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Nose-to-brain drug delivery for the treatment of Alzheimer’s Disease: Current advancements and challenges
Abstract
Introduction
The irreversible destruction of neurons, progressive loss of memory and cognitive behavior, high cost of therapy, and impact on society desire a better, effective, and affordable treatment of AD. The nose-to-brain drug delivery approach holds a great potential to access the brain without any hindrance of BBB and result in higher bioavailability thus better therapeutic efficacy of anti-AD drugs.
Areas covered
The present review article highlighted the current facts and worldwide statistics of AD and its detailed etiology. Followed by barriers to brain delivery, nose-to-brain delivery, their limitations, and amalgamation with various novel carrier systems. We have emphasized recent advancements in nose-to-brain delivery using mucoadhesive, stimuli-responsive carriers, polymeric nanoparticles, lipid nanoparticles, protein/peptide delivery for treatment of AD.
Expert opinion
The available therapies are symptomatic, mitigate the symptoms of AD at the initial stages. In this lieu, nose-to-brain delivery has the ability to overcome these limitations and increase drug bioavailability in the brain. Various novel strategies including stimuli-responsive systems, nanoparticles, etc. enhance the nasal drug permeation, protects the drug, and enhance its therapeutic potency. Although, successful preclinical data does not assure the clinical success of the therapy and hence exhaustive clinical investigations are needed to make the therapy available for patients.
... Alzheimer's disease is a progressive neurodegenerative disorder impairing memory, thinking, and behaviour, with rising prevalence corresponding to population ageing [14]. It is one of the leading indications of the demand for drug delivery strategies that overcome the blood-brain barrier [15]. Currently, donepezil is the first-line treatment in patients with mild to moderate Alzheimer's disease, which is available predominantly in oral solid dosage forms [16]. ...
... Moreover, chitosan can yield thermoresponsive physical gels in the presence of β-glycerophosphate [27]. An almost neutral Pharmaceutics 2023, 15,1660 3 of 29 aqueous solution of chitosan and β-glycerophosphate demonstrates a strong rise in the storage modulus upon heating [6]. ...
Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer's disease. The aim of this study was to develop a chitosan-based, donepezil-loaded thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t1/2 about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation.
... The nose-to-brain delivery approach holds great potential to access the brain without any hindrance of BBB and results in higher bioavailability and thus better therapeutic efficacy of anti-AD drugs. 142 The formulations administered by the intranasal route also show pharmacological activity in the induced AD model. This activity may be related to the direct absorption of the nasal mucosa into the circulatory stream, the drug transport via the olfactory bulb to the brain, or both mechanisms. ...
... 143 On the hand, the use of mucoadhesive formulations in the nasal route has been related to contributing to delivering to the brain. 142,144 Liquid crystal formulations for nasal drug delivery are an interesting strategy for delivering drugs to the brain, however, is a tool scarce exploited. The use of these systems was first described by Carvalho, Campos. ...
Alzheimer's disease (AD) is an illness that affects people aged 65 or older and affects around 6.5 million in the United States. Resveratrol is a chemical obtained from natural products and it exhibits biological activity based on inhibiting the formation, depolymerization of the amyloid, and decreasing neuroinflammation. Due to the insolubility of this compound; its incorporation in surfactant-based systems was proposed to design an intranasal formulation. A range of systems has been produced by mixing oleic acid, CETETH-20 and water. Polarised light microscopy (PLM), small angle x-ray scattering (SAXS) and transmission electron microscopy (TEM) confirm the initial liquid formulation (F) presented as microemulsion (ME). After dilution, the gelled systems were characterized as hexagonal mesophase and they showed feasibility proprieties. Pharmacological assays performed after intranasal administration showed the ability to improve learning and memory in animals, as well as remission of neuroinflammation via inhibition of interleukin.
... route comprise quick onset of action, avoidance of hepatic first-pass metabolism, and good patient compliance. Since then, numerous clinical trials predominantly using drug solutions have been conducted especially in psychiatric and neurodegenerative diseases 38,39 though with relatively low preclinical success rates and limited bench-to-bedside translation 39 . A main constraint of i.n. ...
... administration localizes the delivery at the CNS, lower doses would be required to reach therapeutic efficacy when compared to systemic routes. At the same time, the complex structure of the nasal cavity and the different absorption rates and transport pathways that drugs, especially high molecular weight ones, could undergo (into the systemic circulation or the CNS) have contributed to low clinical success 39 . To overcome the barriers in the nasal mucosa, various types of carriers, some of which contain absorption promoters that modulate the permeability of the nasal mucosa, were designed. ...
Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system (CNS) and result in their damage and death. Neurodevelopmental disorders include intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes. The treatment of neurodegenerative and neurodevelopmental conditions, together affecting ∼120 million people worldwide, is challenged by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS. The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions. This pathway is more efficient for nanoparticles than for solutions, hence, the research on intranasal nano-drug delivery systems has grown exponentially over the last decade. Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility. This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions, the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them. Then, a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.
... Numerous studies have shown that niosomes can cross the blood-brain barrier, offering relief from the symptoms of various autoimmune diseases that impact brain function (112). A similar study reported that niosome-incorporated folic acid was taken up by rat models' brains at an uptake rate of approximately 48.15% (113) (Figure 3). Inflamed areas contain a higher concentration of macrophages, which are immune-related cells responsible for triggering inflammation, making them a primary target for drug development (114). ...
Background
Extracellular vesicles (EVs) are small, transparent vesicles that can be found in various biological fluids and are derived from the amplification of cell membranes. Recent studies have increasingly demonstrated that EVs play a crucial regulatory role in tumorigenesis and development, including the progression of metastatic tumors in distant organs. Brain metastases (BMs) are highly prevalent in patients with lung cancer, breast cancer, and melanoma, and patients often experience serious complications and are often associated with a poor prognosis. The immune microenvironment of brain metastases was different from that of the primary tumor. Nevertheless, the existing review on the role and therapeutic potential of EVs in immune microenvironment of BMs is relatively limited.
Main body
This review provides a comprehensive analysis of the published research literature, summarizing the vital role of EVs in BMs. Studies have demonstrated that EVs participate in the regulation of the BMs immune microenvironment, exemplified by their ability to modify the permeability of the blood-brain barrier, change immune cell infiltration, and activate associated cells for promoting tumor cell survival and proliferation. Furthermore, EVs have the potential to serve as biomarkers for disease surveillance and prediction of BMs.
Conclusion
Overall, EVs play a key role in the regulation of the immune microenvironment of brain metastasis and are expected to make advances in immunotherapy and disease diagnosis. Future studies will help reveal the specific mechanisms of EVs in brain metastases and use them as new therapeutic strategies.
... Alzheimer's disease is a multifactorial progressive neurodegenerative disorder, and most prevalent cause of dementia in older people (Prabakara et al. 2022). Alzheimer's disease (AD) results from loss of neurones and brain atrophy, featuring gradual memory decline, mild to severe cognitive impairment, and total dependence of patients on caregivers (Mary et al. 2022). ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and most common cause of dementia among older people. The main pathological hallmarks of AD are formation of insoluble amyloid beta senile plaques and paired helical filaments of neurofibrillary tangles. AD features gradual memory decline, mild to severe cognitive impairment, eventually total dependence of patients on caregivers. Currently available drugs have not been able to modify AD pathology. This has drawn increasing attention to plant food materials with high nutritional and bioactive constituents as potential complementary therapy for AD. Sorghum bicolor is a widely available cost-effective source of proteins, fats, crude fibres, biopeptides and polyphenols which are vital for human wellbeing. This review discussed the major mechanisms underlying AD pathology. The nutritional and bioactive constituents of Sorghum bicolor grains were extensively described. There is limited report on anti-AD activities of sorghum grains. Therefore, the pharmacological mechanisms of action including scavenging of reactive oxygen species, inhibition of oxidative stress, anti-acetylcholinesterase activity and modulation of mitophagy were only speculated. This comprehensive update suggests more robust innovative studies that will provide critical theoretical details necessary to promote utilization of sorghum grains as functional food or source of bioactive molecules for AD therapy.
... Innovative treatments using combination NPs have emerged as a promising approach for improving the management of AD through intranasal delivery, which offers higher drug accumulation in the brain compared to equivalent drug solution formulations and systemic approaches [33][34][35][36][37][38][39][40][41][42]. Among these approaches, derivatives of the chitosan (Cs) polymer, such as N,N,N-trimethyl chitosan (TMC), have garnered attention due to their positive biological features, including high mucosal absorption capacity, low toxicity, and ease of NP formation through ionic gelation [43,44]. ...
