Composition of Hydroxypropyl-beta-cyclodextrin and Method for Purifying Same

Abstract

The present disclosure relates to compositions that include a mixture of hydroxypropyl-β-cyclodextrins, which may be isomerically purified. The present disclosure also relates to methods for isomerically purifying a mixture of hydroxypropyl-β-cyclodextrins.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 311,661, filed February 18, 2022, entitled "COMPOSITIONS OF HYDROXYPROPYL-BETA-CYCLODEXTRIN AND METHODS OF PURIFYING THE SAME," the entire contents of which are incorporated herein by reference. This disclosure relates to mixtures of beta-cyclodextrin molecules. This disclosure also relates to compositions comprising mixtures of beta-cyclodextrin molecules. Accordingly, this disclosure relates to the fields of chemistry and pharmacy. [Background technology]

[0002] Hydroxypropyl-β-cyclodextrin ("HPBCD") is a common organic molecule with a variety of industrial uses. These include pharmaceutical excipients, polymers, solubilizers, chelating agents, drug delivery vehicles, and various other uses. HPBCD is commercially produced on a large scale. HPBCD is typically prepared by exposing β-cyclodextrin to propylene oxide in the presence of a base to alkylate the cyclodextrin ring with hydroxypropyl groups. Alkylation (or addition of the hydroxypropyl group) can potentially occur at any available alcohol site on the cyclodextrin ring. On an industrial scale, this alkylation process is poorly controlled, and the resulting HPBCD product is typically a crude mixture of HPBCD molecules, ranging from a single hydroxyl substituent to a fully alkylated molecule in which all 21 possible alkylation sites are occupied by hydroxypropyl groups, including all possible substitution combinations in between. Furthermore, subsequent alkylation can occur at any or all of the 21 available hydroxyl sites on the cyclodextrin structure, resulting in an extremely large set of possible substitution patterns. In fact, it has been found that there are 117,655 possible isomeric configurations that can occur on the main face of the cyclodextrin ring structure alone. See Liu, Jiang & Wang, Bo & Przybylski, Cedric & Bistri, Olivia & Menand, Mickael & Zhang, Yongmin & Sollogoub, Matthieu. (2021). Programmed Synthesis of Hepta-Differentiated β-Cyclodextrin: 1 out of 117,655 Arrangements. Angewandte Chemie (International ed. in English). 60.10.1002 / anie.202102182. Even more strikingly, the number of possible substitution patterns when all 21 positions are considered is exponentially larger.

[0003] In many applications of HPBCD, commercially available crude mixtures are acceptable for their intended purposes, and there is generally no technical or economic reason to expend resources to isolate or isomerically purify the mixture into simpler groups or individual compounds. However, there are certain applications of HPBCD that require a more purified mixture or even a single isomer. For example, there may be a need to selectively solubilize or chelate a specific guest molecule found within a mixture of many substituents in a solution or suspension, such as cholesterol in blood or spinal fluid. A crude HPBCD mixture in the presence of a guest molecule may solubilize the guest molecule, but may also solubilize certain bystander molecules that are undesirable for solubilization or chelation. Conversely, there may also be a need to selectively solubilize or deliver a guest molecule (such as a pharmaceutical) to a specific environment or organ. A crude HPBCD mixture may well be capable of carrying the guest molecule, but may not be able to selectively deliver or release the guest molecule to a specific environment or organ. On the other hand, a particular HPBCD isomer or group of isomers may be able to selectively solubilize or deliver a desired guest molecule to a desired environment or organ. Alternatively, if a concise group of HPBCD isomers, or other components in a mixture, can be used to identify, isolate, and / or enrich individual compounds that can selectively solubilize, chelate, deliver, or capture a specific guest molecule of interest, their unique chemical properties can be amplified and utilized, which are not typically available from the use of a crude HPBCD mixture. The specific guest molecule of interest may be cholesterol. The specific guest molecule of interest may be one or more lipids.

[0004] Thus, in view of the above-described shortcomings of commercially available crude mixtures of HPBCD, certain applications require fine-tuning of HPBCD selectivity to capture, deliver, or solubilize guest or target molecules using a particular HPBCD molecule or a concise group of HPBCD isomers that can be isolated from a commercially available crude HPBCD mixture. A concise group of HPBCD isomers may include similar HPBCD molecules isolated in groups, such as by molecular weight, alkylation or substitution pattern, or some other chemical property or characteristic.

[0005] The present invention provides the isolation and use of various specific, similar HPBCD isomers for use as selective solubilizers or chelators, allowing for fine-tuning of selectivity. These isolated groups of HPBCD molecules with similar chemical properties can then be used for very specific purposes. Where crude mixtures may provide generalized results, the use of groups of isomerically similar HPBCD molecules can be used to obtain more precise pharmacological or chemical results. For example, the present invention provides the isolation and use of specific HPBCD molecular mixtures for selectively solubilizing or chelating cholesterol. The improved affinity for cholesterol exhibited by the mixtures of the present invention is advantageous for the treatment or prevention of diseases or conditions, such as Niemann-Pick disease type C, liver disease, cardiovascular disease, familial hypercholesterolemia, and cholesterol deposition.

[0006] Previously applied preparative chromatographic approaches to purify hydroxypropyl-β-cyclodextrin molecules and related materials utilize normal-phase silica gel, which separates the major hydroxypropyl-β-cyclodextrin components based on hydrophilic interactions between the OH groups of the silica gel and the OH groups of the hydroxypropyl-β-cyclodextrin components. However, this approach cannot separate the different isomers of hydroxypropyl-β-cyclodextrin. One reason for this is that the size and molecular weight distribution of the different isomers can be very narrow. Hydroxypropylation of β-cyclodextrin molecules does not add an OH group to the β-cyclodextrin molecule; rather, it simply replaces the OH group of the β-cyclodextrin with the OH group of the hydroxypropyl side chain. Because no ionic groups are added to the β-cyclodextrin molecule, the net charge of the molecule remains unchanged. These aforementioned technical factors make isomer separation by conventional chromatographic means (e.g., ion exchange, size exclusion, reversed-phase or normal-phase silica gel) technically unfeasible and / or economically impractical. Summary of the Invention

[0007] Provided herein are compositions comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the mixture comprising less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% beta-cyclodextrin substituted with one hydroxypropyl group ("DS-1"), the composition comprising an average degree of substitution of 6.02 to 7.98, and the composition suitable for administration to a patient in need thereof via intrathecal, intravenous, oral, or intracerebroventricular administration. In some embodiments, the composition has a pH of 6.0 to 7.9. In some embodiments, the composition has a true density of about 1.096 to 1.098 g / cm. 3In some embodiments, the osmolality of the composition is about 635-695 mOs / kg. In some embodiments, the composition further comprises a container and subvisible particulate matter, wherein the subvisible particulate matter 25 microns or greater in size is present in an amount of 600 / container or less. In some embodiments, the composition comprises 10 ppb or less of propylene glycol as measured by HPLC. In some embodiments, the composition comprises 10 ppb or less of propylene glycol as measured by gas chromatography. In some embodiments, the composition comprises 10 ppb or less of propylene glycol as measured by the PG / EG ratio of propylene glycol to ethylene glycol. In some embodiments, the composition comprises 1 ppm or less of propylene oxide.

[0008] In certain embodiments, the pharmaceutical composition comprises 5 EU / g or less ("NMT") of a beta-cyclodextrin mixture, 4 EU / g or less, 3 EU / g or less, or 2 EU / g or less of a beta-cyclodextrin mixture. In preferred embodiments, the pharmaceutical composition comprises 1.5 EU / g or less of a beta-cyclodextrin mixture. In certain embodiments, the pharmaceutical composition comprises 1.4 EU / g or less of a beta-cyclodextrin mixture, 1.3 EU / g or less, 1.2 EU / g or less, 1.1 EU / g or less, or 1.0 EU / g or less of a beta-cyclodextrin mixture.

[0009] In some embodiments, the total amount of other unspecified impurities is 0.05% or less as measured by HPLC. In some embodiments, the composition has a concentration of about 10 mg / mL to about 200 mg / mL. In some embodiments, the composition has a concentration of the mixture of β-cyclodextrin molecules of about 10 mg / mL to about 200 mg / mL. In some embodiments, the composition exhibits lower toxicity than Trappsol® Cyclo. In some embodiments, the composition has a conductivity of about 200 μS / cm or less. In some embodiments, the composition is stable for at least 6 months. In some embodiments, the composition further comprises at least one of a pharmaceutical excipient, a carrier, a pharmaceutically acceptable diluent, a pH adjuster, and a buffer. In some aspects, the pH adjuster is sodium hydroxide. In some aspects, the buffer comprises monosodium phosphate and disodium phosphate.

[0010] Also provided herein are methods for preparing a purified mixture of beta-cyclodextrin suitable for intrathecal, intravenous, oral, or intracerebroventricular administration to a patient in need thereof, the method comprising nanofiltering beta-cyclodextrin to obtain a purified mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the mixture containing less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% beta-cyclodextrin substituted with one hydroxypropyl group ("DS-1"), with an average degree of substitution between 6.02 and 7.98; and adjusting the pH of the nanofiltered purified mixture of beta-cyclodextrin to achieve a pH between 6.0 and 7.8. In some embodiments, the pH is adjusted with 0.1 M sodium hydroxide.

[0011] Also provided herein is a method for treating Niemann-Pick disease type C, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the mixture comprising less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% beta-cyclodextrin substituted with one hydroxypropyl group ("DS-1"), the composition comprising an average degree of substitution of 6.02 to 7.98, and the composition being suitable for administration to a patient in need thereof via intrathecal, intravenous, oral, or intracerebroventricular administration. Also provided herein is a composition for use in a method for treating Niemann-Pick disease type C, the method comprising administering a therapeutically effective amount of the composition to a patient in need thereof. The composition comprises a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the mixture comprising less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% beta-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). The composition has an average degree of substitution of 6.02 to 7.98, and the composition is suitable for administration to a patient in need thereof via intrathecal, intravenous, oral, or intracerebroventricular administration. Alternatively, the method may be a method for treating liver disease, cardiovascular disease, familial hypercholesterolemia, or cholesterol deposition. In some embodiments, the method comprises administering between about 50 mg and about 2000 mg of the beta-cyclodextrin mixture to the patient. In some examples, between about 50 mg and about 300 mg of the beta-cyclodextrin mixture is administered. In some embodiments, the method comprises administering the composition at 1-day, 2-day, or 3-day intervals. In some embodiments, the method comprises administering the composition once a week. In some embodiments, the composition is administered once every two weeks. In some embodiments, the administering comprises intravenously administering about 200 mg / kg to about 4100 mg / kg of the beta-cyclodextrin mixture to the patient.In some embodiments, administration results in a 75%±5%, 80%±5%, 85%±5%, 90%±5%, or 95%±5% reduction in one or more lipids (e.g., one or more LDL (low-density lipoprotein) and / or triglycerides). In some embodiments, administration prevents the progression of NPC when compared to no administration or administration of a placebo. In some embodiments, administration is sufficient to maintain or reduce one or more domain scores of the NPC severity scale selected from ambulation, fine motor skills, cognition, speech, swallowing, eye movement, memory, hearing, and seizures. In some embodiments, administration occurs within 4 hours. In some embodiments, the duration of administration (which is preferably intravenous administration) is about 4 hours or less.

[0012] Further provided herein is a composition comprising a mixture of β-cyclodextrin molecules, the mixture of β-cyclodextrin molecules being β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"), β-cyclodextrin substituted with six hydroxypropyl groups ("DS-6"), β-cyclodextrin substituted with seven hydroxypropyl groups ("DS-7"), β-cyclodextrin substituted with eight hydroxypropyl groups ("DS-8"), β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-9"), β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-10"), β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-11"), β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-12"), β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-13"), β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-14"), β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-15"), β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-16"). hydroxypropyl groups ("DS-9"), β-cyclodextrin substituted with 10 hydroxypropyl groups ("DS-10"), β-cyclodextrin substituted with 11 hydroxypropyl groups ("DS-11"), β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"), β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"), and β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"), wherein the mixture of β-cyclodextrin molecules contains less than 1% DS-4. In some embodiments, the composition has the HPLC-CAD chromatogram of Figure 4. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has an average HPLC-CAD retention time of about 13.5 minutes. In some embodiments, the mixture of β-cyclodextrin molecules has the DEPT-edited HSQC spectrum of Figure 3. In some embodiments, the mixture of β-cyclodextrin molecules includes from about 0.5 wt% to about 1 wt% DS-4. In some embodiments, the mixture of β-cyclodextrin molecules includes from about 2 wt% to about 5 wt% DS-5. In some embodiments, the mixture of β-cyclodextrin molecules includes from about 7 wt% to about 13 wt% DS-6. In some embodiments, the mixture of β-cyclodextrin molecules includes from about 21 wt% to about 27 wt% DS-7. In some embodiments, the mixture of β-cyclodextrin molecules includes from about 23 wt% to about 29 wt% DS-8.In some embodiments, the mixture of β-cyclodextrin molecules contains about 15% to about 21% w / w of DS-9. In some embodiments, the mixture of β-cyclodextrin molecules contains about 6% to about 12% w / w of DS-10. In some embodiments, the mixture of β-cyclodextrin molecules contains about 2% to about 6% w / w of DS-11. In some embodiments, the mixture of β-cyclodextrin molecules contains about 0.5% to about 4% w / w of DS-12. In some embodiments, the mixture of β-cyclodextrin molecules contains less than about 1% w / w of DS-13. In some embodiments, the composition does not contain DS-0, DS-1, DS-2, and / or DS-3. In some embodiments, the mixture of β-cyclodextrin molecules is suitable for intravenous, intrathecal, or intracerebroventricular administration. In some embodiments, the composition is suitable for intravenous, intrathecal, or intracerebroventricular administration. In some embodiments, the amounts of DS-1, DS-2, DS-3, DS-4, DS-5, DS-6, DS-7, DS-8, DS-9, DS-10, DS-11, DS-12, and DS-13 in a mixture of β-cyclodextrin molecules are determined by MALDI-TOF-MS. In some embodiments, DS-8 has the highest concentration in the mixture of β-cyclodextrin molecules compared to the concentrations of DS-1, DS-2, DS-3, DS-4, DS-5, DS-6, DS-7, DS-9, DS-10, DS-11, DS-12, and DS-13. In some embodiments, the β-cyclodextrin molecules are substituted at the 2-O-position between 35 and 55% of the molecules, at the 3-O-position between 45 and 65%, and at the 6-O-position between 0 and 20%. In some embodiments, the substitution rates at the 2-O-, 3-O-, and 6-O-positions are determined by DEPT-edited HSQC. These positions (2-O-, 3-O-, and 6-O-) on each glucose unit of β-cyclodextrin are identified below. In some embodiments, the composition has an average degree of substitution of about 7 to about 9. In an exemplary embodiment, the composition has an average degree of substitution of about 7.7. In some embodiments, the composition has the MALDI-TOF spectrum of FIG. 1. In some embodiments, the composition has a MALDI-TOF spectrum of about 1.095 g / cm.3 ~Approx. 1.100g / cm 3 In some embodiments, the composition has an osmolality of about 600 mOs / kg to about 750 mOs / kg. In some embodiments, the composition is a clear, colorless solution. In some embodiments, the composition has a pH of about 4.0 to about 6.0. In some embodiments, the composition has a viscosity of 1.5 cP to about 3.0 cP at 20°C. In some embodiments, the composition contains about 0.05% or less impurities. In some embodiments, the composition contains fewer than 600 particles per container having a diameter of 25 microns or greater. In some embodiments, the composition contains fewer than 6,000 particles per container having a diameter of 10 microns or greater.

[0013] Further provided herein is a composition comprising a mixture of β-cyclodextrin molecules, the composition comprising at least one peak at about 5.0-5.4 ppm corresponding to an anomeric proton of the β-cyclodextrin molecule, at least one peak at about 3.2-4.2 ppm corresponding to a proton in the core region of the β-cyclodextrin molecule, and at least one peak at about 1.0-1.2 ppm corresponding to a methyl proton of a side chain of the β-cyclodextrin molecule. 1 In some embodiments, the composition has a H-NMR spectrum of FIG. 1 1 H-NMR.

[0014] Fraction 1 mixture Also provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules, including less than 1% β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"). In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on weight percentage. In some embodiments, the composition comprises less than 1% β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 1% to about 5% β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin contains about 7% to about 13% β-cyclodextrin substituted with six hydroxypropyl groups ("DS-6"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin contains about 8% to about 12% DS-6. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin contains about 16% to about 22% β-cyclodextrin substituted with seven hydroxypropyl groups ("DS-7"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin contains about 17% to about 21% DS-7. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrins contains about 26% to about 32% 8-hydroxypropyl-substituted β-cyclodextrin ("DS-8"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrins contains about 27% to about 31% DS-8.In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin contains about 22% to about 28% β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-9"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin contains about 23% to about 27% DS-9. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin contains about 11% to about 17% β-cyclodextrin substituted with ten hydroxypropyl groups ("DS-10"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin contains about 12% to about 16% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains less than 1% β-cyclodextrin substituted with eleven hydroxypropyl groups ("DS-11"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains less than 1% of β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"), β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"), and β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"). In some embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrins is about 6.4 to about 7.0. In exemplary embodiments, the average degree of substitution is about 6.69. In some embodiments, about 52% to about 58% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some aspects, about 55% to about 56% of the hydroxypropyl substitutions in the β-cyclodextrin molecules are located at the 3-O-position. In some embodiments, about 41% to about 47% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are at the 2-O-position, and in some aspects, about 43% to about 45% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are at the 2-O-position.In some embodiments, the concentration of the composition does not substantially change the time required for nanofiltration. In some aspects, the length of time for nanofiltration of the composition ranges from 1.04 to 1.20 hours per diafiltration volume (kg solution / m2-hr / L solution). In some embodiments, the composition exhibits no substantial difference in HPLC-ELSD analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition exhibits no substantial difference in NMR analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition has a conductivity of 0 to 8.0 μS / cm, 0 to 4.5 μS / cm, 0 to 3 μS / cm, or 0 to 1.5 μS / cm. In some embodiments, the composition has an osmolality of about 600 mOs / kg to about 750 mOs / kg. In some embodiments, the composition is about 1.095 g / cm. 3 ~Approx. 1.100g / cm 3 In some embodiments, the composition has a pH of about 4.0 to about 8.0. In some embodiments, the composition has a viscosity of about 1.5 cP to about 10,000 cP at 20°C.

[0015] Further provided herein is a composition comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, including β-cyclodextrin substituted with 5 hydroxypropyl groups (“DS-5”), β-cyclodextrin substituted with 6 hydroxypropyl groups (“DS-6”), β-cyclodextrin substituted with 7 hydroxypropyl groups (“DS-7”), β-cyclodextrin substituted with 8 hydroxypropyl groups (“DS-8”), β-cyclodextrin substituted with 9 hydroxypropyl groups (“DS-9”), and β-cyclodextrin substituted with 10 hydroxypropyl groups (“DS-10”), wherein the composition contains less than 1% β-cyclodextrin substituted with 4 hydroxypropyl groups (“DS-4”) and less than 1% β-cyclodextrin substituted with 11 hydroxypropyl groups (“DS-11”). In some embodiments, the composition contains 0.0-1.0% of β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), 0.0-1.0% of β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and 0.0-1.0% of β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, the composition contains less than 1% of β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"), β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"), and β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"). In some embodiments, DS-8 has the highest concentration of isomerically purified hydroxypropyl β-cyclodextrin molecules in the mixture when compared to DS-5, DS-6, DS-7, DS-9, and DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 1% to about 5% DS-5, and in some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 7% to about 13% DS-6.In some embodiments, the isomerically purified hydroxypropyl β-cyclodextrin mixture contains about 16% to about 22% DS-7. In some embodiments, the isomerically purified hydroxypropyl β-cyclodextrin mixture contains about 26% to about 32% DS-8. In some embodiments, the isomerically purified hydroxypropyl β-cyclodextrin mixture contains about 22% to about 28% DS-9. In some embodiments, the isomerically purified hydroxypropyl β-cyclodextrin mixture contains about 11% to about 17% DS-10. In some embodiments, the isomerically purified hydroxypropyl β-cyclodextrin mixture has an average degree of substitution of about 6.4 to about 7.0. In an exemplary embodiment, the average degree of substitution is about 6.69. In some embodiments, about 52% to about 58% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are at the 3-O-position. In some embodiments, about 41% to about 47% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are at the 2-O-position. In an exemplary embodiment, the composition has the HPLC-CAD chromatogram of Figure 8. In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has an HPLC-CAD average retention time of about 10.1 minutes. In some embodiments, the composition has an ESI-MS spectrum with peaks at about 653 m / z, about 682 m / z, about 711 m / z, about 741 m / z, about 769 m / z, about 799 m / z, about 828 m / z, and about 857 m / z, and an ESI-MS spectrum with peaks at about 686 m / z, about 715 m / z, about 744 m / z, about 773 m / z, about 802 m / z, about 832 m / z, about 861 m / z, and about 890 m / z. In exemplary embodiments, the composition has the ESI-MS spectrum of Figure 9. In some embodiments, the composition has a MALDI-TOF spectrum with peaks at about 1436 m / z, about 1495 m / z, about 1555 m / z, about 1614 m / z, about 1674 m / z, and about 1733 m / z. In an exemplary embodiment, the composition has the MALDI-TOF spectrum of FIG.In an exemplary embodiment, the composition of FIG. 1 H-NMR spectrum. In exemplary embodiments, the composition has the DEPT-edited HSQC spectrum of FIG. 7. In some embodiments, the composition has an osmolality of about 635-695 mOs / kg. In some embodiments, the composition has a true density of about 1.096-1.098 g / cm. 3 In some embodiments, the composition has a conductivity of 0 to 8.0 μS / cm. In some embodiments, the composition has a pH of about 4.0 to about 8.0. In some embodiments, the composition has a viscosity of about 1.5 cP to about 10,000 cP at 20° C. In some embodiments, the composition contains 10 ppb or less of propylene glycol as measured by HPLC. In some embodiments, the composition contains 1 ppm or less of propylene oxide. In some embodiments, the total amount of other unspecified impurities is 0.05% or less as measured by HPLC. In some embodiments, the composition further contains 0 to 10 ppm of chloride. In some embodiments, the composition is nanofiltered. In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD after nanofiltration compared to the composition before nanofiltration. In some embodiments, the nanofiltered composition shows no substantial difference in NMR after nanofiltration compared to the composition before nanofiltration.

[0016] Fraction 2 Mixture Also provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, including less than 1% of hydroxypropyl β-cyclodextrin having less than 5 hydroxypropyl groups ("DS-5"). In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on weight percentage. In some embodiments, the composition comprises less than 1% of β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not contain DS-1, DS-2, DS-3, and / or DS-4. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 0% to about 6% hydroxypropyl β-cyclodextrin substituted with six hydroxypropyl groups ("DS-6"). In some aspects, the mixture of isomerically purified β-hydroxypropyl cyclodextrin molecules contains from about 1% to about 5% DS-6. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 8% to about 14% hydroxypropyl β-cyclodextrin substituted with seven hydroxypropyl groups ("DS-7"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 9% to about 13% DS-7. In some embodiments, the mixture of isomerically purified β-hydroxypropyl cyclodextrin molecules contains about 19% to about 25% hydroxypropyl β-cyclodextrin substituted with 8 hydroxypropyl groups (“DS-8”).In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 20% to about 24% DS-8. In some embodiments, the mixture of isomerically purified β-hydroxypropyl cyclodextrin molecules contains about 23% to about 29% hydroxypropyl β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-9"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 24% to about 28% DS-9. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 17% to about 23% hydroxypropyl β-cyclodextrin substituted with ten hydroxypropyl groups ("DS-10"). In some embodiments, the mixture of isomerically purified β-hydroxypropyl cyclodextrin molecules contains about 18% to about 22% DS-10. In some embodiments, the mixture of isomerically purified β-hydroxypropyl cyclodextrin molecules contains about 9% to about 15% hydroxypropyl β-cyclodextrin substituted with 11 hydroxypropyl groups ("DS-11"). In some aspects, the mixture of isomerically purified β-cyclodextrin molecules contains about 10% to about 14% DS-11. In some embodiments, the mixture of isomerically purified β-cyclodextrin molecules contains about 2% to about 8% hydroxypropyl β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"). In some aspects, the mixture of isomerically purified β-cyclodextrin molecules contains about 3% to about 7% DS-12. In some embodiments, the mixture of isomerically purified β-cyclodextrin molecules contains less than 1% hydroxypropyl β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13") and / or less than 1% hydroxypropyl β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not contain DS-13 and / or DS-14.In some embodiments, the mixture of isomerically purified β-cyclodextrin molecules has an average degree of substitution of about 7 to about 8. In an exemplary embodiment, the average degree of substitution is about 7.42. In some embodiments, about 36% to about 42% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some aspects, about 37% to about 41% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some embodiments, about 58% to about 64% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In some aspects, about 59% to about 63% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In some embodiments, the concentration of the composition does not substantially change the time required for nanofiltration. In some embodiments, the length of time for nanofiltration of the composition ranges from 1.04 to 1.20 hours per diafiltration volume (kg solution / m2-hr / L solution). In some embodiments, the composition exhibits no substantial difference in HPLC-ELSD analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition exhibits no substantial difference in NMR analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition has a conductivity of 0 to 8.0 μS / cm, 0 to 4.5 μS / cm, 0 to 3 μS / cm, or 0 to 1.5 μS / cm. In some embodiments, the composition has a pH of about 4.0 to about 8.0. In some embodiments, the composition has a viscosity of about 1.5 cP to about 10,000 cP at 20° C.

[0017] Further provided herein are β-cyclodextrins substituted with 6 hydroxypropyl groups ("DS-6"), β-cyclodextrins substituted with 7 hydroxypropyl groups ("DS-7"), β-cyclodextrins substituted with 8 hydroxypropyl groups ("DS-8"), β-cyclodextrins substituted with 9 hydroxypropyl groups ("DS-9"), β-cyclodextrins substituted with 10 hydroxypropyl groups ("DS-10"), β-cyclodextrins substituted with 11 hydroxypropyl groups ("DS-11"), and β-cyclodextrins substituted with 12 hydroxypropyl groups ("DS-12"). a composition comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, including β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-11"), and β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"); the composition contains less than 1% β-cyclodextrin substituted with 5 hydroxypropyl groups ("DS-5"); and the composition contains less than 1% β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"). In some embodiments, the composition contains less than 1% β-cyclodextrin substituted with 4 hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with 3 hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with 2 hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with 1 hydroxypropyl group ("DS-1"). In some embodiments, the composition contains less than 1% of β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13") and hydroxypropyl β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"). In some embodiments, the composition does not contain DS-1, DS-2, DS-3, DS-4, and / or DS-14. In some embodiments, DS-9 has the highest concentration in the composition compared to DS-6, DS-7, DS-8, DS-10, DS-11, and DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 0% to about 6% DS-6.In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 8% to about 14% DS-7. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 19% to about 25% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 23% to about 29% DS-9. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 17% to about 23% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 9% to about 15% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 2% to about 8% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has an average degree of substitution of about 7 to about 8. In some embodiments, about 36% to about 42% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some embodiments, about 58% to about 64% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In an exemplary embodiment, the composition has the HPLC-CAD chromatogram of Figure 13. In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has an average HPLC-CAD retention time of about 11.9 minutes. In some embodiments, the composition has a −ESI-MS spectrum with peaks at about 682 m / z, about 712 m / z, about 740 m / z, about 770 m / z, about 798 m / z, about 828 m / z, about 856 m / z, and about 886 m / z, and a +ESI-MS spectrum with peaks at about 744 m / z, about 773 m / z, about 803 m / z, about 832 m / z, about 860 m / z, about 889 m / z, and about 919 m / z.In some embodiments, the composition has a MALDI-TOF-MS spectrum with peaks at about 1497 m / z, about 1557 m / z, about 1616 m / z, about 1675 m / z, about 1734 m / z, about 1794 m / z, and about 1914 m / z. In an exemplary embodiment, the composition has the MALDI-TOF-MS spectrum of Figure 15. In an exemplary embodiment, the composition has the MALDI-TOF-MS spectrum of Figure 11. 1 In some embodiments, the composition has a H-NMR spectrum. In exemplary embodiments, the composition has a DEPT-edited HSQC spectrum of FIG. 12. In exemplary embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has an ESI-MS spectrum of FIG. 14. In some embodiments, the composition has an osmolality of about 635-695 mOs / kg. In some embodiments, the composition has a true density of about 1.096-1.098 g / cm. 3 In some embodiments, the composition contains 10 ppb or less of propylene glycol as measured by HPLC. In some embodiments, the composition contains 1 ppm or less of propylene oxide. In some embodiments, the total amount of other unspecified impurities is 0.05% or less as measured by HPLC. In some embodiments, the composition contains 0-10 ppm of chloride. In some embodiments, the composition has a conductivity of 0-8 μS / cm. In some embodiments, the composition is nanofiltered. In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD after nanofiltration compared to the composition before nanofiltration. In some embodiments, the nanofiltered composition shows no substantial difference in NMR after nanofiltration compared to the composition before nanofiltration.

[0018] Fraction 3 mixture Further provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, including 1% hydroxypropyl β-cyclodextrin substituted with less than 6 hydroxypropyl groups ("DS-6") and 1% β-cyclodextrin substituted with less than 14 hydroxypropyl groups ("DS-14"). In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on weight percentage. In some embodiments, the composition contains less than 1% of β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"), β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not contain DS-1, DS-2, DS-3, DS-4, and / or DS-5. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 1% to about 7% of β-cyclodextrin substituted with seven hydroxypropyl groups ("DS-7"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 2% to about 6% DS-7. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 16% to about 22% 8-hydroxypropyl-substituted β-cyclodextrin ("DS-8"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 17% to about 21% DS-8.In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 22% to about 28% β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-9"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 23% to about 27% DS-9. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 19% to about 25% β-cyclodextrin substituted with ten hydroxypropyl groups ("DS-10"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 20% to about 24% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 14% to about 20% β-cyclodextrin substituted with 11 hydroxypropyl groups ("DS-11"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 15% to about 19% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 5% to about 11% β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 6% to about 10% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 1% to about 7% β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 2% to about 6% DS-13. In some embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrin is about 8 to about 9. In an exemplary embodiment, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrin is about 8.53.In some embodiments, about 26% to about 32% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some aspects, about 27% to about 31% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some embodiments, about 68% to about 74% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In some aspects, about 69% to about 73% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In some embodiments, the concentration of the composition does not substantially change the time required for nanofiltration. In some aspects, the length of time for nanofiltration of the composition is dependent on the diafiltration volume (kg solution / m). 2 The range of solubility is 1.04 to 1.20 hours per 1000-1000 sq hr / L solution. In some embodiments, the composition shows no substantial difference in HPLC-ELSD analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition shows no substantial difference in NMR analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition has a conductivity of 0 to 8.0 μS / cm, 0 to 4.5 μS / cm, 0 to 3 μS / cm, or 0 to 1.5 μS / cm. In some embodiments, the composition has a pH of about 4.0 to about 8.0. In some embodiments, the composition has a viscosity of about 1.5 cP to about 10,000 cP at 20° C.

