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- Intranasal fosphenytoin: the promise of phosphate esters in nose-to-brain delivery of poorly soluble drugsPublication . Santos, Adriana O.; Pires, Patrícia C.; Rodrigues, Márcio; Alves, Gilberto; Santos, Liliana T.Intranasal administration could increase both safety and efficacy of drugs acting on the central nervous system, but low solubility severely limits administration through this route. Phenytoin’s prodrug, fosphenytoin, is hydrophilic and freely soluble in water, but less permeable since it is dianionic. We aimed to assess whether this phosphoester prodrug could be a suitable alternative to phenytoin in intranasal delivery. Secondly, we aimed to compare simple formulation strategies in fosphenytoin delivery. Fosphenytoin formulations containing thermosensitive and/or mucoadhesive (hydroxypropyl methylcellulose, HPMC) polymers were developed, guided by viscosity, gelling temperatures, osmolality, and in vitro drug release tests. Then, a pharmacokinetic study was performed, comparing an intravenous fosphenytoin solution, an intranasal fosphenytoin solution, and intranasal fosphenytoin mucoadhesive formulations with or without albumin. Formulations containing HPMC allowed high drug strengths, and had a relatively fast release profile, which was not changed by albumin. Intranasal administration of a formulation with HPMC and albumin prolonged drug concentration over time and led to complete or even increased absolute bioavailability. Moreover, phenytoin’s blood levels did not reach the high peak obtained with intravenous administration. In conclusion, the use of phosphate ester prodrugs could be an efficient and safe strategy to increase the intranasal bioavailability of poorly soluble drugs.
- Nanoemulsions and thermosensitive nanoemulgels of phenytoin and fosphenytoin for intranasal administration: Formulation development and in vitro characterizationPublication . Pires, Patrícia C.; Peixoto, Diana; Teixeira, Isaura; Rodrigues, Márcio; Alves, Gilberto; Santos, Adriana O.Phenytoin is a low solubility anticonvulsant drug. It has, nonetheless, other possible therapeutic indications, such as neuropathic pain, including trigeminal neuralgia, or wound healing. Its use has decreased due to side effects, but nasal/intranasal administration could significantly increase drug safety and efficacy. The aim of this work was to develop and study nanoemulsions and thermosensitive nanoemulgels of phenytoin and fosphenytoin, in combination, for intranasal administration, with immediate and sustained release profiles. Nanoemulsions were prepared by adding the aqueous phase, containing gelling polymers in the case of nanoemulgels, to emulsion preconcentrates, followed, in the optimized procedure, by premix membrane emulsification. Formulation design and optimization was guided by drug strength, rheological behavior, osmolality, mean droplet size and polydispersity. Fosphenytoin interfered significantly with Carbopol but not with Pluronic's gelation, and allowed to achieve drug strengths equivalent to 22 or 27 mg/g of phenytoin in lead nanoemulsions, and 16.7 mg/g of phenytoin in the lead nanoemulgel. The final selected low viscosity nanoemulsions had an immediate or prolonged fosphenytoin release profile, depending of anhydrous phase proportion (10% or 40%, respectively). The thermosensitive nanoemulgel, with 10% anhydrous phase, showed prolonged drug release. Future studies will establish whether they are more suited for topical effects or therapeutic brain delivery.
- Nanosystems in nose-to-brain drug delivery: a review of non-clinical brain targeting studiesPublication . Pires, Patrícia C.; Santos, Adriana O.The treatment of neurodegenerative and psychiatric disorders remains a challenge in medical research. Several strategies have been developed over the years, either to overcome the blood-brain barrier or to achieve a safer or faster brain delivery, one of them being intranasal (IN) administration. The possibility of direct nose-to-brain transport offers enhanced targeting and reduced systemic side effects. Nevertheless, labile, low soluble, low permeant and/or less potent drugs might need a formulation other than the common solutions or suspensions. For that, the formulation of nanosystems is considered to be a promising approach, since it can protect drugs from chemical and/or metabolic degradation, enhance their solubility, or offer transport through biological membranes. However, the understanding of the factors promoting efficient brain targeting when using nanosystems through the nasal route is currently patchy and incomplete. The main purpose of the present review was to evaluate the association between brain delivery efficacy (in terms of brain targeting, brain bioavailability and time to reach the brain) and nanosystem type. For that, we performed a systematic bibliographic search and analysis. Furthermore, study designs, nanosystem properties, and reporting quality were also analyzed and discussed. It was found a high heterogeneity in how pre-clinical brain targeting studies have been conducted, analyzed and reported in scientific literature, which surely originates a significant degree of bias and data dispersion. This review attempts to provide some systematization recommendations, which may be useful for researchers entering the field, and assist in increasing the uniformity of future reports. The analysis of literature data confirmed that there is evidence of the advantage of the IN route (when compared to the intravenous route) and in using carrier nanosystems (when compared to IN solutions) for brain delivery of a large set of drugs. Among the most represented nanosystem classes, microemulsions had some of the lowest pharmacokinetic ratios values, while polymeric micelles had some of the best. Nevertheless, brain targeting efficacy comparisons between nanosystem groups had little statistical significance, and the superiority of the polymeric micelles group disappeared when nanosystems were compared to the respective IN drug solutions. In fact, some drugs reached the brain so efficiently, even as drug solutions, that further benefit from formulating them into nanosystems became less evident.