Topical Drug Delivery for Chronic Rhinosinusitis
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Chronic rhinosinusitis is a multifactorial disorder that may be heterogeneous in presentation and clinical course. While the introduction of endoscopic sinus surgery revolutionized surgical management and has led to significantly improved patient outcomes, medical therapy remains the foundation of long-term care of chronic rhinosinusitis, particularly in surgically recalcitrant cases. A variety of devices and pharmaceutical agents have been developed to apply topical medical therapy to the sinuses, and thereby take advantage of the access provided by endoscopic surgery. The goal of topical therapy is to address the inflammation, infection, and mucociliary dysfunction that underlies the disease. Major factors that impact success include the patient’s sinus anatomy and the dynamics of the delivery device. Despite a growing number of topical treatment options, the evidence-based literature to support their use is limited. In this article, we comprehensively review current delivery methods and the available topical agents. We also discuss biotechnological advances that promise enhanced delivery in the future, and evolving pharmacotherapeutical compounds that may be added to the rhinologist’s armamentarium. A complete understanding of topical drug delivery is increasingly essential to the management of chronic rhinosinusitis when traditional forms of medical therapy and surgery have failed.
KeywordsTopical Drug delivery Chronic rhinosinusitis Saline Antimicrobials Corticosteroids
Since its introduction over three decades ago , endoscopic sinus surgery (ESS) has become the standard of care for the treatment of medically recalcitrant chronic rhinosinusitis (CRS). The primary goal of functional endoscopic sinus surgery is to improve patient symptoms by restoring ostial patency and mucociliary function. As experience with endoscopic sinus surgery has grown, it has become apparent that these aims are achieved most successfully when inflammatory sinus disease stems principally from anatomic obstruction. In some forms of CRS, however, there appears to be an intrinsic mucosal inflammatory component that is not directly amenable to surgical correction. In these cases, the goals of the endoscopic procedure shift from reversing the disease process to providing access for long-term sinonasal endoscopic surveillance and the application of topical therapies. Locally-delivered pharmacotherapy has increasingly been viewed as a new frontier in CRS management, and the armamentarium of topical options has greatly expanded over the past decade. To understand the current and future status of topical therapies for CRS, knowledge of the methods of delivery as well as of the available drugs and compounds is needed. The scientific evidence supporting topical therapy for CRS remains most robust for long-utilized agents such as saline and intranasal corticosteroid sprays. While newer topical preparations such as antimicrobials, surfactant agents, and organic natural products are continuing to advance the ability of physicians to manage inflammatory sinus disease, the choice of specific agents and the optimal mechanisms of delivery remain subjects of active investigation and debate.
Three mechanisms have been proposed to centrally contribute to CRS pathophysiology: mucosal inflammation, local infection, and mucociliary dysfunction [2, 3]. Topical medical therapy has been designed to target each of these, and its success relies upon both mechanical irrigation and pharmaceutical delivery [4, 5]. Irrigation helps to remove pollutants, antigens, inflammatory byproducts, mucus, and bacteria from the sinonasal tract. Factors that optimize the mechanical action of topical therapy often do so at the expense of optimal drug delivery, for which prolonged mucosal contact time and minimal depletion are desirable . These competing goals present challenges in developing medications and delivery systems for the treatment of CRS.
Methods of Delivery
Sinonasal drug delivery fluid dynamics is a rapidly growing area of intense research investigation. This high level of interest is directly tied to a number of commercial products, each with variable published experimental support. Studies on delivery methods have focused on the state of the paranasal sinuses (non-operated vs. post-surgical) and the device dynamics (device, techniques, volume, position).
