Intranasal delivery of biologics to the central nervous system

Treatment of central nervous system (CNS) diseases is very difficult due to the blood-brain barrier's (BBB) ability to severely restrict entry of all but small, non-polar compounds. Intranasal administration is a non-invasive method of drug delivery which may bypass the BBB to allow therapeutic substances direct access to the CNS. Intranasal delivery of large molecular weight biologics such as proteins, gene vectors, and stem cells is a potentially useful strategy to treat a variety of diseases/disorders of the CNS including stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease, epilepsy, and psychiatric disorders. Here we give an overview of relevant nasal anatomy and physiology and discuss the pathways and mechanisms likely involved in drug transport from the nasal epithelium to the CNS. Finally we review both pre-clinical and clinical studies involving intranasal delivery of biologics to the CNS.     

Formulation and physiological factors influencing CNS delivery upon intranasal administration

The treatment of central nervous system (CNS) disorders is particularly challenging because of a variety of formidable barriers to effective and persistent delivery of therapeutic compounds. This review discusses the potential of intranasal drug administration as a means to bypass a major barrier, the blood-brain barrier, and allow for direct delivery of drugs into the CNS. The article emphasizes physicochemical properties of intranasal drug formulations as well as relevant anatomical and physiological factors in intranasal delivery of drugs for CNS therapy. Published examples of intranasal administration of small molecular weight drugs, peptides and proteins, and novel formulations for delivering a broad spectrum of molecules are discussed. Finally, the article provides several strategies for effectively enhancing nose-to-brain transport of drug molecules through rational formulation design and optimization.     

Intranasal delivery to the central nervous system: Mechanisms and experimental considerations

The blood–brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal passages and composition of the formulation can influence the pathway a therapeutic follows into the CNS after intranasal administration. Experimental factors, such as head position, volume, and method of administration, and formulation parameters, such as pH, osmolarity, or inclusion of permeation enhancers or mucoadhesives, can influence formulation deposition within the nasal passages and pathways followed into the CNS. Significant research will be required to develop and improve current intranasal treatments and careful consideration should be given to the factors discussed in this review. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1654–1673, 2010     

Clinical trials of intranasal delivery for treating neurological disorders--a critical review

INTRODUCTION: The intranasal delivery of therapeutics to the brain has achieved great success in preclinical studies. These findings are important because there are many neurological disorders without feasible treatments, due to a lack of effective drug delivery methods to the brain. Translating such intranasal delivery strategies from bench to bedside is an important step for curing these neurological diseases. AREAS COVERED: This review summarizes recent clinical trials that have investigated the intranasal delivery of drugs to the brain to treat neurological disorders and their potential mechanisms of action. In addition, the potential opportunities as well as challenges of intranasal delivery in clinical trials are discussed. EXPERT OPINION: The intranasal delivery of drugs to the brain is a novel method with great potential, and it may provide an extraordinary approach to overcome the existing barriers of drug delivery for treating some neurological disorders. Intranasal delivery of central nervous system therapeutics has shown promise in several clinical trials, which demonstrates both the need and importance of further research.     

Targeted Delivery of Nano-Therapeutics for Major Disorders of the Central Nervous System

Major central nervous system (CNS) disorders, including brain tumors, Alzheimer’s disease, Parkinson’s disease, and stroke, are significant threats to human health. Although impressive advances in the treatment of CNS disorders have been made during the past few decades, the success rates are still moderate if not poor. The blood–brain barrier (BBB) hampers the access of systemically administered drugs to the brain. The development of nanotechnology provides powerful tools to deliver therapeutics to target sites. Anchoring them with specific ligands can endow the nano-therapeutics with the appropriate properties to circumvent the BBB. In this review, the potential nanotechnology-based targeted drug delivery strategies for different CNS disorders are described. The limitations and future directions of brain-targeted delivery systems are also discussed.     

Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer’s disease

In recent years, the incidental rate of neurodegenerative disorders has increased proportionately with the aging population. Alzheimer’s disease (AD) is one of the most commonly reported neurodegenerative disorders, and it is estimated to increase by roughly 30% among the aged population. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates – such as acetylcholinesterase inhibitors are currently utilized as an effective clinical therapy. However, targeted drug delivery of these drugs to the central nervous system (CNS) exhibits several limitations including meager solubility, low bioavailability, and reduced efficiency due to the impediments of the blood-brain barrier (BBB). Current advances in nanotechnology present opportunities to overcome such limitations in delivering active drug candidates. Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability. Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop successful therapeutics with sustained release and improved efficacy. Here, we discuss few recently updated nano-drug delivery applications that have been adapted in the field of AD therapeutics, and future prospects on potential molecular targets for nano-drug delivery systems.     

Strategies for Intranasal Delivery of Therapeutics for the Prevention and Treatment of NeuroAIDS

Intranasal drug administration is a noninvasive method of bypassing the blood–brain barrier (BBB) to deliver neurotrophins and other therapeutic agents to the brain and spinal cord. This method allows drugs that do not cross the BBB to be delivered to the central nervous system (CNS) and eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways. Intranasal delivery occurs by an extracellular route and does not require that drugs bind to any receptor or undergo axonal transport. Intranasal delivery also targets the nasal associated lymphatic tissues (NALT) and deep cervical lymph nodes. In addition, intranasally administered therapeutics are observed at high levels in the blood vessel walls and perivascular spaces of the cerebrovasculature. Using this intranasal method in animal models, researchers have successfully reduced stroke damage, reversed Alzheimer’s neurodegeneration, reduced anxiety, improved memory, stimulated cerebral neurogenesis, and treated brain tumors. In humans, intranasal insulin has been shown to improve memory in normal adults and patients with Alzheimer’s disease. Intranasal delivery strategies that can be employed to treat and prevent NeuroAIDS include: (1) target antiretrovirals to reach HIV that harbors in the CNS; (2) target therapeutics to protect neurons in the CNS; (3) modulate the neuroimmune function of moncyte/macrophages by targeting the lymphatics, perivascular spaces of the cerebrovasculature, and the CNS; and (4) improve memory and cognitive function by targeting therapeutics to the CNS. Presented at an NIMH workshop “HIV Preclinical–Clinical Therapeutics Research Meeting,” May 5–16, 2006.     

Intranasal delivery: circumventing the iron curtain to treat neurological disorders

Introduction: The blood–brain barrier (BBB) is like an iron curtain that prevents exogenous substances, including most drugs, from entering the CNS. Intranasal delivery has been demonstrated to circumvent the BBB due to the special anatomy of the olfactory and trigeminal neural pathways that connect the nasal mucosa with the brain and the perivascular pathway within the CNS. In the last two decades, the concepts, mechanisms and pathways of intranasal delivery to the CNS have led to great success both in preclinical and clinical studies. More researchers have translated results from bench to bedside, and a number of publications have reported the clinical application of intranasal delivery.

Areas covered: This review summarizes results from recent clinical trials utilizing intranasal delivery of therapeutics to explore its pharmacokinetics and application to treating neurological disorders. Moreover, existing problems with the methods and possible solutions have also been discussed. The promising results from clinical trials have demonstrated that intranasal delivery provides an extraordinary approach for circumventing the BBB. Many drugs, including high-molecular-weight molecules, could potentially improve the treatment of neurological disorders via intranasal administration.

Expert opinion: Intranasal delivery is a novel method with great potential for delivering and targeting therapeutics to the CNS to treat neurological disorders.     

Intranasal delivery of stem cells to the brain

INTRODUCTION: Stem cell-based therapy has proved to be a promising treatment option for neurological disorders. However, there are difficulties in successfully administrating these stem cells. For example, the brain-blood barrier impedes the entrance of stem cells into the CNS after systemic administration. Direct transplantation or injection may result in brain injury, and these strategies are clinically less feasible. Intranasal administration is a non-invasive and effective alternative for the delivery of drugs, vector-encoded viruses or even phages to the CNS. Recent studies have in fact demonstrated that stem cells may enter the CNS after intranasal administration. These results suggest that intranasal delivery may provide an alternative strategy for stem cell-based therapy. AREAS COVERED: This review summarizes current studies that have applied the intranasal delivery of stem cells into the brain. In addition, the distribution and fate of stem cells in the brain and the potential opportunities as well as challenges of intranasal stem cell delivery are also discussed. EXPERT OPINION: Intranasal delivery of stem cells is a new method with great potential for the transplantation of stem cells into the brain, and it may provide an extraordinary approach to overcoming the existing barriers of stem cell delivery for the treatment of many neurological disorders. This potential benefit emphasizes the importance of future research into intranasal delivery of stem cells.     