Efficient drug delivery remains a critical challenge for treating neurodegenerative diseases, such as Alzheimer’s disease (AD). Using innovative nanomaterials, delivering current medications like acetylcholinesterase inhibitors to the brain through the intranasal route is a promising strategy for managing AD. Here, we developed a unique combinational drug delivery system based on N,N,N-trimethyl chitosan nanoparticles (NPs). These NPs encapsulate rivastigmine, the most potent acetylcholinesterase inhibitor, along with insulin, a complementary therapeutic agent. The spherical NPs exhibited a zeta potential of 17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. Our findings demonstrate significantly improved drug transport efficiency through sheep nasal mucosa using the NPs compared to drug solutions. The NPs exhibited transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, surpassing the efficiencies of the drug solutions, which showed transport efficiencies of 52% for rivastigmine and 21% for insulin ex vivo. These results highlight the potential of a new drug delivery system as a promising approach for enhancing nasal transport efficiency. These combinational mucoadhesive NPs offer a novel strategy for the simultaneous cerebral delivery of rivastigmine and insulin, which could prove helpful in developing effective treatments of AD and other neurodegenerative conditions.
... The introduction of effective medicine for several CNS-related disorders, including AD, by nose-to-brain drug administration, has been considered a revolutionary process [21]. Intranasal insulin is one of these treatments that have shown a beneficial impact on AD patients [11]. ...
... Different dosage forms can be easily self-administered intranasally without pain and the requirement of specific techniques [3]. Therefore, nose-to-brain delivery represents a great opportunity to deliver both conventional drugs and biotherapeutics for the treatment of CNS disorders, such as Parkinson's disease (PD) [4,5] and Alzheimer's disease (AD) [6] while avoiding the use of invasive techniques to reach the brain. ...
Direct nose-to-brain drug delivery offers the opportunity to treat central nervous system disorders more effectively due to the possibility of drug molecules reaching the brain without passing through the blood–brain barrier. Such a delivery route allows the desired anatomic site to be reached while ensuring drug effectiveness, minimizing side effects, and limiting drug losses and degradation. However, the absorption of intranasally administered entities is a complex process that considerably depends on the interplay between the characteristics of the drug delivery systems and the nasal mucosa. Various preclinical models (in silico, in vitro, ex vivo, and in vivo) are used to study the transport of drugs after intranasal administration. The present review article attempts to summarize the different computational and experimental models used so far to investigate the direct delivery of therapeutic agents or colloidal carriers from the nasal cavity to the brain tissue. Moreover, it provides a critical evaluation of the data available from different studies and identifies the advantages and disadvantages of each model.
... The introduction of effective medicine for several CNS-related disorders, including AD, by nose-to-brain drug administration, has been considered a revolutionary process [21]. Intranasal insulin is one of these treatments that has shown a beneficial impact on AD patients [11]. ...
Background and aim: We performed this meta-analysis to evaluate the safety and efficacy of intranasal
insulin in Alzheimer's disease (AD) patients.
Methods: A literature search was conducted for PubMed, Scopus, and Web of Science from inception till
August 2022. Documents were screened for qualified articles, and all concerned outcomes were pooled as
risk ratios (RR) or mean difference (MD) in the meta-analysis models using Review Manager (RevMan
version 5.4).
Results: Our results from 12 studies favored intranasal insulin over placebo in terms of Alzheimer
Disease’s Assessment Scale–cognitive subscale (ADAS-cog) 20IU, (MD = -0.13, 95% CI [-0.22, -0.05],
P = 0.003). The overall effect did not favor either of the two groups for ADAS-cog 40IU, memory
composite 20IU and 40IU, and adverse events. (MD = -0.08, 95% CI [-0.16, 0.01], P = 0.08), (MD =
0.65, 95% CI [-0.08, 1.39], P = 0.08), (MD = 0.25, 95% CI [-0.09, 0.6], P = 0.15), (MD = 1.28, 95% CI
[0.75, 2.21], P = 0.36), respectively.
Conclusion: Ultimately, this meta-analysis showed that intranasal insulin in small doses (20IU)
significantly affects patients with AD. Further studies are recommended on reliable insulin delivery
devices to increase insulin in the central nervous system.
Relevance for patients: Intranasal insulin has shown promising results in treating patients with AD. The
lower doses (20 IU) can play a positive role in improving the disease. As research continues, it is likely
that this treatment will become more widely accepted and utilized in clinical practice.
... Various hypotheses have been put forward to explain the pathogenesis of ATD, including the cholinergic hypothesis, the tau hypothesis and the amyloid cascade hypothesis. In addition, among the main biomarkers of ATD are the deposition of the ß-amyloid peptide, which leads to the formation of ß-amyloid plaques, and the hyperphosphorylation of tau, which leads to the formation of neurofibrillary tangles [11]. Figure 1 shows the main differences between a healthy brain and the brain of a patient with ATD. Figure 1. ...
Alzheimer-type dementia (ATD) treatments face limitations in crossing the blood-brain barrier and systemic adverse effects. Intranasal administration offers a direct route to the brain via the nasal cavity's olfactory and trigeminal pathways. However, nasal physiology can hinder drug absorption and limit bioavailability. Therefore, the physicochemical characteristics of formulations must be optimized by means of technological strategies. Among the strategies that have been explored, lipid-based nanosystems, particularly nanostructured lipid carriers, are promising in preclinical investigations with minimal toxicity and therapeutic efficacy due to their ability to overcome challenges associated with other nanocarriers. We review the studies of nanostructured lipid carriers for intranasal administration in the treatment of ATD. Currently, no drugs for intranasal administration in ATD have marketing approval, with only three candidates, insulin, rivastigmine and APH-1105, being clinically investigated. Further studies with different candidates will eventually confirm the potential of the intranasal route of administration in the treatment of ATD.
... Among these, systemic circulation is only partially involved, reducing the risk of systemic side effects. Advantages of the IN route include ease of administration, high patient compliance, and rapid delivery kinetics within minutes [87,88]. The actual mechanism of IN drug delivery is not yet clear, but there is robust evidence that supports the significance of olfactory and trigeminal nerve pathways because of their direct and immediate connection from the nose to the brain [89]. ...
Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder. Most existing treatments only provide symptomatic solutions. Here, we introduce currently available commercial drugs and new therapeutics, including repositioned drugs, to treat AD. Despite tremendous efforts, treatments targeting the hallmarks of AD show limited efficacy. Challenges in treating AD are partly caused by difficulties in penetrating the blood–brain barrier (BBB). Recently, nanoparticle (NP)-based systems have shown promising potential as precision medicines that can effectively penetrate the BBB and enhance the targeting ability of numerous drugs. Here, we describe how NPs enter the brain by crossing, avoiding, or disrupting the BBB. In addition, we provide an overview of the action of NPs in the microenvironment of the brain for the treatment of AD. Diverse systems, including liposomes, micelles, polymeric NPs, solid-lipid NPs, and inorganic NPs, have been investigated for NP drug loading to relieve AD symptoms, target AD hallmarks, and target moieties to diagnose AD. We also highlight NP-based immunotherapy, which has recently gained special attention as a potential treatment option to disrupt AD progression. Overall, this review focuses on recently investigated NP systems that represent innovative strategies to understand AD pathogenesis and suggests treatment and diagnostic modalities to cure AD.
Intranasal administration is a drug delivery approach to provide a non-invasive pharmacological response in the central nervous system with relatively small peripheral side effects. To improve the residence time of intranasal drug delivery systems in the nasal mucosa, mucoadhesive polymers (e.g., chitosan) can be used. Here, insulin-loaded chitosan nanoparticles were synthesized and their physiochemical properties were evaluated based on requirements of intranasal administration. The nanoparticles were spherical (a hydrodynamic diameter of 165.3 nm, polydispersity index of 0.24, and zeta potential of +21.6 mV) that granted mucoadhesion without any noticeable toxicity to the nasal tissue. We applied a new approach using the Krebs-Henseleit buffer solution along with simulated nasal fluid in a Franz's diffusion cell to study this intranasal drug delivery system. We used the Krebs-Henseleit buffer because of its ability to supply glucose to the cells which serves as a novel ex vivo diffusion medium to maintain the viability of the tissue during the experiment. Based on diffusion rate and histopathological endpoints, the Krebs-Henseleit buffer solution can be a substituent solution to the commonly used simulated nasal fluid for such drug delivery systems.
Neurodegenerative diseases (NDs) have become a serious global health problem as the population ages. Traditionally, treatment strategies for NDs have included oral and intravenous administration; however, the blood–brain barrier (BBB) can prevent drugs from reaching the brain, rendering the treatment incomplete and the effect unsatisfactory. Additionally, the prolonged or excessive use of drugs that can cross the BBB can damage liver and kidney function. Recent studies have shown that nose-to-brain drug delivery can noninvasively bypass the BBB, allowing drugs to enter the brain through the olfactory or trigeminal nerve pathways; additionally, nanoparticle carriers can enhance drug delivery. This review introduces drug carrier nanoparticles for nose-to-brain delivery systems, compares the advantages and disadvantages of different nanoparticles, and discusses the factors influencing nose-to-brain nanomedicine delivery and enhancement strategies. We also summarize nose-to-brain delivery and nanomedicines for treating NDs, the current challenges of this approach, and the future promise of nanomedicine-based ND treatment.
