Methods for treating early stage Alzheimer's disease

Abstract

Provided herein is a method for treating early Alzheimer's disease using hydroxypropyl β-cyclodextrin compositions.Early Alzheimer's disease can be Alzheimer's disease with mild cognitive impairment or mild Alzheimer's disease.In certain embodiments, at the start of administering an effective amount of hydroxypropyl β-cyclodextrin compositions, human patient has a global Clinical Dementia Rating (CDR) scale score of about 0.5 and a CDR memory box score of about 0.5 or more.

Description

[Technical Field]

[0001] cross reference This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 411,935, filed September 30, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background Currently, approximately 5.4 million Americans have Alzheimer's disease, including early Alzheimer's disease, and this number is expected to increase to 13.8 million by 2050. In 2016, an estimated 700,000 Americans aged 65 or older died from Alzheimer's disease. While United States (US) deaths from stroke, heart disease, and prostate cancer all decreased from 2000 to 2014, Alzheimer's disease-related deaths increased by 89% over the same period. Total payments for medical, long-term care, and hospice services for people aged 65 or older with dementia were estimated at $236 billion in 2016. [Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12:459-509.]

[0003] More recently, with a better understanding of disease pathogenesis, drug development has shifted its focus to limiting, preventing, and reducing amyloid-beta (Aβ) and tau accumulation. Numerous treatment strategies have been proposed for amyloid-based therapies that increase Aβ clearance or reduce Aβ aggregation, as well as targeted Aβ immunotherapies. To date, despite numerous attempts, most of these drugs have failed in late-stage clinical trials, many of which enrolled patients in the later stages of dementia.

[0004] Anti-amyloid antibody therapies are associated with manageable but potentially dangerous adverse reactions, such as cerebral edema and microbleeds, leaving doubts about their risk / benefit profile. To date, like Aβ therapies, tau-based therapies have offered early hope, but are currently in early-stage studies and efficacy data will not be available for several years.

[0005] Cholesterol imbalances in Alzheimer's disease patients are well known, and significant research suggests that these imbalances contribute to Aβ and tau accumulation. Because plasma cholesterol concentrations are significantly higher in patients with Alzheimer's disease and those with non-Alzheimer's disease-related dementia, elevated blood cholesterol levels are also associated with an increased risk of dementia.

[0006] Both Aβ production and clearance are regulated by cholesterol. Tau toxicity also depends on cellular cholesterol levels. A high-cholesterol diet increases tau hyperphosphorylation. As cholesterol concentrations increase, neuronal susceptibility to Aβ-dependent calpain activation also increases. [Ferreira A, Bigio E H. Calpain-mediated tau cleavage: a mechanism leading to neurodegeneration shared by multiple tauopathies. Mol Med. 2011;17(7-8):676-685.] Calpain activation cleaves tau, generating toxic fragments. These cleaved tau forms induce neuronal death, synaptic loss, and / or behavioral impairment. Young neurons, which have significantly less cholesterol than aged neurons, also contain less phosphorylated tau. However, when these same young neurons are loaded with cholesterol, increases in both phosphorylated tau and susceptibility to death are observed. Currently, there are no approved therapies for treating early-stage Alzheimer's disease by regulating cholesterol levels. Thus, there remains a need to develop new therapies for the treatment of early-stage Alzheimer's disease. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12:459-509. [Non-patent document 2] Ferreira A, Bigio E H. Calpain-mediated tau cleavage: a mechanism leading to neurodegeneration shared by multiple tauopathies. Mol Med. 2011;17(7-8):676-685. Summary of the Invention [Means for solving the problem]

[0008] Abstract In one aspect, provided herein is a method of treating early Alzheimer's disease in a human patient in need thereof, the method comprising administering to the human patient an overall effective amount of a hydroxypropyl β-cyclodextrin composition.

[0009] In certain embodiments, the early stage Alzheimer's disease is Alzheimer's disease with mild cognitive impairment or mild Alzheimer's disease.

[0010] In certain embodiments, upon initiation of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient exhibits progressive cognitive decline. In certain embodiments, upon initiation of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient exhibits progressive cognitive decline for at least about one year. In certain embodiments, upon initiation of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a Global Clinical Dementia Rating (CDR) scale score of about 0.5 and a CDR memory box score of about 0.5 or greater. In certain embodiments, upon initiation of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a Global Clinical Dementia Rating (CDR) scale score of about 0.5 to about 1.0 and a CDR memory box score of about 0.5 or greater. In certain embodiments, upon initiation of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient exhibits cerebral amyloid-beta (Aβ) pathology. In certain embodiments, at the start of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, the human patient has a Mini-Mental State Examination-2: Standard Edition (MMSE-2:SV) score of between about 20 and about 28.

[0011] In certain embodiments, the human patient has previously been administered a cognitive enhancing drug and / or a symptomatic treatment for early Alzheimer's disease, hi certain embodiments, the human patient has previously been administered an acetylcholinesterase inhibitor and / or memantine.

[0012] In certain embodiments, the human patient is at least 50 years old. In certain embodiments, the human patient is at least 60 years old. In certain embodiments, the human patient is at least 70 years old. In certain embodiments, the human patient is at least 80 years old.

[0013] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition to a human patient. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion every 28 days. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient about 500 mg / kg to about 2000 mg / kg of a hydroxypropyl β-cyclodextrin composition by intravenous infusion every 28 days for a period of at least about 24 weeks.

[0014] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl β-cyclodextrin composition to a human patient. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion every 28 days. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient about 500 mg / kg to about 2000 mg / kg of a hydroxypropyl β-cyclodextrin composition by intravenous infusion every 28 days for a period of at least about 24 weeks.

[0015] In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion over a period of at least about 4 hours. In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion over a period of at least about 6.5 hours.

[0016] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises about 25% (w / v) hydroxypropyl β-cyclodextrin.

[0017] In certain embodiments, a hydroxypropyl β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl β-cyclodextrin species. In certain embodiments, each of the two or more hydroxypropyl β-cyclodextrin species has a different degree of hydroxypropylation of the β-cyclodextrin ring. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.59 to about 1.14. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.59 to about 0.8. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.8 to about 1.0. In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises about 0.2% w / w or less of unsubstituted β-cyclodextrin. In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises about 0.16% w / w or less of unsubstituted β-cyclodextrin.In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises about 2.5% w / w or less of propylene glycol.

[0018] In certain embodiments, the method further comprises administering a second therapeutic agent selected from the group consisting of donepezil, rivastigmine, galantamine, memantine, verubecestat, solanezumab, bapineuzumab, aducanumab, tideglusib, epothilone D, and ABBV-8E12.

[0019] In certain embodiments, the method further comprises administering a second therapeutic agent selected from the group consisting of a cholinesterase inhibitor, an NMDA receptor antagonist, a humanized antibody targeting tau protein, a humanized antibody targeting amyloid beta protein, and a BACE inhibitor.

[0020] In certain embodiments, the method further comprises administering a second therapeutic agent, wherein the second therapeutic agent is selected from any of the therapeutic agents shown in Table 1. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description The present disclosure provides, in part, a method for treating early Alzheimer's disease in a human patient in need thereof. The method generally comprises administering an effective amount of a hydroxypropyl β-cyclodextrin composition to the human patient. The hydroxypropyl β-cyclodextrin composition described herein may be administered intravenously to the human patient. The method described herein can stabilize the progression of early Alzheimer's disease and / or reverse key features of the disease (e.g., cognitive impairment) in the human patient. definition

[0022] To facilitate understanding of the present invention, several terms and phrases are defined below.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0024] Throughout this specification, when compositions and kits are described as having, including, or comprising particular components, it is contemplated that there are also compositions and kits of the invention that consist essentially of or consist of the listed components.

[0025] In this application, when an element or component is said to be included in and / or selected from a list of enumerated elements or components, it is to be understood that the element or component may be any one of the enumerated elements or components, or the element or component may be selected from a group consisting of two or more of the enumerated elements or components.

[0026] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether expressly or implicitly stated herein, may be combined in various ways without departing from the spirit and scope of the present invention. For example, when a particular compound is referenced, that compound may be used in various embodiments of the compositions of the present invention and / or in the methods of the present invention, unless otherwise understood from the context. In other words, although embodiments have been described and illustrated in this application in a manner that allows a clear and concise application to be written and drawn, it is intended and will be understood that the embodiments may be combined or separated in various ways without departing from the present teachings and invention. For example, it will be understood that all features described and illustrated herein are applicable to all aspects of the invention described and illustrated herein.

[0027] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0028] At various places in the present specification, variables or parameters are disclosed in groups or ranges, and the description is specifically intended to include each and every individual subcombination of the members of such groups and ranges. For example, integers in the range of 0 to 40 are specifically intended to disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40 individually; and integers in the range of 1 to 20 are specifically intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 individually.

[0029] The use of any and all examples or exemplary language herein, such as "such as" or "including," is intended merely to better describe the invention and does not impose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0030] The articles "a" and "an" are used in this disclosure, unless the context is inappropriate, to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0031] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0032] The phrase "at least one of" should be understood to include each of the listed items following the phrase individually and various combinations of two or more listed items, unless otherwise understood from context and usage. The phrase "and / or" in connection with three or more listed items should be understood to have the same meaning, unless otherwise understood from context.

[0033] Use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including its grammatical equivalents, should generally be understood to be open-ended and non-limiting, e.g., not excluding further, unrecited elements or steps, unless expressly stated otherwise or understood from the context.

[0034] As used herein, the term "about" means approximately, in the region of, in the region of, or in the region of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. Generally, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%, 5%, 3%, 2%, or 1%.

[0035] "Individual," "patient," and "subject" are used interchangeably and include any animal, including a mammal, e.g., a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, including a human.

[0036] The terms "treat," "treating," or "treatment" include any effect, e.g., lessening, reducing, modulating, alleviating, or eliminating, that results in an improvement of a condition, disease, disorder, etc., or alleviation of a symptom thereof. Treating may also be curing, ameliorating, or at least partially alleviating a disorder. In certain embodiments, treating is curing a disease.

[0037] "Pharmaceutically acceptable" includes molecular entities and formulations that do not produce adverse, allergic, or other untoward reactions when administered appropriately to animals or humans. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0038] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration and absorption of an active agent by a subject and may be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water (e.g., water for injection (WFI)), NaCl, saline, lactated Ringer's, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and / or flavoring substances that do not adversely react with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0039] The pharmaceutical formulations of the present disclosure may be administered to mammals such as humans, but may also be administered to other mammals, such as animals requiring veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the methods of the present disclosure is desirably a mammal in which treatment of early Alzheimer's disease is desired.

[0040] As used herein, a "pharmaceutical composition" or "pharmaceutical formulation" can refer to a combination of an active agent and an inert or active carrier that makes the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0041] As used herein, an "effective amount" or "therapeutically effective amount" can refer to the amount of a compound or composition (e.g., a compound or composition of the present invention) sufficient to produce a beneficial or desired result. An effective amount may be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0042] As used herein, "administer" or "administering" can refer to administration to a subject by oral administration, suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intraventricular, intranasal, or subcutaneous administration, or implantation of a slow-release device, such as a mini-osmotic pump. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration can include, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Co-administering" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., anti-cancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). The compounds of the present invention can be administered to patients alone or simultaneously. Simultaneous administration is intended to include simultaneous or sequential administration of compounds individually or in combination (more than one compound or drug). Thus, if desired, the preparation can also be combined with other active substances (for example, to reduce metabolic degradation).

[0043] As used herein, "hydroxypropyl β-cyclodextrin species," "β-cyclodextrin species," or "β-cyclodextrin" can refer to β-cyclodextrin molecules having a unique chemical composition and / or chemical structure. For example, the hydroxypropyl β-cyclodextrin species of the present invention can have unique properties, including, but not limited to, the average number of hydroxypropyl groups per β-cyclodextrin molecule, the molar substitution value, the distribution of hydroxypropyl groups, the degree of distribution of hydroxypropyl groups, or any combination thereof. In certain embodiments, hydroxypropyl β-cyclodextrin may be referred to by the trade name Trappsol® Cyclo™. The terms "hydroxypropyl β-cyclodextrin," "hydroxypropyl beta-cyclodextrin," "hydroxypropyl-beta-cyclodextrin," "HPβCD," "2-hydroxypropyl-beta-cyclodextrin," "2-hydroxypropyl beta-cyclodextrin," and "2-hydroxypropyl β-cyclodextrin" may be used interchangeably herein. The terms "β-cyclodextrin" and "beta-cyclodextrin" may be used interchangeably herein.

[0044] As used herein, "substituted at one or more hydroxyl positions with hydroxypropyl groups" can refer to the replacement of hydrogens of one or more hydroxyl groups of a beta-cyclodextrin molecule with hydroxypropyl groups or hydroxypropyl oligomers. For example, "substituted at one or more hydroxyl positions with hydroxypropyl groups" can refer to the insertion of one or more CH2CH(CH3)O- substituents into one or more OH bonds on a beta-cyclodextrin molecule, resulting in one or more ether linkages.

[0045] As used herein, a subject's "cognitive function" or "cognitive functioning" can be defined as an intellectual activity or process. Examples of intellectual activity or process include, but are not limited to, attention, processing speed, learning and memory, executive function, verbal fluency, and working memory. For example, the hydroxypropyl-beta-cyclodextrin composition of the present invention can improve cognitive function if it improves one or more intellectual activities or processes in a subject with early Alzheimer's disease.

[0046] For patients with early-stage Alzheimer's disease, the Food and Drug Administration (FDA) considers the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) an exemplary instrument for assessing disease progression. The Clinical Dementia Rating (CDR) is obtained through semi-structured interviews with patients and informants, and cognitive function is assessed across six domains of function: memory, orientation, judgment and problem-solving, community activities, home and hobbies, and self-care. Each domain is rated on a 5-point scale of function as follows: 0 (no impairment), 0.5 (suspected impairment), 1 (mild impairment), 2 (moderate impairment), and 3 (severe impairment). Self-care is scored on a 4-point scale without the 0.5 rating. A global CDR score is calculated algorithmically. The CDR-SB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18. The CDR has demonstrated good reliability and has been validated for neuropathological findings.

[0047] As used herein, "amyloid-beta pathology" or "Aβ pathology" can refer to patients with evidence of amyloid-beta pathology, as assessed by one or more methods and tests validated to predict the likelihood of amyloid plaque burden, or as quantified by PET imaging, cerebrospinal fluid analysis, and / or MRI. The Precivity AD blood test (C2N Diagnostics) is a test for the detection of AD pathology and uses mass spectrometry to measure proteins in the blood (from a single blood sample) that indicate the probability of amyloid deposits in the brain as measured by an amyloid PET scan. The Precivity AD test quantifies plasma concentrations of amyloid-beta 42 and 40 (Aβ42 and Aβ40) and determines the presence of apolipoprotein E proteotype-specific peptides (equivalent to ApoE genotype). These parameters are used to calculate a patient's Aβ42 / 40 ratio and determine their ApoE genotype. The Aβ42 / 40 ratio, ApoE genotype, and patient age are incorporated into the test's statistical algorithm to estimate the APS (e.g., test result). The APS represents an estimated probability, ranging from 0 (low probability) to 100 (high probability), that a patient is currently amyloid-positive on amyloid PET imaging, based on their Aβ42 / 40 ratio, age, and ApoE genotype. A positive amyloid PET scan is consistent with the presence of amyloid plaques and an AD diagnosis. In addition to the APS, the test report also includes the patient's Aβ42 / 40 ratio and ApoE genotype profile. While each of these parameters can individually predict amyloid PET scan status, their use in combination with patient age was included in the modeling to derive the APS, which is associated with better risk prediction. Therefore, the APS is the most important outcome. The APS score roughly classifies patients into one of three categories: low, intermediate, or high, which should be interpreted as follows: Low APS (0-36): A low score is consistent with a negative amyloid PET scan result and therefore a low likelihood of amyloid plaques. The absence of amyloid plaques is inconsistent with the use of one of the approved neuroimaging agents as a tracer for AD diagnosis and indicates that other causes of dementia symptoms should be investigated. Intermediate APS (37-57): An intermediate score does not distinguish between the presence or absence of amyloid plaques and indicates that further diagnostic evaluation may be needed to assess the underlying cause of the patient's dementia symptoms. High APS (58–100): A high score is consistent with a positive amyloid PET scan result and therefore a high likelihood of amyloid plaques. While the presence of amyloid plaques is consistent with a diagnosis of AD in individuals with cognitive decline, it alone is insufficient for a definitive diagnosis; clinical findings and other factors should be considered along with the APS. The combination of a positive Precivity AD blood test, other eligibility criteria including cognitive test results, and quantification of amyloid burden demonstrated by either positron emission tomography amyloid imaging or cerebrospinal fluid analysis provides the basis for evidence of amyloid burden. Aβ-PET scans (using one of the approved neuroimaging agents as a tracer) produce images designated as positive or negative based on a comparison of radioactivity in the cortical gray matter within the region of interest with that in the adjacent white matter. Amyloid CSF analysis evaluates Aβ42, Aβ40, and the Aβ42 / Aβ40 ratio. Other biomarkers include, but are not limited to, phosphorylated tau, total tau, and NfL.

[0048] As used herein, the term "Mini-Mental State Examination-2: Standard Edition" or "MMSE-2:SV" can refer to a widely used test of cognitive function in older adults. It includes tests of orientation, attention, memory, language, and visuospatial ability, and results in an assigned score. [Folstein MF, Folstein SE, White T, Messer MA. MMSE-2® Mini-Mental State Examination, 2nd Edition TMUser's Manual by Marshal F. Available at https: / / www.parinc.com / Products / Pkey / 238. Accessed October 7, 2021.] The test can be used to screen for cognitive impairment, to estimate the severity of cognitive impairment at a given time point, to track the progression of dementia-related cognitive impairment, and to document an individual's response to treatment. [Folstein MF, Folstein SE, McHugh PR. Mini-Mental State Examination. PAR. Available at https: / / www.parinc.com / Products / Pkey / 237. Accessed April 30, 2020.]

[0049] As used herein, the term "molar substitution" or "MS" refers to the number of hydroxypropyl groups per anhydroglucose unit in a mixture of β-cyclodextrins and can be determined according to the procedure set forth in the USP monograph for Hydroxypropyl Betadex (USP NF 2015) ("USP Hydroxypropyl Betadex monograph"), which is incorporated herein by reference in its entirety. In this disclosure, the term "average molar substitution" or "MS" refers to the number of hydroxypropyl groups per anhydroglucose unit in a mixture of β-cyclodextrins and can be determined according to the procedure set forth in the USP monograph for Hydroxypropyl Betadex (USP NF 2015) ("USP Hydroxypropyl Betadex monograph"), which is incorporated herein by reference in its entirety. a " is used synonymously with "MS" as that term is used in the USP Hydroxypropyl Betadex monograph, and the term "glucose unit" is used synonymously with "anhydroglucose unit" as that term is used in the USP Hydroxypropyl Betadex monograph. Hydroxypropyl β-cyclodextrin

[0050] Cyclodextrins are naturally occurring cyclic oligosaccharides derived from the enzymatic conversion of starch and can also be produced synthetically. They are composed of varying numbers of glucopyranose units, which can form a ring-like ring structure consisting of a hydrophobic cavity and a hydrophilic exterior. This ring-like ring structure is sometimes referred to as a "beta-cyclodextrin ring." The number of glucopyranose units determines the size and name of the cyclodextrin cavity; the most common are six, seven, or eight glucopyranose units, termed α-, β-, and γ-cyclodextrin, respectively. The unique structure of cyclodextrins allows them to form water-soluble complexes with otherwise insoluble hydrophobic compounds. This property of cyclodextrins has led to their application as drug delivery vehicles to improve the solubility, stability, and bioavailability of many pharmacologically active agents. As noted above, hydroxypropyl-beta-cyclodextrin (HPβCD), also known as 2-hydroxypropyl-beta-cyclodextrin and sometimes referred to as such herein, is a highly soluble, chemically modified, synthetic derivative of beta-cyclodextrin. HPβCD is one of the most commonly used and least toxic derivatives of naturally occurring cyclodextrin for drug delivery.

