Brain Bioavailability Research Articles

Inhibition of Aβ Aggregation and Tau Phosphorylation with Functionalized Biomimetic Nanoparticles for Synergic Alzheimer's Disease Therapy.

The main pathological mechanisms of Alzheimer's Disease (AD) are extracellular senile plaques caused by β-amyloid (Aβ) deposition and intracellular neurofibrillary tangles derived from hyperphosphorylated Tau protein (p-Tau). However, it is difficult to obtain a good curative effect because of the poor brain bioavailability of drugs, which is attributed to the blood-brain barrier (BBB) restriction and complicated brain conditions. Herein, HM-DK was proposed for synergistic therapy of AD by using hollow mesoporous manganese dioxide (HM) as a carrier to deliver an Aβ-inhibiting peptide and a Dp-peptide inhibitor of Tau-related fibril formation synergistically. Inspired by 4T1 cancer cells promoting BBB penetration during brain metastasis, a prospective biomimetic nanocarrier (HM-DK@CM) encapsulated by 4T1 cell membranes was designed. After crossing the BBB, HM-DK@CM inhibited Aβ aggregation and prevented Tau phosphorylation simultaneously. Moreover, by taking advantage of the catalase-like activity of HM, HM-DK@CM relieved oxidative stress and altered the microenvironment associated with the development of AD. Compared with the single therapeutic drug, HM-DK@CM restored nerve damage and improved AD mice's learning and memory abilities by decreasing Aβ oligomer, p-Tau protein, and inflammation through various pathways for synergistic therapy, which has broad prospects for the effective treatment of AD.

Design Formulation of Nanospanlastic Novel Carriers as a Promising Approach to Enhanced Bioavailability in Intranasal Drug Delivery for Sinusitis: Statistical Optimization and In vitro and In vivo Characterization

Background: Most new biologically active chemicals require better water solubility and slower dissolution rates. Cefdinir (CFD) has a very low bioavailability in its crystalline form and is poorly soluble in water. Objective: By preparing cefdinir's spanlastic nanovesicles (SNVs) using the ethanol injection method, the current study has attempted to enhance the drug's solubility and bioavailability using a statistical design approach. Methods: Independent variables, including the nonionic surfactant concentration, edge activator (EA), sonication time, SNVs entrapment efficiency, particle size, zeta potential, PDI, and in vitro release, have been evaluated. The best CFD-SNVs were positioned within in situ gel with muco-adhesive properties made of hydroxypropyl methylcellulose and deacetylated gellan gum. By contrasting intranasal injection of the produced gel with an IV solution, animal models have been used to investigate CFD's systemic and cerebral dynamics. Results: Statistical analysis has suggested an ideal SNVs formulation with nonionic surfactant (65 mg), EA (15 mg), and sonication (3 min). The sol-gel temperature for forming the mucoad-hesive in situ gel containing SNVs has been found to be 34.03°C, and 18.36 minutes has been the extended mucociliary transit time. Following intranasal injection, compared to SNV dispersion, the gelling system has exhibited higher brain bioavailability (2251.9 ± 75 vs. 5281.6 ± 51%, re-spectively). The gel has also demonstrated effective drug targeting of the brain with higher direct transport percentage indices. Conclusion: Mucoadhesive in situ gel with CFD-loaded SNVs can be administered via the in-tranasal route. To enhance bioavailability in the brain and drug targeting from the nose to the brain, nasal in situ gel loaded with CFD-SNVs could be a new carrier to be employed in sinusitis.

Lyotropic Liquid Crystalline Based Nasal Spray for Improved Parkinson's Treatment: Enhanced Superior Nasal Tract Deposition and Antioxidation Strategy

