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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.
- Síntese de derivados da estrona funcionalizados nos anéis C e D como potenciais agentes anti-cancerígenosPublication . Pires, Patrícia Sofia Cabral; Canário, Catarina; Silvestre, Samuel MartinsNa presente dissertação é apresentada informação relativa à experiência adquirida no estágio curricular em farmácia comunitária, assim como ao trabalho de investigação experimental efetuado paralelamente. O estágio em farmácia comunitária, realizado maioritariamente na farmácia Holon Covilhã, permitiu-me efetuar tarefas e adquirir conhecimentos no âmbito das várias áreas de intervenção farmacêutica: aprovisionamento, atendimento, gestão de documentação, gestão de qualidade e ações perto da comunidade. Permitiu-me não só perceber um pouco melhor qual a extensão do contributo do farmacêutico para a saúde pública, como também adquirir e aprofundar o meu conhecimento das ciências farmacêuticas. A investigação experimental, levada a cabo no Centro de Investigação em Ciências da Saúde da Universidade da Beira Interior, incidiu sobre o desenvolvimento e a avaliação biológica de derivados da molécula de estrona funcionalizados nos anéis C e D com potencial atividade anti-tumoral. Com este objetivo, foram sintetizadas algumas moléculas e efetuou-se a avaliação da sua atividade anti-proliferativa em várias linhas celulares humanas. Os resultados desta avaliação biológica parecem demonstrar que o derivado com a substituição 9a-hidroxi-11ß-nitrooxi tem elevada ação anti-proliferativa nas várias linhas celulares estudadas. Adicionalmente, a introdução de uma dupla ligação entre os carbonos 9 e 11 levou também a um marcado efeito anti-proliferativo, principalmente em células HepaRG. Esta modificação estrutural, bem como a introdução de uma lactona no anel D, têm potencial interesse, uma vez que têm sido associadas a uma redução da estrogenicidade, o que poderá ser benéfico na seletividade da sua ação. São necessários, no entanto, estudos mais aprofundados para confirmação e melhoria dos resultados obtidos.
- The promise of prodrugs and nanosystems in nose-to-brain delivery of poorly soluble drugsPublication . Pires, Patrícia Sofia Cabral; Santos, Adriana Oliveira dos; Alves, Gilberto Lourenço; Rodrigues, Márcio José de Abreu MarquesIn brain-targeted drug delivery, the intranasal route can be a good alternative to parenteral administration. In addition to being associated with a greater comfort for the patient, intranasal drug delivery can reduce systemic drug distribution, resulting in an increased safety, and can allow direct drug transport to the brain, resulting in an increased therapeutic efficacy. For example, benzodiazepines administration for the treatment of acute epileptic episodes has been proven to be at least as effective as their intravenous administration. Nevertheless, their solubilization requires substantial amounts of organic solvents, which can cause lacrimation and nose and throat irritation. Additionally, benzodiazepines can cause somnolence, deleterious cognitive effects and dependence/tolerance. Phenytoin is also an antiepileptic drug, being non-inferior in efficacy, while not having these adverse effects. Although its systemic administration can cause other adverse events (such as cardiovascular complications or liver toxicity), its intranasal administration could increase its safety and even efficacy compared to other non-invasive routes in the treatment of status epilepticus. Yet, phenytoin has low aqueous solubility, being difficult to formulate at a high strength. However, its hydrophilic prodrug, fosphenytoin, has high water solubility. Hence, aqueous liquid water-based formulations of fosphenytoin for intranasal administration were developed. Pharmacokinetic results in mice showed that a fosphenytoin formulation containing hydroxypropyl methylcellulose and albumin prolonged drug concentration in the brain, also producing a high absolute drug bioavailability. The study demonstrated that phosphate ester prodrugs (such as fosphenytoin) can be an efficient strategy to increase the intranasal bioavailability of low solubility drugs (such as phenytoin). In addition, we hypothesized that if there was phenytoin in the formulation, in the active and diffusible form, brain drug delivery could be increased and/or made faster. Thus, nano and microemulsions containing phenytoin (internalized in the oil droplets) and fosphenytoin (solubilized in the aqueous phase) in combination were developed. A microemulsion having good characteristics (reasonably homogeneous, with small droplet size and physically stable for at least 1 week) was selected for pharmacokinetic evaluation in mice. In addition to the intranasal administration of this selected microemulsion, containing both phenytoin and fosphenytoin, a second microemulsion was also administered intranasally, having an identical composition but without phenytoin (with fosphenytoin only), for comparison purposes. Despite the existence of a small amount of phenytoin in the formulation not inducing accelerated brain drug delivery, it led to prolonged and increased drug levels. Moreover, the intranasal administration of the microemulsion containing both drugs led to a maximum brain concentration that was similar to that obtained with the intravenous fosphenytoin solution, also leading to prolonged drug retention. The microemulsion containing both drugs also had a higher bioavailability than any of the intranasally administered formulations containing fosphenytoin only (microemulsion without phenytoin, and simple fosphenytoin formulations). Furthermore, both microemulsions (the one containing both drugs and the one containing fosphenytoin only) led to higher drug concentrations at initial time points than those obtained with the simple intranasal fosphenytoin solution, which suggests that the microemulsion had a drug permeation enhancement effect. Thus, in general this work allowed to prove that the use of phosphate ester prodrugs can be an effective strategy in increasing the intranasal bioavailability of low solubility drugs, albumin is a good strategy to prolong brain targeting, the existence of a small amount of active drug (in addition to the prodrug), in an emulsified form, can increase drug levels at longer time points, and the use of microemulsions can increase brain drug delivery at shorter time points.
- 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.