RESUMEN

OBJECTIVE: The purpose of these studies was to investigate the uptake of atrazine across the nasal mucosa to determine whether direct transport to the brain through the olfactory epithelium is likely to occur. These studies were undertaken to provide important new information about the potential for the enhanced neurotoxicity of herbicides following nasal inhalation. MATERIALS AND METHODS: Transport of atrazine from aqueous solution and from commercial atrazine-containing herbicide products was assessed using excised nasal mucosal tissues. The permeation rate and the role of membrane transporters in the uptake of atrazine across the nasal mucosa were also investigated. Histological examination of the nasal tissues was conducted to assess the effects of commercial atrazine-containing products on nasal tissue morphology. RESULTS: Atrazine showed high flux across both nasal respiratory and olfactory tissues, and efflux transporters were found to play an essential role in limiting its uptake at low exposure concentrations. Commercial atrazine-containing herbicide products showed remarkably high transfer across the nasal tissues, and histological evaluation showed significant changes in the morphology of the nasal epithelium following exposure to the herbicide products. DISCUSSION: Lipophilic herbicides such as atrazine can freely permeate across the nasal mucosa despite the activity of efflux transporters. The adjuvant compounds in commercial herbicide products disrupt the nasal mucosa's epithelial barrier, resulting in even greater atrazine permeation across the tissues. The properties of the herbicide itself and those of the formulated products play crucial roles in the potential for the enhanced neurotoxicity of herbicides following nasal inhalation.

Asunto(s)

Atrazina , Herbicidas , Mucosa Nasal , Atrazina/toxicidad , Atrazina/farmacocinética , Herbicidas/toxicidad , Herbicidas/farmacocinética , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/metabolismo , Animales , Proteínas de Transporte de Membrana/metabolismo , Masculino , Administración Intranasal , Absorción Nasal/efectos de los fármacos

RESUMEN

Ropinirole is a non-ergolinic dopamine agonist used to manage Parkinson's disease and it is characterized by poor oral bioavailability. This study aimed to design and develop advanced drug delivery systems composed of poloxamer 407, a non-ionic surfactant (Tween 80), and cyclodextrins (methyl-ß-CD or hydroxy-propyl-ß-CD) for possible brain targeting of ropinirole after nasal administration for the treatment of Parkinson's disease. The hybrid systems were formed by the thin-film hydration method, followed by an extensive physicochemical and morphological characterization. The in vitro cytotoxicity of the systems on HEK293 cell lines was also tested. In vitro release and ex vivo mucosal permeation of ropinirole were assessed using Franz cells at 34 °C and with phosphate buffer solution at pH 5.6 in the donor compartment, simulating the conditions of the nasal cavity. The results indicated that the diffusion-controlled drug release exhibited a progressive increase throughout the experiment, while a proof-of-concept experiment on ex vivo permeation through rabbit nasal mucosa revealed a better performance of the prepared hybrid systems in comparison to ropinirole solution. The encouraging results in drug release and mucosal permeation indicate that these hybrid systems can serve as attractive platforms for effective and targeted nose-to-brain delivery of ropinirole with a possible application in Parkinson's disease. Further ex vivo and in vivo studies to support the results of the present work are ongoing.

Asunto(s)

Indoles , Enfermedad de Parkinson , Surfactantes Pulmonares , Humanos , Animales , Conejos , Tensoactivos , Polímeros , Células HEK293 , Enfermedad de Parkinson/tratamiento farmacológico , Encéfalo , Lipoproteínas , Mucosa Nasal

RESUMEN

Quercetin (Que) is one of the most studied flavonoids with strong antioxidant properties ascribed to its ability to bind free radicals and inactivate them. However, the low solubility of the compound along with its inadequate absorption after oral administration limit its beneficial effects. Que's complexation with two different cyclodextrin (CD) derivatives (hydroxypropyl-ß-CD and methyl-ß-CD) via the neutralization/lyophilization method has been found to improve its physicochemical properties. Moreover, blends of the lyophilized powders with mannitol/lecithin microparticles (MLMPs) have been proposed as candidates for intranasal (IN) administration after in vitro and ex vivo evaluations. In this context, a comparative pharmacokinetic (PK) study of the IN vs oral administration of Que lyophilized powders and their blends with MLMPs (75:25 w/w) was performed on Wistar rats. The PK parameters estimated by a non-compartmental analysis using the sparse data methodology in Phoenix® 8.3 (Certara, Princeton, NJ, USA) illustrated the effectiveness of IN administration either in brain targeting or in reaching the bloodstream. Significant levels of the compound were achieved at both sites, compared to those after oral delivery which were negligible. These results favor the potential application of the prepared Que nasal powders for systemic and nose-to-brain delivery for the prevention and/or treatment of neuroinflammatory degenerative conditions, such as Parkinson's and Alzheimer's disease.

