Methods for treating early alzheimer's disease

Abstract

Provided herein are methods of treating early Alzheimer's disease using hydroxypropyl beta-cyclodextrin compositions.

Description

[0001] Cross-reference

[0002] This application claims priority and benefit of U.S. Provisional Patent Application No. 63 / 411,935, filed on September 30, 2022, the content of which is incorporated herein by reference in its entirety. Background Art

[0003] Currently, approximately 5.4 million Americans have Alzheimer's disease, including early Alzheimer's disease, and this number is expected to rise to 13.8 million by 2050. In 2016, an estimated 700,000 Americans aged ≥65 years died from Alzheimer's disease. Although the number of deaths from stroke, heart disease, and prostate cancer in the United States (US) has decreased from 2000 to 2014, the number of deaths related to Alzheimer's disease has increased by 89% during the same period. The total expenditure on healthcare, long-term care, and hospice services for people aged ≥65 years with dementia in 2016 was estimated to be $236 billion. [Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016;12:459-509.]

[0004] Recently, with a better understanding of the disease pathogenesis, drug development has shifted its focus to limiting, preventing, and reducing the accumulation of β-amyloid (Aβ) and tau. Many therapeutic strategies have been proposed for amyloid-based therapies to increase Aβ clearance or reduce Aβ aggregation, as well as Aβ-targeted immunotherapies. So far, despite multiple attempts, most of these drugs have failed in late-stage clinical trials, many of which recruited patients in the late stage of dementia.

[0005] Questions remain regarding the risk / benefit profile of anti-amyloid antibody therapies due to their association with potentially dangerous but controllable adverse reactions (such as brain edema and microbleeds). Similar to Aβ therapies, so far, tau-based therapies have generated early hope but are currently in the early research stage and will not produce efficacy data for several years.

[0006] Cholesterol imbalances in Alzheimer's disease patients are well-known, and there is a large body of research indicating that these imbalances lead to the accumulation of Aβ and tau. An increase in blood cholesterol is also associated with an increased risk of dementia, as the plasma concentration of cholesterol is significantly higher in Alzheimer's disease patients and patients with non-Alzheimer's disease-related dementia.

[0007] The generation and clearance of Aβ are both regulated by cholesterol. Tau toxicity also depends on cellular cholesterol levels. A high-cholesterol diet increases tau hyperphosphorylation. As cholesterol concentration increases, the sensitivity of neurons 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 and generates toxic fragments. These cleaved tau forms induce neuronal death, synaptic loss, and / or behavioral deficits. Young neurons have significantly less cholesterol than aged neurons and also contain less phosphorylated tau. However, when these same young neurons are loaded with cholesterol, an increase in phosphorylated tau as well as death susceptibility is observed.

[0008] There are currently no approved therapies for treating early Alzheimer's disease by modulating cholesterol levels. Thus, the development of new therapies for treating early Alzheimer's disease remains an unmet need. Summary of the Invention

[0010] In one aspect, the present disclosure provides a method for treating early Alzheimer's disease in a human patient in need thereof, the method comprising administering to the human patient an effective amount of a hydroxypropyl β-cyclodextrin composition.

[0011] In certain embodiments, the early Alzheimer's disease is Alzheimer's disease with mild cognitive impairment or mild Alzheimer's disease.

[0012] In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient exhibits progressive cognitive decline. In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has exhibited progressive cognitive decline for at least about 1 year. In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has a global Clinical Dementia Rating (CDR) scale score of about 0.5 and a CDR memory item score of about 0.5 or higher. In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has an overall Clinical Dementia Rating (CDR) scale score between about 0.5 and about 1.0 and a CDR memory item score of about 0.5 or higher. In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient exhibits cerebral β-amyloid (Aβ) pathology. In certain embodiments, upon initiation of administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has a Mini-Mental State Examination-2: Standard Version (MMSE-2:SV) score of about 20 to about 28.

[0013] In certain embodiments, the human patient has previously been administered a cognitive enhancing drug and / or symptomatic therapy for early Alzheimer's disease. In certain embodiments, the human patient has previously been administered an acetylcholinesterase inhibitor and / or memantine.

[0014] 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.

[0015] In certain embodiments, administration of an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to the human patient from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition. In certain embodiments, administration of an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to the human patient from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition by intravenous infusion. In certain embodiments, administration of an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to the human patient from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition by intravenous infusion once every 28 days. In certain embodiments, administration of an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to the human patient by intravenous infusion from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition once every 28 days for at least about 24 weeks.

[0016] In certain embodiments, administering an effective amount of a hydroxypropyl-β-cyclodextrin composition comprises administering to a human patient from about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl-β-cyclodextrin composition. In certain embodiments, administering an effective amount of a hydroxypropyl-β-cyclodextrin composition comprises administering to a human patient from about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl-β-cyclodextrin composition by intravenous infusion. In certain embodiments, administering an effective amount of a hydroxypropyl-β-cyclodextrin composition comprises administering to a human patient from about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl-β-cyclodextrin composition by intravenous infusion once every 28 days. In certain embodiments, administering an effective amount of a hydroxypropyl-β-cyclodextrin composition comprises administering to a human patient from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl-β-cyclodextrin composition by intravenous infusion once every 28 days for at least about 24 weeks.

[0017] In certain embodiments, the hydroxypropyl-β-cyclodextrin composition is administered to a human patient by intravenous infusion for a time period of at least about 4 hours. In certain embodiments, the hydroxypropyl-β-cyclodextrin composition is administered to a human patient by intravenous infusion for a time period of at least about 6.5 hours.

[0018] In certain embodiments, the hydroxypropyl-β-cyclodextrin composition comprises about 25% (w / v) hydroxypropyl-β-cyclodextrin.

[0019] 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 value of from about 0.59 to about 1.14. In certain embodiments, the mixture of two or more hydroxypropyl-β-cyclodextrin species has a molar substitution value of from about 0.59 to about 0.8. In certain embodiments, the mixture of two or more hydroxypropyl-β-cyclodextrin species has a molar substitution value of from 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.

[0020] 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.

[0021] In certain embodiments, the method further comprises administering a second therapeutic agent selected from the group consisting of cholinesterase inhibitors, NMDA receptor antagonists, humanized antibodies targeting tau protein, humanized antibodies targeting beta-amyloid, and BACE inhibitors.

[0022] 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 listed in Table 1. Detailed Description of the Invention

[0024] Part of the present disclosure provides a method for treating early Alzheimer's disease in a human patient in need thereof. The method generally comprises administering to the human patient an effective amount of a hydroxypropyl beta-cyclodextrin composition. The hydroxypropyl beta-cyclodextrin composition described herein can 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., impaired cognitive function) in a human patient.

[0025] Definitions

[0026] To facilitate understanding of the present invention, a number of terms and phrases are defined below.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and chemical formulas described herein are constructed according to the standard rules of chemical valence known in the chemical art.

[0028] Throughout the specification, when a composition and a kit are described as having, including, or containing a particular component, it is also contemplated that the compositions and kits of the present invention consist essentially of, or consist of, the recited components.

[0029] In the present application, when an element or component is described as being included in a list of said elements or components and / or selected from a list of said elements or components, it should be understood that the element or component can be any one of the listed elements or components, or the element or component can be selected from a group consisting of two or more of the listed elements or components.

[0030] In addition, it should be understood that the elements and / or features of the compositions or methods described herein can be combined in various ways without departing from the spirit and scope of the invention, whether or not these combinations are explicitly stated or implicit herein. For example, when a particular compound is mentioned, unless the context otherwise dictates, the compound can be used in various embodiments of the compositions of the invention and / or in the methods of the invention. In other words, in the present application, the description and illustration of embodiments are intended to enable the application to be written and drawn clearly and concisely, but it should be understood and expected that these embodiments can be combined or separated in various ways without departing from this teaching and invention. For example, it should be understood that all of the features described and illustrated herein can be applied to all aspects of the invention described and illustrated herein.

[0031] It should be understood that the order of steps or the order of performing certain actions is not important so long as the invention remains operable. In addition, two or more steps or actions can be performed simultaneously.

[0032] In various different parts of this specification, variables or parameters are disclosed in groups or ranges. Specifically, this specification is intended to include each and every individual sub-combination of the members of these groups and ranges. For example, integers in the range from 0 to 40 are specifically intended to be individually disclosed as 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, and integers in the range from 1 to 20 are specifically intended to be individually disclosed as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20.

[0033] Unless otherwise claimed, the use of any and all examples or exemplary language herein, such as "such as" or "including" is merely intended to better illustrate the invention and does not limit the scope of the invention. No language in the specification should be construed as indicating that any unclaimed element is essential for the practice of the invention.

[0034] In the present disclosure, the articles "a" and "an" are used to refer to one or more (i.e., at least one) of the grammatical objects of the article, unless the context does not apply. For example, "an element" means one element or more than one element.

[0035] In the present disclosure, the term "and / or" is used to mean "and" or "or", unless otherwise specified.

[0036] It should be understood that, unless the context and usage are otherwise understood, the expression "at least one of..." individually includes each of the objects recited after the expression and various combinations of two or more of the objects. Unless the context is otherwise understood, the expression "and / or" related to three or more of the objects should be understood to have the same meaning.

[0037] Unless the context specifically states or is otherwise understood, the use of the terms "include", "have", or "contain" (including their grammatical equivalents) is generally to be understood as open-ended and non-limiting, e.g., not excluding additional unrecited elements or steps.

[0038] As used herein, the term "about" means approximately, within the range of, roughly, or around. When the term "about" is used in combination with a numerical range, it modifies the range by extending the boundaries above and below the recited numerical values. Generally, the term "about" is used herein to modify a variance of the numerical value above and below the recited value by 10%, 5%, 3%, 2%, or 1%.

[0039] "Individual", "patient", and "subject" are used interchangeably and include any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, including humans.

[0040] The term "treat" includes any effect, e.g., alleviating, reducing, modulating, improving, or eliminating, that results in an improvement in a condition, disease, disorder, etc., or a remission of its symptoms. Treatment can be a cure, an improvement, or at least a partial remission of the disease. In certain embodiments, treatment is a cure of the disease.

[0041] "Pharmaceutically acceptable" includes molecular entities and formulations that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human, as the case may be. For human administration, the formulations should meet the sterility, pyrogenicity, and general safety and purity standards required by the Office of Biologics Standards of the FDA.

[0042] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that assist in the administration of the active agent to and its absorption by a subject, and can 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 solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorants, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and pigments, etc. Such formulations can be sterilized and, if desired, can be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts affecting osmotic pressure, buffers, colorants, and / or aromatic substances, etc., which do not react harmfully with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0043] The pharmaceutical formulations of the present disclosure can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals in need of veterinary treatment, e.g., 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 mammals to be treated in the methods of the present disclosure are preferably those in which early Alzheimer's disease needs to be treated.

[0044] As used herein, "pharmaceutical composition" or "pharmaceutical formulation" refers to a combination of an active agent with an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0045] As used herein, "effective amount" or "therapeutically effective amount" can refer to the amount of a compound or composition (e.g., the compounds or compositions of the present invention) sufficient to achieve a beneficial or desired result. The effective amount can be administered, applied, or dosed once or multiple times, and is not intended to be limited to a particular formulation or route of administration.

[0046] As used herein, "administer" can refer to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intraventricular, intranasal or subcutaneous administration, or implantation of a sustained release device, e.g., a micro-osmotic pump, into a subject. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other delivery modes include, but are not limited to, use of liposomal formulations, intravenous infusions, transdermal patches, etc. "Co-administer" means to administer the compositions described herein either simultaneously with, immediately before or immediately after the administration of one or more additional therapies (e.g., an anti-cancer agent, a chemotherapeutic agent or treatment of a neurodegenerative disease). The compounds of the invention can be administered alone or can be co-administered to a patient. Co-administration is meant to include administration of the compounds either alone or in combination (more than one compound or agent) simultaneously or sequentially. Thus, when desired, the formulations can also be combined with other active substances (e.g., to reduce metabolic degradation).

[0047] As used herein, "hydroxypropyl β-cyclodextrin species", "β-cyclodextrin species" or "β-cyclodextrin" can refer to β-cyclodextrin molecules having unique chemical compositions and / or chemical structures. For example, the hydroxypropyl β-cyclodextrin species of the 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 can be referred to by the trade name Cyclo TM . The terms "hydroxypropylβ-cyclodextrin", "hydroxypropyl beta-cyclodextrin", "hydroxypropyl-beta-cyclodextrin", "HPβCD", "2-hydroxypropyl-beta-cyclodextrin", "2-hydroxypropyl beta-cyclodextrin" and "2-hydroxypropylβ-cyclodextrin" are used interchangeably herein. The terms "β-cyclodextrin" and "beta-cyclodextrin" are used interchangeably herein.

[0048] As used herein, "substituted at one or more hydroxy positions with hydroxypropyl" can refer to substitution of the hydrogen of one or more hydroxy groups of a β-cyclodextrin molecule with hydroxypropyl or a hydroxypropyl oligomer. For example, "substituted at one or more hydroxy positions with hydroxypropyl" can refer to insertion of one or more CH 2 CH(CH 3 )O-substituents within one or more O-H bonds on the β-cyclodextrin molecule, resulting in one or more ether bonds.

[0049] As used herein, "cognitive function" of a subject can be defined as intellectual activities or processes. Examples of intellectual activities or processes include, but are not limited to, attention, processing speed, learning and memory, executive function, verbal fluency, and working memory. For example, if the hydroxypropyl-β-cyclodextrin composition of the present invention improves one or more intellectual activities or processes of a subject with early Alzheimer's disease, it can improve cognitive function.

[0050] For patients with early Alzheimer's disease, the Food and Drug Administration (FDA) considers the Clinical Dementia Rating Sum of Boxes (CDR-SB) to be an example of a tool for assessing disease progression. The Clinical Dementia Rating (CDR) is obtained through a semi-structured interview of the patient and an informant, and cognitive function is rated in 6 functional domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of function as follows: 0 (no impairment), 0.5 (questionable impairment), 1 (mild impairment), 2 (moderate impairment), and 3 (severe impairment). Personal care is scored on a 4-point scale with no 0.5 level. The global CDR score is calculated via an algorithm. The CDR-SB score is obtained by summing the box scores for each domain, and the score ranges from 0 to 18. The CDR shows good reliability and has been validated against neuropathological findings.

[0051] As used herein, "beta-amyloid pathology" or "Aβ pathology" may refer to a patient with evidence of beta-amyloid pathology, which is verified by one or more methodologies or tests to predict the likelihood of amyloid plaque burden, or is evaluated by PET imaging, cerebrospinal fluid analysis, and / or MRI quantification. The PrecivityAD blood test (C2N Diagnostics) is a test for detecting AD pathology and uses mass spectrometry to measure proteins in blood (derived from a single blood sample) that indicate the likelihood of amyloid deposition in the brain, as measured by amyloid PET scan. The PrecivityAD test quantifies the plasma concentrations of beta-amyloid 42 and 40 (Aβ42 and Aβ40) and determines the presence of apolipoprotein E protein isoform (equivalent to ApoE genotype)-specific peptides. These parameters are used to calculate the patient's Aβ42 / 40 ratio and determine his / her ApoE genotype. The Aβ42 / 40 ratio and ApoE genotype, along with the patient's age, are incorporated into the statistical algorithm of the test to estimate the APS (e.g., the test result). The APS represents the estimated probability from 0 (low probability) to 100 (high probability) that the patient is currently amyloid-positive on amyloid PET imaging based on his or her 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 will also include the patient's Aβ42 / 40 ratio and ApoE genotype profile. While each of these parameters can predict the amyloid PET scan status individually, their combined use with the patient's age is included in the modeling to derive the APS, which is associated with superior risk prediction. Therefore, the APS is the most important outcome. The APS score typically classifies the patient into one of 3 categories: low, medium, or high, which should be interpreted as follows:

[0052] Low APS (0 - 36): A low score is consistent with a negative amyloid PET scan result and thus a low likelihood of amyloid plaques. The absence of amyloid plaques is inconsistent with the use of an approved neuroimaging agent as a tracer for AD diagnosis and indicates that other causes of cognitive symptoms should be investigated.