[0051] In one aspect, provided herein is a hydroxypropyl β-cyclodextrin composition for the treatment of early Alzheimer's disease in a subject in need thereof. In certain embodiments, the subject is a human patient.

[0052] In certain embodiments, the hydroxypropyl β-cyclodextrin compositions described herein may be a mixture of two or more hydroxypropyl-beta-cyclodextrin species. In some embodiments, the mixture of hydroxypropyl β-cyclodextrin species comprises a mixture of β-cyclodextrin molecules substituted at one or more hydroxyl positions with a hydroxypropyl group.

[0053] In certain embodiments, the hydroxypropyl β-cyclodextrin compositions described herein comprise a mixture of two or more hydroxypropyl β-cyclodextrin species. In some embodiments, the hydroxypropyl β-cyclodextrin composition comprises a mixture of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hydroxypropyl β-cyclodextrin species. In some embodiments, each of the two or more hydroxypropyl β-cyclodextrin species in the mixture has a different degree of hydroxypropylation of the β-cyclodextrin ring.

[0054] In certain embodiments, the hydroxypropyl β-cyclodextrin species in the mixture has the structure: [ka] (In the formula, R 1 , R 2 , and R 3 is, independently for each occurrence, H or HP, where HP contains one or more hydroxypropyl groups) glucose units.

[0055] In certain embodiments, HP comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hydroxypropyl groups. In some embodiments, HP comprises one hydroxypropyl group. In certain embodiments, HP consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hydroxypropyl groups. In some embodiments, HP consists of one hydroxypropyl group.

[0056] In certain embodiments, the average number of HP occurrences per beta-cyclodextrin ring is about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 7, about 5 to about 6, or about 6 to about 7. In certain embodiments, the average number of HP occurrences per beta-cyclodextrin ring is about 3, about 4, about 5, about 6, or about 7.

[0057] In certain embodiments, R 3 =The whole existence of HP is R 1 =HP or R 2 = more than all occurrences of either HP. In certain embodiments, R 3 =The whole existence of HP is R 1 =HP and R 2 =More than all of HP's combined existence.

[0058] In certain embodiments, R 1 and R 2 At least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45% of the combined total presence of are HPs.

[0059] In some embodiments, R 1 and R 2 about 50% or less, about 55% or less, about 60% or less, about 65% or less, about 70% or less, about 75% or less, about 80% or less, about 85% or less, about 90% or less, or about 95% or less of the total combined occurrence of are HPs.

[0060] In certain embodiments, R is HP 1 and R 2The combined percentages of are from about 5% to about 95%, from about 10% to about 95%, from about 15% to about 95%, from about 20% to about 95%, from about 25% to about 95%, from about 30% to about 95%, from about 35% to about 95%, from about 40% to about 95%, from about 45% to about 95%, from about 50% to about 95%, from about 55% to about 95%, from about 60% to about 95%, from about 65% to about 95%, from about 70% to about 95%, from about 75% to about 95%, from about 80% to about 95%, from about 85% to about 95%, from about 90% to about 95%; from about 5% to about 90%, from about 10% to about 90%, from about 15% to about 90%, from about 20% to about 90%, from about 25% to about 95%, from about 30% to about 95%, from about 35% to about 95%, from about 40% to about 95%, from about 45% to about 95%, from about 50% to about 95%, from about 55% to about 95%, from about 60% to about 95%, from about 65% to about 95%, from about 70% to about 95%, from about 75% to about 95%, from about 80% to about 95%, from about 85% to about 95%, from about 90% to about 95%; 5% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, about 80% to about 90%, about 85% to about 90%; about 5% to about 85%, about 10% to about 85%, about 15% to about 85%, about 20% to about 85%, about 25% to about 85%, about 30% to about 85%, about 35% to about 85%, about 40% to about 85%, about 45% to about 85%, about 50% to about 85%, about 55% to about 85% %, about 60% to about 85%, about 65% to about 85%, about 70% to about 85%, about 75% to about 85%, about 80% to about 85%; about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 55% to about 80%, about 60% to about 80%, about 65% to about 80%, about 70% to about 80%, about 75% to about 80%; about 5% to about 75%, about 10% to about 75%, about 15% to about 75%, about 20% ~ about 75%, about 25% to about 75%, about 30% to about 75%, about 35% to about 75%, about 40% to about 75%, about 45% to about 75%, about 50% to about 75%, about 55% to about 75%, about 60% to about 75%, about 65% to about 75%, about 70% to about 75%; about 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 35% to about 70%, about 40% to about 70%, about 45% to about 70%, about 50% to about 70%, about 55% to about 70%, about 60% to about 70%, about 65% to about 70%;About 5% to about 65%, about 10% to about 65%, about 15% to about 65%, about 20% to about 65%, about 25% to about 65%, about 30% to about 65%, about 35% to about 65%, about 40% to about 65%, about 45% to about 65%, about 50% to about 65%, about 55% to about 65%, about 60% to about 65%; about 5% to about 60%, about 10% to about 60%, about 15% to about 60%, about 20% to about 60%, about 25% to about 60%, about 30% to about 60%, about 35% to about 60%, about 40% to about 60%, about 45% to about 60%, about 50% to about 60%, about 55% to about 60%; about 5% to about 55%, about 10% to about 55%, about 15% to about 55%, about 20% to about 55%, about 25% to about 55%, about 30% to about 55%, about 35% to about 55%, about 40% to about 55%, about 45% to about 55%, about 50% to about 55%; about 5% to about 50%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 25% to about 50%, about 30% to about 50%, about 3 5% to about 50%, about 40% to about 50%, about 45% to about 50%; about 5% to about 45%, about 10% to about 45%, about 15% to about 45%, about 20% to about 45%, about 25% to about 45%, about 30% to about 45%, about 35% to about 45%, about 40% to about 45%; about 5% to about 40%, about 10% to about 40%, about 15% to about 40%, about 20% to about 40%, about 25% to about 40%, about 30% to about 40%, about 35% to about 40%; about 5% to about 35%, about 10% to about 35% , about 15% to about 35%, about 20% to about 35%, about 25% to about 35%, about 30% to about 35%; about 5% to about 30%, about 10% to about 30%, about 15% to about 30%, about 20% to about 30%, about 25% to about 30%; about 5% to about 25%, about 10% to about 25%, about 15% to about 25%, about 20% to about 25%; about 5% to about 20%, about 10% to about 20%, about 15% to about 20%; about 5% to about 15%, about 10% to about 15%; or about 5% to about 10%.

[0061] In certain embodiments, R 3 At least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% of the present are HPs.

[0062] In certain embodiments, R 3 about 55% or less, about 60% or less, about 65% or less, about 70% or less, about 75% or less, about 80% or less, about 85% or less, about 90% or less, or about 95% or less of the occurrences are HPs.

[0063] In certain embodiments, R is HP 3The percentage of presence of is about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, about 80% to about 90%, about 85% to about 90%, about 20% to about 85%, about 25% to about 85%, about 30% to about 85%, about 35% to about 85%, about 40% to about 85%, about 45% to about 85%, about 50% to about 85%, about 55% to about 85%, about 60% to about 85%, about 65% to about Approximately 85%, approximately 70% to approximately 85%, approximately 75% to approximately 85%, approximately 80% to approximately 85%, approximately 20% to approximately 80%, approximately 25% to approximately 80%, approximately 30% to approximately 80%, approximately 35% to approximately 80%, approximately 40% to approximately 80%, approximately 45% to approximately 80%, approximately 50% to approximately 80%, approximately 55% to approximately 80%, approximately 60% to approximately 80% , about 65% to about 80%, about 70% to about 80%, about 75% to about 80%, about 20% to about 75%, about 25% to about 75%, about 30% to about 75%, about 35% to about 75%, about 40% to about 75%, about 45% to about 75%, about 50% to about 75%, about 55% to about 75%, about 60% to about 75%, about 65 % to about 75%, about 70% to about 75%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 35% to about 70%, about 40% to about 70%, about 45% to about 70%, about 50% to about 70%, about 55% to about 70%, about 60% to about 70%, about 65% to about 70%, about 20% to about 6 5%, about 25% to about 65%, about 30% to about 65%, about 35% to about 65%, about 40% to about 65%, about 45% to about 65%, about 50% to about 65%, about 55% to about 65%, about 60% to about 65%, about 20% to about 60%, about 25% to about 60%, about 30% to about 60%, about 35% to about 60%, about 40% to approximately 60%, approximately 45% to approximately 60%, approximately 50% to approximately 60%, approximately 55% to approximately 60%, approximately 20% to approximately 55%, approximately 25% to approximately 55%, approximately 30% to approximately 55%, approximately 35% to approximately 55%, approximately 40% to approximately 55%, approximately 45% to approximately 55%, approximately 50% to approximately 55%, approximately 20% to approximately 50%, approximately 25% to About 50%, about 30% to about 50%, about 35% to about 50%, about 40% to about 50%, about 45% to about 50%, about 20% to about 45%, about 25% to about 45%, about 30% to about 45%, about 35% to about 45%, about 40% to about 45%, about 5% to about 40%, about 10% to about 40%, about 15% to about 40%,The range is about 20% to about 40%, about 25% to about 40%, about 30% to about 40%, about 35% to about 40%, about 20% to about 35%, about 25% to about 35%, about 30% to about 35%, about 20% to about 30%, about 25% to about 30%, or about 20% to about 25%.

[0064] In certain embodiments, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the β-cyclodextrins have an average number of HP occurrences per β-cyclodextrin overall of about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 7, about 5 to about 6, or about 6 to about 7.

[0065] In some embodiments, the percentage of β-cyclodextrins overall having an average number of HP occurrences per β-cyclodextrin of about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 7, about 5 to about 6, or about 6 to about 7 is about 50% to about 99%, about 55% to about 99%, about 60% to about 99%, about 65% to about 99%, about 70% to about 99%, about 75% to about 99%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%. %, about 95% to about 99%, about 50% to about 97%, about 55% to about 97%, about 60% to about 97%, about 65% to about 97%, about 70% to about 97%, about 75% to about 97%, about 80% to about 97%, about 85% to about 97%, about 90% to about 97%, about 95% to about 97%, about 50% to about 95%, about 55% to about 95%, about 60% to about 95%, about 65% to about 95%, about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95 %, about 90% to about 95%, about 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, about 80% to about 90%, about 85% to about 90%, about 50% to about 85%, about 55% to about 85%, about 60% to about 85%, about 65% to about 85%, about 70% to about 85%, about 75% to about 85%, about 80% to about 85%, about 50% to about 80%, about 55% to about 80%, about 60% to about 80 %, about 65% to about 80%, about 70% to about 80%, about 75% to about 80%, about 50% to about 75%, about 55% to about 75%, about 60% to about 75%, about 65% to about 75%, about 70% to about 75%, about 50% to about 70%, about 55% to about 70%, about 60% to about 70%, about 65% to about 70%, about 50% to about 65%, about 55% to about 65%, about 60% to about 65%, about 50% to about 60%, about 55% to about 60%, or about 50% to about 55%.

[0066] As used herein, "degree of substitution" or "DS" can refer to the total number of hydroxypropyl groups substituted directly or indirectly on a β-cyclodextrin molecule. For example, a β-cyclodextrin molecule containing glucose units, each substituted with one hydroxypropyl group, has a DS of 7. In another example, a β-cyclodextrin molecule in which only one of the seven glucose units is substituted with a hydroxypropyl group, and that hydroxypropyl group is itself substituted with another hydroxypropyl group (e.g., a beta-cyclodextrin having a single occurrence of HP containing two hydroxypropyl groups), has a DS of 2.

[0067] As used herein, "average degree of substitution," "average DS," or "DS a "Average number of hydroxypropyl groups per beta-cyclodextrin," also known as "average number of hydroxypropyl groups per beta-cyclodextrin," can refer to the total number of hydroxypropyl groups in a population of β-cyclodextrin divided by the number of β-cyclodextrin molecules. In one example, a mixture of equal parts of a β-cyclodextrin containing glucose units each substituted with one hydroxypropyl group and a β-cyclodextrin containing glucose units each substituted with two hydroxypropyl groups is known as a DS a = 10.5 (average of equal parts β-cyclodextrins with DS = 7 and DS = 14). In another example, a mixture of 33.3% β-cyclodextrin in which only one of the seven glucose units is substituted with a hydroxypropyl group (DS = 1) and 66.7% β-cyclodextrin containing glucose units each substituted with one hydroxypropyl group (DS = 7) has a DS a = 5.0. a can be determined by multiplying the molar substitution by 7. As used herein, DS a is used synonymously with "degree of substitution" as that term is defined in the USP Hydroxypropyl Betadex monograph.

[0068] In certain embodiments, the hydroxypropyl β-cyclodextrin compositions of the present invention comprise a mixture of unsubstituted β-cyclodextrin molecules and β-cyclodextrin species substituted at one or more hydroxyl positions with hydroxypropyl groups, wherein the mixture has an average number of hydroxypropyl groups per β-cyclodextrin molecule (DS) of about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 7, about 5 to about 6, or about 6 to about 7. a )

[0069] The distribution of the degree of substitution within the hydroxypropyl β-cyclodextrin compositions of the present invention, which comprise a mixture of unsubstituted β-cyclodextrin molecules and β-cyclodextrin species substituted at one or more hydroxyl positions with hydroxypropyl groups, may vary. For example, a mixture of equal parts of a β-cyclodextrin containing glucose units each substituted with one hydroxypropyl group and a β-cyclodextrin containing glucose units each substituted with two hydroxypropyl groups may be expressed as a DS a = 10.5 (average of equal parts β-cyclodextrin with DS = 7 and DS = 14). a = 10.5, but in this example there are no β-cyclodextrins in the mixture with DS = 10 or DS = 11. In other cases, the majority of β-cyclodextrin species in a mixture of β-cyclodextrins have a DS a It has a DS close to

[0070] In certain embodiments, at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin in the mixture is DS a have a DS within ±Xσ (where σ is the standard deviation and X is 1, 2, or 3).

[0071] In certain embodiments, at least about 50% of the β-cyclodextrin in the mixture is DS aIn some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin in the mixture has a DS within ±1σ. a Has a DS within ±1σ.

[0072] In certain embodiments, at least about 50% of the β-cyclodextrin in the mixture is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin in the mixture has a DS within ±2σ. a Has a DS within ±2σ.

[0073] In certain embodiments, at least about 50% of the β-cyclodextrin in the mixture is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin in the mixture has a DS within ±3σ. a Has a DS within ±3σ.

[0074] In certain embodiments, at least about 50% of the β-cyclodextrin is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin has a DS within ±1. a Has a DS within ±1.

[0075] In certain embodiments, at least about 50% of the β-cyclodextrin is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin has a DS within ±0.8. a With DS within ±0.8.

[0076] In certain embodiments, at least about 50% of the β-cyclodextrin is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin has a DS within ±0.6. a With DS within ±0.6.

[0077] In certain embodiments, at least about 50% of the β-cyclodextrin is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin has a DS within ±0.5. a With DS within ±0.5.

[0078] In certain embodiments, at least about 50% of the β-cyclodextrin is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin has a DS within ±0.4. a With DS within ±0.4.

[0079] In certain embodiments, at least about 50% of the β-cyclodextrin is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin has a DS within ±0.3. a Has a DS within ±0.3.

[0080] In certain embodiments, at least about 50% of the β-cyclodextrin is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin has a DS within ±0.2. a With DS within ±0.2.

[0081] In certain embodiments, at least about 50% of the β-cyclodextrin is DS a In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the β-cyclodextrin has a DS within ±0.1. a Has a DS within ±0.1.

[0082] The number of hydroxypropyl groups per anhydroglucose unit in a mixture of β-cyclodextrins is known as "molar substitution" or "MS" and can be determined according to the procedure set forth in the USP monograph for Hydroxypropyl Betadex (USP NF 2015) ("USP Hydroxypropyl Betadex monograph"), which is incorporated herein by reference in its entirety. In this disclosure, the term "average molar substitution" or "MS" is used interchangeably with "MS" to refer to any combination of hydroxypropyl groups per anhydroglucose unit in a mixture of β-cyclodextrins. a " is used synonymously with "MS" as that term is used in the USP Hydroxypropyl Betadex monograph, and the term "glucose unit" is used synonymously with "anhydroglucose unit" as that term is used in the USP Hydroxypropyl Betadex monograph.

[0083] In some embodiments, the MS of the mixture of hydroxypropyl β-cyclodextrin species is from about 0.51 to about 0.8, from about 0.51 to about 0.77, from about 0.51 to about 0.75, from about 0.51 to about 0.73, from about 0.51 to about 0.71, from about 0.51 to about 0.69, from about 0.51 to about 0.67, from about 0.51 to about 0.65, from about 0.51 to about 0.63, from about 0.51 to about 0.61, from about 0.51 to about 0.59, from about 0.51 to about 0.57, from about 0.51 to about 0.55, from about 0.51 to about 0.53, from 0.53 to about 0.8, from 0.53 to about 0.77, from 0.53 to about 0.75, from about 0.53 to about 0.7 3, about 0.53 to about 0.71, about 0.53 to about 0.69, about 0.53 to about 0.67, about 0.53 to about 0.65, about 0.53 to about 0.63, about 0.53 to about 0.61, about 0.53 to about 0.59, about 0.53 to about 0.57, about 0.53 to about 0.55, 0.55 to about 0.8, 0.55 to about 0.77, 0.55 to about 0.75, about 0.55 to about 0.73, about 0.55 to about 0.71, about 0.55 to about 0.69, about 0.55 to about 0.67, about 0.55 to about 0.65, about 0.55 to about 0.63, about 0.55 to about 0.61, about 0.55 to about 0.59, about 0.55 to about 0.57, 0.57 to about 0.8, 0.57 to about 0.77, 0.57 to about 0.75, about 0.57 to about 0.73, about 0.57 to about 0.71, about 0.57 to about 0.69, about 0.57 to about 0.67, about 0.57 to about 0.65, about 0.57 to about 0.63, about 0.57 to about 0.61, about 0.57 to about 0 0.59, 0.59 to about 0.8, 0.59 to about 0.77, 0.59 to about 0.75, about 0.59 to about 0.73, about 0.59 to about 0.71, about 0.59 to about 0.69, about 0.59 to about 0.67, about 0.59 to about 0.65, about 0.59 to about 0.63, about 0.59 to about 0.61, 0.61 to About 0.8, 0.61 to about 0.77, 0.61 to about 0.75, about 0.61 to about 0.73, about 0.61 to about 0.71, about 0.61 to about 0.69, about 0.61 to about 0.67, about 0.61 to about 0.65, about 0.61 to about 0.63, 0.63 to about 0.8, 0.63 to about 0.77, 0.63 to About 0.75, about 0.63 to about 0.73, about 0.63 to about 0.71, about 0.63 to about 0.69, about 0.63 to about 0.67, about 0.63 to about 0.65, 0.65 to about 0.8, 0.65 to about 0.77, 0.65 to about 0.75, about 0.65 to about 0.73, about 0.65 to about 0.71, about 0.65 to about 0.69, about 0.65 to about 0.67, 0.67 to about 0.8, 0.67 to about 0.77, 0.67 to about 0.75, about 0.67 to about 0.73, about 0.67 to about 0.71, about 0.67 to about 0.69, 0.69 to about 0.8, 0.69 to about 0.77, 0.69 to about 0.75, about 0.69 to about 0.73 , about 0.69 to about 0.71, 0.71 to about 0.8, 0.71 to about 0.77, 0.71 to about 0.75, about 0.71 to about 0.73, about 0.73 to about 0.8, about 0.73 to about 0.77, about 0.73 to about 0.75, about 0.75 to about 0.8, about 0.73 to about 0.77, or about 0.77 to about 0.8. In some embodiments, the MS of the mixture of hydroxypropyl β-cyclodextrin species is about 0.59 to about 0.73. In some embodiments, the MS of the mixture of hydroxypropyl β-cyclodextrin species is about 0.59 to about 0.8.

