Intranasal Treatments: Allergies and potentially viral infections

Intranasal drug administration has a long tradition and was and is still used for medical as well as recreational purposes. The most common use is for treatment of local symptoms e.g. nasal congestion in the course of a common rhinitis or inflammation linked to allergic rhinitis. Noted that the medications intended for local activity are well established and can be found across the globe in every pharmacy and drug store. Examples for topical treatment of rhinitis are decongestants (oxymetazoline, xylometazoline, naphazoline), anti-histamines (azelastine, levocabastine, olopatadine) and glucocorticoids (e.g. mometasone, budesonide, fluticasone). For this particular indication, drugs should act fast and only locally while systemic absorption should be as low as possible; this to avoid systemic side effects which are linked with typical oral formulations of comparable drug substances. Dr. Bielory has also recently reported the potential impact of intranasal treatment of allergies has also been shown to have an effect on allergies affecting the eye.

Vaccines may also benefit from the intranasal route. Existing vaccines commonly utilize the intramuscular and oral administration route. While the respiratory and gastrointestinal tract is very immune competent and fights with microbes permanently, the muscle is not the first choice. Intramuscular vaccination primarily induces systemic immune response, mainly via formation of vaccine-strain specific circulating antibodies. Injections of vaccines were done since the early days and they are indeed effective. So for most people today vaccination is equal to getting an intramuscular injection which is linked to pain. For the health care professional it is linked to fears of needle stick injuries, risk of disease transmission and dangerous medical waste.

Intranasal drug delivery for antiviral agents has been studied for many years. Tamiflu®, an antiviral medication that blocks the actions of influenza virus types A and B by inhibiting the binding (landing) of the virus on nasal mucosal cells that can thus treat flu symptoms caused by influenza virus in people that have had symptoms for less than 2 days, but may also be given to prevent influenza in people who may be exposed but do not yet have symptoms. However, this agent does not treat the common cold or coronavirus virus infections and should not replace getting the annual flu vaccination. Of interest, several agents are in development that may have broad-spectrum antiviral activity. As reported recently at Columbia University that scientists have developed a treatment that blocks the virus in the nose and lungs in an animal model involving ferrets, but they still require human safety and efficacy trials prior to implementation. Intranasal drug delivery has potential relevance for future clinical trials in the settings of disease spread prevention and treatment of SARS-CoV-2 and other viral diseases. (Higgins, Wu et al. 2020) ( Reference: Higgins, T. S., et al. (2020). "Intranasal Antiviral Drug Delivery and Coronavirus Disease 2019 (COVID-19): A State of the Art Review." Otolaryngol Head Neck Surg 163(4): 682-694.)

Nasal medication delivery also takes a middle path between slow onset oral medications commonly used in the outpatient setting and invasive and intravenous delivery a predominant role in hospitalized patients. Because the nasal mucosa is highly vascularized, delivery of a thin layer of a therapeutic agent across a broad surface area can result in rapid transmucosal absorption of the medication into the blood stream and cerebral spinal fluid. This results in therapeutic drug levels and effective treatment of seizures, migraine, pain, anxiety, hypoglycemia, opiate overdose, epistaxis (bloody noses), etc without the need to give a shot or a pill.

The therapeutic advantage of intranasal route has been proposed as a non-invasive alternative route for directly targeting the central vervous system in the treatment of seizures, migraines and even cancer. This route bypasses the “blood-brain-barrier” and reduces the systemic side effects. The intranasal route has also been advanced for drug overdose (e.g. heroin and narcotic overdose), insulin induced hypoglycemia, procedural sedation, and acute and chronic pain disorders. Because intra-nasal medication delivery is effective using generic medications, it is quite inexpensive, an advantage in this era of increasingly expensive medical technology.

DRBRX Sinusol® Breathe Easy, Sinusol® Winter Fresh and Sinusol® Antiviral contain a unique holistic formulation of essential oils and is medication-free which provides wonderful relief from nasal sinus symptoms of nasal congestion, runny nose, ,postnasal drip, sneezing, cough, sinus pressure and headaches