[0053] Medium APS (37 - 57): The intermediate score does not distinguish the presence or absence of amyloid plaques and indicates that further diagnostic evaluation may be needed to assess the potential causes of the patient's cognitive symptoms.

[0054] High APS (58 - 100): A high score is consistent with a positive amyloid PET scan result, thus indicating a high likelihood of amyloid plaques. The presence of amyloid plaques is consistent with an AD diagnosis in individuals with cognitive decline, but this alone is not sufficient to make a definitive diagnosis; clinical manifestations and other factors should be considered together with the APS. The combination of a positive PrecivityAD blood test and other eligibility criteria (including cognitive test results and quantification of amyloid burden demonstrated by positron emission tomography amyloid imaging, cerebrospinal fluid analysis) forms the basis of evidence of amyloid burden. An Aβ-PET scan (using an approved neuroimaging agent as a tracer) will produce an image that will be designated as positive or negative based on the comparison of radioactivity in the cortical gray matter with the activity in the adjacent white matter in the region of interest. Amyloid CSF analysis will evaluate the ratio of Aβ42, Aβ40, and Aβ42 / Aβ40. Other biomarkers include, but are not limited to, phosphorylated tau, total tau, and NfL.

[0055] As used herein, the term "Mini-Mental State Examination-2: Standard Version" or "MMSE-2: SV" may refer to a widely used cognitive function test in the elderly. It includes tests of orientation, attention, memory, language, and visuospatial skills, and the results are assigned a numerical score. [Folstein MF, Folstein SE, White T, Messer MA. Mini-Mental State Examination, 2nd Edition TM User's Manual by Marshal F. Available at https: / / www.parinc.com / Products / Pkey / 238. Accessed on October 7, 2021] This test can be used to screen for cognitive impairment, estimate the severity of cognitive impairment at a given time point, track the progression of dementia-related cognitive impairment, and 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 on April 30, 2020.]

[0056] As used herein, the term "molar substitution" or "MS" refers to the number of hydroxypropyl groups per anhydroglucose unit in a β-cyclodextrin mixture and can be determined according to the procedure described in the USP monograph on hydroxypropyl-β-cyclodextrin (USP NF 2015) ("USP Hydroxypropyl-β-Cyclodextrin Monograph"), which is incorporated herein by reference in its entirety. In the present disclosure, the term "average molar substitution" or "MS a " is used synonymously with "MS" as the term is used in the USP Hydroxypropyl-β-Cyclodextrin Monograph, and the term "glucose unit" is used as a synonym for "anhydroglucose unit" as the term is used in the USP Hydroxypropyl-β-Cyclodextrin Monograph.

[0057] Hydroxypropyl β-cyclodextrin

[0058] Cyclodextrins are naturally occurring cyclic oligosaccharides derived from the enzymatic conversion of starch and can also be prepared synthetically. Cyclodextrins are composed of a variable number of glucopyranose units, which can form a hollow conical ring structure consisting of a hydrophobic cavity and a hydrophilic exterior. The hollow conical ring structure can also be referred to as the "β-cyclodextrin ring". The number of glucopyranose units determines the cavity size and nomenclature of the cyclodextrin, and the most common ones are composed of six, seven, or eight glucopyranose units, named α-, β-, and γ-cyclodextrin, respectively. The unique structure of cyclodextrins allows them to form water-soluble complexes with hydrophobic compounds that are otherwise insoluble. This property of cyclodextrins has led to their application as drug delivery carriers to improve the solubility, stability, and bioavailability of many pharmacological active agents. Hydroxypropyl-β-cyclodextrin (HPβCD), as described above, which is also known as and can be referred to herein as 2-hydroxypropyl-β-cyclodextrin, is a highly soluble chemically modified synthetic derivative of β-cyclodextrin. HPβCD is one of the most commonly used and least toxic derivatives of naturally occurring cyclodextrins for drug delivery.

[0059] In one aspect, the present disclosure provides a hydroxypropyl-β-cyclodextrin composition for treating early Alzheimer's disease in a subject in need thereof. In certain embodiments, the subject is a human patient.

[0060] In certain embodiments, the hydroxypropyl-β-cyclodextrin composition described herein can be a mixture of two or more hydroxypropyl-β-cyclodextrin species. In some embodiments, the mixture of hydroxypropyl-β-cyclodextrin species comprises a mixture of β-cyclodextrin molecules substituted with hydroxypropyl groups at one or more hydroxy positions.

[0061] 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 has a different degree of hydroxypropylation of the β-cyclodextrin ring.

[0062] In certain embodiments, the hydroxypropyl β-cyclodextrin species in the mixture comprise glucose units having the following structure:

[0063]

[0064] wherein R 1 , R 2 and R 3 are each independently H or HP at each occurrence, where HP comprises one or more hydroxypropyl groups.

[0065] 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.

[0066] In certain embodiments, the average number of occurrences of HP on each β-cyclodextrin ring is from 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 times. In certain embodiments, the average number of occurrences of HP on each β-cyclodextrin ring is about 3, about 4, about 5, about 6, or about 7 times.

[0067] In certain embodiments, the total number of occurrences of R 3 =HP is greater than the total number of occurrences of R 1 =HP or R 2 =HP. In certain embodiments, the total number of occurrences of R 3 =HP is greater than the total combined number of occurrences of R 1 =HP and R 2 =HP.

[0068] In certain embodiments, R 1 and R 2At 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 total number of occurrences of the combination is HP.

[0069] In some embodiments, R 1 and R 2 No more than about 50%, no more than about 55%, no more than about 60%, no more than about 65%, no more than about 70%, no more than about 75%, no more than about 80%, no more than about 85%, no more than about 90%, or no more than about 95% of the total number of occurrences of the combination is HP.

[0070] In certain embodiments, R 1 and R 2The combinations are in the percentage range of HP 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 90%, from about 30% to about 90%, from about 35% to about 90%, from about 40% to about 90%, from about 45% to about 90%, from about 50% to about 90%, from about 55% to about 90%, from about 60% 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 5% to about 85%, from about 10% to about 85%, from about 15% to about 85%, from about 20% to about 85%, from about 25% to about 85%, from about 30% to about 85%, from about 35% to about 85%, from about 40% to about 85%, from about 45% to about 85%, from about 50% to about 85%, from about 55% to about 85%, 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 5% to about 80%, from about 10% to about 80%, from about 15% to about 80%, from about 20% to about 80%, from about 25% to about 80%, from about 30% to about 80%, from about 35% to about 80%, from about 40% to about 80%, from about 45% to about 80%, from about 50% to about 80%, from about 55% to about 80%, 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 5% to about 75%, from about 10% to about 75%, from about 15% to about 75%, from about 20% to about 75%, from about 25% to about 75%, from about 30% to about 75%, from about 35% to about 75%, from about 40% to about 75%, from about 45% to about 75%, from about 50% to about 75%, from about 55% to about 75%, from about 60% to about 75%, from about 65% to about 75%, from about 70% to about 75%; from about 5% to about 70%, from about 10% to about 70%, from about 15% to about 70%, from about 20% to about 70%, from about 25% to about 70%, from about 30% to about 70%, from about 35% to about 70%, from about 40% to about 70%, from about 45% to about 70%, from about 50% to about 70%, from about 55% to about 70%, from about 60% to about 70%, from about 65% to about 70%;from about 5% to about 65%, from about 10% to about 65%, from about 15% to about 65%, from about 20% to about 65%, from about 25% to about 65%, from about 30% to about 65%, from about 35% to about 65%, from about 40% to about 65%, from about 45% to about 65%, from about 50% to about 65%, from about 55% to about 65%, from about 60% to about 65%; from about 5% to about 60%, from about 10% to about 60%, from about 15% to about 60%, from about 20% to about 60%, from about 25% to about 60%, from about 30% to about 60%, from about 35% to about 60%, from about 40% to about 60%, from about 45% to about 60%, from about 50% to about 60%, from about 55% to about 60%; from about 5% to about 55%, from about 10% to about 55%, from about 15% to about 55%, from about 20% to about 55%, from about 25% to about 55%, from about 30% to about 55%, from about 35% to about 55%, from about 40% to about 55%, from about 45% to about 55%, from about 50% to about 55%; 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%, from about 25% to about 40%, from about 30% to about 40%, from about 35% to about 40%; from about 5% to about 35%, from about 10% to about 35%, from about 15% to about 35%, from about 20% to about 35%, from about 25% to about 35%, from about 30% to about 35%; from about 5% to about 30%, from about 10% to about 30%, from about 15% to about 30%, from about 20% to about 30%, from about 25% to about 30%; from about 5% to about 25%, from about 10% to about 25%, from about 15% to about 25%, from about 20% to about 25%; from about 5% to about 20%, from about 10% to about 20%, from about 15% to about 20%; from about 5% to about 15%, from about 10% to about 15%; or from about 5% to about 10%.;

[0071] 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 occurrences of is HP.

[0072] In certain embodiments, R 3No more than about 55%, no more than about 60%, no more than about 65%, no more than about 70%, no more than about 75%, no more than about 80%, no more than about 85%, no more than about 90%, or no more than about 95% of the occurrences of are HP.

[0073] In certain embodiments, R 3The occurrence is within a percentage range of HP of 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 85%, about 70% to about 85%, about 75% to about 85%, about 80% to about 85%, 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 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 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 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 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 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%, 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%,from about 20% to about 40%, from about 25% to about 40%, from about 30% to about 40%, from about 35% to about 40%, from about 20% to about 35%, from about 25% to about 35%, from about 30% to about 35%, from about 20% to about 30%, from about 25% to about 30%, or from about 20% to about 25%.

[0074] 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 occurrence of HP in each β-cyclodextrin of from about 4 to about 7, from about 4 to about 6, from about 4 to about 5, from about 5 to about 7, from about 5 to about 6, or from about 6 to about.

[0075] In some embodiments, the percentage range of the average occurrence of HP in each β-cyclodextrin of β-cyclodextrin being from about 4 to about 7, from about 4 to about 6, from about 4 to about 5, from about 5 to about 7, from about 5 to about 6, or from about 6 to about 7 is from about 50% to about 99%, 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%, from about 50% to about 97%, from about 55% to about 97%, from about 60% to about 97%, from about 65% to about 97%, from about 70% to about 97%, from about 75% to about 97%, from about 80% to about 97%, from about 85% to about 97%, from about 90% to about 97%, 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 50% to about 90%, from about 55% to about 90%, from about 60% 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 50% to about 85%, from about 55% to about 85%, 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 50% to about 80%, from about 55% to about 80%, 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 50% to about 75%, from about 55% to about 75%, from about 60% to about 75%, from about 65% to about 75%, from about 70% to about 75%, from about 50% to about 70%, from about 55% to about 70%, from about 60% to about 70%, from about 65% to about 70%, from about 50% to about 65%, from about 55% to about 65%, from about 60% to about 65%, from about 50% to about 60%, from about 55% to about 60%, or from about 50% to about 55%.

[0076] As used herein, "degree of substitution" or "DS" may refer to the total number of hydroxypropyl groups directly or indirectly substituted on the β-cyclodextrin molecule. For example, a β-cyclodextrin molecule containing glucose units, where each glucose unit is substituted with one hydroxypropyl group, has a DS = 7. In another example, only one of the seven glucose units in a β-cyclodextrin molecule is substituted with a hydroxypropyl group and that hydroxypropyl group itself is substituted with another hydroxypropyl group (e.g., β-cyclodextrin with a single occurrence of HP containing two hydroxypropyl groups), which has a DS = 2.

[0077] As used herein, "average number of hydroxypropyl groups per β-cyclodextrin", also referred to as "average degree of substitution", "average DS" or "DS a ", may refer to the total number of hydroxypropyl groups in a population of β-cyclodextrin divided by the number of β-cyclodextrin molecules. In an illustrative example, an equimolar mixture of β-cyclodextrin containing glucose units each substituted with one hydroxypropyl group and β-cyclodextrin containing glucose units each substituted with two hydroxypropyl groups has a DS a = 10.5 (average of equimolar β-cyclodextrin with DS = 7 and DS = 14). In another illustrative example, a mixture of 33.3% β-cyclodextrin (where 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. DS a can be determined by multiplying the molar substitution degree by 7. As used herein, DS a is used synonymously with the term "degree of substitution" as defined in the USP hydroxypropyl beta-cyclodextrin monograph.

[0078] In certain embodiments, the hydroxypropyl β-cyclodextrin composition of the present invention comprises a mixture of unsubstituted β-cyclodextrin molecules and β-cyclodextrin species substituted with hydroxypropyl groups at one or more hydroxy positions, wherein the average number of hydroxypropyl groups per β-cyclodextrin molecule in the mixture (DS a ) is from about 3 to about 7, from about 3 to about 6, from about 3 to about 5, from about 3 to about 4, from about 4 to about 7, from about 4 to about 6, from about 4 to about 5, from about 5 to about 7, from about 5 to about 6 or from about 6 to about 7.

[0079] The distribution of the degree of substitution within the hydroxypropyl β-cyclodextrin composition of the present invention (comprising a mixture of unsubstituted β-cyclodextrin molecules and β-cyclodextrin species substituted with hydroxypropyl groups at one or more hydroxy positions) varies. For example, an equimolar mixture of β-cyclodextrin containing glucose units each substituted with one hydroxypropyl group and β-cyclodextrin containing glucose units each substituted with two hydroxypropyl groups has a DS a= 10.5 (average of equimolar β-cyclodextrins with DS = 7 and DS = 14). Although DS a = 10.5, in this example, there is no β-cyclodextrin with DS = 10 or DS = 11 in the mixture. In other cases, most of the β-cyclodextrin species within the β-cyclodextrin mixture have a DS close to DS a .

[0080] 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-cyclodextrins in the mixture have a DS within DS a ± Xσ, where σ is the standard deviation and X is 1, 2 or 3.

[0081] In certain embodiments, at least about 50% of the β-cyclodextrins in the mixture have a DS within DS a ± 1σ. 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-cyclodextrins in the mixture have a DS within DS a ± 1σ.

[0082] In certain embodiments, at least about 50% of the β-cyclodextrins in the mixture have a DS within DS a ± 2σ. 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-cyclodextrins in the mixture have a DS within DS a ± 2σ.

[0083] In certain embodiments, at least about 50% of the β-cyclodextrins in the mixture have a DS within DS a ± 3σ. 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-cyclodextrins in the mixture have a DS within DS a ± 3σ.

[0084] In certain embodiments, at least about 50% of the β-cyclodextrins have a DS within DS a ± 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 β-cyclodextrins have a DS within DS a ± 1.

[0085] In certain embodiments, at least about 50% of the β-cyclodextrins have a DS within DSa within ±0.8. In some embodiments, the DS of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 97% of β-cyclodextrin is within DS a within ±0.8.

[0086] In certain embodiments, the DS of at least about 50% of β-cyclodextrin is within DS a within ±0.6. In some embodiments, the DS of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 97% of β-cyclodextrin is within DS a within ±0.6.

[0087] In certain embodiments, the DS of at least about 50% of β-cyclodextrin is within DS a within ±0.5. In some embodiments, the DS of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 97% of β-cyclodextrin is within DS a within ±0.5.

[0088] In certain embodiments, the DS of at least about 50% of β-cyclodextrin is within DS a within ±0.4. In some embodiments, the DS of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 97% of β-cyclodextrin is within DS a within ±0.4.

[0089] In certain embodiments, the DS of at least about 50% of β-cyclodextrin is within DS a within ±0.3. In some embodiments, the DS of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 97% of β-cyclodextrin is within DS a within ±0.3.

[0090] In certain embodiments, the DS of at least about 50% of β-cyclodextrin is within DS a within ±0.2. In some embodiments, the DS of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 97% of β-cyclodextrin is within DS a within ±0.2.

[0091] In certain embodiments, the DS of at least about 50% of β-cyclodextrin is within DS aWithin ±0.1. In some embodiments, the DS of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 97% of β-cyclodextrin is within DS a Within ±0.1.