Sofosbuvir,a nucleotide polymerase inhibitor,for the treatment of chronic hepatitis C virus infection

Neural cell transplantation is an emerging therapy that may provide an effective treatment for neurodegenerative disorders. The most extensive work with neural transplants has been carried out for Parkinson’s and Huntington’s diseases. However, intensive efforts are also being made for the treatment of other neurological indications, such as spinal cord repair, stroke, epilepsy, multiple sclerosis (MS), Alzheimer’s disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), to name just a few. The major barrier for the successful application of cells as therapeutics is achieving long-term survival and function. The CNS has proven to be ideal for transplantation, in part because immune rejection is attenuated in the CNS compared to peripheral locations. However, some form of immunosuppression is desirable for optimal allograft survival and required for xenograft survival. This review will focus on the challenges of restoring function to something as intricate as the CNS and on the limitations imposed by this complexity on any cellular therapeutic.     

Neramexane: a moderate-affinity NMDA receptor channel blocker: new prospects and indications

N-methyl-D-aspartate (NMDA) receptor antagonists have a potentially wide range of therapeutic applications. Unfortunately, potent NMDA receptor channel blockers produce phencyclidine-like psychotropic symptoms in humans and rodents, and thereby produce numerous side effects. However, recent data indicate that moderate-affinity, voltage-dependent, open-channel blockers, such as memantine and neramexane (MRZ 2/579) are useful therapeutics as they prevent the pathological activation of NMDA receptors but allow their physiological activity and should prove to be useful therapeutics in a wide range of CNS disorders. Indeed, memantine was recently registered in both Europe and the USA for the treatment of moderate-to-severe Alzheimer’s disease (AD). Neramexane is under development as a potential neuroprotectant against various CNS disorders. Although the predicted therapeutic doses of neramexane were very well tolerated in male volunteers, unfortunately, recent Phase II/III clinical trials for moderate-to-severe AD delivered contradictory results. Neramexane also failed in a recent randomized controlled Phase II trial against drug abuse and depression. Although Phase Ib clinical trials for the indications of chronic pain showed positive results, Phase II results indicate no superiority to existing treatments. However, positive study results have been presented recently in a Phase IIb study on the treatment of tinnitus. A Phase III study for this indication is presently ongoing. Another promising application for neramexane as a neuroprotectant might be chronic neurodegeneration, such as Parkinson’s disease, Huntington’s disease, vascular dementia, frontal lobe dementia, Down’s syndrome and AD.     

Intranasal delivery of therapeutic proteins for neurological diseases

INTRODUCTION: Among the range of therapeutic protein candidates for new generation treatments of neurological diseases, neurotrophic factors and recombinant antibodies hold the greatest potential. However, major difficulties in their safe and effective delivery to the brain severely limit these applications. The BBB restricts the exchange of proteins between the plasma and the CNS. Moreover, therapeutic proteins often need to be selectively targeted to the brain, while minimizing their biodistribution to systemic compartments, to avoid peripheral side effects. The intranasal delivery of proteins has recently emerged as a non-invasive, safe and effective method to target proteins to the CNS, bypassing the BBB and minimizing systemic exposure. AREAS COVERED: We critically summarize the main experimental and mechanistic facts about the simple and non-invasive nasal delivery approach, which provides a promising strategy and a potential solution for the severe unmet medical need of safely and effectively delivering protein therapeutics to the brain. EXPERT OPINION: The intranasal route for the effective delivery of recombinant therapeutic proteins represents an emerging and promising non-invasive strategy. Future studies will achieve a detailed understanding of pharmacokinetic and mechanisms of delivery to optimize formulations and fully exploit the nose-to-brain interface in order to deliver proteins for the treatment of neurological diseases. This expanding research area will most likely produce exciting results in the near future towards new therapeutical approaches for the CNS.     

