextrin composition per 1 mL of solution, with a wavelength of 0.6 AU or less at 245 nm to 270 nm; aqueous solutions containing 200 mg of alkylated cyclodextrin composition per 1 mL of solution, with a wavelength of 0.5 AU or less at 245 nm to 270 nm; aqueous solutions containing 300 mg of alkylated cyclodextrin composition per 1 mL of solution, with a wavelength of 0.5 AU or less at 245 nm to 270 nm; and alkylated cyclodextrin composition containing 400 mg per 1 mL of solution. For aqueous solutions containing [the specified substance], the AU emission is 0.5 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 emission is 0.5 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 emission is 0.4 AU or less at wavelengths of 245 nm to 270 nm; and for aqueous solutions containing 300 mg of alkylated cyclodextrin composition per 1 mL of solution, the AU emission is 0.4 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 0.4 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 0.4 AU or less; for aqueous solutions containing 200 mg of alkylated cyclodextrin composition, the AU at wavelengths of 245 nm to 270 nm is 0.3 AU or less; 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 0.3 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 0.3 AU or less; per 1 mL of solution An aqueous solution containing 500 mg of alkylated cyclodextrin composition has an absorption of 0.3 AU or less at wavelengths of 245 nm to 270 nm; an aqueous solution containing 200 mg of alkylated cyclodextrin composition per 1 mL has an absorption of 0.2 AU or less at wavelengths of 245 nm to 270 nm; an aqueous solution containing 300 mg of alkylated cyclodextrin composition per 1 mL has an absorption of 0.2 AU or less at wavelengths of 245 nm to 270 nm; an aqueous solution containing 400 mg of alkylated cyclodextrin composition per 1 mL has an absorption of 0.2 AU or less at wavelengths of 245 nm to 270 nm; or an aqueous solution containing 500 mg of alkylated cyclodextrin composition per 1 mL has an absorption of 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 by UV / vis in absorbance units.

[0128] Impurity components may include, but are not limited to, low molecular weight impurities (i.e., impurities with a molecular weight of approximately 500 Da or less), water-soluble and / or water-insoluble ions (i.e., salts), hydrolyzable 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 cyclodextrins, and / or SAE-CD), unreacted alkylating agents (e.g., 1,4-butanesultone), and combinations thereof.

[0129] 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 of less than 1,000 Da), such as, but not limited to, species that arise as by-products and / or degradation products in the reaction mixture. Therefore, UV-active species may include, but not limited to, glycoside moieties, ring-opened cyclodextrin species, reducing sugars, glucose degradation products (e.g., 3,4-dideoxyglucosone-3-ene, carbonyl-containing degradation products, e.g., 2-fluoraldehyde, 5-hydroxymethyl-2-fluoraldehyde, etc.), and combinations thereof.

[0130] In some embodiments, the alkylated cyclodextrin composition 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.

[0131] In some embodiments, the 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.

[0132] In some embodiments, the alkylated cyclodextrin composition 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 a hydrolyzed alkylating agent.

[0133] In some embodiments, the alkylated cyclodextrin composition 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.

[0134] In some embodiments, the alkylated cyclodextrin composition contains 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.

[0135] The term "complexed" is intended to mean "a portion of a clathrate or inclusion complex with," i.e., a "complexed" therapeutic agent is a portion of a clathrate or inclusion complex with an alkylated cyclodextrin. The term "major portion" refers to 50% or more by weight or molar basis. Therefore, formulations according to the present invention may contain an activator in which more than about 50% by weight is complexed with an alkylated cyclodextrin. The actual percentage of the complexed activator varies according to the complexation equilibrium bonding constant that characterizes the complexation of a particular cyclodextrin with a particular activator. The present invention also includes embodiments in which the activator is not complexed with a cyclodextrin, or in which only a small portion of the activator is complexed with an alkylated cyclodextrin. It should be noted that alkylated cyclodextrins can form one or more ionic bonds with positively charged compounds. This ionic association can occur regardless of whether the positively charged compound is complexed with the cyclodextrin by inclusion complexation.

[0136] Carbon preparation process The purification of crude alkylated cyclodextrin products disclosed herein utilizes a carbon purification process to remove impurities that arise during the synthesis of alkylated cyclodextrins. For example, such a purification process is disclosed in U.S. Patent No. 6,153,746, the contents of which are incorporated herein in their entirety. An improvement on the carbon preparation process is disclosed in U.S. Patent No. 7,635,773, in which activated carbon is washed until a certain conductivity is achieved before the purification of the crude alkylated cyclodextrin. The carbon preparation process described in U.S. Patent No. 7,635,773 removed some impurities, but a large amount of chloride remained in the alkylated cyclodextrin product. Chloride impurities can react with the activator, causing its decomposition.

[0137] In a further improvement of the carbon preparation process disclosed in U.S. Patent No. 9,493,582, the process included washing the carbon until a conductivity level of 10 μS / cm was achieved. U.S. Patent No. 10,040,872 discloses a method for preparing carbon that includes an immersion step. While the methods described in these applications reduce the amount of chloride impurities in the final alkylated cyclodextrin product, 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.

[0138] The conductivity of the aqueous wash eluent for activated carbon can be determined by any method commonly used by those skilled in the art. In some embodiments, the conductivity is measured using a conductivity meter. In some embodiments, the conductivity is measured using ion chromatography.

[0139] In some embodiments, the conductivity of the activated carbon water wash eluent is measured before the addition of the partially purified alkylated cyclodextrin solution. 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 running water over the activated carbon. In some embodiments, the conductivity of the activated carbon water wash eluent before treating the partially purified solution with activated carbon to purify 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, 22 μS / cm The values ​​are ≤cm, ≤21μS / cm, ≤20μS / cm, ≤19μS / cm, ≤18μS / cm, ≤17μS / cm, ≤16μS / cm, ≤15μS / cm, ≤14μS / cm, ≤13μS / cm, ≤12μS / cm, ≤11μS / cm, ≤10μS / cm, ≤9μS / cm, ≤8μS / cm, ≤7μS / cm, ≤6μS / cm, ≤5μS / cm, ≤4μS / cm, ≤3μS / cm, ≤2μS / cm, or ≤1μS / cm. 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.

[0140] 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.

[0141] Even if the activated carbon in the column is washed with water, the wetting of the activated carbon may be insufficient. In this washing procedure, there is no way to control channeling through the carbon bed. It is said that more thorough washing of the activated carbon before circulating the alkylated cyclodextrin solution reduces or removes all further addition of residual chloride from the alkylated cyclodextrin composition product.

[0142] In some embodiments, activated carbon is added to a dedicated tank system equipped with a stirrer and a screen system. The activated carbon is added, followed by several first carbon washes with water at a predetermined stirring rate over a predetermined period of time. After water washing, the aqueous layer is removed from the dedicated tank, and further water washing is performed. After further water washing, the conductivity of the activated carbon is determined, and if the conductivity is below a predetermined level, the activated carbon is suspended in water, and the activated carbon / water slurry is pumped into a column for further processing. In some embodiments, the water and activated carbon are then prepared for flowing water over the activated carbon or for further processing, the processing of which includes the steps of adding a partially purified solution containing alkylated cyclodextrin to the activated carbon, immersing the activated carbon in the partially purified solution, and eluting and discarding the solution. The predetermined conductivity levels are, 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, It may be 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, 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 desired conductivity level can be achieved after about 6 to 12 hours of water washing.