[0092] The number of hydroxypropyl groups per anhydroglucose unit in a β-cyclodextrin mixture is referred to as the “molar degree of substitution” or “MS” and can be determined according to the procedure set forth in the USP Hydroxypropyl Betadex Monograph (USP NF 2015) (“USP Hydroxypropyl Betadex Monograph”), which is incorporated herein by reference in its entirety. In the present disclosure, the term “average molar substitution” or “MS a ” is used synonymously with “MS” as the term is used in the USP Hydroxypropyl Betadex Monograph, and the term “glucose unit” is used as a synonym for “anhydroglucose unit” as the term is used in the USP Hydroxypropyl Betadex Monograph.

[0093] 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 0.73, from about 0.53 to about 0.71, from about 0.53 to about 0.69, from about 0.53 to about 0.67, from about 0.53 to about 0.65, from about 0.53 to about 0.63, from about 0.53 to about 0.61, from about 0.53 to about 0.59, from about 0.53 to about 0.57, from about 0.53 to about 0.55, from 0.55 to about 0.8, from 0.55 to about 0.77, from 0.55 to about 0.75, from about 0.55 to about 0.73, from about 0.55 to about 0.71, from about 0.55 to about 0.69, from about 0.55 to about 0.67, from about 0.55 to about 0.65, from about 0.55 to about 0.63, from about 0.55 to about 0.61, from about 0.55 to about 0.59, from about 0.55 to about 0.57, from 0.57 to about 0.8, from 0.57 to about 0.77, from 0.57 to about 0.75, from about 0.57 to about 0.73, from about 0.57 to about 0.71, from about 0.57 to about 0.69, from about 0.57 to about 0.67, from about 0.57 to about 0.65, from about 0.57 to about 0.63, from about 0.57 to about 0.61, from about 0.57 to about 0.59, from 0.59 to about 0.8, from 0.59 to about 0.77, from 0.59 to about 0.75, from about 0.59 to about 0.73, from about 0.59 to about 0.71, from about 0.59 to about 0.69, from about 0.59 to about 0.67, from about 0.59 to about 0.65, from about 0.59 to about 0.63, from about 0.59 to about 0.61, from 0.61 to about 0.8, from 0.61 to about 0.77, from 0.61 to about 0.75, from about 0.61 to about 0.73, from about 0.61 to about 0.71, from about 0.61 to about 0.69, from about 0.61 to about 0.67, from about 0.61 to about 0.65, from about 0.61 to about 0.63, from 0.63 to about 0.8, from 0.63 to about 0.77, from 0.63 to about 0.75, from about 0.63 to about 0.73, from about 0.63 to about 0.71, from about 0.63 to about 0.69, from about 0.63 to about 0.67, from about 0.63 to about 0.65, from 0.65 to about 0.8, from 0.65 to about 0.77, from 0.65 to about 0.75, from about 0.65 to about 0.73, from about 0.65 to about 0.71, from about 0.65 to about 0.69, from about 0.From about 0.65 to about 0.67, from 0.67 to about 0.8, from 0.67 to about 0.77, from 0.67 to about 0.75, from about 0.67 to about 0.73, from about 0.67 to about 0.71, from about 0.67 to about 0.69, from 0.69 to about 0.8, from 0.69 to about 0.77, from 0.69 to about 0.75, from about 0.69 to about 0.73, from about 0.69 to about 0.71, from 0.71 to about 0.8, from 0.71 to about 0.77, from 0.71 to about 0.75, from about 0.71 to about 0.73, from about 0.73 to about 0.8, from about 0.73 to about 0.77, from about 0.73 to about 0.75, from about 0.75 to about 0.8, from about 0.73 to about 0.77 or from about 0.77 to about 0.8. In some embodiments, the MS of the mixture of hydroxypropyl β-cyclodextrin species is from about 0.59 to about 0.73. In some embodiments, the MS of the mixture of hydroxypropyl β-cyclodextrin species is from about 0.59 to about 0.8.

[0094] In certain embodiments, a mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution (MS) value of from about 0.5 to about 1.2, from about 0.6 to about 1.2, from about 0.7 to about 1.2, from about 0.8 to about 1.2, from about 0.9 to about 1.2, from about 1.0 to about 1.2, from about 1.1 to about 1.2, from about 0.5 to about 1.1, from about 0.5 to about 1.0, from about 0.5 to about 0.9, from about 0.5 to about 0.8, from about 0.5 to about 0.7, from about 0.5 to about 0.6, from about 0.6 to about 1.1, from about 0.6 to about 1.0, from about 0.6 to about 0.9, from about 0.6 to about 0.8, from about 0.6 to about 0.7, from about 0.7 to about 1.1, from about 0.7 to about 1.0, from about 0.7 to about 0.9, from about 0.7 to about 0.8, from about 0.8 to about 1.1, from about 0.8 to about 1.0, from about 0.8 to about 0.9, from about 0.9 to about 1.1, from about 0.9 to about 1.0 or from about 1.0 to about 1.1. In certain embodiments, a mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.59 to about 1.14. In certain embodiments, a mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.59 to 0.73. In certain embodiments, a mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.59 to 0.8. In certain embodiments, a mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.8 to 1.0.

[0095] 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.

[0096] In certain embodiments, the MS of a 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 0.57, 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 a 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.

[0097] Hydroxypropyl can be bound to β-cyclodextrin as a monomer, or it can itself be successively bound to one or more additional hydroxypropyls to form a hydroxypropyl oligomer, which is then bound to β-cyclodextrin. In certain embodiments, hydroxypropyl is substituted at the hydroxy positions of β-cyclodextrin as a hydroxypropyl chain of the structure [CH 2 CH(CH 3 )O] n H, where n ≥ 1 and the average number of hydroxypropyl chains per β-cyclodextrin is from about 3 to about 7. In some embodiments, the average number of hydroxypropyl chains per β-cyclodextrin is from about 3 to about 6, from about 3 to about 5, from about 3 to about 4, from about 4 to about 7, from about 4 to about 6, from about 4 to about 5, from about 5 to about 7, from about 5 to about 6, or from about 6 to about 7. In some embodiments, n is 1, 2, 3, or 4.

[0098] In an illustrative example, CH 2 CH(CH 3)The hydroxypropyl chain of the OH structure contains one hydroxypropyl in the hydroxypropyl chain (n = 1). In another illustrative example, [CH 2 CH(CH 3 )O] 3 The hydroxypropyl chain of the H structure contains three hydroxypropyls in the hydroxypropyl chain (n = 3).

[0099] In certain embodiments, the average number of hydroxypropyl chains in each 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 in each 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 in each 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 in each β-cyclodextrin is 6.0 ± 0.3, 6.2 ± 0.3, 6.4 ± 0.3, 6.6 ± 0.3, or 6.7 ± 0.3.

[0100] In certain embodiments, the average number of hydroxypropyl chains in each 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 in each 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 in each 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 in each 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.

[0101] In certain embodiments, the average number of hydroxypropyl chains in each 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 in each 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 in each 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 in each 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.

[0102] 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.

[0103] In certain embodiments, the percentage of hydroxypropyl chains having n = 1 ranges from about 50% to about 99%, such as 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%; such as from about 50% to about 97%, such as from about 55% to about 97%, from about 60% to about 97%, from about 65% to about 97%, from about 70% to about 97%, from about 75% to about 97%, from about 80% to about 97%, from about 85% to about 97%, from about 90% to about 97%, from about 95% to about 97%; such as 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%; such as from about 50% to about 90%, from about 55% to about 90%, from about 60% 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%; such as from about 50% to about 85%, from about 55% to about 85%, 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%; such as from about 50% to about 80%, from about 55% to about 80%, from about 60% to about 80%, from about 65% to about 80%, from about 70% to about 80%, from about 75% to about 80%; such as from about 50% to about 75%, from about 55% to about 75%, from about 60% to about 75%, from about 65% to about 75%, from about 70% to about 75%; such as from about 50% to about 70%, from about 55% to about 70%, from about 60% to about 70%, from about 65% to about 70%; such as from about 50% to about 65%, from about 55% to about 65%, from about 60% to about 65%; such as from about 50% to about 60%, from about 55% to about 60%; or such as from about 50% to about 55%.

[0104] 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.

[0105] In certain embodiments, the percentage of hydroxypropyl chains having n = 2 ranges from about 5% to about 50%, such as 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%; such as 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%; such as from about 5% to about 40%, from about 10% to about 40%, from about 15% to about 40%, from about 20% to about 40%, from about 25% to about 40%, from about 30% to about 40%, from about 35% to about 40%; such as from about 5% to about 35%, from about 10% to about 35%, from about 15% to about 35%, from about 20% to about 35%, from about 25% to about 35%, from about 30% to about 35%; such as from about 5% to about 30%, from about 10% to about 30%, from about 15% to about 30%, from about 20% to about 30%, from about 25% to about 30%; such as from about 5% to about 25%, from about 10% to about 25%, from about 15% to about 25%, from about 20% to about 25%; such as from about 5% to about 20%, from about 10% to about 20%, from about 15% to about 20%; such as from about 5% to about 15%, from about 10% to about 15%; or from about 5% to about 10%.

[0106] 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.

[0107] In certain embodiments, the percentage of hydroxypropyl chains having n > 2 ranges 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%, from about 25% to about 40%, from about 30% to about 40%, from about 35% to about 40%, from about 5% to about 35%, from about 10% to about 35%, from about 15% to about 35%, from about 20% to about 35%, from about 25% to about 35%, from about 30% to about 35%, from about 5% to about 30%, from about 10% to about 30%, from about 15% to about 30%, from about 20% to about 30%, from about 25% to about 30%, from about 5% to about 25%, from about 10% to about 25%, from about 15% to about 25%, from about 20% to about 25%, from about 5% to about 20%, from about 10% to about 20%, from about 15% to about 20%, from about 5% to about 15%, from about 10% to about 15%, or from about 5% to about 10%.

[0108] In certain embodiments, the average number of hydroxypropyl chains in each β-cyclodextrin is from about 4 to about 6. In some embodiments, at least about 60% of the total β-cyclodextrin has an average of about 4 to about 6 hydroxypropyl chains per β-cyclodextrin. 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-cyclodextrin has an average of about 4 to about 6 hydroxypropyl chains per β-cyclodextrin. In some embodiments, the percentage range of the average number of hydroxypropyl chains per β-cyclodextrin in the total β-cyclodextrin is from about 60% to about 97%, from about 65% to about 97%, from about 70% to about 97%, from about 75% to about 97%, from about 80% to about 97%, from about 85% to about 97%, from about 90% to about 97%, 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 60% 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%.

[0109] In certain embodiments, the hydroxypropyl-β-cyclodextrin compositions as described herein comprise unsubstituted β-cyclodextrin in an amount of 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, about 0.7% w / w or less, about 0.8% w / w or less, about 0.9% w / w or less, about 1.0% w / w or less, about 1.1% w / w or less, about 1.2% w / w or less, about 1.3% w / w or less, about 1.4% w / w or less, about 1.5% w / w or less, about 1.6% w / w or less, about 1.7% w / w or less, about 1.8% w / w or less, about 1.9% w / w or less, or about 2% w / w or less. In some embodiments, the hydroxypropyl-β-cyclodextrin composition comprises unsubstituted β-cyclodextrin in an amount of about 0.2% w / w or less. In some embodiments, the hydroxypropyl-β-cyclodextrin composition comprises unsubstituted β-cyclodextrin in an amount of about 0.15% w / w or less.

[0110] In certain embodiments, the amount of unsubstituted β-cyclodextrin in the hydroxypropyl β-cyclodextrin compositions as 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, from about 0.05% w / w to about 0.5% w / w, from about 0.05% w / w to about 0.4% w / w, from about 0.05% w / w to about 0.3% w / w, from about 0.05% w / w to about 0.2% w / w, from about 0.05% w / w to about 0.1% w / w, from about 0.05% w / w to about 0.07% w / w, from about 0.07% w / w to about 1.5% w / w, from about 0.07% w / w to about 1.4% w / w, from about 0.07% w / w to about 1.3% w / w, from about 0.07% w / w to about 1.2% w / w, from about 0.07% w / w to about 1.1% w / w, from about 0.07% w / w to about 1.0% w / w, from about 0.07% w / w to about 0.8% w / w, from about 0.07% w / w to about 0.6% w / w, from about 0.07% w / w to about 0.5% w / w, from about 0.07% w / w to about 0.4% w / w, from about 0.07% w / w to about 0.3% w / w, from about 0.07% w / w to about 0.2% w / w, from about 0.07% w / w to about 0.1% w / w, from about 0.1% w / w to about 1.5% w / w, from about 0.1% w / w to about 1.4% w / w, from about 0.1% w / w to about 1.3% w / w, from about 0.1% w / w to about 1.2% w / w, from about 0.1% w / w to about 1.1% w / w, from about 0.1% w / w to about 1.0% w / w, from about 0.1% w / w to about 0.8% w / w, from about 0.1% w / w to about 0.6% w / w, from about 0.1% w / w to about 0.5% w / w, from about 0.1% w / w to about 0.4% w / w, from about 0.1% w / w to about 0.3% w / w, from about 0.1% w / w to about 0.2% w / w, from about 0.2% w / w to about 1.5% w / w, from about 0.2% w / w to about 1.4% w / w, from about 0.2% w / w to about 1.3% w / w, from about 0.2% w / w to about 1.2% w / w, from about 0.2% w / w to about 1.1% w / w, from about 0.2% w / w to about 1.0% w / w, from about 0.2% w / w to about 0.8% w / w, from about 0.2% w / w to about 0.6% w / w, from about 0.2% w / w to about 0.5% w / w, from about 0.2% w / w to about 0.4% w / w, from about 0.2% w / w to about 0.3% w / w, from about 0.3% w / w to about 1.5% w / w, from about 0.3% w / w to about 1.4% w / w, from about 0.3% w / w to about 1.3% w / w, from about 0.3% w / w to about 1.2% w / w, from about 0.3% w / w to about 1.1% w / w, from about 0.3% w / w to about 1.0% w / w, from about 0.3% w / w to about 0.8% w / w, from about 0.3% w / w to about 0.6% w / w, from about 0.3% w / w to about 0.5% w / w, from about 0.3% w / w to about 0.4% w / w, from about 0.4% w / w to about 1.5% w / w, from about 0.4% w / w to about 1.4% w / w, from about 0.4% w / w to about 1.3% w / w, from about 0.4% w / w to about 1.2% w / w, from about 0.4% w / w to about 1.1% w / w, from about 0.4% w / w to about 1.0% w / w, from about 0.4% w / w to about 0.8% w / w, from about 0.4% w / w to about 0.6% w / w, from about 0.4% w / w to about 0.5% w / w, from about 0.5% w / w to about 1.5% w / w, from about 0.5% w / w to about 1.4% w / w, from about 0.5% w / w to about 1.3% w / w, from about 0.5% w / w to about 1.2% w / w, from about 0.5% w / w to about 1.1% w / w, from about 0.5% w / w to about 1.0% w / w, from about 0.5% w / w to about 0.8% w / w, from about 0.5% w / w to about 0.6% w / w, from about 0.6% w / w to about 1.5% w / w, from about 0.6% w / w to about 1.4% w / w, from about 0.6% w / w to about 1.3% w / w, from about 0.6% w / w to about 1.2% w / w, from about 0.6% w / w to about 1.1% w / w, from about 0.6% w / w to about 1.0% w / w, from about 0.6% w / w to about 0.8% w / w, from about 0.8% w / w to about 1.5% w / w, from about 0.8% w / w to about 1.4% w / w, from about 0.8% w / w to about 1.3% w / w, from about 0.8% w / w to about 1.2% w / w, from about 0.8% w / w to about 1.1% w / w, from about 0.8% w / w to about 1.0% w / w, from about 1.0% w / w to about 1.5% w / w, from about 1.0% w / w to about 1.4% w / w, from about 1.0% w / w to about 1.3% w / w, from about 1.0% w / w to about 1.2% w / w, from about 1.0% w / w to about 1.1% w / w, from about 1.1% w / w to about 1.5% w / w, from about 1.1% w / w to about 1.4% w / w, from about 1.1% w / w to about 1.3% w / w, from about 1.1% w / w to about 1.2% w / w, from about 1.2% w / w to about 1.5% w / w, from about 1.2% w / w to about 1.4% w / w, from about 1.2% w / w to about 1.3% w / w, from about 1.3% w / w to about 1.5% w / w, from about 1.3% w / w to about 1.4% w / w or from about 1.4% w / w to about 1.5% w / w. In some embodiments, the amount of unsubstituted β-cyclodextrin in the hydroxypropyl-β-cyclodextrin compositions as 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 as described herein is from about 0.1% w / w to about 0.2% w / w.