[0084] In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species may have a hydroxypropyl β-cyclodextrin content of about 0.5 to about 1.2, about 0.6 to about 1.2, about 0.7 to about 1.2, about 0.8 to about 1.2, about 0.9 to about 1.2, about 1.0 to about 1.2, about 1.1 to about 1.2, about 0.5 to about 1.1, about 0.5 to about 1.0, about 0.5 to about 0.9, about 0.5 to about 0.8, about 0.5 to about 0.7, about 0. The hydroxypropyl β-cyclodextrin has a molar substitution (MS) of about 0.5 to about 0.6, about 0.6 to about 1.1, about 0.6 to about 1.0, about 0.6 to about 0.9, about 0.6 to about 0.8, about 0.6 to about 0.7, about 0.7 to about 1.1, about 0.7 to about 1.0, about 0.7 to about 0.9, about 0.7 to about 0.8, about 0.8 to about 1.1, about 0.8 to about 1.0, about 0.8 to about 0.9, about 0.9 to about 1.1, about 0.9 to about 1.0, or about 1.0 to about 1.1. In certain embodiments, a mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.59 to about 1.14. In certain embodiments, a mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.59 to about 0.73. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.59 to 0.8, hi certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.8 to 1.0.

[0085] In certain embodiments, a mixture of two or more hydroxypropyl β-cyclodextrin species has an MS value of about 0.5, about 0.53, about 0.56, about 0.59, about 0.62, about 0.65, about 0.68, about 0.71, about 0.74, about 0.77, about 0.8, about 0.83, about 0.86, about 0.89, about 0.92, about 0.95, about 0.98, about 1, about 1.02, about 1.05, about 1.08, about 1.11, about 1.14, about 1.17, or about 1.2.

[0086] In certain embodiments, the MS of the mixture of hydroxypropyl β-cyclodextrin species is about 0.40, about 0.41, about 0.42, about 0.43, about 0.44, about 0.45, about 0.46, about 0.47, about 0.48, about 0.49, about 0.50, about 0.51, about 0.52, about 0.53, about 0.54, about 0.55, about 0.56, about 0. about 0.57, about 0.58, about 0.59, about 0.60, about 0.61, about 0.62, about 0.63, about 0.64, about 0.65, about 0.66, about 0.69, about 0.68, about 0.69, about 0.70, about 0.71, about 0.72, about 0.73, about 0.74, about 0.75, about 0.76, about 0.77, about 0.78, about 0.79, or about 0.80. In some embodiments, the MS of the mixture of hydroxypropyl β-cyclodextrin species is about 0.59, about 0.60, about 0.61, about 0.62, about 0.63, about 0.64, about 0.65, about 0.66, about 0.69, about 0.68, about 0.69, about 0.70, about 0.71, about 0.72, or about 0.73.

[0087] The hydroxypropyl groups may be attached to the β-cyclodextrin as monomers, or may themselves be sequentially attached to one or more additional hydroxypropyl groups to form hydroxypropyl oligomers, which are then attached to the β-cyclodextrin. In certain embodiments, the hydroxypropyl groups are attached to the hydroxyl positions of the β-cyclodextrin in the form of the structure -[CHCH(CH)O] n H (where n≧1), and the average number of hydroxypropyl chains per β-cyclodextrin is about 3 to about 7. In some embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 7, about 5 to about 6, or about 6 to about 7. In some embodiments, n is 1, 2, 3, or 4.

[0088] In one example, a hydroxypropyl chain of the structure -CHCH(CH)OH contains one hydroxypropyl group in the hydroxypropyl chain (n=1). In another example, a hydroxypropyl chain of the structure -[CHCH(CH)O]H contains three hydroxypropyl groups in the hydroxypropyl chain (n=3).

[0089] In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 3.3±0.3, 3.4±0.3, 3.6±0.3, or 3.8±0.3. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 4.0±0.3, 4.2±0.3, 4.4±0.3, 4.6±0.3, or 4.8±0.3. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 5.0±0.3, 5.2±0.3, 5.4±0.3, 5.6±0.3, or 5.8±0.3. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 6.0±0.3, 6.2±0.3, 6.4±0.3, 6.6±0.3, or 6.7±0.3.

[0090] In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 3.2±0.2, 3.3±0.2, 3.4±0.2, 3.5±0.2, 3.6±0.2, 3.7±0.2, or 3.8±0.2. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 4.0±0.2, 4.1±0.2, 4.2±0.2, 4.3±0.2, 4.4±0.2, 4.5±0.2, 4.6±0.2, 4.7±0.2, or 4.8±0.2. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 5.0±0.2, 5.1±0.2, 5.2±0.2, 5.3±0.2, 5.4±0.2, 5.5±0.2, 5.6±0.2, 5.7±0.2, or 5.8±0.2. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 6.0±0.2, 6.1±0.2, 6.2±0.2, 6.3±0.2, 6.4±0.2, 6.5±0.2, 6.6±0.2, 6.7±0.2, or 6.8±0.2.

[0091] In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 3.1±0.1, 3.2±0.1, 3.3±0.1, 3.4±0.1, 3.5±0.1, 3.6±0.1, 3.7±0.1, 3.8±0.1, or 3.9±0.1. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 4.0±0.1, 4.1±0.1, 4.2±0.1, 4.3±0.1, 4.4±0.1, 4.5±0.1, 4.6±0.1, 4.7±0.1, 4.8±0.1, or 4.9±0.1. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 5.0±0.1, 5.1±0.1, 5.2±0.1, 5.3±0.1, 5.4±0.1, 5.5±0.1, 5.6±0.1, 5.7±0.1, 5.8±0.1, or 5.9±0.1. In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is 6.0±0.1, 6.1±0.1, 6.2±0.1, 6.3±0.1, 6.4±0.1, 6.5±0.1, 6.6±0.1, 6.7±0.1, 6.8±0.1, or 6.9±0.1.

[0092] In certain embodiments, at least about 50% of the hydroxypropyl chains have n=1. In some embodiments, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 97% of the hydroxypropyl chains have n=1. In some embodiments, at least 70% of the hydroxypropyl chains have n=1. In some embodiments, at least 90% of the hydroxypropyl chains have n=1.

[0093] In certain embodiments, the percentage of hydroxypropyl chains having n=1 is from about 50% to about 99%, e.g., from about 55% to about 99%, from about 60% to about 99%, from about 65% to about 99%, from about 70% to about 99%, from about 75% to about 99%, from about 80% to about 99%, from about 85% to about 99%, from about 90% to about 99%, from about 95% to about 99%; e.g., from about 50% to about 97%, e.g., from about 55% to about 97%, from about 60% to about 97%, from about 65% to about 97%, about 70% to about 97%, about 75% to about 97%, about 80% to about 97%, about 85% to about 97%, about 90% to about 97%, about 95% to about 97%; for example, about 50% to about 95%, about 55% to about 95%, about 60% to about 95%, about 65% to about 95%, about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95%, about 90% to about 95%; for example, about 50% to about 90%, about 55% to about 90%, about 60% to about 90%, about 65% to about 90%, about 70% to about 90%, about 75% to about 90%, about 80% to about 90%, about 85% to about 90%; for example, about 50% to about 85%, about 55% to about 85%, about 60% to about 85%, about 65% to about 85%, about 70% to about 85%, about 75% to about 85%, about 80% to about 85%; for example, about 50% to about 80%, about 55% to about 80%, about 60% to about 80%, about 65% to about 80%, about 70% to about 80%, about 7 5% to about 80%; for example, about 50% to about 75%, about 55% to about 75%, about 60% to about 75%, about 65% to about 75%, about 70% to about 75%; for example, about 50% to about 70%, about 55% to about 70%, about 60% to about 70%, about 65% to about 70%; for example, about 50% to about 65%, about 55% to about 65%, about 60% to about 65%; for example, about 50% to about 60%, about 55% to about 60%; or for example, about 50% to about 55%.

[0094] In certain embodiments, less than about 3%, less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% of the hydroxypropyl chains have n=2. In some embodiments, less than about 30% of the hydroxypropyl chains have n=2. In some embodiments, less than 10% of the hydroxypropyl chains have n=2.

[0095] In certain embodiments, the percentage of hydroxypropyl chains having n=2 is about 5% to about 50%, e.g., about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 25% to about 50%, about 30% to about 50%, about 35% to about 50%, about 40% to about 50%, about 45% to about 50%; e.g., about 5% to about 45%, about 10% to about 45%, about 15% to about 45%, about 20% to about 45%, about 25% to about 45%, about 30% to about 45%, about 35% to about 45%, about 40% to about 45%; e.g., about 5% to about 40%, about 10% to about 40%, about 15% to about 40%, about 20% to about 40%, about 2 5% to about 40%, about 30% to about 40%, about 35% to about 40%; for example, about 5% to about 35%, about 10% to about 35%, about 15% to about 35%, about 20% to about 35%, about 25% to about 35%, about 30% to about 35%; for example, about 5% to about 30%, about 10% to about 30%, about 15% to about 30%, about 20% to about 30%, about 25% to about 30%; for example, about 5% to about 25%, about 10% to about 25%, about 15% to about 25%, about 20% to about 25%; for example, about 5% to about 20%, about 10% to about 20%, about 15% to about 20%; for example, about 5% to about 15%, about 10% to about 15%; or about 5% to about 10%.

[0096] In some embodiments, less than about 3%, less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% of the hydroxypropyl chains have n > 2. In some embodiments, less than about 10% of the hydroxypropyl chains have n > 2.

[0097] In certain embodiments, the percentage of hydroxypropyl chains having n>2 is from about 5% to about 50%, from about 10% to about 50%, from about 15% to about 50%, from about 20% to about 50%, from about 25% to about 50%, from about 30% to about 50%, from about 35% to about 50%, from about 40% to about 50%, from about 45% to about 50%, from about 5% to about 45%, from about 10% to about 45%, from about 15% to about 45%, from about 20% to about 45%, from about 25% to about 45%, from about 30% to about 45%, from about 35% to about 45%, from about 40% to about 45%, from about 5% to about 40%, from about 10% to about 40%, from about 15% to about 40%, from about 20% to about 40%. %, about 25% to about 40%, about 30% to about 40%, about 35% to about 40%, about 5% to about 35%, about 10% to about 35%, about 15% to about 35%, about 20% to about 35%, about 25% to about 35%, about 30% to about 35%, about 5% to about 30%, about 10% to about 30%, about 15% to about 30%, about 20% to about 30%, about 25% to about 30%, about 5% to about 25%, about 10% to about 25%, about 15% to about 25%, about 20% to about 25%, about 5% to about 20%, about 10% to about 20%, about 15% to about 20%, about 5% to about 15%, about 10% to about 15%, or about 5% to about 10%.

[0098] In certain embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is from about 4 to about 6. In some embodiments, at least about 60% of the β-cyclodextrins overall have an average number of hydroxypropyl chains per β-cyclodextrin of from about 4 to about 6. In some embodiments, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 97% of the β-cyclodextrins overall have an average number of hydroxypropyl chains per β-cyclodextrin of from about 4 to about 6. In some embodiments, the percentage of β-cyclodextrins overall having an average number of hydroxypropyl chains per β-cyclodextrin of about 4 to about 6 is about 60% to about 97%, about 65% to about 97%, about 70% to about 97%, about 75% to about 97%, about 80% to about 97%, about 85% to about 97%, about 90% to about 97%, about 60% to about 95%, about 65% to about 95%, about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95%, about 90% to about 95%, about 6 The range is from 0% to about 90%, from about 65% to about 90%, from about 70% to about 90%, from about 75% to about 90%, from about 80% to about 90%, from about 85% to about 90%, from about 60% to about 85%, from about 65% to about 85%, from about 70% to about 85%, from about 75% to about 85%, from about 80% to about 85%, from about 60% to about 80%, from about 65% to about 80%, from about 70% to about 80%, from about 75% to about 80%, from about 60% to about 75%, from about 65% to about 75%, from about 70% to about 75%, from about 60% to about 70%, from about 65% to about 70%, or from about 60% to about 65%.

[0099] In certain embodiments, the hydroxypropyl β-cyclodextrin compositions described herein are about 0.05% w / w or less, about 0.06% w / w or less, about 0.07% w / w or less, about 0.08% w / w or less, about 0.09% w / w or less, about 0.1% w / w or less, about 0.15% w / w or less, about 0.2% w / w or less, about 0.3% w / w or less, about 0.4% w / w or less, about 0.5% w / w or less, about 0.6% w / w or less. In some embodiments, the hydroxypropyl β-cyclodextrin composition contains less than about 0.7% w / w, less than about 0.8% w / w, less than about 0.9% w / w, less than about 1.0% w / w, less than about 1.1% w / w, less than about 1.2% w / w, less than about 1.3% w / w, less than about 1.4% w / w, less than about 1.5% w / w, less than about 1.6% w / w, less than about 1.7% w / w, less than about 1.8% w / w, less than about 1.9% w / w, or less than about 2% w / w of unsubstituted β-cyclodextrin. In some embodiments, the hydroxypropyl β-cyclodextrin composition contains less than about 0.2% w / w of unsubstituted β-cyclodextrin. In some embodiments, the hydroxypropyl β-cyclodextrin composition comprises about 0.15% w / w or less of unsubstituted β-cyclodextrin.

[0100] In certain embodiments, the amount of unsubstituted β-cyclodextrin in the hydroxypropyl β-cyclodextrin compositions described herein is from about 0.05% w / w to about 2% w / w, from about 0.05% w / w to about 1.5% w / w, from about 0.05% w / w to about 1.4% w / w, from about 0.05% w / w to about 1.3% w / w, from about 0.05% w / w to about 1.2% w / w, from about 0.05% w / w to about 1.1% w / w, from about 0.05% w / w to about 1.0% w / w, from about 0.05% w / w to about 0.8% w / w, from about 0.05% w / w to about 0.6% w / w, or from about 0.05% w / w to about 0. 5% w / w, about 0.05% w / w to about 0.4% w / w, about 0.05% w / w to about 0.3% w / w, about 0.05% w / w to about 0.2% w / w, about 0.05% w / w to about 0.1% w / w, about 0.05% w / w to about 0.07% w / w, about 0.07% w / w to about 1.5% w / w, about 0. 0.07% w / w to about 1.4% w / w, about 0.07% w / w to about 1.3% w / w, about 0.07% w / w to about 1.2% w / w, about 0.07% w / w to about 1.1% w / w, about 0.07% w / w to about 1.0% w / w, about 0.07% w / w to about 0.8% w / w, about 0.07% w / w to about 0.6 %w / w, about 0.07%w / w to about 0.5%w / w, about 0.07%w / w to about 0.4%w / w, about 0.07%w / w to about 0.3%w / w, about 0.07%w / w to about 0.2%w / w, about 0.07%w / w to about 0.1%w / w, about 0.1%w / w to about 1.5%w / w, about 0.1%w / w to about 1.4% w / w, about 0.1% w / w to about 1.3% w / w, about 0.1% w / w to about 1.2% w / w, about 0.1% w / w to about 1.1% w / w, about 0.1% w / w to about 1.0% w / w, about 0.1% w / w to about 0.8% w / w, about 0.1% w / w to about 0.6% w / w, about 0.1% w / w to about 0.5% w / w, about 0.1% w / w to about 0.4% w / w, about 0.1% w / w to about 0.3% w / w, about 0.1% w / w to about 0.2% w / w, about 0.2% w / w to about 1.5% w / w, about 0.2% w / w to about 1.4% w / w, about 0.2% w / w to about 1.3% w / w, about 0.2 %w / w to about 1.2%w / w, about 0.2%w / w to about 1.1%w / w, about 0.2%w / w to about 1.0%w / w, about 0.2%w / w to about 0.8%w / w, about 0.2%w / w to about 0.6%w / w, about 0.2%w / w to about 0.5%w / w, about 0.2%w / w to about 0.4%w / w, about 0.2% w / w to about 0.3% w / w, about 0.3% w / w to about 1.5% w / w, about 0.3% w / w to about 1.4% w / w, about 0.3% w / w to about 1.3% w / w, about 0.3% w / w to about 1.2% w / w, about 0.3% w / w to about 1.1% w / w, about 0.3% w / w to about 1.0% w / w, about 0.3% w / w to about 0.8% w / w, about 0.3% w / w to about 0.6% w / w, about 0.3% w / w to about 0.5% w / w, about 0.3% w / w to about 0.4% w / w, about 0.4% w / w to about 1.5% w / w, about 0.4% w / w to about 1.4% w / w, about 0.4% w / w to about 1.3% w / w , about 0.4% w / w to about 1.2% w / w, about 0.4% w / w to about 1.1% w / w, about 0.4% w / w to about 1.0% w / w, about 0.4% w / w to about 0.8% w / w, about 0.4% w / w to about 0.6% w / w, about 0.4% w / w to about 0.5% w / w, about 0.5% w / w to about 1.5% w / w / w, about 0.5% w / w to about 1.4% w / w, about 0.5% w / w to about 1.3% w / w, about 0.5% w / w to about 1.2% w / w, about 0.5% w / w to about 1.1% w / w, about 0.5% w / w to about 1.0% w / w, about 0.5% w / w to about 0.8% w / w, about 0.5% w / w to about 0.6 %w / w, about 0.6%w / w to about 1.5%w / w, about 0.6%w / w to about 1.4%w / w, about 0.6%w / w to about 1.3%w / w, about 0.6%w / w to about 1.2%w / w, about 0.6%w / w to about 1.1%w / w, about 0.6%w / w to about 1.0%w / w, about 0.6%w / w to about 0 0.8% w / w, about 0.8% w / w to about 1.5% w / w, about 0.8% w / w to about 1.4% w / w, about 0.8% w / w to about 1.3% w / w, about 0.8% w / w to about 1.2% w / w, about 0.8% w / w to about 1.1% w / w, about 0.8% w / w to about 1.0% w / w, about 1.0% w / w About 1.5% w / w, about 1.0% w / w to about 1.4% w / w, about 1.0% w / w to about 1.3% w / w, about 1.0% w / w to about 1.2% w / w, about 1.0% w / w to about 1.1% w / w, about 1.1% w / w to about 1.5% w / w, about 1.1% w / w to about 1.4% w / w, about 1.1% w / w to about 1.3% w / w, about 1.1% w / w to about 1.2% w / w, about 1.2% w / w to about 1.5% w / w, about 1.2% w / w to about 1.4% w / w, about 1.2% w / w to about 1.3% w / w, about 1.3% w / w to about 1.5% w / w, about 1.3% w / w to about 1.4% w / w, or about 1.In some embodiments, the amount of unsubstituted β-cyclodextrin in the hydroxypropyl β-cyclodextrin compositions described herein is from about 0.05% w / w to about 2% w / w. In some embodiments, the amount of unsubstituted β-cyclodextrin in the hydroxypropyl β-cyclodextrin compositions described herein is from about 0.1% w / w to about 0.2% w / w.

