King Saud University College of Pharmacy Department of Pharmaceutics

1. King Saud University College of Pharmacy Department of Pharmaceutics PHT 540:Drug Delivery Systems Nasal Drug Delivery Systems Possibilities, problems and solutions

2. Introduction Conventionally, the nasal route of delivery has been used for delivery of drugs for treatment of local diseases such as allergy, nasal congestions and nasal infections. Recently years have shown that the nasal route can be exploited for the systemic for the systemic delivery of drugs such as small molecular weigh polar drugs, peptides and proteins that are not easily administered via other route than by injection or where a rapid onset of action is required. Most NDDS drugs are aimed for rapid onset of action for example treatment of pain: nasal morphine and ketamine and for treatment of erectile dysfunction:nasal apomorphine. Lately, NDDS has been used for vaccine delivery.

5. Anatomy and Function The nasal cavity (or nasal fossa) is a large air-filled space above and behind the nose in the middle of the face. The nasal cavity conditions the air to be received by the areas of the respiratory tract and nose. Owing to the large surface area provided, the air passing through the nasal cavity is warmed or cooled to within 1 degree of body temperature. In addition, the air is humidified, and dust and other particulate matter is removed by vibrissae, short, thick hairs, present in the vestibule. The cilia of the respiratory epithelium move the particulate matter towards the pharynx where it is swallowed.

6. Anatomy and Function…cont. The lateral wall of the nasal cavity is mainly made up by the maxilla. The nasal cavity is enclosed by the nasal bone above. The floor of the nasal cavity, which forms the roof of the mouth, is made up by the bones of the hard palate. To the front of the nasal cavity is the nose, while the back is continuous with the pharynx. The nasal cavity is divided in two by a vertical fin called the nasal septum. On the sides of the nasal cavity are three horizontal outgrowths called turbinates or conchae (singular "concha"). These turbinates disrupt the airflow, directing air toward the olfactory epithelium on the surface of the turbinates and the septum. Cilia and mucus along the inside wall of the nasal cavity trap and remove dust and pathogens from the air as it flows through the nasal cavity. The cilia move the mucus down the nasal cavity to the pharynx, where it can be swallowed.

7. Anatomy and Function…cont. The nasal cavity is divided into two segments: the respiratory segment and the olfactory segment. There is a rich blood supply to the nasal cavity. In some animals, such as dogs, the capillary beds flowing through the nasal cavity help cool the blood flow to the brain. Blood supply comes from branches of both the internal and external carotid artery, including branches of the facial artery and maxillary artery.

8. Anatomy and Function…cont. Nasal cavities and sinuses filter, warm, and humidify air, as well as detect smells. The nasal cavities are separated into right and left halves by a partition called the nasal septum, made of bone and cartilage. Nasal cavities contain several drainage openings including: paranasal sinuses (sinuses of the maxillary, frontal, ethmoidal, and sphenoidal) from where mucus drains into the nasal cavity nasolacrimal ducts from where tears drain into the nasal cavity Nasal cavities also contain receptor cells for the sense of smell. Olfactory organs cover the upper parts of the nasal cavity and a part of the nasal septum.

9. Advantages vs. Disadvantages Avoidance of hepatic first pass elimination and or destruction in the GI tract. The rate and extent of absorption and the plasma concentration vs. time profile are relatively comparable to that obtained by intravenous medication. Extensive of a rich vasculature and a highly permeable structure in the nasal membrane for absorption. • Methods and techniques of administration • Site of disposition • Rate of Clearance • Existence of any pathological conditions which may affect the nasal functions

11. Barriers to Nasal Absorption Lipophilic drugs are generally well absorbed from the nasal cavity with pharmacokinetic profiles often identical to those obtained after an intravenous injection and bioavailabilities approaching 100% . A good example of this is the nasal administration of fentanyl where Tmax for both intravenous and nasal administration have been shown to be very rapid (7 min or less) and the bioavailability for the nasal administration was near 80%. However, despite the large surface area of the nasal cavity and the extensive blood supply, the permeability of polar molecules, to include low MW polar drugs(the bioavailability in the region of 10%) and especially large MW peptides and proteins(the bioavailability normally not above 1%).

