Intranasal Drug Delivery PDF

3.6 Intranasal Drug Delivery There are two main respiratory drug delivery approaches: nasal cavity and lungs (pulmonary drug delivery). The focus of this study guide is the nasal cavity, a complex and promising route for drug administration. Products delivered through the nasal...

3.6 Intranasal Drug Delivery There are two main respiratory drug delivery approaches: nasal cavity and lungs (pulmonary drug delivery). The focus of this study guide is the nasal cavity, a complex and promising route for drug administration. Products delivered through the nasal cavity can be for local or systemic purposes. ○ Examples of local delivery: Nasal decongestants. Glucocorticoids (e.g., Flonase). ○ Examples of systemic delivery: Vitamin B12. Pain medications. Anatomy and Physiology of the Nose The two main functions of the nose are olfaction (smelling) and conditioning inspired air. The most important anatomical structures for intranasal drug delivery are the turbinates, located within the nasal cavity. Regions of the Nasal Cavity The nasal cavity has three regions: vestibular, respiratory, and olfactory. Vestibular Region The vestibular region consists of the nasal vestibule and the valve. Its main function is to filter and baffle air. The vestibular region is lined with long hairs and pseudostratified epithelia (skin-like). The nasal valve connects the vestibule to the nasal cavity and is a fairly narrow passageway. Respiratory Region The respiratory region is composed of three turbinates: inferior, middle, and superior. The inferior turbinate communicates with the nasal lacrimal ducts. The middle turbinate communicates with several sinuses. The superior turbinate has less physiological significance compared to the other two. Functions of the respiratory region: ○ Direct, heat, and humidify incoming air before it reaches the lungs. ○ Increase surface area , which can enhance aerosol deposition and drug absorption.  ○ Promote turbulence , which can increase particle impaction and protect the lungs from unwanted substances. The respiratory region is the major site for drug absorption and action. Olfactory Region The olfactory region is located above the respiratory region, beneath the brain. Characteristics of the olfactory region: ○ Very thin layer and barrier between it and the brain. ○ Roof of the nasal cavity. ○ Small surface area. ○ Poorly ventilated , resulting in less spray reaching this area compared to the respiratory region. Due to its proximity to the brain, the olfactory region has the potential for drug delivery to the brain. Nasal Mucosa Respiratory Region Epithelium The anterior one-third of the respiratory region contains various types of epithelia: ○ Squamous. ○ Transitional. ○ Pseudostratified columnar. The posterior two-thirds of the respiratory region is composed of ciliated pseudostratified columnar epithelia. Goblet cells are present and produce mucus. Mucociliary Clearance Cilia play a crucial role in mucociliary clearance, a major mechanism for removing particles and drugs from the nasal cavity. Cilia sweep mucus and trapped substances backward, eventually leading to swallowing. Undissolved drugs are particularly susceptible to mucociliary clearance. The presence and fluidity of mucus are vital for ciliary function. Increased mucus viscosity, as seen in conditions like the common cold, can slow down ciliary movement and clearance. Mucociliary clearance is a significant physiological factor affecting drug absorption. Other Components of the Nasal Mucosa Mucus has various functions, including:  ○ Protecting and hydrating the epithelium. ○ Trapping and transporting inhaled substances. Mucus is continuously secreted and swallowed. Average mucus pH is around 6.3 (slightly acidic). Enzymes are present in the nasal mucosa and contribute to mucociliary clearance. Transporters , such as efflux systems like p-glycoprotein, are expressed in the nasal epithelium and can transport substances out. Blood Supply The nasal epithelium is highly vascularized. Capillaries are fenestrated (have holes), allowing for the passage of large molecules. Drugs that pass through the epithelium can easily enter the bloodstream. There is no hepatic portal system , meaning no hepatic first-pass effect for drugs absorbed through the nasal cavity. Advantages of Intranasal Drug Delivery Avoidance of GI acid and enzymatic degradation , making it suitable for drugs that are unstable in the GI tract. No hepatic first-pass effect. Potential for high rate and extent of absorption due to: ○ Good vasculature. ○ Relatively permeable epithelium. ○ Fenestrated capillaries. Absorption of relatively large molecules , including peptides, which cannot easily penetrate other epithelia. Alternative route for vaccinations due to the presence of nasal-associated lymphoid tissue (NAALT). ○ Immunization in the nasal cavity can provide immunity to other mucous membranes. Disadvantages of Intranasal Drug Delivery Increased intranasal metabolism is possible if the drug is a substrate for enzymes present in the nasal mucosa. Complications can arise from pre-existing nasal conditions , such as: ○ Rhinitis. ○ Hay fever. ○ Asthma. ○ Nasal polyps. These conditions can affect drug deposition, absorption, and clearance.  Environmental factors , such as humidity and temperature, can influence drug delivery: ○ Arid environments can dry up secretions. Medications , particularly anticholinergic drugs and vasoconstrictors, can affect nasal secretions and absorption: ○ Anticholinergic drugs can dry secretions. ○ Vasoconstrictors like Afrin can reduce systemic bioavailability by constricting blood vessels. Considerations for Product Design pH Solutions with a pH range of 4 to 8 minimize damage to the mucociliary apparatus. Ciliary beat frequency is best maintained at a pH of 7 to 10. Formulating at a lower pH (e.g., 5) can potentially increase residence time by slowing mucociliary clearance, but it's essential to consider buffer capacity. Osmolarity Isotonic fluids are preferred to minimize irritation , but a wide range is acceptable for nasal sprays. Sprays have a less dramatic effect on overall osmolarity compared to drops. Viscosity High viscosity can slow mucociliary clearance , increasing residence time. However, excessive viscosity can hinder drug release. Viscosity-enhancing excipients are often used, especially for suspensions. Preservation Antimicrobial preservatives are typically necessary to prevent microbial growth in repeatedly used nasal drops and sprays. Benzalkonium chloride is a commonly used preservative, though there have been concerns about its potential toxicity. Drug Deposition Sprays are the dominant type of intranasal product and are mainly deposited in the anterior region of the nasal cavity. Drops generally provide greater coverage throughout the nasal cavity but are cleared more rapidly. Sprays Most nasal sprays are either metered dose or single-dose mechanical sprays of aqueous formulations. Metered dose sprays deliver a predetermined, accurate volume of drug formulation using metering chambers. Particle size is crucial: ○ Large particles (8-20 microns) are necessary to prevent bypassing the nasal cavity. Spray volume is determined by the metering chamber, typically around 100 microliters. Bottle design facilitates delivery through the nasal valve. Interaction with saliva can lead to taste perception , which can be minimized with proper technique (tilting the head forward and down). Priming Many nasal sprays require priming, which involves spraying into the air or a tissue several times to fill the metering chamber. Priming ensures an accurate dose by preventing partial filling of the chamber. Single-use medications often do not require priming. Product Examples Diazalasine (Afrin) : a nasal decongestant that is bitter-tasting. Corticosteroids : often formulated as suspensions with cellulose derivatives and surfactants. Narcan : a single-use opioid overdose treatment that does not require priming. Migraine relief medications : often single-dose and do not require priming. Nascobal (cyanocobalamin) : a systemic medication for vitamin B12 deficiency, typically in single-day, 8-spray bottles without preservatives. Flumist : a single-use vaccine without preservatives. Administration General steps for administering nasal sprays are available on websites like the safe medication site. It's essential to follow specific recommendations for each product