[0019] Further provided herein are β-cyclodextrins substituted with 7 hydroxypropyl groups ("DS-7"), β-cyclodextrins substituted with 8 hydroxypropyl groups ("DS-8"), β-cyclodextrins substituted with 9 hydroxypropyl groups ("DS-9"), β-cyclodextrins substituted with 10 hydroxypropyl groups ("DS-10"), β-cyclodextrins substituted with 11 hydroxypropyl groups ("DS-11"), β-cyclodextrins substituted with 12 hydroxypropyl groups ("DS-12"). A composition comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, including β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-12"), and β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"), wherein the composition contains less than 1% β-cyclodextrin substituted with 6 hydroxypropyl groups ("DS-6") and less than 1% β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"). In some embodiments, the composition contains less than 1% of β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"), β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, DS-9 has the highest concentration in the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules compared to DS-6, DS-7, DS-8, DS-10, DS-11, DS-12, and DS-13. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 1% to about 7% DS-7. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 16% to about 22% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 22% to about 28% DS-9.In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 19% to about 25% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 14% to about 20% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 5% to about 11% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 1% to about 7% DS-13. In some embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrin is about 8 to about 9. In an exemplary embodiment, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrin is about 8.53. In some embodiments, about 26% to about 32% of the hydroxypropyl substitutions on the β-cyclodextrin molecules are located at the 3-O-position. In some embodiments, about 68% to about 74% of the hydroxypropyl substitutions on the β-cyclodextrin molecules are located at the 2-O-position. In exemplary embodiments, the composition has the HPLC-CAD chromatogram of FIG. 18. In exemplary embodiments, the composition has an HPLC-CAD average retention time of about 13.5 minutes. In some embodiments, the composition has an ESI-MS spectrum with peaks at about 741 m / z, about 769 m / z, about 799 m / z, about 828 m / z, about 856 m / z, and about 886 m / z, and an ESI-MS spectrum with peaks at about 773 m / z, about 803 m / z, about 833 m / z, about 860 m / z, about 889 m / z, and about 920 m / z. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has the ESI-MS spectrum of Figure 19. In some embodiments, the composition has a MALDI-TOF spectrum with peaks at about 1557 m / z, about 1617 m / z, about 1676 m / z, about 1736 m / z, about 1795 m / z, about 1855 m / z, and about 1915 m / z. In an exemplary embodiment, the composition has the MALDI-TOF spectrum of Figure 20.In an exemplary embodiment, the composition has the DEPT-edited HSQC spectrum of Figure 17. In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has the DEPT-edited HSQC spectrum of Figure 16. 1 In some embodiments, the composition has an osmolality of about 635-695 mOs / kg. In some embodiments, the composition has a true density of about 1.096-1.098 g / cm. 3 In some embodiments, the composition contains 10 ppb or less of propylene glycol as measured by HPLC. In some embodiments, the composition contains 1 ppm or less of propylene oxide. In some embodiments, the total amount of other unspecified impurities is 0.05% or less as measured by HPLC. In some embodiments, the composition contains 0-10 ppm of chloride. In some embodiments, the composition contains 0-1 ppm of chloride. In some embodiments, the composition has a conductivity of 0-8 μS / cm. In some embodiments, the composition is nanofiltered. In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD after nanofiltration compared to before nanofiltration. In some embodiments, the nanofiltered composition shows no substantial difference in NMR after nanofiltration compared to before nanofiltration.

[0020] Fraction 4 mixture Also provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, including less than 1% of hydroxypropyl β-cyclodextrin having less than 6 hydroxypropyl groups ("DS-6"). In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on weight percentage. In some embodiments, the composition comprises less than 1% of β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"), β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not contain DS-1, DS-2, DS-3, DS-4, and / or DS-5. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 0% to about 6% β-cyclodextrin substituted with seven hydroxypropyl groups ("DS-7"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 1% to about 5% DS-7. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 13% to about 19% β-cyclodextrin substituted with eight hydroxypropyl groups ("DS-8"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 14% to about 18% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 22% to about 28% β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-9").In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 23% to about 27% DS-9. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 23% to about 29% β-cyclodextrin substituted with 10 hydroxypropyl groups ("DS-10"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 24% to about 28% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 12% to about 18% β-cyclodextrin substituted with 11 hydroxypropyl groups ("DS-11"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 13% to about 17% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 7% to about 13% β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 8% to about 12% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 2% to about 8% β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 3% to about 7% DS-13. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 0% to about 6% β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 1% to about 5% DS-14. In some embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrin is from about 7.5 to about 8.5.In exemplary embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrins is about 8.08. In some embodiments, about 22% to about 28% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some aspects, about 23% to about 27% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some embodiments, about 72% to about 78% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In some aspects, about 73% to about 77% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In some embodiments, the concentration of the composition does not substantially change the time required for nanofiltration. In some aspects, the length of time for nanofiltration of the composition is dependent on the diafiltration volume (kg solution / m). 2 The average solubility (Vol. 1) of the nanofiltered composition ranges from 1.04 to 1.20 hours per 1000-hr / L solution. In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD analysis after nanofiltration compared to before nanofiltration. In some embodiments, the nanofiltered composition shows no substantial difference in NMR analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition has a conductivity of 0 to 8.0 μS / cm, 0 to 4.5 μS / cm, 0 to 3 μS / cm, or 0 to 1.5 μS / cm. In some embodiments, the composition has a pH of about 4.0 to about 8.0. In some embodiments, the composition has a viscosity of about 1.5 cP to about 10,000 cP at 20° C.

[0021] Further provided herein are β-cyclodextrins substituted with 7 hydroxypropyl groups ("DS-7"), β-cyclodextrins substituted with 8 hydroxypropyl groups ("DS-8"), β-cyclodextrins substituted with 9 hydroxypropyl groups ("DS-9"), β-cyclodextrins substituted with 10 hydroxypropyl groups ("DS-10"), β-cyclodextrins substituted with 11 hydroxypropyl groups ("DS-11"), β-cyclodextrins substituted with 12 hydroxypropyl groups ("DS-12"). and β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-12"), β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"), and β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"), wherein the composition contains less than 1% β-cyclodextrin substituted with 6 hydroxypropyl groups ("DS-6"). In some embodiments, the composition contains less than 1% of β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"), β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not contain DS-1, DS-2, DS-3, DS-4, and / or DS-5. In some embodiments, DS-9 and DS-10 have the highest concentrations in the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules compared to DS-7, DS-8, DS-11, DS-12, DS-13, and DS-14, respectively. In some embodiments, DS-9 has the highest concentration in the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules when compared to DS-7, DS-8, DS-10, DS-11, DS-12, DS-13, and DS-14.In some embodiments, DS-10 has the highest concentration in the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules compared to DS-7, DS-8, DS-10, DS-11, DS-12, DS-13, and DS-14. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 0% to about 6% DS-7. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 13% to about 19% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 22% to about 28% DS-9. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 23% to about 29% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 12% to about 18% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 7% to about 13% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 2% to about 8% DS-13. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 0% to about 6% DS-14. In some embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrin is about 7.5 to about 8.5. In some embodiments, about 22% to about 28% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are at the 3-O-position. In some embodiments, about 72% to about 78% of the hydroxypropyl substitutions in the β-cyclodextrin molecules are at the 2-O-position. In exemplary embodiments, the composition has the HPLC-CAD chromatogram of Figure 23. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has an HPLC-CAD average retention time of about 14.3 minutes.In some embodiments, the composition has an ESI-MS spectrum with peaks at about 740 m / z, about 770 m / z, about 798 m / z, about 828 m / z, and about 857 m / z, and an ESI-MS spectrum with peaks at about 803 m / z, about 831 m / z, about 861 m / z, about 889 m / z, and about 919 m / z. In some embodiments, the composition has the ESI-MS spectrum of Figure 24. In some embodiments, the composition has a MALDI-TOF spectrum with peaks at about 1559 m / z, about 1618 m / z, about 1678 m / z, about 1737 m / z, about 1796 m / z, about 1857 m / z, and about 1916 m / z. In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has the MALDI-TOF-MS spectrum of Figure 25. In an exemplary embodiment, the composition has the DEPT-edited HSQC spectrum of Figure 22. In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has the DEPT-edited HSQC spectrum of Figure 21. 1 In some embodiments, the composition has an osmolality of about 635-695 mOs / kg. In some embodiments, the composition has a true density of about 1.096-1.098 g / cm. 3 In some embodiments, the composition contains 10 ppb or less of propylene glycol as measured by HPLC. In some embodiments, the composition contains 1 ppm or less of propylene oxide. In some embodiments, the total amount of other unspecified impurities is 0.05% or less as measured by HPLC. In some embodiments, the composition contains 0-10 ppm of chloride. In some embodiments, the composition has a conductivity of 0-8 μS / cm. In some embodiments, the composition is nanofiltered. In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD after nanofiltration compared to the composition before nanofiltration. In some embodiments, the nanofiltered composition shows no substantial difference in NMR after nanofiltration compared to the composition before nanofiltration.

[0022] Fraction 5 mixture Also provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, including 1% hydroxypropyl β-cyclodextrin having less than 7 hydroxypropyl groups ("DS-7"). In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on weight percentage. In some embodiments, the composition contains less than 1% of β-cyclodextrin substituted with six hydroxypropyl groups ("DS-6"), β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"), β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not include DS-1, DS-2, DS-3, DS-4, DS-5, DS-5, and / or DS-6. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 6% to about 12% β-cyclodextrin substituted with eight hydroxypropyl groups ("DS-8"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 7% to about 11% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 18% to about 24% β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-9"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 19% to about 23% DS-9.In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 24% to about 30% β-cyclodextrin substituted with 10 hydroxypropyl groups ("DS-10"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 25% to about 29% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 18% to about 24% β-cyclodextrin substituted with 11 hydroxypropyl groups ("DS-11"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 19% to about 23% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 10% to about 16% β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 11% to about 15% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 4% to about 10% β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 5% to about 9% DS-13. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 0% to about 6% β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"). In some aspects, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains from about 1% to about 5% DS-14. In some embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrin is from about 9 to about 10. In an exemplary embodiment, the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrin is about 9.65.In some embodiments, about 15% to about 21% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some aspects, about 16% to about 20% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some embodiments, about 79% to about 85% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In some aspects, about 80% to about 84% of the hydroxypropyl substitutions on the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In some embodiments, the concentration of the composition does not substantially change the time required for nanofiltration. In some embodiments, the length of time the composition is nanofiltered depends on the diafiltration volume (kg solution / m). 2 The range of solubility is 1.04 to 1.20 hours per 1000-1000 sq hr / L solution. In some embodiments, the composition shows no substantial difference in HPLC-ELSD analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition shows no substantial difference in NMR analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition has a conductivity of 0 to 8.0 μS / cm, 0 to 4.5 μS / cm, 0 to 3 μS / cm, or 0 to 1.5 μS / cm. In some embodiments, the composition has a pH of about 4.0 to about 8.0. In some embodiments, the composition has a viscosity of about 1.5 cP to about 10,000 cP at 20° C.

[0023] Further provided herein is a composition comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, including β-cyclodextrin substituted with 8 hydroxypropyl groups (“DS-8”), β-cyclodextrin substituted with 9 hydroxypropyl groups (“DS-9”), β-cyclodextrin substituted with 10 hydroxypropyl groups (“DS-10”), β-cyclodextrin substituted with 11 hydroxypropyl groups (“DS-11”), β-cyclodextrin substituted with 12 hydroxypropyl groups (“DS-12”), β-cyclodextrin substituted with 13 hydroxypropyl groups (“DS-13”), and β-cyclodextrin substituted with 14 hydroxypropyl groups (“DS-14”), wherein the composition contains less than 1% β-cyclodextrin substituted with 7 hydroxypropyl groups (“DS-7”). In some embodiments, the composition contains less than 1% of β-cyclodextrin substituted with six hydroxypropyl groups ("DS-6"), 1% of β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"), β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with three hydroxypropyl groups ("DS-3"), β-cyclodextrin substituted with two hydroxypropyl groups ("DS-2"), and β-cyclodextrin substituted with one hydroxypropyl group ("DS-1"). In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not include DS-1, DS-2, DS-3, DS-4, DS-5, and / or DS-6. In some embodiments, DS-10 has the highest concentration in the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules when compared to DS-8, DS-9, DS-11, DS-12, DS-13, and DS-14. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 6% to about 12% DS-8.In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 18% to about 24% DS-9. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 24% to about 30% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 18% to about 24% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 10% to about 16% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 4% to about 10% DS-13. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains about 0% to about 6% DS-14. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin has an average degree of substitution of about 9 to about 10. In some embodiments, about 15% to about 21% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position. In some embodiments, about 79% to about 85% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position. In an exemplary embodiment, the composition has the HPLC-CAD chromatogram of Figure 28. In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules has an average HPLC-CAD retention time of about 15.4 minutes. In some embodiments, the composition has a −ESI-MS spectrum with peaks at about 770 m / z, about 798 m / z, about 828 m / z, about 857 m / z, and about 885 m / z, and a +ESI-MS spectrum with peaks at about 803 m / z, about 831 m / z, about 861 m / z, about 889 m / z, and about 919 m / z. In an exemplary embodiment, the composition has the ESI-MS spectrum of Figure 29.In some embodiments, the composition has a MALDI-TOF spectrum with peaks at about 1614 m / z, about 1673 m / z, about 1733 m / z, about 1792 m / z, about 1852 m / z, about 1912 m / z, and about 1971 m / z. In an exemplary embodiment, the composition has the MALDI-TOF spectrum of Figure 30. In an exemplary embodiment, the composition has the MALDI-TOF spectrum of Figure 26. 1 H-NMR spectrum. In exemplary embodiments, the composition has the DEPT-edited HSQC spectrum of Figure 27. In some embodiments, the composition has an osmolality of about 635-695 mOs / kg. In some embodiments, the composition has a true density of about 1.096-1.098 g / cm 3 In some embodiments, the composition contains 10 ppb or less of propylene glycol as measured by HPLC. In some embodiments, the composition contains 1 ppm or less of propylene oxide. In some embodiments, the total amount of other unspecified impurities is 0.05% or less as measured by HPLC. In some embodiments, the composition contains 0-10 ppm of chloride. In some embodiments, the composition has a conductivity of 0-8 μS / cm. In some embodiments, the composition is nanofiltered. In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD after nanofiltration compared to the composition before nanofiltration. In some embodiments, the nanofiltered composition shows no substantial difference in NMR after nanofiltration compared to the composition before nanofiltration.

[0024] Compositions and mixtures of the present invention Further provided herein is a general subunit structure: [ka] an isomerically purified composition comprising a mixture of hydroxypropyl-β-cyclodextrin molecules having the formula:

[0025] In the formula, n=7=m+k+y+z, m=0 to 7, k=0 to 7, y=0 to 7, z=0 to 7, and R1, R2, and R3 each independently represent H, hydroxypropyl, or [ka] and wherein m refers to the number of subunits where R1 is not H, R2 is H, and R3 is H; k refers to the number of subunits where R1 is H, R2 is not H, and R3 is H; y refers to the number of subunits where R1 is H, R2 is H, and R3 is not H; z refers to the number of subunits where R1 is H, R2 is H, and R3 is H, where R3=H in at least 80% of the subunits. One of skill in the art will understand that R1 is located at the 3-O-position of the subunit structure, R2 is located at the 2-O-position, and R3 is located at the 6-O-position. In some embodiments, R3=H in at least 80% of the subunits, at least 90% of the subunits, at least 95% of the subunits, at least 99% of the subunits, or 100% of the subunits. In some embodiments, y=0. In some embodiments, z=0. In some embodiments, R1 is not H in at least 35% of the subunits, or at least 40% of the subunits. In some embodiments, R1 is not H in about 50% to about 70% of the subunits. In some embodiments, R1 is not H in about 60% to about 80% of the subunits. In some embodiments, R1 is not H in about 65% to about 85% of the subunits. In some embodiments, R1 is not H in about 70% to about 80% of the subunits. In some embodiments, R2 is not H in 65% or less of the subunits. In some embodiments, R2 is not H in about 35% to about 55% of the subunits. In some embodiments, R2 is not H in about 10% to about 30% of the subunits. In some embodiments, the general subunit structure has the following stereochemistry: [ka] It has.

[0026] Further provided herein is an isomerically purified composition comprising a mixture of hydroxypropyl-β-cyclodextrin molecules, wherein 0% to 5% of the hydroxypropyl-β-cyclodextrin subunits are substituted at the 6-O-position.

[0027] Further provided herein are isomerically purified compositions comprising a mixture of hydroxypropyl-β-cyclodextrin molecules, wherein 80% to 100% of the hydroxypropyl-β-cyclodextrin subunits are substituted at the 2-O-position, the 3-O-position, or a combination thereof.

[0028] Further provided herein is an isomerically purified composition comprising a mixture of hydroxypropyl-β-cyclodextrin molecules eluted from a Cholester HPLC column.

[0029] Further provided herein are isomerically purified compositions comprising a 5% (w / w) mixture of hydroxypropyl-β-cyclodextrin HDS (highly substituted) molecules in an aqueous medium, which provide an equilibrium solubility of cholesterol of about 0.2500 to about 0.6000 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.2500 to 0.2700 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.4000 to 0.4200 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.5000 to 0.5200 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.5400 to 0.5600 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.3600 to 0.3800 mg / ml at a temperature of 37°C.

[0030] Further provided herein is an isomerically purified composition comprising a 5% (w / w) mixture of hydroxypropyl-β-cyclodextrin HDS molecules in an aqueous medium, wherein the mixture of hydroxypropyl-β-cyclodextrin HDS molecules is insoluble in water (e.g., insoluble at room temperature (20-25° C.)).

[0031] Further provided herein are isomerically purified compositions comprising a 5% (w / w) mixture of hydroxypropyl-β-cyclodextrin LDS (low substitution) molecules in an aqueous medium, which provide an equilibrium solubility of cholesterol of about 0.1700 to about 0.3200 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.1800 to 0.2000 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.1700 to 0.1900 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.2000 to 0.2200 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.2200 to 0.2400 mg / ml at a temperature of 37°C. In some embodiments, the composition provides an equilibrium solubility of cholesterol of about 0.3100 to 0.3300 mg / ml at a temperature of 37°C.

[0032] Further provided herein is an isomerically purified composition comprising a 20% (w / w) mixture of hydroxypropyl-β-cyclodextrin molecules in an aqueous medium, which provides an equilibrium solubility of cholesterol of about 3.2500 to about 3.7500 mg / ml at a temperature of 37°C.

[0033] Nanofiltration Further provided herein is a composition comprising a purified mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the unpurified mixture of β-cyclodextrin molecules comprises propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer, as well as propylene glycol and sodium chloride, and at least 90% of the propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer, as well as propylene glycol and sodium chloride content is removed after purification.

[0034] In some embodiments, propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer, as well as propylene glycol and at least 95% of the sodium chloride content, are removed after purification. In some additional embodiments, propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer, as well as propylene glycol and at least 96% to at least 99% of the sodium chloride content, are removed after purification.

[0035] In some embodiments, at least 90% of the propylene oxide dimer and propylene oxide trimer content is removed after purification. In some additional embodiments, at least 95% of the propylene oxide dimer and propylene oxide trimer content is removed after purification. In even further embodiments, at least 96% to at least 99% of the propylene oxide dimer and propylene oxide trimer content is removed after purification.

[0036] In some embodiments, at least 90% to at least 95% of the propylene oxide tetramer content is removed.

[0037] In preferred embodiments, the purified composition does not contain detectable amounts of propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer. In other preferred embodiments, the purified composition does not contain detectable amounts of propylene glycol.

[0038] In some embodiments, the purified mixture of β-cyclodextrin molecules has a solution concentration of about 25.0 wt% solids to about 35.0 wt% solids. In some aspects, the purified mixture of β-cyclodextrin molecules has a solution concentration of about 27.5 wt% solids to about 32.5 wt% solids. In preferred embodiments, the purified mixture of β-cyclodextrin molecules has a solution concentration of about 29.0 wt% solids to about 31.0 wt% solids.

[0039] Also provided herein is a method for purifying a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the method comprising diluting the mixture of β-cyclodextrin molecules with water and nanofiltering the mixture at least three times, wherein the removal efficiency (RE) of propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer, as well as propylene glycol and sodium chloride content in the mixture of β-cyclodextrin molecules is at least 90%.

[0040] In some embodiments, the method further comprises isolating the purified mixture of β-cyclodextrin molecules having a solution concentration of about 25.0 wt% solids to about 35.0 wt% solids. In some aspects, the method further comprises isolating the purified mixture of β-cyclodextrin molecules having a solution concentration of about 27.5 wt% solids to about 32.5 wt% solids. In a preferred embodiment, the method further comprises isolating the purified mixture of β-cyclodextrin molecules having a solution concentration of about 29.0 wt% solids to about 31.0 wt% solids.

[0041] In some embodiments, the mixture is nanofiltered at least 4 times. In some preferred embodiments, the mixture is nanofiltered at least 5 times.

[0042] In some embodiments, the mixture is nanofiltered at least once at a temperature of at least about 40° C. to about 50° C. In some aspects, the mixture is nanofiltered at least once at a temperature of at least about 42.5° C. to about 47.5° C. In a preferred embodiment, the mixture is nanofiltered at least once at a temperature of about 45° C.

[0043] In some embodiments, the removal efficiency of propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer, as well as propylene glycol and sodium chloride content in the purified mixture of β-cyclodextrin molecules is at least 95%. In preferred embodiments, the removal efficiency of propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer, as well as propylene glycol and sodium chloride content in the purified mixture of β-cyclodextrin molecules is at least 96% to at least 99%.

[0044] In some embodiments, the removal efficiency of propylene oxide dimer and propylene oxide trimer content in a mixture of β-cyclodextrin molecules is at least 90%. In some aspects, the removal efficiency of propylene oxide dimer and propylene oxide trimer content in a mixture of β-cyclodextrin molecules is at least 95%. In preferred embodiments, the removal efficiency of propylene oxide dimer and propylene oxide trimer content in a mixture of β-cyclodextrin molecules is at least 96% to at least 99%. In some embodiments, the removal efficiency of propylene oxide tetramer content in a mixture of β-cyclodextrin molecules is at least 90% to at least 95%.

[0045] In some embodiments, the water is deionized water or 18.2 MΩ water.

[0046] In some embodiments, the nanofiltration is performed using a filter of at least 100 cm 2 The method is carried out on a membrane having a surface area of ​​1000 .mu.m.

[0047] In some embodiments, nanofiltration is performed at a pressure of about psig to about 500 psig. In some aspects, nanofiltration is performed at a pressure of about 100 psig to about 300 psig. In some additional aspects, nanofiltration is performed at a pressure of about 100 psig to about 200 psig. In further aspects, nanofiltration is performed at a pressure of about 100 psig to about 150 psig. In even further aspects, nanofiltration is performed at a pressure of about 150 psig to about 200 psig. In even further aspects, nanofiltration is performed at a pressure of about 200 psig to about 250 psig.

[0048] In some embodiments, nanofiltration is performed at a rate of about 200 g / (m 2 ·min) ~ approx. 250g / (m 2 In some embodiments, nanofiltration is performed at an operating pressure effective to maintain a flux of about 200 g / (m 2 ·min) ~ approx. 225g / (m 2 In an exemplary embodiment, nanofiltration is performed at an operating pressure effective to maintain a flux of about 217 g / (m 2 · min) at an operating pressure effective to maintain the flux.

[0049] In some embodiments, nanofiltration is carried out at an operating pressure effective to maintain a mass flow rate of about 400 g / min to about 600 g / min. In some aspects, nanofiltration is carried out at an operating pressure effective to maintain a mass flow rate of about 450 g / min to about 550 g / min.

[0050] In some embodiments, the nanofiltration comprises a permeate production rate of about 600 kg / hr to about 1800 kg / hr. In some aspects, the nanofiltration comprises a permeate production rate of about 900 kg / hr to about 1500 kg / hr. In still further aspects, the nanofiltration comprises a permeate production rate of about 1200 kg / hr to about 1500 kg / hr.

[0051] In some embodiments, nanofiltration is performed with a Trisep XN45 membrane, a spiral-wound membrane, a flat-sheet membrane, or a combination thereof. In some aspects, the Trisep XN45 membrane is selected from the group consisting of #1812, #2540, #4040, #8040, and combinations thereof.

[0052] In some embodiments, the method further comprises recycling the permeate for nanofiltration.

[0053] In some embodiments, the method further comprises upconcentrating the mixture of β-cyclodextrin molecules after nanofiltration.

[0054] Further provided herein is a method for purifying a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the method comprising diluting the mixture of hydroxypropyl beta-cyclodextrin molecules with water and nanofiltering the mixture at least three times, wherein after nanofiltration, there are no detectable amounts of β-cyclodextrin molecules in the permeate, and after nanofiltration of the mixture at least three times, the removal efficiency (RE) of propylene oxide monomer, propylene oxide dimer, propylene oxide trimer, and / or propylene oxide tetramer, as well as propylene glycol and sodium chloride content in the mixture of β-cyclodextrin molecules is at least 90%.

[0055] In some embodiments, the composition is nanofiltered at a temperature of about 40° C. to about 50° C. and a pressure of about 100 psig to about 300 psig. In some aspects, the composition is nanofiltered at a temperature of about 42.5° C. to about 47.5° C. and a pressure of about 150 psig to about 250 psig.

[0056] In some embodiments, the composition has a viscosity of about 15 kg / (m 2 ·hr) ~ approx. 35kg / (m 2 In some embodiments, the composition is nanofiltered at a diafiltration flux of about 20 kg / (m 2 ·hr) ~ approx. 30kg / (m 2 In some additional embodiments, the composition is nanofiltered at a diafiltration flux of about 22.5 kg / (m 2 ·hr) ~ approx. 27.5kg / (m 2 The nanofiltration is performed at a diafiltration flux of 0.05 sq. ft. / hr.

[0057] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0058] [Figure 1] 1 is a MALDI-TOF-MS spectrum of an unfractionated mixture of hydroxypropyl-β-cyclodextrins of the present disclosure, showing the distribution of hydroxypropyl-β-cyclodextrin components with different degrees of substitution. [Figure 2] 1H NMR spectrum (DO, 298 K, 600 MHz) of an unfractionated mixture of hydroxypropyl-β-cyclodextrin of the present disclosure. The figure also includes an exemplary hydroxypropyl-β-cyclodextrin molecule with atom labels used for structure elucidation. [Figure 3] 1 is a DEPT-edited HSQC spectrum of an unfractionated mixture of hydroxypropyl-β-cyclodextrins of the present disclosure. [Figure 4] 1 is an HPLC-CAD chromatogram of an unfractionated mixture of hydroxypropyl-β-cyclodextrins of the present disclosure. [Figure 5] FIG. 1 is a schematic diagram of the isomerically purified hydroxypropyl-β-cyclodextrin mixture on an HPLC Cholester column. [Figure 6] 1 is a 1H NMR spectrum of the first HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 7] 1 is a DEPT-edited HSQC spectrum of the first HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 8] 1 is an HPLC-CAD chromatogram of the first HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 9] 1 is an ESI-MS spectrum of the first HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 10] 1 is a MALDI-TOF spectrum of the first HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 11] 1H NMR spectrum of the second HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 12] 1 is a DEPT-edited HSQC spectrum of the second HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 13] 1 is an HPLC-CAD chromatogram of the second HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 14] 1 is an ESI-MS spectrum of a second HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 15] 1 is a MALDI-TOF spectrum of a second HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 16]1 is a 1H NMR spectrum of the third HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 17] 1 is a DEPT-edited HSQC spectrum of the third HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 18] 1 is an HPLC-CAD chromatogram of the third HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 19] 1 is an ESI-MS spectrum of the third HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 20] 1 is a MALDI-TOF spectrum of the third HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 21] 1 is a 1H NMR spectrum of the fourth HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 22] 1 is a DEPT-edited HSQC spectrum of the fourth HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 23] 1 is an HPLC-CAD chromatogram of the fourth HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 24] 1 is an ESI-MS spectrum of the fourth HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 25] 1 is a MALDI-TOF spectrum of the fourth HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 26] 1 is a 1H NMR spectrum of the fifth HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 27] 1 is a DEPT-edited HSQC spectrum of the fifth HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 28]1 is an HPLC-CAD chromatogram of the fifth HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 29] 1 is an ESI-MS spectrum of the fifth HDS fraction of the hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 30] 1 is a MALDI-TOF spectrum of the fifth HDS fraction of a hydroxypropyl-β-cyclodextrin mixture of the present disclosure. [Figure 31] 1 is an HPLC chromatogram showing the HPLC chromatograms of HDS fractions 1-5 overlaid on the HPLC chromatogram of the hydroxypropyl-β-cyclodextrin unfractionated mixture. [Figure 32] FIG. 1 is a schematic diagram of a switching scheme for collecting fractions of hydroxypropyl-β-cyclodextrin. [Figure 33] HPLC chromatogram of the hydroxypropyl-β-cyclodextrin mixture; no fractions were collected. The chromatogram shows where each fraction elutes from the HPLC Cholester column. [Figure 34-1] Figure 34A: Overlaid MALDI-TOF spectra for HDS fractions 1 to 5. Overlaid MALDI-TOF spectra for HDS fractions 1 to 3. [Figure 34-2] Figure 34A: Overlaid MALDI-TOF spectra for HDS fractions 1 to 5. Overlaid MALDI-TOF spectra for HDS fractions 3 to 5. [Figure 35] Overlaid 1H NMR spectra for HDS fractions 1 to 5 are shown. [Figure 36] The trends in the average substitution degrees of HDS fractions 1 to 5 are shown. [Figure 37] The trends in substitution patterns (%) in HDS fractions 1 to 5 are shown. [Figure 38-1] The differences between the DEPT-edited HSQC spectra of HDS fractions 1 and 5 are shown and are used to elucidate substitution patterns. [Figure 38-2](Continued) Differences between DEPT-edited HSQC spectra of HDS fractions 1 and 5 are shown and are used to elucidate substitution patterns. [Figure 39] The predicted structure of the most cholesterol-affinity isomer of hydroxypropyl-β-cyclodextrin is shown. [Figure 40] 1 shows a possible reaction scheme for making the most cholesterol-affinity isomer of hydroxypropyl-β-cyclodextrin. [Figure 41] 1 is an overlaid HPLC chromatogram showing the elution of a hydroxypropyl-β-cyclodextrin mixture and the elution of cholesterol. [Figure 42] 1 shows the equilibrium solubility of cholesterol in the presence of HDS hydroxypropyl-β-cyclodextrin and LDS hydroxypropyl-β-cyclodextrin. [Figure 43] 1 shows the equilibrium solubility of cholesterol in the presence of HDS fractions 1 to 5 of hydroxypropyl-β-cyclodextrin. [Figure 44] 1 shows the equilibrium solubility of cholesterol in the presence of LDS fractions 1 to 5 of hydroxypropyl-β-cyclodextrin. [Figure 45] 1 shows the conductivity of Cavitron HP7, Alcami Kleptose, and Cavitron HP5 before and after nanofiltration using the method described herein. [Figure 46] 1 shows the HPLC-ELSD spectrum of Cavitron HP7 before nanofiltration using the methods described herein. [Figure 47] 1 shows the HPLC-ELSD spectrum of Cavitron HP7 after nanofiltration using the method described herein. [Figure 48] 1 shows the 1H-NMR spectra of Cavitron HP7 before and after nanofiltration using the methods described herein. [Figure 49] Figure 1 shows the HPLC-ELSD spectrum of the permeate of the first diafiltration volume of Cavitron HP7. [Figure 50] Figure 1 shows the HPLC-ELSD spectrum of the permeate of the second diafiltration volume of Cavitron HP7. [Figure 51] Figure 1 shows the HPLC-ELSD spectrum of the permeate of the 4th diafiltration volume of Cavitron HP7. [Figure 52] Figure 1 shows the HPLC-ELSD spectrum of the permeate of the 5th diafiltration volume of Cavitron HP7. [Figure 53] Figure 1 shows the HPLC-ELSD spectrum of the retentate of the first diafiltration volume of the Cavitron HP7. [Figure 54] Figure 1 shows the HPLC-ELSD spectrum of the retentate of the second diafiltration volume of the Cavitron HP7. [Figure 55] Figure 1 shows the HPLC-ELSD spectrum of the retentate of the third diafiltration volume of the Cavitron HP7. [Figure 56] Figure 1 shows the HPLC-ELSD spectrum of the retentate of the 4th diafiltration volume of the Cavitron HP7. [Figure 57] Figure 1 shows the HPLC-ELSD spectrum of the retentate of the 5th diafiltration volume of the Cavitron HP7. [Figure 58] 1 shows process data from nanofiltration on a Cavitron HP7, including permeate mass, permeate mass flow rate, feed mass, combined permeate and feed mass, temperature, and pressure. [Figure 59] Permeate conductivity, permeate Brix, retentate / feed / product, and retentate / feed / product Brix for the Cavitron HP7 purification are shown. [Figure 60] 1 shows process data from nanofiltration on a Cavitron HP5, including permeate mass, permeate mass flow rate, feed mass, temperature, pressure, and pump. [Figure 61] 1 shows the HPLC-ELSD spectrum of Cavitron HP5 before nanofiltration using the methods described herein. [Figure 62] 1 shows the HPLC-ELSD spectrum of Cavitron HP5 after nanofiltration using the method described herein. [Figure 63] 1 shows the 1H-NMR spectra of Cavitron HP5 before and after nanofiltration using the methods described herein. [Figure 64] 1 shows another 1H-NMR spectrum of Cavitron HP5 before and after nanofiltration using the methods described herein. [Figure 65] 1 shows the HPLC-ELSD spectrum of Alcami Kleptose before nanofiltration using the methods described herein. [Figure 66] 1 shows the HPLC-ELSD spectrum of Alcami Kleptose after nanofiltration using the method described herein. [Figure 67] 1 shows the 1H-NMR spectra of Alcami Kleptose before and after nanofiltration using the methods described herein. DETAILED DESCRIPTION OF THE INVENTION

[0059] Various embodiments of the present disclosure are described in detail below. While specific implementations are described, it should be understood that this is done for illustrative purposes only. Those skilled in the relevant art will recognize that other components and arrangements may be used without departing from the spirit and scope of the present disclosure. Accordingly, the following description and drawings are illustrative and should not be construed as limiting. Numerous specific details are set forth to provide a thorough understanding of the present disclosure. However, in certain instances, well-known or conventional details are not described in order to avoid obscuring the description.