[0143] 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.

[0144] In some embodiments, the tank system is maintained at room temperature (25°C) during the water washing process. In some embodiments, the tank system may 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 time 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.

[0145] In some embodiments, the activated carbon transferred to the column may be subjected to a further washing process. The further washing process may include flowing water over the activated carbon. In some embodiments, the column may be filled with purified water from top to bottom or bottom to top and may be held in the column for a 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 over the activated carbon and discharged. In some embodiments, the purified water is flowed in the same direction in which the water was filled in the first carbon washing process. In other embodiments, the water is flowed over the activated carbon in a different direction from in which 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 the water may be flowed over the activated carbon from top to bottom in the second carbon washing process. In some embodiments, water may be filled from top to bottom in the first carbon washing process, and water may be flowed over the activated carbon from bottom to top in the second carbon washing process.

[0146] Water may be flowed over the activated carbon for a set amount of time. For example, water may be flowed over 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 flowed over the activated carbon for about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours. Water may be flowed over the activated carbon at a flow rate of at least 50 liters / hour, 100 liters / hour, 150 liters / hour, 200 liters / hour, 250 liters / hour, 300 liters / hour, 350 liters / hour, 400 liters / hour, 450 liters / hour, 500 liters / hour, or more. For example, water may be flowed over the activated carbon at a flow rate of approximately 100 liters / hour, approximately 200 liters / hour, approximately 300 liters / hour, approximately 400 liters / hour, approximately 500 liters / hour, approximately 600 liters / hour, approximately 700 liters / hour, approximately 800 liters / hour, approximately 900 liters / hour, or approximately 1,000 liters / hour. After the water has been flowed over the activated carbon, the column may then be flushed with purified water from the top of the column for 30 minutes and then drained out of the column.

[0147] 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 from top to bottom or from bottom to top. In embodiments, the activated carbon is immersed for a set amount of time before the partially purified alkylated cyclodextrin solution is eluted. For example, activated carbon can be immersed for at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, 480 minutes, or longer. In one embodiment, activated carbon is immersed for at least 120 minutes.

[0148] In some embodiments, the activated carbon may be stirred during the immersion process at a speed between 5 rpm and 300 rpm, for example. 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 about 40 to 50 rpm.

[0149] In some embodiments, the temperature for immersing the activated 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.

[0150] In some embodiments, the activated carbon may be subjected to a further carbon washing process after the immersion process. This further washing process includes filling the column with purified water and allowing the water to stand for a period of time. In some embodiments, the water is added from the top to the bottom. In other embodiments, the water is added from the bottom to the 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 to determine the conductivity of the activated carbon. When the conductivity is below a desired predetermined level, water may be added to the column and used in the purification of alkylated cyclodextrin. When the conductivity exceeds a desired predetermined level, this further washing process may be repeated. The specified conductivity levels are, 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 values: 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.

[0151] The chloride level of the final alkylated cyclodextrin product can be determined by any method commonly used by those skilled in the art. In some embodiments, the chloride level is measured using charged aerosol detection (CAD). In some embodiments, the chloride level is measured using ion chromatography.

[0152] In some embodiments, the chloride level, measured by weight ratio (w / w) of alkylated cyclodextrin, is 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, 0.01% or less, 0.009% or less, 0.008% or less, 0.007% or less, 0.006% or less, 0.005% or less, 0.004% or less, 0.003% or less, or 0.002% or less. In some embodiments, the chloride levels in the alkylated cyclodextrin composition 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 0.0 The percentages are 7%~0.002%, 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%.

[0153] The final yield of alkylated cyclodextrin (in isolated and / or purified or partially purified form) obtained at the completion of the process may vary. Based on the cyclodextrin starting material, the final yield of alkylated cyclodextrin 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 based on the cyclodextrin starting material is 80% or higher, 85% or higher, 90% or higher, or 95% or higher.

[0154] Use of alkylated cyclodextrin composition Among other uses, the alkylated cyclodextrin compositions of the present invention may be used to solubilize and / or stabilize various different materials to prepare formulations for specific applications. The alkylated cyclodextrin compositions may impart improved solubility and / or improved chemical, thermochemical, hydrolytic, and / or photochemical stability to other components in the composition. For example, alkylated cyclodextrin compositions may be used to stabilize activators in aqueous media. Alkylated cyclodextrin compositions may also be used to increase the solubility of activators in aqueous media.

[0155] The alkylated cyclodextrin composition of the present invention comprises one or more activators. The one or more activators contained in the composition of the present invention may possess a wide range of water solubility, bioavailability, and hydrophilicity. Activators particularly suitable for the present invention 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 composition of the present invention are independently selected in each appearance from any known activators and those disclosed herein. It is not necessary for the one or more activators to form complexes with the alkylated cyclodextrin or to form ionic associations with the alkylated cyclodextrin.

[0156] Activators generally include physiologically or pharmacologically active substances that produce systemic or local effects (may be multiple) on animals and humans. Other examples of activators include pesticides, herbicides, insecticides, antioxidants, plant growth promoters, sterilizers, catalysts, chemical reagents, foods, nutrients, cosmetics, vitamins, infertility inhibitors, fertility promoters, microorganisms, flavorings, sweeteners, cleaning agents, pharmaceutically effective activators, as well as other such compounds for pharmaceutical, veterinary, horticultural, household, food, cooking, agriculture, cosmetics, industrial, cleaning, confectionery, and flavoring applications. Activators may exist in neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomer, isomer, enantiomerically pure, racemic, hydrate, chelate, derivative, analog, or other common forms.

[0157] Representative pharmaceutically effective active agents include nutrients and nutritional supplements, hematological agents, endocrine and metabolic agents, cardiovascular agents, renal and genitourinary agents, respiratory agents, central nervous system agents, gastrointestinal agents, antifungal agents, anti-infective agents, biological and immunological agents, dermatological agents, ophthalmic agents, antitumor agents, and diagnostic agents. Exemplary nutrients and nutritional supplements include minerals, trace elements, amino acids, lipotropic 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 expanders, 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 bisartarate, sodium benzoate and sodium phenylacetate, bromocriptine mesylate, cabergoline, gout agents, and antidotes. Suitable antifungal agents for use with the alkylated cyclodextrin composition of the present invention include, but are not limited to, posaconazole, voriconazole, clotrimazole, ketoconazole, oxiconazole, sertaconazole, metconazole, fluconazole, itraconazole, and miconazole. Suitable antipsychotics for use with the alkylated cyclodextrin composition of the present invention include, but are not limited to, clozapine, prochlorperazine, haloperidol, thioridazine, thiothixen, risperidone, trifloperazine hydrochloride, chlorpromazine, aripiprazole, roxapine, loxitan, olanzapine, quetiapine fumarate, risperidone, and ziprasidone.

