NASAL DRUG DELIVERY VIA THE ORAL ROUTE USING A PMDI

Citation: Le Pennec D, Vecellio L, Regard A, “Nasal Drug Delivery via the Oral Route Using a pMDI”. ONdrugDelivery Magazine, Issue 92 (Nov 2018), pp 48-50.

Laurent Vecellio, Déborah Le Pennec and Alain Regard, Technology Product Manage discuss a study Nemera has funded into the retronose concept, using a pMDI to deliver to the nasal cavity via the oral route during exhalation through the nose.

INTRODUCTION

Nasal drug delivery is a non-invasive method that allows for a rapid, high and local therapeutic effect. It offers significant opportunities for new drug development looking to deliver systemic drugs, vaccines and treatments for the central nervous system. A recent study in patients with chronic rhinosinusitis has shown how deposition of corticosteroids in the nasal cavities can have an impact on clinical outcomes.1 This study demonstrated the importance of the delivery device on drug efficacy.

Figure 1: The retronose concept.

Standard nasal sprays have limitations regarding the reproducibility and the deposition efficacy in the distal region of interest in the nasal cavities. An alternative, the “retronose” concept (Figure 1) has been proposed as a means to reduce variability and improve drug deposition in specific nasal zones, consisting of drug administration through the buccal cavity during the nasal expiratory phase.

Using this method, a different nebuliser concept has been developed for better drug deposition in the distal region of the nose,2,3 without lung deposition. Drug particles enter the nasal cavities through the rhinopharynx, which has a significant impact on drug deposition. Additionally, in a recent study, five asthmatics with rhinosinusitis were successfully treated with an aerosol therapy exhaled through the nose4 using a similar concept.

In the study funded by Nemera presented here, the use of a pressurised metered dose inhaler (pMDI), as an alternative to a nebuliser, for delivering drugs to the nose via the buccal cavity was explored. Specifically, the study focused on the influence of particle size and the expiratory flow rate on particle deposition in an upper airways model using a standard pMDI.

METHOD

A pMDI filled with HFA 134a propellant (no surfactant) was used with a 90 μL valve system (Inhalia®, Nemera) and an actuator (NM200, Bespak, Germany). Three different particle sizes (3, 12 and 20 μm in terms of volume mean diameter) of a model drug were put in the canisters, resulting in three different pMDI suspensions (pMDI-A, pMDI-B, pMDI-C) delivering 100 μg of drug per dose. Aerosol particle size produced was measured using a cascade impactor operating at 30 L/min (Next Generation Impactor, Copley Scientific, UK).

Figure 2: Experimental set up using the VCU upper airways model.

Aerosol deposition in the upper airways (Figure 2) was studied using an anatomical model5 developed by the Virginia Commonwealth University (Richmond, VA, US). The trachea model was connected to an absolute filter (L) and a humidified air source at three different flow rates: 30, 60 and 90 L/min. A vacuum pump connected to an absolute filter (E) was located near to the nose model for collecting the totality of the exhaled aerosol from the model. Eight regions of interest were defined in the upper airway model:

  • Mouth (M)
  • Trachea (T)
  • Oropharynx (O)
  • Rhinopharynx (R)
  • Upper part of the nasal cavity (U)
  • Middle part of the nasal cavity (M)
  • Bottom part of the nasal cavity (B)
  • Nostrils (N).

The active compound was assayed by a spectrophotometric method.

RESULTS

The aerosol particle sizes produced by pMDI-A and pMDI-B, measured by cascade impaction, were characterised by a mass median aerodynamic diameter (MMAD) as shown in Table 1. The MMAD produced by pMDI-C could not be calculated due to its high deposition in the induction port of the cascade impactor. Regarding the percentage of particle size lower than 10 μm. The results obtained with pMDI-C are consistent with the particle size put in the canister (Table 1).

pMDI-ApMDI-BpMDI-C
MMAD (μm)3.7 ± 1.314.8 ± 0.4N/A
Particle size lower than 10 μm (%)70 ± 1729 ± 83 ± 1

Table 1: Aerosol particle size data for the three pMDIs.

An increase of drug penetration into the nasal cavity was observed with a decrease of particle size. No active compound was detected depositing into the filter corresponding to the lung model (L). No statistical difference was observed on the influence of expiratory flow rate on aerosol deposition in the oropharynx, mouth or trachea, and drug penetration into the nasal cavity (p>0.05, Friedman test, GraphPad Prism V5) for all three flow rates were examined.

The drug deposited homogenously in all regions of the nasal cavity (Figure 3). An exception was the upper part of the nasal cavity, where deposition was relatively low (less than 2%), independent of particle size or expiratory flow rate. An increase in particle size was associated with a decrease in exhaled fraction. An increase in expiratory air flow rate was also associated with a decrease in exhaled fraction. There was no statistical influence of expiratory flow rate on deposition fraction in the other regions of the nasal cavity, N, U, M, B and R (p>0.05, Friedman test, GraphPad Prism V5).

Figure 3: Deposition in the nasal cavity model expressed in term of total drug delivered in the nasal cavity (N+U+M+B+E+R) for 3 μm (A), 12 μm (B) and 20 μm (C) (n=3).

CONCLUSION

The concept of nasal drug delivery via the oral route using a pMDI in an upper airways model has been demonstrated in vitro, with promising results. All anatomical regions, except for the upper part of the nasal cavity, were successfully targeted, with relatively homogenous deposition. This nasal drug delivery system could be of interest for both local and systemic drug delivery, and for the delivery of vaccines.

ACKNOWELDGEMENT

The authors would like to thank Dr P Worth Longest of Virgina Commonwealth University (Richmond, VA, US) for providing the upper airways model.

REFERENCES

  1. Reychler G et al, “Effect of three-drug delivery modalities on olfactory function in chronic sinusitis”. Laryngoscope, 2015, Vol 125(3), pp 549–555.
  2. Kobayashi Y et al, “A novel therapeutic use of HFA-BDP metered dose inhaler for asthmatic patients with rhinosinusitis: Case series”. Int J Clin Pharmacol Ther, 2014, Vol 52(10), pp 914–919.
  3. Sutton S, “Navigating the Nose”. The Medicine Maker, Oct 2017.
  4. Vecellio L, Chantrel G, Massardier JM, “Device for oral administration of an aerosol for the rhinopharynx, the nasal cavities or the paranasal sinuses”. Patent WO2011080473.
  5. Longest PW, Tian G, Hindle M, “Improving the Lung Delivery of Nasally Administered Aerosols During Noninvasive Ventilation—An Application of Enhanced Condensational Growth (ECG)”. J Aerosol Med Pulm Drug Deliv, 2011, Vol 24(2), pp 103–118.

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