Drug Transport In Brain Research Articles

Blood-Brain Barrier Permeability is Affected by Changes in Tight Junction Protein Expression at High-Altitude Hypoxic Conditions-this may have Implications for Brain Drug Transport.

Changes to blood-brain barrier structure and function may affect the delivery of drugs into the brain. It is worthwhile to exploring more study on how the blood-brain barrier changes in structure and function and how that affects drug transport in high-altitude hypoxic environment. The DIA high-throughput sequencing technique indicate that the rats blood-brain barrier has been identified to have 7252 proteins overall and 8 tight junction proteins, among which Claudin-7 was a plateau-specific tight junction protein under high-altitude hypoxia, and based on the interaction network study, 2421 proteins are found to interact with one another, with ZO-1 being the primary target. The results of the projected gene function analysis demonstrated that changes in tight junction proteins are related to the control of TRP channels by inflammatory mediators, the wnt signaling pathway, the ABC transporter system, and drug metabolism-CYP450 enzyme regulation. Additionally, the electron microscopy, the Evans blue combination with confocal laser scanning microscopy, and the Western Blot and RT-qPCR revealed that high-altitude hypoxic environment induces blood-brain barrier tight junctions to open, blood-brain barrier permeability increases, ZO-1, Occludin, Claudin-5 protein and mRNA expression decreased. Our research implies that structural and functional alterations in the blood-brain barrier induced by high altitude hypoxia may impact drug transport inside the central nervous system, and that drug transporters and drug-metabolizing enzymes may be key players in this process.

Nose to Brain Drug Delivery System

Abstract: The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to deliver drugs selectively and effectively to the brain. Blood-brainbarrier (BBB) constitutes the major obstacle to the uptake of drugs into the brain following systemic administration. Intranosedelivery offers a non-invasive and convenient method to bypass the BBB and delivery of therapeutics directly to the brain. The review discusses the potential of intranoseroute to deliver drugs to the brain, the mechanisms and pathways of direct nose to brain drug transport, the various factors influencing transnosedrug absorption, the conventional and novel intranosedrug delivery systems, the various intranosedrug delivery techniques and devices, and examples of brain drug transport that have been feasible in treating various brain disorders. Moreover, products on the market, investigational drugs, and the author’s perceptions about the prospect of intranosedelivery for treating brain disorders are also been discussed.

Antipsychotics-Loaded Nanometric Emulsions for Brain Delivery.

Antipsychotic drugs have numerous disabling side effects, and many are lipophilic, making them hard to formulate at high strength. Incorporating them into nanometric emulsions can increase their solubility, protect them from degradation, and increase their brain delivery, being a promising strategy to overcome the current treatment gap. A thorough review was performed to assess the true potential of these formulations for antipsychotic drugs brain delivery. Intranasal administration was preferred when compared to oral or intravenous administration, since it allowed for direct brain drug transport and reduced systemic drug distribution, having increased efficacy and safety. Moreover, the developed systems increased antipsychotic drug solubility up to 4796 times (when compared to water), which is quite substantial. In the in vivo experiments, nanometric emulsions performed better than drug solutions or suspensions, leading to improved brain drug targeting, mainly due to these formulation’s excipients (surfactants and cosolvents) permeation enhancing capability, added to a small droplet size, which leaves a large surface area available for drug absorption to occur. Thus, even if it is difficult to conclude on which formulation composition leads to a best performance (high number of variables), overall nanometric emulsions have proven to be promising strategies to improve brain bioavailability of antipsychotic drugs.

Nose to brain delivery of donepezil through surface modified NLCs: Formulation development, optimization, and brain targeting study