AbstractThe blood–brain barrier is one of the serious challenges in the treatment of Parkinson's disease (PD), which severely hinders the drug's brain bioavailability. In this study, a lyotropic liquid crystalline (LLC) based in situ gel nasal spray loaded with the first‐line drug Levodopa (LDA) for PD is developed to resolve this issue based on a nose‐to‐brain drug delivery approach. Specifically, the two key stages of LLC‐based in situ gel nasal spray, droplet deposition, and drug retention are tailored. By adjusting LLC's precursor solution's viscosity, the droplet deposition on the superior nasal tract can be increased by 18 times. Through nasal mucus‐triggered sol–gel transition, the LDA nasal cavity retention is prolonged by three times. The epigallocatechin gallate is incorporated into the LLC‐based in situ gel nasal spray to inhibit the autoxidation of LDA and alleviate the oxidative stress response in PD. The results show that the LLC‐based in situ gel nasal spray has a 26‐fold higher brain bioavailability of LDA compared to oral administration. The PD rats show a significant improvement in behavioral and cognitive disorders after administration. The LLC‐based in situ gel nasal spray is proved to work by reducing oxidative damage. This study is anticipated to offer a promising strategy for the clinical application of LDA.

Rhamnosomes: A new generation of flexible vesicles for a boosted targeted nose-to-brain delivery of selegiline in the treatment of Parkinson's disease

Extensive hepatic metabolism of Selegiline, a selective monoamine oxidase B inhibitor for newly diagnosed Parkinson's disease patients, causes limited brain bioavailability. To improve efficacy, a new generation of flexible lipidic vesicles, Rhamnosomes, comprising alternating lecithin and Rhamnolipid moieties, and decorated with lactoferrin to actively target Selegiline to the brain is proposed.Rhamnosomes were optimized using design of expert, where lipid amount, Soybean lecithin:Rhamnolipid ratio and sonication time were varied. Polyelectrolyte complexation was employed for Lactoferrin conjugation to Rhamnosomes. A pharmacokinetic study in rat plasma and brain was conducted. Optimized Rhamnosomes had a particle size of 107 nm, polydispersity index of 0.23, zeta potential of −41mV, entrapment efficiency of 78 %, relative deformability of 36sec and ex-vivo skin permeation reaching 60 % after 24 h. The plasma half life of Rhamnosomes was 3.24 times the market product and 2.63 times the intravenous solution, whereas, lactoferrin-conjugated Rhamnosomes exhibited 7 times higher absolute bioavailability than the market product and more than double its brain drug targeting efficiency. Prominent direct nose-to-brain transport values further proved the efficiency of intranasally delivered Selegiline-loaded Lactoferrin conjugated Rhamnosomes to actively target the brain in a non-invasive approach for the treatment of Parkinson's disease.

A tailored phytosomes based nose-to-brain drug delivery strategy: Silver bullet for Alzheimer's disease

With the aging of the population, the incidence of Alzheimer's disease (AD) has increased dramatically, causing severe medical, care, and economic burdens on society and families. The efficacy of rivastigmine hydrogen tartrate (RHT), the first-line clinical treatment, is severely limited by the complex and multiple pathogenesis of AD and low brain bioavailability caused by the blood-brain barrier (BBB). Confronting such two bottlenecks, the development of multi-target agents encapsulated BBB-bypassing drug delivery systems offer tremendous therapeutics possibilities for AD. In this study, a tailored phytosomes based nose-to-brain drug delivery system with appropriate plume was successfully designed and developed. On the one hand, Ginseng RG3-based phytosomes loaded with RHT was designed for the co-delivery of GRg3 and RHT, achieving the multi-target pharmacology for AD treatment. On the other hand, a tailored nose-to-brain drug delivery system was established for the satisfactory nose-to-brain delivery efficiency, avoiding the obstacle of BBB through bypassing it. In the pharmacodynamic study based on AD rat model, GRg3@RHT exhibited obviously synergic effect, effectively break the vicious cycle of AD progression, ultimately markedly ameliorating learning and memory ability as well as behavioral dysfunctions, and delaying the neurodegenerative process associated with AD. In addition, the strong correlation of viscosity-droplet size-plume geometry-olfactory deposition was also established, and further proved by the in vivo pharmacokinetic study, which is proposed to provide evidence to enhance nose-to-brain delivery efficiency. This study is anticipated to provide novel insights into AD treatment strategies while offering innovative ideas for drug delivery approaches targeting nervous system disorders.

Fabrication of Uniform Melatonin Microparticles Potentially for Nasal Delivery: A Comparison of Spray Drying and Spray Freeze Drying.