Objectives:
Oxaliplatininduces chemobrain in cancer patients/survivors. Nutraceuticalnaringin has antioxidant and anti-inflammatory properties with low oralbioavailability. Our aim was to formulate naringin in chitosan nanoparticles fornose to brain delivery and assess its neuroprotective effect against oxaliplatin-inducedchemobrain in rats.
Methods:
Naringinchitosan nanoparticles were prepared by ionic gelation. Rats were administeredoral naringin (80 mg/kg), intranasal naringin (0.3 mg/kg) or intranasal naringin-loadedchitosan nanoparticles (0.3 mg/kg). Naringin's neuroprotective efficacy wasassessed based on behavioral tests, histopathology, and measuring oxidativestress and inflammatory markers.
Results:
Selectednanoparticles formulation showed drug loading of 5%, size of 150 nm and werecationic. Intranasal naringin administration enhanced memory function,inhibited hippocampal acetylcholinesterase activity, and corrected oxaliplatin-inducedhistological changes. Moreover, it reduced malondialdehyde and elevated reducedglutathione hippocampal levels. Furthermore, it decreased levels of inflammatorymarkers: NF-kB and TNF-α by 1.25-fold.Upstream to this inflammatory status, intranasal naringin downregulated thehippocampal protein levels of two pathways: cGAS/STINGand HMGB1/RAGE/TLR2/MYD88.
Conclusion:
Intranasalnaringin-loaded chitosan nanoparticles showed superior amelioration ofoxaliplatin-induced chemobrain in rats at a dose 267-fold lower to thatadministered orally. The potential involvement of cGAS/STINGand HMGB1/RAGE/TLR2/MYD88 pathways in the mechanistic process of eitheroxaliplatin-induced chemobrain or naringin-mediated neuroprotection was evidenced.
The aim of this study was to develop an intranasal in situ thermo-gelling meloxicam-human serum albumin (MEL-HSA) nanoparticulate formulation applying poloxamer 407 (P407), which can be administered in liquid state into the nostril, and to increase the resistance of the formulation against mucociliary clearance by sol-gel transition on the nasal mucosa, as well as to improve drug absorption. Nanoparticle characterization showed that formulations containing 12–15% w/w P407 met the requirements of intranasal administration. The Z-average (in the range of 180–304 nm), the narrow polydispersity index (PdI, from 0.193 to 0.328), the zeta potential (between −9.4 and −7.0 mV) and the hypotonic osmolality (200–278 mOsmol/L) of MEL-HSA nanoparticles predict enhanced drug absorption through the nasal mucosa. Based on the rheological, muco-adhesion, drug release and permeability studies, the 14% w/w P407 containing formulation (MEL-HSA-P14%) was considered as the optimized formulation, which allows enhanced permeability of MEL through blood–brain barrier-specific lipid fraction. Cell line studies showed no cell damage after 1-h treatment with MEL-HSA-P14% on RPMI 2650 human endothelial cells’ moreover, enhanced permeation (four-fold) of MEL from MEL-HSA-P14% was observed in comparison to pure MEL. Overall, MEL-HSA-P14% can be promising for overcoming the challenges of nasal drug delivery.
The management of the central nervous system (CNS) disorders is challenging, due to the need of drugs to cross the blood‒brain barrier (BBB) and reach the brain. Among the various strategies that have been studied to circumvent this challenge, the use of the intranasal route to transport drugs from the nose directly to the brain has been showing promising results. In addition, the encapsulation of the drugs in lipid-based nanocarriers, such as solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) or nanoemulsions (NEs), can improve nose-to-brain transport by increasing the bioavailability and site-specific delivery. This review provides the state-of-the-art of in vivo studies with lipid-based nanocarriers (SLNs, NLCs and NEs) for nose-to-brain delivery. Based on the literature available from the past two years, we present an insight into the different mechanisms that drugs can follow to reach the brain after intranasal administration. The results of pharmacokinetic and pharmacodynamics studies are reported and a critical analysis of the differences between the anatomy of the nasal cavity of the different animal species used in in vivo studies is carried out. Although the exact mechanism of drug transport from the nose to the brain is not fully understood and its effectiveness in humans is unclear, it appears that the intranasal route together with the use of NLCs, SLNs or NEs is advantageous for targeting drugs to the brain. These systems have been shown to be more effective for nose-to-brain delivery than other routes or formulations with non-encapsulated drugs, so they are expected to be approved by regulatory authorities in the coming years.
Chitosan nanoparticles (NPs) are promising polymeric and bio-based NPs, which have received a lot of attention in the last decades. They have great potential as nanocarriers that encapsulate substances such as drugs or active compounds, deliver them to a specific place or site, and provide a controlled release. In the present review, we give a complete overview of the preparation methods, including novel and green procedures, and compile developed applications in medicine, agriculture, and wastewater treatment. Moreover, we highlight the future perspective of chitosan NPs use in PLA-based biodegradable polymers which can be one of the solutions for reducing plastic pollution in nature. Properties of chitosan NPs can be tuned in such a way that they can serve as reinforcement elements in biodegradable plastics leading to much-needed improvements, and also as functional elements that make the application in food packaging with e.g., enhanced antimicrobial activity possible.
An investigation of the interactions between bio-polymeric nanoparticles (NPs) and the RAW 264.7 mouse murine macrophage cell line has been presented. The cell viability, immunological response, and endocytosis efficiency of NPs were studied. Biopolymeric NPs were synthesized from a nanoemulsion using the phase inversion composition (PIC) technique. The two types of biopolymeric NPs that were obtained consisted of a biocompatible polymer, polycaprolactone (PCL), either with or without its copolymer with poly(ethylene glycol) (PCL-b-PEG). Both types of synthesized PCL NPs passed the first in vitro quality assessments as potential drug nanocarriers. Non-pegylated PCL NPs were internalized more effectively and the clathrin-mediated pathway was involved in that process. The investigated NPs did not affect the viability of the cells and did not elicit an immune response in the RAW 264.7 cells (neither a significant increase in the expression of genes encoding pro-inflammatory cytokines nor NO (nitric oxide) production were observed). It may be concluded that the synthesized NPs are promising candidates as nanocarriers of therapeutic compounds.
Over the past 10 years, the interest in intranasal drug delivery in pharmaceutical R&D has increased. This review article summarises information on intranasal administration for local and systemic delivery, as well as for CNS indications. Nasal delivery offers many advantages over standard systemic delivery systems, such as its non-invasive character, a fast onset of action and in many cases reduced side effects due to a more targeted delivery. There are still formulation limitations and toxicological aspects to be optimised. Intranasal drug delivery in the field of drug development is an interesting delivery route for the treatment of neurological disorders. Systemic approaches often fail to efficiently supply the CNS with drugs. This review paper describes the anatomical, histological and physiological basis and summarises currently approved drugs for administration via intranasal delivery. Further, the review focuses on toxicological considerations of intranasally applied compounds and discusses formulation aspects that need to be considered for drug development.
Graphical abstract
Introduction:
Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine.
Methods:
Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine.
Results:
Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median Tmax of 0.5 hour [range 0.5-1.0]). Cmax and AUC0-last increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279, P = 0.0055) compared to placebo after correction for individual baseline performance.
Discussion:
Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.
Background: Alzheimer’s disease is the main reason for dementia among the older section of the community. Administration of drugs through oral route to the patients suffering from neurological disorders is a serious challenge. Intranasal pharmacotherapeutics is an integral part of the modern drug delivery module used as an alternative way due to several therapeutic advantages.
Objective: The objective of this current research was to develop intranasal mucoadhesive microspheres of anti-Alzheimer’s drug donepezil HCl.
Methodology: The formulations were prepared using gellan gum polymer in various drug: polymer ratios from 1:1 to 1:4 by emulsification cross-linking technique with an intention to enhance the onset of action, increase the drug bioavailability, and also to overcome the major obstacle blood-brain barrier. The prepared mucoadhesive microspheres were evaluated in terms of drug loading, entrapment efficiency, ex vivo drug permeation, histopathological characteristics, in vitro drug release, in vitro mucoadhesion, morphology, particle size, production yield, and swelling property. The prepared intranasal microspheres were characterized by differential scanning calorimetry, scanning electron microscopy, and X-ray diffraction study.
Result: The fabricated intranasal microspheres had good spherical nature and excellent swelling property with entirely smooth surfaces. After reaching the nasal mucosa, the mucoadhesive microspheres formulations come in contact with the nasal fluid (containing cations), spontaneous viscous gelation (decreases the clearance rate) occurs in the nasal cavity, and the activity enhances several-folds by elevating the residence duration.