The research was aimed to formulate the Donepezil (DPZ)-loaded nanostructured lipid carriers (NLCs) and coated with chitosan (CH) for brain targeting through the intranasal route. NLCs were prepared by homogenization & sonication technique and optimized by three factors-three levels Box-Behnken design (BBD). The composition of DPZ-loaded CH-NLCs was established by using a mixture of Compritol & Capryol 90 as lipid, poloxamer 188 as a surfactant, and CH as a coating agent. The effect of formulation factors was evaluated on particle size, entrapment efficiency, and polydispersity index (PDI). Finally, ex-vivo permeation, in-situ perfusion as well as in-vivo study was conducted on albino Wistar rats for the detection of pharmacokinetic and neuropharmacokinetic parameters like drug targeting efficiency (% DTE), nose to brain drug transport percentage (DTP), etc of the optimized formulation. Optimized formulation (DPZ-CH-NLCs-OPT2) exhibited an acceptable particle size (192.5 ± 7.3 nm) with 89.85 ± 2.17% entrapment efficiency, 0.298 ± 0.021 PDI, and 38.9 mV zeta potential and particles were spherical shape as shown by TEM. DSC thermogram displayed that the drug existed in amorphous form within the NLCs matrix. Permeability coefficient (Papp) of DPZ-CH-NLCs-OPT2 formulation (10.14 ± 1.73 × 10−3 cm h−1) was two folds than DPZ-Sol (4.55 ± 1.18 × 10−3 cm h−1). The nasal absorption rate constant for DPZ-CH-NLCs-OPT2 (1.4 × 10−3 h−1) was found to be significantly higher than DPZ-Sol (0.5 × 10−3 h−1). The bioavailability of DPZ-CH-NLCs was 2.02 fold than that of DPZ-Sol administered intranasally and 2.41 fold than DPZ-CH-NLCs administered via the intravenous route. Efficient brain targeting and targeting potential was observed as showed by DTE (321.21%) and DTP (74.55%) after intranasal administration of DPZ-CH-NLCs as compared to DPZ-Sol (DTE 158.52% and DTP 36.92%). From the findings, it could be concluded that DPZ-CH-NLCs might be an effective strategy for the brain targeting of DPZ through the intranasal route for the treatment of Alzheimer's disease.

Nose to brain delivery of Efavirenz nanosuspension for effective neuro AIDS therapy: in-vitro, in-vivo and pharmacokinetic assessment

Efavirenz is inhibitor of non-nucleoside reverse transcriptase enzyme; BCS class II drug. The objective of the present research was to prepare and evaluate nanosuspension of Efavirenz for the treatment of neuro-AIDS. Efavirenz is the substrate for drug resistant proteins at BBB prone to efflux and could not reach brain with effective levels. Current need of the therapy is to develop drug delivery systems targeting viral reservoirs at effective concentration in the brain. With this need we developed Efavirenz nanosuspension for nose to brain drug transport to bypass blood brain barrier. Nanosuspension prepared with high-pressure homogenization had a mean particle size of 223 nm, PDI of 0.2 and -21.2 mV zeta potential. Histopathology study on goat nasal mucosa showed no adverse effects of formulation on nasal tissues. Gamma scintigraphy study and in-vivo study on Wistar rat model reveals drug transport to the CNS after nasal administration. Pharmacokinetic parameters and drug targeting potential of 99.46 % suggest direct nose to brain transport of Efavirenz nanoparticle. Results reveal that nose to brain delivery of Efavirenz is the best possible alternative for neuro –AIDS treatment.

Nose to Brain Delivery of Phenytoin Sodium Loaded Nano Lipid Carriers: Formulation, Drug Release, Permeation and In Vivo Pharmacokinetic Studies.

An acute epileptic seizure is a seizure emergency fatal condition that requires immediate medical attention. IV phenytoin sodium remains the second line therapeutic agent for the immediate treatment of status epilepticus. Phenytoin sodium formulated as nanolipid carriers (NLCs) seems to be promising as an intranasal delivery system for controlling acute seizures. Three different nanosized phenytoin sodium loaded NLCs (<50 nm, 50–100 nm and >100 nm) were prepared by melt emulsification and was further characterised. In vitro drug release studies showed immediate drug release from phenytoin sodium loaded NLCs of <50 nm size, which is highly essential for acute seizure control. The ex vivo permeation study indicated greater permeation from <50 nm sized NLC through the olfactory epithelium compared to thecontrol drug solution. Invivo pharmacokinetic studies revealed higher drug concentration in CSF/brain within 5 min upon intranasal administration of <50 nm sized phenytoin sodium NLCs than the control drug solution and marketed IV phenytoin sodium, indicating direct and rapid nose to brain drug transport through the olfactory epithelium. The study has shown that formulation strategies can enhance olfactory uptake, and phenytoin sodium NLCs of desired particle sizes (<50 nm) offer promising potential for nose to brain direct delivery of phenytoin sodium in treating acute epileptic seizures.