[0060] References to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Appearances of the phrase "in one embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments. Furthermore, various features are described that may be exhibited by some embodiments and not by other embodiments. Thus, references to "one embodiment" or "an embodiment" in this disclosure may refer to the same embodiment or any embodiment, and such references refer to at least one of the embodiments.

[0061] The terms used herein generally have their ordinary meanings in the art, within the context of this disclosure and in the specific context in which each term is used. Alternative language and synonyms may be used for any one or more of the terms described herein, and no special emphasis should be placed on whether a term is recited or described herein. In some cases, synonyms for a particular term are provided. The listing of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any term described herein, is for illustrative purposes only and is not intended to further limit the scope and meaning of the disclosure or any exemplary term. Similarly, the disclosure is not limited to the various embodiments provided herein.

[0062] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It should be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values ​​explicitly recited as range limits, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. Illustratively, a numerical range of "about 2 to about 50" should be interpreted not only to include the numerical values ​​2 to 50 explicitly recited, but also to include all individual numerical values ​​and subranges within the stated range. Thus, included within the present numerical ranges are individual values, e.g., 2, 2.4, 3, 3.7, 4, 5.5, 10, 10.1, 14, 15, 15.98, 20, 20.13, 23, 25.06, 30, 35.1, 38.0, 40, 44, 44.6, 45, 48, etc., as well as subranges, e.g., 1-3, 2-4, 5-10, 5-20, 5-25, 5-30, 5-35, 5-40, 5-50, 2-10, 2-20, 2-30, 2-40, 2-50, etc. This same principle applies to ranges reciting only a single numerical value as the minimum or maximum value. Moreover, such interpretation should be applied regardless of the breadth or nature of the range described.

[0063] As used herein, the terms "a," "an," and "the" are understood to include the plural as well as the singular. Thus, the term "a mixture thereof" also relates to "mixtures thereof," and the term "a component" also relates to "components."

[0064] As used herein, the term "about" is used to provide flexibility for the endpoints of a numerical range by allowing for the possibility that a given value may be "slightly above" or "slightly below" the endpoint. For example, the endpoint may be within 10%, 8%, 5%, 3%, 2%, or 1% of the recited value. Furthermore, for convenience and brevity, a numerical range of "about 50 mg / mL to about 80 mg / mL" should also be understood to support the range "50 mg / mL to 80 mg / mL." Endpoints may also be based on the variability allowed by appropriate regulatory agencies, such as the FDA, USP, etc.

[0065] In this disclosure, terms such as "comprises," "comprising," "containing," and "having" may have the meaning ascribed to them in U.S. patent law and may mean "includes," "including," etc., and are generally construed to be open-ended terms. Terms such as "consisting of" or "consists of" are closed terms and include only those components, structures, steps, etc. specifically recited in association with such term, in addition to those that, according to U.S. patent law, are included. Terms such as "consisting essentially of" or "consists essentially of" have the meaning generally ascribed to them by U.S. patent law. In particular, such terms are generally closed terms, except to permit the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or function of the item(s) with which they are used. For example, minor elements present in a composition but which do not affect the properties or characteristics of the composition will be permitted if present under the language "consisting essentially of," even if they are not explicitly recited in the list of items following such terminology. When open-ended terms such as "comprising" or "including" are used herein, it is understood that direct support should be given to the language "consisting of" in addition to the language "consisting essentially of," as if explicitly stated, and vice versa.

[0066] It is understood that where reference is made in this disclosure to a method of treatment that includes administering a product, direct support should also be given to the product for use in such a method of treatment and the use of the product in such a method of treatment, as if expressly stated.

[0067] Additional features and advantages of the present disclosure will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the principles disclosed herein. The features and advantages of the present disclosure may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features of the present disclosure will become more fully apparent from the following description and appended claims, or may be learned by practice of the principles described herein.

[0068] In one aspect, the invention provided herein is a composition comprising a mixture of β-cyclodextrin molecules. The β-cyclodextrin molecules have a degree of substitution (DS) depending on the number of functional groups attached to the β-cyclodextrin molecule or on the hydroxypropyl side chains of the β-cyclodextrin molecule. More specifically, a composition comprising a mixture of hydroxypropyl-β-cyclodextrin molecules is described herein. The hydroxypropyl-β-cyclodextrin molecules may be substituted with one or more hydroxypropyl groups. As used herein, the term "β-cyclodextrin molecule" necessarily provides clear support for "hydroxypropyl-β-cyclodextrin molecule," so that wherever "β-cyclodextrin molecule" is mentioned, it may be optionally replaced with the term "hydroxypropyl-β-cyclodextrin molecule." As used herein, the designation "DS-N" is used to refer to a β-cyclodextrin molecule having a degree of substitution of N. Thus, as a non-limiting example, DS-1 refers to a β-cyclodextrin molecule having a degree of substitution of 1, such as a hydroxypropyl-β-cyclodextrin molecule substituted with one hydroxypropyl group.

[0069] The degree of substitution (e.g., average degree of substitution) of a mixture of β-cyclodextrin molecules may be determined by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The average degree of substitution may be calculated by determining the average number of substituents attached to the cyclodextrin molecules in the compositions described herein. Systems and methods for performing MALDI-TOF-MS and reading the resulting spectra are generally known to those skilled in the art. In some embodiments, the percentage of hydroxypropyl β-cyclodextrin is based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the area percentage from a MALDI-TOF-MS spectrum correlates with a concentration percentage (e.g., molar percentage). In some embodiments, the concentration percentage of hydroxypropyl-β-cyclodextrin may be expressed as a molar percentage, weight percentage (w / w), or volume percentage. In an exemplary embodiment, the percentage of hydroxypropyl β-cyclodextrin is a weight percentage.

[0070] Overview of the compositions provided herein Any of the compositions described herein may have the physical and chemical properties, characteristics, or ingredients provided below unless otherwise specified. For example, any of the compositions described herein that include any of Fractions 1-5 may have the physical and chemical properties, characteristics, or ingredients provided below unless otherwise specified.

[0071] In some embodiments, the composition has a density of about 1.095 g / cm 3 ~Approx. 1.100g / cm 3 In some embodiments, the composition may have a true density of about 1.095 g / cm 3 ~approx. 1.096g / cm 3 , approximately 1.096 g / cm 3 ~Approx. 1.097g / cm 3 , about 1.097g / cm 3 ~Approx. 1.098g / cm 3 , about 1.098g / cm 3 ~Approx. 1.099g / cm 3, about 1.099g / cm 3 ~Approx. 1.100g / cm 3 , about 1.095g / cm 3 ~Approx. 1.097g / cm 3 , about 1.095g / cm 3 ~Approx. 1.098g / cm 3 , about 1.095g / cm 3 ~Approx. 1.099g / cm 3 , approximately 1.096 g / cm 3 ~Approx. 1.100g / cm 3 , about 1.097g / cm 3 ~Approx. 1.100g / cm 3 , about 1.098g / cm 3 ~Approx. 1.100g / cm 3 , approximately 1.096 g / cm 3 ~Approx. 1.098g / cm 3 , or approximately 1.096 g / cm 3 ~Approx. 1.099g / cm 3 In some additional embodiments, the composition may have a true density of about 1.095 g / cm 3 , 1.096g / cm 3 , 1.097g / cm 3 , 1.098g / cm 3 , 1.099g / cm 3 , or approximately 1.100 g / cm 3 In an exemplary embodiment, the composition may have a true density of about 1.096 g / cm 3 ~Approx. 1.098g / cm 3 It has a true density of

[0072] In some embodiments, the composition may have an osmolality of about 600 mOs / kg to about 750 mOs / kg. In some aspects, the composition may have an osmolality of about 600 mOs / kg to about 625 mOs / kg, about 625 mOs / kg to about 650 mOs / kg, about 650 mOs / kg to about 675 mOs / kg, about 675 mOs / kg to about 700 mOs / kg, about 700 mOs / kg to about 725 mOs / kg, or about 725 mOs / kg to about 750 mOs / kg. In some additional embodiments, the composition may have an osmolality of about 600 mOs / kg to about 650 mOs / kg, about 600 mOs / kg to about 675 mOs / kg, about 600 mOs / kg to about 700 mOs / kg, about 600 mOs / kg to about 725 mOs / kg, about 625 mOs / kg to about 750 mOs / kg, about 650 mOs / kg to about 750 mOs / kg, about 675 mOs / kg to about 750 mOs / kg, about 700 mOs / kg to about 750 mOs / kg, about 625 mOs / kg to about 725 mOs / kg, or about 650 mOs / kg to about 700 mOs / kg. In still further embodiments, the composition may have an osmolality of about 600 mOs / kg, 610 mOs / kg, 620 mOs / kg, 630 mOs / kg, 640 mOs / kg, 650 mOs / kg, 660 mOs / kg, 670 mOs / kg, 680 mOs / kg, 690 mOs / kg, 700 mOs / kg, 710 mOs / kg, 720 mOs / kg, 730 mOs / kg, 740 mOs / kg, or about 750 mOs / kg. In exemplary embodiments, the composition has an osmolality of about 635 mOs / kg to about 695 mOs / kg.

[0073] In some embodiments, the composition may have a conductivity of about 0 to about 8 μS / cm. In some aspects, the composition may have a conductivity of about 0 μS / cm to about 1 μS / cm, about 1 μS / cm to about 2 μS / cm, about 3 μS / cm to about 4 μS / cm, about 4 μS / cm to about 5 μS / cm, about 5 μS / cm to about 6 μS / cm, about 6 μS / cm to about 7 μS / cm, or about 7 μS / cm to about 8 μS / cm. In some additional embodiments, the composition comprises from about 0 μS / cm to about 1.5 μS / cm, from about 0 μS / cm to about 2 μS / cm, from about 0 μS / cm to about 2.5 μS / cm, from about 0 μS / cm to about 3 μS / cm, from about 0 to about 3.5 μS / cm, from about 0 μS / cm to about 4 μS / cm, from about 0 to about 4.5 μS / cm, from about 0 μS / cm to about 5 μS / cm, from about 0 to about 5.5 μS / cm, from about 0 μS / cm to about 6 μS / cm, from about 0 to about 6.5, from about 0 μS / cm to about 7 μS / cm, from about 0 to about 7.5, from about 1 μS / cm to about 8 μS / cm, from about 1.5 μS / cm to about 8 μS / cm. S / cm, about 2 μS / cm to about 8 μS / cm, about 2.5 μS / cm to about 8 μS / cm, about 3 μS / cm to about 8 μS / cm, about 3.5 μS / cm to about 8 μS / cm, about 4 μS / cm to about 8 μS / cm, about 4.5 μS / cm to about 8 μS / cm, about 5 μS / cm to about 8 μS / cm, about 5.5 μS / cm to about 8 μS / cm, about 6 μS / cm to about 8 μS / cm, about 6.5 μS / cm to about 8 μS / cm, about 1 μS / cm to about 7 μS / cm, about 2 μS / cm to about 6 μS / cm, or about 3 μS / cm to about 5 μS / cm. In still further embodiments, the composition may have a conductivity of about 0.5 μS / cm, 1.0 μS / cm, 1.5 μS / cm, 2.0 μS / cm, 2.5 μS / cm, 3.0 μS / cm, 3.5 μS / cm, 4.0 μS / cm, 4.5 μS / cm, 5.0 μS / cm, 5.5 μS / cm, 6.0 μS / cm, 6.5 μS / cm, 7.0 μS / cm, 7.5 μS / cm, or about 8.0 μS / cm.

[0074] In some embodiments, the composition may have a pH of about 4.0 to about 8.0, for example, the composition may have a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or about 8.0. The composition may have a pH within a range or subrange including any of the above numbers, including, but not limited to, about 4.0 to about 4.5, about 4.5 to about 5.0, about 5.0 to about 5.5, about 5.5 to about 6.0, about 6.0 to about 6.5, about 6.5 to about 7.0, about 7.0 to about 7.5, or about 7.5 to about 8.0. In some embodiments, the composition may further comprise a pH adjuster, such as hydrochloric acid or sodium hydroxide, to adjust the pH to a desired level. In some embodiments, the composition may further comprise a buffer. In some embodiments, the buffer may comprise monosodium phosphate and disodium phosphate.

[0075] In some embodiments, the composition may have a viscosity measured in centipoise (cP) at 20° C. For example, the composition may have a viscosity of about 1.5 cP to about 3.0 cP at 20° C. In some embodiments, the composition may have a viscosity of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 , 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10.0 cP. In other embodiments, the composition may have a viscosity at 20°C of about 3.0 cP to about 5.0 cP, about 5.0 cP to about 10.0 cP, about 10 to about 15 cP, about 15 to about 20 cP, about 20 cP to about 25 cP, about 25 cP to about 50 cP, about 50 cP to about 80 cP, about 80 cP to about 150 cP, about 150 cP to about 250 cP, about 250 cP to about 500 cP, about 500 cP to about 1,000 cP, about 1,000 cP to about 2,000 cP, about 2,000 cP to about 3,000 cP, about 3,000 cP to about 5,000 cP, or about 5,000 cP to about 10,000 cP.

[0076] The composition may be substantially free of impurities, including particles having a diameter of 25 microns or greater, particles having a diameter of 10 microns or greater, chloride, propylene glycol, propylene oxide, and other unspecified impurities. In some embodiments, the composition may contain about 0.05% or less of impurities, for example, the composition may contain about 0.05%, 0.04%, 0.03%, 0.02%, or about 0.01% or less of impurities.

[0077] In some embodiments, the composition may further comprise a container and non-visible particulate matter. In some embodiments, the composition may be provided in a container. In some embodiments, the composition may further comprise non-visible particulate matter.

[0078] In some embodiments, the composition may comprise fewer than 600 particles per container having a diameter of 25 microns or greater. In some aspects, the composition may comprise fewer than 500, fewer than 400, fewer than 300, fewer than 200, or fewer than 100 particles per container having a diameter of 25 microns or greater.

[0079] In some embodiments, the composition may comprise fewer than 6,000 particles per container having a diameter of 10 microns or greater. In some aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, or 100 particles per container having a diameter of 10 microns or greater. In other aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, or 100 particles per container having a diameter of 10 microns or greater, and the container is 100 mL or less. In other aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, 100, 50, 25, 10, 5, or 3 particles per container having a diameter of 10 microns or greater, and the container is 100 mL or less.

[0080] In some embodiments, the composition may contain 10 ppb or less of propylene glycol. In some aspects, the composition may contain 9 ppb, 8 ppb, 7 ppb, 6 ppb, 5 ppb, 4 ppb, 3 ppb, 2 ppb or less of propylene glycol, or 1 ppb or less of propylene glycol. In some aspects, the amount of propylene glycol in the composition may be determined by HPLC. In some additional aspects, the amount of propylene glycol in the composition may be determined by gas chromatography. In even further aspects, the amount of propylene glycol in the composition may be determined by measuring the PG / EG ratio of propylene glycol to ethylene glycol.

[0081] In some embodiments, the composition may contain 1 ppm or less of propylene oxide. In some aspects, the composition may contain 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, or 0.1 ppm or less of propylene oxide. In some aspects, the amount of propylene oxide in the composition may be determined by HPLC. In some additional aspects, the amount of propylene oxide in the composition may be determined by gas chromatography.

[0082] In some embodiments, the composition contains about 0 ppm to about 10 ppm chloride (e.g., Cl -ions). In some embodiments, the composition may contain about 0 ppm chloride to about 2 ppm chloride, about 2 ppm chloride to about 4 ppm chloride, about 4 ppm chloride to about 6 ppm chloride, about 6 ppm chloride to about 8 ppm chloride, or about 8 to about 10 ppm chloride. In some additional embodiments, the composition may contain about 0 ppm chloride to about 4 ppm chloride, about 0 ppm chloride to about 6 ppm chloride, about 0 ppm chloride to about 8 ppm chloride, about 2 ppm chloride to about 1 ppm chloride, about 4 ppm chloride to about 1 ppm chloride, or about 6 ppm chloride to about 1 ppm chloride. In still further aspects, the composition may comprise about 0 ppm, 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, or about 10 ppm chloride. In exemplary embodiments, the composition may comprise from about 0 ppm to about 1 ppm chloride.

[0083] In some embodiments, the composition contains about 0 ppm to about 10 ppm sodium (e.g., Na + ions). In some embodiments, the composition may comprise about 0 ppm sodium to about 2 ppm sodium, about 2 ppm sodium to about 4 ppm sodium, about 4 ppm sodium to about 6 ppm sodium, about 6 ppm sodium to about 8 ppm sodium, or about 8 to about 10 ppm sodium. In some additional embodiments, the composition may comprise about 0 ppm sodium to about 4 ppm sodium, about 0 ppm sodium to about 6 ppm sodium, about 0 ppm sodium to about 8 ppm sodium, about 2 ppm sodium to about 1 ppm sodium, about 4 ppm sodium to about 1 ppm sodium, or about 6 ppm sodium to about 1 ppm sodium. In even further embodiments, the composition may comprise about 0 ppm, 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, or about 10 ppm sodium. In an exemplary embodiment, the composition may include from about 0 ppm to about 1 ppm sodium.

[0084] In some embodiments, the composition may contain 0.05% or less of other unspecified impurities, for example, the composition may contain 0.05%, 0.04%, 0.03%, 0.02% or less, or 0.01% or less of other unspecified impurities.

[0085] In some embodiments, the composition may be stable for at least 6 months. For example, the composition may be stable for at least 3 months, 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 24 months, or at least 36 months.

[0086] The composition may be nanofiltered. In some embodiments, the concentration of the composition does not substantially change the time required for nanofiltration. Thus, the time for nanofiltration does not increase or decrease when the concentration of the mixture of β-cyclodextrin molecules increases or decreases in the composition. In some aspects, the length of time for nanofiltration of the composition depends on the diafiltration volume (kg solution / m 2 The range is from about 1.04 to about 1.20 hours per 100 mL (hr / L of solution). In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition shows no substantial difference in NMR analysis after nanofiltration compared to before nanofiltration.

[0087] In some embodiments, the composition may be terminally sterilized. Methods of terminal sterilization are generally well known in the art. In some embodiments, the pH of the composition may be adjusted after terminal sterilization.

[0088] In some embodiments, the composition may comprise 10.0 w / w% or less of water, for example, the composition may comprise 10.0 w / w%, 9.5 w / w%, 9.0 w / w%, 8.5 w / w%, 8.0 w / w%, 7.5 w / w%, 7.0 w / w%, 6.5 w / w%, 6.0 w / w%, 5.5 w / w%, 5.0 w / w%, 4.5 w / w%, 4.0 w / w%, 3.5 w / w%, 3.0 w / w%, 2.5 w / w%, 2.0 w / w%, 1.5 w / w%, 1.0 w / w%, 0.5 w / w% or less, or 0.1 w / w% or less of water.

[0089] In some embodiments, the composition can be packaged in a vial suitable for injection into a human subject who needs injection.The vial can be made of glass, plastic, or any other material known in the pharmaceutical arts.The vial can be coated with a material such as silicon dioxide to prevent the composition from leaching out of the vial.

[0090] In some embodiments, the composition may be suitable for administration to a patient in need thereof. In some embodiments, the composition may be suitable for intrathecal administration, intravenous administration, oral administration, intracerebroventricular administration, or a combination thereof (e.g., intravenous and intrathecal administration) to a patient in need thereof. In some aspects, the patient may be a human, such as an adult patient or a pediatric patient. In some examples, the human patient may be an infant (e.g., less than 6 months old) or a newborn (e.g., less than 4 weeks old).

[0091] In some embodiments, the compositions may be effective in treating Niemann-Pick disease. In some embodiments, the compositions may be effective in treating Niemann-Pick disease type C. In some embodiments, the compositions may be effective in treating liver disease. In some embodiments, the compositions may be effective in treating cardiovascular disease. In some embodiments, the compositions may be effective in treating familial hypercholesterolemia. In some embodiments, the compositions may be effective in treating cholesterol deposits.

[0092] In some embodiments, the composition may further comprise a pharmaceutical excipient or carrier. In some embodiments, the composition may further comprise a pharmaceutically acceptable diluent. Examples of pharmaceutical excipients, carriers, and diluents are well known to those skilled in the art.

[0093] In some embodiments, the composition may exhibit less toxicity than Trappsol® Cyclo or Kleptose®. In some embodiments, the composition may exhibit substantially less ototoxicity than Trappsol® Cyclo or Kleptose®. In some embodiments, the composition may exhibit substantially no ototoxicity at all.

[0094] unpurified composition Compositions are provided herein that include a mixture of β-cyclodextrin molecules, where the compositions are not isomerically purified. In some embodiments, the compositions include a mixture of β-cyclodextrin molecules, including β-cyclodextrin substituted with four hydroxypropyl groups ("DS-4"), β-cyclodextrin substituted with five hydroxypropyl groups ("DS-5"), β-cyclodextrin substituted with six hydroxypropyl groups ("DS-6"), β-cyclodextrin substituted with seven hydroxypropyl groups ("DS-7"), β-cyclodextrin substituted with eight hydroxypropyl groups ("DS-8"), and the like. The compositions may include β-cyclodextrin substituted with 9 hydroxypropyl groups ("DS-9"), β-cyclodextrin substituted with 10 hydroxypropyl groups ("DS-10"), β-cyclodextrin substituted with 11 hydroxypropyl groups ("DS-11"), β-cyclodextrin substituted with 12 hydroxypropyl groups ("DS-12"), β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"), and β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14"). In some embodiments, the compositions are clear, colorless solutions.

[0095] The degree of substitution of a mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS. An exemplary MALDI-TOF-MS spectrum for a composition of the present disclosure is shown in Figure 1. In some embodiments, the MALDI-TOF-MS spectrum may include peaks at about 1389 m / z, 1447 m / z, 1505 m / z, 1564 m / z, 1622 m / z, 1680 m / z, 1738 m / z, 1796 m / z, 1855 m / z, and 1914 m / z. In an exemplary embodiment, the composition has a MALDI-TOF-MS spectrum that is DS-4 area 0.73%, DS-5 area 3.49%, DS-6 area 10.66%, DS-7 area 24.10%, DS-8 area 26.43%, DS-9 area 18.09%, DS-10 area 9.39%, DS-11 area 4.58%, DS-12 area 1.84%, and DS-13 area 0.70%.

[0096] In some embodiments, the composition can have an average degree of substitution of about 7 to about 9, e.g., the average degree of substitution can be about 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, or about 9.0. In an exemplary embodiment, the average degree of substitution of the mixture of β-cyclodextrin molecules is about 7.7.

[0097] In some embodiments, the mixture of β-cyclodextrin molecules may contain less than 1% DS-4, for example, the mixture of β-cyclodextrin molecules may contain about 0.9% DS-4, about 0.8% DS-4, about 0.7% DS-4, about 0.6% DS-4, about 0.5% DS-4, about 0.4% DS-4, about 0.3% DS-4, about 0.2% DS-4, or about 0.1% DS-4. In some embodiments, the mixture of β-cyclodextrin molecules may contain less than 1% to about 0.9% DS-4, about 0.9% to about 0.8% DS-4, about 0.8% to about 0.7% DS-4, about 0.7% to about 0.6% DS-4, about 0.7% to about 0.6% DS-4, about 0.6% to about 0.5% DS-4, about 0.5% to about 0.4% DS-4, about 0.4% to about 0.3% DS-4, about 0.3% to about 0.2% DS-4, about 0.2% to about 0.1% DS-4, or less than 0.1% DS-4. In some additional embodiments, the mixture of β-cyclodextrin molecules may contain less than 1% to about 0.8% DS-4, less than 1% to about 0.7% DS-4, less than 1% to about 0.6% DS-4, less than 1% to about 0.5% DS-4, less than 1% to about 0.4% DS-4, less than 1% to about 0.3% DS-4, less than 1% to about 0.2% DS-4, less than 1% to about 0.1% DS-4, about 0.9% to about 0.1% DS-4, about 0.8% to about 0.1% DS-4, about 0.7% to about 0.1% DS-4, about 0.6% to about 0.1% DS-4, about 0.5% to about 0.1% DS-4, about 0.4% to about 0.1% DS-4, or about 0.3% to about 0.1% DS-4. In still further embodiments, the mixture of β-cyclodextrin molecules may contain less than 1% DS-4, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% DS-4. In still further embodiments, the mixture of β-cyclodextrin molecules may contain about 0.001%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or about 1% DS-4.In some embodiments, the amount of DS-4 in a mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-4 in the MALDI-TOF-MS spectrum is 0.73%.

[0098] In some embodiments, the mixture of β-cyclodextrin molecules may contain about 2% to about 5% DS-5. In some aspects, the mixture of β-cyclodextrin molecules may contain about 2% to about 2.5% DS-5, about 2.5% to about 3% DS-5, about 3% to about 3.5% DS-5, about 3.5% to about 4% DS-5, about 4% to about 4.5% DS-5, or about 4.5% to about 5% DS-5. In some additional embodiments, the mixture of β-cyclodextrin molecules may contain about 2% to about 3% DS-5, about 2% to about 3.5% DS-5, about 2% to about 4% DS-5, about 2% to about 4.5% DS-5, about 2.5% to about 5% DS-5, about 3% to about 5% DS-5, about 3.5% to about 5% DS-5, about 4% DS-5 to about 5% DS-5, or about 3% to about 4% DS-5. In still further embodiments, the mixture of β-cyclodextrin molecules may contain about 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or about 5.0% DS-5. In some embodiments, the amount of DS-5 in the mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-5 in the MALDI-TOF-MS spectrum is 3.49%.

[0099] In some embodiments, the mixture of β-cyclodextrin molecules may contain about 7% to about 13% DS-6. In some aspects, the mixture of β-cyclodextrin molecules may contain about 7% to about 7.5% DS-6, about 7.5% to about 8% DS-6, about 8% to about 8.5% DS-6, about 8.5% to about 9% DS-6, about 9% to about 9.5% DS-6, about 9.5% to about 10% DS-6, about 10% to about 10.5% DS-6, about 10.5% to about 11% DS-6, about 11% to about 11.5% DS-6, about 11.5% to about 12% DS-6, about 12% to about 12.5% ​​DS-6, or about 12.5% ​​to about 13% DS-6. In some additional embodiments, the mixture of β-cyclodextrin molecules is from about 7% to about 8% DS-6, from about 7% to about 8.5% DS-6, from about 7% to about 9% DS-6, from about 7% to about 9.5% DS-6, from about 7% to about 10% DS-6, from about 7% to about 10.5% DS-6, from about 7% to about 11% DS-6, from about 7% to about 11.5% DS-6, from about 7% to about 12% DS-6, from about 7% to about 12.5% ​​DS-6, from about 7.5% to about The DS-6 may comprise about 13% DS-6, about 8% to about 13% DS-6, about 8.5% to about 13% DS-6, about 9% to about 13% DS-6, about 9.5% to about 13% DS-6, about 10% to about 13% DS-6, about 10.5% to about 13% DS-6, about 11% to about 13% DS-6, about 11.5% to about 13% DS-6, about 12% to about 13% DS-6, about 8% to about 12% DS-6, or about 9% to about 11% DS-6.In still further embodiments, the mixture of β-cyclodextrin molecules is about 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, 15.0%, 15.1%, 15.2%, 15.3%, 15.4%, 15.5%, 15.6%, %, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, or about 13.0% DS-6. In some embodiments, the amount of DS-6 in a mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-6 in the MALDI-TOF-MS spectrum is 10.66%.