12. Barriers to Nasal Absorption… cont. The most important factor limiting the nasal absorption of polar drugs and especially larges molecular weight polar drugs such as proteins and peptides is the low membrane permeability. Drugs can cross the epithelial cell membrane either by the transcellular route or by paracellular route through the tight junction between the cells. Polar drugs with MW below 1000 Da will generally pass the membrane using paracellular route. Larger proteins and peptides have been shown to be able to pass using endocytotic transport process but only with low amounts. A)- Membrane permeability:

13. Barriers to Nasal Absorption… cont. Another factor of importance for low membrane transport is the general rapid clearance of the administered formulations due to mucociliary mechanism especially for drugs that are not absorbed across the nasal membrane. Liquid and powder formulations that are not mucoadhesive, the half life of the clearance is in the order of 15-20 min. It has been suggested that deposition of a formulation in the anterior part of the nasal cavity can decrease clearance and promote absorption as compared to deposition further back in the nasal cavity. B)- Nasal clearance:

14. Nasal Absorption Enhancer The nasal absorption of polar drugs can be greatly improved if administered in combination with absorption promoting agents, such as: surfactants, bile salts, fatty acids, cyclodextrins,...etc. The enhancer systems work by a variety of mechanisms but generally change the permeability of the epithelial cell layer by modifying phospholipids bilayer or even stripping off the outer layer of the mucosa Some enhancers have an effect on the tight junctions and/or work as enzymatic inhibitors.

15. Nasal Absorption Enhancer… cont. It is a positively charged linear polysaccharide that is bioadhesive and able to interact strongly with the nasal epithelial cells and the overlaying mucus layer thereby providing a longer contact time for drug transport across the nasal membrane before the formulation is cleared by mucociliary clearance mechanism. The type of chitosan most often employed for nasal delivery is a chitosan glutamate salt (MW= 250 kDa, DD= more than 80%). Chitosan:

17. Nasal Absorption Enhancer Morphine is a good example, since for the management of breakthrough pain it is important to obtain a pharmacokinetic profile where an early peak plasma level is achieved and thereby a rapid onset of action is provided. When morphine is administered in a simple chitosan solution formulation a five to six-fold increase in bioavailability to about 60% is achieved with a Tmax of 15 min or less. Pharmacokinetic profile of morphine (10 mg) administered as a slow 30 min infusion (A) and morphine administered nasally in a chitosan solution formulation (B)

18. Applications of NDDS Nose to Brain Route (Nasal delivery to brain)to treat or alleviate symptoms of cerebral tumors Opportunities for nasal delivery in cancer therapy: - Break-through cancer pains - Therapeutic cancer vaccines Nasal Delivery of Vaccines

19. Applications of NDDS…cont. The central nervous system is one of the complex systems in human body. The blood brain barrier (BBB) is the major bottleneck in drug delivery to the brain. For some time the BBB has impeded the development of many potentially intersecting CNS drug candidates due to their poor distribution connection of the nose and the CNS, the intranasal route can deliver therapeutic agents to the brain bypassing the BBB. Absorption of drug across the olfactory region of the nose provides a unique feature and superior option to target drugs to brain. Nasal delivery to brain

20. Applications of NDDS…cont. In order for a drug to reach the CNS from the nasal cavity, it will have to cross the olfactory membrane. Firstly, the drug can use a transcellular pathway, where the drug is transferred by receptor mediated endocytosis or by passive diffusion (small lipophilic molecules or large molecules). Nasal delivery to brain

21. Applications of NDDS…cont. Secondly, the drug can use also the paracellular pathway by passing through the tight junction (small hydrophilic molecules). Thirdly, the drug can be transported through the olfactory neuron cells by intracellular axonal transport primarily to the olfactory bulb. Nasal delivery to brain

22. The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors. The olfactory bulb transmits smell information from the nose to the brain, and is thus necessary for a proper sense of smell. As a neural circuit, the olfactory bulb has one source of sensory input (axons from olfactory receptor neurons of the olfactory epithelium). An olfactory receptor neuron, also called an olfactory sensory neuron, is the primary transduction cell in the olfactory system.

23. Applications of NDDS…cont. Many diseases, such as measles, pertussis, meningitis and influenza are associated with the entry of pathogenic microorganisms across the respiratory mucosal surfaces and re hence candidates for nasal vaccines. A range of different nasal vaccine systems has been described in the literature either using alive or attenuated whole cells with and without adjuvant and delivery systems. Chitosan nasal delivery system has been tested with three different vaccines, namely for influenza, pertussis and diphtheria in various animal models and in man. Nasal delivery of vaccines

24. The Future In the near future we should expect to see a range of novel nasal products reaching the market. At present the required drugs are usually either given by injection, have a not totally appropriate plasma profile or display unwanted pharmacological effects due to inappropriate dosing regiments. In the area of vaccines the future should also see a range of novel nasal vaccines introduced to include DNA based vaccines especially for vaccination against respiratory diseases. Finally, it will be interesting to follow the developments in the area of nose to brain delivery.