[0158] 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 used in shock, potassium-removing resins, disodium edetate, cardioplegic solutions, agents for patent ductus arteriosus, and sclerosing agents. Examples of renal and genitourinary agents include interstitial cystitis agents, sodium cellulose phosphate, anti-sexual dysfunction agents, acetohydroxamic acid (AHA), genitourinary lavage agents, cystine depletion agents, urinary alkalinizing agents, urinary acidifying agents, anticholinergics, urinary cholinergics, polymeric phosphate binders, vaginal preparations, and diuretics. Examples of respiratory agents include bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, respiratory inhalation products, nasal congestion inhibitors, respiratory enzymes, pulmonary surfactants, antihistamines, non-narcotic antitussives, and expectorants. Examples of central nervous system agents include CNS stimulants, narcotic agonist analgesics, narcotic agonist-antagonist analgesics, central analgesics, acetaminophen, salicylates, non-narcotic analgesics, nonsteroidal anti-inflammatory drugs, migraine medications, antiemetics / anti-vertigo agents, anxiolytics, antidepressants, antipsychotics, 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 Helicobacter pylori agents, histamine H2 antagonists, proton pump inhibitors, sucralfate, prostaglandins, antacids, gastrointestinal anticholinergics / antispasmodics, mesalamine, orsalazine sodium, valsalazid disodium, sulfasalazine, celecoxib, infliximab, tegacerod 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, oxazolidinone, lincosamide, oral and parenteral aminoglycosides, colistimethate sodium, polymyxin B sulfate, bacitracin, metronidazole, sulfonamides, nitrofuran, methenamine, folic acid antagonists, antifungal agents, antimalarial preparations, antituberculosis agents, anti-amebic agents, antiviral agents, antiretroviral agents, leprosy treatments, antiprotozoal 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 antihistamine preparations, topical anti-infective agents, anti-inflammatory agents, anti-psoriasis agents, anti-seborrheic agents, 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, lexinoids, scabies insecticides / lice killers, wound healers, emollients, protectants, sunscreens, ointment bases and lotion bases, rubs and ointments, bandages and granules, and physiological perfusions. Exemplary 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 antitumor 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 antimicrobial agents, protein-tyrosine kinase inhibitors, porfimer sodium, mitotane (o,p'-ddd), and arsenic trioxide.Examples of diagnostic agents include in vivo diagnostic aids, in vivo diagnostic biopreparations, and radiopaque agents.

[0159] Examples of exemplary activators include compounds sensitive to chlorine levels. Examples of chloride-sensitive activators include proteasome inhibitors, such as bortezomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, and carfilzomib.

[0160] The activators listed above should not be considered comprehensive, but rather within the scope of the present invention. This is merely an example of many embodiments that are considered to fall within the scope. Many other activators may be administered in conjunction with the formulation of the present invention.

[0161] The formulations of the present invention can be used to deliver two or more different activators. Specific combinations of activators can be conferred in the formulations of the present invention. Some combinations of activators include: 1) a first drug from a first pharmacokinetic classification and a different second drug from the same pharmacokinetic classification; 2) a first drug from a first pharmacokinetic classification and a different second drug from a different pharmacokinetic classification; 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 activators are described herein.

[0162] The activators contained in the formulations of the present invention may exist as pharmaceutically acceptable salts thereof. As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound in which the activator reacts 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 compounds formed from, for example, non-toxic inorganic or organic acids. Suitable 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 others known to those skilled in the art. Salts 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 others known to those skilled in the art. pharmaceutically acceptable salts suitable for use with the present invention can be prepared by conventional chemical methods using activators containing basic or acidic groups. Suitable addition salts are 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 whole.

[0163] The present invention also relates to a method for stabilizing an activator, comprising imparting an alkylated cyclodextrin composition containing alkylated cyclodextrin and less than 0.05% chloride, wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV / Vis spectrophotometric analysis 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 having a path length of 1 cm; and the method comprising combining the alkylated cyclodextrin composition with an activator. In some embodiments, the absorption of less than 1 A.U. is attributed to a drug decomposition agent.

[0164] The present invention also relates to a method for stabilizing an activator, comprising imparting an alkylated cyclodextrin composition containing alkylated cyclodextrin and less than 0.002% chloride, wherein the alkylated cyclodextrin composition has an absorption of less than 1 A.U., as determined by UV / Vis spectrophotometric analysis 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 having a path length of 1 cm; and the method comprising combining the alkylated cyclodextrin composition with an activator. In some embodiments, the absorption of less than 1 A.U. is attributed to a drug decomposition agent.

[0165] A method for stabilizing an activator involves a composition comprising one or more activators and an alkylated cyclodextrin composition containing alkylated cyclodextrin and less than 500 ppm of phosphate, which can be used as a dry solution, a wet solution, an inhalable composition, a parenteral composition, a solid solution, a solid mixture, or granules. It can be implemented in the form of granules, gels, and other activator compositions known to those skilled in the art.

[0166] In some embodiments, a method for stabilizing the activator involves maintaining a composition containing one or more activators and an alkylated cyclodextrin composition containing alkylated cyclodextrin and less than 500 ppm of phosphate at a temperature of 80°C for a period of 120 minutes, after which a drug decomposition agent is added in an amount of 2% or less, 1.5% or less, 1% or less, or 0.5% or less.

[0167] In some embodiments, a method for stabilizing the activator involves adding chloride in amounts of 2% or less, 1.9% or less, 1.8% or less, 1.7% or less, 1.6% or less, 1.5% or less, 1.4% or less, 1.3% or less, 1.2% or less, 1.1% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less, to a composition comprising one or more activators and an alkylated cyclodextrin composition containing alkylated cyclodextrin and less than 500 ppm of phosphate, after which the composition is maintained at a temperature of 80°C for a period of 120 minutes.

[0168] Similarly, in some embodiments, a method for stabilizing the activator involves maintaining a composition containing one or more activators and an alkylated cyclodextrin composition containing alkylated cyclodextrin and less than 500 ppm of phosphate at a temperature of 80°C for a period of 120 minutes, after which an activator assay is performed to obtain 98% or more, 98.5% or more, 99% or more, or 99.5% or more of the activator.

[0169] In some embodiments, the stabilization method involves providing an alkylated cyclodextrin composition containing alkylated cyclodextrin 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.

[0170] In some embodiments, the stabilization method involves providing an alkylated cyclodextrin composition containing alkylated cyclodextrin, wherein the alkylated cyclodextrin composition has an absorption of 0.5 AU or less, as determined by UV / Vis spectrophotometric analysis 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 above absorption of 0.5 AU or less is due to a drug decomposition agent.

[0171] Generally, alkylated cyclodextrins are present in sufficient amounts to stabilize the activator. Sufficient amounts can be in molar ratios 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 (alkylated cyclodextrin:activator).

[0172] Cyclodextrin in a combination composition does not need to bind to other materials present in the formulation containing it, such as activators. However, if cyclodextrin binds to another material, such binding may be formed as a result of inclusion complexation, ion pairing, hydrogen bonding, and / or van der Waals interactions.

[0173] Anionic derivatized cyclodextrins may complex with or otherwise bind to acid-ionizing agents. As used herein, the term acid-ionizing agent is used to mean any compound that becomes or ionizes in the presence of an acid. An acid-ionizing agent comprises at least one acid-ionizing functional group that becomes ionized when exposed to an acid or placed in an acidic medium. Exemplary acid-ionizing functional groups include primary amines, secondary amines, tertiary amines, quaternary amines, aromatic amines, unsaturated amines, and primary amines. Examples include secondary thiols, sulfonium thiols, hydroxyls, enols, and others known to those skilled in the art of chemistry.