Dr. Bielory, as an international member of the World Allergy Organization committee focusing on current and future directions (Dr. Bielory Reference - Naclerio, R., Ansotegui, I. J., Bousquet, J., Canonica, G. W., D'Amato, G., Rosario, N., . . . Rouadi, P. (2020). International expert consensus on the management of allergic rhinitis (AR) aggravated by air pollutants: Impact of air pollution on patients with AR: Current knowledge and future strategies. World Allergy Organ J, 13(3), 100106. doi:10.1016/j.waojou.2020.100106)
, (Dr. Bielory reference Naclerio, R., Ansotegui, I. J., Bousquet, J., Canonica, G. W., D'Amato, G., Rosario, N., . . . Rouadi, P. (2020). International expert consensus on the management of allergic rhinitis (AR) aggravated by air pollutants: Impact of air pollution on patients with AR: Current knowledge and future strategies. World Allergy Organ J, 13(3), 100106. doi:10.1016/j.waojou.2020.100106)






Nasal medication delivery also takes a middle path between slow onset oral medications commonly used in the outpatient setting and invasive and intravenous delivery a predominant role in hospitalized patients. Because the nasal mucosa is highly vascularized, delivery of a thin layer of a therapeutic agent across a broad surface area can result in rapid transmucosal absorption of the medication into the blood stream and cerebral spinal fluid. This results in therapeutic drug levels and effective treatment of seizures, migraine, pain, anxiety, hypoglycemia, opiate overdose, epistaxis (bloody noses), etc without the need to give a shot or a pill.

The therapeutic advantage of intranasal route has been proposed as a non-invasive alternative route for directly targeting the central vervous system in the treatment of seizures, migraines and even cancer. This route bypasses the “blodd-brain-barrier” and reduces the systemic side effects. The intranasal route has also been advanced for drug overdose (e.g. heroin and narcotic overdose), insulin induced hypoglycemia, procedural sedation, and acute and chronic pain disorders. Because intra-nasal medication delivery is effective using generic medications, it is quite inexpensive, an advantage in this era of increasingly expensive medical technology.
Disclaimer: Most IN medications are off label and do not have FDA or other countries regulatory agency approved indications for intranasal delivery.  Clinicians should use them based on patient needs and peer reviewed literature support realizing that many medical therapies and medication uses are used "off-label."

(Bruinsmann, Richter Vaz et al. 2019, Casale, Moffa et al. 2019, Guennoun, Frechou et al. 2019, Lindson, Chepkin et al. 2019, Lobaina Mato 2019, Triarico, Capozza et al. 2019, Wang, Zuo et al. 2019, Zaric, Obradovic et al. 2019)


Bruinsmann, F. A., et al. (2019). "Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials." Molecules 24(23).
Glioblastoma (GBM) is the most lethal form of brain tumor, being characterized by the rapid growth and invasion of the surrounding tissue. The current standard treatment for glioblastoma is surgery, followed by radiotherapy and concurrent chemotherapy, typically with temozolomide. Although extensive research has been carried out over the past years to develop a more effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in terms of the overall survival of patients. Consequently, new therapeutic approaches are urgently needed. Overcoming the blood-brain barrier (BBB) is a major challenge in the development of therapies for central nervous system (CNS) disorders. In this context, the intranasal route of drug administration has been proposed as a non-invasive alternative route for directly targeting the CNS. This route of drug administration bypasses the BBB and reduces the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review is to provide an overview of the strategies that have been developed for delivering anticancer compounds for the treatment of GBM while using nasal administration. In particular, the specific properties of nanomedicines proposed for nose-to-brain delivery will be critically evaluated. The preclinical and clinical data considered supporting the idea that nasal delivery of anticancer drugs may represent a breakthrough advancement in the fight against GBM.

Casale, M., et al. (2019). "Topical Ectoine: A Promising Molecule in the Upper Airways Inflammation-A Systematic Review." Biomed Res Int 2019: 7150942.
To date, topical therapies guarantee a better delivery of high concentrations of pharmacologic agents to the mucosa of the upper airways (UA). Recently, topical administration of ectoine has just been recognized as adjuvant treatment in the Allergic Rhinitis (AR) and Rhinosinusitis (ARS). The aim of this work is to review the published literature regarding all the potential therapeutic effects of ectoine in the acute and chronic inflammatory diseases of UA. Pertinent studies published without temporal limitation were selected searching on MEDLINE the following terms: "ectoine" and "nasal spray," "oral spray," "upper respiratory tract infections," "rhinosinusitis," "rhinitis," "rhinoconjunctivitis," "pharyngitis," and "laryngitis." At the end of our selection process, six relevant publications were included: two studies about the effect of ectoine on AR, one study about ARS, one study about rhinitis sicca anterior, and two studies about acute pharyngitis and/or laryngitis. Due to its moisturizing and anti-inflammatory properties, topical administration of ectoine could play a potential additional role in treatment of acute and chronic inflammatory diseases of UA, in particular in the management of sinonasal conditions improving symptoms and endoscopic findings. However, these results should be viewed cautiously as they are based on a limited number of studies; some of them were probably underpowered because of their small patient samples.