Insomnia is a major health concern, and melatonin (MLT) is key for initiating sleep. Delivering MLT nasally can enhance brain bioavailability by targeting the olfactory region. This study aimed to fabricate MLT embedded microparticles for nasal delivery. MLT-cyclodextrin (CD) derivatives complex microparticles (MCCMPs) were fabricated by spray drying and spray freeze drying MLT and CD derivative solutions. Phase solubility and 1H-1H ROSEY NMR analysis assessed MLT-CD assembly. The effects of formulation compositions and process parameters on microparticle structural attributes were investigated. The in vitro nasal release and deposition performances were evaluated by a modified paddle-over-disk apparatus and 3D-printed nasal cavity cast, respectively. Sodium sulphobutylether-β-cyclodextrin (SBE-β-CD) exhibited the best complexation ability with MLT, with the indole structure of MLT included in its cavity. Spray dried MCCMPs showed dense structure with high density, while the spray freeze dried counterpart showed the brittle and porous structure with low density. Despite the porous structure may promote the release rate of spray freeze dried samples, the high hydrophilicity of the CD derivative overshadows this advantage. Samples prepared by spray drying not only exhibited rapid release rates but also could deposit more effectively in the olfactory region, as they avoid breakage due to their higher mechanical strength. The optimal sample showed ~ 86.70% of the MLT released at 20min and ~ 10.57% of the deposition fraction in the olfactory region. This work compares MCCMPs fabricated by spray drying and spray freeze drying, providing the optimal formulation and process combinations.

Roflumilast-loaded nanostructured lipid carriers attenuate oxidative stress and neuroinflammation in Parkinson’s disease model

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited symptomatic treatment options. Targeting phosphodiesterase 4 (PDE4) has shown a promising result in several preclinical studies. In our study, we aim to repurpose US FDA-approved PDE4 inhibitor for PD. Through in-silico study, we identified roflumilast (ROF) as the potential candidate targeting PDE4B2. In Drosophila PD expressing the A30P mutant α-synuclein model, ROF exhibited anti-PD effects as indicated by negative geotaxis and antioxidant activities. Given the low brain distribution of ROF (<50%) at clinical doses, incorporation into nanostructured lipid carriers (NLCs) was carried out to enhanced blood-brain barrier permeability. In vitro release studies indicated sustained ROF release from NLCs (≈75%) over 24 h. Single-dose oral toxicity studies reported no mortality or toxicity signs. ROF-loaded NLCs significantly alleviated behavioural deficits, increased antioxidant parameters (p < 0.05), and reduced TNF-α and IL-6 levels (p < 0.5) in the striatum compared to pure ROF. ROF-loaded NLCs demonstrated potential anti-PD effects with high efficacy than pure ROF. Our study suggests that nanostructured lipid carriers (NLCs) can be a promising drug delivery system to overcome limitations associated with poor brain bioavailability of lipophilic drugs like ROF for PD treatment. Further investigation related to brain occupancy and underlying mechanisms of our formulation is warranted to confirm and strengthen our current findings.

Intranasal transfersomal based in situ gel for augmenting methylphenidate bioavailability and brain delivery: In vitro and in vivo evaluation

Methylphenidate, a CNS stimulant drug, has poor oral bioavailability due to extensive first-pass effect. In this study, Methylphenidate loaded transfersomes based in situ gel (MPH-TFs Gel) was prepared for brain targeting through intranasal (IN) drug delivery. Methylphenidate transfersomes (MPH-TFs) were prepared using the thin film hydration method. Box-Behnken Design expert software was utilized for the optimization by assessing the effect of independent variables phospholipon 90-G, Tween-80, and Methylphenidate (MPH) on particle size (PS), zeta potential (ZP), Polydispersity index (PDI), and Entrapment Efficiency (EE). The observed mean particle size of the optimized MPH-TFs was found to be 139.7 ± 3.75 nm, mono dispersion with PDI (0.208 ± 0.002), negatively charged (−27.9 ± 0.287 mV) and had an excellent entrapment efficiency (86 ± 3 %). Fourier-Transform Infrared (FTIR) spectra have depicted the compatibility of the components. X-r Diffraction analysis showed the conversion of crystalline structure methylphenidate to amorphous. The optimized MPH-TFs were then subsequently incorporated into an already optimized MPH-TFs Gel. MPH-TFs Gel was then characterized for its physicochemical properties, in vitro and in vivo studies. In vitro release and ex vivo permeation analysis showed sustained release and improved permeation of the MPH-TFs Gel, respectively. Additionally, histopathological studies of nasal membrane affirmed the safety of MPH-TFs Gel after intranasal application. In vivo pharmacokinetic study demonstrated improved brain bioavailability of MPH-TFs Gel compared to orally administered Methylphenidate solution (MPH-Sol).

