Therapeutic Intranasal Drug Delivery

Use the most concentrated form/lowest volume of the medication available – ideal volumes are about 0.25 to 0.3 ml per nostril to reduce runoff but allow maximal mucosal coverage.[1] Use both nostrils to double the absorptive surface area. Deliver the drug as an atomized spray to maximize surface area coverage. Beware of reduced effect in patients with bloody noses or high mucous production in nasal cavity.

Drug volume discussion

The volume of drug administered is a poorly studied but important clinical concept for those who are interested in a deeper understanding of intranasal medication delivery and the pharmaceutical/FDA approach to dosing and concentration versus the approach of clinicians who just want to help their patients. In order for a pharmaceutical company to get a nasal medication approved they need to achieve certain parameters set down by the FDA or other regulatory body. One of those parameters is often a bioavailability test of the nasal drug when compared to an already approved method of delivering the same medication such as via the intramuscular route. For example, the FDA required that  IN naloxone bioavailability needed to be the same as IM naloxone before they would approve the commercially available kit released in 2015. This bioavailability was determined to be 40% compared to the same dose give IV (which for all intents and purposes is 100% bioavailable). To achieve this bioavailability there can be NO waste of drug due to run-off (regardless of whether that waste allows more total drug to be absorbed by giving a higher mg dose). For this reason nasal drugs are highly concentrated and packaged into volumes of around 0.1 ml for delivery. You will see references stating this is the optimal volume clinically but none of the references I have ever seen actually have compared 0.1 ml to any other volumes so this statement should not be accepted at face value. In fact the only study I have ever seen directly comparing volumes was by Aoki in 1976 and they found no difference between 0.1 and 0.75 ml but the study was using vaccines particles and is not really applicable to our question regarding clinical efficacy of various volumes of CNS active drugs.[15] While this small volume (0.1 ml)when delivered in a volunteer setting ensures no run-off and high bioavailability, it is not necessarily optimal for clinical use. Clinicians in the real world want the best clinical effect which is not the same as the best bioavailability. Tiny doses (0.1 ml) are hard to deliver and might accidentally be sprayed onto the nasal ala or septum with little resulting clinical efficacy. Volumes in the 0.3 to 0.5 range are clinically easier to deliver, cover a larger surface area and a little waste is fine as long as the clinical effect is adequate and no additional side effects occur. Furthermore these larger volumes can be administered to both nostrils to allow exposure to a larger absorptive surface. A study by Tsze et al study confirms this concept in the real world and found that the volumes of 0.5 ml  or 1 ml volume are easier to use and preferred by clinicians to a 0.2ml volume.[16] However, its findings are also debatable because they did not give a single dose of 0.2, 0.5 or 1 ml with variable concentrations. Instead they  gave the same weight based volume of the drug to each child but varied the number of administrations using 0.2, 0.5 or 1.0 ml aliquots.  Perhaps a future study will be able to concentrate the IN medication into multiple concentrations (similar to how diamorphine is administered – starting with lyophylized powder and solubilizing it with three different volumes having identical drug doses, then testing that method.)

Therapeutic threshold, Side effect threshold

A common problem with IN medication delivery is that the clinician fails to give an adequate dose of the drug because they are used to using IV medications and are afraid to give a seemingly very high dose of "IV" medication via the nose. For example, to sedate a child for a procedure one needs 0.4 to 0.5 mg/kg of midazolam intranasally. In a 20 kg child that comes out to 10 mg of medication – a seemingly huge dose. Failure to use adequate dosing will lead to inability to achieve a therapeutic threshold and the patient will not have adequate effect from the medication. To understand the reasoning behind administering such "high" doses one must consider several factors. The first is bioavailability. For oral medications we often give 10 to 100 times higher doses of a medication – because it takes that much to achieve adequate blood levels. For IN medications the doses are not that high, but they do need to be more than IV doses to achieve adequate serum levels of medication. How much more will depend on the medication bioavailability.