Guennoun, R., et al. (2019). "Intranasal administration of progesterone: A potential efficient route of delivery for cerebroprotection after acute brain injuries." Neuropharmacology 145(Pt B): 283-291.
Progesterone has been shown to be cerebroprotective in different experimental models of brain injuries and neurodegenerative diseases. The preclinical data provided great hope for its use in humans. The failure of Phase 3 clinical trials to demonstrate the cerebroprotective efficiency of progesterone in traumatic brain injury (TBI) patients emphasizes that different aspects of the design of both experimental and clinical studies should be reviewed and refined. One important aspect to consider is to test different routes of delivery of therapeutic agents. Several studies have shown that the intranasal delivery of drugs could be used in different experimental models of central nervous system diseases. In this review, we will summarize the pharmacokinetic characteristics and practical advantages of intranasal delivery of progesterone. A special emphasis will be placed on describing and discussing our recent findings showing that intranasal delivery of progesterone after transient focal cerebral ischemia: 1) improved motor functions; 2) reduced infarct volume, neuronal loss, blood brain barrier disruption; and 3) reduced brain mitochondrial dysfunctions. Our data suggest that intranasal delivery of progesterone is a potential efficient, safe and non-stressful mode of administration that warrants evaluation for cerebroprotection in patients with brain injuries. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Higgins, T. S., et al. (2020). "Intranasal Antiviral Drug Delivery and Coronavirus Disease 2019 (COVID-19): A State of the Art Review." Otolaryngol Head Neck Surg 163(4): 682-694.
OBJECTIVE: To provide a state of the art review of intranasal antiviral drug delivery and to discuss current applications, adverse reactions, and future considerations in the management of coronavirus disease 2019 (COVID-19). DATA SOURCES: PubMed, Embase, and Clinicaltrials.gov search engines. REVIEW METHODS: A structured search of the current literature was performed of dates up to and including April 2020. Search terms were queried as related to topics of antiviral agents and intranasal applications. A series of video conferences was convened among experts in otolaryngology, infectious diseases, public health, pharmacology, and virology to review the literature and discuss relevant findings. CONCLUSIONS: Intranasal drug delivery for antiviral agents has been studied for many years. Several agents have broad-spectrum antiviral activity, but they still require human safety and efficacy trials prior to implementation. Intranasal drug delivery has potential relevance for future clinical trials in the settings of disease spread prevention and treatment of SARS-CoV-2 and other viral diseases. IMPLICATIONS FOR PRACTICE: Intranasal drug delivery represents an important area of research for COVID-19 and other viral diseases. The consideration of any potential adverse reactions is paramount.