The Proteasome Inhibitor Marizomib Evokes Endoplasmic Reticulum Stress and Promotes Apoptosis in Human Glioblastoma Cells.

Proteasomes play an important role in the physiology of cancer cells, and inhibition of their activity may be used as a promising therapeutic strategy against glioblastoma (GBM). Although certain proteasome inhibitors (PIs) have been approved for the treatment of other malignancies, they have limited effectiveness against GBM due to low brain bioavailability. Marizomib (MZB) is an irreversible, second-generation proteasome inhibitor, which unlike other PIs can penetrate through the blood-brain barrier, making it a promising therapeutic tool in brain malignancies. The antitumor activity of MZB was investigated in LN229 and U118 cells. The MTT test and the ATP-based assay were performed to evaluate cytotoxicity. Flow cytometry analysis was used to determine the apoptotic death of GBM cells. Luminescent assays were used to assess levels of reactive oxygen species (ROS) and the activity of caspase 3/7. RT-qPCR and Western blot analyses were used to determine gene and protein expressions. Marizomib decreased the viability and caused apoptotic death of GBM cells. The proapoptotic effect was accompanied by activation of caspase 3 and overexpression of cl-PARP, Noxa, Cyt C, and DR5. Moreover, treatment with MZB triggered endoplasmic reticulum (ER) stress, as shown by increased expressions of GRP78, IRE1α, p-EIF2α, p-SAPK/JNK, CHOP, ATF6α, and ATF4. On the contrary, overproduction of ROS or increased expressions of ERO1α, LC3 II, Beclin 1, and ATG5 were not detected, suggesting that neither oxidative stress nor autophagy were involved in the process of MZB-induced cell death. Thus, marizomib represents a potentially promising compound for facilitating further progress in brain cancer therapy.

Magnesium-L-threonate improves sleep quality and daytime functioning in adults with self-reported sleep problems: A randomized controlled trial

Objective/BackgroundSleep problems challenge overall wellbeing. Magnesium has been implicated to benefit sleep, although the clinical evidences varied based on the magnesium source used. Magnesium L-threonate (MgT) is a promising intervention due to its brain bioavailability and effects on cognition, memory and mood. We investigated MgT supplementation on sleep quality and daily function. Patients/methodsEighty 35–55-year-olds with self-assessed sleep problems participated in a randomized, double-blind, placebo-controlled, parallel-arm study, taking 1 g/day of MgT or placebo for 21 days. Sleep and daily behaviors were measured subjectively using standardized questionnaires including the Insomnia Severity Index, Leeds Sleep Evaluation Questionnaire, and Restorative Sleep Questionnaire, and objectively using an Oura ring. The Profile of Mood States questionnaire and a daily diary were used to evaluate mood, energy and productivity, and record any safety concerns. ResultsThe MgT group maintained good sleep quality and daytime functioning, while placebo declined. From objective Oura ring measurements, MgT significantly (p < 0.05) improved vs placebo deep sleep score, REM sleep score, light sleep time, and activity and readiness parameters activity score, activity daily movement score, readiness score, readiness activity balance, and readiness sleep balance. From subjective questionnaires, MgT significantly (p < 0.05) improved vs placebo behavior upon awakening, energy and daytime productivity, grouchiness, mood and mental alertness. MgT was safe and well tolerated. ConclusionsThis showed MgT improved sleep quality, especially deep/REM sleep stages, improved mood, energy, alertness, and daily activity and productivity. These are consistent with how MgT works in neuron cells and animal models, suggesting broader positive impacts on overall brain health.