Sinus Surgery is a Prerequisite for Effective Sinus Topical Drug Delivery
It is well established that the delivery of topical solution to the non-operated sinuses is very limited [6•]. Pressurized nasal spray provide only nasal cavity penetration at best, and squeeze bottle and Neti pot irrigation only provide some maxillary sinus and ethmoid sinus penetration [6•]. The frontal and sphenoid sinuses are essentially not accessible prior to surgery [6•]. Olson evaluated three methods of nasal irrigation in healthy non-operated individuals, and found distribution in the nasal cavity but poor distribution in the sinuses with all techniques . With CRS, mucosal inflammation and edema further limit the penetration of nasal irrigation or sprays . Grobler et al. showed that an ostial size of greater than 3.95 mm is required to see penetration into the maxillary sinus .
Endoscopic sinus surgery allows for more effective delivery of topical drugs, although the degree to which access is increased depends on the extent and technique of surgery. With the advent of balloon dilation technology, an even wider variability in the size of “post-surgical” sinus openings exists. This heterogeneity creates a confounding variable in determining the effectiveness of topical drug delivery in post-surgical sinus cavities. In Harvey’s cadaveric study, delivery to the sinuses improved after sinus surgery regardless of the delivery device [6•]. Studies have shown that irrigation with douching or bulb irrigation is more effective than sprays, nebulizers, or atomizers in reaching post-operative sinus cavities [10, 11].
Devices to Deliver Saline
Drug Delivery Devices
Nasal pump sprays are a popular option for topical drug delivery because of their ease of use, and many different formulations are available in this format. The main factors associated with particle penetration include the size of the sinus ostia, the size of the particle, and the flow rate of the aerosol [14, 15]. Particles >10 μm in size usually do not pass the nasal cavity, and particles <5 μm in size are needed to enter into the lungs. Hyo et al. theorized that ideal particle size for maxillary sinus penetration is between 3 and 10 μm, and further work by Saijo et al. demonstrated that smaller particle size (5.63 vs. 16.37 μm), 45° insertion angle (vs. 30° insertional angle), and higher flow rate improved maxillary sinus penetration [14, 16].
Typical nasal pump sprays generate droplets of 50–100 μm in diameter size, and deliver 70–150 μl of drug per puff, at standard velocities of 7.5–20 L/min . A large fraction of the spray is deposited in the anterior nasal cavity without any significant penetration into the paranasal sinuses [17, 18]. Furthermore, half of the aerosol is cleared after approximately 15 min, with minimal activity remaining after 6 h [17, 18]. A breath-actuated bidirectional delivery device (OptiMist™; OptiNose, Oslo, Norway) has been developed to address the limitations of the nasal pump spray. This device, which generates drops of 43 μm diameter, demonstrates larger cumulative deposition in the region of the middle meatus and less anterior segment deposition compared to a conventional nasal pump spray .
Passive-diffusion nebulizers (SinuNeb)
Smaller particles (3 μm)
Vortex-propelled nebulizers (ViaNase)
Larger particles (9–11 μm)
Pulsating aerosol delivery device (PARI Sinus)
Smaller particles (3 μm)
Aerosol stream superimposed by a pulsation
Very slow velocity (3–6 L/min)
Patient Positioning for Drug Delivery
There is no consensus on the most effective position for delivering topical drugs into the nose and paranasal sinuses. Many commercial products recommend a head-down, over-the-sink, or nose-to-ground position for nasal irrigation. This makes the residual runoff easy to collect and is practical for patients. The delivery of nasal drops relative to head position has been studied [13, 22]. One study found that the “Mygind” and “Ragan” (left lateral and supine) positions were more effective than the “Mecca” and “Head-back” positions for delivery into the middle meatus . However, this has not been supported in other studies [13, 23, 24, 25, 26]. Head-down or “vertex-to-floor” position has been suggested to lead to better frontal distribution post-ESS . Positioning is more relevant for low-pressure delivery systems. For example, when using the neti pot, the Mygind head position allows for gravity-dependent drainage into the contralateral nasal wall and sinuses. Positioning with high-pressure delivery systems may have less clinical importance .