Lindson, N., et al. (2019). "Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation." Cochrane Database Syst Rev 4: CD013308.
BACKGROUND: Nicotine replacement therapy (NRT) aims to replace nicotine from cigarettes to ease the transition from cigarette smoking to abstinence. It works by reducing the intensity of craving and withdrawal symptoms. Although there is clear evidence that NRT used after smoking cessation is effective, it is unclear whether higher doses, longer durations of treatment, or using NRT before cessation add to its effectiveness. OBJECTIVES: To determine the effectiveness and safety of different forms, deliveries, doses, durations and schedules of NRT, for achieving long-term smoking cessation, compared to one another. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group trials register, and trial registries for papers mentioning NRT in the title, abstract or keywords. Date of most recent search: April 2018. SELECTION CRITERIA: Randomized trials in people motivated to quit, comparing one type of NRT use with another. We excluded trials that did not assess cessation as an outcome, with follow-up less than six months, and with additional intervention components not matched between arms. Trials comparing NRT to control, and trials comparing NRT to other pharmacotherapies, are covered elsewhere. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. Smoking abstinence was measured after at least six months, using the most rigorous definition available. We extracted data on cardiac adverse events (AEs), serious adverse events (SAEs), and study withdrawals due to treatment. We calculated the risk ratio (RR) and the 95% confidence interval (CI) for each outcome for each study, where possible. We grouped eligible studies according to the type of comparison. We carried out meta-analyses where appropriate, using a Mantel-Haenszel fixed-effect model. MAIN RESULTS: We identified 63 trials with 41,509 participants. Most recruited adults either from the community or from healthcare clinics. People enrolled in the studies typically smoked at least 15 cigarettes a day. We judged 24 of the 63 studies to be at high risk of bias, but restricting the analysis only to those studies at low or unclear risk of bias did not significantly alter results, apart from in the case of the preloading comparison. There is high-certainty evidence that combination NRT (fast-acting form + patch) results in higher long-term quit rates than single form (RR 1.25, 95% CI 1.15 to 1.36, 14 studies, 11,356 participants; I(2) = 4%). Moderate-certainty evidence, limited by imprecision, indicates that 42/44 mg are as effective as 21/22 mg (24-hour) patches (RR 1.09, 95% CI 0.93 to 1.29, 5 studies, 1655 participants; I(2) = 38%), and that 21 mg are more effective than 14 mg (24-hour) patches (RR 1.48, 95% CI 1.06 to 2.08, 1 study, 537 participants). Moderate-certainty evidence (again limited by imprecision) also suggests a benefit of 25 mg over 15 mg (16-hour) patches, but the lower limit of the CI encompassed no difference (RR 1.19, 95% CI 1.00 to 1.41, 3 studies, 3446 participants; I(2) = 0%). Five studies comparing 4 mg gum to 2 mg gum found a benefit of the higher dose (RR 1.43, 95% CI 1.12 to 1.83, 5 studies, 856 participants; I(2) = 63%); however, results of a subgroup analysis suggest that only smokers who are highly dependent may benefit. Nine studies tested the effect of using NRT prior to quit day (preloading) in comparison to using it from quit day onward; there was moderate-certainty evidence, limited by risk of bias, of a favourable effect of preloading on abstinence (RR 1.25, 95% CI 1.08 to 1.44, 9 studies, 4395 participants; I(2) = 0%). High-certainty evidence from eight studies suggests that using either a form of fast-acting NRT or a nicotine patch results in similar long-term quit rates (RR 0.90, 95% CI 0.77 to 1.05, 8 studies, 3319 participants; I(2) = 0%). We found no evidence of an effect of duration of nicotine patch use (low-certainty evidence); 16-hour versus 24-hour daily patch use; duration of combination NRT use (low- and very low-certainty evidence); tapering of patch dose versus abrupt patch cessation; fast-acting NRT type (very low-certainty evidence); duration of nicotine gum use; ad lib versus fixed dosing of fast-acting NRT; free versus purchased NRT; length of provision of free NRT; ceasing versus continuing patch use on lapse; and participant- versus clinician-selected NRT. However, in most cases these findings are based on very low- or low-certainty evidence, and are the findings from single studies.AEs, SAEs and withdrawals due to treatment were all measured variably and infrequently across studies, resulting in low- or very low-certainty evidence for all comparisons. Most comparisons found no evidence of an effect on cardiac AEs, SAEs or withdrawals. Rates of these were low overall. Significantly more withdrawals due to treatment were reported in participants using nasal spray in comparison to patch in one trial (RR 3.47, 95% CI 1.15 to 10.46, 922 participants; very low certainty) and in participants using 42/44 mg patches in comparison to 21/22 mg patches across two trials (RR 4.99, 95% CI 1.60 to 15.50, 2 studies, 544 participants; I(2) = 0%; low certainty). AUTHORS' CONCLUSIONS: There is high-certainty evidence that using combination NRT versus single-form NRT, and 4 mg versus 2 mg nicotine gum, can increase the chances of successfully stopping smoking. For patch dose comparisons, evidence was of moderate certainty, due to imprecision. Twenty-one mg patches resulted in higher quit rates than 14 mg (24-hour) patches, and using 25 mg patches resulted in higher quit rates than using 15 mg (16-hour) patches, although in the latter case the CI included one. There was no clear evidence of superiority for 42/44 mg over 21/22 mg (24-hour) patches. Using a fast-acting form of NRT, such as gum or lozenge, resulted in similar quit rates to nicotine patches. There is moderate-certainty evidence that using NRT prior to quitting may improve quit rates versus using it from quit date only; however, further research is needed to ensure the robustness of this finding. Evidence for the comparative safety and tolerability of different types of NRT use is of low and very low certainty. New studies should ensure that AEs, SAEs and withdrawals due to treatment are both measured and reported.