[0174] The degree to which an acid ionizing agent is bonded by non-covalent ionic bonds and the degree to which it is bonded by inclusion complex formation are, for example, 1 H-NMR, 13 This can be determined by methods such as 13C-NMR or circular dichroism, as well as by analysis of phase solubility data for acid ionizing agents and anionic derivatized cyclodextrins. Those skilled in the art can use these conventional methods to approximate the amount of each type of bond occurring in solution and determine whether interspecies bonding preferentially occurs by non-covalent ionic bonding or inclusion complex formation. Under conditions where non-covalent ionic bonding preferentially occurs over inclusion complex formation, the amount of inclusion complex formation measured by NMR or circular dichroism is reduced even if the phase solubility data shows significant interspecies bonding under these conditions; furthermore, the intrinsic solubility of acid ionizing agents, as determined from the phase solubility data, is generally higher than expected under these conditions.

[0175] As used herein, the term “non-covalent ionic bond” refers to a bond formed between an anionic species and a cationic species. The bond is non-covalent such that these two species combine to form a salt or ion pair. Anionic derivatized cyclodextrins confer the anionic species of the ion pair, and acid-ionizing agents confer the cationic species of the ion pair. Because anionic derivatized cyclodextrins are polyvalent, alkylated cyclodextrins may form ion pairs with one or more acid-ionizing agents or, in other cases, cationic agents.

[0176] The liquid formulations of the present invention can be converted into solid formulations for reconstitution. The reconstituteable solid composition according to the present invention comprises an activator, a derivatized cyclodextrin, and optionally at least one other pharmaceutical excipient. The reconstituteable composition can be reconstituted with an aqueous liquid to form a liquid formulation for storage. The composition may comprise a mixture of solid derivatized cyclodextrin and an activator-containing solid (minimal to no inclusion complexes) and optionally at least one solid pharmaceutical excipient, resulting in the majority of the activator not being complexed by the derivatized cyclodextrin before reconstitution. Alternatively, the composition may comprise a solid mixture of derivatized cyclodextrin and an activator, in which the majority of the activator is complexed by the derivatized cyclodextrin before reconstitution. The reconstituteable solid composition may also comprise derivatized cyclodextrin and an activator, in which substantially all or at least the majority of the activator is complexed by the derivatized cyclodextrin.

[0177] The reconstituteable solid composition may be prepared by any of the following processes: First, the liquid formulation of the present invention is prepared, and then a solid is formed by freeze-drying (freeze-drying), spray-drying, spray freeze-drying, poor solvent precipitation, sterile spray-drying, various processes utilizing supercritical or near-supercritical fluids, or another method known to those skilled in the art for producing solids for reconstitution.

[0178] The liquid vehicle contained in the formulation of the present invention may include an aqueous liquid carrier (e.g., water), an aqueous alcohol, an aqueous organic solvent, a non-aqueous liquid carrier, and combinations thereof.

[0179] The formulations of the present invention may include one or more pharmaceutical excipients, such as conventional preservatives, defoaming agents, antioxidants, buffers, acidifying agents, alkalizing agents, bulking agents, colorants, complexing enhancers, antifreeze agents, electrolytes, glucose, emulsifiers, oils, plasticizers, solubility enhancers, stabilizers, osmotic tension modifiers, flavoring agents, sweeteners, adsorbents, anti-sticking agents, binders, diluents, direct compression excipients, disintegrants, flow enhancers, lubricants, opacifiers, abrasives, complexing agents, fragrances, other excipients known to those skilled in the art for use in formulations, or combinations thereof.

[0180] As used herein, the term “adsorbent” is intended to mean an agent capable of retaining other molecules on its surface by physical or chemical (chemiadsorption) means. Examples of such compounds include, but are not limited to, powders and activated carbon, as well as other materials known to those skilled in the art.

[0181] As used herein, the term “alkalizing agent” is intended to mean a compound used to impart an alkaline medium for the stability of the product. 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, alkaline amino acids and trolamine, as well as others known to those skilled in the art.

[0182] As used herein, the term “acidifying agent” is intended to mean a compound used to impart an acidic medium for the stability of the product. 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 others known to those skilled in the art.

[0183] As used herein, the term “anti-sticking agent” is intended to mean an agent that prevents solid drug formulations from sticking to punches and dies in tablet presses during manufacturing. Examples of such compounds include, but are not limited to, magnesium stearate, talc, calcium stearate, glyceryl behenate, polyethylene glycol, hydrogenated vegetable oils, mineral oils, stearic acid, and other materials known to those skilled in the art.

[0184] As used herein, the term “binder” is intended to mean a substance used to cause adhesion of powder particles in a solid drug formulation. Examples of such compounds include, but are not limited to, acacia, alginic acid, 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.

[0185] A binder may be included in the dosage form as needed. Exemplary binders include acacia, tragacanth, gelatin, starch, cellulose materials, e.g., methylcellulose and sodium carboxymethylcellulose, alginic acid and its salts, polyethylene glycol, guar gum, polysaccharides, bentonite, sugars, invert sugar, and poloxamer (PLURONIC). (商標) F68, PLURONIC (商標) Examples of binders include collagen, albumin, gelatin, cellulose in non-aqueous solvents, combinations thereof, and others known to those skilled in the art. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, combinations thereof, and other materials known to those skilled in the art.

[0186] When used herein, conventional preservatives are compounds used to at least reduce the rate at which bioburden increases, but which maintain bioburden at a steady 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 methyl, ethyl, propyl or butylparabens, as well as others known to those skilled in the art. It is understood that some preservatives may reduce their effectiveness by interacting with alkylated cyclodextrins. Nevertheless, well-preserved formulations can be found by selecting the appropriate preservative and adjusting the concentrations of the preservative and alkylated cyclodextrin.

[0187] As used herein, the terms “diluent” or “filler” are intended to mean an inert substance used as a filler in the preparation of a liquid or solid dosage form to produce desired bulk, fluidity, and compressibility properties. Examples of such compounds include, but are not limited to, liquid vehicles (e.g., water, alcohol, solvents, etc.), dicalcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, and starch, as well as other materials known to those skilled in the art.

[0188] As used herein, the term “direct compression excipient” is intended to mean a compound used in a compressed solid dosage form. Examples of such compounds include, but are not limited to, dicalcium phosphate and other materials known to those skilled in the art.

[0189] As used herein, the term “antioxidant” is intended to mean an agent used to inhibit oxidation and thereby prevent deterioration of a preparation by an 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 others known to those skilled in the art.

[0190] As used herein, the term “buffering agent” is intended to mean a compound used to resist changes in pH during the dilution or 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, monosodium phosphate, disodium phosphate, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, Tris, anhydrous sodium tartrate, and sodium citrate, as well as others known to those skilled in the art.

[0191] A complexing enhancer may be added to the formulation of the present invention. When such an enhancer is present, the cyclodextrin / activator ratio may change. The complexing enhancer is a compound(s) that enhances the complexation of the activator by cyclodextrin. Suitable complexing enhancers include one or more pharmacologically inert water-soluble polymers, hydroxy acids, and other organic compounds typically used in preserved formulations to enhance the complexation of specific agents by cyclodextrin.