RESUMEN

One of the principal impediments for the treatment of neurological conditions is the lack of ability of most of the medicinal agents to evade the blood-brain barrier. Among all the novel approaches to bypass the blood-brain barrier, nose to brain transport is the most patient compliant, non-invasive and effective approach. It directly transports drugs to the CNS via the trigeminal and olfactory nerves present in the nasal cavity. This review article focuses on anatomy and physiology of nasal cavity, potential of intranasal drug delivery, mechanisms of drug transport to brain, its advantages and limitations, novel intranasal formulations, marketed products, factors affecting nose to brain transport, formulation consideration of intranasal products and the future perspectives of CNS targeting via intranasal drug administration.

Asunto(s)

Barrera Hematoencefálica , Nariz , Humanos , Administración Intranasal , Encéfalo , Sistemas de Liberación de Medicamentos

RESUMEN

With advances in nanotechnology, engineered nanomaterial applications are a rapidly growing sector of the economy. Some nanomaterials can reach the brain through nose-to-brain transport. This transport creates concern for potential neurotoxicity of insoluble nanomaterials and a need for toxicity screening tests that detect nose-to-brain transport. Such tests can involve intranasal instillation of aqueous suspensions of nanomaterials in dispersion media that limit particle agglomeration. Unfortunately, protein and some elements in existing dispersion media are suboptimal for potential nose-to-brain transport of nanomaterials because olfactory transport has size- and ion-composition requirements. Therefore, we designed a protein-free dispersion media containing phospholipids and amino acids in an isotonic balanced electrolyte solution, a solution for nasal and olfactory transport (SNOT). SNOT disperses hexagonal boron nitride nanomaterials with a peak particle diameter below 100 nm. In addition, multiwalled carbon nanotubes (MWCNTs) in an established dispersion medium, when diluted with SNOT, maintain dispersion with reduced albumin concentration. Using stereomicroscopy and microscopic examination of plastic sections, dextran dyes dispersed in SNOT are demonstrated in the neuroepithelium of the nose and olfactory bulb of B6;129P2-Omptm3Mom/MomJ mice after intranasal instillation in SNOT. These findings support the potential for SNOT to disperse nanomaterials in a manner permitting nose-to-brain transport for neurotoxicity studies.

Asunto(s)

Nanoestructuras , Nanotubos de Carbono , Administración Intranasal , Animales , Encéfalo/metabolismo , Ratones , Nanoestructuras/toxicidad , Bulbo Olfatorio , Pruebas de Toxicidad

RESUMEN

Neuroinflammation in Alzheimer's disease (AD) revamped the role of a preventive therapeutic action of non steroidal anti-inflammatory drugs; flurbiprofen could delay AD onset, provided its access to brain is enhanced and systemic exposure limited. Nasal administration could enable direct drug access to central nervous system (CNS) via nose-to-brain transport. Here, we investigated the insufflation, deposition, dissolution, transmucosal permeation, and in vivo transport to rat brain of flurbiprofen from nasal powders combined in an active device. Flurbiprofen sodium spray-dried microparticles as such, or soft pellets obtained by agglomeration of drug microparticles with excipients, were intranasally administered to rats by the pre-metered insufflator device. Blood and brain were collected to measure flurbiprofen levels. Excipient presence in soft pellets lowered the metered drug dose to insufflate. Nevertheless, efficiency of powder delivery by the device, measured as emitted fraction, was superior with soft pellets than microparticles, due to their coarse size. Both nasal powders resulted into rapid flurbiprofen absorption. Absolute bioavailability was 33% and 58% for microparticles and pellets, respectively. Compared to intravenous flurbiprofen, the microparticles were more efficient than soft pellets at enhancing direct drug transport to CNS. Direct Transport Percentage index evidenced that more than 60% of the intranasal dose reached the brain via direct nose-to-brain transport for both powders. Moreover, remarkable drug concentrations were measured in the olfactory bulb after microparticle delivery. Bulb connection with the entorhinal cortex, from where AD initiates, makes flurbiprofen sodium administration as nasal powder worth of further investigation in an animal model of neuroinflammation.

