Intranasal drug delivery: opportunities and toxicologic challenges during drug development

Abstract

Over the past 10 years, the interest in intranasal drug delivery in pharmaceutical R&D has increased. This review article summarises information on intranasal administration for local and systemic delivery, as well as for CNS indications. Nasal delivery offers many advantages over standard systemic delivery systems, such as its non-invasive character, a fast onset of action and in many cases reduced side effects due to a more targeted delivery. There are still formulation limitations and toxicological aspects to be optimised. Intranasal drug delivery in the field of drug development is an interesting delivery route for the treatment of neurological disorders. Systemic approaches often fail to efficiently supply the CNS with drugs. This review paper describes the anatomical, histological and physiological basis and summarises currently approved drugs for administration via intranasal delivery. Further, the review focuses on toxicological considerations of intranasally applied compounds and discusses formulation aspects that need to be considered for drug development.

Keywords: Intranasal drug delivery; Nasal toxicity; Nose-to-brain-delivery; Olfactory pathways.

Fig. 1

Nasal cavity of humans (left) and rodents (right), showing the different regions within the nose. Starting with the squamous mucosa (SM) right at the nostril openings. The respiratory epithelium (RE) covers the main part of the nasal cavity in humans. Humans have three turbinates (T), the inferior turbinate, the middle turbinate as a part of the RE and the superior turbinate in the olfactory epithelium (OE). Rodents have the maxilloturbinates and nasoturbinates in the RE and the ethmoturbinates in the OE. The olfactory bulb (OB) is in close proximity to the cribriform plate and connected to the OE via the axons of the sensory neurons projecting towards the brain. The rodent nasal cavity further has a predominant vomeronasal organ (VNO) which also takes part in the olfaction of specific compounds

Fig. 2

Structure and composition of the olfactory mucosa. In the posterior part of the nasal cavity, the olfactory mucosa, together with the olfactory epithelium (OE) and the lamina propria (LP), represents the first contact zone of environmental cues towards the human body. Within the OE, the mature olfactory sensory neurons (OSNm) are projecting their axons towards the olfactory bulb (OB), where they form glomeruli with the dendrites of mitral cells. The axons of OSNms are enclosed by olfactory ensheating cells (OECs) and olfactory nerve fibroblasts (ONFs). The axons together with the OEC and ONF form the olfactory nerve bundles (ONBs) in the lamina propria. The OE further consists of sustentacular (SUS) and mucus producing Bowman’s glands (BGs). In the middle part of the OE are the immature ORN (ORNi). The OE is surrounded by a layer of immature basal cells, the globose (GBC) and horizontal basal cells (HBCs). The lamina propria (LP) is seperated from the OE by a basal lamina (BL). Further, the LP also contains blood vessels (BVs) and lymphatic vessels (LVs)

Fig. 3

There are three different pathways through which a substance can pass the olfactory epithelium (OE). The substance can bind to a receptor and be internalised by for example receptor-mediated endocytosis. Then, it travels through the olfactory sensory neuron (OSN) towards the olfactory bulb (OB). Another possibility is that the substance uses leaky passages within the OE and travels paracellular into the lamina propria. Third, the substance can also be transported transcellular through the sustentacular cells (SUS) to the lamina propria. From there, the substance can (1) be absorbed by local blood vessels (BVs) reaching the circulation or (2) be absorbed by lymphatic vessels and be drained into the deep cervical lymph nodes of the neck. (3) The substance can use perineural spaces between the olfactory ensheating cells and olfactory nerve fibroblasts to travel associated to the olfactory nerves to the OB. After passing the cribriform plate, the substance can theoretically also reach the cerebrospinal fluid and distribute through the different brain regions

Fig. 4

Number of clinical trial papers published at ClinicalTrial.gov using intranasal administration. Filters used contained the recruitment status (recruiting, active (not recruiting), completed); eligibility criteria (differentiated after age groups (child, adult, older adult), all sex); study results (all); study phase (early phase 1, phase 1, phase 2, phase 3, phase 4)