Conclusion: This study opened new avenues for enhancing the pharmaceutical efficacy of donepezil HCl in Alzheimer’s patient through intranasal route.
The complexity of some diseases—as well as the inherent toxicity of certain drugs—has led to an increasing interest in the development and optimization of drug-delivery systems. Polymeric nanoparticles stand out as a key tool to improve drug bioavailability or specific delivery at the site of action. The versatility of polymers makes them potentially ideal for fulfilling the requirements of each particular drug-delivery system. In this review, a summary of the state-of-the-art panorama of polymeric nanoparticles as drug-delivery systems has been conducted, focusing mainly on those applications in which the corresponding disease involves an important morbidity, a considerable reduction in the life quality of patients—or even a high mortality. A revision of the use of polymeric nanoparticles for ocular drug delivery, for cancer diagnosis and treatment, as well as nutraceutical delivery, was carried out, and a short discussion about future prospects of these systems is included.
Liposome possesses a great number of advantages and therefore they can be used for a variety of applications. Among other things, they can serve as useful drug carriers in preclinical and clinical trials. Supercritical fluids assisted technology is an appropriate method for liposome preparation because of its nontoxicity to the environment enables particle size manipulation and solvent-free production. Thus, the use of supercritical fluids (SCFs) provides advanced technology for liposome preparation and may become the dominant technology for their preparation in the future. This review discusses the classification of liposome and gives a short overview of their applications and conventional methods of preparation. Emphasis is placed on the use of various supercritical fluids assisted methods for liposome preparation and their advantages and disadvantages. The reader is also updated about recent developments in supercritical fluids assisted liposome production technology.
Intranasal administration of mucus-penetrating nanoparticles is an emerging trend to increase drug delivery to the brain. In order to overcome rapid nasal mucociliary clearance, low epithelial permeation, and local enzymatic degradation, we investigated the influence of PEGylation on nose-to-brain delivery of polycaprolactone (PCL) nanoparticles (PCL-NPs) encapsulating bexarotene, a potential neuroprotective compound. PEGylation with 1, 3, 5, and 10% PCL-PEG did not affect particle diameter or morphology. Upon incubation with artificial nasal mucus, only 5 and 10% of PCL-PEG coating were able to ensure NP stability and homogeneity in mucus. Rapid mucus-penetrating ability was observed for 98.8% of PCL-PEG5% NPs and for 99.5% of PCL-PEG10% NPs. Conversely, the motion of non-modified PCL-NPs was markedly slower. Fluorescence microscopy showed that the presence of PEG on NP surface did not reduce their uptake by RMPI 2650 cells. Fluorescence tomography images evidenced higher translocation into the brain for PCL-PEG5% NPs. Bexarotene loaded into PCL-PEG5% NPs resulted in area under the curve in the brain (AUCbrain) 3 and 2-fold higher than that for the drug dispersion and for non-PEGylated NPs (p < 0.05), indicating that approximately 4% of the dose was directly delivered to the brain. Combined, these results indicate that PEGylation of PCL-NPs with PCL-PEG5% is able to reduce NP interactions with the mucus, leading to a more efficient drug delivery to the brain following intranasal administration.
Graphical abstract
When assessing the risk and hazard of a non-pharmaceutical compound, the first step is determining acute toxicity, including toxicity following inhalation. Inhalation is a major exposure route for humans, and the respiratory epithelium is the first tissue that inhaled substances directly interact with. Acute inhalation toxicity testing for regulatory purposes is currently performed only in rats and/or mice according to OECD TG403, TG436, and TG433 test guidelines. Such tests are biased by the differences in the respiratory tract architecture and function across species, making it difficult to draw conclusions on the potential hazard of inhaled compounds in humans. Research efforts have been therefore focused on developing alternative, human-relevant models, with emphasis on the creation of advanced In vitro models. To date, there is no In vitro model that has been accepted by regulatory agencies as a stand-alone replacement for inhalation toxicity testing in animals. Here, we provide a brief introduction to current OECD test guidelines for acute inhalation toxicity, the interspecies differences affecting the predictive value of such tests, and the current regulatory efforts to advance alternative approaches to animal-based inhalation toxicity studies. We then list the steps that should allow overcoming the current challenges in validating In vitro alternatives for the successful replacement of animal-based inhalation toxicity studies. These steps are inclusive and descriptive, and should be detailed when adopting in house-produced 3D cell models for inhalation tests. Hence, we provide a checklist of key parameters that should be reported in any future scientific publications for reproducibility and transparency.
Although the global prevalence of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs’ entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices.
Polymeric biomaterials have found widespread applications in nanomedicine, and poly(lactide-co-glycolide), (PLGA) in particular has been successfully implemented in numerous drug delivery formulations due to its synthetic malleability and biocompatibility. However, the need for preconception in these formulations is increasing, and this can be achieved by selection and elimination of design variables in order for these systems to be tailored for their specific applications. The starting materials and preparation methods have been shown to influence various parameters of PLGA-based nanocarriers and their implementation in drug delivery systems, while the implementation of computational simulations as a component of formulation studies can provide valuable information on their characteristics. This review provides a critical summary of the synthesis and applications of PLGA-based systems in bio-medicine and outlines experimental and computational design considerations of these systems.
Biodegradable nanoparticles (NPs) have shown great promise as intracellular imaging probes, nanocarriers and drug delivery vehicles. In this study, we designed and prepared amphiphilic cellulose derivatives via Schiff base reactions between 2,3-dialdehyde cellulose (DAC) and amino compounds. Polymeric NPs were facilely fabricated via the self-assembly of the as-synthesized amphiphilic macromolecules. The size distribution of the obtained NPs can be tuned by changing the amount and length of the grafted hydrophobic side-chains. Anticancer drugs (DOX) were encapsulated in the NPs and the drug-loaded NPs based on cellulose derivatives were stable in neutral and alkaline environments for at least a month. They rapidly decomposed with the efficient release of the drug in acidic tumor microenvironments. These drug-loaded NPs have the potential for application in cancer treatment.
In modern-day medicine, nanotechnology and nanoparticles are some of the indispensable tools in disease monitoring and therapy. The term "nanomaterials" describes materials with nanoscale dimensions (< 100 nm) and are broadly classified into natural and synthetic nanomaterials. However, "engineered" nanomaterials have received significant attention due to their versatility. Although enormous strides have been made in research and development in the field of nanotechnology, it is often confusing for beginners to make an informed choice regarding the nanocarrier system and its potential applications. Hence, in this review, we have endeavored to briefly explain the most commonly used nanomaterials, their core properties and how surface functionalization would facilitate competent delivery of drugs or therapeutic molecules. Similarly, the suitability of carbon-based nanomaterials like CNT and QD has been discussed for targeted drug delivery and siRNA therapy. One of the biggest challenges in the formulation of drug delivery systems is fulfilling targeted/specific drug delivery, controlling drug release and preventing opsonization. Thus, a different mechanism of drug targeting, the role of suitable drug-laden nanocarrier fabrication and methods to augment drug solubility and bioavailability are discussed. Additionally, different routes of nanocarrier administration are discussed to provide greater understanding of the biological and other barriers and their impact on drug transport. The overall aim of this article is to facilitate straightforward perception of nanocarrier design, routes of various nanoparticle administration and the challenges associated with each drug delivery method.
Restricted drug entry to the brain that is closely associated with the existence of the blood brain barrier (BBB) has limited the accessibility of most potential active therapeutic compounds to the brain from the systemic circulation. Recently, evidences for the presence of direct nose-to-brain drug transport pathways have been accumulated by several studies and an intranasal drug administration route has gained attention as a promising way for providing direct access to the brain without the needs to cross to the BBB. Studies aiming for developing nanoparticles as an intranasal drug carrier have shown considerable promise in overcoming the challenges of intranasal drug delivery route. This review gives a comprehensive overview of works having investigated liposomes as a potential vehicle to deliver drugs to the brain through nose-to-brain route while considering the excellent biocompatibility and high potential of liposomes for clinical development. Herein, studies are reviewed with special emphasis on the impact of formulation factors, such as liposome composition and surface modification of liposomes with targeting moieties, in addition to intranasal environmental factors that may affect the extent/site of absorption of intranasally administered, liposome-encapsulated drugs.
Alzheimer's disease (AD) is the most common cause of dementia and cannot be cured. The etiology and pathogenesis of AD is still not fully understood, the genetics is considered to be one of the most important factors for AD onset, and the identified susceptible genes could provide clues to the AD mechanism and also be the potential targets. MicroRNA-146a-5p (miR-146a) is well known in the regulation of the inflammatory response, and the functional SNP of miR-146a was associated with AD risk. In this study, using a noninvasive nasal administration, we discovered that a miR-146a agomir (M146AG) rescued cognitive impairment in the APP/PS1 transgenic mouse and alleviated the overall pathological process in the AD mouse model, including neuroinflammation, glia activation, Aβ deposit, and tau phosphorylation in hippocampi. Furthermore, the transcriptional analysis revealed that besides the effect of neuroinflammation, M146AG may serve as a multi-potency target for intervention in AD. In addition, Srsf6 was identified as a target of miR-146a, which may play a role in AD progression. In conclusion, our study supports that the nasal-to-brain pathway is efficient and operable for the brain administration of microRNAs (miRNAs), and that miR-146a may be a new potential target for AD treatment.