Asunto(s)

Flurbiprofeno , Insuflación , Administración Intranasal , Animales , Encéfalo , Sistemas de Liberación de Medicamentos , Nariz , Ratas

RESUMEN

There are several routes of administration to the brain, including intraparenchymal, intraventricular, and subarachnoid injections. The blood-brain barrier (BBB) impedes the permeation and access of most drugs to the central nervous system (CNS), and consequently, many neurological diseases remain undertreated. For past decades, to circumvent this effect, several nanocarriers have been developed to deliver drugs to the brain. Importantly, intranasal (IN) administration can allow direct delivery of drugs into the brain through the anatomical connection between the nasal cavity and brain without crossing the BBB. In this regard, dendrimers may possess great potential to deliver drugs to the brain by IN administration, bypassing the BBB and reducing systemic exposure and side effects, to treat diseases of the CNS. In this original concise review, we highlighted the few examples advocated regarding the use of dendrimers to deliver CNS drugs directly via IN. This review highlighed the few examples of the association of dendrimer encapsulating drugs (e.g., small compounds: haloperidol and paeonol; macromolecular compounds: dextran, insulin and calcitonin; and siRNA) using IN administration. Good efficiencies were observed. In addition, we will present the in vivo effects of PAMAM dendrimers after IN administration, globally, showing no general toxicity.

Asunto(s)

Barrera Hematoencefálica/metabolismo , Fármacos del Sistema Nervioso Central/farmacología , Dendrímeros/química , Nanocápsulas/química , Acetofenonas/administración & dosificación , Acetofenonas/química , Administración Intranasal , Animales , Transporte Biológico , Calcitonina/administración & dosificación , Calcitonina/química , Dextranos/administración & dosificación , Dextranos/química , Liberación de Fármacos , Haloperidol/administración & dosificación , Haloperidol/química , Humanos , Insulina/administración & dosificación , Insulina/química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Tecnología Farmacéutica

RESUMEN

The nose-to-brain (N-to-B) transport mechanism of nanoparticles through the olfactory epithelium (OE) is not fully understood. Most research utilized nasal epithelial cell models completely deprived of olfactory cells. Aiming to shed light into key cellular pathways, in this work, for the first time, the interaction of polymeric nanoparticles in a 17-483 nm size range and with neutral and negatively and positively charged surfaces with primary olfactory sensory neurons, cortical neurons, and microglia isolated from olfactory bulb (OB), OE, and cortex of newborn rats is investigated. After demonstrating the good cell compatibility of the different nanoparticles, the nanoparticle uptake by confocal laser scanning fluorescence microscopy is monitored. Our findings reveal that neither olfactory nor forebrain neurons internalize nanoparticles. Conversely, it is demonstrated that olfactory and cortical microglia phagocytose the nanoparticles independently of their features. Overall, our findings represent the first unambiguous evidence of the possible involvement of microglia in N-to-B nanoparticle transport and the unlikely involvement of neurons. Furthermore, this approach emerges as a completely new experimental tool to screen the biocompatibility, uptake, and transport of nanomaterials by key cellular players of the N-to-B pathway in nanosafety and nanotoxicology and nanomedicine.

Asunto(s)

Nanopartículas/metabolismo , Mucosa Olfatoria , Polímeros/farmacocinética , Prosencéfalo , Animales , Células Cultivadas , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacocinética , Microglía/citología , Microglía/inmunología , Microglía/metabolismo , Nanopartículas/química , Neuronas/citología , Neuronas/inmunología , Neuronas/metabolismo , Mucosa Olfatoria/citología , Mucosa Olfatoria/inmunología , Mucosa Olfatoria/metabolismo , Tamaño de la Partícula , Polímeros/química , Prosencéfalo/citología , Prosencéfalo/inmunología , Prosencéfalo/metabolismo , Ratas

RESUMEN

Microspheres based on both methyl-ß-cyclodextrins and chitosan were prepared by spray-drying as nasal formulations of a model polar drug to analyze, firstly, how the composition of the carrier affects drug permeation across synthetic membranes and, secondly, how it induces systemic or brain delivery of the drug. Microparticles with different weight ratios of the two penetration enhancers (10⁻90, 50⁻50, 90⁻10) were characterized with respect to morphology, size, structural composition, water uptake, and the in vitro drug permeation profile. The leader formulation (weight ratio of 50⁻50) was then nasally administered to rats; systemic and cerebrospinal fluid (CSF) drug concentrations were analyzed by high performance liquid chromatography (HPLC) over time. Microspheres obtained with a single enhancer, methyl-ß-cyclodextrins or chitosan, were administered in vivo as a comparison. The in vitro properties of combined microspheres appeared modified with regard to the polymeric matrix ratio. In vivo results suggest that the optimal drug distribution between CSF and bloodstream can be easily obtained by varying the amount of these two penetration enhancers studied in the matrix of nasal microspheres.

