Drug Delivery

FORMULATION - Drug Delivery | Intranasal Delivery to the Central Nervous System

By Shyeilla V. Dhuria, PhD, Leah R. Hanson, PhD, and William H. Frey II, PhD

Editor’s Note: This article is excerpted from a longer article that appeared in the April 2010 issue of the Journal of Pharmaceutical Sciences (Vol. 9, No. 4; pp. 1654-1673). 
Despite the immense network of the cerebral vasculature, systemic delivery of therapeutics to the central nervous system (CNS) is not effective for greater than 98% of small molecules and for nearly 100% of large molecules. The lack of effectiveness is due to the presence of the blood-brain barrier (BBB), which prevents most foreign substances, even many beneficial therapeutics, from entering the brain from the circulating blood.
While certain small molecule, peptide, and protein therapeutics given systemically reach the brain parenchyma by crossing the BBB, generally high systemic doses are needed to achieve therapeutic levels, which can lead to adverse effects in the body. Therapeutics can be introduced directly into the CNS by intracerebroventricular or intraparenchymal injections; however, for multiple dosing regimens both delivery methods are invasive, risky, and expensive techniques requiring surgical lexpertise. Additional limitations to the utility of these methods are inadequate CNS exposure due to slow diffusion from the injection site and rapid turnover of the cerebrospinal fluid (CSF). Intranasal delivery has come to the forefront as an alternative to invasive delivery methods to bypass the BBB and rapidly target therapeutics directly to the CNS utilizing pathways along olfactory and trigeminal nerves innervating the nasal passages.
The primary goal of this review is to discuss the present understanding of the pathways and mechanisms underlying intranasal drug delivery to the CNS. With this background in mind, experimental considerations and formulation strategies for enhancing intranasal drug delivery and targeting to the CNS will be discussed. This review will also briefly highlight the diversity of therapeutic drugs that have been shown to be delivered to the CNS intranasally, the details of which have been recently published in several comprehensive reviews.
The intranasal route of administration is not a novel approach for drug delivery to the systemic circulation. The novelty lies in using this noninvasive method to rapidly deliver drugs directly from the nasal mucosa to the brain and spinal cord with the aim of treating CNS disorders while minimizing systemic exposure. Early research demonstrated that tracers, such as wheat-germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), were transported within olfactory nerve axons to reach the olfactory bulbs in the CNS. These findings were subsequently confirmed in a quantitative study comparing intranasal and intravenous administration of WGA-HRP.
Direct intranasal delivery of therapeutics to the brain was first proposed and patented in 1989 by William H. Frey II of the Alzheimer’ s Research Center in St. Paul, Minn. Subsequently, numerous reports have shown that therapeutics given by the intranasal route are delivered to the CNS and have the potential to treat neurological diseases and disorders. Intranasal administration of insulin, which is currently under investigation for the treatment of Alzheimer’s disease, was initially developed as a noninvasive alternative to subcutaneous insulin injections used by diabetic patients. Insulin, like many therapeutic peptides and proteins, is not effective when given orally because of the rapid degradation that occurs in the gastrointestinal tract resulting in a poor pharmacokinetic profile.

Intranasal administration of insulin, which is currently under investigation for the treatment of Alzheimer’s disease, was initially developed as a noninvasive alternative to subcutaneous insulin injections used by diabetic patients.

Intranasal Insulin

In order to enter the systemic circulation, intranasal formulations of insulin have required the use of enzyme inhibitors, mucoadhesives, and absorption enhancers to overcome barriers present in the nasal passages that limit systemic bioavailability. Nasal irritation from these additives, in addition to high and frequent dosing regimens, resulted in limited clinical success with intranasal insulin for diabetes management.
Several decades after initial investigations of intranasal insulin, use of the intranasal method was proposed for direct delivery of insulin to the brain along olfactory pathways for the treatment of Alzheimer’ s disease and other brain disorders. Using this method, researchers discovered profound improvements in memory and mood in normal individuals following intranasal administration of insulin and an insulin analog. Intranasal insulin did not alter blood insulin or glucose levels to cause these effects, consistent with observations noted in earlier investigations.
Instead, the protein rapidly gains direct access to the CSF following intranasal administration and, similar to insulin-like growth factor-I (IGFI), also likely gains direct access to the brain itself from the nasal mucosa. Intranasal insulin is now being considered as a treatment for Alzheimer’s disease, considered by some to involve ‘‘diabetes of the brain’’ or ‘‘ type 3 diabetes,” and clinical investigations are underway in patients with the disease. Intranasal insulin dose-dependently improves memory after acute treatment, and improves attention, memory, and cognitive function after 21 days of intranasal treatment.
In addition to insulin, other peptides and proteins administered by the intranasal route are proving to have beneficial effects in humans. For example, an eight amino acid peptide fragment of activity-dependent neuroprotective protein (ADNP) is in Phase II clinical trials for the treatment of mild cognitive impairment and schizophrenia and is also in development for treating Alzheimer’ s disease. The weight regulatory peptide, melano-cortin, reaches the CSF in humans within minutes of intranasal administration, without affecting blood concentrations, and decreases body weight in normal volunteers after chronic intranasal administration for six weeks.