[0101] In certain embodiments, the hydroxypropyl β-cyclodextrin compositions of the present invention may contain an impurity resulting from the chemical synthesis of the hydroxypropyl β-cyclodextrin species. In some embodiments, the impurity is propylene glycol.

[0102] In certain embodiments, the hydroxypropyl β-cyclodextrin compositions described herein contain about 2.0% or less, about 2.1% or less, about 2.2% or less, about 2.3% or less, about 2.4% or less, about 2.5% or less, about 2.6% or less, about 2.7% or less, about 2.8% or less, about 2.9% or less, or about 3% or less propylene glycol. In some embodiments, the hydroxypropyl β-cyclodextrin compositions described herein contain about 2.5% or less propylene glycol.

[0103] In certain embodiments, the hydroxypropyl β-cyclodextrin compositions described herein contain 2.0% w / w or less, 2.1% w / w or less, 2.2% w / w or less, 2.3% w / w or less, 2.4% w / w or less, 2.5% w / w or less, 2.6% w / w or less, 2.7% w / w or less, 2.8% w / w or less, 2.9% w / w or less, or 3% w / w or less propylene glycol. In some embodiments, the hydroxypropyl β-cyclodextrin compositions described herein contain 2.5% w / w or less propylene glycol.

[0104] In certain embodiments, the amount of propylene glycol in the hydroxypropyl β-cyclodextrin compositions described herein is from about 2.0% w / w to about 3.0% w / w, from about 2.0% w / w to about 2.9% w / w, from about 2.0% w / w to about 2.8% w / w, from about 2.0% w / w to about 2.7% w / w, from about 2.0% w / w to about 2.6% w / w, from about 2.0% w / w to about 2.5% w / w, from about 2.0% w / w to about 2.4% w / w, from about 2.0% w / w to about 2.3% w / w, from about 2.0% w / w to about 2.2% w / w, from about 2.0% w / w to about 2.1% w / w, from about 2.1% w / w to about 2.2% w / w, About 3.0% w / w, about 2.1% w / w to about 2.9% w / w, about 2.1% w / w to about 2.8% w / w, about 2.1% w / w to about 2.7% w / w, about 2.1% w / w to about 2.6% w / w, about 2.1% w / w to about 2.5% w / w, about 2.1% w / w to about 2.4% w / w, about 2.1% w / w ~ about 2.3% w / w, about 2.1% w / w to about 2.2% w / w, about 2.2% w / w to about 3.0% w / w, about 2.2% w / w to about 2.9% w / w, about 2.2% w / w to about 2.8% w / w, about 2.2% w / w to about 2.6% w / w, about 2.2% w / w to about 2.5% w / w, about 2.2% w / w / w to about 2.4% w / w, about 2.2% w / w to about 2.3% w / w, about 2.3% w / w to about 3.0% w / w, about 2.3% w / w to about 2.9% w / w, about 2.3% w / w to about 2.8% w / w, about 2.3% w / w to about 2.7% w / w, about 2.3% w / w to about 2.6% w / w, about 2.3% w / w / w to about 2.5% w / w, about 2.3% w / w to about 2.4% w / w, about 2.4% w / w to about 3.0% w / w, about 2.4% w / w to about 2.9% w / w, about 2.4% w / w to about 2.8% w / w, about 2.4% w / w to about 2.7% w / w, about 2.4% w / w to about 2.6% w / w, about 2.4% w / w to about 2.5% w / w, about 2.5% w / w to about 3.0% w / w, about 2.5% w / w to about 2.9% w / w, about 2.5% w / w to about 2.8% w / w, about 2.5% w / w to about 2.7% w / w, about 2.5% w / w to about 2.6% w / w, about 2.6% w / w to about 3.0% w / w, about 2.6 %w / w to about 2.9%w / w, about 2.6%w / w to about 2.8%w / w, about 2.6%w / w to about 2.7%w / w, about 2.7%w / w to about 3.0%w / w, about 2.7%w / w to about 2.9%w / w, about 2.7%w / w to about 2.8%w / w, about 2.8%w / w to about 3.0%w / w, about 2.8% w / w to about 2.9% w / w, or about 2.9% w / w to about 3.0% w / w. In some embodiments, the amount of propylene glycol in the hydroxypropyl β-cyclodextrin compositions described herein is about 2.0% w / w to about 3.0% w / w.

[0105] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl β-cyclodextrin species, each of the two or more hydroxypropyl β-cyclodextrin species having a different degree of hydroxypropylation of the β-cyclodextrin ring, and the hydroxypropyl β-cyclodextrin composition comprises 0.15% w / w or less unsubstituted β-cyclodextrin.

[0106] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl β-cyclodextrin species, each of the two or more hydroxypropyl β-cyclodextrin species having a different degree of hydroxypropylation of the β-cyclodextrin ring, the mixture of the two or more hydroxypropyl β-cyclodextrin species having a molar substitution value of about 0.59 to about 0.73, and the hydroxypropyl β-cyclodextrin composition comprises 2.5% w / w or less propylene glycol and 0.15% w / w or less unsubstituted β-cyclodextrin.

[0107] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl β-cyclodextrin species, each of the two or more hydroxypropyl β-cyclodextrin species having a different degree of hydroxypropylation of the β-cyclodextrin ring, the mixture of the two or more hydroxypropyl β-cyclodextrin species having a molar substitution value of about 0.59 to about 0.8, and the hydroxypropyl β-cyclodextrin composition comprises 2.5% w / w or less propylene glycol and 0.15% w / w or less unsubstituted β-cyclodextrin.

[0108] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl β-cyclodextrin species, each of the two or more hydroxypropyl β-cyclodextrin species having a different degree of hydroxypropylation of the β-cyclodextrin ring, the mixture of the two or more hydroxypropyl β-cyclodextrin species having a molar substitution value of about 0.8 to about 1.0, and the hydroxypropyl β-cyclodextrin composition comprises less than or equal to 2.5% w / w propylene glycol, preferably less than 0.01% w / w propylene glycol, and most preferably an undetectable amount of propylene glycol, and less than or equal to 0.16% w / w unsubstituted β-cyclodextrin.

[0109] In certain embodiments, the hydroxypropyl β-cyclodextrin composition is from about 5% (w / v) to about 40% (w / v), from about 10% (w / v) to about 40% (w / v), from about 15% (w / v) to about 40% (w / v), from about 20% (w / v) to about 40% (w / v), from about 25% (w / v) to about 40% (w / v), from about 30% (w / v) to about 40% (w / v), or from about 35% (w / v) ~ approx. 40% (w / v), approx. 5% (w / v) ~ approx. 35% (w / v), approx. 5% (w / v) ~ approx. 30% (w / v), approx. 5% (w / v) ~ approx. 25% (w / v), approx. 5% (w / v)~about 20%(w / v), about 5%(w / v)~about 15%(w / v), about 5%(w / v)~about 10%(w / v), about 10%(w / v)~about 35%(w / v), about 10%( w / v) ~ approx. 30% (w / v), approx. 10% (w / v) ~ approx. 25% (w / v), approx. 10% (w / v) ~ approx. 20% (w / v), approx. 10% (w / v) ~ approx. 15% (w / v), approx. (w / v) ~ approx. 35% (w / v), approx. 15% (w / v) ~ approx. 30% (w / v), approx. 15% (w / v) ~ approx. 25% (w / v), approx. 15% (w / v) ~ approx. 20% (w / v), approx. 20 The present invention also includes solutions containing one or more hydroxypropyl β-cyclodextrin species in an amount of from about 20% (w / v) to about 35% (w / v), from about 20% (w / v) to about 30% (w / v), from about 20% (w / v) to about 25% (w / v), from about 25% (w / v) to about 35% (w / v), from about 25% (w / v) to about 30% (w / v), or from about 30% (w / v) to about 35% (w / v).

[0110] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a 5% (w / v), 10% (w / v), 15% (w / v), 20% (w / v), 25% (w / v), 30% (w / v), 35% (w / v), or 40% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species. In some embodiments, the hydroxypropyl β-cyclodextrin composition comprises a 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species. In some embodiments, the 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species is a 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species in water.

[0111] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a Trappsol® Cyclo™ hydroxypropyl β-cyclodextrin composition available from Cyclo Therapeutics, Inc. Treatment of early Alzheimer's disease with hydroxypropyl β-cyclodextrin The impact of cholesterol on early Alzheimer's disease

[0112] The neuropathology of early Alzheimer's disease can be characterized by 1) amyloid-beta (Aβ)-containing plaques, 2) neurofibrillary tangles composed of neurofilaments, or 3) hyperphosphorylated tau protein. Other critical components include LE / LY abnormalities, cholesterol accumulation, APP processing, inflammation, and apoptosis. While the exact role of Aβ plaques and tau tangles in Alzheimer's disease is unclear, they are thought to play a crucial role in blocking communication between neurons and disrupting critical processes cells need for survival. Furthermore, research has demonstrated that Aβ is neurotoxic and there is evidence suggesting that it may be responsible for initiating memory loss associated with Alzheimer's disease.

[0113] Cholesterol is thought to be essential for cell structure, function, and signal transduction. Approximately 23 percent of the body's total cholesterol is found in the brain, with neurons and astrocytes containing the largest amounts. Cholesterol is not uniformly distributed, with variations occurring both within each specific membrane of the same cell and between different membranes. Within each membrane, cholesterol is concentrated in nano- and microdomains called "lipid rafts." In neurons, these rafts are highly dynamic, likely a result of neurons' high metabolic demands and the need for plasticity and remodeling throughout life. Rafts have also been detected at neuronal synapses, where they contribute to pre- and postsynaptic function. Within a single neuron, the relative distribution of cholesterol also varies across intracellular membranes. The majority of cholesterol (>90%) resides within the plasma membrane. Once across the plasma membrane, most cholesterol is transported to endosomes / lysosomes and then to certain organelles for processing, where it may be incorporated into the membranes of other organelles (i.e., mitochondria, lysosomes, endoplasmic reticulum) or may be esterified and stored in the form of cytoplasmic lipid droplets.

[0114] Subjects suffering from Alzheimer's disease (e.g., early Alzheimer's disease) often have cholesterol imbalances, and existing research suggests that these imbalances may contribute to Aβ and tau accumulation. Furthermore, neurons can experience increased levels of oxidative stress due to their high metabolic demands. Oxidative stress has been linked to abnormal cholesterol accumulation and processing. Research has shown that young or immature neurons have lower membrane cholesterol levels than mature neurons. Furthermore, cadaveric studies of Alzheimer's disease patients have shown that cellular cholesterol levels are significantly increased in membranes within vulnerable brain regions, but not in non-vulnerable brain regions. The amount of cholesterol in these membranes has also been found to be higher in patients with more severe cognitive symptoms than in patients with milder functional impairment.

[0115] Because the blood-brain barrier prevents the entry of cholesterol-rich lipoproteins, brain cells are largely cut off from the blood cholesterol supply. Therefore, most CNS cholesterol is produced locally. Meanwhile, there is constant efflux of cholesterol from the brain via the neuron-specific enzyme cytochrome 46A1. This enzyme hydroxylates cholesterol to 24S-hydroxycholesterol (24-OHC), which crosses the blood-brain barrier and enters the circulation. Altered CYP46A1 expression has been associated with several neurodegenerative diseases and cognitive changes. Another mechanism of efflux is HDL, which can cross the blood-brain barrier and transport cholesterol from the brain to plasma and then to the liver for eventual elimination. Low and / or dysfunctional HDL particles are known risk factors for developing AD. Finally, apolipoprotein E (APOE) isoform ε4, a form of LDL that regulates brain cholesterol metabolism and transport, may be the strongest identified genetic risk factor for the development of AD.

[0116] There is a well-established link between Aβ and cholesterol, as both Aβ production and clearance are regulated by cholesterol. As shown in both cell culture and most animal models of AD, increased cholesterol content, particularly in domains such as the plasma membrane, can lead to increased Aβ levels. Tau toxicity may also depend on cellular cholesterol levels. A high-cholesterol diet has been shown to increase tau hyperphosphorylation. Studies have shown that as cholesterol concentrations increase, neuronal susceptibility to Aβ-dependent calpain activation also increases. Calpain activation is known to cleave tau, generating toxic fragments. These cleaved tau forms can induce neuronal death, synaptic loss, and / or behavioral impairment. Young neurons, which have significantly less cholesterol than aged neurons, also contain less phosphorylated tau (p-tau). Treating AD with hydroxypropyl β-cyclodextrin

[0117] In one aspect, provided herein is a method of treating early Alzheimer's disease in a human patient in need thereof, the method comprising administering to the human patient an overall effective amount of a hydroxypropyl β-cyclodextrin composition disclosed herein.

[0118] In certain embodiments, the early stage Alzheimer's disease is Alzheimer's disease with mild cognitive impairment or mild Alzheimer's disease. In certain embodiments, the early stage Alzheimer's disease is Alzheimer's disease with mild cognitive impairment. In certain embodiments, the early stage Alzheimer's disease is mild Alzheimer's disease.

[0119] In some embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, the human patient exhibits progressive cognitive decline.

[0120] In some embodiments, upon initiation of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has been exhibiting progressive cognitive decline for at least about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 1 year and 1 month, about 1 year and 2 months, about 1 year and 3 months, about 1 year and 4 months, about 1 year and 5 months, or about 1 year and 6 months. In some embodiments, upon initiation of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has been exhibiting progressive cognitive decline for at least about 1 year.

[0121] In some embodiments, upon initiation of administration of an effective amount of a hydroxypropyl beta-cyclodextrin composition, the human patient exhibits progressive cognitive decline for about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 1 year and 1 month, about 1 year and 2 months, about 1 year and 3 months, about 1 year and 4 months, about 1 year and 5 months, or about 1 year and 6 months.

[0122] In certain embodiments, at the start of administration of an effective amount of a hydroxypropyl beta-cyclodextrin composition, the human patient has a Global Clinical Dementia Rating (CDR) scale score of about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.0.

[0123] In certain embodiments, at the start of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient receives a hydroxypropyl β-cyclodextrin concentration of about 0.1 to about 0.8, about 0.2 to about 0.8, about 0.3 to about 0.8, about 0.4 to about 0.8, about 0.5 to about 0.8, about 0.6 to about 0.8, about 0.7 to about 0.8, about 0.1 to about 0.9, about 0.2 to 0.9, about 0.3 to about 0.9, about 0.4 to about 0.9, about 0.5 to about 0.9, about 0.6 to about 0.9, about 0.7 to about 0.9, about 0.8 to about 0.9, about 0.1 to about 1.0, about 0.2 to about 1.0, about 0.3 to about 1.0, about 0.4 to about 1.0, about 0.5 to about 1.0, about 0.6 to about 1.0, about 0.7 to about 0.9, about 0.8 to about 0.9 7 to about 1.0, about 0.8 to about 1.0, about 0.9 to about 1.0, about 0.1 to about 1.1, about 0.2 to about 1.1, about 0.3 to about 1.1, about 0.4 to about 1.1, about 0.5 to about 1.1, about 0.6 to about 1.1, about 0.7 to about 1.1, about 0.8 to about 1.1, about 0.9 to about 1.1, about 1.0 to about 1.1, about 0.1 to about In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, the human patient has a Global Clinical Dementia Rating (CDR) scale score of between about 0.5 and about 1.2, about 0.2 to about 1.2, about 0.3 to about 1.2, about 0.4 to about 1.2, about 0.5 to about 1.2, about 0.6 to about 1.2, about 0.7 to about 1.2, about 0.8 to about 1.2, about 0.9 to about 1.2, about 1.0 to about 1.2, or about 1.1 to about 1.2. In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, the human patient has a Global Clinical Dementia Rating (CDR) scale score of between about 0.5 and about 1.

[0124] In certain embodiments, at the start of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has a CDR memory box score of about 0.1 or greater, about 0.2 or greater, about 0.3 or greater, about 0.4 or greater, about 0.5 or greater, about 0.6 or greater, about 0.7 or greater, about 0.8 or greater, about 0.9 or greater, or about 1.0 or greater. In certain embodiments, at the start of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has a CDR memory box score of about 0.5 or greater.

[0125] In certain embodiments, at the start of administration of an effective amount of a hydroxypropyl beta-cyclodextrin composition, a human patient has a Global Clinical Dementia Rating (CDR) scale score of about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.0, and a CDR Memory Box Score of about 0.1 or greater, about 0.2 or greater, about 0.3 or greater, about 0.4 or greater, about 0.5 or greater, about 0.6 or greater, about 0.7 or greater, about 0.8 or greater, about 0.9 or greater, or about 1.0 or greater.

[0126] In certain embodiments, at the start of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a blood glucose level of about 0.1 to about 0.8, about 0.2 to about 0.8, about 0.3 to about 0.8, about 0.4 to about 0.8, about 0.5 to about 0.8, about 0.6 to about 0.8, about 0.7 to about 0.8, about 0.1 to about 0.9, about 0.2 to about 0.9, about 0.3 to about 0.9, about 0.4 to about 0.9, about 0.5 to about 0.9, about 0.6 to about 0.9, about 0.7 to about 0.9, about 0.8 to about 0.9, about 0.1 to about 1.0, about 0.2 to about 1.0, about 0.3 to about 1.0, about 0.4 to about 1.0, about 0.5 to about 1.0, about 0.6 to about 1.0, about 0.7 to about 1.0, about 0.8 to about 1.0, about 0.9 to about 1.0, about 0.1 to about 1.1, about 0.2 to about 1.1, about 0.3 to about 1.1, about 0.4 to about 1.1, about 0.5 to about 1.1, about 0.6 to about a Comprehensive Clinical Dementia Rating (CDR) scale between about 1.1, about 0.7 to about 1.1, about 0.8 to about 1.1, about 0.9 to about 1.1, about 1.0 to about 1.1, about 0.1 to about 1.2, about 0.2 to about 1.2, about 0.3 to about 1.2, about 0.4 to about 1.2, about 0.5 to about 1.2, about 0.6 to about 1.2, about 0.7 to about 1.2, about 0.8 to about 1.2, about 0.9 to about 1.2, about 1.0 to about 1.2, or about 1.1 to about 1.2 and a CDR memory box score of about 0.1 or greater, about 0.2 or greater, about 0.3 or greater, about 0.4 or greater, about 0.5 or greater, about 0.6 or greater, about 0.7 or greater, about 0.8 or greater, about 0.9 or greater, or about 1.0 or greater. In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, the human patient has a Global Clinical Dementia Rating (CDR) scale score of between about 0.5 and about 1.0 and a CDR memory box score of about 0.5 or greater.

