Intranasal drug administration offers both localized exposure and systemic drug delivery. The nasal cavity serves as the primary pathway for inhaled air, which can carry particles, liquids, or gases. Additionally, the nose has dual functions: olfaction and the conditioning of inhaled air by warming, humidifying, and filtering it to protect the lungs. Large and/or irritating particles or droplets can trigger reflexive sneezing, expelling them to prevent deposition in the lungs or systemic absorption.
However, with appropriate formulations and delivery devices, drugs can be absorbed locally or enter systemic circulation via the nasal mucosa, achieving therapeutic effects. Unabsorbed small particles may reach the lungs, where they either act locally, are absorbed systemically, or are cleared through mucociliary action or macrophage uptake. Liquids administered intranasally may either be absorbed within the nasal cavity or delivered to the lungs. Larger inhaled particles may also be cleared through the gastrointestinal tract. These particles or droplets adhere to nasal mucus, are pushed towards the back of the nose by cilia, and are eventually swallowed into the esophagus and stomach. This clearance mechanism not only removes drugs from the nose but may also lead to systemic exposure through the gastrointestinal tract. Therefore, intranasal administration is a route that involves both local and systemic absorption, capable of achieving desired pharmacological effects but also potentially leading to toxic reactions due to unintended exposure.
Intranasal drug delivery offers several advantages: it is simple, non-invasive, and allows most patients, including those who are nauseous or vomiting, to self-administer. Moreover, in addition to direct nasal delivery, it enables drug exposure to various target sites. For instance, approved nasal sprays such as calcitonin and oxytocin achieve systemic therapeutic effects, while sumatriptan and zolmitriptan can be administered nasally for brain-targeted migraine treatment. The proximity of the nasal mucosa to the brain facilitates rapid drug exposure to the brain and/or cerebrospinal fluid. Other drugs under development aim to target lung tissues through intranasal delivery. Due to the relatively large vascular surface area, lipophilic drugs with molecular weights <1 kDa are readily absorbed, achieving systemic exposure comparable to intravenous (IV) routes. In other words, many drugs administered intranasally can achieve higher bioavailability and better tolerability compared to oral administration, as intranasal delivery avoids first-pass metabolism.
However, like any route, intranasal administration has its limitations. Large molecules, such as many proteins, peptides (>1 kDa), and hydrophilic drugs, often exhibit poor nasal absorption, primarily due to rapid mucociliary clearance. Some companies are developing mucoadhesive agents and permeation enhancers to improve the absorption of such drugs. Another drawback of intranasal delivery, despite the absence of first-pass metabolism, is that the nose is a metabolically active organ, and some drugs may be metabolized in the nasal environment. Additionally, the nasal cavity is exposed to the external environment and influenced by physiological conditions, which may result in significant absorption variability.
Fortunately, the anatomical and physiological similarities between animals and humans allow for the extrapolation of human outcomes from animal studies. Animal pharmacological and toxicological research can be used to study formulations, particle size, ventilation rates, dosing volumes, and/or exposure sites to achieve targeted tissue exposure following intranasal administration.
Although the nasal anatomy and physiology of mammals are generally similar across species, there are some differences. When delivering drugs to the nasal cavity and interpreting toxicological study results, interspecies differences in nasal structure and function must be considered. For example, humans and non-human primates have relatively simple nasal turbinate structures, while rodents, rabbits, and dogs have more complex structures. The number and shape of turbinates affect airflow characteristics and, consequently, drug deposition. Turbinate structures can also create a larger surface area, influencing drug absorption.
Multiple factors, including delivery devices, volumes, anesthesia, and administration methods, can affect intranasal drug absorption. Non-rodent animals with large nasal cavity volumes can be dosed using syringes or clinical devices such as liquid pumps or dry powder inhalers for intranasal administration. Animal studies do not mandate the use of clinical devices identical to those used in human trials. In dogs and primates, one technician typically restrains the animal while another administers the drug. Dogs are generally easier to handle and show good tolerability, but handling primates is more challenging, with a higher likelihood of stress, necessitating restrictions on daily dosing volumes and frequencies as shown in the table above.
Various factors, including direct contact with devices, drug solution concentration, extreme pH, and cold liquids, can affect drug deposition and absorption. These chemical and mechanical factors may cause irritation, secretion, tearing, itching, sneezing, bleeding, and pain, all of which can reduce drug absorption.
Using nasal sprays to reduce particle size can potentially enhance drug absorption and may increase drug distribution in the lungs. Additionally, increasing the dosing volume can enhance lung exposure. As previously mentioned, intranasally inhaled drugs may reach the brain via the cavernous sinus, venous sinuses, carotid artery walls, blood-brain barrier, or lymphatic pathways/vascular spaces surrounding the olfactory and trigeminal nerves.
The pain receptors in the nose are not covered by squamous epithelium, so intranasally delivered drugs almost directly reach free nerve endings and may cause upper respiratory tract irritation. If the drug has potential irritant effects, irritation potency should be assessed.
Regarding endpoints, in addition to standard toxicological requirements such as body weight, food consumption, clinical observations, clinical pathology, ophthalmic examinations, necropsy, organ weights, and histopathology, intranasal drug administration requires specific assessments. For instance, clinical observations should focus particularly on the administration site. Additionally, it has been reported that intranasal exposure to compounds may affect olfactory function, including anosmia, which requires evaluation. Simple olfactory tests, such as the buried food-seeking test, can be performed. There are also more complex and sensitive tests, such as measuring negative potentials generated by the olfactory epithelium in olfactory electrograms, similar to electroretinograms for the eyes.
Prisys Biotech's Expertise in Intranasal Administration:
At Prisys Biotech , we have extensive experience in intranasal drug administration across various animal models , with a particular focus on cynomolgus monkeys. Our team leverages advanced delivery systems and precise dosing techniques to ensure accurate and reproducible results in preclinical studies. The anatomical and physiological similarities between these non-human primates and humans make them an ideal model for studying nasal drug delivery and absorption. By combining our deep understanding of intranasal administration with our specialized knowledge of primate models, Prisys Biotech is uniquely positioned to support your drug development needs, from early-stage research to advanced pharmacological and toxicological evaluations.