[0192] Hydrophilic polymers can be used as complexing enhancers, solubility enhancers, and / or water activity reducers to improve the performance of formulations containing CD-based preservatives. Loftsson discloses several polymers suitable for use in combination with cyclodextrins (non-derivativeized or derivatized) to improve the performance and / or properties of cyclodextrins. Suitable polymers are 、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,March 21~24,p.10-15(2000);PCT Public Health Service WO99 / 42111;Pharmazie 53:733(1998);Pharm.Technol.Eur.9:26(1997);J.Pharm.Sci.85:1017(1996);Proceedings of the National Cyclodextrins 0 579 435; Comostela,ES,5 / 31-6 / 3 / 1998,pp.261-264(1999);STPPharma 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.(1997) 14(11),S203;Invest.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);Eur.J.Pharm.Sci.4S:S143(1996);U.S. Pat. This information is disclosed in 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); andInt.J.Pharm.110:169(1994), and the entirety of these disclosures is incorporated herein by reference.

[0193] Other suitable polymers are well-known excipients commonly used in the field of pharmaceutical formulations, for example, Remington's Pharmaceutical Sciences, 18th ed., pp. 291-294, ARGennaro (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); ATFlorence et al., Physicochemical Principles of Pharmacy, 2d ed., pp. 281-334, MacMillan). This is included in Press, London, UK (1988). Further suitable polymers include water-soluble natural polymers, water-soluble semi-synthetic polymers (e.g., water-soluble derivatives of cellulose), and water-soluble synthetic polymers. Examples of natural polymers include polysaccharides, e.g., insulin, pectin, algin derivatives (e.g., sodium alginate), and agar, as well as polypeptides, e.g., casein and gelatin. Examples of semi-synthetic polymers include cellulose derivatives, e.g., methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, mixed ethers thereof, e.g., hydroxypropylmethylcellulose and other mixed ethers, e.g., hydroxyethyl-ethylcellulose and hydroxypropylethylcellulose, hydroxypropylmethylcellulose phthalate, and carboxymethylcellulose and its salts, in particular sodium carboxymethylcellulose. Examples of synthetic polymers include polyoxyethylene derivatives (polyethylene glycol) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone, and polystyrene sulfonate), as well as various copolymers of acrylic acid (e.g., carbomers).Other natural, semi-synthetic, and synthetic polymers not specified herein that meet the criteria of water solubility, pharmaceutically acceptable, and pharmacological inertness are also considered to be within the scope of the present invention.

[0194] As used herein, a fragrance is a relatively volatile substance or combination of such substances that produces a detectable scent, odor, or aroma. Examples of fragrances include those generally accepted as safe by the U.S. Food and Drug Administration.

[0195] As used herein, the term “flow enhancer” is intended to mean an agent used in a solid drug formulation to enhance 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.

[0196] As used herein, the term “lubricant” is intended to mean a substance used in a solid drug 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, and zinc stearate, as well as other materials known to those skilled in the art.

[0197] As used herein, the term “opacifier” is intended to mean a compound used to make a coating opaque. Opacifiers may 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.

[0198] 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.

[0199] 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 are more readily dispersed or dissolved. Exemplary disintegrants include, without limitation, starches, e.g., corn starch, potato starch, their gelatinized and modified forms, sweeteners, clay, bentonite, microcrystalline cellulose (e.g., Avicel). (登録商標) ), carboxymethylcellulose calcium, croscarmellose sodium, alginic acid, sodium alginate, cellulose polariphosphate potassium (for example, Amberlite (登録商標) Examples include alginates, sodium starch glycolate, gum, agar, guar, locust bean, karaya, pectin, tragacanth, crospovidone, and other materials known to those skilled in the art.

[0200] 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 reduce the therapeutic activity of the agent. 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, glycerol, polyethylene glycol, sodium caprylate and sodium saccharin, and others known to those skilled in the art.

[0201] As used herein, the term “osmotic tension modifier” is intended to mean a compound(s) that can be used to modulate the osmotic tension of a liquid formulation. Suitable osmotic tension modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose, and others known to those skilled in the art. In some embodiments, the osmotic tension of the liquid formulation approximates that of blood or plasma.

[0202] As used herein, the term “defoaming agent” is intended to mean a compound(s) that prevents or reduces the amount of foaming formed on the surface of a liquid formulation. Suitable defoaming agents include dimethicone, simethicone, octoxynol, and others known to those skilled in the art.

[0203] As used herein, the term “bulking agent” is intended to mean a compound used to add bulk to a solid product and / or to help control the properties of the formulation during lyophilization. Examples of such compounds include, but are not limited to, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethyl sulfoxide, glycerol, albumin, calcium lactobionate, and others known to those skilled in the art.

[0204] As used herein, the term “antifreeze” is intended to mean a compound used to protect an active therapeutic agent from physical or chemical degradation during freeze-drying. Examples of such compounds include, but are not limited to, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol, and others known to those skilled in the art.

[0205] 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 for the purpose of stabilizing 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, 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 others known to those skilled in the art.

[0206] A solubility enhancer may be added to the formulation of the present invention. The solubility enhancer is a compound(s) that improves the solubility of the activator when present in a liquid formulation. When such an agent is present, the cyclodextrin / activator ratio may change. Suitable solubility enhancers include one or more organic solvents, typically used in parenteral formulations to improve the solubility of a particular agent. Examples include cleaning agents, soaps, surfactants, and other organic compounds.

[0207] Suitable organic solvents include, for example, ethanol, glycerin, polyethylene glycol, propylene glycol, poloxamer, and others known to those skilled in the art.

[0208] Preparations comprising the alkylated cyclodextrin composition of the present invention may also 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 glycerides, acetylated fatty acid glycerides, and combinations thereof. Preparations comprising the alkylated cyclodextrin composition of the present invention may also include alcohols (e.g., ethanol, isopropanol, hexadecyl alcohol, glycerol, propylene glycol, etc.), glycerol 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.

[0209] Compounds used in the field of pharmaceutical formulations should generally be understood to serve a variety of functions or purposes. Therefore, when a compound designated herein is mentioned only once or used to define more than one term herein, its purpose or function should not be construed as being exclusively limited to the designated purpose(s) or function(s).

[0210] The formulations comprising the alkylated cyclodextrin composition of the present invention may also comprise biological salts, sodium chloride, potassium chloride, and other electrolytes.

[0211] Since some activators are subjected to oxidative degradation, the liquid formulations according to the present invention may be substantially oxygen-free. For example, the headspace of a container containing the liquid formulation may become oxygen-free, substantially oxygen-free, or have reduced oxygen levels 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 activators subjected to oxidative degradation may be stored in an oxygen-free or oxygen-reduced environment. Removal of oxygen from the formulation improves its preservation against aerobic microorganisms; on the other hand, addition of oxygen to the formulation improves its preservation against anaerobic microorganisms.

[0212] The phrase “pharmaceutically acceptable” is used herein to mean a compound, material, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and which corresponds to a reasonable benefit-risk ratio.

[0213] As used herein, the terms “patient” or “subject” are used to mean, for example, warm-blooded animals such as mammals, such as cats, dogs, mice, guinea pigs, horses, cattle, cows, sheep, non-humans, and humans.