[0127] In certain embodiments, upon initiation of administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient exhibits cerebral amyloid-beta (Aβ) pathology.

[0128] In certain embodiments, at the start of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient may have a blood glucose level of about 16 to about 25, about 17 to about 25, about 18 to about 25, about 19 to about 25, about 20 to about 25, about 21 to about 25, about 22 to about 25, about 23 to about 25, about 24 to about 25, about 16 to about 26, about 17 to about 26, about 18 to about 26, About 19 to about 26, about 20 to about 26, about 21 to about 26, about 22 to about 26, about 23 to about 26, about 24 to about 26, about 16 to about 27, about 17 to about 27, about 18 to about 27, about 19 to about 27, about 20 to about 27, about 21 to about 27, about 22 to about 27, about 23 to about 27, about 24 to about 27, about 16 to about 28, about 17 to about 28, about 18 to about 28, about 19 to about 2 8, about 20 to about 28, about 21 to about 28, about 22 to about 28, about 23 to about 28, about 24 to about 28, about 16 to about 29, about 17 to about 29, about 18 to about 29, about 19 to about 29, about 20 to about 29, about 21 to about 29, about 22 to about 29, about 23 to about 29, about 24 to about 29, about 16 to about 30, about 17 to about 30, about 18 to about 30, about 19 to about 30, about 20 to and a Mini-Mental State Examination-2: Standard Edition (MMSE-2:SV) score of between about 30, about 21 to about 30, about 22 to about 30, about 23 to about 30, about 24 to about 30, about 16 to about 31, about 17 to about 31, about 18 to about 31, about 19 to about 31, about 20 to about 31, about 21 to about 31, about 22 to about 31, about 23 to about 31, or about 24 to about 31. In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, the human patient has a Mini-Mental State Examination-2: Standard Edition (MMSE-2:SV) score of between about 20 and about 28.

[0129] In certain embodiments, the human patient has previously been administered a cognitive enhancing drug and / or symptomatic treatment for early Alzheimer's disease.

[0130] In certain embodiments, the human patient has previously received an acetylcholinesterase inhibitor and / or memantine and / or the combination medication of Namenda and Aricept (sold as Namzaric).

[0131] In certain embodiments, the human patient is at least 30 years old, at least 40 years old, at least 50 years old, at least 60 years old, at least 70 years old, at least 80 years old, or at least 90 years old. In certain embodiments, the human patient is at least 30 years old. In certain embodiments, the human patient is at least 40 years old. In certain embodiments, the human patient is at least 50 years old. In certain embodiments, the human patient is at least 60 years old. In certain embodiments, the human patient is at least 70 years old. In certain embodiments, the human patient is at least 80 years old.

[0132] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition can provide a therapeutically effective dose of about 100 mg / kg to about 1000 mg / kg, about 200 mg / kg to about 1000 mg / kg, about 300 mg / kg to about 1000 mg / kg, about 400 mg / kg to about 1000 mg / kg, about 500 mg / kg to about 1000 mg / kg, about 600 mg / kg to about 1000 mg / kg, about 700 mg / kg to about 1000 mg / kg, about 750 mg / kg to about 1000 mg / kg, about 800 mg / kg to about 1000 mg / kg, about 900 mg / kg ~1000mg / kg, 100mg / kg~2000mg / kg, 200mg / kg~2000mg / kg, 300mg / kg~2000mg / kg, 400mg / kg~2000mg / kg, 500mg / kg~2000mg / kg, 600mg / kg kg~about 2000mg / kg, about 700mg / kg~about 2000mg / kg, about 750mg / kg~about 2000mg / kg, about 800mg / kg~about 2000mg / kg, about 900mg / kg~about 2000mg / kg, about 1000mg / kg~about 2000mg / kg, about 11 00mg / kg~about 2000mg / kg, about 1200mg / kg~about 2000mg / kg, about 1250mg / kg~about 2000mg / kg, about 1300mg / kg~about 2000mg / kg, about 1400mg / kg~about 2000mg / kg, about 1500mg / kg~about 2000 mg / kg, about 1600mg / kg to about 2000mg / kg, about 1700mg / kg to about 2000mg / kg, about 1800mg / kg to about 2000mg / kg, about 1900mg / kg to about 2000mg / kg, about 100mg / kg to about 2100mg / kg, about 200mg / k g~2100mg / kg, 300mg / kg~2100mg / kg, 400mg / kg~2100mg / kg, 500mg / kg~2100mg / kg, 600mg / kg~2100mg / kg, 700mg / kg~2100mg / kg, 750m g / kg~about 2100mg / kg, about 800mg / kg~about 2100mg / kg, about 900mg / kg~about 2100mg / kg, about 1000mg / kg~about 2100mg / kg, about 1100mg / kg~about 2100mg / kg, about 1200mg / kg~about 2100mg / kg,Approximately 1250mg / kg to approximately 2100mg / kg, approximately 1300mg / kg to approximately 2100mg / kg, approximately 1400mg / kg to approximately 2100mg / kg, approximately 1500mg / kg to approximately 2100mg / kg, approximately 160 0mg / kg~about 2100mg / kg, about 1700mg / kg~about 2100mg / kg, about 1800mg / kg~about 2100mg / kg, about 1900mg / kg~about 2100mg / kg, about 2000mg / kg kg~about 2100mg / kg, about 100mg / kg~about 2500mg / kg, about 200mg / kg~about 2500mg / kg, about 300mg / kg~about 2500mg / kg, about 400mg / kg~about 2500 mg / kg, about 500 mg / kg to about 2500 mg / kg, about 600 mg / kg to about 2500 mg / kg, about 700 mg / kg to about 2500 mg / kg, about 750 mg / kg to about 2500 mg / kg, about 8 00mg / kg~about 2500mg / kg, about 900mg / kg~about 2500mg / kg, about 1000mg / kg~about 2500mg / kg, about 1100mg / kg~about 2500mg / kg, about 1200mg / kg kg~about 2500mg / kg, about 1250mg / kg~about 2500mg / kg, about 1300mg / kg~about 2500mg / kg, about 1400mg / kg~about 2500mg / kg, about 1500mg / kg~about The present invention relates to a method for treating a hydroxypropyl β-cyclodextrin disease, and the method includes administering to a human patient an effective amount of a hydroxypropyl β-cyclodextrin composition, such as about 2500 mg / kg, about 1600 mg / kg to about 2500 mg / kg, about 1700 mg / kg to about 2500 mg / kg, about 1800 mg / kg to about 2500 mg / kg, about 1900 mg / kg to about 2500 mg / kg, about 2000 mg / kg to about 2500 mg / kg, or about 2100 mg / kg to about 2500 mg / kg of the hydroxypropyl β-cyclodextrin composition. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition includes administering to a human patient an effective amount of a hydroxypropyl β-cyclodextrin composition, such as about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition includes administering to a human patient an effective amount of a hydroxypropyl β-cyclodextrin composition, such as about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl β-cyclodextrin composition. ,

[0133] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition can provide a therapeutically effective dose of about 100 mg / kg to about 1000 mg / kg, about 200 mg / kg to about 1000 mg / kg, about 300 mg / kg to about 1000 mg / kg, about 400 mg / kg to about 1000 mg / kg, about 500 mg / kg to about 1000 mg / kg, about 600 mg / kg to about 1000 mg / kg, about 700 mg / kg to about 1000 mg / kg, about 750 mg / kg to about 1000 mg / kg, about 800 mg / kg to about 1000 mg / kg, about 900 mg / kg ~1000mg / kg, 100mg / kg~2000mg / kg, 200mg / kg~2000mg / kg, 300mg / kg~2000mg / kg, 400mg / kg~2000mg / kg, 500mg / kg~2000mg / kg, 600mg / kg kg~about 2000mg / kg, about 700mg / kg~about 2000mg / kg, about 750mg / kg~about 2000mg / kg, about 800mg / kg~about 2000mg / kg, about 900mg / kg~about 2000mg / kg, about 1000mg / kg~about 2000mg / kg, about 11 00mg / kg~about 2000mg / kg, about 1200mg / kg~about 2000mg / kg, about 1250mg / kg~about 2000mg / kg, about 1300mg / kg~about 2000mg / kg, about 1400mg / kg~about 2000mg / kg, about 1500mg / kg~about 2000 mg / kg, about 1600mg / kg to about 2000mg / kg, about 1700mg / kg to about 2000mg / kg, about 1800mg / kg to about 2000mg / kg, about 1900mg / kg to about 2000mg / kg, about 100mg / kg to about 2100mg / kg, about 200mg / k g~2100mg / kg, 300mg / kg~2100mg / kg, 400mg / kg~2100mg / kg, 500mg / kg~2100mg / kg, 600mg / kg~2100mg / kg, 700mg / kg~2100mg / kg, 750m g / kg~about 2100mg / kg, about 800mg / kg~about 2100mg / kg, about 900mg / kg~about 2100mg / kg, about 1000mg / kg~about 2100mg / kg, about 1100mg / kg~about 2100mg / kg, about 1200mg / kg~about 2100mg / kg,Approximately 1250mg / kg to approximately 2100mg / kg, approximately 1300mg / kg to approximately 2100mg / kg, approximately 1400mg / kg to approximately 2100mg / kg, approximately 1500mg / kg to approximately 2100mg / kg, approximately 1600 mg / kg~about 2100mg / kg, about 1700mg / kg~about 2100mg / kg, about 1800mg / kg~about 2100mg / kg, about 1900mg / kg~about 2100mg / kg, about 2000mg / kg ~2100mg / kg, 100mg / kg~2500mg / kg, 200mg / kg~2500mg / kg, 300mg / kg~2500mg / kg, 400mg / kg~2500mg / kg kg, about 500mg / kg to about 2500mg / kg, about 600mg / kg to about 2500mg / kg, about 700mg / kg to about 2500mg / kg, about 750mg / kg to about 2500mg / kg, about 800mg / kg~about 2500mg / kg, about 900mg / kg~about 2500mg / kg, about 1000mg / kg~about 2500mg / kg, about 1100mg / kg~about 2500mg / kg, about 1200mg / kg~about 2 500mg / kg, about 1250mg / kg to about 2500mg / kg, about 1300mg / kg to about 2500mg / kg, about 1400mg / kg to about 2500mg / kg, about 1500mg / kg to about 2500mg In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion includes administering about 500 mg / kg to about 2000 mg / kg of a hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 1000 mg / kg of a hydroxypropyl β-cyclodextrin composition to a human patient via intravenous infusion.

[0134] In certain embodiments, an effective amount of a hydroxypropyl β-cyclodextrin composition is administered to a human patient every 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 days. In certain embodiments, an effective amount of a hydroxypropyl β-cyclodextrin composition is administered to a human patient every 28 days.

[0135] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition can provide a therapeutically effective dose of about 100 mg / kg to about 1000 mg / kg, about 200 mg / kg to about 1000 mg / kg, about 300 mg / kg to about 1000 mg / kg, about 400 mg / kg to about 1000 mg / kg, about 500 mg / kg to about 1000 mg / kg, about 600 mg / kg to about 1000 mg / kg, about 700 mg / kg to about 1000 mg / kg, about 750 mg / kg to about 1000 mg / kg, about 800 mg / kg to about 1000 mg / kg, about 900 mg / kg ~1000mg / kg, 100mg / kg~2000mg / kg, 200mg / kg~2000mg / kg, 300mg / kg~2000mg / kg, 400mg / kg~2000mg / kg, 500mg / kg~2000mg / kg, 600mg / kg kg~about 2000mg / kg, about 700mg / kg~about 2000mg / kg, about 750mg / kg~about 2000mg / kg, about 800mg / kg~about 2000mg / kg, about 900mg / kg~about 2000mg / kg, about 1000mg / kg~about 2000mg / kg, about 11 00mg / kg~about 2000mg / kg, about 1200mg / kg~about 2000mg / kg, about 1250mg / kg~about 2000mg / kg, about 1300mg / kg~about 2000mg / kg, about 1400mg / kg~about 2000mg / kg, about 1500mg / kg~about 2000 mg / kg, about 1600mg / kg to about 2000mg / kg, about 1700mg / kg to about 2000mg / kg, about 1800mg / kg to about 2000mg / kg, about 1900mg / kg to about 2000mg / kg, about 100mg / kg to about 2100mg / kg, about 200mg / k g~2100mg / kg, 300mg / kg~2100mg / kg, 400mg / kg~2100mg / kg, 500mg / kg~2100mg / kg, 600mg / kg~2100mg / kg, 700mg / kg~2100mg / kg, 750m g / kg~about 2100mg / kg, about 800mg / kg~about 2100mg / kg, about 900mg / kg~about 2100mg / kg, about 1000mg / kg~about 2100mg / kg, about 1100mg / kg~about 2100mg / kg, about 1200mg / kg~about 2100mg / kg,Approximately 1250mg / kg to approximately 2100mg / kg, approximately 1300mg / kg to approximately 2100mg / kg, approximately 1400mg / kg to approximately 2100mg / kg, approximately 1500mg / kg to approximately 2100mg / kg, approximately 1600mg / kg to approximately 21 00mg / kg, about 1700mg / kg to about 2100mg / kg, about 1800mg / kg to about 2100mg / kg, about 1900mg / kg to about 2100mg / kg, about 2000mg / kg to about 2100mg / kg, about 100mg / kg~about 2500mg / kg, about 200mg / kg~about 2500mg / kg, about 300mg / kg~about 2500mg / kg, about 400mg / kg~about 2500mg / kg, about 500mg / kg~about 2500mg / kg, about 60 0mg / kg~about 2500mg / kg, about 700mg / kg~about 2500mg / kg, about 750mg / kg~about 2500mg / kg, about 800mg / kg~about 2500mg / kg, about 900mg / kg~about 2500mg / kg, Approximately 1000mg / kg to approximately 2500mg / kg, approximately 1100mg / kg to approximately 2500mg / kg, approximately 1200mg / kg to approximately 2500mg / kg, approximately 1250mg / kg to approximately 2500mg / kg, approximately 1300mg / kg to approximately 25 00mg / kg, about 1400mg / kg to about 2500mg / kg, about 1500mg / kg to about 2500mg / kg, about 1600mg / kg to about 2500mg / kg, about 1700mg / kg to about 2500mg / kg, about 1800m The method includes administering to a human patient by intravenous infusion every 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 days an amount of a hydroxypropyl β-cyclodextrin composition in an amount of about 1900 mg / kg to about 2500 mg / kg, about 2000 mg / kg to about 2500 mg / kg, or about 2100 mg / kg to about 2500 mg / kg.

[0136] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 2000 mg / kg of a hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion every 28 days. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering about 500 mg / kg to about 1000 mg / kg of a hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion every 28 days.

[0137] In certain embodiments, an effective amount of a hydroxypropyl β-cyclodextrin composition is administered to a human patient at regular intervals (e.g., every 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days) for a period of at least about 20 weeks, at least about 21 weeks, at least about 22 weeks, at least about 23 weeks, at least about 24 weeks, at least about 25 weeks, at least about 26 weeks, at least about 27 weeks, or at least about 28 weeks. In certain embodiments, an effective amount of a hydroxypropyl β-cyclodextrin composition is administered to a human patient at regular intervals (e.g., every 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days) for the duration of the human patient's life.

[0138] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition can provide a therapeutically effective dose of about 100 mg / kg to about 1000 mg / kg, about 200 mg / kg to about 1000 mg / kg, about 300 mg / kg to about 1000 mg / kg, about 400 mg / kg to about 1000 mg / kg, about 500 mg / kg to about 1000 mg / kg, about 600 mg / kg to about 1000 mg / kg, about 700 mg / kg to about 1000 mg / kg, about 750 mg / kg to about 1000 mg / kg, about 800 mg / kg to about 1000 mg / kg, about 900 mg / kg ~1000mg / kg, 100mg / kg~2000mg / kg, 200mg / kg~2000mg / kg, 300mg / kg~2000mg / kg, 400mg / kg~2000mg / kg, 500mg / kg~2000mg / kg, 600mg / kg kg~about 2000mg / kg, about 700mg / kg~about 2000mg / kg, about 750mg / kg~about 2000mg / kg, about 800mg / kg~about 2000mg / kg, about 900mg / kg~about 2000mg / kg, about 1000mg / kg~about 2000mg / kg, about 11 00mg / kg~about 2000mg / kg, about 1200mg / kg~about 2000mg / kg, about 1250mg / kg~about 2000mg / kg, about 1300mg / kg~about 2000mg / kg, about 1400mg / kg~about 2000mg / kg, about 1500mg / kg~about 2000 mg / kg, about 1600mg / kg to about 2000mg / kg, about 1700mg / kg to about 2000mg / kg, about 1800mg / kg to about 2000mg / kg, about 1900mg / kg to about 2000mg / kg, about 100mg / kg to about 2100mg / kg, about 200mg / k g~2100mg / kg, 300mg / kg~2100mg / kg, 400mg / kg~2100mg / kg, 500mg / kg~2100mg / kg, 600mg / kg~2100mg / kg, 700mg / kg~2100mg / kg, 750m g / kg~about 2100mg / kg, about 800mg / kg~about 2100mg / kg, about 900mg / kg~about 2100mg / kg, about 1000mg / kg~about 2100mg / kg, about 1100mg / kg~about 2100mg / kg, about 1200mg / kg~about 2100mg / kg,1250mg / kg~2100mg / kg, 1300mg / kg~2100mg / kg, 1400mg / kg~2100mg / kg, 1500mg / kg~2100mg / kg, 1600mg / kg~2100mg / kg, 1700 mg / kg~about 2100mg / kg, about 1800mg / kg~about 2100mg / kg, about 1900mg / kg~about 2100mg / kg, about 2000mg / kg~about 2100mg / kg, about 100mg / kg~about 2500mg / kg, about 200mg / kg~about 2500mg / kg, about 300mg / kg to about 2500mg / kg, about 400mg / kg to about 2500mg / kg, about 500mg / kg to about 2500mg / kg, about 600mg / kg to about 2500mg / kg, about 700mg / kg to about 2500mg / kg, Approximately 750mg / kg to approximately 2500mg / kg, approximately 800mg / kg to approximately 2500mg / kg, approximately 900mg / kg to approximately 2500mg / kg, approximately 1000mg / kg to approximately 2500mg / kg, approximately 1100mg / kg to approximately 2500mg / kg, approximately 1200mg / k about 1250mg / kg to about 2500mg / kg, about 1300mg / kg to about 2500mg / kg, about 1400mg / kg to about 2500mg / kg, about 1500mg / kg to about 2500mg / kg, about 1600mg / kg to about 2500mg / kg, about 1700mg / kg to about 2500mg / kg, about 1800mg / kg to about 2500mg / kg, about 1900mg / kg to about 2500mg / kg, about 2000mg / kg to about 2500mg / kg, or about 2100mg / kg to about 2500mg / kg mg / kg of a hydroxypropyl β-cyclodextrin composition to a human patient by intravenous infusion every 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 days for a period of at least about 20 weeks, at least about 21 weeks, at least about 22 weeks, at least about 23 weeks, at least about 24 weeks, at least about 25 weeks, at least about 26 weeks, at least about 27 weeks, or at least about 28 weeks.

