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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.
- Development and application of an ex vivo fosphenytoin nasal bioconversion/permeability evaluation methodPublication . Viegas, Daniel Antunes; Rodrigues, Márcio; Francisco, Joana; Falcão, Amílcar; Alves, Gilberto; Santos, Adriana O.There is an increasing interest in the intranasal delivery of central nervous system-active drugs due to the existence of a direct nose-to-brain connection. However, poor solubility limits the amount of drug that can be administered within an aqueous solution. In the present work, the objectives were to develop an ex vivo bioconversion/permeability evaluation method and to study the ex vivo bioconversion of the hydrophilic phosphate ester prodrug fosphenytoin (FOS) to the active drug phenytoin (PHT) and their comparative nasal permeation. Bioconversion/permeability studies were performed in excised porcine nasal mucosa mounted in Ussing chambers. The physical integrity of the tissues was evaluated by measurement of the transepithelial electrical resistance (TEER). The simultaneous quantitative assay of FOS, PHT and its major metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) was developed and validated according to international guidelines using a liquid chromatography analytical method. The FOS bioconversion rate and PHT and FOS apparent permeability coefficients (Papp) were determined at different time points. FOS bioconversion was also qualitatively investigated in human nasal mucus. The developed liquid chromatography method combines a fast and inexpensive sample preparation with inactivation of the enzymatic metabolism of the prodrug during sample manipulation and storage. It was linear, precise, accurate, and presented a high analyte recovery. FOS was converted ex vivo to PHT but the metabolite HPPH was not detected. The bioconversion rate increased with FOS concentration and with time, which suggests a diffusion-limited process. FOS was also converted to its active drug by human nasal mucus. A novel mathematical data analysis method was developed to reduce the bias introduced by variable mucosal TEER in the permeability results. At comparable FOS and PHT concentrations the ln(Papp(PHT)) of both compounds showed little difference, which indicates that the use of a hydrophilic and charged prodrug did not hinder overall drug permeation. At the highest tested FOS concentration it was possible to quantify FOS in the receiver chambers, meaning that at a sufficiently high concentration the FOS permeation rate overcame its bioconversion rate. The ln(Papp(PHT)) tended to similar equilibrium values as the assay progressed, but with higher FOS concentrations that equilibrium was attained faster. Acidic pH reduced the permeability of both PHT and FOS. The developed bioconversion/permeability evaluation method will constitute an important tool to select the most promising formulations before proceeding to in vivo studies. Importantly, it allowed the demonstration of phosphatase activity and FOS bioconversion in nasal mucosa, as well as the prodrug's nasal permeation potential. Furthermore, this study demonstrates the possibility of formulating phosphate prodrugs of poorly soluble central nervous system-active drugs as a strategy to increase the solubilized drug doses administered through the nasal route.
- 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.
- Antimicrobial and antitumor activity of S-methyl dithiocarbazate Schiff base zinc(II) complexesPublication . Gomes, Filipa Ramilo; Addis, Yemataw; Tekamo, Israel; Cavaco, Isabel; Campos, Débora L.; Pavan, Fernando R.; Gomes, Clara S.B.; Brito, Vanessa; Santos, Adriana O.; Domingues, F.C.; Luís, Ângelo; Marques, M. Matilde; Pessoa, João Costa; Ferreira, Susana; Silvestre, Samuel; Correia, IsabelSchiff bases (SB) obtained from S-methyl dithiocarbazate and aromatic aldehydes: salicylaldehyde (H2L1), o-vanillin (H2L2), pyridoxal (H2L3) and 2,6-diformyl-4-methylphenol (H3L4), and their corresponding Zn(II)-complexes (1-4), are synthesized. All compounds are characterized by elemental analyses, infrared, UV-Vis, nuclear magnetic resonance spectroscopy and mass spectrometry. The structures of H2L2 and [Zn2(L1)2(H2O)(DMF)] (1a) (DMF = dimethylformamide) are solved by single crystal X-ray diffraction. The SB coordinates the metal center through the Ophenolate, Nimine and Sthiolate atoms. The radical scavenging activity is tested using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, with all ligand precursors showing IC50 values ~40 μM. Cytotoxicity studies with several tumor cell lines (PC-3, MCF-7 and Caco-2) as well as a non-tumoral cell line (NHDF) are reported. Interestingly, 1 has relevant and selective antiproliferative effect against Caco-2 cells (IC50 = 9.1 μM). Their antimicrobial activity is evaluated in five bacterial strains (Klebsiella pneumoniae, Acinetobacter baumannii, Listeria monocytogenes, Pseudomonas aeruginosa and Staphylococcus aureus) and two yeast strains (Candida albicans and Candida tropicalis) with some compounds showing bacteriostatic and fungicidal activity. The minimal inhibitory concentration (MIC90) of HnL against Mycobacterium tuberculosis is also reported, with H2L2 and H3L4 showing very high activity (MIC90 < 0.6 μg/mL). The ability of the compounds to bind bovine serum albumin (BSA) and DNA is evaluated for H3L4 and [Zn2(L4)(CH3COO)] (4), both showing high binding constants to BSA (ca. 106 M-1) and ability to bind DNA. Overall, the reported compounds show relevant antitumor and antimicrobial properties, our data indicating they may be promising compounds in several fields of medicinal chemistry.
- 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.