RESUMEN

Many of the therapeutics used for the treatment of brain disorders are not effective and not delivered to the brain due to the complex structure and its barriers. In recent years, many advanced approaches have emerged for the brain drug delivery. Intranasal drug delivery is one of non-invasive approach has gained interest because of direct transport of drugs circumventing the brain barriers through olfactory and trigeminal nerve pathways. Eventhough through these pathways the therapeutics have direct access to the brain, the main limitations of this approach are only limited drug absorption, and nasal permeability. To overcome the issues related to the brain targeting via nasal drug delivery encourage the development of novel drug delivery by combining with nanotechnology. This article will discuss pathways of drug transport form nose to brain, toxicity of nanoparticles role and need of nanostructured lipid carriers (NLCs) and recent advance in combination of NLCs with intranasal drug delivery for targeting the brain.

Asunto(s)

Encefalopatías/tratamiento farmacológico , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Lípidos , Nanopartículas , Mucosa Nasal/metabolismo , Administración Intranasal , Animales , Transporte Biológico Activo , Encefalopatías/metabolismo , Encefalopatías/patología , Humanos , Lípidos/química , Lípidos/farmacocinética , Lípidos/uso terapéutico , Nanopartículas/química , Nanopartículas/uso terapéutico , Nervio Olfatorio/metabolismo , Nervio Trigémino/metabolismo

RESUMEN

To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [18F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1-3) substrate, using PET to measure local tissue concentrations. Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 min. A CT was obtained for anatomical co-registration and attenuation correction. Time-activity curves (TACs) were generated for the olfactory bulb (OB) and remaining brain, and the area-under-the-curve (AUC) for each TAC was calculated to determine the total tissue exposure of FLT. FLT concentrations were higher in the OB than in the rest of the brain following IN administration. IP administration of NBMPR resulted in increased OB and brain FLT exposure following both IN and IV administration, suggesting that NBMPR decreases the clearance rate of FLT from the brain. When FLT and NBMPR were co-administered IN, there was a decrease in the OB AUC while an increase in the brain AUC was observed. The decrease in OB exposure was likely the result of inhibition of ENT1 uptake activity in the nose-to-brain transport pathway. FLT distribution patterns show that nucleoside transporters, including ENT1, play a key role in the distribution of transporter substrates between the nasal cavity and the brain via the OB.

Asunto(s)

Didesoxinucleósidos/farmacocinética , Mucosa Nasal/metabolismo , Proteínas de Transporte de Nucleósidos/fisiología , Bulbo Olfatorio/metabolismo , Tomografía de Emisión de Positrones , Animales , Área Bajo la Curva , Ratas , Ratas Sprague-Dawley , Tioinosina/análogos & derivados , Tioinosina/farmacología , Distribución Tisular

RESUMEN

We designed a delivery system to obtain an efficient and optimal nose-to-brain transport of BACE1 siRNA, potentially useful in the treatment of Alzheimer's disease. We selected a cell-penetrating peptide, the short peptide derived from rabies virus glycoprotein known as RVG-9R, to increase the transcellular pathway in neuronal cells. The optimal molar ratio between RVG-9R and BACE1 siRNA was elucidated. The complex between the two was then encapsulated. We propose chitosan-coated and uncoated solid lipid nanoparticles (SLNs) as a nasal delivery system capable of exploiting both olfactory and trigeminal nerve pathways. The coating process had an effect on the zeta potential, obtaining positively-charged nanoparticles, and on siRNA protection. The positive charge of the coating formulation ensured mucoadhesiveness to the particles and also prolonged residence time in the nasal cavity. We studied the cellular transport of siRNA released from the SLNs using Caco-2 as a model of epithelial-like phenotypes. We found that siRNA permeates the monolayer to a greater extent when released from any of the studied formulations than from bare siRNA, and primarily from chitosan-coated SLNs.

