1. Different routs of administration (nasal, ocular)
Dr. Jwan Mohammed

2. Nasal route of administration
Ocular route of administration

3. Nasal route of administration
The nasal cavity is 120–140 mm from the nostrils to the nasopharynx. The total surface area of both cavities is about 160 cm2 and the total volume is about 15 mL.
The first part of the nasal cavity (the nasal vestibule) is the narrowest part of the nasal cavity with a cross-sectional area of 30 mm2 on each side, it contains hair and is high in blood vessels
The second part is the turbinate region, composed of mucus-secreting goblet cells, ciliated and nonciliated cells and basal cells comprising 80– 90% of the total surface area of the nasal epithelium
The third part is the olfactory region containing the olfactory sensory neurons

4. Olfactory region

5. Drugs are administered to the nasal cavity for
a ) localized
b ) systemic action
c ) vaccine delivery
d ) possible direct nose-brain delivery

6. Local Nasal drug delivery
The most common reason for introducing a drug into the nasal cavity is to provide a convenient and accessible route for rapidly and efficiently managing the localized symptoms associated with allergic rhinitis, nasal congestion and nasal infection.
Drugs applied topically for such purposes include antihistamines, corticosteroids, sodium cromoglicate, sympathomimetics and antiseptics/ antibiotics
These drugs are administered either in liquid form ( from a spray or as drops) or as creams/ ointments.

7. Systemic nasal drug delivery
The intranasal route has also been exploited for the delivery of drugs to the systemic circulation because;
1) It provide a rapid onset of action (e.g. in the treatment of pain, migraine and erectile dysfunction)
2) the avoidance of gastrointestinal and hepatic pre-systemic metabolism (e.g. for susceptible peptides, such as calcitonin and other drugs such as hyoscine and morphine), despite the nasal cavity containing inherent enzymatic activity
3) More acceptable alternative of oral delivery compared to parenteral or rectal routes

8. 4) the lower costs incurred by the pharmaceutical industry (in comparison to parenteral products) since there is no requirement for sterilization of the final product
5) the management of chronic disorders; providing the medicine does not induce irritation then it can be used for prolonged periods.
6) Intranasal delivery can also be useful in emergency situations, such as in the treatment of opioid overdose (using naloxone) or in the treatment of intractable childhood seizures (using benzodiazepines).
7) Drug delivery via this route is also well-suited to drugs that , when administered orally, cause emesis e.g. galantamine used to treat dementia.

9. Anatomical and physiological factors affecting systemic delivery
For a drug molecule to enter the systemic circulation it must first be absorbed across the nasal epithelium.
This may occur via the mechanisms of passive diffusion via the transcellular or paracellular routes
The transcellular pathway is the principal route of absorption for lipophilic molecules,
while small, hydrophilic molecules diffuse between the epithelial cells (paracellularly) via the tight junctions

10. The paracellular pathway avoids the need for the drug molecules to partition into and out of the lipophilic membrane of the epithelial cells, but imposes a size restriction of between 0.39–0.84 nm.
Transcellular absorption can also occur via endocytosis, the route exploited by large hydrophilic molecules (>1 kD a), and via active transport mechanisms where drug molecules with a similar structure to a natural substrate can interact with a carrier protein to cross the epithelial cells

11. Since most drug absorption takes place by passive diffusion, the relatively large surface area of the nasal cavity and its rich blood supply aid this process.
Factors that reduce the absorption of drug include barriers presented by mucus and the epithelium itself and the nasal clearance mechanisms including mucociliary clearance and metabolism.
The nasal cavity contains mucus which is propelled by cilia towards the nasopharynx. This mechanism, termed mucociliary clearance, removes drugs from the nasal cavity therefore short residence time of drug in the nasal cavity

12. The nasal cavity contains a broad range of enzymes, including proteases, which can provide a metabolic barrier to the absorption of both small molecular weight drugs and peptides, and inactivate locally-acting drugs
Drugs may be metabolized in the lumen of the nasal cavity or as they pass across the nasal epithelium. However, the metabolic activity of the nasal cavity is less than that of the gastrointestinal tract and first pass effect of liver.