Oxytocin Delivery

The peptide hormone, oxytocin, has been intranasally delivered to humans, resulting in significant changes in centrally mediated behaviors, such as increased trust, decreased fear and anxiety, and improved social behavior and social memory. In animals, detailed pharmacokinetic and pharmacodynamic studies have shown that a broad spectrum of therapeutics not only reach specific areas of the brain, but also have effects on CNS-mediated behaviors within a short timeframe, making the case for a rapid, extracellular pathway into the brain following intranasal administration. Small, lipophilic molecules, such as cocaine, morphine, raltitrexed, and testosterone, are able to reach the brain after intranasal administration in rodents. Intranasal studies with these drugs dem-onstrate that in addition to a portion of the drug being absorbed into the blood from the nasal mucosa, the drug gains access to the brain via direct pathways from the nasal cavity. Cocaine effects are observable within minutes of nasal administration, even before being detectable in the blood, indicating that an alternative pathway into the brain exists. Benzoylecgonine, the polar metabolite of cocaine, also reached the brain after intranasal administration via direct pathways, to a greater extent than cocaine.
Intranasal administration of larger therapeutics, such as the protein hormone, leptin, results in direct delivery to the CNS, with significant reductions in food intake in rats. Recently, intranasal leptin was shown to have anti-convulsant effects in rodent models of epilepsy. The largest therapeutic protein reported to be delivered to the brain after intranasal administration in animals is nerve growth factor (NGF, 27.5 kDa), which reached multiple brain regions in rats, with the greatest concentrations in the olfactory bulbs. Further, intranasal administration of NGF demonstrated neuroprotective effects in cerebral ischemic rats and reduced tau hyperphosphorylation and Ab accumulation in mouse model of Alzheimer’s disease.

FIGURE 1. Pathways of drug distribution in the nasal cavity and central nervous system (CNS). Following intranasal administration, drugs (blue circles) come into contact with the nasal mucosa. (A) In the respiratory region, trigeminal nerve endings residing in the respiratory and olfactory epithelium convey chemosensory information to the CNS. (B) After reaching the lamina propria, drugs can enter channels created by olfactory ensheathing cells surrounding the olfactory nerves, where they can access the cerebrospinal fluid (CSF) and olfactory bulbs (dashed arrows). (C) From the CSF, drugs can be distributed via bulk flow mechanisms and mix with brain interstitial fluid throughout the brain (dashed arrows).

Recently, it was shown that intranasal administration of an oligonucleotide inhibited brain tumor growth and increased survival in rats. Further, different sizes of plasmid DNA, ranging from 3.5 to 14.2 kb, were successfully delivered to the brain intact after intranasal administration in rats. A recent report demonstrated that mesenchymal stem cells and glioma cells were delivered to the brain within one hour of intranasal administration to rodents, indicating that intranasal delivery may facilitate the use of stem cells for treating CNS disorders.
Although there are numerous examples of the success and potential of intranasal delivery to rapidly target a great diversity of CNS therapeutics to the brain and spinal cord, direct transport following intranasal administration is not always evident. Researchers from Leiden University maintain that for several different therapeutics evaluated in their lab, including hydroxycobalamin (vitamin B12), melatonin, and estradiol, no evidence has been found for direct transport into the CSF following intranasal compared to intravenous administration.
Using microdialysis, other researchers have observed limited distribution of lidocaine, fluorescein labeled dextran, and stavudine following intranasal compared to intravenous administration. Interestingly, while van den Berg et al concluded that intranasal estradiol held no advantage in drug targeting to the CSF over intravenous administration, other groups have shown that intranasal estradiol, as well as an estradiol prodrug, significantly target the brain relative to the intravenous route. Born et al have shown that melatonin and vitamin B12 reach the CSF in humans within minutes of nasal administration without changing blood concentration.
These contrasting conclusions for similar drugs may be due to differences in methodologies employed in studies and raise important issues relating to experimental and formulation factors that can significantly influence the outcome of studies. Understanding the pathways and mechanisms underlying intranasal delivery to the CNS is critical to advance the development of intranasal treatments for neurological diseases and disorders.