Asunto(s)

Secretasas de la Proteína Precursora del Amiloide/genética , Ácido Aspártico Endopeptidasas/genética , Encéfalo/metabolismo , Péptidos de Penetración Celular/metabolismo , Portadores de Fármacos/química , Nanopartículas/química , Mucosa Nasal/metabolismo , ARN Interferente Pequeño/metabolismo , Enfermedad de Alzheimer/metabolismo , Células CACO-2 , Quitosano/química , Humanos , ARN Interferente Pequeño/administración & dosificación

RESUMEN

Intranasal administration can potentially deliver drugs to the brain because of the proximity of the delivery site to the olfactory lobe. We prepared triturates of micronized or crystalline zolmitriptan with a GRAS substance, nicotinamide, to form a eutectic. We characterized the formulation using differential scanning calorimetry, powder X-ray diffraction, and FTIR spectroscopy to confirm its eutectic nature and generated a phase diagram. The eutectic formulation was aerosolized using an in-house insufflator into the nares of rats. Groups of rats received zolmitriptan intravenously or intranasally, or intranasal eutectic formulation. Zolmitriptan was estimated in the olfactory lobe, cerebral cortex, cerebellum, and blood plasma at different time-points by LC-MS. Pharmacokinetics in these tissues indicated the superiority of the intranasal eutectic formulation for brain targeting when compared with results of IV solution and intranasal pure zolmitriptan powder. Enhancement of nose-to-brain transport is likely to have resulted from more rapid dissolution of the eutectic as compared to pure drug.

Asunto(s)

Administración Intranasal/métodos , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Mucosa Nasal/metabolismo , Oxazolidinonas/administración & dosificación , Oxazolidinonas/farmacocinética , Triptaminas/administración & dosificación , Triptaminas/farmacocinética , Animales , Rastreo Diferencial de Calorimetría , Cromatografía Líquida de Alta Presión , Tamaño de la Partícula , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría de Masas en Tándem , Difracción de Rayos X

RESUMEN

Glyphosate is one of the most commonly used herbicides worldwide due to its broad spectrum of activity and reported low toxicity to humans. Glyphosate has an amino acid-like structure that is highly polar and shows low bioavailability following oral ingestion and low systemic toxicity following intravenous exposures. Spray applications of glyphosate in agricultural or residential settings can result in topical or inhalation exposures to the herbicide. Limited systemic exposure to glyphosate occurs following skin contact, and pulmonary exposure has also been reported to be low. The results of nasal inhalation exposures, however, have not been evaluated. To investigate the mechanisms of glyphosate absorption across epithelial tissues, the permeation of glyphosate across Caco-2 cells, a gastrointestinal epithelium model, was compared with permeation across nasal respiratory and olfactory tissues excised from cows. Saturable glyphosate uptake was seen in all three tissues, indicating the activity of epithelial transporters. The uptake was shown to be ATP and Na(+) independent, and glyphosate permeability could be significantly reduced by the inclusion of competitive amino acids or specific LAT1/LAT2 transporter inhibitors. The pattern of inhibition of glyphosate permeability across Caco-2 and nasal mucosal tissues suggests that LAT1/2 play major roles in the transport of this amino-acid-like herbicide. Enhanced uptake into the epithelial cells at barrier mucosae, including the respiratory and gastrointestinal tracts, may result in more significant local and systemic effects than predicted from glyphosate's passive permeability, and enhanced uptake by the olfactory mucosa may result in further CNS disposition, potentially increasing the risk for brain-related toxicities.

Asunto(s)

Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Monitoreo del Ambiente/métodos , Células Epiteliales/metabolismo , Glicina/análogos & derivados , Herbicidas/metabolismo , Mucosa Nasal/metabolismo , Absorción Fisiológica/efectos de los fármacos , Sistemas de Transporte de Aminoácidos/genética , Animales , Disponibilidad Biológica , Transporte Biológico/efectos de los fármacos , Células CACO-2 , Bovinos , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Femenino , Glicina/metabolismo , Glicina/toxicidad , Herbicidas/toxicidad , Humanos , Mucosa Nasal/efectos de los fármacos , Mucosa Olfatoria/efectos de los fármacos , Mucosa Olfatoria/metabolismo , Permeabilidad , Glifosato

