| Autor: Dr. Felix Häberlein, Philipp Wissel
Chances and challenges of intranasal applications for systemic drug delivery
In the pharmaceutical context, the intranasal route, in addition to predominantly local drug application, is also of great interest for systemic application. The COVID-19 pandemic revealed once again the role of the nose as a portal of entry for pathogens. The nasal mucosa has shown to be not only the main portal of entry of the SARS-CoV-2 virus into the human body, but also an important site for replication of the virus. Within this context, the topic of the nasal mucosa as a site of entry for viruses, but also as a route of administration of systemic therapies and vaccines, is intensively discussed.
Promising therapeutic opportunities
The advantages of nasal applications for systemic administration have been known for a long time: It is a simple, noninvasive application with rapid onset of action while bypassing the gastrointestinal and hepatic first-pass effects. In addition, the olfactory nasal mucosa provides the only direct non-invasive access into the central nervous system, the so-called "nose-to-brain transport". This nose-to-brain transport offers promising therapeutic opportunities for diseases such as epilepsy, Alzheimer's disease, multiple sclerosis or glioblastoma.
To understand the advantages and limitations of nasal applications for systemic administration, it is important to recapitulate the anatomy and physiology of the nose. The nasal cavity consists of three zones:
The anterior vestibular zone followed by the respiratory zone, which is the largest in area, and the olfactory zone. The air passing through the respiratory zone is warmed, humidified and cleaned of coarse particles. The respiratory zone is also the relevant zone for local and systemic drug applications. The olfactory zone is responsible for the reception and transmission of odor stimuli. The nasal mucosa is characterized by a ciliated epithelium whose cilia beat down the pharynx and represent the nasal cleaning system. This so-called mucociliary clearance limits the residence time of drugs in the nose and thus the temporal absorption window for active substances through the nasal mucosa. Systemic absorption of drugs via the nasal mucosa can occur from both aqueous and non-aqueous carrier systems. Due to the anatomy of the nasal mucosa, the biophysical properties of the active substance determine its bioavailability. Small, lipophilic substances penetrate the nasal mucosa better than large, hydrophilic substances. This is one of the limitations of nasal application and the spectrum of active substances that can be applied.
Innovative development approaches
Innovative development approaches for the nasal application of hormones or vaccines are known today. Nevertheless, the potential of the nasal drug administration is not yet fully exploited. Commonly, the active ingredient is present in solubilized form in in nasal drug formulations. However, in addition to classical solutions, aqueous and non-aqueous suspensions can also be administered nasally as spray or gel. This is particularly relevant because many active ingredients are poorly soluble in water (or physiological media). The number of poorly water-soluble active ingredients most likely will increase highlighting the great potential for intranasal drug delivery.
A variety of applicator systems are used for intranasal application such as single-dose and multi-dose containers with either spray, drip or syringe applicators. In this blog article we will focus on intranasal application via non-pressurised multiple use metered dose sprays.
The European Pharmacopoeia, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) impose strict quality requirements on nasal sprays. In addition to the well-known requirements, such as the assay and purity of the active ingredient in the drug, the uniformity of the applied dose (or mass) within a container (intra-container) and between containers (inter-container) must be demonstrated. These are directly related to the formulation and its spray properties with the application device. Following the EMA "Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products", the geometry of the spray cone and the droplet size distribution must be characterized. These must not change significantly during use within the specified shelf live of the product. The EMA also defines requirements for the proportion of droplets in the spray cone that are smaller than 10 µm. In relation to the total number of droplets in the spray cone, these must not exceed 5%, because particles of that size provide a risk of inhalation with possible adverse effects in deeper lung tissue.
Droplet size distribution and "shaking requirements"
Furthermore, recommendations regarding the mean average droplet size, the so-called D50 value, can be found in the literature. According to that the D50 value should not exceed 120 µm. This recommendation is usually justified by the fact that droplets with a size greater than 120 µm are deposited mainly in the anterior nasal region and could therefore run out of the nose. However, when nasal spray applicators are triggered, a high pressure is generated. Furthermore, the nasal piece is inserted into the patient's nostril. Therefore, it can be argued that droplets larger than 120 µm are also administered into the respiratory zone. Neither the EMA guideline nor the European Pharmacopoeia specify an upper limit for the D50 value of the droplet size distribution.