Pathways and Mechanisms

While the exact mechanisms underlying intranasal drug delivery to the CNS are not entirely understood, an accumulating body of evidence demonstrates that pathways involving nerves connecting the nasal passages to the brain and spinal cord are important. In addition, pathways involving the vasculature, CSF, and lymphatic system have been implicated in the transport of molecules from the nasal cavity to the CNS. It is likely that a combination of these pathways is responsible, although one pathway may predominate, depending on the properties of the therapeutic, the characteristics of the formulation, and the delivery device used.
Protective barriers in the nasal mucosa contribute to the low efficiency of delivery observed following intranasal administration, with typically less than 1% of the administered dose reaching the brain. Research efforts have focused on the development of formulation strategies to overcome the barriers present in the nasal mucosa to improve intranasal delivery efficiency and targeting to the CNS. Nasal mucociliary clearance mechanisms are in place to remove foreign substances towards the nasopharynx, which is accomplished by dissolution of substances in the mucus layer and transport by ciliated cells in the nasal epithelium.
Efflux transport proteins, such as p-glycoprotein (P-gp) and multidrug resistance associated protein (MRP1), are expressed in the nasal mucosa, and can significantly limit the uptake of substrates into the brain. In addition, there is evidence of drug metabolizing enzymes and tight junction proteins in the nasal epithelium, which can limit the efficiency of intranasal delivery to the CNS. The nasal vasculature can also be a limiting factor as it clears inhaled toxins and intranasally applied therapeutics into the systemic circulation for detoxification and elimination.
Common themes in formulation approaches to overcome these barriers involve improving drug solubility, increasing permeability across the nasal epithelium, reducing clearance from the nasal passages, or a combination approach. While recently published reviews discuss formulation considerations for intranasal delivery, here we focus on how changes in formulation parameters can affect CNS distribution and drug targeting after intranasal administration.

Formulation Strategies

In order for a therapeutic to have adequate absorption and bioavailability in the CNS after intranasal administration, it should have sufficient solubility at the site of delivery in the nasal epithelium. Drugs can be encapsulated in carriers, such as cyclodextrins, microemulsions, and nanoparticles to overcome these issues for intranasal delivery to the CNS. Cyclodextrin inclusion complexes containing a hydrophobic cavity and a hydrophilic shell improve the solubility of poorly water-soluble drugs, enhancing brain uptake after intranasal administration.
Galanin-like peptide (GALP) mixed with alphacyclodextrin resulted in enhanced delivery to all brain regions by two- to threefold, with the greatest uptake in the olfactory bulbs and hypothalamus, while GALP mixed with betacyclodextrin resulted in enhanced uptake of GALP specifically to the olfactory bulbs compared to a simple intranasal solution. It may be possible that alpha-cyclodextrin modulates the transport of GALP in perivascular spaces, which could explain the increased concentrations observed throughout the brain. Beta-cyclodextrin appears to specifically enhance intranasal delivery to the CNS along olfactory pathways. These results indicate that in addition to improving drug solubility, cyclodextrins added to intranasal formulations can allow for targeting to specific brain regions.
Microemulsion and nanoemulsion formulations can improve drug solubility and opportunities for direct transport into the CNS. These oil-in-water dispersions demonstrate increased brain uptake for small molecule therapeutics such as clonazepam, sumatriptan, risperidone, zolmitriptan, and nimodipine. However, for clonazepam, sumatriptan succinate, and risperidone, the increased brain uptake was accompanied by increased uptake into the blood, resulting in drug targeting efficiencies that were comparable to simple intranasal solutions.
Increased systemic exposure can lead to adverse side effects, which could be problematic for certain therapeutics. Studies with nimodipine showed the greatest increase in targeting in the olfactory bulbs (4.5-fold), suggesting that delivery along olfactory pathways was enhanced with this microemulsion formulation approach. An emulsion-like formulation was recently patented for use with water-insoluble peptides and proteins, and preliminary data presented at the 2007 Society for Neuroscience meeting demonstrate that a lipid emulsion of growth differentiation factor 5 (GDF5) increased delivery to all regions of the CNS and to the trigeminal nerve, compared to an intranasal formulation of GDF5 in acidic buffer.
Polymeric nanoparticles, comprised of a hydrophobic core of polylactic acid (PLA) and a hydrophilic shell of methoxy-poly(ethylene glycol) (MPEG), have been evaluated for improving solubility and intranasal drug targeting to the CNS. Unlike the microemulsion formulation of nimodipine, nimodipine loaded into MPEG-PLA nanoparticles resulted in the greatest targeting increase to the CSF (14-fold) compared to a simple nimodipine solution, indicating that pathways involving the CSF were affected with this nanoparticle formulation.
The regional differences in targeting between the microemulsion and nanoparticle nimodipine formulations could be due to differences in particle size. Dramatic increases in CSF targeting using nanoparticles are not always observed. For example, chitosan nanoparticles loaded with estradiol modestly improved targeting to the CSF by 1.3-fold compared to an intranasal solution. Taken together, these formulation approaches to improve solubility show promise for enhancing intranasal delivery efficiency to the CNS.