[0139] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient about 500 mg / kg to about 1000 mg / kg of a hydroxypropyl β-cyclodextrin composition by intravenous infusion every 28 days for a period of at least about 24 weeks. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient about 500 mg / kg to about 2000 mg / kg of a hydroxypropyl β-cyclodextrin composition by intravenous infusion every 28 days for a period of at least about 24 weeks.

[0140] In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion over a period of at least about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, or about 8 hours. In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion over a period of at least about 4 hours. In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion over a period of at least about 6.5 hours.

[0141] In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion over a period of about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, or about 8 hours. In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion over a period of about 4 hours. In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion over a period of about 6.5 hours.

[0142] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises about 20% (w / v), about 21% (w / v), about 22% (w / v), about 23% (w / v), about 24% (w / v), about 25% (w / v), about 26% (w / v), about 27% (w / v), about 28% (w / v), about 29% (w / v), or about 30% (w / v) hydroxypropyl β-cyclodextrin. In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises about 25% (w / v) hydroxypropyl β-cyclodextrin.

[0143] In certain embodiments, the hydroxypropyl β-cyclodextrin is a hydroxypropyl β-cyclodextrin described herein. In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl β-cyclodextrin species. In certain embodiments, each of the two or more hydroxypropyl β-cyclodextrin species has a different degree of hydroxypropylation of the β-cyclodextrin ring. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.59 to about 1.14. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.59 to about 0.73. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.59 to about 0.8. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution of about 0.8 to about 1.0. In certain embodiments, the hydroxypropyl β-cyclodextrin composition contains about 0.2% w / w or less unsubstituted β-cyclodextrin. In certain embodiments, the hydroxypropyl β-cyclodextrin composition contains about 0.15% w / w or less unsubstituted β-cyclodextrin. In certain embodiments, the hydroxypropyl β-cyclodextrin composition contains about 0.16% w / w or less unsubstituted β-cyclodextrin. In certain embodiments, the hydroxypropyl β-cyclodextrin composition contains about 2.5% w / w or less propylene glycol.

[0144] In certain embodiments, the method further comprises administering to the human patient a second therapeutic agent selected from the group consisting of donepezil, rivastigmine, galantamine, memantine, verubecestat, solanezumab, bapineuzumab, aducanumab, tideglusib, epothilone D, and ABBV-8E12.

[0145] In certain embodiments, the method further comprises administering to the human patient a second therapeutic agent selected from the group consisting of a cholinesterase inhibitor, an NMDA receptor antagonist, a humanized antibody targeting tau protein, a humanized antibody targeting amyloid beta protein, and a BACE inhibitor.

[0146] In certain embodiments, the method further comprises administering a second therapeutic agent to the human patient, wherein the second therapeutic agent is selected from any of the therapeutic agents shown in Table 1. [Table 1] Pharmaceutical Composition

[0147] In one aspect, the present disclosure provides a pharmaceutical composition for the treatment of early Alzheimer's disease in a human patient in need thereof, the pharmaceutical composition collectively comprising an effective amount of a hydroxypropyl β-cyclodextrin composition disclosed herein and one or more pharmaceutically acceptable excipients.

[0148] In some embodiments, the pharmaceutical compositions described herein may contain about 20,000 mg, about 21,000 mg, about 22,000 mg, about 23,000 mg, about 24,000 mg, about 25,000 mg, about 26,000 mg, about 27,000 mg, about 28,000 mg, about 29,000 mg, or about 30,000 mg of a hydroxypropyl beta-cyclodextrin composition.

[0149] In some embodiments, the concentration of hydroxypropyl β-cyclodextrin in the pharmaceutical compositions described herein is about 100 mg / mL, about 150 mg / mL, about 200 mg / mL, about 250 mg / mL, about 300 mg / mL, or about 350 mg / mL.

[0150] In certain embodiments, the pharmaceutical composition may comprise from about 5% (w / v) to about 40% (w / v), from about 10% (w / v) to about 40% (w / v), from about 15% (w / v) to about 40% (w / v), from about 20% (w / v) to about 40% (w / v), from about 25% (w / v) to about 40% (w / v), from about 30% (w / v) to about 40% (w / v), from about 35% (w / v) to about 40% (w / v), from about 40% (w / v), from about 45 ... w / v), about 5% (w / v) to about 35% (w / v), about 5% (w / v) to about 30% (w / v), about 5% (w / v) to about 25% (w / v), about 5% (w / v) to about 20% ( w / v), about 5% (w / v) to about 15% (w / v), about 5% (w / v) to about 10% (w / v), about 10% (w / v) to about 35% (w / v), about 10% (w / v) to about 30% (w / v), approximately 10% (w / v) ~ approximately 25% (w / v), approximately 10% (w / v) ~ approximately 20% (w / v), approximately 10% (w / v) ~ approximately 15% (w / v), approximately 15% (w / v) ~ Approximately 35% (w / v), approximately 15% (w / v) ~ approximately 30% (w / v), approximately 15% (w / v) ~ approximately 25% (w / v), approximately 15% (w / v) ~ approximately 20% (w / v), approximately 20% (w / v) to about 35% (w / v), about 20% (w / v) to about 30% (w / v), about 20% (w / v) to about 25% (w / v), about 25% (w / v) to about 35% (w / v), about 25% (w / v) to about 30% (w / v), or about 30% (w / v) to about 35% (w / v) of one or more hydroxypropyl β-cyclodextrin species.

[0151] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a 5% (w / v), 10% (w / v), 15% (w / v), 20% (w / v), 25% (w / v), 30% (w / v), 35% (w / v), or 40% (w / v) aqueous solution of one or more hydroxypropyl β-cyclodextrin species. In some embodiments, an effective amount of the hydroxypropyl β-cyclodextrin composition comprises a 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species. In some embodiments, the 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species is a 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species in water.

[0152] In certain embodiments, the pharmaceutical composition comprises a 5% (w / v), 10% (w / v), 15% (w / v), 20% (w / v), 25% (w / v), 30% (w / v), 35% (w / v), or 40% (w / v) aqueous solution of one or more hydroxypropyl β-cyclodextrin species. In some embodiments, an effective amount of the pharmaceutical composition comprises a 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species. In some embodiments, the 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species is a 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species in water.

[0153] In some embodiments, the one or more pharmaceutically acceptable excipients are selected from the group consisting of a diluent, a buffer, a preservative, a stabilizer, a solubilizer, or any combination thereof.

[0154] In certain embodiments, the pharmaceutical composition may be formulated for administration as a liquid dosage form suitable for intracavitary, intradermal, intramuscular, intrathecal, intravenous, subcutaneous, or intracerebroventricular administration.

[0155] In certain embodiments, the liquid dosage forms of the pharmaceutical compositions described herein further comprise a diluent. In some embodiments, the inert diluent is saline.

[0156] In certain embodiments, the liquid dosage form of the pharmaceutical composition described herein further comprises a buffer.For example, buffers suitable for use with the present disclosure include citrate buffer (e.g., monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture), succinate buffer (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture), tartaric acid buffer (e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture), fumaric acid buffer (e.g., fumaric acid-monosodium fumarate mixture, fumaric acid-disodium fumarate mixture, monosodium fumarate- These include, but are not limited to, both organic and inorganic acids and their salts, such as disodium fumarate mixtures, gluconate buffers (e.g., gluconic acid-sodium gluconate mixtures, gluconic acid-sodium hydroxide mixtures, gluconic acid-potassium gluconate mixtures), oxalate buffers (e.g., oxalic acid-sodium oxalate mixtures, oxalic acid-sodium hydroxide mixtures, oxalic acid-potassium oxalate mixtures, etc.), lactate buffers (e.g., lactic acid-sodium lactate mixtures, lactic acid-sodium hydroxide mixtures, lactic acid-potassium lactate mixtures, etc.), and acetate buffers (e.g., acetic acid-sodium acetate mixtures, acetic acid-sodium hydroxide mixtures, etc.). Additionally, phosphate buffers, histidine buffers, and trimethylamine salts such as Tris may also be used.

[0157] In certain embodiments, the liquid dosage form of the pharmaceutical composition described herein further comprises a pH adjuster. For example, suitable pH adjusters include, but are not limited to, 1N sodium hydroxide and 37% hydrochloric acid (HCl).

[0158] In certain embodiments, the liquid dosage form of the pharmaceutical composition described herein further comprises a preservative.For example, preservatives suitable for use with the present disclosure include, but are not limited to, phenol, benzyl alcohol, meta-cresol, methylparaben, propylparaben, octadecyldimethylbenzylammonium chloride, benzalkonium halides (e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkylparabens (e.g., methyl or propylparaben, catechol, resorcinol, cyclohexanol, and 3-pentanol).

[0159] In certain embodiments, the liquid dosage form of the pharmaceutical composition described herein further comprises a stabilizer. For example, suitable stabilizers include, but are not limited to, polyhydric sugar alcohols, trihydric or higher sugar alcohols, amino acids, organic sugars or sugar alcohols, polyvinylpyrrolidone, monosaccharides, trisaccharides, polysaccharides, proteins, sulfur-containing reducing agents, amino acid polymers, and polyethylene glycol.

[0160] In certain embodiments, the liquid dosage form of the pharmaceutical composition described herein further comprises a solubilizing agent. In some embodiments, the solubilizing agent is an ionic surfactant. Examples of non-ionic surfactants include, but are not limited to, polysorbates, poloxamers, Pluronic® polyols, and polyoxyethylene sorbitan monoethers.

[0161] In certain embodiments, pharmaceutical compositions of the hydroxypropyl β-cyclodextrin compositions disclosed herein may be prepared for storage as lyophilized formulations or aqueous solutions by mixing the hydroxypropyl β-cyclodextrin compositions with optional pharmaceutically acceptable carriers, excipients, or stabilizers typically used in the art (e.g., buffers, stabilizers, preservatives, tonicity agents, non-ionic surfactants, antioxidants, and various other additives).

[0162] In certain embodiments, pharmaceutical compositions comprising the hydroxypropyl β-cyclodextrin compositions disclosed herein are chemically and / or physically stable at RT (15-25° C.) for about 6 months, about 1 year, about 1 year and 6 months, about 2 years, about 2 years and 6 months, about 3 years, about 3 years and 6 months, about 4 years, about 4 years and 6 months, or about 5 years.

[0163] In certain embodiments, the pharmaceutical compositions described herein further comprise a second therapeutic agent. In some embodiments, the second therapeutic agent is used to treat early Alzheimer's disease. In some embodiments, the second therapeutic agent is selected from the group consisting of donepezil, rivastigmine, galantamine, memantine, verubecestat, solanezumab, bapineuzumab, aducanumab, tideglusib, epothilone D, and ABBV-8E12. In some embodiments, the second therapeutic agent is selected from the group consisting of a cholinesterase inhibitor, an NMDA receptor antagonist, a humanized antibody targeting tau protein, a humanized antibody targeting amyloid beta protein, and a BACE inhibitor. In some embodiments, the second therapeutic agent is selected from the group consisting of Aricept®, Namenda®, donepezil, memantine, Excelon®, Namenda XR®, galantamine, Aricept® ODT, rivastigmine, vitamin e, Razadyne® ER, donepezil / memantine, Razadyne®, Namzaric®, Alpha E®, Hydergine®, ergoloid mesylates, Aqua-E®, Aqua Gem-E®, etanercept, Reminyl®, Vita-Plus E natural, Aquasol E®, Aquavite-E®, and E-400 clear.

[0164] In some embodiments, the second therapeutic agent is selected from any of the therapeutic agents shown in Table 1.

[0165] In certain embodiments, the second therapeutic agent is selected from the group consisting of ABBV-8E12 (anti-tau antibody), AC-1204 (glucose stimulator), ACI-24 (anti-Abeta vaccine), ACI-35 (anti-p-tau vaccine), aducanumab (BIIB037) (amyloid beta mAb), AGB101 (levetiracetam low dose), ALZ-801 (amyloid beta-protein inhibitor), ALZT-OP1 (amyloid beta-protein inhibitor / inflammatory mediator inhibitor), AMG520 / CNP520 (BACE1 protein inhibitor), ANAVEX (trademark ) 2-73 (M1 muscarinic receptor agonist / intracellular sigma-1 receptor agonist), AstroStem (mesenchymal stem cell therapy, AUS-131 (non-hormonal estrogen receptor agonist), AVN-101 (serotonin 6 receptor antagonist), AVN-322 (serotonin 6 receptor antagonist), AVP-786 (dextromethorphan analog / ultra-low dose quinidine), AXS-05 (bupropion / dextromethorphan), azeliragon (TTP488) (RAGE antagonist), BAN2401 (anti-amyloid beta m Ab), bexarotene (RXR-selective retinoid analog), BI409306 (PDE9A inhibitor), BIIB076 (anti-tau antibody), BIIB092 (anti-extracellular tau antibody), BNC375 (positive allosteric modulator), BPN14770 (type 4 cyclic nucleotide phosphodiesterase inhibitor), bryostatin 1 (protein kinase C stimulator), CAD106 (amilomotide) (VLP immunotherapy vaccine), Corplex donepezil (donepezil transdermal patch), Corplex memantine (memantine transdermal patch), CPC-201 ( Donepezil / Solifenacin combination), CPC-212 (next-generation acetylcholinesterase inhibitor), CPC-250 (next-generation acetylcholinesterase inhibitor), crenezumab (anti-amyloid beta antibody), CSP-1103 (amyloid beta-protein inhibitor), CSTC1 (BAC), CT1812 (amyloid beta oligomer receptor antagonist), E2027 (PDE9 inhibitor), E2609 (BACE1 protein inhibitor), EVT302 (MAO-B inhibitor), gantenerumab (amyloid beta-protein inhibitor),GC021109 (P2Y6 purinergic receptor agonist), HSRx-888 (donepezil / food-based compound), immunoglobulin / albumin, INP-102 intranasal, intepirdine (RVT-101) (serotonin 6 receptor antagonist), IONIS-MAPTRx (tau-targeting protein), JNJ-54861911 (BACE inhibitor), JOT106 (oral capsules of trans-resveratrol), KPAX002-2 (proprietary version of methylphenidate), lanabecestat (BACE inhibitor), LM11A-31 (p75 neurotrophin receptor), LMTX (tau protein aggregation inhibitor / TDP-43 aggregation inhibitor), LY3002813 (N3pG-amyloid beta antibody), LY3202626 (BACE inhibitor), LY3303560 (tau antibody), M1 agonist (selective M1 receptor agonist), MEDI1814 (anti-amyloid beta 42 mAb), mesenchymal stem cell therapy, MP-101 (mGluR2 / mGluR3 agonist), MSDC-0160 (mTOT modulator), NBXT-001 + Nobilis™ inhalation device (NMDA receptor antagonist), neflamapimod (VX-745) (p38 mitogen-activated protein kinase inhibitor), NGP555 (gamma secretase complex modulator), nilvadipine soluble amyloid reduction / clearing agent), NPT088 (GAIM targeting amyloid-beta, tau, and a-synuclein) Ig fusion), Nuplazid® pimavanserin, PF-05251749 (casein kinase 1 delta / epsilon), PF-06648671 (gamma secretase complex modulator), PF-06751979 (enzyme inhibitor), pioglitazone (low dose) (PPARγ agonist), piromelatine (melatonin agonist), Posiphen® R-phenserine, Rexulti® brexpiprazole, RG6100 (tau protein inhibitor), RVT-103 + RVT-104 (QAAM + cholinesterase inhibitor), SAR228810 (anti-protofibril AB mAb), selective BACE1 inhibitor, solanezumab (amyloid beta protein inhibitor), SUVN-502 (serotonin 6 receptor antagonist),Selected from the group consisting of SUVN-D4010 (serotonin 4 receptor agonist), SUVN-G3031 (histamine H3 receptor antagonist), T-817MA (amyloid beta-protein inhibitor), T3D-959 (PPAR-delta / gamma agonist), TAK-071 (muscarinic M1 receptor modulator), TPI287 (next-generation taxane), UB-311 (anti-amyloid endobody vaccine), UE-2343 (11β-HSD1 inhibitor), verubecestat (MK-8931) (BACE1 protein inhibitor), or a combination thereof.

[0166] In certain embodiments, the pharmaceutical compositions of the present disclosure are administered to a subject by intracavitary, intradermal, intramuscular, intrathecal, intravenous, subcutaneous, or intracerebroventricular administration. kit

[0167] In various embodiments, the present invention provides kits for treating early-stage Alzheimer's disease in a human patient in need thereof. In some embodiments, the kit generally includes: i) instructions for administering a hydroxypropyl β-cyclodextrin composition or pharmaceutical composition described herein to a human patient suffering from early-stage Alzheimer's disease; and ii) a hydroxypropyl β-cyclodextrin composition or pharmaceutical composition described herein. In some embodiments, the kit may include one or more unit dosage forms containing an amount of a hydroxypropyl β-cyclodextrin composition or pharmaceutical composition described herein effective to treat early-stage Alzheimer's disease in a human patient.

[0168] In certain embodiments, the kit includes: (i) instructions for administering a hydroxypropyl β-cyclodextrin composition or pharmaceutical composition described herein to a human patient in need thereof; and (ii) one or more 100 mL vials containing a 25% (w / v) hydroxypropyl β-cyclodextrin composition described herein. In some embodiments, the hydroxypropyl β-cyclodextrin composition is a Trappsol® Cyclo™ hydroxypropyl β-cyclodextrin composition.

[0169] In some embodiments, the kit further comprises one or more selected from the group comprising a sterile syringe, a sterile needle, a sterile IV bag, an infusion pump, or any combination thereof.