[0100] In some embodiments, the mixture of β-cyclodextrin molecules may comprise about 21% to about 27% DS-7. In some aspects, the mixture of β-cyclodextrin molecules may comprise about 21% to about 21.5% DS-7, about 21.5% to about 22% DS-7, about 22% to about 22.5% DS-7, about 22.5% to about 23% DS-7, about 23% to about 23.5% DS-7, about 23.5% to about 24% DS-7, about 24% to about 24.5% DS-7, about 24.5% to about 25% DS-7, about 25% to about 25.5% DS-7, about 25.5% to about 26% DS-7, about 26% to about 26.5% DS-7, or about 26.5% to about 27% DS-7. In some additional embodiments, the mixture of β-cyclodextrin molecules is from about 21% to about 22% DS-7, from about 21% to about 22.5% DS-7, from about 21% to about 23% DS-7, from about 21% to about 23.5% DS-7, from about 21% to about 24% DS-7, from about 21% to about 24.5% DS-7, from about 21% to about 25% DS-7, from about 21% to about 25.5% DS-7, from about 21% to about 26% DS-7, from about 21% to about 26.5% DS-7, from about 21% to about 26.5% DS-7, or from about 21% to about 26.5% DS-7. The DS-7 may comprise from about 0.5% to about 27% DS-7, from about 22% to about 27% DS-7, 22.5% to about 27% DS-7, from about 23% to about 27% DS-7, from about 23.5% to about 27% DS-7, from about 24% to about 27% DS-7, from about 24.5% to about 27% DS-7, from about 25% to about 27% DS-7, from about 25.5% to about 27% DS-7, from about 26% to about 27% DS-7, from about 22% to about 26% DS-7, or from about 23% to about 25% DS-7.In still further embodiments, the mixture of β-cyclodextrin molecules is about 21.0%, 21.1%, 21.2%, 21.3%, 21.4%, 21.5%, 21.6%, 21.7%, 21.8%, 21.9%, 22.0%, 22.1%, 22.2%, 22.3%, 22.4%, 22.5%, 22.6%, 22.7%, 22.8%, 22.9%, 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 30.0%, In some embodiments, the amount of DS-7 may be 3.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, or about 27.0% DS-7. In some embodiments, the amount of DS-7 may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-7 in the MALDI-TOF-MS spectrum is 24.10%.

[0101] In some embodiments, the mixture of β-cyclodextrin molecules may contain about 23% to about 29% DS-8. In some aspects, the mixture of β-cyclodextrin molecules may contain about 23% to about 23.5% DS-8, about 23.5% to about 24% DS-8, about 24% to about 24.5% DS-8, about 24.5% to about 25% DS-8, about 25% to about 25.5% DS-8, about 25.5% to about 26% DS-8, about 26% to about 26.5% DS-8, about 26.5% to about 27% DS-8, about 27% to about 27.5% DS-8, about 27.5% to about 28% DS-8, about 28% to about 28.5% DS-8, or about 28.5% to about 29% DS-8. In some additional embodiments, the mixture of β-cyclodextrin molecules is from about 23% to about 24% DS-8, from about 23% to about 24.5% DS-8, from about 23% to about 25% DS-8, from about 23% to about 25.5% DS-8, from about 23% to about 26% DS-8, from about 23% to about 26.5% DS-8, from about 23% to about 27% DS-8, from about 23% to about 27.5% DS-8, from about 23% to about 28% DS-8, from about 23% to about 28.5% DS-8, from about 23.5% to about 29% DS-8, % DS-8, about 24% to about 29% DS-8, about 24.5% to about 29% DS-8, about 25% to about 29% DS-8, about 25.5% to about 29% DS-8, about 26% to about 29% DS-8, about 26.5% to about 29% DS-8, about 27% to about 29% DS-8, about 27.5% to about 29% DS-8, about 28% to about 29% DS-8, about 24% to about 28% DS-8, or about 25% to about 27% DS-8.In still further embodiments, the mixture of β-cyclodextrin molecules is about 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 30.0%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30.9%, 31.0%, 31.1%, 31.2%, 31.3%, 31.4%, 31.5%, 31.6%, 31.7%, 31.8%, 31.9%, 31.10%, %, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, or about 29.0%. In some embodiments, the amount of DS-8 in the composition may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-8 in the MALDI-TOF-MS spectrum is 26.43%.

[0102] In some embodiments, the mixture of β-cyclodextrin molecules may contain about 15% to about 21% DS-9. In some aspects, the mixture of β-cyclodextrin molecules may contain about 15% to about 15.5% DS-9, about 15.5% to about 16% DS-9, about 16% to about 16.5% DS-9, about 16.5% to about 17% DS-9, about 17% to about 17.5% DS-9, about 17.5% to about 18% DS-9, about 18% to about 18.5% DS-9, about 18.5% to about 19% DS-9, about 19% to about 19.5% DS-9, about 19.5% to about 20% DS-9, about 20% to about 20.5% DS-9, or about 20.5% to about 21% DS-9. In some additional embodiments, the mixture of β-cyclodextrin molecules is from about 15% to about 16% DS-9, from about 15% to about 16.5% DS-9, from about 15% to about 17% DS-9, from about 15% to about 17.5% DS-9, from about 15% to about 18% DS-9, from about 15% to about 18.5% DS-9, from about 15% to about 19% DS-9, from about 15% to about 19.5% DS-9, from about 15% to about 20% DS-9, from about 15% to about 20.5% DS-9, from about 15% to about 20.5% DS-9, or from about 15% to about 20.5% DS-9. The composition may comprise from about 0.5% to about 21% DS-9, from about 16% to about 21% DS-9, from about 16.5% to about 21% DS-9, from about 17% to about 21% DS-9, from about 17.5% to about 21% DS-9, from about 18% to about 21% DS-9, from about 18.5% to about 21% DS-9, from about 19% to about 21% DS-9, from about 19.5% to about 21% DS-9, from about 20% to about 21% DS-9, from about 16% to about 20% DS-9, or from about 17% to about 19% DS-9.In still further embodiments, the mixture of β-cyclodextrin molecules is about 15.0%, 15.1%, 15.2%, 15.3%, 15.4%, 15.5%, 15.6%, 15.7%, 15.8%, 15.9%, 16.0%, 16.1%, 16.2%, 16.3%, 16.4%, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.10%, 18.11%, 18.12%, 18.13%, 18.14%, 18.15%, 18.16%, 18.17%, 18.18%, 18.19%, 18.20%, 18.21%, 18.22%, 18.23%, 18.24%, 18.25%, 18.26%, 18.27%, 18.28%, 18.29%, 18.30%, 18.31%, 18.32%, 18.33%, 18.34%, 18.35%, 18.36%, 18.37%, 18.38%, 18.39%, 18.40%, 18.41%, 18.42%, 18.43%, 18.44%, 18.45%, 18.46%, 18.47%, 18.48%, 18.49%, 18.50%, 18.51%, 18.52%, 18.53 In some embodiments, the composition may contain 7.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, 20.0%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, or about 21.0% DS-9. In some embodiments, the amount of DS-9 in the composition may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-9 in the MALDI-TOF-MS spectrum is 18.09%.

[0103] In some embodiments, the mixture of β-cyclodextrin molecules may contain about 6% to about 12% DS-10. In some aspects, the mixture of β-cyclodextrin molecules may contain about 6% to about 6.5% DS-10, about 6.5% to about 7% DS-10, about 7% to about 7.5% DS-10, about 7.5% to about 8% DS-10, about 8% to about 8.5% DS-10, about 8.5% to about 9% DS-10, about 9% to about 9.5% DS-10, about 9.5% to about 10% DS-10, about 10% to about 10.5% DS-10, about 10.5% to about 11% DS-10, about 11% to about 11.5% DS-10, or about 11.5% to about 12% DS-10. In some additional embodiments, the mixture of β-cyclodextrin molecules is from about 6% to about 7% DS-10, from about 6% to about 7.5% DS-10, from about 6% to about 8% DS-10, from about 6% to about 8.5% DS-10, from about 6% to about 9% DS-10, from about 6% to about 9.5% DS-10, from about 6% to about 10% DS-10, from about 6% to about 10.5% DS-10, from about 6% to about 11% DS-10, from about 6% to about 11.5% DS-10, from about 6.5% to about 1 The DS-10 may contain 2% DS-10, about 7% to about 12% DS-10, about 7.5% to about 12% DS-10, about 8% to about 12% DS-10, about 8.5% to about 12% DS-10, about 9% to about 12% DS-10, about 9.5% to about 12% DS-10, about 10% to about 12% DS-10, about 10.5% to about 12% DS-10, about 11% to about 12% DS-10, about 7% to about 11% DS-10, or about 8% to about 10% DS-10.In still further embodiments, the mixture of β-cyclodextrin molecules is about 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, The mixture of β-cyclodextrin molecules may contain 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, or about 12.0% DS-10. In some embodiments, the amount of DS-10 in the mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-10 in the MALDI-TOF-MS spectrum is 9.39%.

[0104] In some embodiments, the mixture of β-cyclodextrin molecules may contain about 2% to about 6% DS-11. In some aspects, the mixture of β-cyclodextrin molecules may contain about 2% to about 2.5% DS-11, about 2.5% to about 3% DS-11, about 3% to about 3.5% DS-11, about 3.5% to about 4% DS-11, about 4% to about 4.5% DS-11, about 4.5% to about 5% DS-11, about 5% to about 5.5% DS-11, or about 5.5% to about 6% DS-11. In some additional embodiments, the mixture of β-cyclodextrin molecules may contain about 2% to about 3% DS-11, about 2% to about 3.5% DS-11, about 2% to about 4% DS-11, about 2% to about 4.5% DS-11, about 2% to about 5% DS-11, about 2% to about 5.5% DS-11, about 2.5% to about 6% DS-11, about 3% to about 6% DS-11, about 3.5% to about 6% DS-11, about 4% to about 6% DS-11, about 4.5% to about 6% DS-11, about 5% to about 6% DS-11, or about 3% to about 5% DS-11. In still additional embodiments, the mixture of β-cyclodextrin molecules may contain about 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, or about 6.0% DS-11. In some embodiments, the amount of DS-11 in a mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-11 in the MALDI-TOF-MS spectrum is 4.58%.

[0105] In some embodiments, the mixture of β-cyclodextrin molecules can contain about 0.5% to about 4% DS-12. In some aspects, the mixture of β-cyclodextrin molecules can contain about 0.5% to about 1% DS-12, about 1% to about 1.5% DS-12, about 1.5% to about 2% DS-12, about 2% to about 2.5% DS-12, about 2.5% to about 3% DS-12, about 3% to about 3.5% DS-12, or about 3.5% to about 4% DS-12. In some additional embodiments, the mixture of β-cyclodextrin molecules may contain about 0.5% to about 1.5% DS-12, about 0.5% to about 2% DS-12, about 0.5% to about 2.5% DS-12, about 0.5% to about 3% DS-12, about 0.5% to about 3.5% DS-12, about 1% to about 4% DS-12, about 1.5% to about 4% DS-12, about 2% to about 4% DS-12, about 2.5% to about 4% DS-12, about 3% to about 4% DS-12, or about 1% to about 3% DS-12. In still further embodiments, the mixture of β-cyclodextrin molecules may contain about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, or about 4.0%. In some embodiments, the amount of DS-12 in the mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS. In an exemplary embodiment, the area of ​​DS-12 in the MALDI-TOF-MS spectrum is 1.84%.

[0106] In some embodiments, the mixture of β-cyclodextrin molecules may contain less than 1% DS-13, for example, the mixture of β-cyclodextrin molecules may contain about 0.9% DS-13, about 0.8% DS-13, about 0.7% DS-13, about 0.6% DS-13, about 0.5% DS-13, about 0.4% DS-13, about 0.3% DS-13, about 0.2% DS-13, or about 0.1% DS-13. In some embodiments, the mixture of β-cyclodextrin molecules can contain less than 1% to about 0.9% DS-13, about 0.9% to about 0.8% DS-13, about 0.8% to about 0.7% DS-13, about 0.7% to about 0.6% DS-13, about 0.7% to about 0.6% DS-13, about 0.6% to about 0.5% DS-13, about 0.5% to about 0.4% DS-13, about 0.4% to about 0.3% DS-13, about 0.3% to about 0.2% DS-13, about 0.2% to about 0.1% DS-13, or less than 0.1% DS-13. In some additional embodiments, the mixture of β-cyclodextrin molecules comprises less than 1% to about 0.8% DS-13, less than 1% to about 0.7% DS-13, less than 1% to about 0.6% DS-13, less than 1% to about 0.5% DS-13, less than 1% to about 0.4% DS-13, less than 1% to about 0.3% DS-13, less than 1% to about 0.2% DS-13, It may contain less than 1% to about 0.1% DS-13, about 0.9% to about 0.1% DS-13, about 0.8% to about 0.1% DS-13, about 0.7% to about 0.1% DS-13, about 0.6% to about 0.1% DS-13, about 0.5% to about 0.1% DS-13, about 0.4% to about 0.1% DS-13, or about 0.3% to about 0.1% DS-13. In still further aspects, the mixture of β-cyclodextrin may contain less than 1% DS-13, less than 0.9% DS-13, less than 0.8% DS-13, less than 0.7% DS-13, less than 0.6% DS-13, less than 0.5% DS-13, less than 0.4% DS-13, less than 0.3% DS-13, less than 0.2% DS-13, or less than 0.1% DS-13. In some embodiments, the amount of DS-13 in the mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS.In an exemplary embodiment, the area of ​​DS-13 in the MALDI-TOF-MS spectrum is 0.70%.

[0107] In some embodiments, the composition may contain less than 1% DS-14, for example, a mixture of β-cyclodextrin molecules may contain about 0.9% DS-14, about 0.8% DS-14, about 0.7% DS-14, about 0.6% DS-14, about 0.5% DS-14, about 0.4% DS-14, about 0.3% DS-14, about 0.2% DS-14, or about 0.1% DS-14. In some embodiments, the mixture of β-cyclodextrin molecules may contain less than 1% to about 0.9% DS-14, about 0.9% to about 0.8% DS-14, about 0.8% to about 0.7% DS-14, about 0.7% to about 0.6% DS-14, about 0.7% to about 0.6% DS-14, about 0.6% to about 0.5% DS-14, about 0.5% to about 0.4% DS-14, about 0.4% to about 0.3% DS-14, about 0.3% to about 0.2% DS-14, about 0.2% to about 0.1% DS-14, or less than 0.1% DS-14. In some additional embodiments, the mixture of β-cyclodextrin molecules comprises less than 1% to about 0.8% DS-14, less than 1% to about 0.7% DS-14, less than 1% to about 0.6% DS-14, less than 1% to about 0.5% DS-14, less than 1% to about 0.4% DS-14, less than 1% to about 0.3% DS-14, less than 1% to about 0.2% DS-14, It may contain less than 1% to about 0.1% DS-14, about 0.9% to about 0.1% DS-14, about 0.8% to about 0.1% DS-14, about 0.7% to about 0.1% DS-14, about 0.6% to about 0.1% DS-14, about 0.5% to about 0.1% DS-14, about 0.4% to about 0.1% DS-14, or about 0.3% to about 0.1% DS-14. In still further embodiments, the mixture of β-cyclodextrin may optionally contain less than 1% DS-14, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% DS-4. In still further embodiments, the mixture of β-cyclodextrin molecules may optionally contain about 0.001%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or about 1% DS-14.In some embodiments, the amount of DS-14 in a mixture of β-cyclodextrin molecules may be determined by MALDI-TOF-MS. In some embodiments, DS-14 is absent from the composition.

[0108] In an exemplary embodiment, the composition comprises a mixture of β-cyclodextrin molecules, wherein the mixture of β-cyclodextrin molecules includes DS-4, DS-5, DS-6, DS-7, DS-8, DS-9, DS-10, DS-11, DS-12, DS-13, and DS-14, and wherein the mixture of β-cyclodextrin molecules includes less than 1% of DS-1, DS-2, DS-3, and DS-4.

[0109] A mixture of β-cyclodextrin molecules was analyzed by proton nuclear magnetic resonance spectroscopy ( 1 It may be characterized using H-NMR. 1 Methods for performing H-NMR and reading the resulting spectra are generally known to those skilled in the art. In some embodiments, the composition comprises at least one peak at about 5.0-5.4 ppm corresponding to an anomeric proton of the β-cyclodextrin molecule, at least one peak at about 3.2-4.2 ppm corresponding to a proton in the core region of the β-cyclodextrin molecule, and at least one peak at about 1.0-1.2 ppm corresponding to a methyl proton in a side chain of the β-cyclodextrin molecule. 1 1 H-NMR spectrum. 1 The H-NMR spectrum is provided in Figure 2.

[0110] The mixture of β-cyclodextrin molecules may be substituted at one or more of the 2-O-, 3-O-, or 6-O-positions on each of the cyclodextrin subunits. Additionally, the mixture of β-cyclodextrin molecules may be substituted on a single side chain emanating from one or more of the above positions. This substitution pattern may be qualitatively determined using DEPT-edited heteronuclear single quantum coherence (DEPT-edited HSQC). Methods for performing DEPT-edited HSQC and reading the resulting spectra are generally well known to those skilled in the art. An exemplary DEPT-edited HSQC spectrum for a mixture of β-cyclodextrins of the present disclosure is provided in FIG. 3.

[0111] In some embodiments, the mixture of β-cyclodextrin molecules may be substituted at the 2-O-position at about 35% to about 55% (i.e., about 35% to about 55% of the 2-O-positions in the β-cyclodextrin molecules are substituted). In some aspects, the mixture of β-cyclodextrin molecules may be substituted at the 2-O-position at about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, or about 50% to about 55%. In some additional aspects, the mixture of β-cyclodextrin molecules may be substituted at the 2-O-position at about 35% to about 45%, about 35% to about 50%, about 40% to about 55%, about 45% to about 55%, or about 40% to about 50%. In still further aspects, the mixture of β-cyclodextrin molecules may be about 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, or about 55% substituted at the 2-O-position. In some embodiments, the mixture of β-cyclodextrin molecules may be about 46% substituted at the 2-O-position.

[0112] In some embodiments, the mixture of β-cyclodextrin molecules may be about 45% to about 65% substituted at the 3-O-position. In some aspects, the mixture of β-cyclodextrin molecules may be about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, or about 60% to about 65% substituted at the 3-O-position. In some additional aspects, the mixture of β-cyclodextrin molecules may be about 45% to about 55%, about 45% to about 60%, about 50% to about 65%, about 55% to about 65%, or about 50% to about 60% substituted at the 3-O-position. In still further embodiments, the mixture of β-cyclodextrin molecules may be about 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, or about 65% substituted at the 3-O-position, hi some embodiments, the mixture of β-cyclodextrin molecules may be about 54% substituted at the 3-O-position.

[0113] In some embodiments, the mixture of β-cyclodextrin molecules may be substituted at the 6-O-position at about 0% to about 20%. In some aspects, the mixture of β-cyclodextrin molecules may be substituted at the 6-O-position at about 0% to about 5%, about 5% to about 10%, about 10% to about 15%, or about 15% to about 20%. In some additional aspects, the β-cyclodextrin molecules may be substituted at the 6-O-position at about 0% to about 10%, about 0% to about 15%, about 5% to about 20%, about 10% to about 20%, or about 5% to about 15%. In still further aspects, the β-cyclodextrin molecules may be substituted at the 6-O-position at about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or about 20%. In some embodiments, the β-cyclodextrin molecules may be substituted at the 6-O-position at about 10%.

[0114] In some embodiments, about 4-10% of the hydroxypropyl substituents are in an oligomerized state, for example, the hydroxypropyl substituents in an oligomerized state have the following formula: [ka] In some aspects, the percentage of hydroxypropyl substituents in the oligomerized state may be about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, or about 9% to about 10%. In some additional aspects, the percentage of hydroxypropyl substituents in the oligomerized state may be about 4% to about 6%, about 4% to about 7%, about 4% to about 8%, about 4% to about 9%, about 5% to about 10%, about 6% to about 10%, about 7% to about 10%, about 8% to about 10%, about 5% to about 9%, or about 6% to about 8%. In an exemplary embodiment, about 7% of the hydroxypropyl substituents are in the oligomerized state.

[0115] The composition may be characterized by HPLC-CAD using methods known in the art. An exemplary HPLC-CAD chromatogram is shown in Figure 4. In some embodiments, the average retention time of the composition may be about 11 minutes to about 13 minutes, e.g., the average retention time may be about 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, or about 13.0 minutes. In an exemplary embodiment, the average retention time is about 12 minutes.

[0116] Also provided herein are compositions comprising a mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the mixture comprising less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1. In some embodiments, the composition has an average degree of substitution of about 6.02 to about 7.98. The average degree of substitution is 1In some embodiments, the amounts of DS-0 and DS-1 are determined by peak heights in electrospray MS spectra.

[0117] In some embodiments, the composition may have a pH of about 6.0 to about 7.9. In some aspects, the composition may have a pH of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or about 7.9. Preferably, the composition has a pH of about 7.1 to 7.7, more preferably about 7.3 to 7.5.

[0118] In some embodiments, the composition may be purified by alumina adsorption chromatography, solvent precipitation, or a combination thereof, or by other methods known to those skilled in the art.

[0119] Also provided herein is a method for preparing a purified mixture of β-cyclodextrin suitable for intrathecal, intravenous, oral, or intracerebroventricular administration to a patient in need thereof. The method includes nanofiltering β-cyclodextrin to obtain a purified mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, and then adjusting the pH of the nanofiltered purified mixture of β-cyclodextrin to achieve a pH of about 6.0 to about 7.8. The mixture may contain less than 0.05% DS-0 and less than 0.05% DS-1. The mixture may have an average degree of substitution of about 6.02 to 7.98. The pH may be adjusted with sodium hydroxide, such as 0.1 M sodium hydroxide.

[0120] Further provided herein is a method of treating Niemann-Pick disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1. Also provided herein is a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1, for use in a method of treating Niemann-Pick disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of the composition, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1.

[0121] Also provided herein is a method of treating Niemann-Pick type C disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1. Also provided herein is a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1, for use in a method of treating Niemann-Pick type C disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of the composition, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1.

[0122] Also provided herein is a method of treating liver disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1. Also provided herein is a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1, for use in a method of treating liver disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of the composition, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1.

[0123] Further provided herein is a method of treating cardiovascular disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1. Also provided herein is a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1, for use in a method of treating cardiovascular disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of the composition, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1.

[0124] Further provided herein is a method of treating familial hypercholesterolemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1. Also provided herein is a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1, for use in a method of treating familial hypercholesterolemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of the composition, wherein the mixture comprises less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1.

[0125] Further provided herein is a method of treating cholesterol deposits, the method comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the mixture comprising less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1. Also provided herein is a composition comprising a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with hydroxypropyl groups, the mixture comprising less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1, for use in a method of treating cholesterol deposits, the method comprising administering to a patient in need thereof a therapeutically effective amount of the composition, the mixture comprising less than 0.05% unsubstituted beta-cyclodextrin ("DS-0") and less than 0.05% DS-1.

[0126] In some embodiments, the method may include administering to the patient about 50 mg to about 2000 mg of β-cyclodextrin. In some aspects, the method may include administering to the patient about 50 mg to about 100 mg, about 100 mg to about 250 mg, about 250 mg to about 500 mg, about 500 mg to about 750 mg, about 750 mg to about 1000 mg, about 1000 mg to about 1250 mg, about 1250 mg to about 1500 mg, about 1500 mg to about 1750 mg, or about 1750 mg to about 2000 mg of β-cyclodextrin. In some additional embodiments, the method may include administering to the patient about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1000 mg, about 50 mg to about 1250 mg, about 50 mg to about 1500 mg, about 50 mg to about 1750 mg, about 100 mg to about 2000 mg, about 250 mg to about 2000 mg, about 500 mg to about 2000 mg, about 750 mg to about 2000 mg, about 1000 mg to about 2000 mg, about 1250 mg to about 2000 mg, or about 1500 mg to about 2000 mg of β-cyclodextrin. In an exemplary embodiment, the method includes administering to the patient about 50 mg to about 300 mg of β-cyclodextrin.

[0127] In some embodiments, the method may include administering the composition at 1-, 2-, or 3-day intervals. In other embodiments, the method may include administering the composition at least once a week. In yet further embodiments, the method may include administering the composition once every two weeks.

[0128] In some embodiments, the method comprises intravenously administering to the patient about 200 mg / kg to about 4100 mg / kg of β-cyclodextrin. In some aspects, the method comprises intravenously administering about 200 mg / kg to about 500 mg / kg, about 500 mg / kg to about 1000 mg / kg, about 1000 mg / kg to about 1500 mg / kg, about 1500 mg / kg to about 2000 mg / kg, about 2000 mg / kg to about 2500 mg / kg, about 2500 mg / kg to about 3000 mg / kg, about 3000 mg / kg to about 3500 mg / kg, or about 3500 mg / kg to about 4100 mg / kg. In some additional embodiments, the methods comprise intravenously administering about 200 mg / kg to about 1000 mg / kg, about 200 mg / kg to about 1500 mg / kg, about 200 mg / kg to about 2000 mg / kg, about 200 mg / kg to about 2500 mg / kg, about 200 mg / kg to about 3000 mg / kg, about 200 mg / kg to about 3500 mg / kg, about 500 mg / kg to about 4100 mg / kg, about 1000 mg / kg to about 4100 mg / kg, about 1500 mg / kg to about 4100 mg / kg, about 2000 mg / kg to about 4100 mg / kg, about 2500 mg / kg to about 4100 mg / kg, or about 3000 mg / kg to about 4100 mg / kg.

[0129] In some embodiments, administration may be performed within 4 hours. For example, administration may be performed within 4 hours, 3 hours, 2 hours, 1 hour, or 30 minutes. In some embodiments, the administration period (preferably intravenous administration) may be about 4 hours or less. For example, the administration period is about 4 hours or less, about 3 hours or less, about 2 hours or less, about 1 hour or less, or about 30 minutes or less.

[0130] In some embodiments, administration may result in a 75%±5%, 80%±5%, 85%±5%, 90%±5%, or 95%±5% reduction in one or more lipids, hi some embodiments, administration may be sufficient to modulate plasma levels of one or more of 7-ketocholesterol, 7β-hydroxycholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, and cholestane-3β,5α,6β-triol.

[0131] In some embodiments, administration may be sufficient to maintain or reduce one or more domain scores of the NPC severity scale selected from ambulation, fine motor skills, cognition, speech, swallowing, eye movement, memory, hearing, and seizures. NPC severity scales and methods for using them are known to those skilled in the art.

[0132] In some embodiments, administration may prevent the progression of NPC when compared to no administration or administration of a placebo.

[0133] Fractionation The unfractionated compositions described above may be isomerically purified by the purification methods described below.

[0134] Without being bound by theory, isomers of hydroxypropyl-β-cyclodextrin differ from each other, their starting material (β-cyclodextrin), and their by-product (propylene glycol) by their ability to form noncovalent inclusion complexes with hydrophobic complexes. Therefore, the present inventors have created an inclusion-assisted HPLC method for separating hydroxypropyl-β-cyclodextrin isomers and separating other components from a composition. Inclusion-assisted HPLC methods are generally known and described in the art. In the inclusion-assisted HPLC method of the present invention, a hydrophobic species may be grafted onto the silica surface of the HPLC stationary phase. Components that cannot form inclusion complexes (e.g., degradation products of propylene glycol and hydroxypropyl-β-cyclodextrin) or can only form weak inclusion complexes with the silica-grafted species (e.g., unsubstituted β-cyclodextrin or DS-1) are eluted with no or short retention times. Components that form stronger inclusion complexes are eluted with longer retention times (DS-2, DS-3, DS-4, etc.).

[0135] Provided herein is a method for isomerically purifying a mixture of hydroxypropyl-β-cyclodextrin molecules, the method comprising separating the hydroxypropyl-β-cyclodextrin molecules by high-performance liquid chromatography (HPLC). The column used to isomerically purify the mixture of hydroxypropyl-β-cyclodextrin molecules is a chromatography column (also referred to herein as a "Cholester HPLC" column) having cholesteryl moieties immobilized on the surface of silica gel. This allows for inclusion-type interactions between the immobilized cholesteryl moieties and the cyclodextrin cavity, resulting in the separation of β-cyclodextrin and propylene glycol from the hydroxypropyl-β-cyclodextrin isomers into subfractions. The cholesteryl moieties immobilized on the surface of silica gel (the stationary phase of the "Cholester HPLC" column) have the following properties: [ka] A schematic diagram of the separation mechanism is provided in FIG.

[0136] Also provided herein is an isomerically purified composition comprising a mixture of hydroxypropyl-β-cyclodextrin molecules eluted from a Cholester HPLC column. The mixture of hydroxypropyl-β-cyclodextrin molecules may have a low degree of substitution (LDS) or a high degree of substitution (HDS). In some embodiments, a mixture of about five LDS hydroxypropyl-β-cyclodextrins and about five HDS hydroxypropyl-β-cyclodextrins may be eluted from a Cholester HPLC column. Each of the mixtures is referred to herein as a "fraction."

[0137] Further provided herein is an isomerically purified composition comprising a 5% (w / w) mixture of hydroxypropyl-β-cyclodextrin HDS molecules in an aqueous medium, which provides an equilibrium solubility of cholesterol of about 0.2500 to about 0.6000 mg / mL at a temperature of 37° C. In some embodiments, the composition may provide an equilibrium solubility of about 0.2500 mg / mL to about 0.3000 mg / mL, about 0.3000 mg / mL to about 0.3500 mg / mL, about 0.3500 mg / mL to about 0.4000 mg / mL, about 0.4000 mg / mL to about 0.4500 mg / mL, about 0.4500 mg / mL to about 0.5000 mg / mL, about 0.5000 mg / mL to about 0.5500 mg / mL, or about 0.6000 mg / mL at a temperature of 37° C. In some additional embodiments, the composition has a saturation level of about 0.2500 mg / mL to about 0.3500 mg / mL, about 0.2500 mg / mL to about 0.4000 mg / mL, about 0.2500 mg / mL to about 0.4500 mg / mL, about 0.2500 mg / mL to about 0.5000 mg / mL, about 0.2500 mg / mL to about 0.5500 mg / mL, about 0.3000 mg / mL to about 0.6000 mg / mL at a temperature of 37° C. / mL, about 0.3500 mg / mL to about 0.6000 mg / mL, about 0.4000 mg / mL to about 0.6000 mg / mL, about 0.4500 mg / mL to about 0.6000 mg / mL, about 0.5000 mg / mL to about 0.6000 mg / mL, about 0.3000 mg / mL to about 0.5500 mg / mL, or about 0.3500 mg / mL to about 0.5000 mg / mL.