Intranasal delivery of therapeutic proteins for neurological diseases

Introduction: Among the range of therapeutic protein candidates for new generation treatments of neurological diseases, neurotrophic factors and recombinant antibodies hold the greatest potential. However, major difficulties in their safe and effective delivery to the brain severely limit these applications. The BBB restricts the exchange of proteins between the plasma and the CNS. Moreover, therapeutic proteins often need to be selectively targeted to the brain, while minimizing their biodistribution to systemic compartments, to avoid peripheral side effects. The intranasal delivery of proteins has recently emerged as a non-invasive, safe and effective method to target proteins to the CNS, bypassing the BBB and minimizing systemic exposure.

Areas covered: We critically summarize the main experimental and mechanistic facts about the simple and non-invasive nasal delivery approach, which provides a promising strategy and a potential solution for the severe unmet medical need of safely and effectively delivering protein therapeutics to the brain.

Expert opinion: The intranasal route for the effective delivery of recombinant therapeutic proteins represents an emerging and promising non-invasive strategy. Future studies will achieve a detailed understanding of pharmacokinetic and mechanisms of delivery to optimize formulations and fully exploit the nose-to-brain interface in order to deliver proteins for the treatment of neurological diseases. This expanding research area will most likely produce exciting results in the near future towards new therapeutical approaches for the CNS.     

Nicotinic systems in central nervous systems disease: degenerative disorders and beyond

Advances in the understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors has provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realization that such receptors are changed in degenerative neurologic diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Ongoing investigations of the molecular substructure of CNS nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioral, motor, and sensory functioning. Clues from careful studies of human cognition and behavior are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Modulation of these receptors with the ultimate goal of producing therapeutic benefits is the goal of these investigations and drug development. This paper will review studies from our laboratory and others that point to the importance of CNS nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in disease states. In addition, this paper will examine potential clinical applications of nicotine and/or nicotinic agonists in a variety of CNS disorders with particular emphasis on structural brain disease including: movement disorders such as Parkinson's disease and Tourette's syndrome, cognitive/behavioral disorders such as Alzheimer's disease, attention deficit/hyperactivity disorder, and schizophrenia, and other more speculative applications. Important results from early therapeutic studies of nicotine and/or nicotinic agonists in these disease states are presented. For example, recent studies with nicotine and novel nicotinic agonists such as ABT-418 by our group in AD patients suggest that nicotinic stimulation can improve the acquisition and retention of verbal information and decrease errors. Preliminary results from a series of studies examining the acute and subchronic quantitative effects of nicotine on cognitive and motor functioning in Parkinson's disease suggest that acute nicotine administration and stimulation improves some aspects of cognitive and motor performance and may improve the processing speed of more complex tasks. The most likely near-term applications of novel nicotinic agonists in CNS disorders are likely to be in those disorders that are degenerative in nature, e.g. Parkinson's disease and Alzheimer's disease, or other movement disorders such as Tourette's syndrome. The most likely direct therapeutic role for nicotinic agonists is as augmentation therapy in combination with other agents rather than as monotherapy, except early in disease states or as a prophylactic or preventative treatment.     

The 23rd Scientific Conference of the Society on Neuroimmune Pharmacology

Targeting and delivering macromolecular therapeutics to the central nervous system (CNS) has been a major challenge. The blood–brain barrier (BBB) is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Therefore, much effort has been channelled into improving transport of therapeutics across the BBB and into the CNS including the use of nanoparticles. In this thematic issue, several reviews and original research are presented that address “Nanomedicines for CNS Diseases.” The articles in this issue are concentrated on either CNS-HIV disease or CNS tumors. In regards to CNS-HIV disease, there are two reviews that discuss the role of nanoparticles for improving the delivery of HIV therapeutics to the CNS. In addition, there are two original articles focusing on therapies for CNS-HIV, one of them uses nanoparticles for delivery of siRNA specific to a key protein in autophagy to microglia, and another discusses nanoparticle delivery of a soluble mediator to suppress neuroinflammation. Furthermore, a comprehensive review about gene therapy for CNS neurological diseases is also included. Finally, this issue also includes review articles on enhanced drug targeting to CNS tumors. These articles include a review on the use of nanoparticles for CNS tumors, a review on functionalization (ligands) of nanoparticles for drug targeting to the brain tumor by overcoming BBB, and the final review discusses the use of macrophages as a delivery vehicle to CNS tumors. This thematic issue provides a wealth of knowledge on using nanomedicines for CNS diseases.     

