Formulation and device design to increase nose to brain drug delivery
Graphical abstract
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.
Section snippets
Nasal formulations to enhance brain drug delivery
As with other routes of drug delivery, formulation design has been shown to help in overcoming many of the barriers for direct nose-to-brain drug delivery. Table 1 provides a list of examples that have so far been reported in the literature on formulations, and their effects on nose-to-brain delivery. As can be seen in Table 1, formulations that have so far been utilized to enhance nose-to-brain delivery include: solutions, microemulsion, mucoadhesive formulations, polymeric nanoparticles,
Delivery devices for enhanced nose to brain drug delivery
Successful targeting of nose-to-brain drug delivery requires formulation to be administered in such a way that the amount deposited on the olfactory epithelium is maximized. As can be seen in Table 1, there have been several studies focused on formulations to increase transport of medications into the brain, however, the number of studies focused on the delivery devices to target these medications for nose to brain delivery is more scarce. The deposition from various nasal devices is typically
Conclusion
Many studies have attempted different formulation techniques to improve brain delivery by direct nose-to-brain mechanisms. By utilizing mucoadhesive excipients in nasal formulations, it is possible to increase the amount of medications delivered to the brain. While mucoadhesives are effective at increasing brain concentrations, experiments combining their use with other formulation techniques have produced even greater brain uptake. Using formulation characteristics to increase the
Author contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
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