Transdermal drugs delivery systems TDDSs

Drug delivery systems

1. NASAL DELIVERY SYSTEM Introduction NDDS offers non-invasive and convenient route for drug administration directly to the nasal mucosa Offers rapid onset of drug Avoidance of first-pass metabolism Improves patient’s compliance.

2. Anatomy and Physiology The nasal cavity runs from the nasal vestibule to the nasopharynx which has a depth of 12-14cm. The nasal vestibule, the respiratory region and the olfactory region are the three main regions of the nasal cavity. The sub mucosal zone of the nasal mucosa directly connects the systemic circulation, thus avoids first past metabolism. The lateral walls of the nasal cavity includes a folded structure which enlarges the surface area in the nose to about 150cm 2 The folded structure includes three turbinates, the superior, medium and inferior.

3. These turbinates increases the area of absorption Nasal cavity is about 60mm in length The nasal cavity is covered with the mucous membrane which can be divided into olfactory and nonolfactory epithelium areas. The nonolfactory area includes the nasal vestibule and respirator region. Nasal blood flow involves the external and internal carotid artery. Composition; 95% water, 1 – 2%salt, 2 – 3% mucin , trace amount of K, Na, Ca , albumin. Nasal enzymes; monooxygenase , lactate dehydrogenase, oxidoreductase , phosphates, hydrolases, esterase etc. Nasal pH 5.5 – 6.5 (adults), 5.0 – 6.7 (infants and children)

4. Advantages of Nasal Delivery System Drug degradation is absent Hepatic first pass metabolism is absent Rapid drug absorption Quick onset of action The bioavailability of the larger drug can be improved by the means of absorption enhancers or other approach Better nasal bioavailability for smaller drug molecule Drugs which cannot be absorbed orally may be delivered to the systemic circulation through the nasal drug delivery system. Convenient route when compared with parenteral route for long term therapy

5. Disadvantages of Nasal Delivery System The absorption enhancers used to improve nasal drug delivery system may have histological toxicity which is not yet clearly established Absorption surface area is less when compared to the GIT Once the drug is administered, it cannot be removed Nasal irritation

6. Mechanism of Absorption Trans cellular Process : transportation of liphophilic drugs through the cell membrane by active transport or transport through the opening of the tight junction, e.g. Lavedopa , Carbodopa . Paracellular Process : it involves aqueous route of transport. It is slow and passive e.g insulin ACTH, MSH

7. Barriers to Nasal Drug Absorption Low Bioavailability : due to low membrane permeability. This is a limiting factor for high mol. weight polar drugs like protein and peptides Low Membrane transport: rapid clearance of administered drug due to MCC especially liquid and powdered formulation. Enzymatic Degradation: degradation of protein and peptides by exopeptidase and ednopeptidase .

8. Factors Affecting Absorption Chemical Form: Drug form is important in determining it absorption. For example nasal absorption of carboxylic acid esters of L-Tyrosine is significantly greater than that of L -Tyrosine. Polymerization: this affects dissolution rate, solubility of drug and thus their absorption through biological membrane. Molecular Weight: absorption rate decreases if the there is higher molecular weight. Particle Size : particles of size 10 – 20um are deposited in the nasal cavity, less than 2um are retained in the lungs while greater than 20um are exhaled with air. Solubility and Dissolution Rate : different dissolution rate for powders and suspension. Nasal pH Mucociliary clearance It is a preventive function The clearing of mucus and absorbed/dissolved drug substances into the GIT.

9. Strategy to Improve Nasal Absorption Nasal enzymes inhibitors; e.g. peptidases, protease, tripsin , aprotinin , borovaline , etc Formulation Design; Modifying Drug Structure: Particualate drug delivery Absorption enhancers

10. Formulation Consideration pH of the Formulation To avoid irritation To allow drug to be available in unionized form for absorption To prevent bacterial growth in the nasal passage To sustain normal physiological ciliary moments Humectants To prevent dehydration, adequate intranasal moisture is required Prevent nasal irritation Examples of humectants; glycerin, sorbitol, mannitol

11. Osmotic Agents Higher concentration of drugs may lead to toxicity to the nasal epithelium. Examples of osmotic agents are sodium chloride, sodium sulfite, sodium acid phosphate. Solubilizers: To address issue of solubility, e.g. glycerol, small quantity of alcohol, medium chain glycerides, cyclodextrin, etc. Gelling/Viscosity Agents Forming Carrier Increase viscosity may provide means of prolonging the therapeutic effects of nasal preparations. e.g. Carbopol, cellulose agents, starch, dextran, chitosan etc.