[0111] In certain embodiments, the hydroxypropyl-β-cyclodextrin compositions of the present invention may contain impurities resulting from the chemical synthesis of the hydroxypropyl-β-cyclodextrin species. In some embodiments, the impurity is propylene glycol.

[0112] In certain embodiments, the hydroxypropyl-β-cyclodextrin compositions described herein contain about 2.0% or less, about 2.1% w / w or less, about 2.2% w / w or less, about 2.3% w / w or less, about 2.4% w / w or less, about 2.5% w / w or less, about 2.6% w / w or less, about 2.7% w / w or less, about 2.8% w / w or less, about 2.9% w / w or less or about 3% w / w or less of propylene glycol. In some embodiments, the hydroxypropyl-β-cyclodextrin compositions described herein contain about 2.5% w / w or less of propylene glycol.

[0113] In certain embodiments, the hydroxypropyl-β-cyclodextrin compositions described herein contain 2.0% 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 of propylene glycol. In some embodiments, the hydroxypropyl-β-cyclodextrin compositions as described herein contain 2.5% w / w or less of propylene glycol.

[0114] 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 3.0% w / w, from about 2.1% w / w to about 2.9% w / w, from about 2.1% w / w to about 2.8% w / w, from about 2.1% w / w to about 2.7% w / w, from about 2.1% w / w to about 2.6% w / w, from about 2.1% w / w to about 2.5% w / w, from about 2.1% w / w to about 2.4% w / w, from about 2.1% w / w to about 2.3% w / w, from about 2.1% w / w to about 2.2% w / w, from about 2.2% w / w to about 3.0% w / w, from about 2.2% w / w to about 2.9% w / w, from about 2.2% w / w to about 2.8% w / w, from about 2.2% w / w to about 2.6% w / w, from about 2.2% w / w to about 2.5% w / w, from about 2.2% w / w to about 2.4% w / w, from about 2.2% w / w to about 2.3% w / w, from about 2.3% w / w to about 3.0% w / w, from about 2.3% w / w to about 2.9% w / w, from about 2.3% w / w to about 2.8% w / w, from about 2.3% w / w to about 2.7% w / w, from about 2.3% w / w to about 2.6% w / w, from about 2.3% w / w to about 2.5% w / w, from about 2.3% w / w to about 2.4% w / w, from about 2.4% w / w to about 3.0% w / w, from about 2.4% w / w to about 2.9% w / w, from about 2.4% w / w to about 2.8% w / w, from about 2.4% w / w to about 2.7% w / w, from about 2.4% w / w to about 2.6% w / w, from about 2.4% w / w to about 2.5% w / w, from about 2.5% w / w to about 3.0% w / w, from about 2.5% w / w to about 2.9% w / w, from about 2.5% w / w to about 2.8% w / w, from about 2.5% w / w to about 2.7% w / w, from about 2.5% w / w to about 2.6% w / w, from about 2.6% w / w to about 3.0% w / w, from about 2.6% w / w to about 2.9% w / w, from about 2.6% w / w to about 2.8% w / w, from about 2.6% w / w to about 2.7% w / w, from about 2.7% w / w to about 3.0% w / w, from about 2.7% w / w to about 2.9% w / w, from about 2.7% w / w to about 2.8% w / w, from about 2.8% w / w to about 3.0% w / w, from about 2.8% w / w to about 2.9% w / w or from about 2.9% w / w to about 3.0% w / w. In some embodiments, the amount of propylene glycol in the hydroxypropyl-β-cyclodextrin composition as described herein is from about 2.0% w / w to about 3.0% w / w.

[0115] In certain embodiments, the hydroxypropyl-β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl-β-cyclodextrin species, wherein each of the two or more hydroxypropyl-β-cyclodextrin species has a different degree of hydroxypropylation of the β-cyclodextrin ring, and wherein the hydroxypropyl-β-cyclodextrin composition comprises 0.15% w / w or less of unsubstituted β-cyclodextrin.

[0116] In certain embodiments, the hydroxypropyl-β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl-β-cyclodextrin species, wherein each of the two or more hydroxypropyl-β-cyclodextrin species has a different degree of hydroxypropylation of the β-cyclodextrin ring, wherein the mixture of the two or more hydroxypropyl-β-cyclodextrin species has a molar substitution value of from about 0.59 to about 0.73, and wherein the hydroxypropyl-β-cyclodextrin composition comprises 2.5% w / w or less of propylene glycol and 0.15% w / w or less of unsubstituted β-cyclodextrin.

[0117] In certain embodiments, the hydroxypropyl-β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl-β-cyclodextrin species, wherein each of the two or more hydroxypropyl-β-cyclodextrin species has a different degree of hydroxypropylation of the β-cyclodextrin ring, wherein the mixture of the two or more hydroxypropyl-β-cyclodextrin species has a molar substitution value of from about 0.59 to about 0.8, and wherein the hydroxypropyl-β-cyclodextrin composition comprises 2.5% w / w or less of propylene glycol and 0.15% w / w or less of unsubstituted β-cyclodextrin.

[0118] In certain embodiments, the hydroxypropyl-β-cyclodextrin composition comprises a mixture of two or more hydroxypropyl-β-cyclodextrin species, wherein each of the two or more hydroxypropyl-β-cyclodextrin species has a different degree of hydroxypropylation of the β-cyclodextrin ring, wherein the mixture of the two or more hydroxypropyl-β-cyclodextrin species has a molar substitution value of from about 0.8 to about 1.0, and wherein the hydroxypropyl-β-cyclodextrin composition comprises 2.5% w / w or less of propylene glycol, preferably less than 0.01% w / w of propylene glycol, and most preferably an undetectable amount of propylene glycol, and 0.16% w / w or less of unsubstituted β-cyclodextrin.

[0119] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises a solution that comprises one or more hydroxypropyl β-cyclodextrin species at about 5% (w / v) to about 40% (w / v), about 10% (w / v) to about 40% (w / v), about 15% (w / v) to about 40% (w / v), about 20% (w / v) to about 40% (w / v), about 25% (w / v) to about 40% (w / v), about 30% (w / v) to about 40% (w / v), about 35% (w / v) to about 40% (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), about 10% (w / v) to about 25% (w / v), about 10% (w / v) to about 20% (w / v), about 10% (w / v) to about 15% (w / v), about 15% (w / v) to about 35% (w / v), about 15% (w / v) to about 30% (w / v), about 15% (w / v) to about 25% (w / v), about 15% (w / v) to about 20% (w / v), about 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).

[0120] 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 two or more hydroxypropyl β-cyclodextrin species. In some embodiments, the 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species is an aqueous 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species.

[0121] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises Cyclo TM a hydroxypropyl β-cyclodextrin composition, available from Cyclo Therapeutics, Inc.

[0122] Treatment of Early Alzheimer's Disease with Hydroxypropyl β-cyclodextrin

[0123] Effect of Cholesterol on Early Alzheimer's Disease

[0124] The characteristics of early Alzheimer's disease neuropathology can be 1) plaques containing beta-amyloid (Aβ), 2) neurofibrillary tangles composed of neurofilaments, or 3) hyperphosphorylated tau protein. Other key components include LE / LY abnormalities, cholesterol accumulation, APP processing inflammation, and apoptosis. Although the exact role of Aβ plaques and tau tangles in Alzheimer's disease is not clear, they are thought to play a key role in blocking communication between nerve cells and disrupting key processes required for cell survival. In addition, studies have demonstrated that Aβ is neurotoxic, and there is evidence suggesting that it may be the cause of memory loss associated with Alzheimer's disease.

[0125] Cholesterol is considered essential for cell structure, function, and signaling. Approximately 23% of the body's cholesterol is located in the brain; neurons and astrocytes contain the most. Cholesterol is not evenly distributed: there are differences within each specific membrane of the same cell and across different membranes. Within each membrane, cholesterol is concentrated in nano / micron domains called "lipid rafts". In neurons, these rafts are highly dynamic and are thought to be the result of their high metabolic demands and the need for plasticity and remodeling throughout life. Rafts have also been detected at neuronal synapses, where they contribute to presynaptic and postsynaptic function. Within a single neuron, the relative distribution of cholesterol on intracellular membranes also varies. The vast majority (>90%) of cholesterol is located within the plasma membrane. Once across the plasma membrane, most cholesterol is shuttled to endosomes / lysosomes and then to certain organelles for processing, where it can be incorporated into other organelle membranes (i.e., mitochondria, lysosomes, endoplasmic reticulum) or esterified and stored in the form of cytoplasmic lipid droplets.

[0126] Subjects with Alzheimer's disease (e.g., early Alzheimer's disease) typically have cholesterol imbalances, and existing studies suggest that these imbalances may be the cause of Aβ and tau accumulation. In addition, due to the high metabolic demands of neurons, they may experience increased levels of oxidative stress. Oxidative stress is associated with abnormal cholesterol accumulation and processing. Studies have shown that the membrane cholesterol levels of young or juvenile neurons are lower than those of mature neurons. In addition, postmortem studies of Alzheimer's patients have also shown that cellular cholesterol levels are significantly increased in the membranes of vulnerable brain regions but not in non-vulnerable brain regions. It has also been found that the amount of cholesterol in these membranes is greater in patients with more severe cognitive symptoms than in those with mild impairment.

[0127] Brain cells are largely isolated from the blood cholesterol supply because the blood-brain barrier prevents cholesterol-rich lipoproteins from entering. Thus, most CNS cholesterol is locally produced. On the other hand, cholesterol continuously effluxes 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 to enter the circulation. Altered CYP46A1 expression has been associated with several neurodegenerative diseases and cognitive alterations. A second efflux mechanism is HDL, which can cross the blood-brain barrier and transport cholesterol from the brain to plasma and then to the liver, where it is ultimately cleared. Low and / or dysfunctional HDL particles are known risk factors for the development of AD. Finally, apolipoprotein E (APOE) ε4 isoform, which is a form of LDL and regulates brain cholesterol metabolism and transport, may be the strongest genetic risk factor identified to date for the development of AD.

[0128] There is an established link between Aβ and cholesterol because both the production and clearance of Aβ are regulated by cholesterol. Increasing cholesterol content (especially in domains such as the plasma membrane) can lead to increased Aβ levels, as shown in cell culture and most animal models of AD. Tau toxicity can also depend on cellular cholesterol levels. A high-cholesterol diet has been shown to increase tau hyperphosphorylation. Studies have shown that as cholesterol concentration increases, the sensitivity of neurons to Aβ-dependent calpain activation also increases. Calpain activation is known to cleave tau and generate toxic fragments. These cleaved tau forms can induce neuronal death, synaptic loss, and / or behavioral deficits. Young neurons have significantly less cholesterol than aging neurons and also contain less phosphorylated tau (p-tau).

[0129] Treatment of AD with Hydroxypropyl β-cyclodextrin

[0130] In one aspect, the present disclosure provides a method for treating early Alzheimer's disease in a human patient in need thereof, the method comprising administering to the human patient an effective amount of the hydroxypropyl β-cyclodextrin composition disclosed herein.

[0131] In certain embodiments, the early Alzheimer's disease is Alzheimer's disease with mild cognitive impairment or mild Alzheimer's disease. In certain embodiments, the early Alzheimer's disease is Alzheimer's disease with mild cognitive impairment. In certain embodiments, the early Alzheimer's disease is mild Alzheimer's disease.

[0132] In some embodiments, the human patient exhibits progressive cognitive decline at the initiation of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition.

[0133] In some embodiments, when initiating administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has exhibited 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 1 month, about 1 year 2 months, about 1 year 3 months, about 1 year 4 months, about 1 year 5 months, or about 1 year 6 months. In some embodiments, when initiating administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has already exhibited progressive cognitive decline for at least about 1 year.

[0134] In some embodiments, when initiating administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has exhibited 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 1 month, about 1 year 2 months, about 1 year 3 months, about 1 year 4 months, about 1 year 5 months, or about 1 year 6 months.

[0135] In certain embodiments, when initiating administration of an effective amount of a hydroxypropyl β-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.

[0136] In certain embodiments, when initiating administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a global Clinical Dementia Rating (CDR) scale score of from about 0.1 to about 0.8, from about 0.2 to about 0.8, from about 0.3 to about 0.8, from about 0.4 to about 0.8, from about 0.5 to about 0.8, from about 0.6 to about 0.8, from about 0.7 to about 0.8, from about 0.1 to about 0.9, from about 0.2 to about 0.9, from about 0.3 to about 0.9, from about 0.4 to about 0.9, from about 0.5 to about 0.9, from about 0.6 to about 0.9, from about 0.7 to about 0.9, from about 0.8 to about 0.9, from about 0.1 to about 1.0, from about 0.2 to about 1.0, from about 0.3 to about 1.0, from about 0.4 to about 1.0, from about 0.5 to about 1.0, from about 0.6 to about 1.0, from about 0.7 to about 1.0, from about 0.8 to about 1.0, from about 0.9 to about 1.0, from about 0.1 to about 1.1, from about 0.2 to about 1.1, from about 0.3 to about 1.1, from about 0.4 to about 1.1, from about 0.5 to about 1.1, from about 0.6 to about 1.1, from about 0.7 to about 1.1, from about 0.8 to about 1.1, from about 0.9 to about 1.1, from about 1.0 to about 1.1, from about 0.1 to about 1.2, from about 0.2 to about 1.2, from about 0.3 to about 1.2, from about 0.4 to about 1.2, from about 0.5 to about 1.2, from about 0.6 to about 1.2, from about 0.7 to about 1.2, from about 0.8 to about 1.2, from about 0.9 to about 1.2, from about 1.0 to about 1.2, or from about 1.1 to about 1.2. In certain embodiments, when initiating administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a global Clinical Dementia Rating (CDR) scale score of from about 0.5 to about 1.

[0137] In certain embodiments, when initiating administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a CDR memory item score of about 0.1 or higher, about 0.2 or higher, about 0.3 or higher, about 0.4 or higher, about 0.5 or higher, about 0.6 or higher, about 0.7 or higher, about 0.8 or higher, about 0.9 or higher, or about 1.0 or higher. In certain embodiments, when initiating administration of an effective amount of the hydroxypropyl β-cyclodextrin composition, the human patient has a CDR memory item score of about 0.5 or higher.

[0138] In certain embodiments, when initiating 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 0.1, 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 item score of about 0.1 or higher, about 0.2 or higher, about 0.3 or higher, about 0.4 or higher, about 0.5 or higher, about 0.6 or higher, about 0.7 or higher, about 0.8 or higher, about 0.9 or higher, or about 1.0 or higher.

[0139] In certain embodiments, when initiating administration of an effective amount of a hydroxypropyl β - cyclodextrin composition, a human patient has a global Clinical Dementia Rating (CDR) scale score of 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 item score of about 0.1 or higher, about 0.2 or higher, about 0.3 or higher, about 0.4 or higher, about 0.5 or higher, about 0.6 or higher, about 0.7 or higher, about 0.8 or higher, about 0.9 or higher, or about 1.0 or higher. In certain embodiments, when initiating administration of an effective amount of a hydroxypropyl β - cyclodextrin composition, a human patient has a global Clinical Dementia Rating (CDR) scale score between about 0.5 and about 1.0 and a CDR memory item score of about 0.5 or higher.

[0140] In certain embodiments, when initiating administration of an effective amount of a hydroxypropyl β - cyclodextrin composition, a human patient exhibits cerebral β - amyloid (Aβ) pathology.