Drugs and Compounds
Saline irrigations and sprays are the most commonly used intervention for rhinitis and rhinosinusitis. Nasal saline has its roots in homeopathic medicine. Nasal washing is an ancient Ayurvedic technique known as “Jala neti”, which means nasal cleansing in Sanskrit. Today, it is often used as an adjunctive treatment for chronic rhinosinusitis. Its use has been advocated both before and following sinus surgery, and in the latter case to thoroughly cleanse the sinonasal passages and promote mucosal healing. Much of the support for this intervention has been anecdotal; however, recent literature has provided evidence to support the use of nasal saline for symptom improvement [28••].
The physiological basis for the benefit of saline is unclear. The mechanical clearance of mucus by saline is thought to be the most important factor. Both isotonic and hypertonic saline appear to have a positive effect on mucociliary transport time [29, 30]. This is thought to be due to improved rheologic properties of the sol layer rather than improved ciliary beat frequency [31, 32], although the data regarding ciliary beat frequency have been conflicting [32, 33]. Other theories on the beneficial effects of saline include its nasal mucosal protective effect and its ability to remove antigens, inflammatory mediators, and biofilm.
A Cochrane review reported that saline improves symptoms and disease specific quality of life scores when compared to no treatment, either as a single modality or as an adjunctive treatment [28••]. Although there is evidence that hypertonic solutions improve mucociliary clearance [30, 34], no difference was found in symptoms scores when comparing isotonic (0.9 %) to hypertonic saline [28••]. Hypertonic preparations have been shown to elicit some pain and discomfort at concentrations above 2.7 % . At concentrations approaching 5.4 %, patients experience significant nasal obstruction due to vasodilation, and there is reduced airspace as determined by acoustic rhinometry .
The common delivery methods of topical saline include squeeze bottle, atomized spray, and Neti pot. There have been few studies comparing the efficiency of saline on symptom scores by means of delivery mechanism. Pynnonen et al. showed greater efficacy of saline irrigation versus saline spray for providing short-term relief of chronic nasal symptoms . This study focused on a community population of patients with sinonasal complaints and excluded patients with recent sinus surgery. The efficacy of saline in non-operated versus post-surgical must be inferred from the aforementioned anatomic studies [28••].
Saline is the cornerstone of treatment in the rhinologist’s armamentarium of topical therapy for CRS, in part because it is very low risk with minimal adverse effects. The Cochrane study showed no serious adverse event in over 1,650 patients in published trials [28••]. Most patients tolerate nasal saline irrigation well, and even recommend this to family and friends with sinus problems . A small subset of patients will not tolerate nasal saline irrigation due to discomfort or inconvenience. The most common minor complaints include nasal burning, irritation, and nausea [28••]. Delivery systems have developed around topical saline to improve distribution and patient compliance. Since there are currently no approved drugs for the treatment of CRS, saline delivery systems are often employed to deliver common drugs for off-label use as topical agents.
Corticosteroids are potent medications that broadly target pro-inflammatory pathways. While CRS is a heterogeneous disorder with a multifactorial etiology, mucosal inflammation is a cardinal feature of the disease that contributes to the symptoms and histopathology. Both systemic and topical corticosteroids are used to treat chronic rhinosinusitis with and without nasal polyposis (CRSwNP and CRSsNP, respectively). Topical corticosteroids are favored over systemic corticosteroids because of the decreased potential for significant side effects, especially with prolonged use.
Topical nasal steroids are effective for the treatment of CRSwNP, and are often considered a first-line treatment option [38, 39•]. Currently, only one intranasal steroid, mometasone furoate, is Food and Drug Administration (FDA)-approved for the treatment of nasal polyps in CRS. However, various non-approved topical steroids are commonly used in practice today. There is strong evidence for the treatment of CRSwNP with intranasal steroids in terms of reducing polyp size on endoscopic examination [39•]. Topical mometasone, fluticasone, and budesonside have the best evidence for use, especially in the post-ESS state [39•]. On the other hand, the evidence for intranasal steroids for CRSsNP is not well established. A Cochrane review on CRSsNP found that intranasal steroids improved symptoms overall, but the pooled studies were diverse in outcome measures, delivery methods, and surgical status . Similarly, a meta-analysis found insufficient evidence that intranasal steroids demonstrated a clear benefit in CRSsNP [41•].
