Distribution strategies: intranasal cavity

Regardless of the choice of agent, the mechanism of action of all intranasal pharmaceuticals is predicated on successful delivery to the respiratory mucosa. Because of the complex geometry and dynamic air flow patterns of the sinonasal labyrinth, efficient and predictable drug delivery in an unoperated patient is a challenge. Multiple variables including particle size, flow rate volume, pressure, and spray angle have all been shown to have a significant effect on delivery. The major mechanism of drug deposition relies on inertial impaction on the nasal mucosa while gravitational sedimentation and Brownian diffusion play secondary roles. As a result, particulate size and density affect the degree and site of deposition. Particles greater than 10 μm will tend to remain within the nasal vault whereas those smaller than 5 μm remain aerosolized and are absorbed in the lower airways. Using a cast model, Saijo and colleagues demonstrated that efficiency of intranasal particle deposition could be further increased not only by altering the size but also the flow rate of the application. As a result, most commercial nasal delivery sprays use a monodroplet dispersion system with particle sizes of 50 to 70 μm and flow rates between 7 and 20 L/min. Despite these strategies, a significant volume of each dose is deposited in the anterior nasal vault where it is rapidly cleared, severely limiting its systemic or local pharmacologic efficacy ( Fig. 1 ).

Distribution and clearance of 120 mL of fluorescein-dyed saline administered by positive pressure irrigation bottle (S, septum; I, inferior turbinate). Note the predominant accumulation in the squamous portion of the vestibule and almost complete clearance of fluorescein from the inferior turbinate within 10 minutes.

Distribution strategies: paranasal sinus

This significant drug loss confounds efforts to determine optimal dosing regimens for systemic distribution because the percentage of medication actually reaching the respiratory mucosa is variable and difficult to predict. The problem is further compounded when addressing intraluminal sinus disease, because the treatment may never reach the intended site of action even if it does penetrate the nasal cavity. Olson and colleagues looked at the distribution of 40 mL of radiopaque contrast by computed tomography (CT) in 8 unoperated patients using a range of delivery methods, and found that contrast reached the sphenoid in only 1 of 8 patients. While contrast was seen in the frontal recess in 2 patients, there was no penetration seen within the frontal sinus itself. Regardless of the mechanism of delivery, estimates of luminal delivery in an unoperated patient are less than 5% of the total volume administered. In fact, Grobler and colleagues demonstrated that an ostial diameter of at least 3.95 mm is required to achieve any significant luminal penetration. However, following functional endoscopic sinus surgery, high-volume pressurized irrigations have been shown to be superior to other methods in achieving intraluminal delivery. Miller and colleagues compared the degree of deposition of several delivery methods in postsurgical patients with chronic rhinosinusitis using a blinded endoscopic grading system, and found that while the bulb syringe offered the greatest distribution, all methods produced significant deposition in the anterior nasal vault.

Distribution strategies: paranasal sinus

This significant drug loss confounds efforts to determine optimal dosing regimens for systemic distribution because the percentage of medication actually reaching the respiratory mucosa is variable and difficult to predict. The problem is further compounded when addressing intraluminal sinus disease, because the treatment may never reach the intended site of action even if it does penetrate the nasal cavity. Olson and colleagues looked at the distribution of 40 mL of radiopaque contrast by computed tomography (CT) in 8 unoperated patients using a range of delivery methods, and found that contrast reached the sphenoid in only 1 of 8 patients. While contrast was seen in the frontal recess in 2 patients, there was no penetration seen within the frontal sinus itself. Regardless of the mechanism of delivery, estimates of luminal delivery in an unoperated patient are less than 5% of the total volume administered. In fact, Grobler and colleagues demonstrated that an ostial diameter of at least 3.95 mm is required to achieve any significant luminal penetration. However, following functional endoscopic sinus surgery, high-volume pressurized irrigations have been shown to be superior to other methods in achieving intraluminal delivery. Miller and colleagues compared the degree of deposition of several delivery methods in postsurgical patients with chronic rhinosinusitis using a blinded endoscopic grading system, and found that while the bulb syringe offered the greatest distribution, all methods produced significant deposition in the anterior nasal vault.

Radiologic distribution studies

These findings suggest that the full potential of self-administered intranasal drug delivery is yet to be achieved. The advent of nuclear emission imaging has offered new insights into the mechanism of drug distribution and has led to novel delivery devices that seek to overcome the limitations of current techniques. Technetium-99m is the most commonly used radiotracer for planar imaging; however, radionuclides are not commonly found in the drugs themselves and therefore it is not possible to label the drug. Validation of the tracer is important because it must not independently affect the behavior or distribution of the drug. Therefore, these tracers typically provide an accurate representation of the distribution of the drug until absorption into the tissue, binding, and evaporation result in uncoupling of the drug and the tracer. Thus only the initial deposition can be accurately measured, although this may be the most important aspect. Particulate tracers for dry powder formulations also exist and may include polystyrene, albumin microspheres, and technetium-iron oxide. While useful, one critique of planar imaging is that the data are acquired in only 2 dimensions and while there are algorithms that can create 3-dimensional reconstructions, there are important attenuation effects by the intervening soft tissue that must be taken into account.

