Applications of chemically-modified cyclodextrins: Use of hydroxypropyl-β-cyclodextrin as an enabling excipient for brain targeting, redox-based derivatives of estradiol: A review of preclinical and clinical findings

Estrogen depletion associated with the menopause produces a constellation of debilitating symptoms which range the gamut from vasomotor complaints which severely affect over one-third of all climacteric women to cognitive deficits. While many of these complications can be alleviated with traditional hormone replacement therapy (HRT), fear of cancer, cardiovascular problems and other metabolic diseases prompt many women to avoid treatment. Surveys suggest that over 30% of all prescriptions written for HRT are never filled due to these concerns and recent findings from Woman's Health Initiative trials have only added to these trepidations. Selective brain delivery of estrogens, in general, and estradiol, in particular, may address these items. One approach to accomplish CNS deposition is the use of a chemical delivery system for estradiol that selectively targets the central nervous system and may, therefore, reduce the incidence or severity of peripherally manifested side-effects. Owing to the very poor water solubility and limited stability of these derivatives, hydroxypropyl-β-cyclodextrin has proved to be enabling excipients in the development of these drug candidates. Various preclinical evaluations have demonstrated the organ-targeting potential of an estradiol-chemical delivery systems (E2-CDS) and therefore its potential usefulness as a therapeutic adjunct in certain subpopulations of menopausal women including those at risk to breast carcinomas. A very exciting potential use of the E2-CDS is in neurodegenerative diseases. Data suggest that estrogens may improve the mental performance of elderly patents suspected of having Alzheimer's disease.