Self-assembled low molecular weight chitosan-bilobalide microsuspension protects hippocampal toxicity in amyloid beta(25–35) induced mice

Alzheimer's disease (AD) is a progressive neurological disorder and is characterized by the accumulation of amyloid beta (Aβ) peptide and hyperphosphorylated tau as a pathological hallmark. Bilobalide (BB) being a highly hydrophobic compound, has poor aqueous solubility, stability, and brain bioavailability. In the present study, we prepared self-assembled low molecular weight chitosan-bilobalide microsuspension (BBC) and examined its neuroprotective effect against intracerebroventricular induction of Aβ(25–35) toxicity in mice. Results showed that BBC has a particle size of 5.77 µm with a desired zeta potential of +42.2 ± 2 mV. BBC displayed aqueous solubility with sustained release kinetics in vitro and had better intracellular transport (70 %) of BB from BBC in Caco-2 cells. Further, treatment with BBC showed increased content [BBC (10 mg), 83.4 ng; BB (10 mg), 15.8 ng] of BB in brain and alleviated Aβ(25–35) induced memory impairment in mice. Moreover, BBC diminished oxidative stress, neuroinflammation, and synaptic dysfunction in Aβ(25–35) induced AD model. In addition, our western blot data suggested that treatment with BBC ameliorated Aβ(25–35) induced hyperphosphorylation of tau protein through regulation of aberrant phosphorylation of Akt/GSK3β/MAPK pathway. The current study may confirm the application of BBC as an oral supplement in the food and pharmaceutical industries for AD conditions.

Small Particles, Big Potential: Polymeric Nanoparticles for Drug Delivery in Parkinson's Disease.

Despite the availability of a number of efficacious treatments for Parkinson's disease, their limitations and drawbacks, particularly related to low brain bioavailability and associated side effects, emphasize the need for alternative and more effective therapeutic approaches. Nanomedicine, the application of nanotechnology in medicine, has received considerable interest in recent years as a method of effectively delivering potentially therapeutic molecules to the brain. In particular, polymeric nanoparticles, constructed from biodegradable polymer, have shown great promise in enhancing therapeutic efficacy, reducing toxicity, and ensuring targeted delivery. However, their clinical translation remains a considerable challenge. This article reviews recent in vitro and in vivo studies using polymeric nanoparticles as drug and gene delivery systems for Parkinson's disease with their challenges and future directions. We are also particularly interested in the technical properties, mechanism, drugs release patterns, and delivery strategies to overcome the blood-brain barrier. © 2024 International Parkinson and Movement Disorder Society.

A novel mucoadhesive paliperidone-nanoemulsion developed using the ultrasonication method in the treatment of schizophrenia.