Lobaina Mato, Y. (2019). "Nasal route for vaccine and drug delivery: Features and current opportunities." Int J Pharm 572: 118813.
Mucosal administration, and specifically nasal route, constitutes an alternative and promising strategy for drug and vaccine delivery. Mucosal routes have several advantages supporting their selective use for different pathologies. Currently, many efforts are being made to develop effective drug formulations and novel devices for nasal delivery. This review described the structure and main characteristics of the nasal cavity. The advantages, achievements and challenges of the nasal route use for medical purposes are discussed, with particular focus on vaccine delivery. Compelling evidences support the potentialities and safety of the nasal delivery of vaccines and drugs. This alternative route could become a solution for many unmet medical issues and also may facilitate and cheapen massive immunization campaigns or long-lasting chronic treatments. Nowadays, in spite of certain remaining skepticism, the field of nasal delivery of drugs and vaccines is growing fast, bolstered by current developments in nanotechnology, imaging and administration devices. A notable increase in the number of approved drugs for nasal administration is envisaged.

Triarico, S., et al. (2019). "Intranasal therapy with opioids for children and adolescents with cancer: results from clinical studies." Support Care Cancer 27(10): 3639-3645.
Opioids are essential for the treatment of pain, which is a serious symptom for children and adolescents affected by cancer. Intranasal opioids may be very useful for the treatment of breakthrough pain in children and adolescents with cancer, for their little invasiveness, ease of administration, rapid onset of action, and high bioavailability. Intranasal drug delivery may be influenced by anatomical and physiological factors (nasal mucosa absorption area, mucociliary clearance, enzymatic activity, anatomical anomalies, chronic or inflammatory alterations of nasal mucosa), drug-related factors (molecular weight, solubility), and delivery device. Fentanyl is a lipophilic opioid commonly proposed for intranasal use among pediatric patients, but no studies have been conducted yet about intranasal use of other available opioids for management of pediatric cancer pain. In this review, we analyze several elements which may influence absorption of intranasal opioids in children and adolescents, with a focus on pharmacokinetics and therapeutic aspects of each opioid currently available for intranasal use.

Wang, Q., et al. (2019). "Updates on thermosensitive hydrogel for nasal, ocular and cutaneous delivery." Int J Pharm 559: 86-101.
Thermosensitive hydrogels are in situ gelling systems composed of hydrophilic homopolymers or block copolymers which remain as solutions at room temperature and form gels after administration into the body. Its application in advanced drug delivery has gained significant attention in recent years. The tunable characteristics of thermosensitive hydrogels make them versatile and capable of incorporating both hydrophilic and lipophilic compounds and macromolecules. The drug molecules can be included as free molecules or preformulated into nano- or micro-particles or liposomes. Although there were several reviews on the materials of thermosensitive hydrogels, the compatibility between the drug and thermosensitive material as well as its in vitro release mechanisms and in vivo performance have barely been investigated. The current review is proposed aiming to not only provide an update on the recent development in thermosensitive hydrogel formulations for nasal, ocular and cutaneous deliveries, but also identify the relationship between the drug characteristics and the loading strategies, and their impacts on the release mechanisms and the in vivo performance. Our current update for the first time highlights the essential features for successful development of in situ thermosensitive hydrogels to facilitate nasal, ocular or cutaneous drug deliveries.

Zaric, B. L., et al. (2019). "Drug Delivery Systems for Diabetes Treatment." Curr Pharm Des 25(2): 166-173.
BACKGROUND: Insulin is essential for the treatment of Type 1 diabetes mellitus (T1DM) and is necessary in numerous cases of Type 2 diabetes mellitus (T2DM). Prolonged administration of anti-diabetic therapy is necessary for the maintenance of the normal glucose levels and thereby preventing vascular complications. A better understanding of the disease per se and the technological progress contribute to the development of new approaches with the aim to achieve better glycemic control. OBJECTIVE: Current therapies for DM are faced with some challenges. The purpose of this review is to analyze in detail the current trends for insulin delivery systems for diabetes treatment. RESULTS: Contemporary ways have been proposed for the management of both types of diabetes by adequate application of drug via subcutaneous, buccal, oral, ocular, nasal, rectal and pulmonary ways. Development of improved oral administration of insulin is beneficial regarding mimicking physiological pathway of insulin and minimizing the discomfort of the patient. Various nanoparticle carriers for oral and other ways of insulin delivery are currently being developed. Engineered specific properties of nanoparticles (NP): controlling toxicity of NP, stability and drug release, can allow delivery of higher concentration of the drug to the desired location. CONCLUSIONS: The successful development of any drug delivery system relies on solving three important issues: toxicity of nanoparticles, stability of nanoparticles, and desired drug release rate at targeted sites. The main goals of future investigations are to improve the existing therapies by pharmacokinetic modifications, development of a fully automatized system to mimic insulin delivery by the pancreas and reduce invasiveness during admission.