An emerging trend for the treatment of refractory CRSwNP is the use of “off label” otic, ophthalmic, or respiratory formulations of corticosteroids as topical agents delivered to the nose [42, 43, 44]. Budesonide irrigations have gained significant recent interest in the U.S. They are often prescribed as 0.5 mg in 2-mL respules diluted in a 240-mL squeeze bottle irrigation to be used twice daily. Initial studies have shown no evidence of adrenal suppression [44, 45, 46]. In the United Kingdom and other areas of Europe, solutions of either betamethasone or fluticasone propionate are commercially available as nasal drops and used to treat CRSwNP .
Nasal pump sprays, the most common delivery method of intranasal corticosteroids, have almost no sinus penetration in non-operated patients [6•, 21]. Snidvongs et al. found no difference in terms of symptom scores or response to treatment between non-operated and post-operative patients . Other methods for delivery of corticosteroids into the sinonasal cavity include aerosol, irrigation, and nasal drops. Some studies have reported delivery via direct cannulation via an intranasal tube  or intrasinus tube [49, 50]. The Cochrane review showed no difference in outcomes based on delivery method . Topical corticosteroids can cause minor side effects of headaches, epistaxis, dryness, or burning, but significant adverse events are extremely rare .
Oral antibiotics are effective in the treatment of chronic sinusitis and its acute exacerbations [52, 53, 54]. Topical antibiotics have thus emerged as adjunctive treatment for CRS because they offer the potential for high local concentration at the desired target site with minimization of systemic side effects. The literature supports both nebulized- and irrigation-type preparations of topical antibiotics. A systematic review found some evidence for irrigated or nebulized antimicrobials, but no evidence for delivery by nasal sprays [55••]. Irrigation with topical antibiotics has been shown to be effective in CRS [55••, 56], and nebulized antibiotics result in longer infection-free periods compared to standard oral and intravenous antibiotics .
Topical tobramycin is a common topical antibiotics used to treat CRS. Aerosolized forms of this antibiotic were initially used in the treatment of pseudomonal pulmonary infections in cystic fibrosis (CF) patients. Studies of tobramycin nasal irrigations in CF patients suggest reduction in the likelihood of repeat sinus surgery  and improvement in outcome scores . Mupirocin is a topical antibiotic that is effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). It displays very high levels of activity against Staphylococcus aureus even in nasal secretions , and possibly has antibiofilm activity in vitro . Muporicin is most often employed in patients with Staphylococcus aureus-related CRS who have failed medical or surgical therapy [61, 62]. A growing concern is the development of mupirocin resistance, and mupirocin-resistant strains of MRSA may make the topical use of mupirocin obsolete in the future.
A subset of patients with CRS have evidence of fungus in the sinonasal tract, although a consistent role of fungus in disease pathophysiology is not well established. In allergic fungal sinusitis, fungal elements are believed to underlie an IgE-mediated hypersensitivity that drives the eosinophilic inflammatory process. Antifungals have been suggested as systemic or topical preparations when fungus-related sinus inflammation is suspected. Since systemic antifungals have significant side effects that involve the liver and kidney, topical antifungals are more often advocated as a form of treatment for CRS . There is conflicting literature on the efficacy of topical antifungals. Ponikau et al. showed a benefit of intranasal amphotericin B in a double-blinded randomized control trial . Others have not been able to replicate these findings, and found no benefit of topical antifungals [65, 66, 67, 68]. A Cochrane study also found no evidence to support the use of antifungals in CRS [69••]; however, there was significant heterogeneity of the surgical state, delivery technique, and medication concentration in the included studies. Amphotericin B dosage in the literature has ranged from 100 to 300 µg/ml [69••]. The FDA-approved concentration is 100 µg/ml, but Shirazi et al. showed that concentrations of at least 200 µg/ml are needed for fungicidal activity in vitro .
