Advances in nasal delivery of antibiotics

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In a recent study published in the Journal of the Science and Technology of Drug Deliveryresearchers reviewed the advances and challenges of intranasal antibiotic delivery.

Antibiotics are substances that act against bacteria to prevent or treat infectious diseases. In particular, overuse of antibiotics contributes to growing bacterial resistance. Therefore, oral administration of antibiotics has been popular and preferred. However, oral administration could cause adverse effects on systemic distribution. Therefore, the route of administration of antibiotics is critical to increasing bioavailability and minimizing unwanted side effects and the risk of resistance.

Nasal administration of antibiotics could be essential for upper respiratory tract infections. Intranasal administration is non-invasive and offers several advantages, such as rapid onset of action, ease of application, and local and systemic availability. In the present review, researchers have discussed various approaches for intranasal administration of antibiotics.

Journal article – Nasal Route for Antibiotic Delivery: Advances, Challenges, and Future Opportunities Applying Quality-by-Design Concepts. Image Credit: Josep Suria/Shutterstock

Mechanism of nasal drug delivery

The nasal cavity is primarily used to treat upper respiratory diseases such as nasal/lung infections, sinusitis, allergic rhinitis and congestion. The meatus is the best area for local treatment because it is connected to the sinus openings. Any locally acting drug requires a longer residence time, and lower doses could be used for direct delivery to the site of action.

The respiratory tract is the largest area of ​​nasal passages with a vascularized mucosa and is essential for systemic drug absorption. In addition, the nasal arterial blood supply, primarily through the sphenopalatine, ophthalmic, and facial arteries, is essential for systemic absorption. Furthermore, systemic absorption also facilitates drug entry into the brain parenchyma via the blood-brain barrier (BBB).

As such, it may attenuate the systemic side effects of agents acting on the central nervous system (CNS). Other possible mechanisms of drug entry into the brain include the olfactory and trigeminal nerve pathways. Intranasal delivery could circumvent the two critical challenges of drug delivery to the brain – hepatic metabolism and the BBB.

Limitations of nasal administration

Nasal mucociliary clearance limits drug residence time in the nasal cavity and reduces drug permeability through the nasal mucosa. Additionally, enzymatic degradation and transporter proteins are significant barriers to drug bioavailability. Efflux systems and transporters are crucial for the uptake and distribution of drugs into the CNS and systemic circulation. Additionally, several enzymes in the nasal passages impact drug metabolism.

Antibiotics administered nasally

Several antibiotics have been tested for nasal administration. These include mupirocin, gentamicin, vancomycin, ciprofloxacin, polymyxin B, thiamphenicol, rifamycin, azithromycin, and doxycycline, among others. One study reported that gentamicin intranasal solution, given as drops in sodium glycolate or individually, was well tolerated and effective in humans.

Another study showed that intranasal irrigation of mupirocin in normal saline effectively reduced the number of Staphylococcus aureus in the maxillary sinus. Similarly, vancomycin nasal irrigation has been applied for naso-sinus polyposis. Additionally, intranasal delivery devices have been created to improve clinical outcomes.

Optimization of intranasal administration of antibiotics

Quality by design (QbD) is a knowledge and risk-based tool for quality management in pharmaceutical development. The QbD methodology includes the review of Quality Target Product Profiles (QTPPs), identification of Critical Quality Attributes (CQAs) of products, and Risk Assessment (RA).

Application of these QbD concepts may offer logical ways to design the best formulation strategies early in development to optimize antibiotic delivery during nasal administration. The QTPP parameters of intranasal antibiotics are mainly related to the ability of the product to be retained in the nasal cavity, avoiding mucociliary clearance and releasing the drug (distribution profile).

AQCs are physical, biological, microbiological or chemical characteristics that influence the quality of the final product. For example, CQA parameters for intranasal antibiotics affect adhesion, stability, distribution, dissolution, permeability, and solubility. Among the various innovative approaches developed for the intranasal administration of antibiotics, In situ gels are the most promising.

On the spot the gels exhibit a sol-gel transition in response to external stimuli and offer a sustained release profile, extended retention time and higher nasal absorption. The gelation mechanism depends on the type of polymer and, in general, three types of polymers are used in these gels: heat-sensitive, ionic and pH-sensitive polymers. These polymers facilitate the sol-gel transition as physiological conditions change.

Final remarks

Appropriate use of antibiotics is essential to minimize the risk of resistance. This could be achieved through innovations in drug formulations and delivery. As such, the nasal route of administration is advantageous in the treatment of local, systemic and cerebral infections. With the application of QbD concepts and on the spot gels, intranasal administration of drugs could increase the efficacy and retention time of antibiotics and, therefore, reduce the risk of antibiotic resistance.

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