[0141] In certain embodiments, when initiating administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has a Mini-Mental State Examination-2: Standard Version (MMSE-2:SV) score 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 28, 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 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, when initiating administration of an effective amount of a hydroxypropyl β-cyclodextrin composition, a human patient has a Mini-Mental State Examination-2: Standard Version (MMSE-2:SV) score between about 20 and about 28.

[0142] In certain embodiments, the human patient has previously been administered a cognitive enhancer and / or symptomatic therapy for early Alzheimer's disease.

[0143] In certain embodiments, the human patient has previously been administered a combination of an acetylcholinesterase inhibitor and / or memantine and / or Namenda and Aricept (sold as Namzaric).

[0144] 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.

[0145] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient from about 100 mg / kg to about 1000 mg / kg, from about 200 mg / kg to about 1000 mg / kg, from about 300 mg / kg to about 1000 mg / kg, from about 400 mg / kg to about 1000 mg / kg, from about 500 mg / kg to about 1000 mg / kg, from about 600 mg / kg to about 1000 mg / kg, from about 700 mg / kg to about 1000 mg / kg, from about 750 mg / kg to about 1000 mg / kg, from about 800 mg / kg to about 1000 mg / kg, from about 900 mg / kg to about 1000 mg / kg, 100 mg / kg to about 2000 mg / kg, from about 200 mg / kg to about 2000 mg / kg, from about 300 mg / kg to about 2000 mg / kg, from about 400 mg / kg to about 2000 mg / kg, from about 500 mg / kg to about 2000 mg / kg, from about 600 mg / kg to about 2000 mg / kg, from about 700 mg / kg to about 2000 mg / kg, from about 750 mg / kg to about 2000 mg / kg, from about 800 mg / kg to about 2000 mg / kg, from about 900 mg / kg to about 2000 mg / kg, from about 1000 mg / kg to about 2000 mg / kg, from about 1100 mg / kg to about 2000 mg / kg, from about 1200 mg / kg to about 2000 mg / kg, from about 1250 mg / kg to about 2000 mg / kg, from about 1300 mg / kg to about 2000 mg / kg, from about 1400 mg / kg to about 2000 mg / kg, from about 1500 mg / kg to about 2000 mg / kg, from about 1600 mg / kg to about 2000 mg / kg, from about 1700 mg / kg to about 2000 mg / kg, from about 1800 mg / kg to about 2000 mg / kg, from about 1900 mg / kg to about 2000 mg / kg, 100 mg / kg to about 2100 mg / kg, from about 200 mg / kg to about 2100 mg / kg, from about 300 mg / kg to about 2100 mg / kg, from about 400 mg / kg to about 2100 mg / kg, from about 500 mg / kg to about 2100 mg / kg, from about 600 mg / kg to about 2100 mg / kg, from about 700 mg / kg to about 2100 mg / kg, from about 750 mg / kg to about 2100 mg / kg, from about 800 mg / kg to about 2100 mg / kg, from about 900 mg / kg to about 2100 mg / kg, from about 1000 mg / kg to about 2100 mg / kg, from about 1100 mg / kg to about 2100 mg / kg, from about 1200 mg / kg to about 2100 mg / kg, from about 1250 mg / kg to about 2100 mg / kg,A hydroxypropyl-β-cyclodextrin composition of from about 1300 mg / kg to about 2100 mg / kg, from about 1400 mg / kg to about 2100 mg / kg, from about 1500 mg / kg to about 2100 mg / kg, from about 1600 mg / kg to about 2100 mg / kg, from about 1700 mg / kg to about 2100 mg / kg, from about 1800 mg / kg to about 2100 mg / kg, from about 1900 mg / kg to about 2100 mg / kg, from about 2000 mg / kg to about 2100 mg / kg, from about 100 mg / kg to about 2500 mg / kg, from about 200 mg / kg to about 2500 mg / kg, from about 300 mg / kg to about 2500 mg / kg, from about 400 mg / kg to about 2500 mg / kg, from about 500 mg / kg to about 2500 mg / kg, from about 600 mg / kg to about 2500 mg / kg, from about 700 mg / kg to about 2500 mg / kg, from about 750 mg / kg to about 2500 mg / kg, from about 800 mg / kg to about 2500 mg / kg, from about 900 mg / kg to about 2500 mg / kg, from about 1000 mg / kg to about 2500 mg / kg, from about 1100 mg / kg to about 2500 mg / kg, from about 1200 mg / kg to about 2500 mg / kg, from about 1250 mg / kg to about 2500 mg / kg, from about 1300 mg / kg to about 2500 mg / kg, from about 1400 mg / kg to about 2500 mg / kg, from about 1500 mg / kg to about 2500 mg / kg, from about 1600 mg / kg to about 2500 mg / kg, from about 1700 mg / kg to about 2500 mg / kg, from about 1800 mg / kg to about 2500 mg / kg, from about 1900 mg / kg to about 2500 mg / kg, from about 2000 mg / kg to about 2500 mg / kg or from about 2100 mg / kg to about 2500 mg / kg. In certain embodiments, administering an effective amount of the hydroxypropyl-β-cyclodextrin composition comprises administering to a human patient from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl-β-cyclodextrin composition. In certain embodiments, administering an effective amount of the hydroxypropyl-β-cyclodextrin composition comprises administering to a human patient from about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl-β-cyclodextrin composition.

[0146] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient by intravenous infusion from about 100 mg / kg to about 1000 mg / kg, from about 200 mg / kg to about 1000 mg / kg, from about 300 mg / kg to about 1000 mg / kg, from about 400 mg / kg to about 1000 mg / kg, from about 500 mg / kg to about 1000 mg / kg, from about 600 mg / kg to about 1000 mg / kg, from about 700 mg / kg to about 1000 mg / kg, from about 750 mg / kg to about 1000 mg / kg, from about 800 mg / kg to about 1000 mg / kg, from about 900 mg / kg to about 1000 mg / kg, 100 mg / kg to about 2000 mg / kg, from about 200 mg / kg to about 2000 mg / kg, from about 300 mg / kg to about 2000 mg / kg, from about 400 mg / kg to about 2000 mg / kg, from about 500 mg / kg to about 2000 mg / kg, from about 600 mg / kg to about 2000 mg / kg, from about 700 mg / kg to about 2000 mg / kg, from about 750 mg / kg to about 2000 mg / kg, from about 800 mg / kg to about 2000 mg / kg, from about 900 mg / kg to about 2000 mg / kg, from about 1000 mg / kg to about 2000 mg / kg, from about 1100 mg / kg to about 2000 mg / kg, from about 1200 mg / kg to about 2000 mg / kg, from about 1250 mg / kg to about 2000 mg / kg, from about 1300 mg / kg to about 2000 mg / kg, from about 1400 mg / kg to about 2000 mg / kg, from about 1500 mg / kg to about 2000 mg / kg, from about 1600 mg / kg to about 2000 mg / kg, from about 1700 mg / kg to about 2000 mg / kg, from about 1800 mg / kg to about 2000 mg / kg, from about 1900 mg / kg to about 2000 mg / kg, 100 mg / kg to about 2100 mg / kg, from about 200 mg / kg to about 2100 mg / kg, from about 300 mg / kg to about 2100 mg / kg, from about 400 mg / kg to about 2100 mg / kg, from about 500 mg / kg to about 2100 mg / kg, from about 600 mg / kg to about 2100 mg / kg, from about 700 mg / kg to about 2100 mg / kg, from about 750 mg / kg to about 2100 mg / kg, from about 800 mg / kg to about 2100 mg / kg, from about 900 mg / kg to about 2100 mg / kg, from about 1000 mg / kg to about 2100 mg / kg, from about 1100 mg / kg to about 2100 mg / kg, from about 1200 mg / kg to about 2100 mg / kg, from about 1250 mg / kg to about 2100 mg / kg,A hydroxypropyl β - cyclodextrin composition of from about 1300 mg / kg to about 2100 mg / kg, from about 1400 mg / kg to about 2100 mg / kg, from about 1500 mg / kg to about 2100 mg / kg, from about 1600 mg / kg to about 2100 mg / kg, from about 1700 mg / kg to about 2100 mg / kg, from about 1800 mg / kg to about 2100 mg / kg, from about 1900 mg / kg to about 2100 mg / kg, from about 2000 mg / kg to about 2100 mg / kg, from about 100 mg / kg to about 2500 mg / kg, from about 200 mg / kg to about 2500 mg / kg, from about 300 mg / kg to about 2500 mg / kg, from about 400 mg / kg to about 2500 mg / kg, from about 500 mg / kg to about 2500 mg / kg, from about 600 mg / kg to about 2500 mg / kg, from about 700 mg / kg to about 2500 mg / kg, from about 750 mg / kg to about 2500 mg / kg, from about 800 mg / kg to about 2500 mg / kg, from about 900 mg / kg to about 2500 mg / kg, from about 1000 mg / kg to about 2500 mg / kg, from about 1100 mg / kg to about 2500 mg / kg, from about 1200 mg / kg to about 2500 mg / kg, from about 1250 mg / kg to about 2500 mg / kg, from about 1300 mg / kg to about 2500 mg / kg, from about 1400 mg / kg to about 2500 mg / kg, from about 1500 mg / kg to about 2500 mg / kg, from about 1600 mg / kg to about 2500 mg / kg, from about 1700 mg / kg to about 2500 mg / kg, from about 1800 mg / kg to about 2500 mg / kg, from about 1900 mg / kg to about 2500 mg / kg, from about 2000 mg / kg to about 2500 mg / kg or from about 2100 mg / kg to about 2500 mg / kg. In certain embodiments, 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 a human patient by intravenous infusion. In certain embodiments, 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 a human patient by intravenous infusion.

[0147] In certain embodiments, an effective amount of the hydroxypropyl β - cyclodextrin composition is administered to a human patient every 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days or 36 days. In certain embodiments, an effective amount of the hydroxypropyl β - cyclodextrin composition is administered to a human patient every 28 days.

[0148] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient by intravenous infusion 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 to about 1000 mg / kg, 100 mg / kg to about 2000 mg / kg, about 200 mg / kg to about 2000 mg / kg, about 300 mg / kg to about 2000 mg / kg, about 400 mg / kg to about 2000 mg / kg, about 500 mg / kg to about 2000 mg / kg, about 600 mg / kg to about 2000 mg / kg, about 700 mg / kg to about 2000 mg / kg, about 750 mg / kg to about 2000 mg / kg, about 800 mg / kg to about 2000 mg / kg, about 900 mg / kg to about 2000 mg / kg, about 1000 mg / kg to about 2000 mg / kg, about 1100 mg / kg to about 2000 mg / kg, about 1200 mg / kg to about 2000 mg / kg, about 1250 mg / kg to about 2000 mg / kg, about 1300 mg / kg to about 2000 mg / kg, about 1400 mg / kg to about 2000 mg / kg, about 1500 mg / kg to about 2000 mg / kg, about 1600 mg / kg to about 2000 mg / kg, about 1700 mg / kg to about 2000 mg / kg, about 1800 mg / kg to about 2000 mg / kg, about 1900 mg / kg to about 2000 mg / kg, about 100 mg / kg to about 2100 mg / kg, about 200 mg / kg to about 2100 mg / kg, about 300 mg / kg to about 2100 mg / kg, about 400 mg / kg to about 2100 mg / kg, about 500 mg / kg to about 2100 mg / kg, about 600 mg / kg to about 2100 mg / kg, about 700 mg / kg to about 2100 mg / kg, about 750 mg / kg to about 2100 mg / kg, about 800 mg / kg to about 2100 mg / kg, about 900 mg / kg to about 2100 mg / kg, about 1000 mg / kg to about 2100 mg / kg every 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, or 36 days.A hydroxypropyl-β-cyclodextrin composition of about 1100 mg / kg to about 2100 mg / kg, about 1200 mg / kg to about 2100 mg / kg, about 1250 mg / kg to about 2100 mg / kg, about 1300 mg / kg to about 2100 mg / kg, about 1400 mg / kg to about 2100 mg / kg, about 1500 mg / kg to about 2100 mg / kg, about 1600 mg / kg to about 2100 mg / kg, about 1700 mg / kg to about 2100 mg / kg, about 1800 mg / kg to about 2100 mg / kg, about 1900 mg / kg to about 2100 mg / kg, about 2000 mg / kg to about 2100 mg / kg, about 100 mg / kg to about 2500 mg / kg, about 200 mg / kg to about 2500 mg / kg, about 300 mg / kg to about 2500 mg / kg, about 400 mg / kg to 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 800 mg / kg to about 2500 mg / kg, about 900 mg / kg to about 2500 mg / kg, about 1000 mg / kg to about 2500 mg / kg, about 1100 mg / kg to about 2500 mg / kg, about 1200 mg / kg to about 2500 mg / kg, about 1250 mg / kg to about 2500 mg / kg, about 1300 mg / kg to about 2500 mg / kg, about 1400 mg / kg to about 2500 mg / kg, about 1500 mg / kg to 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.

[0149] In certain embodiments, administering an effective amount of the hydroxypropyl-β-cyclodextrin composition comprises administering to a human patient by intravenous infusion about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl-β-cyclodextrin composition once every 28 days. In certain embodiments, administering an effective amount of the hydroxypropyl-β-cyclodextrin composition comprises administering to a human patient by intravenous infusion about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl-β-cyclodextrin composition once every 28 days.

[0150] 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 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) during the lifetime of the human patient.

[0151] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient by intravenous infusion 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 to about 1000 mg / kg, 100 mg / kg to about 2000 mg / kg, about 200 mg / kg to about 2000 mg / kg, about 300 mg / kg to about 2000 mg / kg, about 400 mg / kg to about 2000 mg / kg, about 500 mg / kg to about 2000 mg / kg, about 600 mg / kg to about 2000 mg / kg, about 700 mg / kg to about 2000 mg / kg, about 750 mg / kg to about 2000 mg / kg, about 800 mg / kg to about 2000 mg / kg, about 900 mg / kg to about 2000 mg / kg, about 1000 mg / kg to about 2000 mg / kg, about 1100 mg / kg to about 2000 mg / kg, about 1200 mg / kg to about 2000 mg / kg, about 1250 mg / kg to about 2000 mg / kg, about 1300 mg / kg to about 2000 mg / kg, about 1400 mg / kg to about 2000 mg / kg, about 1500 mg / kg to about 2000 mg / kg, about 1600 mg / kg to about 2000 mg / kg, about 1700 mg / kg to about 2000 mg / kg, about 1800 mg / kg to about 2000 mg / kg, about 1900 mg / kg to about 2000 mg / kg, about 100 mg / kg to about 2100 mg / kg, about 200 mg / kg to about 2100 mg / kg, about 300 mg / kg to about 2100 mg / kg, about 400 mg / kg to about 2100 mg / kg, about 500 mg / kg to about 2100 mg / kg, about 600 mg / kg to about 2100 mg / kg, about 700 mg / kg to about 2100 mg / kg, about 750 mg / kg to about 2100 mg / kg, about 800 mg / kg to about 2100 mg / kg, about 900 mg / kg to about 2100 mg / kg, about 1000 mg / kg to about 2100 mg / kg, every 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, or 36 days.A hydroxypropyl-β-cyclodextrin composition of about 1100 mg / kg to about 2100 mg / kg, about 1200 mg / kg to about 2100 mg / kg, about 1250 mg / kg to about 2100 mg / kg, about 1300 mg / kg to about 2100 mg / kg, about 1400 mg / kg to about 2100 mg / kg, about 1500 mg / kg to about 2100 mg / kg, about 1600 mg / kg to about 2100 mg / kg, about 1700 mg / kg to about 2100 mg / kg, about 1800 mg / kg to about 2100 mg / kg, about 1900 mg / kg to about 2100 mg / kg, about 2000 mg / kg to about 2100 mg / kg, about 100 mg / kg to about 2500 mg / kg, about 200 mg / kg to about 2500 mg / kg, about 300 mg / kg to about 2500 mg / kg, about 400 mg / kg to 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 800 mg / kg to about 2500 mg / kg, about 900 mg / kg to about 2500 mg / kg, about 1000 mg / kg to about 2500 mg / kg, about 1100 mg / kg to about 2500 mg / kg, about 1200 mg / kg to about 2500 mg / kg, about 1250 mg / kg to about 2500 mg / kg, about 1300 mg / kg to about 2500 mg / kg, about 1400 mg / kg to about 2500 mg / kg, about 1500 mg / kg to 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, 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 26 weeks, at least about 27 weeks or at least about 28 weeks.