Positron emission tomography (PET) scanning represents a superior imaging modality, as isotropic substitution may be used to make the drug the tracer. These images may be acquired in 3 dimensions and can be coregistered with CT or magnetic resonance imaging to create precise anatomic correlations. Furthermore, PET imaging uses positron emitting radionuclides which, when annihilated, give off 2 511-keV gamma rays thereby allowing PET to quantify the volume of drug distribution. PET imaging has already been used to aid in the development of delivery techniques to the lower airways and has great potential in intranasal drug administration. Several novel nasal delivery techniques have been designed using knowledge gleaned from these imaging modalities, including controlled air-particle streams and bidirectional vortical airflow devices, although their clinical utility is yet to be fully elucidated.

Mucus barrier and mucociliary clearance

Even if adequate nasal penetration is achieved, various physiologic obstacles remain that may impair the therapeutic efficacy ( Fig. 2 ). The nasal cavity can be divided into the vestibule (0.6–1 cm ² ), respiratory epithelium (150 cm ² ), and olfactory epithelium (20–40 cm ² ). The vestibule is composed of stratified squamous epithelium and while it is resistant to dehydration and noxious substances, its permeability to drugs is very poor. The respiratory epithelium is composed of pseudostratified columnar epithelial cells with cilia, goblet cells, basal cells, and seromucinous ducts. Each ciliated cell contains approximately 100 cilia and all cells contain about 300 microvilli, which serve to further increase the absorptive surface area. The secretory glands operate under autonomic control, and parasympathetic input leads to dilation of the capacitance vessels and increased seromucinous secretion.

Multiple sequential obstacles to topical drug delivery. 1, distribution to mucosal surface to enable inertial impaction; 2, mucus layer demonstrating superficial gel and periciliary sol layer; 3, ciliary beat driving mucociliary transit with subsequent drug clearance; 4, cellular lipid bilayer comprising the principal transcellular transport barrier; 5, intercellular TJ (bound to cytoskeleton) comprising the principal paracellular transport barrier.

Following nasal deposition, the mucus blanket is the first obstacle encountered by a pharmaceutical agent. Daily, 1.5 to 2 L of mucus is secreted by approximately 100,000 submucosal glands in a 5-μm blanket. While most mucus is composed of hydrated mucin, it also contains a host of proteins including albumin, immunoglobulins, lysozymes, and lactoferrin. Mucin is a high molecular weight glycoprotein cross-linked with disulfide bridges and ionic bonds, which contains a large number of reactive free hydroxyl groups. Although this mucus blanket is over 100 times thinner than the equivalent layer in the lower gastrointestinal tract, it still represents a significant size-dependent barrier to diffusion. For smaller molecules, the degree of lipophilicity largely governs the permeability whereas for larger molecules, such as peptides, hydrogen bonding and ionic interactions between the molecule and the mucus glycopeptide chains can limit diffusion. Several strategies to enhance epithelial drug deposition have focused on disruption of the mucus barrier. Dornase alfa, an rhDNase, acts to decrease mucus viscosity through selective hydrolysis of entangled DNA, and is commonly used in the cystic fibrosis population. Despite its mucolytic effects, high-resolution multiple particle tracking in sputum of patients with cystic fibrosis treated with Dornase alfa failed to show a significant enhancement in average particle diffusion rates. Alternatively, N -acetylcysteine (NAC), another mucolytic that functions through hydrogen and disulfide bond disruption, has been shown to improve transmucosal cationic molecular delivery to the epithelial surface.

The mucus barrier effect is further enhanced by the relatively rapid clearance of xenobiotics because of gravity and mucociliary clearance, which has a half-life of approximately 15 to 20 minutes. One strategy that has been investigated to circumvent this effect is the use of bioadhesive pharmaceutical carriers. The use of bioadhesive carriers has been shown to prolong nasal residence for more than a week. Following hydration, bioadhesive polymers swell, leading to interpenetration between the polymer chains and those of the mucus. Factors influencing mucoadhesion include type of functional group, cross-linking density, spatial orientation, and environmental pH. Spatial orientation becomes important when structures such as helices result in the shielding of active sites, leading to a reduction in bioadhesive strength.

In addition to its role as a physical barrier, the mucus layer acts to prolong drug exposure to various degrading enzymes present in the mucus and at the epithelial surface. These drugs may be subjected to hydrolysis, oxidation, isomerization, photochemical decomposition, or polymerization. As a result, chemical and physical stability of the compound play an important role. Cytochrome P450 has a broad ability to oxidize lipophilic xenobiotics in a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent manner, and is present in the nasal mucosa at levels second only to those in the liver. In addition, multiple proteases capable of cleaving the N and C termini such as exopeptidases, mono/diaminopeptidases, and endopeptidases including serine, cysteine, and aspartic proteinases are found within the mucosa. As a result, peptides and protein-based drugs tend to be more fragile than lower molecular weight compounds. These effects can be countered by the coadministration of protease inhibitors and moieties that resist oxidation, such as bestatin and l -aspartase, respectively.