**7. From Patents to Clinical Trials of Inositols**

The industrialized market for nutritional products, such as dietary supplements, has experienced spectacular growth during the late 1990s and the last decade, and has been focused on the development of functional and nutraceutical food products. One of the reasons for the expansion has been the change in the trend of consumers towards the use of supplements with a natural origin. Because there is no worldwide legislation that establishes a precise definition of nutraceuticals, their protection and marketing have both raised certain doubts. Generally, an updated term for nutraceuticals is a product of natural origin that possesses study-based beneficial effects on health.

As we have described throughout this review, inositols fall within these characteristics. The fact that they are molecules with multiple beneficial functions for health (i.e., via their antioxidant capacity, improvement of insulin resistance, and treatment of cardiovascular problems) has led to a high competitiveness to patent their use in an ambit where effective treatments are not available. This is the figure associated with the Alzheimer's market. Since the mid-2000s, there has been a significant increase in the number of patents related to the use of inositols in AD. To document this, we have performed an advanced search on the World Intellectual Property Organization (WIPO) database, combining results for all nine inositol stereoisomers and derivatives, excluding phosphate-linked forms of inositols and Alzheimer's disease. After compiling all the results that contained the terms described in the title, abstract, or claims, we carried out a refinement process (elimination of duplicates, exclusion of "inositol derivatives" if not specified) and obtained a total of 26 patents distributed according to the mentioned compounds (Figure 5).

In this race to patent publication, however, it should be kept in mind that while some justify the substantiated use of a specific compound, others rely on general formulations of inositols. On the other hand, some of the studies that support the claims include AD either as the main objective in a set of common diseases, or secondarily due to the overlap of previous patents or the lack of consistency for results in an AD model. Despite the tendency slowing, the number of patents has continued to increase during 2020s, with the search for functional radical-substituted inositol derivatives prioritized over inositol stereoisomers. Although not depicted, many patents have emerged regarding the use of inositols as "carriers" of other substances, allowing them to access targets in the brain.

The late goal of nutraceutical compounds is to be approved in clinical trials. The importance of this resides in the definition of an adequate dose and the approval for use as adjuvant therapies, as in the case of AD. Since nutraceuticals are generally marketed for safe human use, this results in an advantage over synthetic drugs. From 2007 on, at least five phase II clinical trials for SI and two phase II clinical trials for DPIN have been completed for AD and AD-like dementia (Table 3). As mentioned earlier, some concerns have arisen regarding high dosages of SI. Nevertheless, a 250 mg dose of SI results in some significant improvements in the biochemical and cognitive parameters of subjects. Moreover, given the outcome of SI in prevention of AD in DS patients, it is expected that a phase III trial will begin, as the phase II trial mentioned here only enrolled 23 participants. It should also be expected that clinical trials for DPIN and DCI will be extended in the following years, as these are the most promising candidates for the palliation of AD development.

**Figure 5.** (**A**) Graphical illustration of patents claiming the use of inositols for Alzheimer's disease, including patents mentioning more than one inositol stereoisomer and/or derivative. (**B**) Number of patents mentioning and claiming use of inositols for AD treatment in the last two decades.

**Table 3.** Clinical trials of scyllo-inositol and d-pinitol in Alzheimer's disease-related patients. Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Alzheimer's Disease Cooperative Study Clinician's Global Impression of Change (ADCS-CCGIC), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), NPI-C Combined Agitation and Aggression Subscores (NPI-C A+A), Neuropsychological Test Battery (NTB), Treatment Emergent Adverse Events (TEAEs).



**Table 3.** *Cont.*