[0170] The above description describes multiple aspects and embodiments of the present invention, including hydroxypropyl β-cyclodextrin compositions, methods of using hydroxypropyl β-cyclodextrin compositions to treat subjects with early-stage Alzheimer's disease, pharmaceutical compositions comprising hydroxypropyl β-cyclodextrin compositions, and kits. This patent application specifically contemplates all combinations and permutations of aspects and embodiments. [Example]

[0171] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compositions and methods provided herein and should not be construed in any way as limiting the scope thereof. Abbreviation A. Amyloid burden Aβ amyloid-beta Aβ40 amyloid beta 40 Aβ42 Amyloid beta 42 AD Alzheimer's disease ADAS-Cog-14 Alzheimer's Disease Assessment Scale-Cognitive Function Subscale 14 ADCS-ADL Alzheimer's Disease Collaborative Study - Activities of Daily Living ADCS-CGIC Alzheimer's Disease Collaborative Study - Clinical Global Impression of Change AE Adverse Event APP amyloid precursor protein processing ApoE Apolipoprotein E APS Amyloid Probability Score APOE Apolipoprotein E aPTT activated partial thromboplastin ARIA Amyloid-related imaging abnormalities ARIA-E Amyloid-related imaging abnormality - edema ARIA-H Amyloid-related imaging abnormality - hemorrhage ATN Amyloid / Tau / Neurodegeneration BACE β-site APP cleaving enzyme CDR Clinical Dementia Rating Scale CDR-SB Clinical Dementia Rating Scale Total Boxes CNS central nervous system CSF cerebrospinal fluid C-SSRS Columbia-Suicide Severity Rating Scale CT Computed Tomography DS / DS a average degree of substitution DSMB Data and Safety Monitoring Board DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition EAD Early Alzheimer's disease ECG electrocardiogram eGFR Estimated glomerular filtration rate End of Study EOT End of action End of Study ET Early Termination FDA Food and Drug Administration Geriatric Depression Scale (GDS) - Short version Geriatric Depression Rating Scale-Short Form HDL high density lipoprotein HIS Modified Hachinski Ischemia Score HPβCD Hydroxypropyl-beta-cyclodextrin INR International Normalized Ratio IV (intravenous) LE late endosome LDL low-density lipoprotein LY late lysosomes MCI Mild cognitive impairment MDD Major depressive disorder MDRD modification of diet in renal disease MMSE-2:SV Mini-Mental State Examination-2 Standard Version MRI Magnetic Resonance Imaging MS / MS a Average molar substitution NfL neurofilament light chain NIA-AA National Institute on Aging-Alzheimer's Association NMDA N-methyl-D-aspartate PD Pharmacodynamics PET Positron Emission Tomography PK Pharmacokinetics PT Prothrombin Time SoA assessment schedule TdP Torsades de pointes TEAE Treatment-emergent adverse events TSH thyroid-stimulating hormone USP United States Pharmacopoeia WFI water for injection WOCBP Women of childbearing potential Example 1 A randomized, placebo-controlled, double-blind, parallel-group, 6-month study to evaluate the safety, tolerability, and potential efficacy of monthly Trappsol® Cyclo™ (hydroxypropyl beta-cyclodextrin, HPβCD) infusions in patients with early Alzheimer's disease 1. Purpose

[0172] To evaluate the safety and tolerability of Trappsol® Cyclo™ over 24 weeks in patients with early Alzheimer's disease (EAD).

[0173] To investigate the potential efficacy of Trappsol® Cyclo™ over 24 weeks in patients with EAD.

[0174] To determine the pharmacokinetics (PK) of Trappsol® Cyclo™ over a 24-week period in patients with EAD. 2.Research design

[0175] This is a randomized, placebo-controlled, double-blind, parallel-group study evaluating the safety, tolerability, and potential efficacy of Trappsol® Cyclo™ in patients with EAD as defined by the FDA Guidance for Industry on Early Alzheimer's Disease: Developing Drugs for Treatment. [Vellas B, Bateman R, Blennow K, et al. Endpoints for pre-dementia AD trials: a report from the EU / US / CTAD Task Force. J Prev Alzheimers Dis. 2015;2(2):128-135.]

[0176] The study will enroll approximately 120 (30 patients / treatment group) male and female patients, aged 50-80 years at screening, who meet the National Institute on Aging-Alzheimer's Association (NIA-AA) or FDA Guidance for Industry on Early Alzheimer's Disease: Developing Drugs for Treatment criteria for either AD with mild cognitive impairment (MCI) or mild AD, collectively known as EAD (stages 3 and 4), and have characteristic pathophysiological changes of Alzheimer's disease (AD). [Cummings J. The National Institute on Aging-Alzheimer's Association Framework on Alzheimer's disease: application to clinical trials. Alzheimers Dement. 2019;15(1):172-178., Kantner I, Erben RG. Long-term parental administration of 2-hydroxypropyl β-cyclodextrin causes bone loss. Toxicol Pathol. 2012;40(5):742-50., Vellas B, Bateman R, Blennow K, et al. Endpoints for pre-dementia AD trials: a report from the EU / US / CTAD Task Force. J Prev Alzheimers Dis. 2015;2(2):128-135.] Enrolled patients have evidence of progressive cognitive decline in the previous year as determined by serial cognitive test scores, when available, or as reported by the patient or informant / caregiver / study partner (hereafter referred to as caregiver) as documented by the investigator.

[0177] Due to the nature of the EAD, patients will identify a primary caregiver prior to enrollment to assist them in their study participation. Patients will be accompanied to each clinic visit by their caregiver. The caregiver will have face-to-face contact with the patient for a minimum of approximately 10 hours per week, spread over two to five days per week (e.g., two hours / day, five days per week, or five hours / day, twice per week). The legal representative may be a caregiver. Caregivers do not need to be family members.

[0178] During the screening period (up to 42 days prior to Visit [V]2 / Baseline), all potential patients and their primary caregivers will provide written consent to participate in the study before any study-related assessments are conducted. Blood samples will be collected from all patients at the screening visit (V1) for PrecivityAD™ blood testing and / or clinical laboratory evaluation.

[0179] Patients will also have a magnetic resonance imaging (MRI) within 12 months prior to the screening visit (V1) to confirm the diagnosis of EAD in the absence of any other clinically significant pathology. A computed tomography (CT) scan may be substituted only if the patient has an absolute contraindication to MRI.

[0180] Although the FDA Guidance for Industry on Early Alzheimer's Disease: Developing Drugs for Treatment [Vellas B, Bateman R, Blennow K, et al. Endpoints for pre-dementia AD trials: a report from the EU / US / CTAD Task Force. J Prev Alzheimers Dis. 2015;2(2):128-135.] remains silent on the specific biomarkers to be used to meet the recent consensus statement on amyloid / tau / neurodegeneration (ATN) criteria, the protocol provides further requirements for the detection of amyloid burden (A).

[0181] In particular, to support diagnostic criteria based on the relevant guidelines of the NIA-AA criteria [Cummings J. The National Institute on Aging-Alzheimer's Association Framework on Alzheimer's disease: application to clinical trials. Alzheimers Dement. 2019;15(1):172-178., Kantner I, Erben RG. Long-term parenteral administration of 2-hydroxypropyl β-cyclodextrin causes bone loss. Toxicol Pathol. 2012;40(5):742-50.], all eligible patients should undergo a lumbar puncture and have a CSF biomarker profile consistent with a diagnosis of AD or a high amyloid probability score (APS [58-100]) and a Precivity AD blood test during the screening period.

[0182] Patients who meet enrollment criteria based on results from the PrecivityAD blood test and other eligibility criteria must also demonstrate evidence of pre-enrollment cerebral amyloid-beta (Aβ) pathology at the baseline visit (V2) based on cerebrospinal fluid (CSF) analysis assessing Aβ42 / 40 levels, or patients with MCI must meet the criteria of a CSF Aβ42 / 40 ratio <0.72, and patients with EAD must meet the criteria of an Aβ42 / 40 ratio <0.72 and CSF P-tau >50 pg / mL.

[0183] Physical examination, vital signs, and a 12-lead electrocardiogram (ECG) as well as the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), Mini-Mental State Examination-2: Standard Edition (MMSE-2:SV), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Columbia-Suicide Severity Rating Scale (C-SSRS) are used to support a diagnosis of AD based on the diagnostic guidelines of the NIA-AA criteria [Cummings J. The National Institute on Aging-Alzheimer's Association Framework on Alzheimer's disease: application to clinical trials. Alzheimers Dement. 2019;15(1):172-178. Kantner I, Erben RG. Long-term parenteral administration of 2-hydroxypropyl β-cyclodextrin causes bone loss. Toxicol Pathol. 2012;40(5):742-50.]. The Geriatric Depression Rating Scale-Short Form (GDS-SF) and the Modified Hachinski Ischemia Scale (HIS) will be used to rule out underlying diagnoses. Previous and current medications will be recorded. Further required assessments will be itemized on the Schedule of Assessments (SoA, Table 2). [Table 2] 1. After patients meet enrollment criteria based on results from the PrecivityAD blood test and other eligibility criteria, a CSF analysis evaluating Aβ42 / 40 levels must be performed to confirm a diagnosis of Alzheimer's disease. If CSF assessments have already been performed before screening, repeating these tests is not necessary, provided results from the PrecivityAD blood test meet enrollment criteria. All patients must also be willing to consent to a lumbar puncture and CSF analysis at the EOT / EOS visit. Blood coagulation tests (prothrombin time [PT] / international normalized ratio [INR] and activated partial thromboplastin time [aPTT]) will be performed before the lumbar puncture. Platelet measurements will be included in the clinical laboratory safety testing at the screening visit. At the investigator's discretion, further coagulation testing before the lumbar puncture may be performed in patients with abnormal coagulation results or because of increased bleeding risk. 2. Vital signs include temperature, respiratory rate, weight, supine and sitting radial pulse rates, and sitting systolic and diastolic blood pressure. Sitting recordings are taken after the patient has been sitting for at least 3 minutes with feet firmly planted on the floor and arms relaxed and bent at the elbows. The method for obtaining temperature depends on the site's standard practice but should be obtained by the same method for a given patient throughout the study. Vital signs are measured before the start of the infusion. Height for calculation of body mass index is obtained during the physical examination. 3. Standard triplicate 12-lead ECGs will be evaluated at each site for the presence of clinically relevant abnormalities. ECGs will be obtained after the patient has rested supine for approximately 3 minutes, using the same ECG machine each time. ECGs will be evaluated by a medically qualified investigator at each site for the presence of clinically relevant abnormalities during the infusion. Triplicate ECGs will be obtained at screening to confirm QTcF <450 ms for men and <460 ms for women; for all other visits as indicated, ECG readings will be completed before the start of the infusion, +60 minutes after the start of the infusion, and immediately after the completion of the infusion. At baseline, triplicate ECGs will be collected at three different time points (-60, -45, and -30 minutes) starting at -60 minutes before administration of the first dose (Week 0). Triplicate 12-lead ECGs will be timed with PK sampling (PK sampling should ideally follow EGC tracings within 2 minutes) at weeks 0 (baseline), 4, and 8. 4. Safety laboratory tests include hematology (red blood cell count, white blood cell count, lymphocytes, neutrophils, eosinophils, basophils, monocytes, hemoglobin, hematocrit, and platelets), chemistry (alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, gamma-glutamyltransferase, blood urea nitrogen, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, creatinine, eGFR according to MDRD, alkaline phosphatase, lactate dehydrogenase, sodium, potassium, calcium, chloride, albumin, uric acid, and glucose), C-terminal telopeptide, and urinalysis (macroscopic analysis with microscopic analysis only if indicated by dipstick). Analyses include color, turbidity, specific gravity, pH, glucose, protein, ketones, urobilinogen, bilirubin, blood nitrite, and leukocyte esterase. At screening, laboratory tests will also include serology (HIV-1, HIV-2, hepatitis C surface antigen, and hepatitis C virus antibody), coagulation (PT / INR and aPTT), TSH, T3, and T4 in patients with clinical suspicion of severe hypothyroidism, eGFR by MDRD, and vitamin B12. Laboratory tests will be completed before the start of the infusion. 5. PK sampling will be completed in all patients at baseline (Week 0, V2), Week 4 (V3), and Week 8 (V4) prior to the start of the study drug infusion, 1 and 3 hours after the infusion begins, at the completion of the infusion, 50-60 minutes after the infusion, and 2 hours after the infusion. PK sampling for trough levels will be obtained prior to the start of the study drug infusion at Week 12 (V5) and Week 24 (V8). Participation of ET patients in PK procedures is not required unless safety observations prompt discontinuation of study medication. PK sampling will be timed with triplicate 12-lead ECGs at Weeks 0 (baseline), 4, and 8 (PK sampling should follow the tracing, ideally within 2 minutes). 6. A POC urine pregnancy test will be administered to female patients of childbearing potential at each visit. Any positive POC urine pregnancy test will be confirmed with a serum pregnancy test before the patient continues on the study. 7. Urine drug screens will be performed at screening (V1) and at baseline (V2) prior to infusion. 8. Any remaining blood and / or plasma from the PD marker analysis is saved for subsequent analysis. 9. MRI evaluations are planned for both ARIA-E and ARIA-H, and the results will be reviewed by the DSMB. 10. Patients will complete hearing assessments (e.g., mean hearing level / pure tone 1-8 kHz audiometry or auditory evoked potentials / auditory brainstem response) during Screening (V1), within 1 week prior to each study drug administration at Visit 3 (audiometry results will be available for investigator review prior to the next study drug administration), and at Week 24 (EOT / EOS, V8). Additionally, further assessments may be scheduled at the investigator's discretion based on the patient's report of hearing loss. Patients will be encouraged to report any hearing loss prior to study drug infusion and during follow-up phone calls. 11. Study medication will be administered in the clinic after all assessments have been performed, by IV infusion over 4 hours every 4 weeks until Week 24. If agreed upon between the investigator, sponsor, and patient / caregiver, study medication may be administered at home by appropriately trained personnel. The minimum interval between infusions is 25 days, and the maximum interval is 42 days; any exceptions to this guideline should be reviewed by the medical monitor.

[0184] At the baseline visit (V2), patients who meet all eligibility criteria will be randomly assigned in a 1:1:1:1 ratio to receive one of three study treatments: I. 500 mg / kg Trappsol® Cyclo™ II. 1000 mg / kg Trappsol® Cyclo™ III. 2000 mg / kg Trappsol® Cyclo™ IV. Placebo

[0185] Study medication will be administered by intravenous infusion over 4 hours every 4 weeks until week 24. Each patient will receive up to 7 doses of study medication.

[0186] Patients and their caregivers visit the clinic every 4 weeks (V2 through V8). Caregivers are not required to be present for the entire visit. Safety will be assessed throughout the study with repeated physical examinations, vital signs, laboratory tests, 12-lead ECG, C-SSRS, and recording of concomitant medications and adverse events (AEs). Potential efficacy of the study drug will be assessed throughout the study with collection of the Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog-14), CDR-SB, and MMSE-2:SV. Specific assessments at each visit are itemized in the SoA (Table 2).

[0187] Safety assessments will be obtained at a follow-up visit (V9) 2 weeks after the last dose of study medication. Specific assessments at each visit are itemized in the SoA (Table 2).

[0188] MRI evaluations are planned over the 6 months of treatment for both amyloid-related imaging abnormalities - edema (ARIA-E) and amyloid-related imaging abnormalities - hemorrhage (ARIA-H). Scans are scheduled at screening (V1) and 8 weeks (V4), 16 weeks (V6), and 6 months (V8) after each patient begins double-blind study medication. On-site readings for these radiological evaluations are always performed as part of safety evaluations; central readings may also be performed. A Data and Safety Monitoring Board (DSMB) will monitor the results of these evaluations in a fully blinded manner to determine whether amyloid-related imaging abnormalities (ARIA) are detected in patients randomized to active treatment.

[0189] The safety of study participants will be assessed throughout the study by repeated physical examinations, vital signs, safety laboratory tests, 12-lead ECGs, the occurrence of ARIA, and evaluation of treatment-emergent adverse events (TEAEs). Periodic safety reviews will be conducted during the study. The frequency of these assessments, based on the percentage of patients and time on study, will be defined in a DSMB declaration prepared prior to study initiation.

[0190] PK sampling will be completed in all patients at baseline (Week 0, V2), Week 4 (V3), and Week 8 (V4) prior to the start of study drug infusion, 1 and 3 hours after the start of the infusion, at the completion of the infusion, 50-60 minutes after the infusion, and 2 hours after the infusion. Sampling for potential analysis of PK trough levels will be completed in all patients prior to the start of study drug infusion at Week 12 (V5) and Week 24 (V8). ECG triplicate tracings will be timed with the PK samples at Weeks 0 (baseline), 4, and 8. 3. Duration of treatment

[0191] The study will consist of three periods: a screening period of up to 42 days, a treatment period of up to 24 weeks, and a 2-week safety follow-up period. The total duration of patient participation in the study will be up to 32 weeks. 4. Planned sample size and treatment groups

[0192] The planned sample size is approximately 120 randomized patients. The study will include three groups: 500 mg / kg Trappsol® Cyclo™, 1000 mg / kg, or 2000 mg / kg Trappsol® Cyclo™, or placebo in a 1:1:1:1 ratio (30 patients / group). All patients will receive study drug or placebo intravenously. 5. Target population

[0193] Patients with EAD. 6. Study population

[0194] The study will enroll approximately 120 generally healthy male and female patients aged ≥50 and ≤80 years who have experienced progressive cognitive decline in the previous year, meet all of the criteria listed below, and have EAD (patients with MCI due to AD and mild AD) according to the NIA-AA criteria [Cummings J. The National Institute on Aging-Alzheimer's Association Framework on Alzheimer's disease: application to clinical trials. Alzheimers Dement. 2019;15(1):172-178. Kantner I, Erben RG. Long-term parenteral administration of 2-hydroxypropyl β-cyclodextrin causes bone loss. Toxicol Pathol. 2012;40(5):742-50.]. Randomization will be constrained at the study level rather than the site level, but sites will aim to enroll approximately equal percentages of patients with MCI due to AD and mild AD, with neither group exceeding 60%. 7. Eligibility Criteria