Aim: To develop paliperidone mucoadhesive-nanoemulsion (PLP-NE) to enhance brain bioavailability. To evaluate comparative effects of PLP-NE and CS-PLP-NE in the treatment of schizophrenia, followed by a toxicity study of opt-NE. Material and methods: Oil: oleic acid, surfactant: Tween-80, and co-surfactant: Labrasol were chosen based on the solubility and maximum nanoemulsion area. The ultrasonication technique was applied with the aqueous micro titration method for the development of PLP-NE. The optimization of the method for the excellent PLP-NE was performed using a central composite design based on a five-factor and four-level. Oil (% v/v), S mix (v/v%), ultrasonication intensity in percentage, ultrasonication time in minutes, and temperature (°C) were optimized and used to the independent variables. Results: The parameters i.e., oil (5%), S mix (10%), ultrasonication time (5.0 min), ultrasonication intensity (25%), and temperature (38 °C) were optimized and used as independent and dependent variables for the development of novel PLP-NE. Based on experimental data, the dependent variables, i.e., globule size (53.90 ± 4.01 nm), % transmittance (92.56% ± 1.06%), PDI (0.218 ± 0.007), and zeta potential (-11.60 ± 0.031 mV), were determined. The smooth near about spherical shaped of PLP-NE globules with, refractive index i.e., 1.62 ± 0.021, viscosity: 39 ± 6 cp with the pH: 7.40 ± 0.089, and content of drug (97.98 ± 0.39%) for optimized-PLP-NE. The optimized PLP-NE with oleic acid, Tween-80, and Labrasol was used to improve brain bioavailability with good permeation via the intranasal route. CS-PLP-NE yielded good mucoadhesive property results compared to paliperidone-nanoemulsion, and PLP-S containing a 0.751 minutes retention time with their deuterated-IS (0.806 min) and m/z of 427.2/207.2 with IS (m/z: 431.2/211.2) for PLP and PLP-IS. A calibration curve was plotted with a linear range of 1-2000 ng mL-1 with inter- and intraday accuracy (97.03-99.31%) and precision (1.69-50.05%). The results of AUC(0-24) and C max for PLP were found to be highly significant (p < 0.001) as an improvement of brain bioavailability in rats via intranasal delivery of CS-PLP-NE. Furthermore, the locomotion test, social interaction, and forced swimming test (forced swimming, climbing, and immobility) of a mucoadhesive CS-PLP-NE (intranasally) provided highly significant results with the improvement of behavioral analysis when compared to the PLP-NE and PLP-S studies. Conclusion: CS-PLP-NE (i.n.) showed highly significant results, i.e., p < 0.001 for the improvement of bioavailability of the brain in the treatment of schizophrenia. Optimized-mucoadhesive-CS-based-PLP-NE is safe and shows no toxicity.

PH-Sensitive In Situ Gel of Mirtazapine Invasomes for Rectal Drug Delivery: Protruded Bioavailability and Anti-Depressant Efficacy.

The present research emphasizes fabrication alongside the assessment of an innovative nano-vesicular membranous system known as invasomes (NVMs) laden with Mirtazapine for rectal administration. This system could circumvent the confines of orally administered counterparts regarding dose schedules and bioavailability. Mirtazapine invasomes were tailored by amalgamating phospholipid, cineole, and ethanol through a thin-film hydration approach rooted in the Box-Behnken layout. Optimization of composition parameters used to fabricate desired NVMs' physicochemical attributes was undertaken using the Design-Expert® program. The optimal MRZ-NVMs were subsequently transformed to a pH-triggered in situ rectal gel followed by animal pharmacodynamic and pharmacokinetic investigations relative to rectal plain gel and oral suspension. The optimized NVMs revealed a diameter size of 201.3 nm, a z potential of -28.8 mV, an entrapment efficiency of 81.45%, a cumulative release within 12 h of 67.29%, and a cumulative daily permeated quantity of 468.68 µg/cm2. Compared to the oral suspension, pharmacokinetic studies revealed a 2.85- and 4.45-fold increase in calculated rectal bioavailability in circulation and brain, respectively. Pharmacodynamic and immunohistopathology evaluations exposed superior MRZ-NVMs attributed to the orally administered drug. Consequently, rectal MRZ-NVMs can potentially be regarded as a prospective nanoplatform with valuable pharmacokinetics and tolerability assets.

Intranasal bilosomes in thermosensitive hydrogel: advancing desvenlafaxine succinate delivery for depression management

Depression, the second biggest cause of disability worldwide, is widespread. Many antidepressant medications, including Desvenlafaxine Succinate (D.V.S.), function by elevating neurotransmitter levels at the synapse through the inhibition of reabsorption by neurons. However, the effectiveness of these treatments is often limited by their inability to reach the brain using conventional administration methods. Bilosome-stabilized nanovesicles containing bile salts have drawn much interest because of their adaptability and versatility in various applications. This study aimed to address this issue by formulating intranasal bilosomes incorporated into a mucoadhesive in situ gel to deliver D.V.S. directly to the brain for depression treatment. The desvenlafaxine-loaded bilosomes were developed using a thin film hydration method based on the l-optimal design. They were intended to provide a more convenient route of administration for antidepressants, enhancing bioavailability and brain targeting through intranasal delivery. The study assessed the optimized bilosomes for particle size (311.21 ± 0.42 nm), Zeta potential (–37.35 ± 0.43)and encapsulation efficiency (99.53 ± 0.41%) and further evaluated them in ex vivo and in vivo pharmacokinetics studies. Pharmacokinetic data reveal enhanced brain uptake compared to a free drug. A statistically optimized bilosome formulation was determined. The intranasal administration of mucoadhesive in situ gel containing desvenlafaxine succinate-loaded bilosomes facilitated direct nose-to-brain drug delivery, improving brain bioavailability.