[0138] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.4000 to 0.4200 mg / ml at a temperature of 37°C.

[0139] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.5000 to 0.5200 mg / ml at a temperature of 37°C.

[0140] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.5400 to 0.5600 mg / ml at a temperature of 37°C.

[0141] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.3600 to 0.3800 mg / ml at a temperature of 37°C.

[0142] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.2400 to about 0.2600 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is HDS Fraction 1, which provides an equilibrium solubility of cholesterol of about 0.2400 to about 0.2600 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.2400 to about 0.2450 mg / ml, about 0.2400 to about 0.2500 mg / ml, about 0.2400 to about 0.2550 mg / ml, about 0.2400 to about 0.2600 mg / ml, about 0.2450 to about 0.2600 mg / ml, about 0.2500 to about 0.2600 mg / ml, or about 0.2550 to about 0.2600 mg / ml. In additional embodiments, HDS Fraction 1 may provide an equilibrium solubility of cholesterol of about 0.2400 to about 0.2450 mg / ml, about 0.2400 to about 0.2500 mg / ml, about 0.2400 to about 0.2550 mg / ml, about 0.2400 to about 0.2600 mg / ml, about 0.2450 to about 0.2600 mg / ml, about 0.2500 to about 0.2600 mg / ml, or about 0.2550 to about 0.2600 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.2400, 0.2410, 0.2420, 0.2430, 0.2440, 0.2450, 0.2460, 0.2470, 0.2480, 0.2490, 0.2500, 0.2510, 0.2520, 0.2530, 0.2540, 0.2550, 0.2560, 0.2570, 0.2580, 0.2590, or about 0.2600 mg / ml. In still further embodiments, HDS Fraction 1 may provide an equilibrium solubility of cholesterol of about 0.2400, 0.2410, 0.2420, 0.2430, 0.2440, 0.2450, 0.2460, 0.2470, 0.2480, 0.2490, 0.2500, 0.2510, 0.2520, 0.2530, 0.2540, 0.2550, 0.2560, 0.2570, 0.2580, 0.2590, or about 0.2600 mg / ml.

[0143] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.4000 to about 0.4200 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is HDS Fraction 2, which provides an equilibrium solubility of cholesterol of about 0.4000 to about 0.4200 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.4000 to about 0.4050 mg / ml, about 0.4000 to about 0.4100 mg / ml, about 0.4000 to about 0.4150 mg / ml, about 0.4000 to about 0.4200 mg / ml, about 0.4050 to about 0.4200 mg / ml, about 0.4100 to about 0.4200 mg / ml, or about 0.4150 to about 0.4200 mg / ml. In additional embodiments, HDS Fraction 2 may provide an equilibrium solubility of cholesterol of about 0.4000 to about 0.4050 mg / ml, about 0.4000 to about 0.4100 mg / ml, about 0.4000 to about 0.4150 mg / ml, about 0.4000 to about 0.4200 mg / ml, about 0.4050 to about 0.4200 mg / ml, about 0.4100 to about 0.4200 mg / ml, or about 0.4150 to about 0.4200 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.4000, 0.4010, 0.4020, 0.4030, 0.4040, 0.4050, 0.4060, 0.4070, 0.4080, 0.4090, 0.4100, 0.4110, 0.4120, 0.4130, 0.4140, 0.4150, 0.4160, 0.4170, 0.4180, 0.4190, or about 0.4200 mg / ml. In still further embodiments, HDS Fraction 2 may provide an equilibrium solubility of cholesterol of about 0.4000, 0.4010, 0.4020, 0.4030, 0.4040, 0.4050, 0.4060, 0.4070, 0.4080, 0.4090, 0.4100, 0.4110, 0.4120, 0.4130, 0.4140, 0.4150, 0.4160, 0.4170, 0.4180, 0.4190, or about 0.4200 mg / ml.

[0144] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.5000 to about 0.5200 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is HDS Fraction 3, which provides an equilibrium solubility of cholesterol of about 0.5000 to about 0.5200 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.5000 to about 0.5050 mg / ml, about 0.5000 to about 0.5100 mg / ml, about 0.5000 to about 0.5150 mg / ml, about 0.5000 to about 0.5200 mg / ml, about 0.5050 to about 0.5200 mg / ml, about 0.5100 to about 0.5200 mg / ml, or about 0.5150 to about 0.5200 mg / ml. In additional embodiments, HDS Fraction 3 may provide an equilibrium solubility of cholesterol of about 0.5000 to about 0.5050 mg / ml, about 0.5000 to about 0.5100 mg / ml, about 0.5000 to about 0.5150 mg / ml, about 0.5000 to about 0.5200 mg / ml, about 0.5050 to about 0.5200 mg / ml, about 0.5100 to about 0.5200 mg / ml, or about 0.5150 to about 0.5200 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.5000, 0.5010, 0.5020, 0.5030, 0.5040, 0.5050, 0.5060, 0.5070, 0.5080, 0.5090, 0.5100, 0.5110, 0.5120, 0.5130, 0.5140, 0.5150, 0.5160, 0.5170, 0.5180, 0.5190, or about 0.5200 mg / ml. In still further embodiments, HDS Fraction 3 may provide an equilibrium solubility of cholesterol of about 0.5000, 0.5010, 0.5020, 0.5030, 0.5040, 0.5050, 0.5060, 0.5070, 0.5080, 0.5090, 0.5100, 0.5110, 0.5120, 0.5130, 0.5140, 0.5150, 0.5160, 0.5170, 0.5180, 0.5190, or about 0.5200 mg / ml.

[0145] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.5400 to about 0.5600 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is HDS Fraction 4, which provides an equilibrium solubility of cholesterol of about 0.5400 to about 0.5600 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.5400 to about 0.5450 mg / ml, about 0.5400 to about 0.5500 mg / ml, about 0.5400 to about 0.5550 mg / ml, about 0.5400 to about 0.5600 mg / ml, about 0.5450 to about 0.5600 mg / ml, about 0.5500 to about 0.5600 mg / ml, or about 0.5550 to about 0.5600 mg / ml. In some additional embodiments, HDS Fraction 4 may provide an equilibrium solubility of cholesterol of about 0.5400 to about 0.5450 mg / ml, about 0.5400 to about 0.5500 mg / ml, about 0.5400 to about 0.5550 mg / ml, about 0.5400 to about 0.5600 mg / ml, about 0.5450 to about 0.5600 mg / ml, about 0.5500 to about 0.5600 mg / ml, or about 0.5550 to about 0.5600 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.5400, 0.5410, 0.5420, 0.5430, 0.5440, 0.5450, 0.5460, 0.5470, 0.5480, 0.5490, 0.5500, 0.5510, 0.5520, 0.5530, 0.5540, 0.5550, 0.5560, 0.5570, 0.5580, 0.5590, or about 0.5600 mg / ml. In still further embodiments, HDS Fraction 4 may provide an equilibrium solubility of cholesterol of about 0.5400, 0.5410, 0.5420, 0.5430, 0.5440, 0.5450, 0.5460, 0.5470, 0.5480, 0.5490, 0.5500, 0.5510, 0.5520, 0.5530, 0.5540, 0.5550, 0.5560, 0.5570, 0.5580, 0.5590, or about 0.5600 mg / ml.

[0146] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.3600 to about 0.3800 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is HDS Fraction 5, which provides an equilibrium solubility of cholesterol of about 0.3600 to about 0.3800 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.3600 to about 0.3650 mg / ml, about 0.3600 to about 0.3700 mg / ml, about 0.3600 to about 0.3750 mg / ml, about 0.3600 to about 0.3800 mg / ml, about 0.3650 to about 0.3800 mg / ml, about 0.3700 to about 0.3800 mg / ml, or about 0.3750 to about 0.3800 mg / ml. In some additional embodiments, HDS Fraction 5 may provide an equilibrium solubility of cholesterol of about 0.3600 to about 0.3650 mg / ml, about 0.3600 to about 0.3700 mg / ml, about 0.3600 to about 0.3750 mg / ml, about 0.3600 to about 0.3800 mg / ml, about 0.3650 to about 0.3800 mg / ml, about 0.3700 to about 0.3800 mg / ml, or about 0.3750 to about 0.3800 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.3600, 0.3610, 0.3620, 0.3630, 0.3640, 0.3650, 0.3660, 0.3670, 0.3680, 0.3690, 0.3700, 0.3710, 0.3720, 0.3730, 0.3740, 0.3750, 0.3760, 0.3770, 0.3780, 0.3790, or about 0.3800 mg / ml. In still further embodiments, HDS Fraction 5 may provide an equilibrium solubility of cholesterol of about 0.3600, 0.3610, 0.3620, 0.3630, 0.3640, 0.3650, 0.3660, 0.3670, 0.3680, 0.3690, 0.3700, 0.3710, 0.3720, 0.3730, 0.3740, 0.3750, 0.3760, 0.3770, 0.3780, 0.3790, or about 0.3800 mg / ml.

[0147] Also provided herein is an isomerically purified composition comprising a 5% (w / w) mixture of hydroxypropyl-β-cyclodextrin HDS molecules in an aqueous medium, wherein the mixture of hydroxypropyl-β-cyclodextrin HDS molecules is insoluble in water. In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin HDS molecules can be water-soluble (e.g., soluble at room temperature (20-25° C.)) in the presence of cholesterol.

[0148] Further provided herein are isomerically purified compositions comprising a 5% (w / w) mixture of hydroxypropyl-β-cyclodextrin LDS molecules in an aqueous medium, which provide an equilibrium solubility of cholesterol of about 0.1700 to about 0.3200 mg / mL at a temperature of 37° C. In some embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.1700 mg / mL to about 0.2200 mg / mL, about 0.2200 mg / mL to about 0.2700 mg / mL, or about 0.2700 to about 0.3200 mg / mL at a temperature of 37° C. In some additional embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.1700 mg / mL to about 0.2700 mg / mL or about 0.2200 mg / mL to about 0.3200 mg / mL at a temperature of 37° C.

[0149] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.1800 to about 0.2000 mg / ml at a temperature of 37°C.

[0150] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.1700 to about 0.1900 mg / ml at a temperature of 37°C.

[0151] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.2000 to about 0.2200 mg / ml at a temperature of 37°C.

[0152] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.2200 to about 0.2400 mg / ml at a temperature of 37°C.

[0153] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.3100 to about 0.3300 mg / ml at a temperature of 37°C.

[0154] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.1800 to about 0.2000 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is LDS Fraction 1, which provides an equilibrium solubility of cholesterol of about 0.1800 to about 0.2000 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.1800 to about 0.1850 mg / ml, about 0.1800 to about 0.1900 mg / ml, about 0.1800 to about 0.1950 mg / ml, about 0.1800 to about 0.2000 mg / ml, about 0.1850 to about 0.2000 mg / ml, about 0.1900 to about 0.2000 mg / ml, or about 0.1950 to about 0.2000 mg / ml. In additional embodiments, LDS Fraction 1 may provide an equilibrium solubility of cholesterol of about 0.1800 to about 0.1850 mg / ml, about 0.1800 to about 0.1900 mg / ml, about 0.1800 to about 0.1950 mg / ml, about 0.1800 to about 0.2000 mg / ml, about 0.1850 to about 0.2000 mg / ml, about 0.1900 to about 0.2000 mg / ml, or about 0.1950 to about 0.2000 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.1800, 0.1810, 0.1820, 0.1830, 0.1840, 0.1850, 0.1860, 0.1870, 0.1880, 0.1890, 0.1900, 0.1910, 0.1920, 0.1930, 0.1940, 0.1950, 0.1960, 0.1970, 0.1980, 0.1990, or about 0.2000 mg / ml. In still further embodiments, LDS Fraction 1 may provide an equilibrium solubility of cholesterol of about 0.1800, 0.1810, 0.1820, 0.1830, 0.1840, 0.1850, 0.1860, 0.1870, 0.1880, 0.1890, 0.1900, 0.1910, 0.1920, 0.1930, 0.1940, 0.1950, 0.1960, 0.1970, 0.1980, 0.1990, or about 0.2000 mg / ml.

[0155] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.1700 to about 0.1900 mg / ml, such as about 0.1700 to about 0.1790 mg / ml, at a temperature of 37° C. In an exemplary embodiment, the composition is LDS Fraction 2, which provides an equilibrium solubility of cholesterol of about 0.1700 to about 0.1900 mg / ml, such as about 0.1700 to about 0.1790 mg / ml, at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.1700 to about 0.1750 mg / ml, about 0.1700 to about 0.1800 mg / ml, about 0.1700 to about 0.1850 mg / ml, about 0.1700 to about 0.1900 mg / ml, about 0.1750 to about 0.1900 mg / ml, about 0.1800 to about 0.1900 mg / ml, or about 0.1850 to about 0.1900 mg / ml. In additional embodiments, LDS Fraction 2 may provide an equilibrium solubility of cholesterol of about 0.1700 to about 0.1750 mg / ml, about 0.1700 to about 0.1800 mg / ml, about 0.1700 to about 0.1850 mg / ml, about 0.1700 to about 0.1900 mg / ml, about 0.1750 to about 0.1900 mg / ml, about 0.1800 to about 0.1900 mg / ml, or about 0.1850 to about 0.1900 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.1700, 0.1710, 0.1720, 0.1730, 0.1740, 0.1750, 0.1760, 0.1770, 0.1780, 0.1790, 0.1800, 0.1810, 0.1820, 0.1830, 0.1840, 0.1850, 0.1860, 0.1870, 0.1880, 0.1890, or about 0.1900 mg / ml. In still further embodiments, LDS Fraction 2 may provide an equilibrium solubility of cholesterol of about 0.1700, 0.1710, 0.1720, 0.1730, 0.1740, 0.1750, 0.1760, 0.1770, 0.1780, 0.1790, 0.1800, 0.1810, 0.1820, 0.1830, 0.1840, 0.1850, 0.1860, 0.1870, 0.1880, 0.1890, or about 0.1900 mg / ml.

[0156] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.2000 to about 0.2200 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is LDS Fraction 3, which provides an equilibrium solubility of cholesterol of about 0.2000 to about 0.2200 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.2000 to about 0.2050 mg / ml, about 0.2000 to about 0.2100 mg / ml, about 0.2000 to about 0.2150 mg / ml, about 0.2000 to about 0.2200 mg / ml, about 0.2050 to about 0.2200 mg / ml, about 0.2100 to about 0.2200 mg / ml, or about 0.2150 to about 0.2200 mg / ml. In additional embodiments, LDS Fraction 3 may provide an equilibrium solubility of cholesterol of about 0.2000 to about 0.2050 mg / ml, about 0.2000 to about 0.2100 mg / ml, about 0.2000 to about 0.2150 mg / ml, about 0.2000 to about 0.2200 mg / ml, about 0.2050 to about 0.2200 mg / ml, about 0.2100 to about 0.2200 mg / ml, or about 0.2150 to about 0.2200 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.2000, 0.2010, 0.2020, 0.2030, 0.2040, 0.2050, 0.2060, 0.2070, 0.2080, 0.2090, 0.2100, 0.2110, 0.2120, 0.2130, 0.2140, 0.2150, 0.2160, 0.2170, 0.2180, 0.2190, or about 0.2200 mg / ml. In still further embodiments, LDS Fraction 3 may provide an equilibrium solubility of cholesterol of about 0.2000, 0.2010, 0.2020, 0.2030, 0.2040, 0.2050, 0.2060, 0.2070, 0.2080, 0.2090, 0.2100, 0.2110, 0.2120, 0.2130, 0.2140, 0.2150, 0.2160, 0.2170, 0.2180, 0.2190, or about 0.2200 mg / ml.

[0157] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.2200 to about 0.2400 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is LDS Fraction 4, which provides an equilibrium solubility of cholesterol of about 0.2200 to about 0.2400 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.2200 to about 0.2250 mg / ml, about 0.2200 to about 0.2300 mg / ml, about 0.2200 to about 0.2350 mg / ml, about 0.2200 to about 0.2400 mg / ml, about 0.2250 to about 0.2400 mg / ml, about 0.2300 to about 0.2400 mg / ml, or about 0.2350 to about 0.2400 mg / ml. In additional embodiments, LDS Fraction 4 may provide an equilibrium solubility of cholesterol of about 0.2200 to about 0.2250 mg / ml, about 0.2200 to about 0.2300 mg / ml, about 0.2200 to about 0.2350 mg / ml, about 0.2200 to about 0.2400 mg / ml, about 0.2250 to about 0.2400 mg / ml, about 0.2300 to about 0.2400 mg / ml, or about 0.2350 to about 0.2400 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.2200, 0.2210, 0.2220, 0.2230, 0.2240, 0.2250, 0.2260, 0.2270, 0.2280, 0.2290, 0.2300, 0.2310, 0.2320, 0.2330, 0.2340, 0.2350, 0.2360, 0.2370, 0.2380, 0.2390, or about 0.2400 mg / ml. In still further embodiments, LDS Fraction 4 may provide an equilibrium solubility of cholesterol of about 0.2200, 0.2210, 0.2220, 0.2230, 0.2240, 0.2250, 0.2260, 0.2270, 0.2280, 0.2290, 0.2300, 0.2310, 0.2320, 0.2330, 0.2340, 0.2350, 0.2360, 0.2370, 0.2380, 0.2390, or about 0.2400 mg / ml.

[0158] In some embodiments, the composition may provide an equilibrium solubility of cholesterol of about 0.3100 to about 0.3300 mg / ml at a temperature of 37° C. In an exemplary embodiment, the composition is LDS Fraction 5, which provides an equilibrium solubility of cholesterol of about 0.3100 to about 0.3300 mg / ml at a temperature of 37° C. For example, the composition may provide an equilibrium solubility of cholesterol of about 0.3100 to about 0.3150 mg / ml, about 0.3100 to about 0.3200 mg / ml, about 0.3100 to about 0.3250 mg / ml, about 0.3100 to about 0.3300 mg / ml, about 0.3150 to about 0.3300 mg / ml, about 0.3200 to about 0.3300 mg / ml, or about 0.3250 to about 0.3300 mg / ml. In some additional embodiments, LDS Fraction 5 may provide an equilibrium solubility of cholesterol of about 0.3100 to about 0.3150 mg / ml, about 0.3100 to about 0.3200 mg / ml, about 0.3100 to about 0.3250 mg / ml, about 0.3100 to about 0.3300 mg / ml, about 0.3150 to about 0.3300 mg / ml, about 0.3200 to about 0.3300 mg / ml, or about 0.3250 to about 0.3300 mg / ml. In still further embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 0.3100, 0.3110, 0.3120, 0.3130, 0.3140, 0.3150, 0.3160, 0.3170, 0.3180, 0.3190, 0.3200, 0.3210, 0.3220, 0.3230, 0.3240, 0.3250, 0.3260, 0.3270, 0.3280, 0.3290, or about 0.3300 mg / ml. In still further embodiments, LDS Fraction 5 may provide an equilibrium solubility of cholesterol of about 0.3100, 0.3110, 0.3120, 0.3130, 0.3140, 0.3150, 0.3160, 0.3170, 0.3180, 0.3190, 0.3200, 0.3210, 0.3220, 0.3230, 0.3240, 0.3250, 0.3260, 0.3270, 0.3280, 0.3290, or about 0.3300 mg / ml.

[0159] Further provided herein are isomerically purified compositions comprising a 20% (w / w) mixture of hydroxypropyl-β-cyclodextrin molecules in an aqueous medium, which provide an equilibrium solubility of cholesterol of about 3.2500 mg / mL to about 3.7500 mg / mL at a temperature of 37° C. In some embodiments, the compositions may provide an equilibrium solubility of cholesterol of about 3.2500 mg / mL to about 3.3500 mg / mL, about 3.3500 mg / mL to about 3.4500 mg / mL, about 3.4500 mg / mL to about 3.5500 mg / mL, about 3.5500 mg / mL to about 3.6500 mg / mL, or about 3.6500 mg / mL to about 3.7500 mg / mL. In some additional embodiments, the composition may provide an equilibrium solubility of cholesterol of about 3.2500 mg / mL to about 3.4500 mg / mL, about 3.2500 mg / mL to about 3.5500 mg / mL, about 3.2500 mg / mL to about 3.6500 mg / mL, about 3.3500 mg / mL to about 3.7500 mg / mL, about 3.4500 mg / mL to about 3.7500 mg / mL, or about 3.5500 mg / mL to about 3.7500 mg / mL.

[0160] Further provided herein is a method for increasing the solubility of a mixture of hydroxypropyl β-cyclodextrin molecules in water (e.g., at 37° C.) by increasing the substitution at the 2-O-position of the hydroxypropyl β-cyclodextrin molecules. Also provided herein is a method for increasing the solubility of a mixture of hydroxypropyl β-cyclodextrin molecules in water (e.g., at 37° C.) by increasing the substitution at the 2-O-position of the hydroxypropyl β-cyclodextrin molecules without increasing the hydroxypropyl substitution at other positions of the hydroxypropyl β-cyclodextrin molecules. Further provided herein is a method for increasing the solubility of a mixture of hydroxypropyl β-cyclodextrin molecules in water (e.g., at 37° C.) by increasing the substitution at the 2-O-position of the hydroxypropyl β-cyclodextrin molecules, while maintaining hydroxypropyl substitution at other positions (e.g., the 3-O and / or 6-O positions) of the hydroxypropyl β-cyclodextrin molecules at no more than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, or 50% by weight. In yet another embodiment, provided herein is a method for increasing the solubility of a mixture of hydroxypropyl β-cyclodextrin molecules in water (e.g., at 37° C.) by increasing the substitution at the 2-O-position of the hydroxypropyl β-cyclodextrin molecules, without substantially increasing the hydroxypropyl substitution at the 3-O position. Without wishing to be bound by theory, the solubility of hydroxypropyl β-cyclodextrin may be primarily influenced by the interaction between the hydroxyl groups of the molecule and those in water. When the hydroxypropyl group is substituted at the 3-O-position, the hydroxyl groups of water may be sterically hindered from interacting with the hydroxyl groups of the hydroxypropyl moiety, and therefore, water solubility may decrease. When the hydroxypropyl group is substituted at the 2-O-position, the hydroxyl groups of water may be sterically unhindered from interacting with the hydroxyl groups of the hydroxypropyl moiety, and therefore, water solubility may increase.

[0161] Without wishing to be bound by theory, it is believed that the increased solubility of Fraction 5 in water upon the addition of cholesterol is caused by a conformational change in the hydroxypropyl β-cyclodextrin molecule, which forms an inclusion complex with the cholesterol molecule. When the hydroxypropyl β-cyclodextrin molecule has an oligomerization side chain at the 2-O-position, the hydroxyl group of the oligomerization side chain may form a self-inclusion complex and therefore cannot interact with the hydroxyl group of the water molecule. When cholesterol is added to the solution, the cholesterol molecule interacts with the hydroxypropyl β-cyclodextrin molecule, causing a conformational change in the hydroxypropyl β-cyclodextrin molecule. This frees the hydroxyl group of the side chain to interact with the hydroxyl group of the water molecule, thereby increasing the solubility of Fraction 5.

[0162] Also provided herein are compositions comprising a mixture of hydroxypropyl β-cyclodextrin molecules and cholesterol, wherein the mixture of hydroxypropyl β-cyclodextrin molecules is present in a molar equivalent or molar excess relative to cholesterol. The composition may include a solvent such as water. The mixture of hydroxypropyl β-cyclodextrin molecules may have a concentration of about 5% to about 20% by weight in the composition. In some embodiments, the mixture of hydroxypropyl β-cyclodextrin molecules may have a concentration of about 5% to about 10% by weight, about 10% to about 15% by weight, about 10% to about 20% by weight, or about 15% to about 20% by weight (wherein weight percent refers to the weight percent of the composition in some embodiments). In some embodiments, the presence of cholesterol substantially increases the solubility of the mixture of hydroxypropyl β-cyclodextrin molecules in water. In some embodiments, the presence of cholesterol substantially increases the solubility of the mixture of hydroxypropyl β-cyclodextrin molecules in water. Surprisingly, in some embodiments, the aqueous solubility of hydroxypropyl β-cyclodextrin (e.g., at 37°C) increases in the presence of cholesterol by about 2.5% to about 200%, such as about 10% to about 100%. Accordingly, one aspect of the present invention is a composition comprising a mixture of hydroxypropyl β-cyclodextrin molecules and cholesterol, wherein the solubility of the hydroxypropyl β-cyclodextrin molecules (e.g., at 37°C) increases in the presence of cholesterol by about 2.5% to about 200%, such as about 10% to about 100%. Another aspect of the present invention is a composition comprising a mixture of hydroxypropyl β-cyclodextrin molecules and cholesterol, wherein the aqueous solubility of the hydroxypropyl β-cyclodextrin (e.g., at 37°C) increases in the presence of cholesterol by about 2.5% to about 200%, such as about 10% to about 100%, due to a conformational change in the hydroxypropyl β-cyclodextrin molecules bound and / or complexed to cholesterol.In some embodiments, the presence of cholesterol substantially increases the aqueous solubility (e.g., at 37°C) of the mixture of hydroxypropyl β-cyclodextrin molecules by about 2.5% to about 5%, 5% to about 10%, about 10% to about 15%, about 15% to about 25%, about 25% to about 50%, about 50% to about 75%, about 75% to about 100%, about 100% to about 150%, or about 150% to about 200%.

[0163] In some embodiments, the hydroxypropyl β-cyclodextrin may be present in the composition in a molar ratio relative to cholesterol of about 100:1 to about 1:1. In some aspects, the hydroxypropyl β-cyclodextrin may be present in the composition in a molar ratio relative to cholesterol of about 1:1 to about 25:1, about 25:1 to about 50:1, about 50:1 to about 75:1, or about 75:1 to about 100:1. In some embodiments, the solubility of the hydroxypropyl β-cyclodextrin is increased by about 10% to about 100% in the presence of a mixture of cholesterol and a molar excess of hydroxypropyl β-cyclodextrin molecules (e.g., Fraction 5).

[0164] In other embodiments, the hydroxypropyl β-cyclodextrin may be present in the composition in a molar ratio relative to cholesterol of about 1:1 to about 1:100 (i.e., a molar excess). In some aspects, the hydroxypropyl β-cyclodextrin may be present in the composition in a molar ratio relative to cholesterol of about 1:1 to about 1:25, about 1:25 to about 1:50, about 1:50 to about 1:75, or about 1:75 to about 1:100.

[0165] Also provided herein is a composition comprising a mixture of hydroxypropyl β-cyclodextrin molecules, in which the substitution at the 3-O-position is dimerized. Without wishing to be bound by theory, in hydroxypropyl β-cyclodextrin molecules with two or more substitutions at the 3-O-position, the hydroxyl groups of the hydroxypropyl moieties may react to form hydroxypropyl dimers. In these molecules, the hydroxyl group at the 3-O-position becomes inaccessible to water, thus reducing solubility in water.

[0166] Also provided herein are compositions containing a mixture of hydroxypropyl β-cyclodextrin molecules that form self-inclusion complexes due to substitution at the 3-O-position. Without wishing to be bound by theory, in hydroxypropyl β-cyclodextrin molecules with two or more substitutions at the 3-O-position, the hydroxyl groups of the hydroxypropyl moieties may interact to form self-inclusion complexes. In these molecules, the hydroxyl group at the 3-O-position becomes inaccessible to water, thus reducing solubility in water.

[0167] Also provided herein are methods for increasing the surface polarity of hydroxypropyl β-cyclodextrin molecules, the methods comprising increasing the substitution level at the 2-O-position. In some embodiments, the methods can further comprise increasing the substitution level at the 3-O-position of the hydroxypropyl β-cyclodextrin molecules.

[0168] Fraction 1 HDS Provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules containing less than 1% DS-4. In some embodiments, the percentage of hydroxypropyl-β-cyclodextrin is based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the percentage of hydroxypropyl-β-cyclodextrin can be weight percentage, mole percentage, or volume percentage. In an exemplary embodiment, the percentage of hydroxypropyl-β-cyclodextrin is weight percentage.

[0169] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain less than 1% DS-3, DS-2, and DS-1. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain less than 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% DS-3, DS-2, and DS-1. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain less than 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% DS-4, DS-3, DS-2, and / or DS-1. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not include DS-3, DS-2, and / or DS-1.

[0170] In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain less than 1% DS-12, DS-13, and DS-14. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain less than 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% DS-12, DS-13, and DS-14. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain less than 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% DS-12, DS-13, and / or DS-14. In some embodiments, the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules does not include DS-12, DS-13 and / or DS-14.

[0171] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules contains about 1% to about 5% DS-5. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules contains about 1% to about 1.5% DS-5, about 1.5% to about 2% DS-5, about 2% to about 2.5% DS-5, about 2.5% to about 3% DS-5, about 3% DS-5 to about 3.5% DS-5, about 3.5% to about 4% DS-5, about 4% to about 4.5% DS-5, or about 4.5% to about 5% DS-5. In some additional embodiments, the mixture of isomerically purified β-cyclodextrin molecules comprises between about 1% and about 2% DS-5, between about 1% and about 2.5% DS-5, between about 1% and about 3% DS-5, between about 1% and about 3.5% DS-5, between about 1% and about 4% DS-5, between about 1% and about 4.5% DS-5, between about 1.5% and about 5% DS-5, between about 2% and about 5% DS-5, between about 2.5% and about 5% DS-5, between about 3% and about 5% DS-5, between about 3.5% and about 5% DS-5, between about 4% and about 5% DS-5, between about 1.5% and about 4.5% DS-5, between about 2% and about 4% DS-5, or between about 2.5% and about 3.5% DS-5. In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or about 5.0% DS-5. In an exemplary embodiment, the area of ​​DS-5 in the MALDI-TOF-MS spectrum is 2.83%.

[0172] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules comprises about 7% to about 13% DS-6. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain between about 7% and about 7.5% DS-6, between about 7.5% and about 8% DS-6, between about 8% and about 8.5% DS-6, between about 8.5% and about 9% DS-6, between about 9% and about 9.5% DS-6, between about 9.5% and about 10% DS-6, between about 10% and about 10.5% DS-6, between about 10.5% and about 11% DS-6, between about 11% and about 11.5% DS-6, between about 11.5% and about 12% DS-6, between about 12% and about 12.5% ​​DS-6, or between about 12.5% ​​and about 13% DS-6. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 7% to about 8% DS-6, from about 7% to about 8.5% DS-6, from about 7% to about 9% DS-6, from about 7% to about 9.5% DS-6, from about 7% to about 10% DS-6, from about 7% to about 10.5% DS-6, from about 7% to about 11% DS-6, from about 7% to about 11.5% DS-6, from about 7% to about 12% DS-6, from about 7% to about 12.5% ​​DS-6, from about 7.5% to about 13% DS-6, from about 8% to about 13% DS-6, or from about 8% to about 13% DS-6. DS-6, about 8.5% to about 13% DS-6, about 9% to about 13% DS-6, about 9.5% to about 13% DS-6, about 10% to about 13% DS-6, about 10.5% to about 13% DS-6, about 11% to about 13% DS-6, about 11.5% to about 13% DS-6, about 12% to about 13% DS-6, about 7.5% to about 12.5% ​​DS-6, about 8% to about 12% DS-6, about 8.5% to about 11.5% DS-6, about 9% to about 11% DS-6, or about 9.5% to about 10.5% DS-6.In yet additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is at least about 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, The MALDI-TOF-MS spectrum may contain 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, or about 13.0% DS-6. In an exemplary embodiment, the area of ​​DS-6 in the MALDI-TOF-MS spectrum is 10.64%.