[0152] In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient by intravenous infusion from about 500 mg / kg to about 1000 mg / kg of the hydroxypropyl β-cyclodextrin composition once every 28 days for at least about 24 weeks. In certain embodiments, administering an effective amount of a hydroxypropyl β-cyclodextrin composition comprises administering to a human patient by intravenous infusion from about 500 mg / kg to about 2000 mg / kg of the hydroxypropyl β-cyclodextrin composition once every 28 days for at least about 24 weeks.

[0153] In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion for 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 for 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 for a period of at least about 6.5 hours.

[0154] In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion for 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 for a period of about 44 hours. In certain embodiments, the hydroxypropyl β-cyclodextrin composition is administered to a human patient by intravenous infusion for a period of about 6.5 hours.

[0155] In certain embodiments, the hydroxypropyl β-cyclodextrin composition comprises from 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.

[0156] In certain embodiments, the hydroxypropyl β-cyclodextrin is the 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 value of from about 0.59 to about 1.14. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.59 to about 0.73. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from about 0.59 to about 0.8. In certain embodiments, the mixture of two or more hydroxypropyl β-cyclodextrin species has a molar substitution value of from 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 0.15% 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.

[0157] In certain embodiments, the method further comprises administering to a 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.

[0158] In certain embodiments, the method further comprises administering to a human patient a second therapeutic agent selected from the group consisting of cholinesterase inhibitors, NMDA receptor antagonists, humanized antibodies targeting tau protein, humanized antibodies targeting β-amyloid, and BACE inhibitors.

[0159] In certain embodiments, the method further comprises administering to a human patient a second therapeutic agent, wherein the second therapeutic agent is selected from any of the therapeutic agents listed in Table 1.

[0160] Table 1 Therapeutic agents for the treatment of Alzheimer's disease.

[0161]

[0162]

[0163]

[0164]

[0165] Pharmaceutical Composition

[0166] In one aspect, the present disclosure provides a pharmaceutical composition for treating early Alzheimer's disease in human patients in need thereof, the pharmaceutical composition generally comprising an effective amount of a hydroxypropyl β-cyclodextrin composition disclosed herein and one or more pharmaceutically acceptable excipients.

[0167] In some embodiments, the pharmaceutical composition described herein may comprise 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 β-cyclodextrin composition.

[0168] In some embodiments, the concentration of hydroxypropyl β-cyclodextrin in the pharmaceutical composition 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.

[0169] In certain embodiments, the pharmaceutical composition comprises a solution that comprises 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 5% (w / v) to about 35% (w / v), from about 5% (w / v) to about 30% (w / v), from about 5% (w / v) to about 25% (w / v), from about 5% (w / v) to about 20% (w / v), from about 5% (w / v) to about 15% (w / v), from about 5% (w / v) to about 10% (w / v), from about 10% (w / v) to about 35% (w / v), from about 10% (w / v) to about 30% (w / v), from about 10% (w / v) to about 25% (w / v), from about 10% (w / v) to about 20% (w / v), from about 10% (w / v) to about 15% (w / v), from about 15% (w / v) to about 35% (w / v), from about 15% (w / v) to about 30% (w / v), from about 15% (w / v) to about 25% (w / v), from about 15% (w / v) to about 20% (w / v), 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) of one or more hydroxypropyl β-cyclodextrin species.

[0170] 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 two or more hydroxypropyl β-cyclodextrin species. In some embodiments, a 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species is a 25% (w / v) aqueous solution of one or more hydroxypropyl β-cyclodextrin species.

[0171] In certain embodiments, the pharmaceutical composition comprises an aqueous solution of 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) 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 two or more hydroxypropyl β-cyclodextrin species. In some embodiments, a 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species is an aqueous 25% (w / v) solution of one or more hydroxypropyl β-cyclodextrin species.

[0172] In some embodiments, one or more pharmaceutically acceptable excipients are selected from the group consisting of diluents, buffers, preservatives, stabilizers, solubilizers, or any combination thereof.

[0173] In certain embodiments, the pharmaceutical composition can be formulated for administration as a liquid dosage form suitable for intra-cavitary, intradermal, intramuscular, intrathecal, intravenous, subcutaneous, or intraventricular administration.

[0174] In certain embodiments, the liquid dosage form of the pharmaceutical composition as described herein further comprises a diluent. In some embodiments, the diluent is a salt solution.

[0175] In certain embodiments, the liquid dosage form of the pharmaceutical composition as described herein further comprises a buffer. For example, suitable buffers for the present disclosure include, but are not limited to, organic and inorganic acids and their salts, such as citrate buffers (e.g., monosodium citrate - disodium citrate mixture, citric acid - trisodium citrate mixture, citric acid - monosodium citrate mixture), succinate buffers (e.g., succinic acid - monosodium succinate mixture, succinic acid - sodium hydroxide mixture, succinic acid - disodium succinate mixture), tartrate buffers (e.g., tartaric acid - sodium tartrate mixture, tartaric acid - potassium tartrate mixture, tartaric acid - sodium hydroxide mixture), fumarate buffers (e.g., fumaric acid - monosodium fumarate mixture, fumaric acid - disodium fumarate mixture, monosodium fumarate - disodium fumarate mixture), gluconate buffers (e.g., gluconic acid - sodium gluconate mixture, gluconic acid - sodium hydroxide mixture, gluconic acid - potassium gluconate mixture), oxalate buffers (e.g., oxalic acid - sodium oxalate mixture, oxalic acid - sodium hydroxide mixture, oxalic acid - potassium oxalate mixture, etc.), lactate buffers (e.g., lactic acid - sodium lactate mixture, lactic acid - sodium hydroxide mixture, lactic acid - potassium lactate mixture, etc.) and acetate buffers (e.g., acetic acid - sodium acetate mixture, acetic acid - sodium hydroxide mixture, etc.). Additionally, phosphate buffer, histidine buffer, and trimethylamine salts such as Tris can be used.

[0176] In certain embodiments, the liquid dosage form of the pharmaceutical composition as described herein further comprises a pH regulator. For example, suitable pH regulators include, but are not limited to, IN sodium hydroxide and 37% hydrochloric acid (HCl).

[0177] In certain embodiments, the liquid dosage form of the pharmaceutical composition as described herein further comprises a preservative. For example, suitable preservatives for use in the present disclosure include, but are not limited to, phenol, benzyl alcohol, m-cresol, methyl paraben, propyl paraben, octadecyl dimethyl benzyl ammonium chloride, benzalkonium halides (e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkyl esters of p-hydroxybenzoic acid (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, catechol, resorcinol, cyclohexanol, and 3-pentanol).

[0178] In certain embodiments, the liquid dosage form of the pharmaceutical composition as described herein further comprises a stabilizer. For example, suitable stabilizers include, but are not limited to, polyhydric alcohols, trihydric or higher polyols, amino acids, organic sugars or sugar alcohols, polyvinylpyrrolidone, monosaccharides, trisaccharides, polysaccharides, proteins, sulfur-containing reducing agents, amino acid polymers, and polyethylene glycols.

[0179] In certain embodiments, the liquid dosage form of the pharmaceutical composition as described herein further comprises a solubilizer. In some embodiments, the solubilizer is an ionic surfactant. Examples of nonionic surfactants include, but are not limited to, polysorbates, poloxamers, pluronic polyols, and polyoxyethylene sorbitan monoethers.

[0180] In certain embodiments, the pharmaceutical composition of the hydroxypropyl-β-cyclodextrin composition disclosed herein can be prepared for storage as a lyophilized formulation or an aqueous solution by mixing the hydroxypropyl-β-cyclodextrin composition with optional pharmaceutically acceptable carriers, excipients, or stabilizers commonly employed in the art (e.g., buffers, stabilizers, preservatives, isotonic agents, nonionic detergents, antioxidants, and other miscellaneous additives).

[0181] In certain embodiments, the pharmaceutical composition comprising the hydroxypropyl-β-cyclodextrin composition disclosed herein is 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.

[0182] In certain embodiments, the pharmaceutical compositions described herein further comprise a second therapeutic agent. In some embodiments, the second therapeutic agent is indicated for the treatment of 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 cholinesterase inhibitors, NMDA receptor antagonists, humanized antibodies targeting tau protein, humanized antibodies targeting beta-amyloid, and BACE inhibitors. In some embodiments, the second therapeutic agent is selected from the group consisting of: donepezil, memantine, Namenda galantamine, ODT, rivastigmine, vitamin E, ER, donepezil / memantine, ergoloid mesylates, Aqua etanercept, natural vitamin E supplement, and clear E-400.

[0183] In some embodiments, the second therapeutic agent is selected from any of the therapeutic agents listed in Table 1.

[0184] 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-Aβ vaccine), ACI-35 (anti-pTau vaccine), aducanumab (BIIB037) (beta-amyloid mAb), AGB101 (levetiracetam low dose), ALZ-801 (beta-amyloid-protein inhibitor), ALZT-OP1 (beta-amyloid-protein inhibitor / inflammatory mediator inhibitor), AMG520 / CNP520 (BACE1 protein inhibitor), ANAVEX TM2-73 (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 analogue / ultra-low dose quinidine), AXS-05 (bupropion / dextromethorphan), azeliragon (TTP488) (RAGE antagonist), BAN2401 (anti-beta amyloid mAb), Bexarotene (RXR-selective retinoid analogue), BI 409306 (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 (new generation acetylcholinesterase inhibitor), CPC-250 (new generation acetylcholinesterase inhibitor), Crenezumab (anti-beta amyloid antibody), CSP-1103 (beta amyloid-protein inhibitor), CSTC1 (BAC), CT1812 (beta amyloid oligomer receptor antagonist), E2027 (PDE9 inhibitor), E2609 (BACE1 protein inhibitor), EVT302 (MAO-B inhibitor), gantenerumab (beta amyloid-protein inhibitor), GC021109 (purinergic receptor P2Y6 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 capsule of trans-resveratrol), KPAX002-2 (proprietary version of methylphenidate), lanabecestat (BACE inhibitor), LM11A-31 (p75neutrophin receptor), LMTX (tau protein aggregation inhibitor / TDP-43 aggregation inhibitor), LY3002813 (N3pG-β amyloid antibody), LY3202626 (BACE inhibitor), LY3303560 (tau antibody), M1 agonist (selective M1 receptor agonist), MEDI1814 (anti-β amyloid 42 mAb), mesenchymal stem cell therapy, MP-101 (mGluR2 / mGluR3 agonist), MSDC-0160 (mTOT regulator), NBXT-001 + Nobilis TM Inhalation device (NMDA receptor antagonist), neflamapimod (VX-745) (p38 mitogen-activated protein kinase inhibitor), NGP 555 (γ-secretase complex regulator), nilvadipine (soluble amyloid reducing / clearing agent), NPT088 (GAIM Ig fusion targeting β-amyloid, tau, a-synuclein), pimavanserin, PF-05251749 (casein kinase 1δ / ε), PF-06648671 (γ-secretase complex regulator), PF-06751979 (enzyme inhibitor), pioglitazone (low dose) (PPARγ agonist), piromelatine (melatonin agonist), R-phenserine, brexpiprazole, RG6100 (tau protein inhibitor), RVT-103 + RVT-104 (QAAM + cholinesterase inhibitor), SAR228810 (anti-fibrillar AB mAb), selective BACE 1 inhibitor, solanezumab (β-amyloid inhibitor), SUVN-502 (5-hydroxytryptamine 6 receptor antagonist), SUVN-D4010 (5-hydroxytryptamine 4 receptor antagonist), SUVN-G3031 (histamine H3 receptor antagonist), T-817MA (β-amyloid inhibitor), T3D-959 (PPAR-δ / γ agonist), TAK-071 (muscarinic M1 receptor modulator), TPI 287 (new generation taxane), UB-311 (anti-amyloid endosome vaccine), UE-2343 (11β-HSD1 inhibitor), verubecestat (MK-8931) (BACE1 protein inhibitor) or a combination thereof.

[0185] In certain embodiments, the pharmaceutical compositions of the present disclosure are administered to a subject by intracavitary, intradermal, intramuscular, intrathecal, intravenous, subcutaneous, or intraventricular routes.

[0186] Kit

[0187] In various embodiments, the present invention provides a kit for treating early Alzheimer's disease in human patients in need thereof. In some embodiments, the kit generally comprises: i) instructions for administering the hydroxypropyl-β-cyclodextrin composition or pharmaceutical composition described herein to a human patient suffering from early Alzheimer's disease, and ii) a hydroxypropyl-β-cyclodextrin composition or pharmaceutical composition as described herein. In some embodiments, the kit may comprise one or more unit dosage forms containing an amount of the hydroxypropyl-β-cyclodextrin composition or pharmaceutical composition as described herein alone that is effective to treat early Alzheimer's disease in a human patient.

[0188] In certain embodiments, the kit comprises: i) instructions for administering the 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 as described herein. In some embodiments, the hydroxypropyl-β-cyclodextrin composition is the CycloTM hydroxypropyl-β-cyclodextrin composition.

[0189] In some embodiments, the kit further comprises one or more selected from the group consisting of: a sterile syringe, a sterile needle, a sterile IV bag, an infusion pump, or any combination thereof.

[0190] The above description describes various aspects and embodiments of the present invention, including hydroxypropyl-β-cyclodextrin compositions, methods of treating subjects suffering from early Alzheimer's disease using hydroxypropyl-β-cyclodextrin compositions, pharmaceutical compositions comprising hydroxypropyl-β-cyclodextrin compositions, and kits. This patent application specifically contemplates all combinations and permutations of the various aspects and embodiments. Examples

[0191] To more fully understand the disclosure described herein, the following examples are set forth. The examples described in this application are provided to illustrate the compositions and methods provided herein and are not to be construed in any way as limiting their scope.

[0192] Abbreviations

[0193] Aβ amyloid load

[0194] Aβ β-amyloid

[0195] Aβ40 β-amyloid 40

[0196] Aβ42 β-amyloid 42

[0197] AD Alzheimer's disease

[0198] ADAS-Cog-14 Alzheimer's Disease Assessment Scale - Cognitive Subscale 14

[0199] ADCS-ADL Alzheimer's Disease Cooperative Study - Activities of Daily Living

[0200] ADCS-CGIC Alzheimer's Disease Cooperative Study - Change in Global Impression of Change

[0201] AE Adverse Event

[0202] APP Amyloid Precursor Protein Processing

[0203] ApoE Apolipoprotein E

[0204] APS Amyloid Probability Score

[0205] APOE Apolipoprotein E

[0206] aPTT Activated Partial Thromboplastin

[0207] ARIA Amyloid-Related Imaging Abnormalities

[0208] ARIA-E Amyloid-Related Imaging Abnormalities - Edema

[0209] ARIA-H Amyloid-Related Imaging Abnormalities - Hemorrhage

[0210] ATN Amyloid / tau / Neurodegeneration

[0211] BACE β-site APP Cleaving Enzyme

[0212] CDR Clinical Dementia Rating

[0213] CDR-SB Clinical Dementia Rating - Sum of Boxes

[0214] CNS Central Nervous System

[0215] CSF Cerebrospinal Fluid

[0216] C-SSRS Columbia-Suicide Severity Rating Scale

[0217] CT Computed Tomography

[0218] DS / DS a Average Degree of Substitution

[0219] DSMB Data and Safety Monitoring Board

[0220] DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition

[0221] EAD Early Alzheimer's Disease

[0222] ECG Electrocardiogram

[0223] eGFR Estimated glomerular filtration rate

[0224] EOS End of study

[0225] EOT End of treatment

[0226] EOS End of study

[0227] ET Early termination

[0228] FDA Food and Drug Administration

[0229] GDS Geriatric Depression Scale - Short Form

[0230] GDS-SF Geriatric Depression Scale - Short Form

[0231] HDL High - density lipoprotein

[0232] HIS Modified Hachinski Ischemia Scale

[0233] HPβCD Hydroxypropyl - β - cyclodextrin

[0234] INR International Normalized Ratio

[0235] IV Intravenous

[0236] LE Late endosome

[0237] LDL Low - density lipoprotein

[0238] LY Late lysosome

[0239] MCI Mild cognitive impairment

[0240] MDD Major depressive disorder

[0241] MDRD Modification of Diet in Renal Disease

[0242] MMSE-2:SV Mini - Mental State Examination - 2 Standard Version

[0243] MRI Magnetic resonance imaging

[0244] MS / MS a Average molar substitution

[0245] NfL Neurofilament light chain

[0246] NIA-AA National Institute on Aging - Alzheimer's Association

[0247] NMDA N - methyl - D - aspartic acid

[0248] PD Pharmacodynamics

[0249] PET Positron Emission Tomography

[0250] PK Pharmacokinetics

[0251] PT Prothrombin Time

[0252] SoA Assessment Schedule

[0253] TdP Torsades de Pointes

[0254] TEAE Treatment Emergent Adverse Events

[0255] TSH Thyroid Stimulating Hormone

[0256] USP United States Pharmacopeia

[0257] WFI Water for Injection

[0258] WOCBP Women of Childbearing Potential

[0259] Example 1. A randomized, placebo-controlled, double-blind, parallel-group, 6-month study to evaluate the safety, tolerability, and potential efficacy of monthly infusions of Cyclo TM (hydroxypropyl-β-cyclodextrin, HPβCD) in patients with early Alzheimer's disease

[0260] 1. Objectives

[0261] Evaluate Cyclo TM The safety and tolerability of Cyclo over 24 weeks in patients with early Alzheimer's disease (EAD).