The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood–brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system.
With ageing of the global society, the frequency of ageing-related neurodegenerative diseases such as Alzheimer's disease (AD) is on the rise worldwide. Currently, there is no cure for AD, and the four drugs approved for AD only have very small effects on AD symptoms. Consequently, there are enormous efforts worldwide to identify new targets for treatment of AD. Approaches that interfere with classical neuropathologic features of AD, such as extracellular senile plaques formed of aggregated amyloid-beta (Abeta), and intracellular neurofibrillary tangles of hyperphosphorylated tau have not been successful so far. In search for a treatment approach of AD, we found that inhibition of the angiotensin-converting enzyme (ACE) by a centrally acting ACE inhibitor retards symptoms of neurodegeneration, Abeta plaque formation and tau hyperphosphorylation in experimental models of AD. Our approach is currently being investigated in a clinical setting. Initial evidence with AD patients shows that a brain-penetrating ACE inhibitor counteracts the process of neurodegeneration and dementia. Moreover, centrally acting ACE inhibitors given in addition to the standard therapy, cholinesterase inhibition, can improve cognitive function of AD patients for several months. This is one of the most promising results for AD treatment since more than a decade.
The blood–brain barrier (BBB) plays a fundamental role in protecting the brain from toxic substances and therefore also controls and restricts the entry of therapeutic agents. The nasal administration of drugs using the nose-to-brain pathway allows direct drug targeting into the brain, avoiding the first-pass effect and bypassing the BBB. Through the nasal route, the drug can access the brain directly along the trigeminal and olfactory nerves, which are located in the upper part of the nasal cavity. Nanoemulsions are formulations belonging to the field of nanomedicine. They consist of emulsions (commonly oil in water) stabilized by one or more surfactants—and eventually co-surfactants—delivered in droplets of small dimensions (sizes of 100–300 nm or less) with a high surface area. A mucoadhesive polymer such as chitosan can be added to the formulation to impair rapid nasal clearance. Nanoemulsions represent promising formulations to deliver drugs directly into the brain through the intranasal route. Therefore, they can be used as a possible alternative to oral administration, avoiding problems such as low solubility in water, poor bioavailability, enzymatic degradation and slow onset of action. This review focuses the present situation in literature regarding the use of nanoemulsions for nose-to-brain targeting, with particular attention to recent publications. Nasal nanoemulsions appear to be effective, non-invasive and safe drug delivery systems to achieve brain targeting for the treatment of neurological diseases.
Background and purpose
Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD‐related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL‐17 has not been well addressed. Herein, we investigate the effects of IL‐17 neutralizing antibody (IL‐17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid‐β (Aβ)‐induced neuroinflammation and memory impairment in mice.
Experimental approach
Aβ1–42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL‐17Ab via i.c.v. either at 1 h prior to Aβ1–42 injection or IN 5 and 12 days after Aβ1–42 injection. After 7 and 14 days of Aβ1–42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas.
Key results
Pretreatment with IL‐17Ab, given, i.c.v., markedly reduced Aβ1–42‐induced neurodegeneration, improved memory function, and prevented the increase of pro‐inflammatory mediators in a dose‐dependent manner at 7 and 14 days. Similarly, the double IN administration of IL‐17Ab after Aβ1–42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines.
Conclusion and implications
These findings suggest that the IL‐17Ab reduced neuroinflammation and behavioural symptoms induced by Aβ. The efficacy of IL‐17Ab IN administration in reducing Aβ1–42 neurodegeneration points to a possible future therapeutic approach in patients with AD.
Linked Articles
This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc
Globally, the central nervous system (CNS) disorders appear as the most critical pathological threat with no proper cure. Alzheimer’s disease (AD) is one such condition frequently observed with the aged population and sometimes in youth too. Most of the research utilizes different animal models for in vivo study of AD pathophysiology and to investigate the potency of the newly developed therapy. These in vivo models undoubtably provide a powerful investigation tool to study human brain. Although, it sometime fails to mimic the exact environment and responses as the human brain owing to the distinctive genetic and anatomical features of human and rodent brain. In such condition, the in vitro cell model derived from patient specific cell or human cell lines can recapitulate the human brain environment. In addition, the frequent use of animals in research increases the cost of study and creates various ethical issues. Instead, the use of in vitro cellular models along with animal models can enhance the translational values of in vivo models and represent a better and effective mean to investigate the potency of therapeutics. This strategy also limits the excessive use of laboratory animal during the drug development process. Generally, the in vitro cell lines are cultured from AD rat brain endothelial cells, the rodent models, human astrocytes, human brain capillary endothelial cells, patient derived iPSCs (induced pluripotent stem cells) and also from the non-neuronal cells. During the literature review process, we observed that there are very few reviews available which describe the significance and characteristics of in vitro cell lines, for AD investigation. Thus, in the present review article, we have compiled the various in vitro cell lines used in AD investigation including HBMEC, BCECs, SHSY-5Y, hCMEC/D3, PC-2 cell line, bEND3 cells, HEK293, hNPCs, RBE4 cells, SK-N-MC, BMVECs, CALU-3, 7W CHO, iPSCs and cerebral organoids cell lines and different types of culture media such as SCM, EMEM, DMEM/F12, RPMI, EBM and 3D-cell culture.
Graphical Abstract
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Alzheimer's disease (AD) is a multifaceted and progressive neurodegenerative disease characterized by accumulation of amyloid-beta (Aβ) and deficits of acetylcholine. Accordingly, the intra−/extra-cerebral level of high density lipoprotein (HDL) is crucial on the pathogenesis of AD; and most of all, various HDL-protein subtypes play a double-edged role in AD pathology, of which apolipoprotein A-I (apoA-I) gives protective outcomes. Inspired from “HDL bionics” we proposed biologically reassembled nanodrugs, donepezil-loaded apolipoprotein A-I-reconstituted HDL (rHDL/Do) that concurrently executed dual-missions of Aβ-targeting clearance and acetylcholinesterase (AChE) inhibition in AD therapy. Once prepared, rHDL/Do nanodrug achieved high drug encapsulation efficiency of 90.47%, and mimicked the configurations and properties of natural lipoproteins aiming to significantly enhance BBB penetration and modulate Aβ-induced neuronal damage both in vitro and in vivo. Surface plasmon resonance (SPR) analysis confirmed that rHDL/Do facilitated microglial-mediated Aβ intake and degradation, demonstrating low KD value with Aβ affinity (2.45 × 10⁻⁸ of Aβ monomer and 2.78 × 10⁻⁸ of Aβ oligomer). In AD animal models, daily treatment of rHDL/Do efficiently inhibited AChE activity, ameliorated neurologic variation, promoted Aβ clearance, and rescued memory loss at a safe level. The collective findings indicated that the biological nanodrug was provided with the capacities of BBB penetration, Aβ capture and degradation via microglial cells, and cholinergic dysfunction amelioration after controlled donepezil release. In summary, rHDL/Do nanodrugs could offer a promising strategy to synergize both symptom control and disease modification in AD therapy.
Background
Development of biocompatible multifunctional polymeric drug carriers is crucial in modern pharmaceutics aimed to create “smart” drugs. The high potential of the PEGylated comb-like polymeric nanocarrier (PNC) in delivering both traditional and experimental drugs to tumor cells in vitro and in vivo has been demonstrated previously. In the present study, we investigated the general toxicity of polyethylene glycol (PEG) processed with both covalent and non-covalent attachments of PEG to compose a comb-like polymer that behaves like a simple chain of n monomers decorated with swollen side chains. The PNC possesses properties of a water-soluble surfactant containing methyl-terminated PEG side branches in some monomer units attached covalently to the carbon chain backbone.
Results
We have demonstrated that the synthesized PNC possesses weak toxic effects toward human leukemia cells (HL-60 and Jurkat lines), as well as toward hepatocellular (HepG2), colon (HCT116) and breast (MCF-7) tumor cell lines. Additionally, after a long period (20 days) of intraperitoneal administration, the PNC had no significant toxic effects in laboratory white mice (470 mg/kg body mass in 1 ml) and Wistar rats (440 mg/kg body mass in 10 ml).
Conclusion
The developed PNC we studied can be qualified as a compound of grade 4 toxicity (low toxicity substance). The reduced toxicity of this PNC in combination with its improved bioavailability and previously detected capability to enhance cytotoxicity toward tumor cells in vitro and potential tumor treatment effects in vivo suggests its potential as a safe drug delivery platform for treating various diseases, especially cancer.