Surfactants are compounds that lower the surface tension of liquids and are thought to improve mucocilliary clearance by reducing the adherence of mucus to the epithelial layer. Surfactants can also interfere with microbial cell membrane permeability and disrupt cell membranes. Of recent interest, surfactants have been suggested to have a preventive role against bacterial biofilm formation [71, 72]. There are many commercially available surfactant products on the market. Treatment with Johnson & Johnson baby shampoo (a combination of PEG-80 sorbital laurate, cocamidopropyl betaine, and sodium trideceth sulphate) at 1 % concentration has demonstrated improved patient symptom scores in the treatment refractory CRS . Citric acid/zwitterionic surfactant (CAZS) has been investigated in animal studies and has been shown to be effective at reducing biofilms . A recent cadaver study showed that, when combined with surfactant, saline irrigations improved penetration into non-operated sinus ostia .
There is limited literature investigating the safety of topical surfactants. Chiu et al. demonstrated that topical surfactant did not cause any significant damage to the cilia or epithelial cells after a short exposure in murine nasal explants . However, a rabbit study using CAZS demonstrated a temporarily denudement of the respiratory cilia . Clinically, patients have complained of minor side effects of nasal and skin irritation, but there have been no serious adverse side effects reported in the literature . There have been anecdotal reports of olfactory dysfunction associated with prolonged use of one commercial surfactant product, leading to temporary withdrawal from the market and subsequent patient warnings. Further investigations are needed to examine the consequences of supra-physiologic exposure to surfactant.
Natural and Homeopathic Agents: Manuka Honey and Phytopharmaceuticals
Manuka honeys derived from the floral source in tea trees (Leptospermum spp) in New Zealand have recently been described as a natural, inexpensive, and non-toxic topical therapy for CRS . The benefit of Manuka honey is suggested to be from the antimicrobial activity against a broad spectrum of Gram-positive and Gram-negative bacteria in their planktonic states [78, 79] and potentially against biofims . Methylglyoxal (MGO), a derivative from the manuka flower, is thought to be the main antimicrobial agent, with honey potentiating its effects through an unknown mechanism . In vivo studies are needed to determine clinical efficacy. Phytopharmaceuticals are compound medications composed of numerous herbal products. Studies from Europe have reported the use of phytopharmaceuticals to treat sinusitis [82, 83]. No clear evidence exists for these alternative therapies, and thus counseling homeopathically-biased patients is important.
New and Future Directions
Further refinement of intranasal drug delivery will demand increasingly sophisticated delivery devices and techniques. Currently, topical drug delivery methods are optimized in cadaveric models or by employing dyes and radioisotopes to study drug penetration in live human subjects. Advances in computer modeling capability now allow detailed experiments of sinonasal drug penetration to be performed in silico . However, at this time, such computer-aided models cannot accurately reflect physiologic factors inherent in CRS. In the laboratory, human sinonasal epithelial cell cultures have been advanced as a model system to study cellular and molecular mechanisms affecting topical drug delivery . There is still great potential in the U.S. market for intranasal drug delivery, given the shortcomings of current products and the challenges with drug delivery devices. Together, the integration of anatomic and physiologic models along with the growing market demand will pave the way for future research and provide the best information on topical drug delivery to the sinonasal cavities.
Ideal characteristics for delivery devices include accurate and repeatable dosing, consistent delivery to targeted site, patient-independent actuation, and effective compliance monitoring . Ideal characteristics for the medication include prolonged mucosal contact time, high local absorption, and minimal depletion . Newer drug delivery strategies, such as drug-eluting stents, are addressing the shortcomings of existing nasal aerosol delivery techniques. The promise of liposomal and nanoparticle technology may yield devices for human trial for the treatment of CRS in the near future.