[0262] Explore Cyclo TM The potential efficacy of Cyclo over 24 weeks in patients with EAD.

[0263] Determine Cyclo TM The pharmacokinetics (PK) of Cyclo over 24 weeks in patients with EAD.

[0264] 2. Study Design

[0265] This is a randomized, placebo-controlled, double-blind, parallel-group study that evaluates, in accordance with the FDA Early Alzheimer's Disease Industry Guide: Developing Drugs for Treatment, Safety, Tolerability, and Potential Efficacy of CycloTM in Patients with EAD. [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.]

[0266] The study enrolled approximately 120 male and female patients (30 patients per treatment group) aged 50 to 80 years at screening with characteristic pathophysiological changes of Alzheimer's disease (AD) who met the National Institute on Aging - Alzheimer's Association (NIA - AA) or FDA industry guidelines for early Alzheimer's disease: treatment criteria for AD with mild cognitive impairment (MCI) or mild AD (stages 3 and 4), collectively referred to as EAD, for drug development. [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., 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.] The enrolled patients had evidence of progressive cognitive decline in the past year, which was determined by serial cognitive test scores (if available) or information reported by the researcher's informant or caregiver / study partner (hereinafter referred to as caregiver).

[0267] Due to the nature of EAD, a primary caregiver is identified for the patient prior to study participation, who assists the patient in participating in the study. The patient is accompanied by their caregiver at each visit. The caregiver has at least approximately 10 hours of face-to-face contact with the patient per week, distributed over 2 to 5 days of the week (e.g., 2 hours per day for 5 days per week or 5 hours twice a week). A legally authorized representative may be the caregiver. The caregiver does not have to be a family member.

[0268] During the screening period (up to 42 days before Visit [V]2 / baseline), all potential patients and their primary caregivers provide written informed consent to participate in the study prior to any study-related assessments. Blood samples are collected from all patients at the screening visit (V1) for PrecivityAD TM blood testing and / or clinical laboratory evaluations.

[0269] Patients also undergo magnetic resonance imaging (MRI) within 12 months prior to the screening visit (V1) to confirm the diagnosis of EAD and rule out any other clinically significant conditions. Computed tomography (CT) may be substituted only if the patient has an absolute contraindication to MRI.

[0270] Although the FDA's industry guidance on early Alzheimer's disease: Therapeutic drug development [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.] is silent on specific biomarkers used to meet the recent consensus statement on amyloid / tau / neurodegeneration (ATN) criteria, the protocol provides additional requirements (A) for amyloid load detection.

[0271] Specifically, to support the diagnostic criteria of relevant guidelines based on the NIA-AA standard [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.], during screening, all eligible patients are required to undergo a lumbar puncture and have CSF biomarker characteristics consistent with a diagnosis of AD or a PrecivityAD blood test with a high amyloid probability score (APS [58-100]).

[0272] Patients meeting the inclusion criteria based on the PrecivityAD blood test results and other eligibility criteria also show evidence of cerebral β-amyloid (Aβ) pathology at the pre-treatment baseline visit (V2) according to cerebrospinal fluid (CSF) analysis evaluating Aβ42 / 40 levels; or patients with MCI need to meet the criterion of CSF Aβ42 / 40 ratio < 0.72, and patients with EAD need to meet the criteria of Aβ42 / 40 ratio < 0.72 and CSF P-tau > 50 pg / mL.

[0273] The Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination-2: Standard Version (MMSE-2:SV), Alzheimer's Disease Cooperative Study-Clinician's 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) were obtained to support the diagnosis of AD according to the NIA-AA criteria-based diagnostic guidelines [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.] as well as physical examination, vital signs, and 12-lead electrocardiogram (ECG). The Geriatric Depression Scale-Short Form (GDS-SF) and the modified Hachinski Ischemic Scale (HIS) were used to rule out potential diagnoses. Previous and current medications were recorded. Other required assessments are listed in the Schedule of Assessments (SoA, Table 2).

[0274] Table 2 Schedule of Assessments

[0275]

[0276]

[0277] Note: On a case-by-case basis, if a patient is unable to complete all assessments within 1 study visit day, the study visit can be extended for more than 2 days with the agreement of the sponsor in consultation with the medical monitor and the investigator. Efficacy assessments and specific safety assessments (vital signs, AEs) will be completed on the first day, and IMP IV infusion, safety assessments (laboratory tests, vital signs, ECG, AEs, safety scales), and PK sampling will be completed on the second day.

[0278] 1. After the patient meets the inclusion criteria based on the PrecivityAD blood test results and other eligibility criteria, a CSF analysis to assess Aβ42 / 40 levels must be performed to confirm the diagnosis of Alzheimer's disease. If a CSF assessment has been performed prior to screening, these tests do not need to be repeated as long as the results of the PrecivityAD blood test meet the inclusion criteria. All patients are also required to consent to lumbar puncture and CSF analysis at the EOT / EOS visit. Coagulation tests (prothrombin time [PT] / international normalized ratio [INR] and activated partial thromboplastin time [aPTT]) are performed prior to lumbar puncture. Clinical laboratory safety tests at the screening visit include platelet measurement. Additional coagulation tests may be performed prior to lumbar puncture at the discretion of the investigator for patients with abnormal coagulation results or increased bleeding risk.

[0279] 2. Vital signs include body temperature, respiratory rate, weight, supine and sitting radial artery pulse rate, and sitting systolic and diastolic blood pressure. The sitting measurements are taken after the patient has been sitting for at least 3 minutes with feet flat on the floor, arms relaxed, and elbows bent. The method for obtaining body temperature will follow the standard practice at each site, but should be the same method for a given patient throughout the study. Vital signs are measured prior to the start of the infusion. Height for calculating body mass index is recorded during the physical examination.

[0280] 3. A standard 12-lead ECG in triplicate is evaluated at each center for clinically relevant abnormalities. The ECG is obtained using the same machine each time after the patient has been quietly supine for approximately 3 minutes. The ECG is evaluated by a medically qualified investigator at each center for clinically relevant abnormalities during the infusion. A 12-lead ECG in triplicate is obtained at screening to confirm QTcF < 450 ms for males and QTcF < 460 ms for females; for all other designated visits, the ECG readings will be done immediately before the start of the infusion, +60 minutes after the start of the infusion, and immediately after the infusion is completed. At baseline, a 12-lead ECG in triplicate is collected at three different time points (-60, -45, and -30 minutes) starting -60 minutes prior to the first administration (Week 0). At Week 0 (baseline), Week 4, and Week 8, the 12-lead ECG in triplicate is time-matched with PK sampling (PK sampling should be done after the tracer, preferably within 2 minutes).

[0281] 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, γ-glutamyl transferase, blood urea nitrogen, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, creatinine, eGFR by MDRD, alkaline phosphatase, lactate dehydrogenase, sodium, potassium, calcium, chloride, albumin, uric acid, and glucose), C-terminal telopeptide, and urine analysis (macroscopic analysis, microscopic analysis only if indicated by dipstick). Analysis includes color, turbidity, specific gravity, pH, glucose, protein, ketones, urobilinogen, bilirubin, blood nitrite, and leukocyte esterase. At screening, laboratory tests 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 clinically suspected severe hypothyroidism, eGFR by MDRD, and vitamin B12. Laboratory tests are completed before the start of the infusion.

[0282] 5. All patients will have PK sampling completed before the start of the study drug infusion at baseline (Week 0, V2), Week 4 (V3), and Week 8 (V4), at 1 and 3 hours after the infusion, at the end of the infusion, at 50 to 60 minutes after the infusion, and at 2 hours after the infusion. PK sampling to obtain trough concentrations is obtained before the start of the study drug infusion at Week 12 (V5) and Week 24 (V8). ET patients are not required to participate in the PK procedure unless safety observations suggest discontinuation of the study drug. At Week 0 (baseline), Week 4, and Week 8, PK sampling is time-matched with a 12-lead ECG in triplicate (PK sampling should be performed after the tracer, preferably within 2 minutes).

[0283] 6. At each visit, a POC urine pregnancy test is performed on female patients of childbearing potential. Any positive POC urine pregnancy test is confirmed by a serum pregnancy test before the patient continues in the study.

[0284] 7. Urine drug screening is performed at screening (V1) and before the baseline infusion (V2).

[0285] 8. Any residual blood and / or plasma from PD biomarker analysis is saved for subsequent analysis.

[0286] 9. MRI evaluations of ARIA-E and ARIA-H are planned; the results are evaluated by the DSMB.

[0287] 10. The patient will complete an auditory assessment (e.g., pure tone average / pure tone audiometry 1 to 8 kHz or auditory evoked potential / auditory brainstem response) during the screening period (V1), within one week before each administration of the study drug starting from the 3rd visit (the hearing test results are available for the researcher to review before the next administration of the study drug), and at week 24 (EOT / EOS, V8). In addition, the researcher may arrange additional assessments according to the patient's reported hearing loss. Prompt the patient to report any hearing loss before the study drug infusion and during the follow-up phone calls.

[0288] 11. After all assessments are conducted, a certain dose of the study drug will be administered at the clinic every 4 weeks by IV infusion for 4 hours until week 24. If the researcher, the sponsor, and the patient / caregiver agree, the study drug can be administered at home by appropriately trained personnel. The minimum interval between infusions is 25 days, and the maximum interval is 42 days; exceptions to this guideline should be reviewed by the medical monitor.

[0289] At the baseline visit (V2), patients meeting all eligibility criteria will be randomly assigned in a 1:1:1:1 ratio to receive one of 3 study treatments:

[0290] I. 500 mg / kg CycloTM

[0291] II. 1000 mg / kg CycloTM

[0292] III. 2000 mg / kg CycloTM

[0293] IV. Placebo

[0294] A dose of the study drug will be administered by intravenous infusion for 4 hours every 4 weeks until week 24. Each patient will receive a maximum of 7 doses of the study drug.

[0295] The patient and their caregiver will visit the clinic every 4 weeks (V2 to V8). The caregiver does not need to be present throughout the visit. Throughout the study, safety will be evaluated by repeated physical examinations, vital signs, clinical laboratory tests, 12-lead ECG, C-SSRS, and recording concomitant medications and adverse events (AE). Throughout the study, the potential efficacy of the study drug will be evaluated by collecting the Alzheimer's Disease Assessment Scale - Cognitive Subscale 14 (ADAS-Cog-14), CDR-SB, and MMSE-2:SV. The specific assessments for each visit are listed item by item in the SoA (Table 2).

[0296] At the follow-up visit (V9) 2 weeks after the last dose of the study drug, a safety assessment will be obtained. The specific assessments for each visit are listed item by item in the SoA (Table 2).

[0297] MRI evaluations of amyloid-related imaging abnormalities - edema (ARIA-E) and amyloid-related imaging abnormalities - hemorrhage (ARIA-H) are planned during the 6-month treatment period. Each patient is planned to have scans at screening (V1), 8 weeks (V4), 16 weeks (V6), and 6 months (V8) after starting the double-blind study drug. Local readings of these radiological evaluations are always performed as part of the safety assessment; central readings can also be achieved. The Data and Safety Monitoring Board (DSMB) oversees the results of these evaluations in a fully blinded manner to determine whether amyloid-related imaging abnormalities (ARIA) are detected in patients randomly assigned to receive active therapy.

[0298] Throughout the study, the safety of study participants is evaluated by repeated physical examinations, vital signs, safety laboratory tests, 12-lead ECG, the occurrence of ARIA, and the assessment of treatment-emergent adverse events (TEAE). Regular safety reviews are conducted during the study. The frequency of these evaluations based on patient percentages and study time is defined in the DSMB charter developed before the start of the study.

[0299] All patients complete PK sampling before the start of the study drug infusion at baseline (week 0, V2), week 4 (V3), week 8 (V4), 1 and 3 hours after the infusion, at the end of the infusion, 50 to 60 minutes after the infusion, and 2 hours after the infusion. All patients complete sampling for trough concentration potential analysis before the start of the study drug infusion at week 12 (V5) and week 24 (V8). At week 0 (baseline), week 4, and week 8, ECG tracings in triplicate are time-matched with the PK samples.

[0300] 3. Treatment Duration

[0301] This study consists of 3 phases: a screening period of up to 42 days, a treatment period of up to 24 weeks, and a safety follow-up period of 2 weeks. The total duration of a patient's participation in the study is up to 32 weeks.

[0302] 4. Planned Sample Size and Treatment Groups

[0303] The planned sample size is approximately 120 randomized patients. This study consists of 3 groups: 500 mg / kg Cyclo TM 、1000 mg / kg or 2000 mg / kg Cyclo TM ,or placebo, in a ratio of 1:1:1:1 (30 patients / group). All patients receive the study drug or placebo intravenously.

[0304] 5. Target Population

[0305] Patients with EAD.

[0306] 6. Study Population

[0307] The study enrolled approximately 120 male and female patients who were generally healthy, aged ≥50 years and ≤80 years, and had 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.], who had experienced progressive cognitive decline in the past year and met all the criteria listed below. The goal at each site was to enroll approximately the same proportion of patients with MCI due to AD and mild AD so that the proportion in each group did not exceed 60%, but randomization was not restricted to the site level but to the study level.

[0308] 7. Eligibility Criteria

[0309] Patients were eligible to participate in this study if they met the inclusion criteria and did not meet any of the following exclusion criteria.

[0310] I. Inclusion criteria: Patients were eligible to participate in this study if they met all of the following criteria:

[0311] 1. Males or females aged ≥50 to ≤80 years at consent.

[0312] a. At least an eighth-grade education.

[0313] b. The primary language of patients in the United States must be English, and the patient should be able to understand and read English at a level that will ensure adequate completion of the study procedures, including all cognitive tests.

[0314] 2. According to the FDA Early Alzheimer's Disease Industry Guide: Therapeutic Drug Development [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.], MCI due to AD (Phase 3).

[0315] a. Meeting the NIA-AA criteria for MCI due to 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 parenteral administration of 2-hydroxypropyl β-cyclodextrin causes bone loss. Toxicol Pathol. 2012;40(5):742-50.]

[0316] b. At screening (V1) and baseline (V2), the overall Clinical Dementia Rating (CDR) scale score is 0.5, and the CDR memory item score is 0.5 or higher.

[0317] c. A history of memory complaints / deterioration that gradually appeared and slowly progressed within 1 year prior to screening (V1), reported by the patient or their partner / caregiver.

[0318] d. Based on the review by the patient and caregiver, the investigator believes there is relatively preserved functional ability and activities of daily living.