The current study focuses on development of nasal mucoadhesive microspheres for nose-to-brain delivery of rivastigmine for Alzheimer treatment. A systematic development was employed for optimization of the formulation and process parameters influential on the quality attributes of the microspheres. The risk assessment study revealed major influence of the polymer concentration (ethylcellulose: chitosan), the concentration of surfactant solution (polyvinyl alcohol), and stirring speed as the critical factors for optimization of the microspheres. These factors were systematically optimized using Box-Behnken design and microspheres were evaluated for the particle size, entrapment efficiency, and in vitro drug release as the response variables. The optimized microspheres containing 4.4% wt/vol polymers, 1% wt/vol surfactant, and stirring speed at 1500 rpm showed particle size of 19.9 µm, entrapment efficiency of 77.8%, and drug release parameters as T80% of 7.3 h. The surface modification of microspheres was performed with lectin by carbodiimide activation reaction and confirmed by difference in surface charge before and after chemical functionalization by zeta potential measurement which was found to be − 25.7 mV and 20.5 mV, respectively. Ex vivo study for bioadhesion strength evaluation on goat nasal mucosa indicated a significant difference (p < 0.001) between the plain (29%) and lectin functionalized microspheres (64%). In vivo behavioral and biochemical studies in the rats treated with lectin functionalized microspheres showed markedly better memory-retention vis-à-vis test and pure drug solution treated rats (p < 0.001). In a nutshell, the present studies showed successful development of nasal microspheres for enhanced brain delivery of rivastigmine for Alzheimer’s treatment.
Although nanoparticles, polymeric micelles, liposomes, nanoemulsions, and microemulsions were extensively evaluated as formulations for nasal administration of drugs, lyotropic liquid crystal (LLC) mesophases have been few studied. The phase transition from a low-viscosity microemulsion to a more viscous LLC may improve the mucoadhesion of the formulation. Donepezil is a drug administered orally in the treatment of Alzheimer’s disease, and with gastrointestinal side effects that are typical of acetylcholinesterase inhibitors. Based on this, donepezil administration by nasal pathway using a mucoadhesive LLC may be a feasible alternative. A colloidal formulation was selected from a ternary diagram, combining CETETH-10, oleic acid, and water (40:45:15, w/w). Donepezil was incorporated into the formulation, and the characterisation included in vitro studies, such as mucoadhesion and drug release. Pharmacokinetics in Wistar rats included evaluations by the nasal pathway with donepezil incorporated into microemulsion. A phase transition from an isotropic to an anisotropic system was observed after the swelling of the microemulsion with artificial nasal fluid (12-20%). The release of donepezil in vitro occurred in a sustained manner. Significant levels of donepezil were achieved in the brain after nasal administration of the microemulsion, as a promising strategy for the treatment of Alzheimer´s disease.
The present investigation explores the potential of novel dual drug-loaded niosomes for nasal delivery of Rivastigmine (RIV) and N-Acetyl Cysteine (NAC) to the brain. The dual niosomes showed a particle size of 162.4 nm and % entrapment efficiencies of 97.7 for RIV and 85.9 % for NAC. The niosomes were statistically validated using Box-Behnken experimental design (BBD) with good significance. Ultrastructural and chemical characterization of the niosomes using various analytical techniques like Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Transmission electron microscopy (TEM) showcased drug-excipient compatibility and robust stability of 6 months in a liquid state at 4-8°C. The dual drug-loaded niosomes showed a sustained drug release pattern up to 2 days. Acetylcholinesterase (AChE) and DPPH (1, 1-diphenyl-2- picrylhydrazyl) enzyme inhibition assays showed a better combinative effect than the free drug solutions. A 2-day nasal permeation proved the effectiveness and biocompatibility of the niosomes. In-vivo pharmacokinetic and organ biodistribution studies revealed a better drug profile and greater distribution of the niosomes in the brain compared to other organs, thereby indicating a direct nose-to-brain delivery of the niosomes.
Alzheimer's disease (AD) is a non-recoverable progressive neurodegenerative disorder most prevalent but not limited to the old age population. After all the scientific efforts, there are still many unmet criteria and loopholes in available treatment and diagnostic strategies, limiting their efficacy. The poor drug efficacy is attributed to various biological hurdles, including blood-brain barrier (BBB) and peripheral side effects as most prominent ones and the lack of promising carriers to precisely deliver the drug to the brain by conserving its therapeutic potency. The increasing disease prevalence and unavailability of effective therapy calls for developing a more innovative, convenient and affordable way to treat AD. To fulfill such need, researchers explored various biomaterials to develop potential vectors or other forms to target the bioactives in the brain by preserving their inherent properties, improving the existing lacuna like poor solubility, permeability and bioavailability etc. and minimize the side effect. The unique characteristic properties of biomaterials are used to develop different drug carriers, surface modifying target active ligands, functional carriers, drug conjugate, biosensing probe, diagnostic tool and many more. The nanoparticulate system and other colloidal carriers like hydrogel and biodegradable scaffold can effectively target the drug moieties to the brain. Also, the use of different target-acting ligands and stimuli-responsive carriers assures the site-specificity and controlled release at the desired site by interaction with receptors and various exo- and endogenous stimuli. This review article has highlighted the application of biomaterials for targeting the drug to the brain and as promising diagnostic tools to detect the markers for better AD management. The work particularly focuses on the use of biomaterials as smart drug carriers including pH, thermo, photo, electro and magnetically triggered system; novel drug carriers for brain targeting including polymeric carriers (polymeric nanoparticle, dendrimer and polymeric micelle); lipid carrier (liposome, nanoemulsion, NLC and SLN); inorganic nanoparticles (quantum dots, gold nanoparticles etc.); and other drug vectors (hydrogel, biodegradable scaffold, and carbon nanotube) in treatment of AD. It also highlighted the application of some novel carrier systems and biomaterials as biosensor and other diagnostic tools for early and precise AD diagnosis.
In last two decades, the lipid nanocarriers have been extensively investigated for their drug targeting efficiency towards the critical areas of the human body like CNS, cardiac region, tumor cells, etc. Owing to the flexibility and biocompatibility, the lipid-based nanocarriers, including nanoemulsion, liposomes, SLN, NLC etc. have gained much attention among various other nanocarrier systems for brain targeting of bioactives. Across different lipid nanocarriers, NLC remains to be the safest, stable, biocompatible and cost-effective drug carrier system with high encapsulation efficiency. Drug delivery to the brain always remains a challenging issue for scientists due to the complex structure and various barrier mechanisms surrounding the brain. The application of a suitable nanocarrier system and the use of any alternative route of drug administration like nose-to-brain drug https://doi. T delivery could overcome the hurdle and improves the therapeutic efficiency of CNS acting drugs thereof. NLC, a second-generation lipid nanocarrier, upsurges the drug permeation across the BBB due to its unique structural properties. The biocompatible lipid matrix and nano-size make it an ideal drug carrier for brain targeting. It offers many advantages over other drug carrier systems, including ease of manufacturing and scale-up to industrial level, higher drug targeting, high drug loading, control drug release, compatibility with a wide range of drug substances, non-toxic and non-irritant behavior. This review highlights recent progresses towards the development of NLC for brain targeting of bioactives with particular reference to its surface modifications, formulations aspects, pharmacokinetic behavior and efficacy towards the treatment of various neurological disorders like AD, PD, schizophrenia, epilepsy, brain cancer, CNS infection (viral and fungal), multiple sclerosis, cerebral ischemia, and cerebral malaria. This work describes in detail the role and application of NLC, along with its different fabrication techniques and associated limitations. Specific emphasis is given to compile a summary and graphical data on the area explored by scientists and researchers worldwide towards the treatment of neurological disorders with or without NLC. The article also highlights a brief insight into two prime approaches for brain targeting, including drug delivery across BBB and direct nose-to-brain drug delivery along with the current global status of specific neurological disorders.
The diagnosis and treatment of neurological ailments always remain an utmost challenge for research fraternity due to the presence of BBB. The intranasal route appeared as an attractive and alternative route for brain targeting of therapeutics without the intrusion of BBB and GI exposure. This route directly and effectively delivers the therapeutics to different regions of the brain via olfactory and trigeminal nerve pathways. However, shorter drug retention time and mucociliary clearance curtail the efficiency of the intranasal route. The in situ mucoadhesive gel overthrow the limitations of direct nose-to-brain delivery by not only enhancing nasal residence time but also minimizing the mucociliary clearance and enzymatic degradation. This delivery system further improves the nasal absorption as well as bioavailability of drugs in the brain. The in situ mucoadhesive gel is a controlled and sustained release system that facilitates the absorption of various proteins, peptides and other larger lipophilic and hydrophilic moieties. Owing to multiple benefits, in situ gelling system has been widely explored to target the brain via nasal route. However, very few review works are reported which explains the application of in situ nasal gel for brain delivery of CNS acting moieties. Hence, in this piece of work, we have initially discussed the global statistics of neurological disorders reported by WHO and other reputed T organizations, nasal anatomy, mechanism and challenges of nose-to-brain drug delivery. The work mainly fo-cused on the use of different stimuli-responsive polymers, specifically thermoresponsive, pH-responsive, and ion triggered systems for the development of an effective and controlled dosage form, i.e., in situ nasal gel for brain targeting of bioactives. We have also highlighted the origin, structure, nature and phase transition behavior of the smart polymers found suitable for nasal administration, including poloxamer, chitosan, EHEC, xyloglucan, Carbopol, gellan gum and DGG along with their application in the treatment of neurological disorders. The article is aimed to gather all the information of the past 10 years related to the development and application of stimuli-responsive in situ nasal gel for brain drug delivery.
