Formulation and device design to increase nose to brain drug delivery

Abstract

A major limiting factor for the treatment of central nervous system (CNS) related disorders is the inability for drug substances to cross the blood-brain barrier. Some medications may possess dose-limiting systemic side effects that hinder their ability to reach maximum effective concentrations in the CNS.

Over the last several decades, scientists have studied the ability for drugs to be transported from the nose directly to the brain, and compared to intravenous injections, many studies have reported higher brain concentrations from formulations administered intranasally. The primary focus of this paper is to review the formulation and device approaches that have been reported to increase drug delivery into the CNS through the nose-to-brain delivery pathway.

Introduction

There are several barriers that a drug must overcome to treat a CNS related disorder and provide a pharmacological response. These include the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier [1]. The BBB is comprised of tight junctions, an enzymatic barrier, and transport proteins that selectively prevent substances from entering the brain interstitial fluid from the blood [2]. Over the last several decades, it has been discovered that materials can be transported directly to the brain interstitial fluid and cerebrospinal fluid when administered intranasally [3], [4]. By using intranasal administration, it is possible to circumvent the barriers of the BBB by taking advantage of the only place the CNS is in direct contact with the environment, the olfactory epithelium [4]. In bypassing the BBB, drugs that normally cannot enter the CNS may be found to be therapeutically beneficial when administered intranasally. In addition, drugs that pass the BBB but require large doses to provide therapeutically relevant brain levels, may be effective at significantly lower doses, with a subsequent decrease in adverse effects [5]. In the past, invasive methods such as intraparenchymal, intrathecal, and intracerebroventricular injections have been used to achieve clinically relevant brain concentrations for therapeutic efficacy. More recently, semi-invasive methods that transiently permeabilize the BBB have been reported [6], [7]. However, using targeted administration to the olfactory epithelium, it may be possible to achieve the same effects in a patient-friendly manner that is conducive for chronic therapy [1]. In animal models, it has been shown that small molecules [8], peptides [4] and even viruses [9] can reach the brain using direct nose-to-brain pathways. Direct nose-to-brain delivery refers to intranasal administration of a drug substance to the nasal cavity followed by absorption and transport of the drug directly into the brain, bypassing the BBB. Limitations of nose-to-brain delivery have also been identified, and include a relatively small volume for administration of the drug, limited surface area of the olfactory epithelium and short retention time for drug absorption [10].

Despite these potential limitations, the nasal route of administration for brain delivery has shown promise for therapeutic efficacy based on animal models and clinical trials in humans [11], [12] For an in-depth review of the mechanisms and pathways by which drugs are transported to the brain from the nose, readers are pointed to previous works by Dhuria et al. [13], Pardeshi et al. [8], Lockhead et al. [14] and Baker et al. [15] The present review is focused specifically on how formulation and device design differences enhance drug uptake into the brain.