[0319] Or

[0320] According to the FDA's Early Alzheimer's Disease Industry Guidance: Therapeutic Drug Development [Vellas B, Bateman R, Blennow K, et al. Endpoints for pre-dementia AD trials: a report EU / US / CTAD Task Force. J Prev Alzheimers Dis. 2015;2(2):128-135.], mild AD (stage 4) dementia

[0321] e. Meet the 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.]

[0322] f. At screening (V1) and baseline (V2), have a global CDR score of 0.5 to 1.0 and a CDR memory item score of 0.5 or higher.

[0323] 3. All patients should have an MMSE-2:SV score of ≥20 and ≤28 at screening (V1) and baseline (V2), with a change of no more than 3 points between visits.

[0324] 4. During screening, the AD positive PrecivityAD blood test biomarker has a high APS (58-100); or CSF biomarkers used to support the diagnosis of AD.

[0325] a. Only after determining a positive PrecivityAD biomarker or brain AD pathology, evidence of brain Aβ pathology must also be demonstrated based on CSF analysis, evaluating Aβ42 / 40 and tau levels, meeting the criteria of CSF Aβ42 / 40 ratio <0.72 for patients with MCI and CSF P-tau >50 pg / mL for patients with EAD. The test results for determining brain Aβ pathology must be known before enrollment at baseline (V2).

[0326] 5. Brain MRI performed during screening or within 12 months prior to screening, which generally supports AD after local reading.

[0327] 6. Local or central MRI of ARIA shows fewer than 4 microbleeds.

[0328] 7. The patient must have a primary caregiver with sufficient access, who is able to provide an assessment of cognitive and functional changes and is willing to assume the primary responsibility for monitoring the patient and assessing the patient's condition throughout the study according to the protocol requirements. The primary caregiver must meet the following criteria:

[0329] a. Be able to and willing to provide the information required for efficacy assessments such as CDR-SB.

[0330] b. Be willing to sign the caregiver informed consent form.

[0331] 8. During the trial, it is unlikely to experience changes in living conditions (e.g., institutionalization, moving to another city, etc.) or changes in the primary caregiver.

[0332] 9. The use of pro-cognitive drugs or the use of acetylcholinesterase inhibitors and / or memantine for background symptomatic treatment of AD is permitted, as long as the dose has been stable for at least 60 days before screening (V1) and is expected to remain stable during the study. Note: Untreated patients can enter the study, but should not start AD treatment during the study.

[0333] 10. The use of background drugs for other stable chronic diseases not explicitly prohibited is permitted, provided that they remain stable during the study:

[0334] a. Psychotropic drugs, such as antidepressants and antipsychotics, must have a stable dose for at least 30 days before screening (V1) and remain stable throughout the study within the framework and protocol of Section 6.7.

[0335] b. Short-acting benzodiazepines for sleep can be used up to 3 times / week, but not within 24 hours of cognitive assessment.

[0336] 11. All patients must pass a brief audiological examination, including pure tone audiometry.

[0337] 12. Body mass index at screening (V1) is between 17 and ≤35 kg / m2, with a weight upper limit of 110 kg.

[0338] 13. Women participating in the study must meet one of the following criteria:

[0339] a. Surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, or tubal ligation) for at least 6 months or postmenopausal (postmenopausal women must have had no menstrual bleeding for at least 1 year) or

[0340] b. If not postmenopausal, agree to use highly effective contraception, including combined (estrogen and progestin) hormonal contraception associated with ovulation suppression (oral, intravaginal, or transdermal); progestin-only hormonal contraception associated with ovulation suppression (oral, injectable, or implantable); intrauterine device; intrauterine hormonal release system; or a vasectomized partner, and have a negative urine pregnancy test at screening. Highly effective contraception must be used during the study and for 3 months after the last dose of study treatment.

[0341] 14. All sexually active male patients with WOCBP partners (after menarche) must use condoms with or without spermicide during the study and for 3 months after the last dose of study treatment, in addition to the contraceptive measures used by their partners.

[0342] 15. Age-appropriate estimated glomerular filtration rate calculated by diet modification in kidney disease studies.

[0343] II. Exclusion Criteria: Patients are not eligible to participate in this study if they meet any of the following exclusion criteria:

[0344] 1. Clinically significant kidney disease that, in the opinion of the investigator, prevents the patient from participating in the study.

[0345] 2. Evidence of neurodegenerative disease other than AD or any history or brain imaging abnormality that the investigator believes may lead to dementia, including but not limited to vascular dementia, chronic traumatic encephalopathy, or uncontrolled major depressive disorder (MDD).

[0346] 3. Severe hypothyroidism, defined as hypothyroidism resistant to standard treatment and unresponsive or underresponsive to clinically relevant doses of levothyroxine (as determined by thyroid-stimulating hormone, T3, and T4), with clinical signs and symptoms.

[0347] 4. Abnormally low serum vitamin B12 levels (below the lower limit of normal for laboratory testing).

[0348] 5. Imaging should generally support the diagnosis of EAD, and importantly, be inconsistent with other neurodegenerative diseases or differential dementia diagnoses. For example, any signs of vascular disease, including multiple infarcts involving large vessels or a single localized infarct (angular gyrus, thalamus, anterior cerebral artery, and posterior cerebral artery regions), multiple lacunes in the basal ganglia or white matter, or extensive periventricular white matter lesions or a combination of several lesions, are considered exclusionary. In addition, any single lacune in a region known to affect cognition (such as the hippocampus) will also be excluded.

[0349] a. In the case where a previous MRI scan was used for inclusion, if there is any evidence of new neurological symptoms between that scan and the screening (V1), a repeat scan is required.

[0350] b. Exclude those without vascular dementia defined by HIS ≤ 4.

[0351] 6. Lack of visual, auditory acuity, and / or language ability sufficient for cognitive assessment.

[0352] 7. History of any disease requiring systemic treatment within the past 5 years, such as cancer, except for localized basal cell carcinoma of the skin and carcinoma in situ of the cervix successfully treated by surgery; history of severe heart failure (New York Heart Association scale class 2 or higher), severe stroke, uncontrolled epilepsy, or other diseases that the researchers believe will increase the risk of the patient's participation in the study or affect the study assessment.

[0353] 8. Patients identified during screening with the following measurements:

[0354] a. Platelet count < 50,000 / μL.

[0355] b. International normalized ratio > 1.5.

[0356] c. Patients with a bleeding tendency (activated partial thromboplastin time > 1.5 times the upper limit of normal).

[0357] 9. At screening (V1), positive blood screening for human immunodeficiency virus (HIV-1 and HIV-2), hepatitis B surface antigen, or hepatitis C virus antibody, unless they have successfully received a curative treatment for hepatitis C (e.g., Harvoni), and there is documentation that hepatitis B / C virus was not detected 3 months after completion of treatment.

[0358] 10. Any planned surgery requiring general anesthesia during the study. If the investigator believes that local anesthesia will not interfere with the study procedures and patient safety, the surgery is allowed during outpatient surgery.

[0359] 11. History of severe mental illness or current evidence according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), such as schizophrenia, bipolar disorder, or MDD; or, if the GDS-SF score at screening (V1) > 8, exclude MDD.

[0360] 12. History of violent or aggressive behavior requiring pharmacological control.

[0361] 13. Suicidal thoughts, intentions, or behaviors captured during C-SSRS screening, or a history of suicide attempts within 2 years prior to screening (V1). Note: There should be no active suicidal thoughts (Type 4 or 5 on the C-SSRS) within 6 months prior to screening (V1) or at baseline (V2); or a history of suicide attempts within the past 2 years; or a high risk of suicide as determined by the investigator's clinical judgment.

[0362] 14. A history of alcohol or drug abuse or dependence within 12 months after screening as defined by DSM-5. Note: If a patient has a positive urine screen for drug abuse (including methadone, cocaine, and amphetamines), they will be excluded; a positive urine screen for opioids, barbiturates, or benzodiazepines without a prescription at screening (V1).

[0363] 15. History of treatment with Aduhelm, donanemab, or investigational AD vaccine therapies for amyloid or tau; or participation in a clinical study involving monoclonal antibodies or derivatives or immunoglobulins within 12 months prior to screening (V1), unless it can be demonstrated that the patient was randomly assigned to the placebo group.

[0364] 16. Treatment with any known moderate or strong cytochrome P450 enzyme inhibitor / inducer (e.g., barbiturates, phenothiazines, cimetidine, carbamazepine) within 30 days prior to the first dose of the study drug, and the investigator determines that these drugs may affect the safety of the patient or the validity of the study results.

[0365] 17. Having any of the following otology-related exclusion criteria:

[0366] a. Current use or use within 60 days prior to study enrollment of ototoxic drugs, including but not limited to, aminoglycoside antibiotics (gentamicin, tobramycin, amikacin, streptomycin); platinum-containing chemotherapy (cisplatin, carboplatin, oxaliplatin); or loop diuretics (furosemide).

[0367] b. History of idiopathic sensorineural hearing loss, otosclerosis, or vestibular schwannoma.

[0368] c. History of middle ear or inner ear surgery or middle ear effusion.

[0369] i. A history of recurrent otitis media that the investigator believes may affect patient eligibility.

[0370] d. Current unilateral or bilateral conductive or sensorineural hearing loss (observed grade 3 hearing loss, defined as a loss > 25 decibels at 3 consecutive frequencies between 1 kHz and 8 kHz).

[0371] 18. Risk of QTc prolongation, such as a history of additional risk factors for TdP or sudden death (e.g., heart failure, hypokalemia, family history of long QT syndrome, unexplained syncope, concomitant use of antidepressant agents known to prolong QT / QTc).

[0372] 8. Study Drug

[0373] CycloTM (obtained from Cyclo Therapeutics, Inc.) and placebo (0.45% sodium chloride for intravenous infusion as control [1 / 2 normal saline]).

[0374] 9. Safety Endpoints

[0375] Incidence and severity of TEAE.

[0376] Adverse events of special interest (AESI): (1) MRI assessment of amyloid-related imaging abnormalities - hemorrhage (ARIA-H) or amyloid-related imaging abnormalities - edema (ARIA-E), (2) audiological examination based on hearing loss, and (3) infusion reactions.

[0377] Vital signs and / or physical examination.

[0378] Safety clinical laboratory values (hematology, clinical biochemistry, and urine analysis), including C-terminal telopeptide.

[0379] Twelve-lead electrocardiograms (ECGs) were performed in triplicate to support cardiac dynamics assessment, including concentration-QTc analysis. At Week 0 (baseline), Week 4, and Week 8, the triplicate ECGs were time-matched with PK samples.

[0380] Columbia-Suicide Severity Rating Scale (C-SSRS).

[0381] 10. Secondary Endpoints

[0382] Mean change in ADAS-Cog-14 total score from baseline (V2) to Week 12 (V5) and to Week 24 (V8).

[0383] Change in CDR-SB from baseline (V2) to Week 12 (V5) and to Week 24 (V8).

[0384] Change in MMSE-2:SV total score from baseline (V2) to Week 12 (V5) and to Week 24 (V8).

[0385] Change in ADCS-CGIC from baseline (V2) to Week 12 (V5) and to Week 24 (V8).

[0386] Changes in ADCS-ADL from baseline (V2) to week 12 (V5) and to week 24 (V8).

[0387] 11. Exploratory Endpoints

[0388] Changes in composite Z-scores for various outcome measures and cognitive domains from baseline (V2) to week 12 (V5) and to week 24 (V8): (1) ADAS-Cog-14, (2) CDR-SB, and (3) MMSE-2:SV.

[0389] Pharmacodynamic blood / plasma evaluations of Aβ, Aβ42, tau, total tau, phosphorylated tau, 24S-hydroxycholesterol, neuronal extracellular vesicle biomarkers, neurogranin, NfL, and other disease-related biomarkers.

[0390] 12. Pharmacokinetic Endpoints

[0391] Calculated PK parameters include but are not limited to Cmax, Tmax, half-life, AUClast, AUCinf, T1 / 2, Clast, and Tlast (see Table 10.1 in the master protocol). Plasma levels were measured at baseline (before the start of study drug infusion at week 0 (V2), week 4 (V3), week 8 (V4)), 1 and 3 hours after infusion, after infusion completion, and 2 hours after infusion, and 50 to 60 minutes after infusion. Plasma samples were collected before the start of study drug infusion at week 12 (V5) and week 24 (V8) for potential analysis of PK trough concentrations.

[0392] 13. Statistical Procedures

[0393] Descriptive statistics for ordinal (e.g., Likert scale) and continuous variables include the number of patients with non-missing values, mean, median, standard deviation, minimum, and maximum.

[0394] Safety analysis was based on the safety population, defined as all randomly assigned patients who received at least 1 dose of study drug. Efficacy analysis used the full analysis set based on the intention-to-treat principle.

[0395] For each efficacy endpoint, changes from baseline to each applicable post-baseline visit were evaluated using a repeated measures mixed model to analyze treatment group differences, which included the following factors: study site, treatment group, weeks, and the interaction of treatment group and weeks, and used the baseline response variable value as a covariate.

[0396] As a sensitivity analysis, analysis of covariance was used, where the fixed factors included study site and treatment group, and the baseline value was used as a covariate.

[0397] Additionally, subgroup analyses can be performed. Subgroup analyses can include, but are 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 groupings of patients.

[0398] AEs can be classified according to the System Organ Class and Preferred Terms in the Medical Dictionary for Regulatory Activities. The summary table of TEAEs includes the number and percentage of patients who experienced TEAEs by System Organ Class and Preferred Term.

[0399] The mean changes in safety clinical laboratory parameters (hematology, clinical chemistry, and urinalysis), including C-terminal telopeptide and vital signs, from baseline to each post-baseline visit were descriptively summarized. Safety clinical laboratory results that the investigator considered to be of clinical importance were determined.

[0400] The planned statistical analysis methods are described in more detail in the Statistical Analysis Plan, which is completed prior to database lock.

[0401] Incorporated by reference

[0402] For all purposes, the entire disclosure of each patent document and scientific article mentioned herein is incorporated herein by reference.

[0403] Equivalents

[0404] Without departing from the basic characteristics of the present disclosure, the present disclosure may be implemented in other specific forms. Accordingly, the foregoing embodiments are to be considered illustrative rather than limiting the disclosure described herein. The scope of the present disclosure is indicated by the appended claims rather than by the foregoing description, and all changes within the meaning and scope of the claims are intended to be included within the scope of the present disclosure.

Claims

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

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

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

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

5. The method of any one of claims 1-4, wherein the human patient has a global clinical dementia rating (CDR) scale score of about 0.5 and a CDR memory item score of about 0.5 or higher at the start of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition.

6. The method of any one of claims 1-4, wherein the human patient has a global clinical dementia rating (CDR) scale score of about 0.5 to about 1.0 and a CDR memory item score of about 0.5 or higher at the start of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition.

7. The method of any one of claims 1-6, wherein the human patient exhibits brain β-amyloid (Aβ) pathology at the start of administration of the effective amount of the hydroxypropyl β-cyclodextrin composition.

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

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

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

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

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

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

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

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

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

17. The method according to any one of claims 1-15, 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. The method according to any one of claims 1-17, 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. The method according to any one of claims 1-15 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, once every 28 days.

20. The method according to any one of claims 1-19, 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, once every 28 days.

21. The method according to any one of claims 1-15, 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, once every 28 days, for a period of at least about 24 weeks.

22. The method according to any one of claims 1-21, 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, once every 28 days, for a period of at least about 24 weeks.

23. The method according to any one of claims 17-22, 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. The method according to any one of claims 17-22, 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. The method according to any one of claims 1-24, wherein the hydroxypropyl-β-cyclodextrin composition comprises about 25% (w / v) hydroxypropyl-β-cyclodextrin.

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

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

14.

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

8.

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

0.

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

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

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

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

35. The method according to any one of claims 1-33, further comprising administering a second therapeutic agent selected from the group consisting of cholinesterase inhibitors, NMDA receptor antagonists, humanized antibodies targeting tau protein, humanized antibodies targeting β-amyloid, and BACE inhibitors.

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

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