Alzheimer's disease (AD), a highly complex, irreversible, progressive, challenging as well as fatal neurodegenerative disease of the brain, affects 35 million people around the world. It is estimated that 100 million people are expected to suffer from the disorder by 2050. It was found that sitagliptin (SIT), a dipeptidyl peptidase-4 (DPP-4) inhibitor, produced symptomatic relief of AD. Sitagliptin loaded chitosan nanoparticles (SIT-CS-NPs) were prepared and evaluated for their potential to target sitagliptin into the brain following intranasal (IN) administration. The SIT-CS-NPs were formulated by ionic gelation method. The mean size and zeta potential was 188.4 ± 48.1 nm and 20.8 mV respectively. In vitro SIT release in pH 6.4 phosphate buffer ranged between 49.55 ± 2.62 %w/w and 73.77 ± 2.12 %w/w for 24 h. Animal studies revealed that SIT-CS-NPs increased SIT levels in the brain by 5.07 fold in comparison with free SIT after IN administration.
This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality and morbidity, use and costs of care, and the overall impact on caregivers and society. The Special Report discusses the future challenges of meeting care demands for the growing number of people living with Alzheimer's dementia in the United States with a particular emphasis on primary care. By mid‐century, the number of Americans age 65 and older with Alzheimer's dementia may grow to 13.8 million. This represents a steep increase from the estimated 5.8 million Americans age 65 and older who have Alzheimer's dementia today. Official death certificates recorded 122,019 deaths from AD in 2018, the latest year for which data are available, making Alzheimer's the sixth leading cause of death in the United States and the fifth leading cause of death among Americans age 65 and older. Between 2000 and 2018, deaths resulting from stroke, HIV and heart disease decreased, whereas reported deaths from Alzheimer's increased 146.2%. In 2019, more than 16 million family members and other unpaid caregivers provided an estimated 18.6 billion hours of care to people with Alzheimer's or other dementias. This care is valued at nearly $244 billion, but its costs extend to family caregivers’ increased risk for emotional distress and negative mental and physical health outcomes. Average per‐person Medicare payments for services to beneficiaries age 65 and older with AD or other dementias are more than three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 23 times as great. Total payments in 2020 for health care, long‐term care and hospice services for people age 65 and older with dementia are estimated to be $305 billion. As the population of Americans living with Alzheimer's dementia increases, the burden of caring for that population also increases. These challenges are exacerbated by a shortage of dementia care specialists, which places an increasing burden on primary care physicians (PCPs) to provide care for people living with dementia. Many PCPs feel underprepared and inadequately trained to handle dementia care responsibilities effectively. This report includes recommendations for maximizing quality care in the face of the shortage of specialists and training challenges in primary care.
Nucleic acid-based therapeutics, including the use of messenger-RNA (mRNA) as a drug molecule has tremendous potential in the treatment of chronic diseases, such as age-related neurodegenerative diseases. In this study, we have developed cationic liposomal formulation of mRNA and evaluated the potential of intranasal delivery to the brain in murine models. Preliminary in vitro studies in J774A.1 murine macrophages showed GFP expression up to 24 h and stably expressed GFP protein in the cytosol. Upon intranasal administration of GFP-mRNA/cationic liposomes (3 mg/kg dose), there was significantly higher GFP-mRNA expression in the brain post-24 h as compared to either naked mRNA or vehicle-treated group in mice. Luciferase mRNA encapsulated in cationic liposomes was used for quantification of expression in distribution in the brain. The results showed increased luciferase activity in the whole brain in a dose-dependent manner. Specifically, luciferase-mRNA/cationic liposome group (3 mg/kg dose) showed significantly higher luciferase activity in cortex, striatum, and midbrain regions as compared with the control groups, with minimal systemic exposure. Overall, the results of this study demonstrate the feasibility of brain-specific, non-viral mRNA delivery for the treatment of various neurological disorders.
Cerebral ischemia reperfusion injury (CIRI), one of the major causes of death from stroke in the world, not only causes tremendous damage to human health, but also brings heavy economic burden to society. Current available treatments for CIRI, including mechanical therapies and drug therapies, are often accompanied by significant side-effects. Therefore, it is necessary to discovery new strategies for treating CIRI. Many studies have confirmed that the herbal medicine has the advantages of abundant resources, good curative effect and little side effects, which can be used as potential drug for treatment of CIRI through multiple targets. It’s known that oral administration commonly has low bioavailability, and injection administration is inconvenient and unsafe. Many drugs can’t delivery to brain through routine pathways due to the blood-brain-barrier (BBB). Interestingly, increasing evidences have suggested the nasal administration is a potential direct route to transport drug into brain avoiding the BBB and has the characteristics of high bioavailability for treating brain diseases. Therefore, intranasal administration can be treated as an alternative way to treat brain diseases. In the present review, effective methods to treat CIRI by using active ingredients derived from herbal medicine through nose to brain drug delivery (NBDD) are updated and discussed, and some related pharmacological mechanisms have also been emphasized. Our present study would be beneficial for the further drug development of natural agents from herbal medicines via NBDD.
Alzheimer's disease, a progressive neurodegenerative disorder, is one of the leading causes of death in the USA, along with cancer and cardiac disorders. AD is characterized by various neurological factors like amyloid plaques, tau hyperphosphorylation, mitochondrial dysfunction, acetylcholine deficiency, etc. Together, impaired insulin signaling in the brain is also observed as essential factor to be considered in AD pathophysiology. Hence, currently researchers focused on studying the effect of brain insulin metabolism and relation of diabetes with AD. Based on the investigations, AD is also considered as type 3 or brain diabetes. Besides the traditional view of correlating AD with aging, a better understanding of various pathological factors and effects of other physical ailments is necessary to develop a promising therapeutic approach. There is a vast scope of studying the relation of systemic insulin level, insulin signaling, its neuroprotective potency and effect of diabetes on AD progression. The present work describes worldwide status of AD and its relation with diabetes mellitus and insulin metabolism; pathophysiology of AD; different metabolic pathways associating insulin metabolism with AD; insulin receptor and signaling in the brain; glucose metabolism; insulin resistance; and various preclinical and clinical studies reported insulin-based therapies to treat AD via systemic route and through direct intranasal delivery to the brain.
NLC is a next-generation lipid nanocarrier which holds many advantages over other colloidal lipid carrier system like higher drug loading, better and controlled release and enhanced stability. Owing to the unique structural composition, i.e. crystallized solid and liquid lipid blend it offers excellent biocompatibility and higher permeation across physiological membranes like BBB. Moreover, the surface of NLC can be easily modified with target-specific ligands, proteins, peptides, etc. which makes it a potential candidate for brain targeting of CNS acting drugs. NLC has found various applications in treatment of various CNS disorders including Alzheimer’s disease, Parkinson’s disease, schizophrenia, epilepsy, migraine, cerebral ischemia etc. Among these, the application of NLC towards the treatment of AD has been well explored in past two decades. In this piece of work, we have discussed the types of NLC, its composition, fabrication techniques, characterization, stability profile and application in the treatment of AD.
This special report gives an insight in the rationale of utilizing the nasal cavity for drug administration and the formulation as well as characterization of nasal preparations. As the nose is an easy-to-access, noninvasive and versatile location for absorption, this route of delivery will play an increasingly important role in future drug product development both for new and repurposed drugs. The nose can be utilized for local and systemic delivery including drug delivery to the central nervous system and the immune system. Typical formulation strategies and future developments are reviewed, which nowadays mostly comprise liquid formulations. Although they are straight forward to develop, a number of aspects from choice of solvent, osmolarity, pH, viscosity and more need to be considered, which determine formulation characteristics, not at least nasal deposition. Nasal powders offer higher stability and, along with more sophisticated nasal devices, may play a major role in the future.