Intranasal dolutegravir sodium loaded nanoparticles of hydroxypropyl-beta-cyclodextrin for brain delivery in Neuro-AIDS

Dolutegravir sodium (DTG) loaded nanoparticles (NPs) were prepared by cross-linking Hydroxypropyl-β-cyclodextrin (HPβCD) with diphenyl carbonate to enhance its CNS uptake via intranasal delivery. NPs were characterized for various parameters like size, drug loading, in vitro release, safety and CNS uptake and optimized using quadratic response surface methodology (RSM) employing 2-factor, 5-level circumscribed central composite design. The batch of NPs containing DTG:HPβCD; 1:4.16 was considered optimum as uniform small NPs (size; 81±3 nm, PDI 0.378 ± 0.04) with high drug loading (14.9 ± 1.4%) and entrapment efficiency (77 ± 3.35%). NPs produced sustained drug release (89.51 ± 0.56% in 6 h) by Fickian diffusion mechanism, they provided 2.54 folds greater permeability of DTG compared to free drug and were non-toxic to L929 cell line. Significantly higher concentration of DTG in the CSF (24.89±4.56μg/mL) and higher CSF:Plasma ratio(1.64) was achieved from intranasal NPs as compared to the reported DTG concentration in the CSF (18 ng/mL) and CSF:Plasma ratio (0.11–0.66) following oral administration of tablet. High brain drug transport percentage (83.47%) from intranasal NPs confirms nose to brain transport of the drug. Gamma scintigraphy studies in rats revealed enhanced CNS uptake of drug from NPs. These results suggest that the present investigation hold promise for management of Neuro-AIDS.

Disease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer's Disease : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla.

Alzheimer's disease (AD) may disturb functions of the blood-brain barrier and change the disposition of drugs to the brain. This study assessed the disease-induced changes in drug transporters in the brain capillaries of transgenic AD mice. Eighteen drug transporters and four tight junction-associated proteins were analyzed by RT-qPCR in cortex, hippocampus and cerebellum tissue samples of 12-16-month-old APdE9, Tg2576 and APP/PS1 transgenic mice and their healthy age-matched controls. In addition, microvessel fractions enriched from 1-3-month-old APdE9 mice were analyzed using RT-qPCR and Western blotting. Brain transport of methotrexate in APdE9 mice was assessed by in vivo microdialysis. The expression profiles of studied genes were similar in brain tissues of AD and control mice. Instead, in the microvessel fraction in APdE9 mice, >2-fold alterations were detected in the expressions of 11 genes but none at the protein level. In control mice strains, >5-fold changes between different brain regions were identified for Slc15a2, Slc22a3 and occludin. Methotrexate distribution into hippocampus of APdE9 mice was faster than in controls. The expression profile of mice carrying presenilin and amyloid precursor protein mutations is comparable to controls, but clear regional differences exist in the expression of drug transporters in brain.

Drug Delivery Systems from Nose to Brain

The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to deliver drugs selectively and effectively to the brain. Blood-brain-barrier (BBB) constitutes the major obstacle to the uptake of drugs into the brain following systemic administration. Intranasal delivery offers a non-invasive and convenient method to bypass the BBB and delivery of therapeutics directly to the brain. The review discusses the potential of intranasal route to deliver drugs to the brain, the mechanisms and pathways of direct nose to brain drug transport, the various factors influencing transnasal drug absorption, the conventional and novel intranasal drug delivery systems, the various intranasal drug delivery techniques and devices, and examples of brain drug transport that have been feasible in treating various brain disorders. Moreover, products on the market, investigational drugs, and the author's perceptions about the prospect of intranasal delivery for treating brain disorders are also been discussed.

Predictive models for pressure-driven fluid infusions into brain parenchyma

Direct infusions into brain parenchyma of biological therapeutics for serious brain diseases have been, and are being, considered. However, individual brains, as well as distinct cytoarchitectural regions within brains, vary in their response to fluid flow and pressure. Further, the tissue responds dynamically to these stimuli, requiring a nonlinear treatment of equations that would describe fluid flow and drug transport in brain. We here report in detail on an individual-specific model and a comparison of its prediction with simulations for living porcine brains. Two critical features we introduced into our model—absent from previous ones, but requirements for any useful simulation—are the infusion-induced interstitial expansion and the backflow. These are significant determinants of the flow. Another feature of our treatment is the use of cross-property relations to obtain individual-specific parameters that are coefficients in the equations. The quantitative results are at least encouraging, showing a high fraction of overlap between the computed and measured volumes of distribution of a tracer molecule and are potentially clinically useful. Several improvements are called for; principally a treatment of the interstitial expansion more fundamentally based on poroelasticity and a better delineation of the diffusion tensor of a particle confined to the interstitial spaces.