[0173] In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may include about 16% to about 22% DS-7. In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain about 16% to about 16.5% DS-7, about 16.5% to about 17% DS-7, about 17% to about 17.5% DS-7, about 17.5% to about 18% DS-7, about 18% to about 18.5% DS-7, about 18.5% to about 19% DS-7, about 19% to about 19.5% DS-7, about 19.5% to about 20% DS-7, about 20% to about 20.5% DS-7, about 20.5% to about 21% DS-7, about 21% to about 21.5% DS-7, or about 21.5% to about 22% DS-7. In some additional embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules is from about 16% to about 17% DS-7, from about 16% to about 17.5% DS-7, from about 16% to about 18% DS-7, from about 16% to about 18.5% DS-7, from about 16% to about 19% DS-7, from about 16% to about 19.5% DS-7, from about 16% to about 20% DS-7, from about 16% to about 20.5% DS-7, from about 16% to about 21% DS-7, from about 16% to about 21.5% DS-7, from about 16.5% to about 22% DS-7, from about 17% to about 22% DS-7, about 17.5% to about 22% DS-7, about 18% to about 22% DS-7, about 18.5% to about 22% DS-7, about 19% to about 22% DS-7, about 19.5% to about 22% DS-7, about 20% to about 22% DS-7, about 20.5% to about 22% DS-7, about 21% to about 22% DS-7, about 16.5% to about 21.5% DS-7, about 17% to about 21% DS-7, about 17.5% to about 20.5% DS-7, about 18% to about 20% DS-7, or about 18.5% to about 19.5% DS-7.In still further embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules is about 16.0%, 16.1%, 16.2%, 16.3%, 16.4%, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 20.1%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, 21.0%, 21.1%, 21.2%, 21.3%, 21.4%, 21.5%, 21.6%, 21.7%, 21.8%, 21.9%, 22.0%, 22.1%. DS-7 may comprise about 0.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, 20.0%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, 21.0%, 21.1%, 21.2%, 21.3%, 21.4%, 21.5%, 21.6%, 21.7%, 21.8%, 21.9%, or about 22.0% of the area of ​​DS-7 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-7 in the MALDI-TOF-MS spectrum is 19.30%.

[0174] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 26% to about 32% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 26% to about 26.5% DS-8, about 26.5% to about 27% DS-8, about 27% to about 27.5% DS-8, about 27.5% to about 28% DS-8, about 28% to about 28.5% DS-8, about 28.5% to about 29% DS-8, about 29% to about 29.5% DS-8, about 29.5% to about 30% DS-8, about 30% to about 30.5% DS-8, about 30.5% to about 31% DS-8, about 31% to about 31.5% DS-8, or about 31.5% to about 32% DS-8. In some additional embodiments, the isomerically purified β-cyclodextrin mixture is from about 26% to about 27% DS-8, from about 26% to about 27.5% DS-8, from about 26% to about 28% DS-8, from about 26% to about 28.5% DS-8, from about 26% to about 29% DS-8, from about 26% to about 29.5% DS-8, from about 26% to about 30% DS-8, from about 26% to about 30.5% DS-8, from about 26% to about 31% DS-8, from about 26% to about 31.5% DS-8, from about 26.5% to about 32% DS-8, from about 27% to about 32% DS-8, or from about 26% to about 32% DS-8. S-8, about 27.5% to about 32% DS-8, about 28% to about 32% DS-8, about 28.5% to about 32% DS-8, about 29% to about 32% DS-8, about 29.5% to about 32% DS-8, about 30% to about 32% DS-8, about 30.5% to about 32% DS-8, about 31% to about 32% DS-8, about 26.5% to about 31.5% DS-8, about 27% to about 31% DS-8, about 27.5% to about 30.5% DS-8, about 28% to about 30% DS-8, or about 28.5% to about 29.5% DS-8.In still further embodiments, the mixture of isomerically purified β-cyclodextrin molecules is about 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 30.0%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30.9%, 31.0%, 31.1%, 31.2%, 31.3%, 31.4%, 31.5%, 31.6%, 31.7%, 31.8%, 31.9%, 32.0%, 32.1%, 32.2%, 32.3%, 32.4%, 32.5%, 32.6%, 32.7%, 32.8%, 32.9%, 33.0%, 33.1%, 33.1%. DS-8 may comprise 0.8%, 28.9%, 29.0%, 29.1%, 29.2%, 29.3%, 29.4%, 29.5%, 29.6%, 29.7%, 29.8%, 29.9%, 30.0%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30.9%, 31.0%, 31.1%, 31.2%, 31.3%, 31.4%, 31.5%, 31.6%, 31.7%, 31.8%, 31.9%, or about 32.0% of the total area of ​​DS-8 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-8 in the MALDI-TOF-MS spectrum is 29.30%.

[0175] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 22% to about 28% DS-9. In some aspects, the mixture of isomerically purified β-cyclodextrin molecules contains about 22% to about 22.5% DS-9, about 22.5% to about 23% DS-9, about 23% to about 23.5% DS-9, about 23.5% to about 24% DS-9, about 24% to about 24.5% to about 25% DS-9, about 25% to about 25.5% DS-9, about 25.5% to about 26% DS-9, about 26% to about 26.5% DS-9, about 26.5% to about 27% DS-9, about 27% to about 27.5% DS-9, or about 27.5% to about 28% DS-9. In some additional embodiments, the mixture of isomerically purified β-cyclodextrins is about 22% to about 23% DS-9, about 22% to about 23.5% DS-9, about 22% to about 24% DS-9, about 22% to about 24.5% DS-9, about 22% to about 25% DS-9, about 22% to about 25.5% DS-9, about 22% to about 26% DS-9, about 22% to about 26.5% DS-9, about 22% to about 27% DS-9, about 22% to about 27.5% DS-9, about 22.5% to about 28% DS-9, about 23% to about 28% DS-9, or about 28% DS-9. S-9, about 23.5% to about 28% DS-9, about 24% to about 28% DS-9, about 24.5% to about 28% DS-9, about 25% to about 28% DS-9, about 25.5% to about 28% DS-9, about 26% to about 28% DS-9, about 26.5% to about 28% DS-9, about 27% to about 28% DS-9, about 22.5% to about 27.5% DS-9, about 23% to about 27% DS-9, about 23.5% to about 26.5% DS-9, about 24% to about 26% DS-9, or about 24.5% to about 25.5% DS-9.In still further embodiments, the mixture of isomerically purified β-cyclodextrin molecules is about 22.0%, 22.1%, 22.2%, 22.3%, 22.4%, 22.5%, 22.6%, 22.7%, 22.8%, 22.9%, 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 30.0%, 30.1%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, or about 28.0% of the DS-9 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-9 in the MALDI-TOF-MS spectrum is 25.30%.

[0176] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 11% to about 17% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 11% to about 11.5% DS-10, about 11.5% to about 12% DS-10, about 12% to about 12.5% ​​DS-10, about 12.5% ​​to about 13% DS-10, about 13% to about 13.5% DS-10, about 13.5% to about 14% DS-10, about 14% to about 14.5% DS-10, about 14.5% to about 15% DS-10, about 15% to about 15.5% DS-10, about 15.5% to about 16% DS-10, about 16% to about 16.5% DS-10, or about 16.5% to about 17% DS-10. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 11% to about 12% DS-10, from about 11% to about 12.5% ​​DS-10, from about 11% to about 13% DS-10, from about 11% to about 13.5% DS-10, from about 11% to about 14% DS-10, from about 11% to about 14.5% DS-10, from about 11% to about 15% DS-10, from about 11% to about 15.5% DS-10, from about 11% to about 16% DS-10, from about 11% to about 16.5% DS-10, from about 11.5% to about 17% DS-10, from about 12% to about The DS-10 may comprise 17% DS-10, about 12.5% ​​to about 17% DS-10, about 13% to about 17% DS-10, about 13.5% to about 17% DS-10, about 14% to about 17% DS-10, about 14.5% to about 17% DS-10, about 15% to about 17% DS-10, about 15.5% to about 17% DS-10, about 16% to about 17% DS-10, about 11.5% to about 16.5% DS-10, about 12% to about 16% DS-10, about 12.5% ​​to about 15.5% DS-10, about 13% to about 15% DS-10, or about 13.5% to about 14.5% DS-10.In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules has an isomerization ratio of about 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.1%. 16.0%, 16.1%, 16.2%, 16.3%, 16.4%, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, or about 17.0% of the DS-10 area in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-10 in the MALDI-TOF-MS spectrum is 14.30%.

[0177] In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 1% to about 5% DS-5, from about 7% to about 13% DS-6, from about 16% to about 22% DS-7, from about 26% to about 32% DS-8, from about 22% to about 28% DS-9, and from about 11% to about 17% DS-10.

[0178] Also provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules, including DS-5, DS-6, DS-7, DS-8, DS-9, and DS-10. In some embodiments, the composition comprises less than 1% DS-4. In some additional embodiments, the composition comprises less than 1% DS-11. In some embodiments, DS-8 may have the highest concentration in the composition when compared to DS-5, DS-6, DS-7, DS-9, and DS-10.

[0179] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules contains about 1% to about 5% DS-5. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules contains about 1% to about 1.5% DS-5, about 1.5% to about 2% DS-5, about 2% to about 2.5% DS-5, about 2.5% to about 3% DS-5, about 3% DS-5 to about 3.5% DS-5, about 3.5% to about 4% DS-5, about 4% to about 4.5% DS-5, or about 4.5% to about 5% DS-5. In some additional embodiments, the mixture of isomerically purified β-cyclodextrin molecules comprises between about 1% and about 2% DS-5, between about 1% and about 2.5% DS-5, between about 1% and about 3% DS-5, between about 1% and about 3.5% DS-5, between about 1% and about 4% DS-5, between about 1% and about 4.5% DS-5, between about 1.5% and about 5% DS-5, between about 2% and about 5% DS-5, between about 2.5% and about 5% DS-5, between about 3% and about 5% DS-5, between about 3.5% and about 5% DS-5, between about 4% and about 5% DS-5, between about 1.5% and about 4.5% DS-5, between about 2% and about 4% DS-5, or between about 2.5% and about 3.5% DS-5. In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or about 5.0% DS-5. In an exemplary embodiment, the area of ​​DS-5 in the MALDI-TOF-MS spectrum is 2.83%.

[0180] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules comprises about 7% to about 13% DS-6. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain between about 7% and about 7.5% DS-6, between about 7.5% and about 8% DS-6, between about 8% and about 8.5% DS-6, between about 8.5% and about 9% DS-6, between about 9% and about 9.5% DS-6, between about 9.5% and about 10% DS-6, between about 10% and about 10.5% DS-6, between about 10.5% and about 11% DS-6, between about 11% and about 11.5% DS-6, between about 11.5% and about 12% DS-6, between about 12% and about 12.5% ​​DS-6, or between about 12.5% ​​and about 13% DS-6. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 7% to about 8% DS-6, from about 7% to about 8.5% DS-6, from about 7% to about 9% DS-6, from about 7% to about 9.5% DS-6, from about 7% to about 10% DS-6, from about 7% to about 10.5% DS-6, from about 7% to about 11% DS-6, from about 7% to about 11.5% DS-6, from about 7% to about 12% DS-6, from about 7% to about 12.5% ​​DS-6, from about 7.5% to about 13% DS-6, from about 8% to about 13% DS-6, or from about 8% to about 13% DS-6. DS-6, about 8.5% to about 13% DS-6, about 9% to about 13% DS-6, about 9.5% to about 13% DS-6, about 10% to about 13% DS-6, about 10.5% to about 13% DS-6, about 11% to about 13% DS-6, about 11.5% to about 13% DS-6, about 12% to about 13% DS-6, about 7.5% to about 12.5% ​​DS-6, about 8% to about 12% DS-6, about 8.5% to about 11.5% DS-6, about 9% to about 11% DS-6, or about 9.5% to about 10.5% DS-6.In yet additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is at least about 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, The MALDI-TOF-MS spectrum may contain 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, or about 13.0% DS-6. In an exemplary embodiment, the area of ​​DS-6 in the MALDI-TOF-MS spectrum is 10.64%.

[0181] In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may include about 16% to about 22% DS-7. In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain about 16% to about 16.5% DS-7, about 16.5% to about 17% DS-7, about 17% to about 17.5% DS-7, about 17.5% to about 18% DS-7, about 18% to about 18.5% DS-7, about 18.5% to about 19% DS-7, about 19% to about 19.5% DS-7, about 19.5% to about 20% DS-7, about 20% to about 20.5% DS-7, about 20.5% to about 21% DS-7, about 21% to about 21.5% DS-7, or about 21.5% to about 22% DS-7. In some additional embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules is from about 16% to about 17% DS-7, from about 16% to about 17.5% DS-7, from about 16% to about 18% DS-7, from about 16% to about 18.5% DS-7, from about 16% to about 19% DS-7, from about 16% to about 19.5% DS-7, from about 16% to about 20% DS-7, from about 16% to about 20.5% DS-7, from about 16% to about 21% DS-7, from about 16% to about 21.5% DS-7, from about 16.5% to about 22% DS-7, from about 17% to about 22% DS-7, about 17.5% to about 22% DS-7, about 18% to about 22% DS-7, about 18.5% to about 22% DS-7, about 19% to about 22% DS-7, about 19.5% to about 22% DS-7, about 20% to about 22% DS-7, about 20.5% to about 22% DS-7, about 21% to about 22% DS-7, about 16.5% to about 21.5% DS-7, about 17% to about 21% DS-7, about 17.5% to about 20.5% DS-7, about 18% to about 20% DS-7, or about 18.5% to about 19.5% DS-7.In still further embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules is about 16.0%, 16.1%, 16.2%, 16.3%, 16.4%, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 20.1%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, 21.0%, 21.1%, 21.2%, 21.3%, 21.4%, 21.5%, 21.6%, 21.7%, 21.8%, 21.9%, 22.0%, 22.1%. DS-7 may comprise about 0.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, 20.0%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, 21.0%, 21.1%, 21.2%, 21.3%, 21.4%, 21.5%, 21.6%, 21.7%, 21.8%, 21.9%, or about 22.0% of the area of ​​DS-7 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-7 in the MALDI-TOF-MS spectrum is 19.30%.

[0182] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 26% to about 32% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 26% to about 26.5% DS-8, about 26.5% to about 27% DS-8, about 27% to about 27.5% DS-8, about 27.5% to about 28% DS-8, about 28% to about 28.5% DS-8, about 28.5% to about 29% DS-8, about 29% to about 29.5% DS-8, about 29.5% to about 30% DS-8, about 30% to about 30.5% DS-8, about 30.5% to about 31% DS-8, about 31% to about 31.5% DS-8, or about 31.5% to about 32% DS-8. In some additional embodiments, the isomerically purified β-cyclodextrin mixture is from about 26% to about 27% DS-8, from about 26% to about 27.5% DS-8, from about 26% to about 28% DS-8, from about 26% to about 28.5% DS-8, from about 26% to about 29% DS-8, from about 26% to about 29.5% DS-8, from about 26% to about 30% DS-8, from about 26% to about 30.5% DS-8, from about 26% to about 31% DS-8, from about 26% to about 31.5% DS-8, from about 26.5% to about 32% DS-8, from about 27% to about 32% DS-8, or from about 26% to about 32% DS-8. S-8, about 27.5% to about 32% DS-8, about 28% to about 32% DS-8, about 28.5% to about 32% DS-8, about 29% to about 32% DS-8, about 29.5% to about 32% DS-8, about 30% to about 32% DS-8, about 30.5% to about 32% DS-8, about 31% to about 32% DS-8, about 26.5% to about 31.5% DS-8, about 27% to about 31% DS-8, about 27.5% to about 30.5% DS-8, about 28% to about 30% DS-8, or about 28.5% to about 29.5% DS-8.In still further embodiments, the mixture of isomerically purified β-cyclodextrin molecules is about 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 30.0%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30.9%, 31.0%, 31.1%, 31.2%, 31.3%, 31.4%, 31.5%, 31.6%, 31.7%, 31.8%, 31.9%, 32.0%, 32.1%, 32.2%, 32.3%, 32.4%, 32.5%, 32.6%, 32.7%, 32.8%, 32.9%, 33.0%, 33.1%, 33.1%. DS-8 may comprise 0.8%, 28.9%, 29.0%, 29.1%, 29.2%, 29.3%, 29.4%, 29.5%, 29.6%, 29.7%, 29.8%, 29.9%, 30.0%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30.9%, 31.0%, 31.1%, 31.2%, 31.3%, 31.4%, 31.5%, 31.6%, 31.7%, 31.8%, 31.9%, or about 32.0% of the total area of ​​DS-8 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-8 in the MALDI-TOF-MS spectrum is 29.30%.

[0183] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 22% to about 28% DS-9. In some aspects, the mixture of isomerically purified β-cyclodextrin molecules contains about 22% to about 22.5% DS-9, about 22.5% to about 23% DS-9, about 23% to about 23.5% DS-9, about 23.5% to about 24% DS-9, about 24% to about 24.5% to about 25% DS-9, about 25% to about 25.5% DS-9, about 25.5% to about 26% DS-9, about 26% to about 26.5% DS-9, about 26.5% to about 27% DS-9, about 27% to about 27.5% DS-9, or about 27.5% to about 28% DS-9. In some additional embodiments, the mixture of isomerically purified β-cyclodextrins is about 22% to about 23% DS-9, about 22% to about 23.5% DS-9, about 22% to about 24% DS-9, about 22% to about 24.5% DS-9, about 22% to about 25% DS-9, about 22% to about 25.5% DS-9, about 22% to about 26% DS-9, about 22% to about 26.5% DS-9, about 22% to about 27% DS-9, about 22% to about 27.5% DS-9, about 22.5% to about 28% DS-9, about 23% to about 28% DS-9, or about 28% DS-9. S-9, about 23.5% to about 28% DS-9, about 24% to about 28% DS-9, about 24.5% to about 28% DS-9, about 25% to about 28% DS-9, about 25.5% to about 28% DS-9, about 26% to about 28% DS-9, about 26.5% to about 28% DS-9, about 27% to about 28% DS-9, about 22.5% to about 27.5% DS-9, about 23% to about 27% DS-9, about 23.5% to about 26.5% DS-9, about 24% to about 26% DS-9, or about 24.5% to about 25.5% DS-9.In still further embodiments, the mixture of isomerically purified β-cyclodextrin molecules is about 22.0%, 22.1%, 22.2%, 22.3%, 22.4%, 22.5%, 22.6%, 22.7%, 22.8%, 22.9%, 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 30.0%, 30.1%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, or about 28.0% of the DS-9 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-9 in the MALDI-TOF-MS spectrum is 25.30%.

[0184] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 11% to about 17% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 11% to about 11.5% DS-10, about 11.5% to about 12% DS-10, about 12% to about 12.5% ​​DS-10, about 12.5% ​​to about 13% DS-10, about 13% to about 13.5% DS-10, about 13.5% to about 14% DS-10, about 14% to about 14.5% DS-10, about 14.5% to about 15% DS-10, about 15% to about 15.5% DS-10, about 15.5% to about 16% DS-10, about 16% to about 16.5% DS-10, or about 16.5% to about 17% DS-10. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 11% to about 12% DS-10, from about 11% to about 12.5% ​​DS-10, from about 11% to about 13% DS-10, from about 11% to about 13.5% DS-10, from about 11% to about 14% DS-10, from about 11% to about 14.5% DS-10, from about 11% to about 15% DS-10, from about 11% to about 15.5% DS-10, from about 11% to about 16% DS-10, from about 11% to about 16.5% DS-10, from about 11.5% to about 17% DS-10, from about 12% to about The DS-10 may comprise 17% DS-10, about 12.5% ​​to about 17% DS-10, about 13% to about 17% DS-10, about 13.5% to about 17% DS-10, about 14% to about 17% DS-10, about 14.5% to about 17% DS-10, about 15% to about 17% DS-10, about 15.5% to about 17% DS-10, about 16% to about 17% DS-10, about 11.5% to about 16.5% DS-10, about 12% to about 16% DS-10, about 12.5% ​​to about 15.5% DS-10, about 13% to about 15% DS-10, or about 13.5% to about 14.5% DS-10.In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules has an isomerization ratio of about 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.1%. 16.0%, 16.1%, 16.2%, 16.3%, 16.4%, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, or about 17.0% of the DS-10 area in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-10 in the MALDI-TOF-MS spectrum is 14.30%.

[0185] In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 1% to about 5% DS-5, from about 7% to about 13% DS-6, from about 16% to about 22% DS-7, from about 26% to about 32% DS-8, from about 22% to about 28% DS-9, and from about 11% to about 17% DS-10.

[0186] In another exemplary embodiment, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules comprises DS-5, DS-6, DS-7, DS-8, DS-9, and DS-10, and the composition comprises less than 1% of DS-4, DS-3, DS-2, and DS-1, and the composition comprises less than 1% of DS-11, DS-12, DS-13, and DS-14. In another exemplary embodiment, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules comprises DS-5, DS-6, DS-7, DS-8, DS-9, and DS-10, and the composition does not comprise DS-11, DS-12, DS-13, and / or DS-14. In another exemplary embodiment, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules includes DS-5, DS-6, DS-7, DS-8, DS-9, and DS-10, and the composition does not include DS-4, DS-3, DS-2, and / or DS-1.

[0187] In some embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules can be from about 6.4 to about 7.0. In some aspects, the average degree of substitution of the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules can be about 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or about 7.0. In an exemplary embodiment, the average degree of substitution of the mixture of hydroxypropyl-β-cyclodextrin molecules can be about 6.69.

[0188] The position of substitution in a mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may be determined using methods known to those skilled in the art. In some embodiments, the composition comprises: 1 In some embodiments, the compound may be characterized by H-NMR. 1 H-NMR may be used to determine the degree of substitution of the composition. 1 The H-NMR spectrum is provided in Figure 6. In some embodiments, the composition may be characterized by DEPT-edited HSQC. An exemplary DEPT-edited HSQC spectrum is provided in Figure 7.

[0189] In some embodiments, about 52% to about 58% of the hydroxypropyl substitutions in the hydroxypropyl-β-cyclodextrin molecules can be at the 3-O-position. In some aspects, the percentage of substitution at the 3-O-position in a mixture of hydroxypropyl-β-cyclodextrin molecules can be about 52% to about 53%, about 53% to about 54%, about 54% to about 55%, about 55% to about 56%, about 56% to about 57%, or about 57% to about 58%. In some additional embodiments, the percentage of substitution at the 3-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules can be about 52% to about 54%, about 52% to about 55%, about 52% to about 56%, about 52% to about 57%, about 53% to about 58%, about 54% to about 58%, about 55% to about 58%, about 56% to about 58%, about 53% to about 57%, or about 54% to about 56%. In an exemplary embodiment, the percentage of substitution at the 3-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules is about 55.43%.

[0190] In some embodiments, about 41% to about 47% of the hydroxypropyl substitutions in the hydroxypropyl-β-cyclodextrin molecules are at the 2-O-position. In some aspects, the percentage of substitution at the 2-O-position in a mixture of hydroxypropyl-β-cyclodextrin molecules is about 41% to about 42%, about 42% to about 43%, about 43% to about 44%, about 44% to about 45%, about 45% to about 46%, or about 46% to about 47%. In some additional embodiments, the percentage of substitution at the 2-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules is about 41% to about 43%, about 41% to about 44%, about 41% to about 45%, about 41% to about 46%, about 42% to about 47%, about 43% to about 47%, about 44% to about 47%, about 45% to about 47%, about 42% to about 46%, or about 43% to about 45%. In an exemplary embodiment, the percentage of substitution at the 2-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules is about 44.57%.

[0191] In some embodiments, the percentage of substitution at the 6-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules is about 0%.

[0192] In some embodiments, the composition may have the HPLC-CAD chromatogram of Figure 8. In some aspects, the average retention time of the composition may be about 9 minutes to about 11 minutes as measured by HPLC-CAD. In some additional aspects, the average retention time of the composition may be about 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, or about 11 minutes. In an exemplary embodiment, the average retention time is about 10.1 minutes.

[0193] In some embodiments, the composition may have an ESI-MS spectrum with peaks at about 653 m / z, about 682 m / z, about 711 m / z, about 741 m / z, about 769 m / z, about 799 m / z, about 828 m / z, and about 857 m / z. In some embodiments, the composition may have an ESI-MS spectrum with peaks at about 686 m / z, about 715 m / z, about 744 m / z, about 773 m / z, about 802 m / z, about 832 m / z, about 861 m / z, and about 890 m / z. In an exemplary embodiment, the composition has the ESI-MS spectrum shown in FIG.

[0194] The percent of hydroxypropyl-β-cyclodextrin may be based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the composition may have a MALDI-TOF-MS spectrum with peaks at about 1436 m / z, about 1495 m / z, about 1555 m / z, about 1614 m / z, about 1674 m / z, and about 1733 m / z. In an exemplary embodiment, the composition has the MALDI-TOF-MS spectrum shown in FIG. 10. In an exemplary embodiment, the composition has a MALDI-TOF-MS spectrum with an area of ​​DS-5 of 2.83%, an area of ​​DS-6 of 10.64%, an area of ​​DS-7 of 19.30%, an area of ​​DS-8 of 29.30%, an area of ​​DS-9 of 25.30%, and an area of ​​DS-10 of 14.30%.

[0195] In some embodiments, the composition has a density of about 1.095 g / cm 3 ~Approx. 1.100g / cm 3 In some embodiments, the composition may have a true density of about 1.095 g / cm 3 ~approx. 1.096g / cm 3 , approximately 1.096 g / cm 3 ~Approx. 1.097g / cm 3 , about 1.097g / cm 3 ~Approx. 1.098g / cm 3 , about 1.098g / cm 3 ~Approx. 1.099g / cm 3 , about 1.099g / cm 3 ~Approx. 1.100g / cm 3 , about 1.095g / cm 3 ~Approx. 1.097g / cm 3 , about 1.095g / cm 3 ~Approx. 1.098g / cm 3 , about 1.095g / cm 3 ~Approx. 1.099g / cm 3 , approximately 1.096 g / cm 3 ~Approx. 1.100g / cm 3 , about 1.097g / cm 3 ~Approx. 1.100g / cm 3 , about 1.098g / cm 3 ~Approx. 1.100g / cm3 , approximately 1.096 g / cm 3 ~Approx. 1.098g / cm 3 , or approximately 1.096 g / cm 3 ~Approx. 1.099g / cm 3 In some additional embodiments, the composition may have a true density of about 1.095 g / cm 3 , 1.096g / cm 3 , 1.097g / cm 3 , 1.098g / cm 3 , 1.099g / cm 3 , or approximately 1.100 g / cm 3 In an exemplary embodiment, the composition may have a true density of about 1.096 g / cm 3 ~Approx. 1.098g / cm 3 It has a true density of

[0196] In some embodiments, the composition may have an osmolality of about 600 mOs / kg to about 750 mOs / kg. In some aspects, the composition may have an osmolality of about 600 mOs / kg to about 625 mOs / kg, about 625 mOs / kg to about 650 mOs / kg, about 650 mOs / kg to about 675 mOs / kg, about 675 mOs / kg to about 700 mOs / kg, about 700 mOs / kg to about 725 mOs / kg, or about 725 mOs / kg to about 750 mOs / kg. In some additional embodiments, the composition may have an osmolality of about 600 mOs / kg to about 650 mOs / kg, about 600 mOs / kg to about 675 mOs / kg, about 600 mOs / kg to about 700 mOs / kg, about 600 mOs / kg to about 725 mOs / kg, about 625 mOs / kg to about 750 mOs / kg, about 650 mOs / kg to about 750 mOs / kg, about 675 mOs / kg to about 750 mOs / kg, about 700 mOs / kg to about 750 mOs / kg, about 625 mOs / kg to about 725 mOs / kg, or about 650 mOs / kg to about 700 mOs / kg. In still further embodiments, the composition may have an osmolality of about 600 mOs / kg, 610 mOs / kg, 620 mOs / kg, 630 mOs / kg, 640 mOs / kg, 650 mOs / kg, 660 mOs / kg, 670 mOs / kg, 680 mOs / kg, 690 mOs / kg, 700 mOs / kg, 710 mOs / kg, 720 mOs / kg, 730 mOs / kg, 740 mOs / kg, or about 750 mOs / kg. In exemplary embodiments, the composition has an osmolality of about 635 mOs / kg to about 695 mOs / kg.

[0197] In some embodiments, the composition may have a conductivity of about 0 to about 8 μS / cm. In some aspects, the composition may have a conductivity of about 0 μS / cm to about 1 μS / cm, about 1 μS / cm to about 2 μS / cm, about 3 μS / cm to about 4 μS / cm, about 4 μS / cm to about 5 μS / cm, about 5 μS / cm to about 6 μS / cm, about 6 μS / cm to about 7 μS / cm, or about 7 μS / cm to about 8 μS / cm. In some additional embodiments, the composition comprises from about 0 μS / cm to about 1.5 μS / cm, from about 0 μS / cm to about 2 μS / cm, from about 0 μS / cm to about 2.5 μS / cm, from about 0 μS / cm to about 3 μS / cm, from about 0 to about 3.5 μS / cm, from about 0 μS / cm to about 4 μS / cm, from about 0 to about 4.5 μS / cm, from about 0 μS / cm to about 5 μS / cm, from about 0 to about 5.5 μS / cm, from about 0 μS / cm to about 6 μS / cm, from about 0 to about 6.5, from about 0 μS / cm to about 7 μS / cm, from about 0 to about 7.5, from about 1 μS / cm to about 8 μS / cm, from about 1.5 μS / cm to about 8 μS / cm. S / cm, about 2 μS / cm to about 8 μS / cm, about 2.5 μS / cm to about 8 μS / cm, about 3 μS / cm to about 8 μS / cm, about 3.5 μS / cm to about 8 μS / cm, about 4 μS / cm to about 8 μS / cm, about 4.5 μS / cm to about 8 μS / cm, about 5 μS / cm to about 8 μS / cm, about 5.5 μS / cm to about 8 μS / cm, about 6 μS / cm to about 8 μS / cm, about 6.5 μS / cm to about 8 μS / cm, about 1 μS / cm to about 7 μS / cm, about 2 μS / cm to about 6 μS / cm, or about 3 μS / cm to about 5 μS / cm. In still further embodiments, the composition may have a conductivity of about 0.5 μS / cm, 1.0 μS / cm, 1.5 μS / cm, 2.0 μS / cm, 2.5 μS / cm, 3.0 μS / cm, 3.5 μS / cm, 4.0 μS / cm, 4.5 μS / cm, 5.0 μS / cm, 5.5 μS / cm, 6.0 μS / cm, 6.5 μS / cm, 7.0 μS / cm, 7.5 μS / cm, or about 8.0 μS / cm.