Alzheimer's disease (AD) is a common and severe brain disease with a high mortality among the elders, but no highly efficient medications are currently available. For example, timosaponin BII, an efficient anti-AD agent, has low oral bioavailability. Here, timosaponin BII was formulated in a temperature/ion-sensitive in situ hydrogel (ISG) that was well transformed into gels in the nasal environment. Timosaponin BII protected the PC12 cells injured by lipopolysaccharides (LPS) by decreasing TNF-α and IL-1β and stabilizing F-actin. Timosaponin BII ISGs were intranasally administered to the mice every day for 38 days. On Day 36, LPS was injected to the mice to establish an AD model. Morris water maze experiments showed that the number of the animals that were able to cross the platform returned to normal and the total distance over which the animals moved in the open field also increased, which demonstrated that the spatial memory and spontaneous behavior were improved after treatment compared to the model. Moreover, an AD improver, inducible nitric oxide synthase (iNOS) in the brain, was reduced after treatment. High brain targeting effect of timosaponin BII ISGs was confirmed by in vivo fluorescence imaging. The nasal timosaponin BII dually sensitive ISGs can serve as a promising medication for local prevention of AD.
Since health care systems dedicate substantial resources to Alzheimer's disease (AD), it poses an increasing challenge to scientists and health care providers worldwide, especially that many decades of research in the medical field revealed no optimal effective treatment for this disease. The intranasal administration route seems to be a preferable route of anti-AD drug delivery over the oral one as it demonstrates an ability to overcome the related obstacles reflected in low bioavailability, limited brain exposure and undesired pharmacokinetics or side effects. This delivery route can bypass the systemic circulation through the intraneuronal and extraneuronal pathways, providing truly needleless and direct brain drug delivery of the therapeutics due to its large surface area, porous endothelial membrane, the avoidance of the first-pass metabolism, and ready accessibility. Among the different nano-carrier systems developed, lipid-based nanosystems have become increasingly popular and have proven to be effective in managing the common symptoms of AD when administered via the nose-to-brain delivery route, which provides an answer to circumventing the BBB. The design of such lipid-based nanocarriers could be challenging since many factors can contribute to the quality of the final product. Hence, according to the authors, it is recommended to follow the quality by design methodology from the early stage of development to ensure high product quality while saving efforts and costs. This review article aims to draw attention to the up-to-date findings in the field of lipid-based nanosystems and the potential role of developing such forms in the management of AD by means of the nose-to-brain delivery route, in addition to highlighting the significant role of applying QbD methodology in this development.
In recent years, nanomedicines have emerged as a promising method for central nervous system drug delivery, enabling the drugs to overcome the blood-brain barrier and accumulate preferentially in the brain. Despite the current success of brain-targeted nanomedicines, limitations still exist in terms of the targeting specificity. Based on the molecular mechanism, the exact cell populations and subcellular organelles where the injury occurs and the drugs take effect have been increasingly accepted as a more specific target for the next generation of nanomedicines. Dual and multi-targeted nanoparticles integrate different targeting functionalities and have provided a paradigm for precisely delivering the drug to the pathological site inside the brain. The targeting process often involves the sequential or synchronized navigation of the targeting moieties, which allows highly controlled drug delivery compared to conventional targeting strategies. Herein, we focus on the up-to-date design of pathological site-specific nanoparticles for brain drug delivery, highlighting the dual and multi-targeting strategies that were employed and their impact on improving targeting specificity and therapeutic effects. Furthermore, the background discussion of the basic properties of a brain-targeted nanoparticle and the common lesion features classified by neurological pathology are systematically summarized.
Why is nose-to-brain delivery considered to be a strategy that directly allows the access of antidepressants to the brain? In which circumstances can the intranasal pathway be applicable? Are there any requirements to follow? What triggers the antidepressant market? Which constraints are imposed during discovery programs? What opportunities can arise and what is their current status of development? Are they already translated into clinical practice? Which challenges are expected from recent development strategies? This review aims at providing a critical appraisal of nose-to-brain delivery of antidepressants, framed within a comprehensive analysis of drivers, restraints, opportunities and challenges.
Mucoadhesion is defined as the adherence of a synthetic or natural polymer to a mucosal membrane via physical or chemical interactions. Mucoadhesive materials are widely used to develop dosage forms for transmucosal drug delivery via ocular, nasal, esophageal, oral, vaginal, rectal, and intravesical routes of administration. This review will discuss some of the most prominent and recent synthetic methodologies employed to modify polymeric materials in order to enhance their mucoadhesive properties. This includes chemical conjugation of polymers with molecules bearing thiol‐, catechol‐, boronate‐, acrylate‐, methacrylate‐, maleimide‐, and N‐hydroxy(sulfo)succinimide ester‐ groups. The recent progress in the synthesis and application of polymers with enhanced ability to adhere to mucosal tissues is discussed.
The global prevalence of neurologic disorders is rising, and yet we are still unable to deliver most drug molecules, in therapeutic quantities, to the brain. The blood brain barrier consists of a tight layer of endothelial cells surrounded by astrocyte foot processes, and these anatomic features constitute a significant barrier to drug transport from the blood to the brain. One way to bypass the blood brain barrier and thus treat diseases of the brain is to use the nasal route of administration and deposit drugs at the olfactory region of the nares, from where they travel to the brain via mechanisms that are still not clearly understood, with travel across nerve fibers and travel via a perivascular pathway both being hypothesized. The nose-to-brain route has been demonstrated repeatedly in preclinical models, with both solution and particulate formulations. The nose-to-brain route has also been demonstrated in human studies with solution and particle formulations. The entry of device manufacturers into the arena will enable the benefits of this delivery route to become translated into approved products. The key factors that determine the efficacy of delivery via this route include the following: delivery to the olfactory area of the nares as opposed to the respiratory region, a longer retention time at the nasal mucosal surface, penetration enhancement of the active through the nasal epithelia, and a reduction in drug metabolism in the nasal cavity. Indications where nose-to-brain products are likely to emerge first include the following: neurodegeneration, post-traumatic stress disorder, pain, and glioblastoma.
Intranasal delivery has shown to circumvent blood-brain-barrier (BBB)and deliver the drugs into the CNS at a higher rate and extent than other conventional routes. The mechanism of drug transport from nose-to-brain is not fully understood yet, but several neuronal pathways are considered to be involved. Intranasal nanoemulsion for brain targeting is investigated extensively. Higher brain distribution of drug after administering intranasal nanoemulsion was established by many researchers. Issues with nasomucosal clearance are solved by formulating modified nanoemulsion; for instance, mucoadhesive nanoemulsion or in situ nanoemulgel. However, no intranasal nanoemulsion for brain targeted drug delivery has been able to cross the way from ‘benches to bed-side’ of patients. Possibilities of toxicity by repeated administration, irregular nasal absorption during the diseased condition, use of a high amount of surfactants are few of the persisting challenges that need to overcome in coming days. Understanding the ways how current developments has solved some challenges is necessary. At the same time, the future direction of the research on intranasal nanoemulsion should be figured out based on existing challenges. This review is focused on the current developments of intranasal nanoemulsion with special emphasis on the existing challenges that would help to set future research direction.
The chapter gives an up-to-date overview on basic
concepts relevant to nanoparticles and their impact on bioavailability, as well as
the effect of particle size and surface characteristics on biodistribution and cellular uptake of nanoparticles and biomedical application of nanoparticles
Eudragit® E PO (EPO) is a terpolymer based on N,N-dimethylaminoethyl methacrylate with methylmethacrylate and butylmethacrylate, produced by Evonik Industries AG as a pharmaceutical excipient. In this work, EPO was chemically modified through reaction with acryloyl chloride. The successful modification of EPO was confirmed by FTIR, NMR-spectroscopy, elemental and thermal analysis. The degree of acrylation was determined by permanganatometric titration. The slug mucosal irritation test was used to demonstrate non-irritant nature of EPO and its acrylated derivatives (AEPO). The mucoadhesive properties of EPO and AEPO were evaluated using freshly excised sheep nasal mucosa and it was demonstrated that acrylated polymers facilitated greater retention of sodium fluorescein on mucosal surfaces compared to solution mixture of this dye solution with EPO as well as free dye.
The purpose of the present study was to formulate resveratrol loaded nanostructured lipid carrier based in situ gel for intranasal administration. Resveratrol loaded lipid carrier was prepared by a melt emulsification-probe sonication method, characterized and optimized. Nanostructured lipid carrier was then incorporated into in situ gel and characterized. The resveratrol nanostructured lipid carrier was formulated and evaluated for particle size (132 ± 12 nm), polydispersity index (0.165 ± 0.002), zeta potential (−23 ± 4 mV), drug loading (10 ± 3%) and entrapment efficiency (74 ± 6%). A pharmacokinetic study showed the higher drug distribution in the brain from in situ gel which indicated safety and efficacy of developed formulation upon administration through nasal route. Thus, we can conclude that partially drug might have absorbed via an olfactory route from developed formulation and hence the intranasal route could be a promising approach for the treatment of Alzheimer's disease.