[0214] The formulations of the present invention contain an active agent present in an effective amount. The term "effective amount" refers to an amount or quantity of the active agent sufficient to elicit the required or desired response; in other words, an amount sufficient to elicit a substantial biological response when administered to a subject.

[0215] The compositions of the present invention can be, for example, reconfigurable solids, tablets, capsules, pills, lozenges, and more. It may exist in the form of a stick, osmotic device, stick formulation, suppository, implant, gum, effervescent composition, liquid for injection, eye drops or nasal drops, or formulation for inhalable powder or solution.

[0216] The present invention also provides a method for preparing a liquid formulation comprising one or more activators and an alkylated cyclodextrin composition, wherein the alkylated cyclodextrin composition comprises alkylated cyclodextrin and a phosphate in an amount of less than 500 ppm. The first method comprises: forming a first aqueous solution comprising the alkylated cyclodextrin composition; forming a second solution or suspension comprising one or more activators; and mixing the first and second solutions to form a liquid formulation. A similar second method comprises directly adding one or more activators to the first solution without forming a second solution. The third method comprises directly adding the alkylated cyclodextrin composition to a solution / suspension containing one or more activators. The fourth method comprises adding a solution containing one or more activators to a powdered or particulate alkylated cyclodextrin composition. The fifth method comprises directly adding one or more activators to a powdered or particulate alkylated cyclodextrin composition and adding the resulting mixture to a second solution. The sixth method comprises producing a liquid formulation by any of the above methods, and then isolating the solid 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 solid for reconstitution.

[0217] Specific embodiments of a method for preparing a liquid formulation include: 1) the method further comprising sterile filtering the formulation using a filter medium having a pore size of 0.1 μm or larger; 2) the liquid formulation being sterilized by irradiation or autoclaving; 3) the method further comprising isolating a solid from a solution; and 4) the solution being purged with nitrogen, argon, or other inert, pharmaceutically acceptable gas such that a substantial portion of the oxygen dissolved in and / or in surface contact with the solution is removed.

[0218] The present invention also provides a reconstitutable solid pharmaceutical composition comprising one or more active agents, an alkylated cyclodextrin composition and optionally at least one other pharmaceutical excipient. The composition can be administered to a subject by injection, by infusion, topically, by inhalation, or orally when reconstituted with an aqueous liquid to form a preserved liquid formulation.

[0219] In some embodiments of the reconstitutable solid pharmaceutical composition: 1) the pharmaceutical composition comprises a mixture of an alkylated cyclodextrin composition and a solid comprising one or more active agents and optionally at least one solid pharmaceutical excipient, such that most of the active agent does not complex with the alkylated cyclodextrin prior to reconstitution; and / or 2) the composition comprises a solid mixture of an alkylated cyclodextrin composition and one or more active agents, such that most of the one or more active agents complex with the alkylated cyclodextrin prior to reconstitution; are included.

[0220] The compositions of the present invention can be used in pharmaceutical dosage forms, pharmaceutical compositions, or other such combinations of materials. These alkylated cyclodextrin compositions are also useful as, but not limited to, analytical reagents, food and cosmetic adjuvants and / or additives, and environmental purifying agents.

[0221] In view of the above description and the following examples, those skilled in the art will be able to practice the claimed invention without undue experimentation. The above will be better understood by reference to the following examples which detail certain procedures for the preparation of the molecules, compositions, and formulations according to the present invention. All references to these examples are for illustrative purposes. The following examples should not be considered to be inclusive, but merely illustrate some of the many embodiments contemplated by the present invention.

Example

[0222] Example 1 SBE 6.6 -β-CD synthesis SBE6.6 -β-CD composition is synthesized by the following procedure: β-cyclodextrin in an alkaline aqueous medium is derivatized with an SBE precursor, and then SBE 6.6 -β-CD is formed. An aqueous solution of sodium hydroxide is prepared by adding 61.8 kg of sodium hydroxide to 433 kg of water to make a 12.5% ​​w / w solution. After heating the contents of the reactor to between 40°C and 50°C, the addition of 270 kg of β-CD is started over 30 to 60 minutes. After adjusting the reaction temperature to between 65°C and 95°C, 259 kg of 1,4-butanesultone is added over 30 to 60 minutes. For the next 6 hours, the pH of the solution is maintained above 9 using an aqueous solution of sodium hydroxide. After the reaction, a further 13.5 kg of sodium hydroxide, which is a 20% solution, is added to the reaction. The contents are maintained at a temperature between 70°C and 80°C until the residual level of 1,4-butanesultone is sufficiently low. The contents are cooled to below 30°C, and the reaction solution is adjusted to a pH of 6.5 to 7.5 with an aqueous solution of hydrochloric acid. This process generates 350-450 kg of SAE-CD.

[0223] Example 2 SBE 6.6 -β-CD dialysis filtration and ultrafiltration SBE of Example 1 6.6 -β-CD is purified by the following procedure: Dilute the reaction solution with 800 kg of water. Transfer the solution and further dilute it with 500 kg of water. Dialysis filtration is performed for at least 750 ft 2 The process is initiated using a Millipore Helicon automated ultrafiltration system with a 1000MWCO spiral-type regenerated cellulose membrane having a membrane surface area, and maintaining a constant solution volume (±1%) until the returnate sample contains 25 ppm or less of sodium chloride. The solution is then concentrated by ultrafiltration until an appropriate solution mass is achieved.

[0224] Example 3 Activated carbon purification using a multi-step washing / immersion process Approximately 500 liters of water and 38 kg of SHIRASAGI® DC32 granular activated carbon are added to the first and second tanks respectively, and the mixture is stirred at 60-80 rpm. While draining the water from the tanks, more water is added, and the conductivity of the drained water is measured. The activated carbon is continuously washed for approximately 6-12 hours until a conductivity of 10 μS / cm or less is achieved. Once the desired conductivity level is reached, the water is drained from the tanks, and the tank contents (carbon / water slurry) are added to the first and second columns.

[0225] When filling the first and second columns, fill the columns from top to bottom with purified water. Once full, hold the water in the columns for 30-45 minutes. Then, flush the columns with purified water, draining from the bottom. After 30 minutes of continuous flushing, stop the water flow and allow the water to drain out of the columns.

[0226] Next, approximately 250-300 L of partially purified alkylated cyclodextrin solution is added to each column by pouring it in from the bottom. The solution is immersed in the column at room temperature while stirring at approximately 40-50 rpm. After 2 hours, the partially purified alkylated cyclodextrin solution is drained from the column and discarded. The column is then flushed with purified water from the top for 30 minutes. The water is then drained from the column.

[0227] Next, purified water is added to the column from the bottom to the top, left for 30 minutes, and then the water is drained out. Purified water is then added to the top of the column and drained out from the bottom. This flushing is continued for at least 1 hour, and the conductivity of the drained water is measured. 10 μS / cm Repeat the process until the following conductivity is achieved. Once the desired conductivity is reached, fill the column with purified water and prepare the activated carbon for use in the preparation of the final purified alkylated cyclodextrin solution described in Example 4.