[0195] Patients are eligible to participate in this study if they meet the inclusion criteria and do not meet any of the exclusion criteria listed below. I. Inclusion Criteria: Patients are eligible to participate in this study if they meet all of the following criteria: 1. Male or female aged ≥ 50 to ≤ 80 years at the time of consent. a. Have at least an 8th grade education. b. The primary language of US-based patients must be English, and patients should be able to understand and read English at a level that will ensure satisfactory completion of study procedures, including all cognitive testing. 2. MCI due to AD (stage 3) according to FDA Guidance for Industry on Early Alzheimer's Disease: Developing Drugs for Treatment: [Vellas B, Bateman R, Blennow K, et al. Endpoints for pre-dementia AD trials: a report from the EU / US / CTAD Task Force. J Prev Alzheimers Dis. 2015;2(2):128-135.] Meets NIA-AA criteria for mild cognitive impairment (MCI) due to Alzheimer's disease. [Cummings J. The National Institute on Aging-Alzheimer's Association Framework on Alzheimer's disease: application to clinical trials. Alzheimers Dement. 2019;15(1):172-178., Kantner I, Erben RG. Long-term parenteral administration of 2-hydroxypropyl β-cyclodextrin causes bone loss. Toxicol Pathol. 2012;40(5):742-50.] b. Have a Global Clinical Dementia Rating (CDR) scale score of 0.5 and a CDR memory box score of 0.5 or greater at both screening (V1) and baseline (V2). c. History of memory complaints / decline reported by patient or partner / caregiver with gradual onset and slow progression over the past year prior to screening (V1). d. Relatively preserved functional abilities and activities of daily living in the opinion of the investigator based on patient and caregiver recollections. or Mild AD dementia (stage 4) according to FDA Guidance for Industry on Early Alzheimer's Disease: Developing Drugs for Treatment: [Vellas B, Bateman R, Blennow K, et al. Endpoints for pre-dementia AD trials: a report from the EU / US / CTAD Task Force. J Prev Alzheimers Dis. 2015;2(2):128-135.] e. Meets NIA-AA criteria for mild AD dementia. [Cummings J. The National Institute on Aging-Alzheimer's Association Framework on Alzheimer's disease: application to clinical trials. Alzheimers Dement. 2019;15(1):172-178., Kantner I, Erben RG. Long-term parenteral administration of 2-hydroxypropyl β-cyclodextrin causes bone loss. Toxicol Pathol. 2012;40(5):742-50.] f. Have a global CDR score of 0.5-1.0 and a CDR memory box score of 0.5 or greater at both screening (V1) and baseline (V2). 3. All patients should have an MMSE-2:SV score of ≥ 20 and ≤ 28 at both screening (V1) and baseline (V2), with no change of more than 3 points between visits. 4. Positive PrecivityAD blood test biomarkers for AD, or CSF biomarkers supporting a diagnosis of AD, accompanied by a high APS (58-100) during the screening period. a. Only after demonstrating a positive Precivity AD biomarker or brain AD pathology must evidence of brain Aβ pathology be demonstrated based on CSF analysis assessing Aβ42 / 40 and tau levels that meet the following criteria: CSF Aβ42 / 40 ratio <0.72 for patients with MCI and CSF Aβ42 / 40 ratio <0.72 and CSF P-tau >50 pg / mL for patients with EAD. Laboratory results to determine brain Aβ pathology must be known prior to enrollment at baseline (V2). 5. Brain MRI performed during the screening period or within the past 12 months that is generally supportive of AD on-site reading. 6. Local or centrally read MRI of ARIA suggestive of less than four microbleeds. 7. Have a primary caregiver who has sufficient contact with the patient, can provide assessments of cognitive and functional changes, and is willing to assume primary responsibility for managing the patient throughout the study and assessing the patient's status according to protocol requirements. The primary caregiver must meet the following criteria: Able and willing to provide information necessary for effectiveness evaluations such as the CDR-SB. b. Willingness to sign the caregiver informed consent. 8. Unlikely to experience a change in living conditions (e.g., institutionalization, moving to another town, etc.) or a change in primary caregiver during study participation. 9. Background symptomatic treatment of AD with cognitive enhancing medications or acetylcholinesterase inhibitors and / or memantine is permitted as long as the dose has been stable for at least 60 days prior to Screening (V1) and is expected to remain stable for the duration of the study. Note: Treatment-naive patients may participate in the study but should not begin AD treatment for the duration of the study. 10. Background medications used for other stable chronic illnesses that are not explicitly prohibited are also permitted, provided they remain stable for the duration of the study: a. Psychotropic medications, such as antidepressants and antipsychotics, must be at a stable dose for at least 30 days prior to screening (V1) and must remain stable throughout the duration of the study within the framework and regimen in Section 6.7. b. Short-acting benzodiazepines for sleep may be used up to three times per week, but not within 24 hours of a cognitive assessment. 11. All patients must pass a short hearing test, including pure-tone audiometry. 12. Body mass index between 17 and ≤35 kg / m2 at screening (V1), with an upper weight limit of 110 kg. 13. Women participating in the study must meet one of the following criteria: a. Have been surgically sterilized (e.g., hysterectomy, bilateral oophorectomy, or tubal ligation) for at least 6 months or are postmenopausal (postmenopausal women must not have had menstrual bleeding for at least 1 year) or If not postmenopausal, agree to use a highly effective method of birth control, including combined (estrogen- and progestogen-containing) hormonal contraceptives (oral, intravaginal, or transdermal) associated with the inhibition of ovulation; progestogen-only hormonal contraceptives (oral, injectable, or implantable) associated with the inhibition of ovulation; intrauterine device; intrauterine hormone-releasing system; or a vasectomized partner and have a negative urine pregnancy test at screening. Highly effective contraception must be used throughout the study and until 3 months after the last dose of study treatment. 14. All sexually active male patients with WOCBP partners (postmenarcheal) must use condoms with or without spermicide in addition to the birth control used by their partners during the study and until 3 months after the last dose of study treatment. 15. Age-appropriate estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease Study. II. Exclusion Criteria: Patients are not eligible to participate in this study if they meet any of the following exclusion criteria: 1. Clinically significant renal disease that, in the opinion of the investigator, prevents the patient from participating in the study. 2. Evidence of neurodegenerative disease other than AD or any medical history or brain imaging abnormality that, in the opinion of the investigator, may cause dementia, including but not limited to vascular dementia, chronic traumatic encephalopathy, or uncontrolled major depressive disorder (MDD). 3. Severe hypothyroidism, defined as hypothyroidism refractory to standard treatment, with no or inadequate response to clinically relevant doses of levothyroxine as determined by thyroid-stimulating hormones T3 and T4, and presenting clinical signs and symptoms. 4. Abnormally low levels of serum vitamin B12 (below the lower limit of normal laboratory level). 5. Imaging should generally support the diagnosis of EAD and, importantly, should not be consistent with other neurodegenerative disorders or the differential diagnosis of dementia. For example, any suggestion of vascular disease, including multiple infarcts involving large vessels or focal single infarcts (angular gyrus, thalamus, anterior cerebral artery, and posterior cerebral artery territories), multiple lacunae in the basal ganglia or white matter, or widespread lesions or combinations of lesions in the periventricular white matter, is considered exclusionary. Furthermore, any single lacunae in areas known to affect cognition, such as the hippocampus, is exclusionary. For prior MRI scans used for enrollment, a rescan is required if there is evidence of new neurological symptoms between that scan and screening (V1). b. Absence of vascular dementia as defined by HIS≦4 is an exclusion. 6. Inability to see, hear, and / or speak sufficiently to perform a cognitive assessment. 7. History of any medical illness, such as cancer, requiring systemic treatment within the past 5 years, except for localized basal cell carcinoma of the skin and cervical intraepithelial carcinoma successfully treated with surgical excision; history of severe heart failure (grade 2 or higher on the New York Heart Association scale), serious stroke, uncontrolled seizure disorder, or any other medical illness that, in the investigator's opinion, increases the patient's risk for study participation or confounds the study assessments. 8. Patients with the following measurements identified during screening: a. Platelet count <50,000 / μL. b. International normalized ratio >1.5. c. Patients with bleeding tendency (activated partial thromboplastin time >1.5 times the upper limit of normal). 9. Positive blood screen for human immunodeficiency virus (HIV-1 and HIV-2), hepatitis B surface antigen, or hepatitis C virus antibody at screening (V1), unless receiving successful curative treatment for hepatitis C (e.g., Harvoni) with documented proof of undetectable hepatitis B / C virus 3 months after completion of treatment. 10. Any planned surgery requiring general anesthesia performed during the study. Regional anesthesia during outpatient surgery is permitted if, in the opinion of the investigator, this procedure does not interfere with study procedures and patient safety. 11. History or current evidence of serious mental illness such as schizophrenia, bipolar disorder, or MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); or MDD will be excluded if GDS-SF score >8 at screening (V1). 12. History of violent or aggressive behavior requiring medication to control. 13. History of suicidal ideation, intention, or behavior captured during screening by C-SSRS or suicide attempt in the 2 years prior to screening (V1). Note: Patients should not have had active suicidal ideation (C-SSRS type 4 or 5) in the 6 months prior to screening (V1) or at baseline (V2), nor should they have a history of suicide attempts in the past 2 years, nor should they be at significant suicide risk in the investigator's clinical judgment. 14. History of alcohol or drug abuse or dependence within 12 months of screening as defined by DSM-5. Note: Patients will be excluded if they have a positive urine screen at screening (V1) for drugs of abuse, including methadone, cocaine, and amphetamines, or a positive urine screen for non-prescription opiates, barbiturates, or benzodiazepines. 15. Previous or ongoing treatment with Aduhelm, donanemab, or investigational AD vaccine therapy for amyloid or tau; or participation in a clinical study involving a monoclonal antibody, or derivative, or immunoglobulin within 12 months prior to Screening (V1), unless patient can document that they were randomized to placebo. 16. Has been treated with any known drug within 30 days prior to the first dose of study medication that is a moderate or strong inhibitor / inducer of cytochrome P450 enzymes (e.g., barbiturates, phenothiazines, cimetidine, carbamazepine) that, in the investigator's judgment, may affect patient safety or the validity of the study results. 17. Have any of the following otologic-related exclusion criteria: a. Current use of or within 60 days prior to study enrollment of ototoxic medications, including but not limited to aminoglycoside antibiotics (gentamicin, tobramycin, amikacin, streptomycin); platinum-containing chemotherapy (cisplatin, carboplatin, oxaliplatin); or loop diuretics (furosemide). b. History of idiopathic sensorineural hearing loss, otosclerosis, or vestibular schwannoma. c. History of middle or inner ear surgery or middle ear effusion. i. History of recurrent otitis media which, in the opinion of the investigator, may affect the patient's eligibility. d. Current conductive or sensorineural hearing loss, unilateral or bilateral (Grade 3 hearing loss, defined as hearing loss of >25 dB at three consecutive frequencies between 1 kHz and 8 kHz, is observed). 18. Risk of QTc prolongation such as history of TdP or additional risk factors for sudden death (e.g., heart failure, hypokalemia, family history of long QT syndrome, unexplained fainting, concomitant medications including antidepressants known to prolong QT / QTc). 8. Study Drugs

[0196] Trappsol® Cyclo™ (available from Cyclo Therapeutics, Inc.) and placebo (0.45% sodium chloride [½ normal saline] for intravenous infusion as control). 9. Safety Endpoints

[0197] Incidence and severity of TEAEs.

[0198] Adverse events of special interest (AESI): (1) MRI evaluation of amyloid-related imaging abnormality-hemorrhage (ARIA-H) or amyloid-related imaging abnormality-edema (ARIA-E), (2) hearing loss based on audiology, and (3) infusion reaction.

[0199] Vital signs and / or physical examination.

[0200] Safety laboratory values ​​(hematology, clinical chemistry, and urinalysis) including C-terminal telopeptide.

[0201] Triplicate 12-lead electrocardiograms (ECGs) to support cardiac dynamic assessment, including concentration-QTc analysis. Triplicate ECGs will be time-matched with PK samples at weeks 0 (baseline), 4, and 8.

[0202] Columbia-Suicide Severity Rating Scale (C-SSRS). 10. Secondary endpoints

[0203] Mean change in total ADAS-Cog-14 score from baseline (V2) to week 12 (V5) and week 24 (V8).

[0204] Change in CDR-SB from baseline (V2) to week 12 (V5) and week 24 (V8).

[0205] Change in MMSE-2:SV total score from baseline (V2) to week 12 (V5) and week 24 (V8).

[0206] Change in ADCS-CGIC from baseline (V2) to week 12 (V5) and week 24 (V8).

[0207] Change in ADCS-ADL from baseline (V2) to week 12 (V5) and week 24 (V8). 11. Exploratory Endpoints

[0208] Change in composite Z-score from baseline (V2) to weeks 12 (V5) and 24 (V8) for various outcome measures and cognitive domains: (1) ADAS-Cog-14, (2) CDR-SB, and (3) MMSE-2:SV.

[0209] Pharmacodynamic blood / plasma assessment of Aβ, Aβ42, tau, total tau, phosphorylated tau, 24S-hydroxycholesterol, neuronal extracellular vesicle biomarkers, neurogranin, NfL, and other disease-related biomarkers. 12. Pharmacokinetic endpoints

[0210] PK parameters will be calculated, including but not limited to Cmax, Tmax, half-life, AUClast, AUCinf, T1 / 2, Clast, and Tlast (see Table 10.1 in the main protocol). Plasma levels will be measured at baseline (Week 0 (V2), Week 4 (V3), Week 8 (V4) prior to the start of the study drug infusion, 1 and 3 hours after the infusion begins, at the completion of the infusion, 50-60 minutes post-infusion, and 2 hours post-infusion. Plasma samples will be collected for potential analysis of PK trough levels measured prior to the start of the study drug infusion at Week 12 (V5) and Week 24 (V8). 13. Statistical Procedures

[0211] Descriptive statistics for ordinal (eg, Likert scale) and continuous variables include the number of patients with non-missing values, mean, median, standard deviation, minimum, and maximum.

[0212] Safety analyses will be based on the safety analysis set, defined as all randomly assigned patients receiving at least one dose of study drug. Efficacy analyses will use the full analysis set based on the intention-to-treat principle.

[0213] For each efficacy endpoint, the change from baseline to each applicable post-baseline visit will be assessed for treatment group differences using a repeated measures mixed model with factors for study site, treatment, week, and treatment-by-week interaction, and baseline response variable value as a covariate.

[0214] As a sensitivity analysis, analysis of covariance with fixed factors of study site and treatment and baseline value as a covariate will be used.

[0215] Additionally, subgroup analyses may be performed, including, but not limited to, the presence or absence of ongoing approved AD treatments (e.g., acetylcholinesterase inhibitors or memantine or both) and ApoE4 status (i.e., ApoE4 positive or negative) or other classifications of patients.

[0216] AEs are classified by system organ class and preferred term using the Medical Dictionary for Regulatory Activities. TEAE summary tables include the number and percentage of patients experiencing TEAEs by system organ class and preferred term.

[0217] The mean changes from baseline to each post-baseline visit in safety laboratory parameters (haematology, clinical chemistry, and urinalysis), including C-terminal telopeptide and vital signs, will be summarized narratively. Safety laboratory findings considered clinically important by the investigator will be identified.

[0218] The planned statistical analysis methods will be described in more detail in the statistical analysis plan that will be established prior to database lock. Incorporation by Reference

[0219] The entire disclosure of each of the patent documents and scientific articles referenced herein is incorporated by reference for all purposes. equivalent

[0220] The present disclosure may be embodied in other specific forms without departing from its essential characteristics. Accordingly, the foregoing embodiments should be considered illustrative rather than limiting on the disclosure described herein. The scope of the present disclosure is indicated by the appended claims, rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A method for treating early stage Alzheimer's disease in a human patient in need thereof, comprising administering to said human patient an effective amount of a hydroxypropyl β-cyclodextrin composition.

2. The method of claim 1, wherein the early stage Alzheimer's disease is Alzheimer's disease with mild cognitive impairment or mild Alzheimer's disease.

3. 3. The method of claim 1 or 2, wherein the human patient exhibits progressive cognitive decline upon initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition.

4. 4. The method of any one of claims 1 to 3, wherein the human patient has been exhibiting progressive cognitive decline for at least about one year at the start of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition.

5. 5. The method of any one of claims 1 to 4, wherein, upon initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a Global Clinical Dementia Rating (CDR) scale score of about 0.5 and a CDR memory box score of about 0.5 or greater.

6. 5. The method of any one of claims 1 to 4, wherein, upon initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a Global Clinical Dementia Rating (CDR) scale score of between about 0.5 and about 1.0 and a CDR memory box score of about 0.5 or greater.

7. 7. The method of any one of claims 1 to 6, wherein the human patient exhibits cerebral amyloid-beta (Aβ) pathology upon initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition.

8. 8. The method of any one of claims 1 to 7, wherein the human patient has a Mini-Mental State Examination-2: Standard Version (MMSE-2:SV) score of between about 20 and about 28 upon initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition.

9. 9. The method of any one of claims 1 to 8, wherein the human patient has previously been administered a cognitive enhancing drug and / or a symptomatic treatment for early Alzheimer's disease.

10. 10. The method of any one of claims 1 to 9, wherein the human patient has previously been administered an acetylcholinesterase inhibitor and / or memantine.

11. 11. The method of any one of claims 1 to 10, wherein the human patient is at least 50 years old.

12. 12. The method of any one of claims 1 to 11, wherein the human patient is at least 60 years old.

13. 13. The method of any one of claims 1 to 12, wherein the human patient is at least 70 years old.

14. 14. The method of any one of claims 1 to 13, wherein the human patient is at least 80 years old.

15. 15. The method of any one of claims 1 to 14, wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition to the human patient.

16. 16. The method of any one of claims 1 to 15, wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering from about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl β-cyclodextrin composition to the human patient.

17. 16. The method of any one of claims 1 to 15, wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition to the human patient by intravenous infusion.

18. 18. The method of any one of claims 1 to 17, wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering from about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl β-cyclodextrin composition to the human patient by intravenous infusion.

19. 18. The method of any one of claims 1 to 15 and 17, wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition to the human patient by intravenous infusion every 28 days.

20. 20. The method of any one of claims 1 to 19, wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering from about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl β-cyclodextrin composition to the human patient by intravenous infusion every 28 days.

21. 20. The method of any one of claims 1 to 15, 17, and 19, wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition to the human patient by intravenous infusion every 28 days for a period of at least about 24 weeks.

22. 22. The method of any one of claims 1 to 21, wherein administering an effective amount of the hydroxypropyl β-cyclodextrin composition comprises administering from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition to the human patient by intravenous infusion every 28 days for a period of at least about 24 weeks.

23. 23. The method of any one of claims 17 to 22, wherein the hydroxypropyl β-cyclodextrin composition is administered to the human patient by intravenous infusion over a period of at least about 4 hours.

24. 23. The method of any one of claims 17 to 22, wherein the hydroxypropyl β-cyclodextrin composition is administered to the human patient by intravenous infusion over a period of at least about 6.5 hours.

25. 25. The method of any one of claims 1 to 24, wherein the hydroxypropyl β-cyclodextrin composition comprises about 25% (w / v) hydroxypropyl β-cyclodextrin.

26. 26. The method of any one of claims 1 to 25, wherein the hydroxypropyl β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl β-cyclodextrin species.

27. 27. The method of claim 26, wherein each of the two or more hydroxypropyl β-cyclodextrin species has a different degree of hydroxypropylation of the β-cyclodextrin ring.

28. 27. The method of claim 26, wherein the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.59 to about 1.

14.

29. 27. The method of claim 26, wherein the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.59 to about 0.

8.

30. 27. The method of claim 26, wherein the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.8 to about 1.

0.

31. 31. The method of any one of claims 1 to 30, wherein the hydroxypropyl β-cyclodextrin composition comprises about 0.2% w / w or less of unsubstituted β-cyclodextrin.

32. 31. The method of any one of claims 1 to 30, wherein the hydroxypropyl β-cyclodextrin composition comprises about 0.16% w / w or less of unsubstituted β-cyclodextrin.

33. 33. The method of any one of claims 1 to 32, wherein the hydroxypropyl β-cyclodextrin composition comprises about 2.5% (w / w) or less propylene glycol.

34. 34. The method of any one of claims 1 to 33, further comprising administering a second therapeutic agent selected from the group consisting of donepezil, rivastigmine, galantamine, memantine, verubecestat, solanezumab, bapineuzumab, aducanumab, tideglusib, epothilone D, and ABBV-8E12.

35. 34. The method of any one of claims 1 to 33, further comprising administering a second therapeutic agent selected from the group consisting of a cholinesterase inhibitor, an NMDA receptor antagonist, a humanized antibody targeting tau protein, a humanized antibody targeting amyloid beta protein, and a BACE inhibitor.

36. 34. The method of any one of claims 1 to 33, further comprising administering a second therapeutic agent, wherein the second therapeutic agent is selected from any of the therapeutic agents shown in Table 1.

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