Nasal suspensions must be re-homogenised before use. To demonstrate that re-homogenisation is possible before use, appropriate studies should be carried out. During these studies, the so-called "shaking requirements" are to be evaluated. Within the scope of these studies, it must also be demonstrated via evaluating the uniformity of delivered dose that excessive shaking does not lead to foaming and consequently to inaccurate dosing. These requirements must be recorded in the application instruction.
Suspension particles can significantly influence the spray properties or clog the riser pipe. Therefore, special galenic and analytical challenges are faced during formulation development of nasal suspensions. When developing suspensions, special attention must be paid not only to the physical stability of the suspension but also to the sprayability with the nasal spray applicator. Often a compromise between physical stability and sprayability of the suspension must be found.
Sedimentation and resuspension
The physical stability of suspensions is mainly determined by their sedimentation and resuspension properties. The sedimentation of suspended drug particles can be decelerated by reducing the particle size and stabilization using surface-active and sterically active additives or by increasing the viscosity. The reduction of the particle size also decreases the risk of clogging the nasal spray applicator. Particle size reduction can be achieved technologically by micronization or nanoization techniques such as bead milling or high-pressure homogenization. Thereby a narrow particle size distribution should be aimed for.
In a best-case scenario, sedimentation is delayed to a maximum and a loose sediment is formed, which can be easily resuspended keeping a homogeneous suspension with a constant particle size distribution. Furthermore, the sedimentation tendency of suspensions can be decelerated by increasing viscosity.
Notably, these galenic tools for improving the physical stability of suspensions have a direct impact on the sprayability. For example, the addition of surfactants can directly affect the droplet size distribution. A suspension that is too viscous reveals poor sprayability and usually unreproducible droplet size distribution.
Furthermore, there is a risk of clogging of the riser tube of the application device when the formulation is too viscous. One initially mentioned limitation of systemic absorption via the nasal mucosa is the limited residence time of drugs in the nose due to the mucociliary clearance. However, with the help of innovative formulation approaches, this limitation can be circumvented, and the resorption window can be prolonged. One of these approaches is the use of mucoadhesive agents.
Another approach is the use of certain polymers that increase their viscosity upon contact with the nasal mucosa, thereby forming mucoadhesive gels. The formation of this so-called in-situ hydrogels is based on the cross-linking of the polymer chains. This cross-linking can be induced by changes in external conditions (e.g. temperature, pH, ion concentrations) such as the contact with the nasal mucosa. As a result, these formulations have a significantly longer residence time on the nasal mucosa and can still be sprayed with conventional spray applicators.
According to pharmacopoeial requirements aqueous nasal drugs in multi-dose containers should be preserved. Preservatives, especially benzalkonium chloride, have been the subject of criticism for many years because of their allergenic and cytotoxic side effects. Technological developments in application devices and suitable manufacturing processes have ensured that nasal sprays in multi-dose containers can certainly be preservative-free. Spray devices from certain manufacturers are designed with an integrated sterile filter system so that external microbes are prevented from entering the device during air intake after each stroke. Furthermore, microbiological contamination via the riser tube is prevented by a valve in the riser tube (or at the outlet of the nozzle). In addition, manufacturing and filling under low-bioburden or even aseptic conditions can ensure low initial microbial load of the formulation. In combination with the above-mentioned novel applicators and manufacturing processes, preservation can also be circumvented in multi-dose containers of aqueous formulations.
Thus, intranasal application for systemic administration provides great potential. Innovative galenic approaches not only enable intranasal application of poorly soluble substances, but also help to circumvent fundamental limitations of the nasal route (such as the application of large molecules, short absorption windows) and are steadily expanding the field of application of nasal therapies.
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