[0198] In some embodiments, the composition may have a pH of about 4.0 to about 8.0, for example, the composition may have a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or about 8.0. The composition may have a pH within a range or subrange including any of the above numbers, including, but not limited to, about 4.0 to about 4.5, about 4.5 to about 5.0, about 5.0 to about 5.5, about 5.5 to about 6.0, about 6.0 to about 6.5, about 6.5 to about 7.0, about 7.0 to about 7.5, or about 7.5 to about 8.0. In some embodiments, the composition may further comprise a pH adjuster, such as hydrochloric acid or sodium hydroxide, to adjust the pH to a desired level. In some embodiments, the composition may further comprise a buffer. In some embodiments, the buffer may comprise monosodium phosphate and disodium phosphate.

[0199] In some embodiments, the composition may have a viscosity measured in centipoise (cP) at 20° C. For example, the composition may have a viscosity of about 1.5 cP to about 3.0 cP at 20° C. In some embodiments, the composition may have a viscosity of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 , 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10.0 cP. In other embodiments, the composition may have a viscosity at 20°C of about 3.0 cP to about 5.0 cP, about 5.0 cP to about 10.0 cP, about 10 to about 15 cP, about 15 to about 20 cP, about 20 cP to about 25 cP, about 25 cP to about 50 cP, about 50 cP to about 80 cP, about 80 cP to about 150 cP, about 150 cP to about 250 cP, about 250 cP to about 500 cP, about 500 cP to about 1,000 cP, about 1,000 cP to about 2,000 cP, about 2,000 cP to about 3,000 cP, about 3,000 cP to about 5,000 cP, or about 5,000 cP to about 10,000 cP.

[0200] The composition may be substantially free of impurities, including particles having a diameter of 25 microns or greater, particles having a diameter of 10 microns or greater, chloride, propylene glycol, propylene oxide, and other unspecified impurities. In some embodiments, the composition may contain about 0.05% or less of impurities, for example, the composition may contain about 0.05%, 0.04%, 0.03%, 0.02%, or about 0.01% or less of impurities.

[0201] In some embodiments, the composition may further comprise a container and non-visible particulate matter. In some embodiments, the composition may be provided in a container. In some embodiments, the composition may further comprise non-visible particulate matter.

[0202] In some embodiments, the composition may comprise fewer than 600 particles per container having a diameter of 25 microns or greater. In some aspects, the composition may comprise fewer than 500, fewer than 400, fewer than 300, fewer than 200, or fewer than 100 particles per container having a diameter of 25 microns or greater.

[0203] In some embodiments, the composition may comprise fewer than 6,000 particles per container having a diameter of 10 microns or greater. In some aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, or 100 particles per container having a diameter of 10 microns or greater. In other aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, or 100 particles per container having a diameter of 10 microns or greater, and the container is 100 mL or less. In other aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, 100, 50, 25, 10, 5, or 3 particles per container having a diameter of 10 microns or greater, and the container is greater than 100 mL.

[0204] In some embodiments, the composition may contain 10 ppb or less of propylene glycol. In some aspects, the composition may contain 9 ppb, 8 ppb, 7 ppb, 6 ppb, 5 ppb, 4 ppb, 3 ppb, 2 ppb or less of propylene glycol, or 1 ppb or less of propylene glycol. In some aspects, the amount of propylene glycol in the composition may be determined by HPLC. In some additional aspects, the amount of propylene glycol in the composition may be determined by gas chromatography. In even further aspects, the amount of propylene glycol in the composition may be determined by measuring the PG / EG ratio of propylene glycol to ethylene glycol.

[0205] In some embodiments, the composition may contain 1 ppm or less of propylene oxide. In some aspects, the composition may contain 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, or 0.1 ppm or less of propylene oxide. In some aspects, the amount of propylene oxide in the composition may be determined by HPLC. In some additional aspects, the amount of propylene oxide in the composition may be determined by gas chromatography.

[0206] In some embodiments, the composition contains about 0 ppm to about 10 ppm chloride (e.g., Cl -ions). In some embodiments, the composition may contain about 0 ppm chloride to about 2 ppm chloride, about 2 ppm chloride to about 4 ppm chloride, about 4 ppm chloride to about 6 ppm chloride, about 6 ppm chloride to about 8 ppm chloride, or about 8 to about 10 ppm chloride. In some additional embodiments, the composition may contain about 0 ppm chloride to about 4 ppm chloride, about 0 ppm chloride to about 6 ppm chloride, about 0 ppm chloride to about 8 ppm chloride, about 2 ppm chloride to about 1 ppm chloride, about 4 ppm chloride to about 1 ppm chloride, or about 6 ppm chloride to about 1 ppm chloride. In still further aspects, the composition may comprise about 0 ppm, 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, or about 10 ppm chloride. In exemplary embodiments, the composition may comprise from about 0 ppm to about 1 ppm chloride.

[0207] In some embodiments, the composition contains about 0 ppm to about 10 ppm sodium (e.g., Na + ions). In some embodiments, the composition may comprise about 0 ppm sodium to about 2 ppm sodium, about 2 ppm sodium to about 4 ppm sodium, about 4 ppm sodium to about 6 ppm sodium, about 6 ppm sodium to about 8 ppm sodium, or about 8 to about 10 ppm sodium. In some additional embodiments, the composition may comprise about 0 ppm sodium to about 4 ppm sodium, about 0 ppm sodium to about 6 ppm sodium, about 0 ppm sodium to about 8 ppm sodium, about 2 ppm sodium to about 1 ppm sodium, about 4 ppm sodium to about 1 ppm sodium, or about 6 ppm sodium to about 1 ppm sodium. In even further embodiments, the composition may comprise about 0 ppm, 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, or about 10 ppm sodium. In an exemplary embodiment, the composition may include from about 0 ppm to about 1 ppm sodium.

[0208] In some embodiments, the composition may contain 0.05% or less of other unspecified impurities, for example, the composition may contain 0.05%, 0.04%, 0.03%, 0.02% or less, or 0.01% or less of other unspecified impurities.

[0209] In some embodiments, the composition may be stable for at least 6 months. For example, the composition may be stable for at least 3 months, 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 24 months, or at least 36 months.

[0210] The composition may be nanofiltered. In some embodiments, the concentration of the composition does not substantially change the time required for nanofiltration. Thus, the time for nanofiltration does not increase or decrease when the concentration of the mixture of β-cyclodextrin molecules increases or decreases in the composition. In some aspects, the length of time for nanofiltration of the composition depends on the diafiltration volume (kg solution / m 2 The range is from about 1.04 to about 1.20 hours per 100 mL (hr / L of solution). In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition shows no substantial difference in NMR analysis after nanofiltration compared to before nanofiltration.

[0211] In some embodiments, the composition may be terminally sterilized. Methods of terminal sterilization are generally well known in the art. In some embodiments, the pH of the composition may be adjusted after terminal sterilization.

[0212] In some embodiments, the composition may comprise 10.0 w / w% or less of water, for example, the composition may comprise 10.0 w / w%, 9.5 w / w%, 9.0 w / w%, 8.5 w / w%, 8.0 w / w%, 7.5 w / w%, 7.0 w / w%, 6.5 w / w%, 6.0 w / w%, 5.5 w / w%, 5.0 w / w%, 4.5 w / w%, 4.0 w / w%, 3.5 w / w%, 3.0 w / w%, 2.5 w / w%, 2.0 w / w%, 1.5 w / w%, 1.0 w / w%, 0.5 w / w% or less, or 0.1 w / w% or less of water.

[0213] In some embodiments, the composition can be packaged in a vial suitable for injection into a human subject who needs injection.The vial can be made of glass, plastic, or any other material known in the pharmaceutical arts.The vial can be coated with a material such as silicon dioxide to prevent the composition from leaching out of the vial.

[0214] In some embodiments, the composition may be suitable for administration to a patient in need thereof. In some embodiments, the composition may be suitable for intrathecal administration, intravenous administration, oral administration, intracerebroventricular administration, or a combination thereof (e.g., intravenous and intrathecal administration) to a patient in need thereof. In some aspects, the patient may be a human, such as an adult patient or a pediatric patient. In some examples, the human patient may be an infant (e.g., less than 6 months old) or a newborn (e.g., less than 4 weeks old).

[0215] In some embodiments, the compositions may be effective in treating Niemann-Pick disease. In some embodiments, the compositions may be effective in treating Niemann-Pick disease type C. In some embodiments, the compositions may be effective in treating liver disease. In some embodiments, the compositions may be effective in treating cardiovascular disease. In some embodiments, the compositions may be effective in treating familial hypercholesterolemia. In some embodiments, the compositions may be effective in treating cholesterol deposits.

[0216] In some embodiments, the composition may further comprise a pharmaceutical excipient or carrier. In some embodiments, the composition may further comprise a pharmaceutically acceptable diluent. Examples of pharmaceutical excipients, carriers, and diluents are well known to those skilled in the art.

[0217] In some embodiments, the composition may exhibit less toxicity than Trappsol® Cyclo or Kleptose®. In some embodiments, the composition may exhibit substantially less ototoxicity than Trappsol® Cyclo or Kleptose®. In some embodiments, the composition may exhibit substantially no ototoxicity at all.

[0218] Fraction 2 HDS Provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules containing less than 1% DS-5 and less than 1% DS-13. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain less than 1% DS-4, DS-3, DS-2, and DS-1. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% DS-4, DS-3, DS-2, and DS-1. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is free of DS-4, DS-3, DS-2, and / or DS-1.

[0219] In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain less than 1% DS-13 and DS-14. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% DS-13 and DS-14.

[0220] In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain less than 1% DS-13 and / or DS-14. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may optionally contain less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% DS-13 and / or DS-14. In preferred embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is free of DS-14.

[0221] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules contains about 0% to about 6% DS-6. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 0% to about 0.5% DS-6, about 0.5% to about 1% DS-6, about 1% to about 1.5% DS-6, about 1.5% to about 2% DS-6, about 2% to about 2.5% DS-6, about 2.5% to about 3% DS-6, about 3% to about 3.5% DS-6, about 3.5% to about 4% DS-6, about 4% to about 4.5% DS-6, about 4.5% to about 5% DS-6, about 5% to about 5.5% DS-6, or about 5.5% to about 6% DS-6. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 0% to about 1% DS-6, from about 0% to about 1.5% DS-6, from about 0% to about 2% DS-6, from about 0% to about 2.5% DS-6, from about 0% to about 3% DS-6, from about 0% to about 3.5% DS-6, from about 0% to about 4% DS-6, from about 0% to about 4.5% DS-6, from about 0% to about 5% DS-6, from about 0% to about 5.5% DS-6, from about 0.5% to about 6% DS-6, from about 1% to about 2 ... % to about 6% DS-6, about 1.5% to about 6% DS-6, about 2% to about 6% DS-6, about 2.5% to about 6% DS-6, about 3% to about 6% DS-6, about 3.5% to about 6% DS-6, about 4% to about 6% DS-6, about 4.5% to about 6% DS-6, about 5% to about 6% DS-6, about 0.5% to about 5.5% DS-6, about 1% to about 5% DS-6, about 1.5% to about 4.5% DS-6, about 2% to about 4% DS-6, or about 2.5% to about 3.5% DS-6.In yet additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is at about 0.0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.10%, 4.11%, 4.12%, 4.13%, 4.14%, 4.15%, 4.16%, 4.17%, 4.18%, 4.19%, 4.20%, 4.21%, 4.22%, 4.23%, 4.24%, 4.25%, 4.26%, 4.27%, 4.28%, 4.29%, 4.30%, 4.31%, 4.32%, 4.33%, 4.34%, 4.35%, 4.36%, 4.37%, 4.38%, 4.39%, 4.40%, 4.41%, 4.42%, 4.43%, 4.44%, 4.45%, 4.46%, 4.47%, 4.48%, 4.49%, 4.50%, 4.51%, 4.52%, 4.53%, 4.54%, 4.55 , 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, or about 6.0% DS-6. In an exemplary embodiment, the area of ​​DS-6 in the MALDI-TOF-MS spectrum is 2.91%.

[0222] In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain about 8% to about 14% DS-7. In some aspects, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain about 8% to about 8.5% DS-7, about 8.5% to about 9% DS-7, about 9% to about 9.5% DS-7, about 9.5% to about 10% DS-7, about 10% to about 10.5% DS-7, about 10.5% to about 11% DS-7, about 11% to about 11.5% DS-7, about 11.5% to about 12% DS-7, about 12% to about 12.5% ​​DS-7, about 12.5% ​​to about 13% DS-7, about 13% to about 13.5% DS-7, or about 13.5% to about 14% DS-7. In some additional embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules is from about 8% to about 9% DS-7, from about 8% to about 9.5% DS-7, from about 8% to about 10% DS-7, from about 8% to about 10.5% DS-7, from about 8% to about 11% DS-7, from about 8% to about 11.5% DS-7, from about 8% to about 12% DS-7, from about 8% to about 12.5% ​​DS-7, from about 8% to about 13% DS-7, from about 8% to about 13.5% DS-7, from about 8.5% to about 14% DS-7, from about 9% to about 14% DS-7, It may contain about 9.5% to about 14% DS-7, about 10% to about 14% DS-7, about 10.5% to about 14% DS-7, about 11% to about 14% DS-7, about 11.5% to about 14% DS-7, about 12% to about 14% DS-7, about 12.5% ​​to about 14% DS-7, about 13% to about 14% DS-7, about 8.5% to about 13.5% DS-7, about 9% to about 13% DS-7, about 9.5% to about 12.5% ​​DS-7, about 10% to about 12% DS-7, or about 10.5% to about 11.5% DS-7.In still further embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules is about 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, The area of ​​DS-7 in the MALDI-TOF-MS spectrum may be 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, or about 14.0%. In an exemplary embodiment, the area of ​​DS-7 in the MALDI-TOF-MS spectrum is 10.93%.

[0223] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 19% to about 25% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 19% to about 19.5% DS-8, about 19.5% to about 20% DS-8, about 20% to about 20.5% DS-8, about 20.5% to about 21% DS-8, about 21% to about 21.5% DS-8, about 21.5% to about 22% DS-8, about 22% to about 22.5% DS-8, about 22.5% to about 23% DS-8, about 23% to about 23.5% DS-8, about 23.5% to about 24% DS-8, about 24% to about 24.5% DS-8, or about 24.5% to about 25% DS-8. In some additional embodiments, the mixture of isomerically purified β-cyclodextrins is from about 19% to about 20% DS-8, from about 19% to about 20.5% DS-8, from about 19% to about 21% DS-8, from about 19% to about 21.5% DS-8, from about 19% to about 22% DS-8, from about 19% to about 22.5% DS-8, from about 19% to about 23% DS-8, from about 19% to about 23.5% DS-8, from about 19% to about 24% DS-8, from about 19% to about 24.5% DS-8, from about 19.5% to about 25% DS-8, from about 20% to about 25% DS-8, or from about 25% to about 26% DS-8. S-8, about 20.5% to about 25% DS-8, about 21% to about 25% DS-8, about 21.5% to about 25% DS-8, about 22% to about 25% DS-8, about 22.5% to about 25% DS-8, about 23% to about 25% DS-8, about 23.5% to about 25% DS-8, about 24% to about 25% DS-8, about 19.5% to about 24.5% DS-8, about 20% to about 24% DS-8, about 20.5% to about 23.5% DS-8, about 21% to about 23% DS-8, or about 21.5% to about 22.5% DS-8.In still further embodiments, the mixture of isomerically purified β-cyclodextrin molecules is at least about 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, 20.0%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, 21.0%, 21.1%, 21.2%, 21.3%, 21.4%, 21.5%, 21.6%, 21.7%, 21.8%, 21.9%, 22.0%, 22.1%, 22.2%, 22.3%, 22.4%, 22.5%, 22.6%, 22.7%, 22.8%, 22.9%, 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, or about 25.0% of the DS-8 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-8 in the MALDI-TOF-MS spectrum is 22.52%.

[0224] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 23% to about 29% DS-9. In some aspects, the mixture of isomerically purified β-cyclodextrin molecules contains about 23% to about 23.5% DS-9, about 23.5% to about 24% DS-9, about 24% to about 24.5% to about 25% DS-9, about 25% to about 25.5% DS-9, about 25.5% to about 26% DS-9, about 26% to about 26.5% DS-9, about 26.5% to about 27% DS-9, about 27% to about 27.5% DS-9, about 27.5% to about 28% DS-9, about 28% to about 28.5% DS-9, or about 28.5% to about 29% DS-9. In some additional embodiments, the mixture of isomerically purified β-cyclodextrins is about 23% to about 24% DS-9, about 23% to about 24.5% DS-9, about 23% to about 25% DS-9, about 23% to about 25.5% DS-9, about 23% to about 26% DS-9, about 23% to about 26.5% DS-9, about 23% to about 27% DS-9, about 23% to about 27.5% DS-9, about 23% to about 28% DS-9, about 23% to about 28.5% DS-9, about 23.5% to about 29% DS-9, about 24% to about 29% DS-9, or about 29% DS-9. S-9, about 24.5% to about 29% DS-9, about 25% to about 29% DS-9, about 25.5% to about 29% DS-9, about 26% to about 29% DS-9, about 26.5% to about 29% DS-9, about 27% to about 29% DS-9, about 27.5% to about 29% DS-9, about 28% to about 29% DS-9, about 23.5% to about 28.5% DS-9, about 24% to about 28% DS-9, about 24.5% to about 27.5% DS-9, about 25% to about 27% DS-9, or about 25.5% to about 26.5% DS-9.In still further embodiments, the mixture of isomerically purified β-cyclodextrin molecules is about 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 29.1%, 30.0%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30.9%, 31.0%, 31.1%, 31.2%, 31.3%, 31.4%, 31.5%, 31.6%, 31.7%, 31.8%, 31 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, or about 29.0% of the DS-9 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-9 in the MALDI-TOF-MS spectrum is 26.42%.

[0225] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 17% to about 23% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 17% to about 17.5% DS-10, about 17.5% to about 18% DS-10, about 18% to about 18.5% DS-10, about 18.5% to about 19% DS-10, about 19% to about 19.5% DS-10, about 19.5% to about 20% DS-10, about 20% to about 20.5% DS-10, about 20.5% to about 21% DS-10, about 21% to about 21.5% DS-10, about 21.5% to about 22% DS-10, about 22% to about 22.5% DS-10, or about 22.5% to about 23% DS-10. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 17% to about 18% DS-10, from about 17% to about 18.5% DS-10, from about 17% to about 19% DS-10, from about 17% to about 19.5% DS-10, from about 17% to about 20% DS-10, from about 17% to about 20.5% DS-10, from about 17% to about 21% DS-10, from about 17% to about 21.5% DS-10, from about 17% to about 22% DS-10, from about 17% to about 22.5% DS-10, from about 17.5% to about 23% DS-10, from about 18% to about 23% DS-10, about 18.5% to about 23% DS-10, about 19% to about 23% DS-10, about 19.5% to about 23% DS-10, about 20% to about 23% DS-10, about 20.5% to about 23% DS-10, about 21% to about 23% DS-10, about 21.5% to about 23% DS-10, about 22% to about 23% DS-10, about 17.5% to about 22.5% DS-10, about 18% to about 22% DS-10, about 18.5% to about 21.5% DS-10, about 19% to about 21% DS-10, or about 19.5% to about 20.5% DS-10.In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules has an isomerization ratio of about 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19 ...1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, 19.0%, 19.1%, 19.1%, 19.1%, 19.1%, 19.1%, 19.1%, 19.1%, 19.1%, 22.0%, 22.1%, 22.2%, 22.3%, 22.4%, 22.5%, 22.6%, 22.7%, 22.8%, 22.9%, or about 23.0% of the DS-10 area in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-10 in the MALDI-TOF-MS spectrum is 20.35%.

[0226] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 9% to about 15% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 9% to about 9.5% DS-11, about 9.5% to about 10% DS-11, about 10% to about 10.5% DS-11, about 10.5% to about 11% DS-11, about 11% to about 11.5% DS-11, about 11.5% to about 12% DS-11, about 12% to about 12.5% ​​DS-11, about 12.5% ​​to about 13% DS-11, about 13% to about 13.5% DS-11, about 13.5% to about 14% DS-11, about 14% to about 14.5% DS-11, or about 14.5% to about 15% DS-11. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 9% to about 10% DS-11, from about 9% to about 10.5% DS-11, from about 9% to about 11% DS-11, from about 9% to about 11.5% DS-11, from about 9% to about 12% DS-11, from about 9% to about 12.5% ​​DS-11, from about 9% to about 13% DS-11, from about 9% to about 13.5% DS-11, from about 9% to about 14% DS-11, from about 9% to about 14.5% DS-11, from about 9.5% to about 15% DS-11, from about 10% to about 15% DS-11, S-11, about 10.5% to about 15% DS-11, about 11% to about 15% DS-11, about 11.5% to about 15% DS-11, about 12% to about 15% DS-11, about 12.5% ​​to about 15% DS-11, about 13% to about 15% DS-11, about 13.5% to about 15% DS-11, about 14% to about 15% DS-11, about 9.5% to about 14.5% DS-11, about 10% to about 14% DS-11, about 10.5% to about 13.5% DS-11, about 11% to about 13% DS-11, or about 11.5% to about 12.5% ​​DS-11.In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is at least about 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, 15.0%, 15.1%. 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, or about 15.0% of DS-11. In an exemplary embodiment, the area of ​​DS-11 in the MALDI-TOF-MS spectrum is 12.02%.

[0227] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 2% to about 8% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain between about 2% and about 2.5% DS-12, between about 2.5% and about 3% DS-12, between about 3% and about 3.5% DS-12, between about 3.5% and about 4% DS-12, between about 4% and about 4.5% DS-12, between about 4.5% and about 5% DS-12, between about 5% and about 5.5% DS-12, between about 5.5% and about 6% DS-12, between about 6% and about 6.5% DS-12, between about 6.5% and about 7% DS-12, between about 7% and about 7.5% DS-12, or between about 7.5% and about 8% DS-12. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 2% to about 3% DS-12, from about 2% to about 3.5% DS-12, from about 2% to about 4% DS-12, from about 2% to about 4.5% DS-12, from about 2% to about 5% DS-12, from about 2% to about 5.5% DS-12, from about 2% to about 6% DS-12, from about 2% to about 6.5% DS-12, from about 2% to about 7% DS-12, from about 2% to about 7.5% DS-12, from about 2.5% to about 8% DS-12, from about 3% to about 4% DS-12, from about 3% to about 5 ... The DS-12 may comprise about 8% to about 8% DS-12, about 3.5% to about 8% DS-12, about 4% to about 8% DS-12, about 4.5% to about 8% DS-12, about 5% to about 8% DS-12, about 5.5% to about 8% DS-12, about 6% to about 8% DS-12, about 6.5% to about 8% DS-12, about 7% to about 8% DS-12, about 2.5% to about 7.5% DS-12, about 3% to about 7% DS-12, about 3.5% to about 6.5% DS-12, about 4% to about 6% DS-12, or about 4.5% to about 5.5% DS-12.In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is at least about 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, The DS-12 may comprise 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, or about 8.0% of the DS-12. In an exemplary embodiment, the area of ​​DS-12 in the MALDI-TOF-MS spectrum is 4.85%.

[0228] Also provided herein are compositions comprising a mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules, including DS-6, DS-7, DS-8, DS-9, DS-10, DS-11, and DS-12. In some embodiments, the composition comprises less than 1% DS-5. In some additional embodiments, the composition comprises less than 1% DS-13. In some embodiments, DS-9 may have the highest concentration in the composition when compared to DS-6, DS-7, DS-8, DS-10, DS-11, and DS-12.

[0229] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules contains about 0% to about 6% DS-6. In some aspects, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 0% to about 0.5% DS-6, about 0.5% to about 1% DS-6, about 1% to about 1.5% DS-6, about 1.5% to about 2% DS-6, about 2% to about 2.5% DS-6, about 2.5% to about 3% DS-6, about 3% to about 3.5% DS-6, about 3.5% to about 4% DS-6, about 4% to about 4.5% DS-6, about 4.5% to about 5% DS-6, about 5% to about 5.5% DS-6, or about 5.5% to about 6% DS-6. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 0% to about 1% DS-6, from about 0% to about 1.5% DS-6, from about 0% to about 2% DS-6, from about 0% to about 2.5% DS-6, from about 0% to about 3% DS-6, from about 0% to about 3.5% DS-6, from about 0% to about 4% DS-6, from about 0% to about 4.5% DS-6, from about 0% to about 5% DS-6, from about 0% to about 5.5% DS-6, from about 0.5% to about 6% DS-6, from about 1% to about 2 ... % to about 6% DS-6, about 1.5% to about 6% DS-6, about 2% to about 6% DS-6, about 2.5% to about 6% DS-6, about 3% to about 6% DS-6, about 3.5% to about 6% DS-6, about 4% to about 6% DS-6, about 4.5% to about 6% DS-6, about 5% to about 6% DS-6, about 0.5% to about 5.5% DS-6, about 1% to about 5% DS-6, about 1.5% to about 4.5% DS-6, about 2% to about 4% DS-6, or about 2.5% to about 3.5% DS-6.In yet additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is at about 0.0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.10%, 4.11%, 4.12%, 4.13%, 4.14%, 4.15%, 4.16%, 4.17%, 4.18%, 4.19%, 4.20%, 4.21%, 4.22%, 4.23%, 4.24%, 4.25%, 4.26%, 4.27%, 4.28%, 4.29%, 4.30%, 4.31%, 4.32%, 4.33%, 4.34%, 4.35%, 4.36%, 4.37%, 4.38%, 4.39%, 4.40%, 4.41%, 4.42%, 4.43%, 4.44%, 4.45%, 4.46%, 4.47%, 4.48%, 4.49%, 4.50%, 4.51%, 4.52%, 4.53%, 4.54%, 4.55 , 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, or about 6.0% DS-6. In an exemplary embodiment, the area of ​​DS-6 in the MALDI-TOF-MS spectrum is 2.91%.

[0230] In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain about 8% to about 14% DS-7. In some aspects, the mixture of hydroxypropyl-β-cyclodextrin molecules may contain about 8% to about 8.5% DS-7, about 8.5% to about 9% DS-7, about 9% to about 9.5% DS-7, about 9.5% to about 10% DS-7, about 10% to about 10.5% DS-7, about 10.5% to about 11% DS-7, about 11% to about 11.5% DS-7, about 11.5% to about 12% DS-7, about 12% to about 12.5% ​​DS-7, about 12.5% ​​to about 13% DS-7, about 13% to about 13.5% DS-7, or about 13.5% to about 14% DS-7. In some additional embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules is from about 8% to about 9% DS-7, from about 8% to about 9.5% DS-7, from about 8% to about 10% DS-7, from about 8% to about 10.5% DS-7, from about 8% to about 11% DS-7, from about 8% to about 11.5% DS-7, from about 8% to about 12% DS-7, from about 8% to about 12.5% ​​DS-7, from about 8% to about 13% DS-7, from about 8% to about 13.5% DS-7, from about 8.5% to about 14% DS-7, from about 9% to about 14% DS-7, It may contain about 9.5% to about 14% DS-7, about 10% to about 14% DS-7, about 10.5% to about 14% DS-7, about 11% to about 14% DS-7, about 11.5% to about 14% DS-7, about 12% to about 14% DS-7, about 12.5% ​​to about 14% DS-7, about 13% to about 14% DS-7, about 8.5% to about 13.5% DS-7, about 9% to about 13% DS-7, about 9.5% to about 12.5% ​​DS-7, about 10% to about 12% DS-7, or about 10.5% to about 11.5% DS-7.In still further embodiments, the mixture of hydroxypropyl-β-cyclodextrin molecules is about 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, The area of ​​DS-7 in the MALDI-TOF-MS spectrum may be 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, or about 14.0%. In an exemplary embodiment, the area of ​​DS-7 in the MALDI-TOF-MS spectrum is 10.93%.

[0231] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 19% to about 25% DS-8. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 19% to about 19.5% DS-8, about 19.5% to about 20% DS-8, about 20% to about 20.5% DS-8, about 20.5% to about 21% DS-8, about 21% to about 21.5% DS-8, about 21.5% to about 22% DS-8, about 22% to about 22.5% DS-8, about 22.5% to about 23% DS-8, about 23% to about 23.5% DS-8, about 23.5% to about 24% DS-8, about 24% to about 24.5% DS-8, or about 24.5% to about 25% DS-8. In some additional embodiments, the mixture of isomerically purified β-cyclodextrins is from about 19% to about 20% DS-8, from about 19% to about 20.5% DS-8, from about 19% to about 21% DS-8, from about 19% to about 21.5% DS-8, from about 19% to about 22% DS-8, from about 19% to about 22.5% DS-8, from about 19% to about 23% DS-8, from about 19% to about 23.5% DS-8, from about 19% to about 24% DS-8, from about 19% to about 24.5% DS-8, from about 19.5% to about 25% DS-8, from about 20% to about 25% DS-8, or from about 25% to about 26% DS-8. S-8, about 20.5% to about 25% DS-8, about 21% to about 25% DS-8, about 21.5% to about 25% DS-8, about 22% to about 25% DS-8, about 22.5% to about 25% DS-8, about 23% to about 25% DS-8, about 23.5% to about 25% DS-8, about 24% to about 25% DS-8, about 19.5% to about 24.5% DS-8, about 20% to about 24% DS-8, about 20.5% to about 23.5% DS-8, about 21% to about 23% DS-8, or about 21.5% to about 22.5% DS-8.In still further embodiments, the mixture of isomerically purified β-cyclodextrin molecules is at least about 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, 20.0%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, 21.0%, 21.1%, 21.2%, 21.3%, 21.4%, 21.5%, 21.6%, 21.7%, 21.8%, 21.9%, 22.0%, 22.1%, 22.2%, 22.3%, 22.4%, 22.5%, 22.6%, 22.7%, 22.8%, 22.9%, 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, or about 25.0% of the DS-8 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-8 in the MALDI-TOF-MS spectrum is 22.52%.