Box-Behnken Design-Based Optimization and Evaluation of Lipid-Based Nano Drug Delivery System for Brain Targeting of Bromocriptine.

Bromocriptine (BCR) presents poor bioavailability when administered orally because of its low solubility and prolonged first-pass metabolism. This poses a significant challenge in its utilization as an effective treatment for managing Parkinson's disease (PD). The utilization of lipid nanoparticles can be a promising approach to overcome the limitations of BCR bioavailability. The aim of the research work was to develop and evaluate bromocriptine-loaded solid lipid nanoparticles (BCR-SLN) and bromocriptine-loaded nanostructured lipid carriers (BCR-NLC) employing the Box-Behnken design (BBD). BCR-SLNs and BCR-NLCs were developed using the high-pressure homogenization method. The prepared nanoparticles were characterized for particle size (PS), polydispersity index (PDI), and entrapment efficiency (EE). In vitro drug release, cytotoxicity studies, in vivo plasma pharmacokinetic, and brain distribution studies evaluated the optimized lipid nanoparticles. The optimized BCR-SLN had a PS of 219.21 ± 1.3 nm, PDI of 0.22 ± 0.02, and EE of 72.2 ± 0.5. The PS, PDI, and EE of optimized BCR-NLC formulation were found to be 182.87 ± 2.2, 0.16 ± 0.004, and 83.57 ± 1.8, respectively. The in vitro release profile of BCR-SLN and BCR-NLC showed a biphasic pattern, immediate release, and then trailed due to the sustained release. Furthermore, a pharmacokinetic study indicated that both the optimized BCR-SLN and BCR-NLC formulations improve the plasma and brain bioavailability of the drug compared to the BCR solution. Based on the research findings, it can be concluded that the BCR-loaded lipid nanoparticles could be a promising carrier by enhancing the BBB penetration of the drug and helping in the improvement of the bioavailability and therapeutic efficacy of BCR in the management of PD.

Effect of particle size versus surface charge on the brain targeting behavior of elastic nanovesicles: In-vitro characterization, comparison between I-optimal and D-optimal statistical optimization and in-vivo pharmacokinetic evaluation

Rasagiline mesylate (RM) is a potent monoamine oxidase-B inhibitor that suffers from extensive hepatic metabolism, low bioavailability, and low brain distribution. Thus, this study aimed to formulate an intranasal nanovesicular system with high RM encapsulation (EE%) and enhanced delivery to the brain tissues. In this perspective, negatively and positively charged RM-transfersomal vesicles were prepared, characterized and the formulation parameters were statistically optimized as per two different response surface methodologies namely, I-optimal and D-optimal design. Although both statistical designs acted almost similarly in terms of experimental response analysis; the I-optimal design might be functioning better in terms of formulations’ optimization and response prediction with higher desirability factors. Consequently, the optimized negative transfersomes (particle size: 213 nm, EE%:62.55 %) and positive transfersomes (particle size: 515 nm, EE%:70.9 %) suggested by the I-optimal design were furtherly formulated, characterized for their in-vitro release, elasticity, transmission electron microscope and pH. Finally, both systems were administered intranasally and compared to an intravenous RM solution where the optimized positive transfersomes has shown significantly higher brain targeting efficiency, positive direct transfer percentage values and longer brain mean residence time. These results suggested that the surface charge of the formulated vesicles could be more effective factor -than the particle size-in enhancing the brain bioavailability of the administered drugs.