Intranasal delivery of stem cells to the brain

Introduction: Stem cell-based therapy has proved to be a promising treatment option for neurological disorders. However, there are difficulties in successfully administrating these stem cells. For example, the brain–blood barrier impedes the entrance of stem cells into the CNS after systemic administration. Direct transplantation or injection may result in brain injury, and these strategies are clinically less feasible. Intranasal administration is a non-invasive and effective alternative for the delivery of drugs, vector-encoded viruses or even phages to the CNS. Recent studies have in fact demonstrated that stem cells may enter the CNS after intranasal administration. These results suggest that intranasal delivery may provide an alternative strategy for stem cell-based therapy.

Areas covered: This review summarizes current studies that have applied the intranasal delivery of stem cells into the brain. In addition, the distribution and fate of stem cells in the brain and the potential opportunities as well as challenges of intranasal stem cell delivery are also discussed.

Expert opinion: Intranasal delivery of stem cells is a new method with great potential for the transplantation of stem cells into the brain, and it may provide an extraordinary approach to overcoming the existing barriers of stem cell delivery for the treatment of many neurological disorders. This potential benefit emphasizes the importance of future research into intranasal delivery of stem cells.     

Intravail: highly effective intranasal delivery of peptide and protein drugs

Recent development of a new class of patented alkylsaccharide transmucosal delivery enhancement agents, collectively designated as Intravail (Aegis Therapeutics) absorption enhancers, has created opportunities for new therapeutic options across a broad spectrum of human diseases. Intravail absorption enhancers provide unsurpassed intranasal bioavailabilities, comparable to those that are achieved by injection for protein, peptide and other macromolecular therapeutics. These novel, highly effective and non-irritating excipients circumvent the two primary limitations of intranasal drug delivery, namely mucosal irritation and poor bioavailability, and offer the promise of more convenient, more effective and safer therapeutics for patients and physicians alike. For pharmaceutical companies, Intravail provides a means to capitalise on two important industry dynamics: rapidly growing industry interest in commercialising peptide and protein drugs, and increasing interest in, and use of, the intranasal route for systemic drug delivery.     

The blood-brain barrier choline transporter

Drug delivery to the brain is made difficult by the blood-brain barrier (BBB) which is selectively permeable to organic drug compounds. Several membrane solute and nutrient transporters are expressed in the BBB vasculature, which may be utilized as mechanism of delivery of drugs to the brain. Of interest to us, are the organic cation transporters which could be used to transport cationic compounds into the CNS. In this mini-review, we will review the current understanding of the structural requirements for designing compounds which could effectively use organic cation transporters (OCT). For the first time, structural requirements for both OCT1 and OCT2 versus the BBB choline transporter (BBBCHT) are discussed and compared. The information gained here could increase the success rate in successful CNS drug delivery and therapeutics.     

Evaluation of memantine for neuroprotection in dementia

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer’s disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer’s disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.     

Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: Advances,challenges, and future perspectives

Considerable advances have been made in the research and development of oligonucleotide therapeutics (OTs) for treating central nervous system (CNS) diseases, such as psychiatric and neurodegenerative disorders, because of their promising mode of action. However, due to the tight barrier function and complex physiological structure of the CNS, the efficient delivery of OTs to target the brain has been a major challenge, and intensive efforts have been made to overcome this limitation. In this review, we summarize the representative methodologies and current knowledge of biodistribution, along with the pharmacokinetic/pharmacodynamic (PK/PD) relationship of OTs in the CNS, which are critical elements for the successful development of OTs for CNS diseases. First, quantitative bioanalysis methods and imaging-based approaches for the evaluation of OT biodistribution are summarized. Next, information available on the biodistribution profile, distribution pathways, quantitative PK/PD modeling, and simulation of OTs following intrathecal or intracerebroventricular administration are reviewed. Finally, the latest knowledge on the drug delivery systems to the brain via intranasal or systemic administration as noninvasive routes for improved patient quality of life is reviewed. The aim of this review is to enrich research on the successful development of OTs by clarifying OT distribution profiles and pathways to the target brain regions or cells, and by identifying points that need further investigation for a mechanistic approach to generate efficient OTs.