[0228] Example 4 SBE of the present invention 6.6 -β-CD carbon treatment After dialysis filtration and ultrafiltration in Example 2, SBE 6.6 -β-CD is carbon purified using the following procedure: 32 kg (approximately 11-12% (11.8-12% by weight) of β-cyclodextrin starting material) of Shirasagi is placed in the column. (登録商標) DC32 granular activated carbon is added and prepared using the procedure described herein in Example 3. SBE 6.6 The ratio of β-CD to activated carbon is approximately 8.4:1 to 8.5:1 (approximately 8.44:1). After washing, the reaction solution is passed through the activated carbon for at least 2 hours (recirculated) to complete the first treatment cycle.

[0229] In the second column, 32 kg (approximately 11-12% by weight of β-cyclodextrin as starting material) of Shirasagi (登録商標) Add DC32 granular activated carbon and prepare it using the procedure described herein in Example 3. After washing, pass the reaction solution through the activated carbon for at least 2 hours to complete the second treatment cycle.

[0230] Example 5 SBE 6.6 -β-CD enrichment and isolation The carbon-treated SBE prepared in Example 4 6.6 - The β-CD solution is concentrated and isolated using the following procedure: SBE 6.6 -β-CD solution was filtered through 0.65 μm and 0.22 μm filters, and then 50% w / w SBE was added while stirring at 70 rpm to 100 rpm at a temperature of 65°C to 72°C under reduced pressure of -0.6 bar to -0.7 bar. 6.6 The solution is concentrated until a solution with a β-CD concentration is obtained. The concentrated solution is cooled to below 60°C and then filtered through 0.65 μm and 0.22 μm filters. The filtered solution is then spray-dried using a fluidized spray dryer ("FSD") system with an inlet temperature of 170°C and an initial pressure of 20 bar, and chambers 1-3 having setpoints of 125°C, 105°C, and 100°C, respectively.

[0231] Example 6 SBE6.6 Comparative carbon treatment of -β-CD Exemplary SBE 6.6 Purify -β-CD by carbon in the following procedure: Charge 32 kg of Shirasagi (登録商標) DC32 granular activated carbon into the column and wash it thoroughly with water until the washed sample has a substantially constant conductivity. After washing, pass the reaction solution through the above activated carbon for at least 2 hours.

[0232] Example 7 SBE 6.6 Comparative carbon treatment of -β-CD Exemplary SBE 6.6 Purify -β-CD by carbon in the following procedure: Charge 32 kg of SHIRASAGI (registered trademark) DC32 granular activated carbon (β-cyclodextrin with a starting amount of about 11-12 wt% (11.8-12 wt%)) into the column and wash it thoroughly with water until the washed sample has a constant conductivity. The ratio of SBE6.6-β-CD to activated carbon is about 8.4:1 - 8.5:1 (about 8.44:1). Once washed, pass the reaction solution through the above activated carbon for at least 2 hours (recycle) to complete the first treatment cycle.

[0233] Charge 32 kg of SHIRASAGI (registered trademark) DC32 granular activated carbon (β-cyclodextrin with a starting amount of about 11-12 wt%) into the second column and wash it thoroughly with water until the washed sample has a substantially constant conductivity. Once washed, pass the reaction solution through the above activated carbon for at least 2 hours to complete the second treatment cycle.

[0234] After the second treatment cycle, analyze SBE6.6-β-CD using ion chromatography to determine the chloride concentration.

[0235] Example 8 SBE 6.6 Comparative carbon treatment of -β-CD Exemplary SBE 6.6-β-CD was carbon-purified by the following procedure: 32 kg of SHIRASAGI (registered trademark) DC32 granular activated carbon (β-cyclodextrin at a starting amount of about 11-12 wt% (11.8-12 wt%)) was charged into a column and washed thoroughly with water until the conductivity level of the wash sample had a conductivity level of less than 10 μS / cm. The conductivity was determined using ion chromatography (mobile phase of 4 mM sodium bicarbonate in methanol / water (1:9), flow rate 1 mL / min, sample volume 20 μL and run time 10 min, at 25 °C, using a 4.0X250 mm USP packing L50 or similar).

[0236] The ratio of SBE6.6-β-CD to activated carbon is about 8.4:1 to 8.5:1 (about 8.44:1). Once washed, the reaction solution was passed (recirculated) through the activated carbon for at least 2 hours to complete the first treatment cycle.

[0237] 32 kg of SHIRASAGI (registered trademark) DC32 granular activated carbon (β-cyclodextrin at a starting amount of about 11-12 wt%) was charged into a second column and washed thoroughly with water until the wash sample had a conductivity level of less than 10 μS / cm (measured by ion chromatography (mobile phase of 4 mM sodium bicarbonate in methanol / water (1:9), flow rate 1 mL / min, sample volume 20 μL and run time 10 min, at 25 °C, using a 4.0X250 mm USP packing L50 or similar)). Once washed, the reaction solution was passed through the activated carbon for at least 2 hours to complete the second treatment cycle.

[0238] After the second treatment cycle, SBE6.6-β-CD can be analyzed using ion chromatography to determine the chloride concentration.

[0239] Example 9 SBE 6.6 -β-CD Comparative Carbon Treatment Exemplary SBE 6.6-β-CD is purified by the following procedure: 32 kg of SHIRASAGI® DC32 granular activated carbon (approximately 11-12% by weight (11.8-12% by weight) of alkylated cyclodextrin) filled with purified water is introduced into the first and second columns in a reverse flow (bottom to top) direction and left to stand. After 30 minutes, the water is drained from the columns. The first and second columns are again filled with purified water in a reverse flow (bottom to top) direction and left to stand. After 30 minutes, the water is drained from the columns. The first and second columns are filled with purified water for the third time in a reverse flow (bottom to top) direction and left to stand. After 30 minutes, the water is drained from the columns.

[0240] Next, purified water is packed into the first and second columns in a reverse flow direction and left to stand. After 4 hours, the purified water is passed through the columns in a reverse flow direction for 3 hours at a rate of approximately 100 liters / hour in the first column and approximately 300 liters / hour in the second column.

[0241] Next, purified water is passed through the first and second columns in a parallel flow direction. After approximately 1,000 liters of purified water, the conductivity of the water is tested. The washing process is considered complete when the measured conductivity is less than 10 μS / cm.

[0242] If the measured conductivity exceeds 10 μS / cm, follow the further washing procedure. First, drain the water from the first and second columns. Next, fill the first and second columns with purified water in the reverse direction and let stand. After 2 hours, pass purified water through the columns in the reverse direction for 2 hours at a rate of approximately 100 liters / hour in the first column and approximately 300 liters / hour in the second column. Next, pass purified water through the first and second columns in the parallel direction. After approximately 1,000 liters of purified water, test the conductivity of the water. The washing process is considered complete when the measured conductivity is less than 10 μS / cm. If the measured conductivity is greater than 10 μS / cm, repeat the steps in this paragraph until the measured conductivity is less than 10 μS / cm.