[0232] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 23% to about 29% DS-9. In some aspects, the mixture of isomerically purified β-cyclodextrin molecules contains about 23% to about 23.5% DS-9, about 23.5% to about 24% DS-9, about 24% to about 24.5% to about 25% DS-9, about 25% to about 25.5% DS-9, about 25.5% to about 26% DS-9, about 26% to about 26.5% DS-9, about 26.5% to about 27% DS-9, about 27% to about 27.5% DS-9, about 27.5% to about 28% DS-9, about 28% to about 28.5% DS-9, or about 28.5% to about 29% DS-9. In some additional embodiments, the mixture of isomerically purified β-cyclodextrins is about 23% to about 24% DS-9, about 23% to about 24.5% DS-9, about 23% to about 25% DS-9, about 23% to about 25.5% DS-9, about 23% to about 26% DS-9, about 23% to about 26.5% DS-9, about 23% to about 27% DS-9, about 23% to about 27.5% DS-9, about 23% to about 28% DS-9, about 23% to about 28.5% DS-9, about 23.5% to about 29% DS-9, about 24% to about 29% DS-9, or about 29% DS-9. S-9, about 24.5% to about 29% DS-9, about 25% to about 29% DS-9, about 25.5% to about 29% DS-9, about 26% to about 29% DS-9, about 26.5% to about 29% DS-9, about 27% to about 29% DS-9, about 27.5% to about 29% DS-9, about 28% to about 29% DS-9, about 23.5% to about 28.5% DS-9, about 24% to about 28% DS-9, about 24.5% to about 27.5% DS-9, about 25% to about 27% DS-9, or about 25.5% to about 26.5% DS-9.In still further embodiments, the mixture of isomerically purified β-cyclodextrin molecules is about 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 24.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27.3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 29.1%, 30.0%, 30.1%, 30.2%, 30.3%, 30.4%, 30.5%, 30.6%, 30.7%, 30.8%, 30.9%, 31.0%, 31.1%, 31.2%, 31.3%, 31.4%, 31.5%, 31.6%, 31.7%, 31.8%, 31 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, or about 29.0% of the DS-9 in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-9 in the MALDI-TOF-MS spectrum is 26.42%.

[0233] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 17% to about 23% DS-10. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 17% to about 17.5% DS-10, about 17.5% to about 18% DS-10, about 18% to about 18.5% DS-10, about 18.5% to about 19% DS-10, about 19% to about 19.5% DS-10, about 19.5% to about 20% DS-10, about 20% to about 20.5% DS-10, about 20.5% to about 21% DS-10, about 21% to about 21.5% DS-10, about 21.5% to about 22% DS-10, about 22% to about 22.5% DS-10, or about 22.5% to about 23% DS-10. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 17% to about 18% DS-10, from about 17% to about 18.5% DS-10, from about 17% to about 19% DS-10, from about 17% to about 19.5% DS-10, from about 17% to about 20% DS-10, from about 17% to about 20.5% DS-10, from about 17% to about 21% DS-10, from about 17% to about 21.5% DS-10, from about 17% to about 22% DS-10, from about 17% to about 22.5% DS-10, from about 17.5% to about 23% DS-10, from about 18% to about 23% DS-10, about 18.5% to about 23% DS-10, about 19% to about 23% DS-10, about 19.5% to about 23% DS-10, about 20% to about 23% DS-10, about 20.5% to about 23% DS-10, about 21% to about 23% DS-10, about 21.5% to about 23% DS-10, about 22% to about 23% DS-10, about 17.5% to about 22.5% DS-10, about 18% to about 22% DS-10, about 18.5% to about 21.5% DS-10, about 19% to about 21% DS-10, or about 19.5% to about 20.5% DS-10.In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules has an isomerization ratio of about 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19 ...1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, 19.0%, 19.1%, 19.1%, 19.1%, 19.1%, 19.1%, 19.1%, 19.1%, 19.1%, 22.0%, 22.1%, 22.2%, 22.3%, 22.4%, 22.5%, 22.6%, 22.7%, 22.8%, 22.9%, or about 23.0% of the DS-10 area in the MALDI-TOF-MS spectrum. In an exemplary embodiment, the area of ​​DS-10 in the MALDI-TOF-MS spectrum is 20.35%.

[0234] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 9% to about 15% DS-11. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain about 9% to about 9.5% DS-11, about 9.5% to about 10% DS-11, about 10% to about 10.5% DS-11, about 10.5% to about 11% DS-11, about 11% to about 11.5% DS-11, about 11.5% to about 12% DS-11, about 12% to about 12.5% ​​DS-11, about 12.5% ​​to about 13% DS-11, about 13% to about 13.5% DS-11, about 13.5% to about 14% DS-11, about 14% to about 14.5% DS-11, or about 14.5% to about 15% DS-11. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 9% to about 10% DS-11, from about 9% to about 10.5% DS-11, from about 9% to about 11% DS-11, from about 9% to about 11.5% DS-11, from about 9% to about 12% DS-11, from about 9% to about 12.5% ​​DS-11, from about 9% to about 13% DS-11, from about 9% to about 13.5% DS-11, from about 9% to about 14% DS-11, from about 9% to about 14.5% DS-11, from about 9.5% to about 15% DS-11, from about 10% to about 15% DS-11, S-11, about 10.5% to about 15% DS-11, about 11% to about 15% DS-11, about 11.5% to about 15% DS-11, about 12% to about 15% DS-11, about 12.5% ​​to about 15% DS-11, about 13% to about 15% DS-11, about 13.5% to about 15% DS-11, about 14% to about 15% DS-11, about 9.5% to about 14.5% DS-11, about 10% to about 14% DS-11, about 10.5% to about 13.5% DS-11, about 11% to about 13% DS-11, or about 11.5% to about 12.5% ​​DS-11.In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is at least about 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, 15.0%, 15.1%. 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, or about 15.0% of DS-11. In an exemplary embodiment, the area of ​​DS-11 in the MALDI-TOF-MS spectrum is 12.02%.

[0235] In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 2% to about 8% DS-12. In some embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain between about 2% and about 2.5% DS-12, between about 2.5% and about 3% DS-12, between about 3% and about 3.5% DS-12, between about 3.5% and about 4% DS-12, between about 4% and about 4.5% DS-12, between about 4.5% and about 5% DS-12, between about 5% and about 5.5% DS-12, between about 5.5% and about 6% DS-12, between about 6% and about 6.5% DS-12, between about 6.5% and about 7% DS-12, between about 7% and about 7.5% DS-12, or between about 7.5% and about 8% DS-12. In some additional embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is from about 2% to about 3% DS-12, from about 2% to about 3.5% DS-12, from about 2% to about 4% DS-12, from about 2% to about 4.5% DS-12, from about 2% to about 5% DS-12, from about 2% to about 5.5% DS-12, from about 2% to about 6% DS-12, from about 2% to about 6.5% DS-12, from about 2% to about 7% DS-12, from about 2% to about 7.5% DS-12, from about 2.5% to about 8% DS-12, from about 3% to about 4% DS-12, from about 3% to about 5 ... The DS-12 may comprise about 8% to about 8% DS-12, about 3.5% to about 8% DS-12, about 4% to about 8% DS-12, about 4.5% to about 8% DS-12, about 5% to about 8% DS-12, about 5.5% to about 8% DS-12, about 6% to about 8% DS-12, about 6.5% to about 8% DS-12, about 7% to about 8% DS-12, about 2.5% to about 7.5% DS-12, about 3% to about 7% DS-12, about 3.5% to about 6.5% DS-12, about 4% to about 6% DS-12, or about 4.5% to about 5.5% DS-12.In still further embodiments, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules is at least about 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, The DS-12 may comprise 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, or about 8.0% of the DS-12. In an exemplary embodiment, the area of ​​DS-12 in the MALDI-TOF-MS spectrum is 4.85%.

[0236] In an exemplary embodiment, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may contain from about 0.5% to about 6% DS-6, from about 8% to about 14% DS-7, from about 19% to about 25% DS-8, from about 23% to about 29% DS-9, from about 17% to about 23% DS-10, from about 9% to about 15% DS-11, and from about 2% to about 8% DS-12.

[0237] In another exemplary embodiment, the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may include DS-6, DS-7, DS-8, DS-9, DS-10, DS-11, and DS-12, wherein the mixture includes less than 1% of DS-5, DS-4, DS-3, DS-2, and DS-1, and wherein the mixture includes less than 1% of DS-13 and DS-14.

[0238] In some embodiments, the average degree of substitution of the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules can be about 7 to about 8. In some aspects, the average degree of substitution of the mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules can be about 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or about 8.0. In an exemplary embodiment, the average degree of substitution of the mixture of hydroxypropyl-β-cyclodextrin molecules can be about 7.42.

[0239] The position of substitution in a mixture of isomerically purified hydroxypropyl-β-cyclodextrin molecules may be determined using methods known to those skilled in the art. In some embodiments, the composition comprises: 1 In some embodiments, the compound may be characterized by H-NMR. 1 H-NMR may be used to determine the degree of substitution of the composition. 1 The H-NMR spectrum is provided in Figure 11. In some embodiments, the composition may be characterized by DEPT-edited HSQC. An exemplary DEPT-edited HSQC spectrum is provided in Figure 12.

[0240] In some embodiments, about 36% to about 42% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules can be at the 3-O-position. In some aspects, the percentage of substitution at the 3-O-position in a mixture of hydroxypropyl β-cyclodextrin molecules can be about 36% to about 37%, about 37% to about 38%, about 38% to about 39%, about 39% to about 40%, about 40% to about 41%, or about 41% to about 42%. In some additional embodiments, the percentage of substitution at the 3-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules can be about 36% to about 38%, about 36% to about 39%, about 36% to about 40%, about 36% to about 41%, about 37% to about 42%, about 38% to about 42%, about 39% to about 42%, about 40% to about 42%, about 37% to about 41%, or about 38% to about 40%. In an exemplary embodiment, the percentage of substitution at the 3-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules is about 39.00%.

[0241] In some embodiments, about 58% to about 64% of the hydroxypropyl substitutions in the hydroxypropyl-β-cyclodextrin molecules are at the 2-O-position. In some aspects, the percentage of substitution at the 2-O-position in a mixture of hydroxypropyl-β-cyclodextrin molecules is about 58% to about 59%, about 59% to about 60%, about 60% to about 61%, about 61% to about 62%, about 62% to about 63%, or about 63% to about 64%. In some additional embodiments, the percentage of substitution at the 2-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules is about 58% to about 60%, about 58% to about 61%, about 58% to about 62%, about 58% to about 63%, about 59% to about 64%, about 60% to about 64%, about 61% to about 64%, about 62% to about 64%, about 59% to about 63%, or about 60% to about 62%. In an exemplary embodiment, the percentage of substitution at the 2-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules is about 61.14%.

[0242] In some embodiments, the percentage of substitution at the 6-O-position in the mixture of hydroxypropyl-β-cyclodextrin molecules is about 0%.

[0243] In some embodiments, the composition may have the HPLC-CAD chromatogram of Figure 13. In some aspects, the average retention time of the composition may be about 11 minutes to about 13 minutes as measured by HPLC-CAD. In some additional aspects, the average retention time of the composition may be about 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, or about 13.0 minutes. In an exemplary embodiment, the average retention time is about 11.9 minutes.

[0244] In some embodiments, the composition may have an ESI-MS spectrum with peaks at about 682 m / z, about 712 m / z, about 740 m / z, about 770 m / z, about 798 m / z, about 828 m / z, about 856 m / z, and about 886 m / z. In some embodiments, the composition may have an ESI-MS spectrum with peaks at about 744 m / z, about 773 m / z, about 803 m / z, about 832 m / z, about 860 m / z, about 889 m / z, and about 919 m / z. In an exemplary embodiment, the composition has the ESI-MS spectrum shown in FIG. 14.

[0245] The percent of hydroxypropyl-β-cyclodextrin may be based on area percentage from a MALDI-TOF-MS spectrum. In some embodiments, the composition may have a MALDI-TOF-MS spectrum with peaks at about 1497 m / z, about 1557 m / z, about 1616 m / z, about 1675 m / z, about 1734 m / z, about 1794 m / z, and about 1914 m / z. In an exemplary embodiment, the composition has the MALDI-TOF-MS spectrum shown in FIG. 15. In an exemplary embodiment, the composition has a MALDI-TOF-MS spectrum that is DS-6 area 2.91%, DS-7 area 10.93%, DS-8 area 22.52%, DS-9 area 26.42%, DS-10 area 20.35%, DS-11 area 12.02%, and DS-12 area 4.85%.

[0246] In some embodiments, the composition has a density of about 1.095 g / cm 3 ~Approx. 1.100g / cm 3 In some embodiments, the composition may have a true density of about 1.095 g / cm 3 ~approx. 1.096g / cm 3 , approximately 1.096 g / cm 3 ~Approx. 1.097g / cm 3 , about 1.097g / cm 3 ~Approx. 1.098g / cm 3 , about 1.098g / cm 3 ~Approx. 1.099g / cm 3 , about 1.099g / cm 3 ~Approx. 1.100g / cm 3 , about 1.095g / cm 3 ~Approx. 1.097g / cm 3 , about 1.095g / cm 3 ~Approx. 1.098g / cm 3 , about 1.095g / cm 3 ~Approx. 1.099g / cm 3 , approximately 1.096 g / cm 3 ~Approx. 1.100g / cm 3 , about 1.097g / cm 3 ~Approx. 1.100g / cm 3, about 1.098g / cm 3 ~Approx. 1.100g / cm 3 , approximately 1.096 g / cm 3 ~Approx. 1.098g / cm 3 , or approximately 1.096 g / cm 3 ~Approx. 1.099g / cm 3 In some additional embodiments, the composition may have a true density of about 1.095 g / cm 3 , 1.096g / cm 3 , 1.097g / cm 3 , 1.098g / cm 3 , 1.099g / cm 3 , or approximately 1.100 g / cm 3 In an exemplary embodiment, the composition may have a true density of about 1.096 g / cm 3 ~Approx. 1.098g / cm 3 It has a true density of

[0247] In some embodiments, the composition may have an osmolality of about 600 mOs / kg to about 750 mOs / kg. In some aspects, the composition may have an osmolality of about 600 mOs / kg to about 625 mOs / kg, about 625 mOs / kg to about 650 mOs / kg, about 650 mOs / kg to about 675 mOs / kg, about 675 mOs / kg to about 700 mOs / kg, about 700 mOs / kg to about 725 mOs / kg, or about 725 mOs / kg to about 750 mOs / kg. In some additional embodiments, the composition may have an osmolality of about 600 mOs / kg to about 650 mOs / kg, about 600 mOs / kg to about 675 mOs / kg, about 600 mOs / kg to about 700 mOs / kg, about 600 mOs / kg to about 725 mOs / kg, about 625 mOs / kg to about 750 mOs / kg, about 650 mOs / kg to about 750 mOs / kg, about 675 mOs / kg to about 750 mOs / kg, about 700 mOs / kg to about 750 mOs / kg, about 625 mOs / kg to about 725 mOs / kg, or about 650 mOs / kg to about 700 mOs / kg. In still further embodiments, the composition may have an osmolality of about 600 mOs / kg, 610 mOs / kg, 620 mOs / kg, 630 mOs / kg, 640 mOs / kg, 650 mOs / kg, 660 mOs / kg, 670 mOs / kg, 680 mOs / kg, 690 mOs / kg, 700 mOs / kg, 710 mOs / kg, 720 mOs / kg, 730 mOs / kg, 740 mOs / kg, or about 750 mOs / kg. In exemplary embodiments, the composition has an osmolality of about 635 mOs / kg to about 695 mOs / kg.

[0248] In some embodiments, the composition may have a conductivity of about 0 to about 8 μS / cm. In some aspects, the composition may have a conductivity of about 0 μS / cm to about 1 μS / cm, about 1 μS / cm to about 2 μS / cm, about 3 μS / cm to about 4 μS / cm, about 4 μS / cm to about 5 μS / cm, about 5 μS / cm to about 6 μS / cm, about 6 μS / cm to about 7 μS / cm, or about 7 μS / cm to about 8 μS / cm. In some additional embodiments, the composition comprises from about 0 μS / cm to about 1.5 μS / cm, from about 0 μS / cm to about 2 μS / cm, from about 0 μS / cm to about 2.5 μS / cm, from about 0 μS / cm to about 3 μS / cm, from about 0 to about 3.5 μS / cm, from about 0 μS / cm to about 4 μS / cm, from about 0 to about 4.5 μS / cm, from about 0 μS / cm to about 5 μS / cm, from about 0 to about 5.5 μS / cm, from about 0 μS / cm to about 6 μS / cm, from about 0 to about 6.5, from about 0 μS / cm to about 7 μS / cm, from about 0 to about 7.5, from about 1 μS / cm to about 8 μS / cm, from about 1.5 μS / cm to about 8 μS / cm. S / cm, about 2 μS / cm to about 8 μS / cm, about 2.5 μS / cm to about 8 μS / cm, about 3 μS / cm to about 8 μS / cm, about 3.5 μS / cm to about 8 μS / cm, about 4 μS / cm to about 8 μS / cm, about 4.5 μS / cm to about 8 μS / cm, about 5 μS / cm to about 8 μS / cm, about 5.5 μS / cm to about 8 μS / cm, about 6 μS / cm to about 8 μS / cm, about 6.5 μS / cm to about 8 μS / cm, about 1 μS / cm to about 7 μS / cm, about 2 μS / cm to about 6 μS / cm, or about 3 μS / cm to about 5 μS / cm. In still further embodiments, the composition may have a conductivity of about 0.5 μS / cm, 1.0 μS / cm, 1.5 μS / cm, 2.0 μS / cm, 2.5 μS / cm, 3.0 μS / cm, 3.5 μS / cm, 4.0 μS / cm, 4.5 μS / cm, 5.0 μS / cm, 5.5 μS / cm, 6.0 μS / cm, 6.5 μS / cm, 7.0 μS / cm, 7.5 μS / cm, or about 8.0 μS / cm.

[0249] In some embodiments, the composition may have a pH of about 4.0 to about 8.0, for example, the composition may have a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or about 8.0. The composition may have a pH within a range or subrange including any of the above numbers, including, but not limited to, about 4.0 to about 4.5, about 4.5 to about 5.0, about 5.0 to about 5.5, about 5.5 to about 6.0, about 6.0 to about 6.5, about 6.5 to about 7.0, about 7.0 to about 7.5, or about 7.5 to about 8.0. In some embodiments, the composition may further comprise a pH adjuster, such as hydrochloric acid or sodium hydroxide, to adjust the pH to a desired level. In some embodiments, the composition may further comprise a buffer. In some embodiments, the buffer may comprise monosodium phosphate and disodium phosphate.

[0250] In some embodiments, the composition may have a viscosity measured in centipoise (cP) at 20° C. For example, the composition may have a viscosity of about 1.5 cP to about 3.0 cP at 20° C. In some embodiments, the composition may have a viscosity of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 , 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10.0 cP. In other embodiments, the composition may have a viscosity at 20°C of about 3.0 cP to about 5.0 cP, about 5.0 cP to about 10.0 cP, about 10 to about 15 cP, about 15 to about 20 cP, about 20 cP to about 25 cP, about 25 cP to about 50 cP, about 50 cP to about 80 cP, about 80 cP to about 150 cP, about 150 cP to about 250 cP, about 250 cP to about 500 cP, about 500 cP to about 1,000 cP, about 1,000 cP to about 2,000 cP, about 2,000 cP to about 3,000 cP, about 3,000 cP to about 5,000 cP, or about 5,000 cP to about 10,000 cP.

[0251] The composition may be substantially free of impurities, including particles having a diameter of 25 microns or greater, particles having a diameter of 10 microns or greater, chloride, propylene glycol, propylene oxide, and other unspecified impurities. In some embodiments, the composition may contain about 0.05% or less of impurities, for example, the composition may contain about 0.05%, 0.04%, 0.03%, 0.02%, or about 0.01% or less of impurities.

[0252] In some embodiments, the composition may further comprise a container and non-visible particulate matter. In some embodiments, the composition may be provided in a container. In some embodiments, the composition may further comprise non-visible particulate matter.

[0253] In some embodiments, the composition may comprise fewer than 600 particles per container having a diameter of 25 microns or greater. In some aspects, the composition may comprise fewer than 500, fewer than 400, fewer than 300, fewer than 200, or fewer than 100 particles per container having a diameter of 25 microns or greater.

[0254] In some embodiments, the composition may comprise fewer than 6,000 particles per container having a diameter of 10 microns or greater. In some aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, or 100 particles per container having a diameter of 10 microns or greater. In other aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, or 100 particles per container having a diameter of 10 microns or greater, and the container is 100 mL or less. In other aspects, the composition may comprise fewer than 5,000, 4,000, 3,000, 2,000, 1,000, 500, 100, 50, 25, 10, 5, or 3 particles per container having a diameter of 10 microns or greater, and the container is greater than 100 mL.

[0255] In some embodiments, the composition may contain 10 ppb or less of propylene glycol. In some aspects, the composition may contain 9 ppb, 8 ppb, 7 ppb, 6 ppb, 5 ppb, 4 ppb, 3 ppb, 2 ppb or less of propylene glycol, or 1 ppb or less of propylene glycol. In some aspects, the amount of propylene glycol in the composition may be determined by HPLC. In some additional aspects, the amount of propylene glycol in the composition may be determined by gas chromatography. In even further aspects, the amount of propylene glycol in the composition may be determined by measuring the PG / EG ratio of propylene glycol to ethylene glycol.

[0256] In some embodiments, the composition may contain 1 ppm or less of propylene oxide. In some aspects, the composition may contain 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, or 0.1 ppm or less of propylene oxide. In some aspects, the amount of propylene oxide in the composition may be determined by HPLC. In some additional aspects, the amount of propylene oxide in the composition may be determined by gas chromatography.

[0257] In some embodiments, the composition contains about 0 ppm to about 10 ppm chloride (e.g., Cl -ions). In some embodiments, the composition may contain about 0 ppm chloride to about 2 ppm chloride, about 2 ppm chloride to about 4 ppm chloride, about 4 ppm chloride to about 6 ppm chloride, about 6 ppm chloride to about 8 ppm chloride, or about 8 to about 10 ppm chloride. In some additional embodiments, the composition may contain about 0 ppm chloride to about 4 ppm chloride, about 0 ppm chloride to about 6 ppm chloride, about 0 ppm chloride to about 8 ppm chloride, about 2 ppm chloride to about 1 ppm chloride, about 4 ppm chloride to about 1 ppm chloride, or about 6 ppm chloride to about 1 ppm chloride. In still further aspects, the composition may comprise about 0 ppm, 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, or about 10 ppm chloride. In exemplary embodiments, the composition may comprise from about 0 ppm to about 1 ppm chloride.

[0258] In some embodiments, the composition contains about 0 ppm to about 10 ppm sodium (e.g., Na + ions). In some embodiments, the composition may comprise about 0 ppm sodium to about 2 ppm sodium, about 2 ppm sodium to about 4 ppm sodium, about 4 ppm sodium to about 6 ppm sodium, about 6 ppm sodium to about 8 ppm sodium, or about 8 to about 10 ppm sodium. In some additional embodiments, the composition may comprise about 0 ppm sodium to about 4 ppm sodium, about 0 ppm sodium to about 6 ppm sodium, about 0 ppm sodium to about 8 ppm sodium, about 2 ppm sodium to about 1 ppm sodium, about 4 ppm sodium to about 1 ppm sodium, or about 6 ppm sodium to about 1 ppm sodium. In even further embodiments, the composition may comprise about 0 ppm, 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, or about 10 ppm sodium. In an exemplary embodiment, the composition may include from about 0 ppm to about 1 ppm sodium.

[0259] In some embodiments, the composition may contain 0.05% or less of other unspecified impurities, for example, the composition may contain 0.05%, 0.04%, 0.03%, 0.02% or less, or 0.01% or less of other unspecified impurities.

[0260] In some embodiments, the composition may be stable for at least 6 months. For example, the composition may be stable for at least 3 months, 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 24 months, or at least 36 months.

[0261] The composition may be nanofiltered. In some embodiments, the concentration of the composition does not substantially change the time required for nanofiltration. Thus, the time for nanofiltration does not increase or decrease when the concentration of the mixture of β-cyclodextrin molecules increases or decreases in the composition. In some aspects, the length of time for nanofiltration of the composition depends on the diafiltration volume (kg solution / m 2 The range is from about 1.04 to about 1.20 hours per 100 mL (hr / L of solution). In some embodiments, the nanofiltered composition shows no substantial difference in HPLC-ELSD analysis after nanofiltration compared to before nanofiltration. In some embodiments, the composition shows no substantial difference in NMR analysis after nanofiltration compared to before nanofiltration.

[0262] In some embodiments, the composition may be terminally sterilized. Methods of terminal sterilization are generally well known in the art. In some embodiments, the pH of the composition may be adjusted after terminal sterilization.

[0263] In some embodiments, the composition may comprise 10.0 w / w% or less of water, for example, the composition may comprise 10.0 w / w%, 9.5 w / w%, 9.0 w / w%, 8.5 w / w%, 8.0 w / w%, 7.5 w...

Claims

1. 1. A composition comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, β-cyclodextrin substituted with eight hydroxypropyl groups ("DS-8"); β-cyclodextrin substituted with nine hydroxypropyl groups ("DS-9"); β-cyclodextrin substituted with 10 hydroxypropyl groups (“DS-10”); β-cyclodextrin substituted with 11 hydroxypropyl groups ("DS-11"); β-cyclodextrin substituted with 12 hydroxypropyl groups (“DS-12”); β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13"), and β-cyclodextrin substituted with 14 hydroxypropyl groups (“DS-14”), The composition, wherein the composition comprises less than 1% of β-cyclodextrin substituted with 7 hydroxypropyl groups ("DS-7").

2. 2. The composition of claim 1, wherein the composition comprises β-cyclodextrin substituted with less than 1% of six hydroxypropyl groups ("DS-6"), 1% of five hydroxypropyl groups ("DS-5"), four hydroxypropyl groups ("DS-4"), three hydroxypropyl groups ("DS-3"), two hydroxypropyl groups ("DS-2"), and one hydroxypropyl group ("DS-1") substituted β-cyclodextrin.

3. 3. The composition of claim 1 or 2, wherein the DS-10 has the highest concentration in the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules when compared to DS-8, DS-9, DS-11, DS-12, DS-13, and DS-14.

4. 10. The composition of claim 1, wherein the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules comprises 6% to 12% DS-8.

5. 10. The composition of claim 1, wherein the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules comprises 18% to 24% DS-9.

6. 10. The composition of claim 1, wherein the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules comprises 24% to 30% DS-10.

7. 10. The composition of claim 1, wherein the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules comprises 18% to 24% DS-11.

8. 10. The composition of claim 1, wherein the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules comprises 10% to 16% DS-12.

9. 10. The composition of claim 1, wherein the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules comprises 4% to 10% DS-13.

10. 10. The composition of claim 1, wherein the mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules contains 0% to 6% DS-14.

11. 2. The composition of claim 1, wherein the average degree of substitution of the mixture of isomerically purified hydroxypropyl β-cyclodextrins is 9-10.

12. 2. The composition of claim 1, wherein 15% to 21% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecule are located at the 3-O-position.

13. 2. The composition of claim 1, wherein 79% to 85% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecule are located at the 2-O-position.

14. 20. The composition of claim 1, wherein the composition has the HPLC-CAD chromatogram of FIG.

15. 15. The composition of claim 14, wherein the composition has an average retention time of 15.4 minutes.

16. The composition of claim 1, wherein the composition has an ESI-MS spectrum with peaks at 770 m / z, 798 m / z, 828 m / z, 857 m / z, and 885 m / z.

17. 10. The composition of claim 1, wherein the composition has an ESI-MS spectrum with peaks at 803 m / z, 831 m / z, 861 m / z, 889 m / z, and 919 m / z.

18. 20. The composition of claim 1, wherein the composition has the ESI-MS spectrum of FIG.

19. The composition of claim 1, having a MALDI-TOF spectrum with peaks at 1614 m / z, 1673 m / z, 1733 m / z, 1792 m / z, 1852 m / z, 1912 m / z, and 1971 m / z.

20. The composition of claim 1, having the MALDI-TOF spectrum of Figure 30.

21. 21. The composition of claim 20, wherein the DS-8 area is 8.53%.

22. the DS-9 area is 21.33% and / or the DS-10 area is 26.58%; and / or the area of ​​the DS-11 is 20.90%; and / or the DS-12 area is 13.31%; and / or the DS-13 area is 6.74%; and / or the DS-14 area is 2.60%.

23. The composition of claim 1, having a H-NMR spectrum of FIG.

24. 28. The composition of claim 1, having the DEPT-edited HSQC spectrum of Figure 27.

25. the composition has an osmolality of 635 to 695 mOs / kg; and / or the composition has a true density of 1.096 to 1.098 g / cm3.

26. 10. The composition of claim 1, wherein the composition contains 10 ppb or less of propylene glycol as measured by HPLC.

27. 10. The composition of claim 1, wherein the composition contains 10 ppb or less of propylene glycol as measured by gas chromatography.

28. 10. The composition of claim 1, wherein the composition comprises 10 ppb or less of propylene glycol as measured by the PG / EG ratio of propylene glycol to ethylene glycol.

29. 10. The composition of claim 1, wherein the composition comprises 1 ppm or less of propylene oxide.

30. 10. The composition of claim 1, wherein the total amount of other unspecified impurities is 0.05% or less as measured by HPLC.

31. The composition of claim 1, wherein the composition comprises 0 to 10 ppm chloride.

32. The composition of claim 1, wherein the composition has a conductivity of 0 to 8 μS / cm.

33. The composition of claim 1 , wherein the composition is nanofiltered.

34. 34. The composition of claim 33, wherein no substantial difference is observed in HPLC-ELSD after nanofiltration when the nanofiltered composition is compared to before nanofiltration.

35. 34. The composition of claim 33, wherein no substantial difference is observed in the NMR of the nanofiltered composition after nanofiltration compared to before nanofiltration.

36. 1. A composition comprising a mixture of isomerically purified hydroxypropyl β-cyclodextrin molecules, β-cyclodextrin substituted with 6% to 12% of eight hydroxypropyl groups ("DS-8"); β-cyclodextrin substituted with 18% to 24% of nine hydroxypropyl groups ("DS-9"); β-cyclodextrin substituted with 24% to 30% of 10 hydroxypropyl groups ("DS-10"); β-cyclodextrin substituted with 18% to 24% of 11 hydroxypropyl groups ("DS-11"); β-cyclodextrin substituted with 10% to 16% of 12 hydroxypropyl groups (“DS-12”); The composition comprises 4% to 10% of a β-cyclodextrin substituted with 13 hydroxypropyl groups ("DS-13") and 0% to 6% of a β-cyclodextrin substituted with 14 hydroxypropyl groups ("DS-14").

37. A pharmaceutical composition comprising the composition of claim 1 or 36 for treating or preventing a disease or condition.

38. A pharmaceutical composition comprising the composition described in claim 1 or 36 for treating or preventing a disease or condition selected from Niemann-Pick disease type C, liver disease, cardiovascular disease, familial hypercholesterolemia, and / or cholesterol deposition.

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