Research progress on intranasal treatment for Parkinson's disease

AbstractParkinson's disease (PD) is the second most prevalent neurodegenerative disorder globally, significantly affecting the quality of life of affected individuals. Systemic drug delivery to the brain is inefficient because of first‐pass metabolism, the blood‐brain barrier (BBB), and the blood‐cerebrospinal fluid barrier. This inefficiency necessitates increased dosage as the disease progresses, leading to severe side effects that compromise the efficacy of the medication. Nose‐to‐brain (N2B) administration bypasses the BBB, allowing delivery of both small molecules and large protein substances to the central nervous system. Compared with systemic administration, this method enhances brain bioavailability, reduces enzymatic degradation, and minimizes systemic adverse reactions. However, the N2B delivery system is associated with several critical challenges, including mucociliary clearance, enzymatic degradation, and drug translocation via efflux mechanisms. This paper provides a comprehensive overview of the current research progress in intranasal treatment of PD, considering both preclinical and clinical studies, and discusses the physiological aspects and limitations of its delivery system.

BBD assisted in-situ nanoliposomes of esculin hydrate via intranasal delivery for the amelioration of Parkinson's disease

The objective of this research was to develop and optimise esculin Hydrate loaded nanoliposomes (ESH-NLs). The nanoliposomes were prepared by solvent evaporation method and optimized using a three-factor, three-level Box-Behnken design. Phospholipid 90G (X1), cholesterol (X2), and sonication time (X3) were used as independent variables, and their effects on vesicle size (Y1), entrapment efficiency (Y2), and Polydispersity index (Y3) were observed. The opt-ESH-NLs were further characterised for in-vitro drug release, DPPH assay, confocal laser scanning microscopy, and ex-vivo permeation. Opt-ESH-NLs had a vesicle size of 88.36 nm, a PDI of 0.06, an entrapment efficiency of 94.22 ± 0.93 %, and a drug release of 76.776 ± 1.127 %. Compared to standard ascorbic acid, the antioxidant activity was found to be 78.52 ± 0.148 %. Ex-vivo permeation studies revealed that opt-ESH-NLs had significantly enhanced permeation (79.484 ± 0.754 %) compared to ESH suspension (38.326 ± 1.279 %). Pharmacokinetic study revealed that opt-ESH-NLs when compared with Oral ESH suspension had a significant bioavailability in Brain as compared to plasma. The stability study of nanoliposomes at 4 °C reveals there is no significant change in the formulation. It was concluded that opt-ESH-NLs is a promising and effective formulation for intranasal administration for direct delivery of drug in the brain for amelioration of PD.

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery.

Natural products hold immense potential for drug discovery, yet many remain unexplored in vast libraries and databases. In an attempt to fill this gap and meet the growing demand for effective drugs, this study delves into the promising world of ent-kaurane diterpenoids, a class of natural products with huge therapeutic potential. With a dataset of 570 ent-kaurane diterpenoids obtained from the literature, we conducted an in silico analysis, evaluating their physicochemical, pharmacokinetic, and toxicological properties with a focus on their therapeutic implications. Notably, these natural compounds exhibit drug-like properties, aligning closely with those of FDA-approved drugs, indicating a high potential for drug development. The ranges of the physicochemical parameters were as follows: molecular weights-288.47 to 626.82 g/mol; number of heavy atoms-21 to 44; the number of hydrogen bond donors and acceptors-0 to 8 and 1 to 11, respectively; the number of rotatable bonds-0 to 11; fraction Csp3-0.65 to 1; and TPSA-20.23 to 189.53 Ų. Additionally, the majority of these molecules display favorable safety profiles, with only 0.70%, 1.40%, 0.70%, and 46.49% exhibiting mutagenic, tumorigenic, reproduction-enhancing, and irritant properties, respectively. Importantly, ent-kaurane diterpenoids exhibit promising biopharmaceutical properties. Their average lipophilicity is optimal for drug absorption, while over 99% are water-soluble, facilitating delivery. Further, 96.5% and 28.20% of these molecules exhibited intestinal and brain bioavailability, expanding their therapeutic reach. The predicted pharmacological activities of these compounds encompass a diverse range, including anticancer, immunosuppressant, chemoprotective, anti-hepatic, hepatoprotectant, anti-inflammation, antihyperthyroidism, and anti-hepatitis activities. This multi-targeted profile highlights ent-kaurane diterpenoids as highly promising candidates for further drug discovery endeavors.