13. Advantages of intranasal drug delivery
Large surface area for absorption ( approximately 160 cm2)
Good blood supply and lymphatic system
Avoids hepatic first-pass metabolism
Epithelium is permeable to small, lipophilic drug molecules; rapid absorption and onset of action
Non-invasive, so minimal infection risk during application and low risk of disease transmission (unlike parenteral route)
Easy to self-administer and adjust dose

14. Disadvantages
Limited to small delivery volumes (25–200 µL) therefore require potent drugs
Mucociliary clearance, mucus barrier reduce bioavailability
Enzymatic activity ( pseudo first-pass effect)
Low epithelial permeability for hydrophilic drugs; require absorption enhancers and large doses

15. Formulation strategies to improve absorption include
a ) improvement of aqueous solubility (e.g co-solvents and cyclodextrins),
b ) reduction of enzymatic degradation (e.g encapsulation, use of prodrugs and inclusion of enzyme inhibitors ),
c ) increase of mucosal contact time (e g incorporate mucoadhesives)
d ) promotion of permeability (e g increase solubility, use of permeability enhancers )

16. Nasal Vaccine delivery
The nasal cavity has also been utilized, or proposed, as a portal for the delivery of vaccines, particularly for infections associated with the respiratory tract such as influenza and possibly, eventually, tuberculosis.
intranasal vaccination has been studied with a view to combating noroviruses, the measles and herpes viruses, diphtheria and tetanus microorganisms.
An intranasal vaccine containing live attenuated influenza vaccine has been marketed

17. Nose-brain delivery
The nasal rout could be a possible direct nose-brain delivery since the olfactory region contains a direct physiological link between the environment to the central nervous system (CNS)
this would have great potential in treating conditions such as: Alzheimer’s disease, brain tumours, epilepsy, pain and sleep disorders.
The efficiency of direct nose-brain transport is generally low (usually less than 1% of the administered dose)

18. Ocular drug delivery
Drug delivery to the eye is one of the most important areas of modern ocular therapy and presents many opportunities and challenges.
The front of the eye is accessible and conditions affecting it can be treated by simple topical eye drops.
The back of the eye is, however, treated as an entirely separate ocular region, and more advanced delivery systems have been designed for its treatment , including intraocular injections and implants that can provide sustained drug release over two years.

20. Ocular drug delivery routes
(Roman numbers referred to in the graph)
I.) The cornea is the main route through which ocular topically administered drugs reach the aqueous humour.
II.) The blood retinal barrier (retinal pigment epithelium and retinal capillary endothelium) restricts entry of drugs from the systemic circulation into posterior segment of the eye.
III.) Intravireal delivery route to directly reach the back of the eye

21. Ocular elimination pathways
(Numbers represented in the graph)
1.) drug elimination from the aqueous humour into the systemic uveoscleral circulation
2.) aqueous humour outflow through the trabecular meshwork and Schlemm’s canal.
3.)Drug elimination from the vitreous humor via diffusion into the anterior chamber.
4.) Drug elimination via posterior route across blood retinal barrier

22. Drug delivery routes available for treating ocular conditions are topical, systemic (oral or injection), intra ocular or periocular (injection or implant)
Topical ophthalmic preparations can be classffied into solutions , suspensions , ointments, gels and sub-microne emulsions
Important considerations in the design of topical ophthalmic preparations include ; volume , osmolality, pH, surface tension and viscosity

23. Topical ophthalmic route
The front of the eye can be effectively treated with topical ophthalmic preparations.
The topical route provides selectivity with an enhanced therapeutic index, it also avoids first pass metabolism and drugs can be administered in a simple, non-invasive manner.
Another ocular deffence mechanism which protects the eye from the outside environment is the metabolism of xenobiotics.
Both phase I and phase II metabolism reactions take place in ocular tissue

24. Barriers to the topical ocular absorption of drug
Its main short coming, however, is its inefficiency, whereby only 1–5% of the instilled dose reaches the aqueous humour.
The highly efficient lacrimal drainage system and the corneal barrier to drug permeation are the mechanisms mainly responsible for this low ocular drug bioavailability.
Drug binding to proteins also reduces absorption, and protein levels of lacrimal fluids are higher in inflamed or infected eyes.