[0243] Example 9 Measurement of impurities at each stage of processing SBE as the final product after reaction inspection, ultrafiltration, carbon treatment, and concentration 6.6 The -β-CD sample is separated, identified, and quantified using a Shimadzu Prominence20A HPLC device and a ZIC® pHILIC column (150x4.6 mm, 5 μm, 200 Å, PEEK Merck SeQuant (商標) SN1479) with a Corona (ESA Bioscience) Charged Aerosol Detector. The gradient mobile phase method is carried out using a solution of 100 mM ammonium formate (adjusted to pH 4.6) in methanol, 2-propanol, and acetonitrile 15 / 5 / 20 / 65 (A), and a solution of 30 mM ammonium formate (adjusted to pH 4.6) in methanol, 2-propanol, and acetonitrile 65 / 5 / 20 / 10 (B). A Captisol® sample solution is prepared at a concentration of approximately 40 mg / mL in HPLC grade acetonitrile / water and analyzed against a prepared reference solution of known concentrations of 4-hydroxybutane-1-sulfonic acid, disodium bis(4-sulfobutyl) ether, chloride, sodium, phosphate, silicon dioxide, and β-cyclodextrin in acetonitrile / water at the impurity specification limits. Validation tests showed that the method was specific, linear within the impurity specification range, accurate, and stable. The gradient used is shown in the following table.

Table 6

[0244] Example 10 Measurement of chloride concentration SBE as the final product after reaction inspection, ultrafiltration, carbon treatment, and concentration 6.6 The -β-CD sample is analyzed using a Corona (ESA Bioscience) Charged Aerosol Detector or using ion chromatography.

[0245] Example 11 Measurement of chloride concentration SBE 6.6 -β-CD samples were prepared using carbon treatment methods similar to those in Examples 3 and 6-9, and their chloride levels were determined (Figure 1). Batch HE00083-HE00096 were prepared using a carbon treatment method similar to that of Example 3, while the other batches shown were prepared using the carbon treatment methods of Examples 6-9. The results show that all batches prepared using the carbon treatment method similar to that of Example 3 had significantly higher chloride levels compared to batches prepared using the carbon treatment methods of Examples 6-9. All batches produced after HE00083 had chloride levels of less than 0.05% (w / w), as shown in the table below. [Table 7]

[0246] Conclusion These examples illustrate possible embodiments of the present invention. While various embodiments of the present invention 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 in form and detail can be made herein without departing from the spirit and scope of the present invention. Therefore, the breadth and scope of the present invention should not be limited by any of the above exemplary embodiments, but should be defined solely by the following claims and their equivalents.

[0247] It should be noted that the detailed description section, rather than the summary and abstract section, is intended to be used to interpret the claims. The summary and abstract section may describe one or more exemplary embodiments of the invention envisioned by the inventors(s), rather than all of them, and is therefore not intended to limit the scope of the invention and the appended claims.

[0248] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0249] 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 incorporated herein by reference in their entirety, including all data, tables, drawings, and text contained herein.

Claims

1. 1. A method for making an alkylated cyclodextrin composition, comprising: (a) combining a cyclodextrin with an alkylating agent to form a reaction environment containing an alkylated cyclodextrin; (b) performing one or more separations to form a partially purified solution comprising said alkylated cyclodextrin; (c) preparing activated carbon, the carbon washing process comprising: subjecting activated carbon to a carbon washing process, the carbon washing process comprising adding a portion of the partially purified solution containing the alkylated cyclodextrin to activated carbon, soaking the activated carbon in the partially purified solution, and eluting and discarding the solution; and (d) treating the remaining partially purified solution with the activated carbon prepared in step (c) to produce a final purified alkylated cyclodextrin composition. The method comprising:

2. 10. The method of claim 1, wherein the one or more separations are ultrafiltration, diafiltration, centrifugation, extraction, solvent precipitation, or dialysis.

3. 3. The method of claim 1 or claim 2, wherein the activated carbon in step (c) is first subjected to an initial washing process comprising adding water to the activated carbon and eluting the water, the eluted wash water having a residual conductivity of 10 μΞ / cm or less.

4. 4. The method of any one of claims 1 to 3, wherein the residual conductivity of the elution wash water is 8 μS or less.

5. 4. The method of any one of claims 1 to 3, wherein the residual conductivity of the elution wash water is 6 μS or less.

6. The method of any one of claims 3 to 5, wherein the initial carbon cleaning process is carried out for about 6 hours.

7. The method of any one of claims 3 to 5, wherein the initial carbon cleaning process is carried out for about 12 hours.

8. 8. The method of any one of claims 3 to 7, wherein the activated carbon of (c) is further subjected to a washing process comprising flowing water over the activated carbon after the initial carbon washing process.

9. 9. The method of claim 8, wherein the water is allowed to flow over the activated carbon for at least 30 minutes.

10. 9. The method of claim 8, wherein the water is allowed to flow over the activated carbon for at least two hours.

11. 11. The method of any one of claims 1 to 10, wherein the activated carbon of step (c) is subsequently subjected to a washing process comprising adding water to the activated carbon and eluting the water, wherein the eluted wash water has a residual conductivity of 10 μS / cm or less.

12. 12. The method of claim 11, wherein the residual conductivity of said elution wash water from said subsequent carbon wash process is 8 μS or less.

13. 12. The method of claim 11, wherein the residual conductivity of said elution wash water from said subsequent carbon wash process is 6 μS or less.

14. The method of any one of claims 1 to 13, wherein the activated carbon is phosphate-free.

15. The method of any one of claims 1 to 13, wherein the activated carbon is in granular form.

16. 16. The method of any one of claims 1 to 15, wherein the final purified alkylated cyclodextrin composition contains less than 500 ppm phosphate.

17. 16. The method of any one of claims 1 to 15, wherein the final purified alkylated cyclodextrin composition contains less than 125 ppm phosphate.

18. 18. The method of any one of claims 1 to 17, wherein the final purified alkylated cyclodextrin composition contains less than 0.1% (w / w) chloride.

19. 18. The method of any one of claims 1 to 17, wherein the final purified alkylated cyclodextrin composition contains less than 0.05% (w / w) chloride.

20. 18. The method of any one of claims 1 to 17, wherein the final purified alkylated cyclodextrin composition contains less than 0.01% (w / w) chloride.

21. 18. The method of any one of claims 1 to 17, wherein the final purified alkylated cyclodextrin composition further comprises less than 0.002% (w / w) chloride.

22. 18. The method of any one of claims 1 to 17, wherein the final purified alkylated cyclodextrin composition has an average degree of substitution of 2 to 9.

23. 23. The method of any one of claims 1 to 22, wherein the final purified alkylated cyclodextrin composition has an average degree of substitution of 4.5 to 7.

5.

24. 23. The method of any one of claims 1 to 22, wherein the final purified alkylated cyclodextrin composition has an average degree of substitution of 6 to 7.

5.

25. The alkylated cyclodextrin is a sulfoalkyl ether cyclodextrin of formula (II): 【Chemistry 1】 where p is 4, 5, or 6; R １ is —OH or —O—(C ２ -C ６ (alkylene)-SO ３ － -T, where T is independently selected at each occurrence from a pharmaceutically acceptable cation, with the proviso that at least one R １ is —OH, and at least one R １ is O-(C ２ -C ６ (alkylene)-SO ３ － -Let be T; The method according to any one of claims 1 to 24, wherein

26. R １ is —OH or —O—(C ４ (alkylene)-SO ３ － -T, independently selected at each occurrence from Na ＋ 26. The method of claim 25, wherein:

27. 27. The method of any one of claims 1 to 26, further comprising combining the alkylated cyclodextrin composition with one or more excipients.

28. 27. The method of any one of claims 1 to 26, further comprising combining the alkylated cyclodextrin composition with an active agent.

29. A product prepared by the method of any one of claims 1 to 28.

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