Drug transport in brain via the cerebrospinal fluid

The human brain has no lymphatic system, but produces over a half-liter each day of cerebrospinal fluid. The cerebrospinal fluid is secreted at the choroid plexus and occupies the cavities of the four ventricles, as well as the cranial and spinal sub-arachnoid space. The cerebrospinal fluid moves over the surfaces of the brain and spinal cord and is rapidly absorbed into the general circulation. The choroid plexus forms the blood-cerebrospinal fluid barrier, and this barrier is functionally distinct from the brain microvascular endothelium, which forms the blood-brain barrier. Virtually all non-cellular substances in blood distribute into cerebrospinal fluid, and drug entry into cerebrospinal fluid is not an index of drug transport across the blood-brain barrier. Drug injected into the cerebrospinal fluid rapidly moves into the blood via bulk flow, but penetrates into brain tissue poorly owing to the limitations of diffusion. Drug transport into cerebrospinal fluid vs. brain interstitial fluid requires knowledge of the relative expression of transporters at the choroid plexus versus the brain microvascular endothelium.

Intranasal nanoemulsion based brain targeting drug delivery system of risperidone

The objective of investigation was to prepare nanoemulsion containing risperidone (RSP) to accomplish the delivery of drug to the brain via nose. Risperidone nanoemulsion (RNE) and mucoadhesive nanoemulsion (RMNE) were characterized for drug content, pH, percentage transmittance, globule size and zeta potential. Biodistribution of RNE, RMNE, and risperidone solution (RS) in the brain and blood of Swiss albino rats following intranasal (i.n.) and intravenous (i.v.) administration was examined using optimized technetium labeled ( 99mTc-labeled) RSP formulations. Gamma scintigraphy imaging of rat brain following i.v. and i.n. administrations were performed to ascertain the localization of drug in brain. The brain/blood uptake ratio of 0.617, 0.754, 0.948, and 0.054 for RS (i.n.), RNE (i.n.), RMNE (i.n.), and RNE (i.v.), respectively, at 0.5 h are indicative of direct nose to brain transport bypassing the blood–brain barrier. Higher drug transport efficiency (DTE%) and direct nose to brain drug transport (direct transport percentage, DTP%) for mucoadhesive nanoemulsions indicated more effective and best brain targeting of RSP amongst the prepared nanoemulsions. Studies conclusively demonstrated rapid and larger extent of transport of RSP by RMNE (i.n.) when compared to RS (i.n.), RNE (i.n.) and RNE (i.v.) into the rat brain.

Blood–Brain Barrier Transport of Therapeutics via Receptor-Mediation

Drug delivery to the brain is hindered by the presence of the blood-brain barrier (BBB). Although the BBB restricts the passage of many substances, it is actually selectively permeable to nutrients necessary for healthy brain function. To accomplish the task of nutrient transport, the brain endothelium is endowed with a diverse collection of molecular transport systems. One such class of transport system, known as a receptor-mediated transcytosis (RMT), employs the vesicular trafficking machinery of the endothelium to transport substrates between blood and brain. If appropriately targeted, RMT systems can also be used to shuttle a wide range of therapeutics into the brain in a noninvasive manner. Over the last decade, there have been significant developments in the arena of RMT-based brain drug transport, and this review will focus on those approaches that have been validated in an in vivo setting.

Receptor-coupled uptake of valproate in rat astroglial primary cultures

Various receptor ligands were investigated for their effects on the uptake of the antiepileptic drug valproic acid (VPA) in primary astroglial cultures from cerebral cortex of neonatal rats. After stimulation with the α 1-adrenoceptor agonist phenylephrine, 5-hydroxytryptamine (5-HT) or the glutamate receptor agonists glutamate, quisqualate and kainate, the V max and K m values for the drug transport increased. On the contrary, after exposure to the α 2-adrenoceptor agonist clonidine, V max and K m decreased. The effects were reversed in comparison to the control level in the presence of selective receptor antagonists. The data indicate a specific coupling between receptors and the uptake system for VPA. Furthermore, the results may have significant implications, as they suggest that receptors on astrocytes can be involved in the local regulation of drug transport in brain.