Stents allow for the slow release of topical drugs at targeted sites, and have been reported for use in the paranasal sinuses since the early 2000s. In animal models, drug-eluting stents have shown decreased granulation tissue without any epithelial damage, decreased post-operative osteoneogenesis and stromal proliferation, and negligible systemic absorption [87, 88]. Most drug-eluting stents have focused on corticosteroids, but antimicrobial-eluting stents have also been described [89, 90]. The Relieva Stratus Spacer (Acclarent, Menlo Park, CA, USA), introduced in 2009, is a non-bioabsorbable stent designed for the ethmoid cavity. The device is approved for saline; however, in an attempt to deliver corticosteroids, physicians have placed triamcinolone into the device reservoir. Investigations have revealed that the device eludes 0.3 ml of triamcinolone acetate 40 mg/ml over 2–4 weeks . Approved by the FDA in 2011, the Propel sinus implant (Intersect ENT, Palo Alto, CA, USA) is a newer bioabsorbable implant that self-expands in the sinus cavity and releases 370 μg of mometasone furoate over 4 weeks . Prospective double-blinded trials on a bioabsorbable drug-eluting stent used after ESS in patients with CRS have shown significantly reduced inflammation and prevention of significant adhesion compared to a control stent . One critique of the current stents on the market is that the total dosage of corticosteroid is low, and may not be sufficient to combat the degree of inflammation, especially in cases of recalcitrant CRS. Designing stents with larger dosage of steroid or longer duration of drug elution may improve the efficacy of these devices. Drug-eluting stents are a promising new technology in the treatment armamentarium for CRS.
Nanoparticles, Microspheres and Liposomes
Nanoparticles are solid colloidal drug carriers ranging from 10 to 1,000 nm in diameter and composed of synthetic, natural, or semi-synthetic polymers encapsulating the drug molecule; microspheres are larger versions of these drug-encapsulating polymers that range from 1 to 1,000 μm in diameter, with most under 200 μm . The major nanoparticle material that has been studied for nasal drug delivery is chitosan. Chitosan is a biocompatible cationic polysaccharide consisting of N-acetylclucosamine and d-glucosamine units that is produced by the deacetylation of chitin, the main component of crustacean exoskeleton [94, 95]. As a drug carrier, chitosan nanoparticles inhibit enzymatic metabolism and thus allow for slow and sustained drug release . Nanoparticles conjugated with vaccines have been developed for nasal vaccination, and the nasal delivery of insulin, heparin, and other proteins via chitosan nanoparticles has been described [93, 94, 96]. Liposomes are phospholipid vesicles composed by lipid bilayers enclosing aqueous compartments that have the advantage of encapsulating molecules of various sizes and solubility profiles to increased membrane penetration . Intranasal applications of liposomes have also been reported [97, 98, 99]. Although their application for the treatment of CRS has yet to be studied, nanoparticle- and liposome-based delivery devices may represent a future trend for the delivery of anti-inflammatory and antimicrobial agents to the paranasal sinuses.
Summary of evidence for topical delivery
Harvey et al. 2007 [28••]
Cochrane review; Included 8 RCTs
Saline irrigation is well tolerated; no significant adverse effects; beneficial effect for treatment of CRS
Joe et al. 2008 [39•]
CRSwNP: systematic review and meta-analysis; included 13 studies; 6 of these used for meta-analysis
Topical steroids decreased polyp size in CRSwNP
Snidvongs et al. 2011 
CRSsNP: Cochrane review; included 10 RCTs
Topical steroids are beneficial for CRSsNP in symptom control; adverse effects are minor
Lim et al. 2008 [55••]
Systematic review; included 10 studies (2 RCTs, 2 controlled studies, 5 cohorts, 1 expert report)
Not first-line therapy; stronger evidence (level IIb) for cystic fibrosis patient; can use in refractory cases
Lim et al. 2008 [55••]
Systematic review: included 4 studies (3 RCTs, 1 cohort)
No evidence for antifungals in CRS
Sacks et al. 2011 [69••]
Cochrane review: included 6 RCTs
No evidence for antifungal in CRS
No potential conflicts of interest relevant to this article were reported.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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