RESUMEN

Intranasal Microemulsions (MEs) for nose to brain delivery of a novel combination of Albendazole sulfoxide (ABZ-SO) and Curcumin (CUR) for Neurocysticercosis (NCC), a brain infection are reported. MEs prepared by simple solution exhibited a globule size <20nm, negative zeta potential and good stability. The docosahexaenoic acid (DHA) ME revealed high and rapid ex vivo permeation of drugs through sheep nasal mucosa. Intranasal DHA ME resulted in high brain concentrations and 10.76 (ABZ-SO) and 3.24 (CUR) fold enhancement in brain area-under-the-curve (AUC) compared to intravenous DHA MEs at the same dose. Direct nose to brain transport (DTP) of >95% was seen for both drugs. High drug targeting efficiency (DTE) to the brain compared to Capmul ME and drug solution (P<0.05) suggested the role of DHA in aiding nose to brain delivery. Histopathology study confirmed no significant changes. High efficacy of ABZ-SO: CUR (100:10ng/mL) DHA ME in vitro on Taenia solium cysts was confirmed by complete ALP inhibition and disintegration of cysts at 96h. Considering that the brain concentration at 24h was 1400±160.1ng/g (ABZ-SO) and 120±35.2ng/g (CUR), the in vitro efficacy seen at a 10 fold lower concentration of the drugs strongly supports the assumption of clinical efficacy. The intranasal DHA ME is a promising delivery system for targeted nose to brain delivery.

Asunto(s)

Albendazol/análogos & derivados , Antihelmínticos/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Barrera Hematoencefálica/efectos de los fármacos , Curcumina/administración & dosificación , Ácidos Docosahexaenoicos/química , Sistemas de Liberación de Medicamentos , Administración Intranasal , Albendazol/administración & dosificación , Albendazol/química , Albendazol/metabolismo , Albendazol/farmacocinética , Animales , Antihelmínticos/química , Antihelmínticos/metabolismo , Antihelmínticos/farmacocinética , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/farmacocinética , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/ultraestructura , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Curcumina/química , Curcumina/metabolismo , Curcumina/farmacocinética , Combinación de Medicamentos , Composición de Medicamentos , Estabilidad de Medicamentos , Emulsiones , Femenino , Técnicas In Vitro , Masculino , Absorción Nasal , Neurocisticercosis/sangre , Neurocisticercosis/tratamiento farmacológico , Neurocisticercosis/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Vehículos Farmacéuticos/química , Ratas Sprague-Dawley , Oveja Doméstica , Distribución Tisular

RESUMEN

We propose the formulation and characterization of solid microparticles as nasal drug delivery systems able to increase the nose-to-brain transport of deferoxamine mesylate (DFO), a neuroprotector unable to cross the blood brain barrier and inducing negative peripheral impacts. Spherical chitosan chloride and methyl-ß-cyclodextrin microparticles loaded with DFO (DCH and MCD, respectively) were obtained by spray drying. Their volume-surface diameters ranged from 1.77 ± 0.06 µm (DCH) to 3.47 ± 0.05 µm (MCD); the aerodynamic diameters were about 1.1 µm and their drug content was about 30%. In comparison with DCH, MCD enhanced the in vitro DFO permeation across lipophilic membranes, similarly as shown by ex vivo permeation studies across porcine nasal mucosa. Moreover, MCD were able to promote the DFO permeation across monolayers of PC 12 cells (neuron-like), but like DCH, it did not modify the DFO permeation pattern across Caco-2 monolayers (epithelial-like). Nasal administration to rats of 200 µg DFO encapsulated in the microparticles resulted in its uptake into the cerebrospinal fluid (CSF) with peak values ranging from 3.83 ± 0.68 µg/mL (DCH) to 14.37 ± 1.69 µg/mL (MCD) 30 min after insufflation of microparticles. No drug CSF uptake was detected after nasal administration of a DFO water solution. The DFO systemic absolute bioavailabilities obtained by DCH and MCD nasal administration were 6% and 15%, respectively. Chitosan chloride and methyl-ß-cyclodextrins appear therefore suitable to formulate solid microparticles able to promote the nose to brain uptake of DFO and to limit its systemic exposure.

Asunto(s)

Quitosano/química , Deferoxamina , Portadores de Fármacos , Microesferas , Sideróforos , beta-Ciclodextrinas/química , Animales , Transporte Biológico , Encéfalo/metabolismo , Línea Celular Tumoral , Química Farmacéutica , Deferoxamina/administración & dosificación , Deferoxamina/química , Deferoxamina/farmacocinética , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Masculino , Membranas Artificiales , Mucosa Nasal/metabolismo , Permeabilidad , Ratas Wistar , Sideróforos/administración & dosificación , Sideróforos/química , Sideróforos/farmacocinética , Porcinos