25. The corneal barrier
Drugs can permeate the cornea by passive diffusion, facilitated diffusion or active transport.
Facilitated diffusion and active transport occur via transporter proteins expressed on the corneal epithelium.
Passive diffusion does not require transporters, however it is determined by the physicochemical properties of the drug.
Ophthalmic drugs with modest lipophilicity and low molecular weight are absorbed more efficiently via the corneal route compared to hydrophilic , ionized drugs

26. Drugs can penetrate this layer by partitioning through the cells (transcellular) or by passing between the cells (paracellular).
The epithelium, however, has tightly adherent cells with tight junctions (more than the intestine, lung and nasal mucosa) which excludes macmolecules having a radius >1 nm. Only small drugs of MW <350 Da and ions can permeate through the paracellular route.
Most of the lipophilic compounds can pass through the corneal epithelium via the transcellular route.

27. Another type of cells available in the corneal barrier called stroma.
It is a cellular, aqueous environment. It is open join allowing hydrophilic molecules to pass through relatively easily. It however limits the penetration of highly lipophilic or large molecular weight compounds.

28. Non-corneal route of absorption
absorption can also occur via the conjunctiva-scleral layer; particularly for large hydrophilic molecules such as timolol maleate, and carbonic anhydrase inhibitors as well as proteins and peptides which can be used as carriers
The conjunctiva has 5–15 layers of squamous epithelial cells with tight junctions at the apical end.
It is more permeable or leaky than the cornea and allows drugs to permeate through the paracellular as well as transcellular routes.

29. The conjunctiva is highly vascularized so drug absorption often results in systemic distribution of the drug away rom the eye.
the conjunctival-scleral route is considered a non-productive route (not efficient) because the blood vessels in the conjunctiva rapidly absorb the instilled drug which dissipates into the systemic circulation rather than ending up in the aqueous humour

30. Blood retinal barrier
The blood retinal barrier (BRB) (route II) restricts the entry of drugs from the systemic circulation into the posterior segment of the eye.
It is composed of two parts; an outer part formed by the retinal pigment epithelium (RPE) and an inner part , comprising endothelial cells of the retinal vessels.
These two parts are connected to each other by tight junctions which pose a barrier to the perfusion of hydrophilic drugs.
The blood retinal barrier has been shown to have some structural similarities to the blood brain barrier.

31. Targeting the posterior segment of the eye
1) systemic drug delivery:
it needs to be able to cross the blood-retina barrier to reach the retina and vitreous.
only a small fraction of blood flow circulates through the posterior segment of the eye and therefore high systemic doses need to be administered which can lead to systemic side effects
verteporn (Visudyne®, N ovart is) has been successfully developed and licensed for intravenous (IV) administration for the photodynamic treatment of wet age-related macular degeneration (AMD), diabetic retinopathy and optic nerve damage associated with glaucoma

32. 2) Intra vitreal injections:
Intravitreal injections provide the most efficient means of drug delivery to the back of the eye.
The drug bypasses the blood ocular barriers thus achieving higher intraocular levels which improve treatment efficacy. Systemic side effects are also minimized.
It is effective for a variety of low molecular weight drugs and monoclonal antibodies.
Repeated intravitreal injections cause patient discomfort and associated complications include retinal detachment , endophthalmitis, vitreous haemorrhage and infection. The lens can also be affected and cataracts may form.
Although these events have a low incidence they can be sight threatening

33. 3) intra ocular implants
Sustained-release implants are being developed to overcome the problems occur with intravitreal injections and to achieve steady concentrations of the drug while minimizing the peaks and troughs in drug levels.
Patient compliance is also improved.