12. Absorption Enhancers Used in drugs with high molecular size, lack of lipophilicity, enzymatic degradation. Antioxidant e.g. sodium metabisulfite. Sodium sulfite, butylated hydroxytoluene, tocopherol. Preservatives Parabens, benzalkonium chloride, phenyl ethyl alcohol

13. DELIVERY SYSTEM

14. Nasal Drops Nasal drops are one of the most simple and convenient systems developed for nasal delivery. They deliver drugs to a larger area back in the nasal cavity. Their main disadvantage is lack of dose precision. It is an aqueous preparation that is instilled into the nostrils. Oily vehicles are not used because they inhibit the movement of cilia and produce lipoid pneumonia. They are isotonic with blood plasma. Phosphate buffer of pH 6.5 is used. It is used as antibacterial and for nasal decongestion. E.g ephedrine nasal drop. Nasal drops should be packed in coloured, fluted container with dropper.

15. How to Use Nasal Drops Blow your nose gently. Drop the required number of drops into each nostril. The aim is to get the liquid to spread over all the inside surface of the nose - including the upper surface. A good position is to lie on a bed with your head hanging back over the edge.

16. Nasal Spray With the aid of metered dose pumps and actuators, nasal spray can deliver an exact dose from 25 to 20um. How to Use a Nasal Spray Close the nostril that is not receiving the medication. Do this by gently pressing on that side of your nose. Gently insert the bottle tip into the other nostril. Breathe in deeply through that nostril as you squeeze the bottle. ... Repeat if directed. ... If directed, repeat steps 1–4 for the other nostril.

17. Types of Nasal Sprays and their Benefits For treating common nasal conditions, relieving symptoms of allergic rhinitis and chronic sinusitis, as well as nasal congestion. Steroid Nasal Sprays In fact in cases of persistent, moderate or severe allergic rhinitis it is the first line of treatment. A steroid nasal spray,​ if used as prescribed, will not cause a rebound effect or dependency. It works topically on the nasal lining and is safe even if a small amount is swallowed and enters the bloodstream. “Of the small amount that may be swallowed, most of it is metabolized by the liver before it enters the bloodstream,” it’s important to carefully follow the doctor’s instructions when using a steroid nasal spray. “Prescription inhalers will have detailed instructions regarding their use and patients should not go beyond the prescribed dose,” say doctors.

18. Saline Sprays and Rinses Are a safe and effective option for long-term relief of the symptoms of allergic rhinitis and chronic sinusitis. These rinses and sprays use a salt solution to flush out the nasal cavity, which relieves nasal congestion. While an over-the-counter nasal spray can provide relief for a few days, it can have a rebound effect if used for a longer period of time – it can actually worsen your nasal congestion instead of alleviating it. Furthermore, excessive use can even damage your nasal membrane.​ What happens under this rebound effect is that the swelling inside your nose returns after the effect of the nasal spray wears off, and your congestion will appear to be worse than before. This rebound congestion, known as rhinitis medicamentosa.

19. How do you use normal saline spray? Place the  spray bottle under the nostril  to which you are applying it to an aim away from the septum (the middle of your nose) so you don't damage it. Close your mouth and inhale slightly through the nostril while gently squeezing or pumping the spray applicator. The usual instructions are to apply two.

20. Can an over-the-counter nasal spray be​ addictive? Rebound congestion can cause a dependency on an over-the-counter nasal spray. This dependency may appear to be an addiction but it actually isn’t. It is a psychological need and not a physiological need, and therefore, does not count as an addiction. “For adults, the general rule of thumb for over-the-counter nasal spray is no more than five days of continuous use. Since there is a real risk of contamination when using saline sprays and rinses, it is important to carefully follow the product care and usage instructions. These are some tips for the safe use of saline rinses and sprays: Keep the rinse bottle clean and follow the manufacturer’s instructions on care and replacement of the bottle. Keep bottle dry between uses. To avoid possible contamination, it is advisable to use cooled boiled tap water to dissolve the premixed salt sachet.

21. Menthol Nasal Sprays For the temporary relief of nasal congestion. Works by acting on the menthol receptor in the nose but doesn’t actually relieve nasal congestion, even though the patient may feel better. Caution Temporary burning, stinging, dryness in the nose, runny nose, and sneezing may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

22. Nasal Gels High viscosity thickened solution or suspension. There is reduction of post nasal drip due to high viscosity. Reduction of taste impact due to reduced swallowing. Reduction of leakage of the formulation. Reduction of irritation (by using emollient).

23. Disadvantages Drugs may undergo chemical and enzymatic degradation in the gastrointestinal tract. Low permeability in mucosa. First pass metabolism in liver. Parental route provide good bioavailability but also suffers from certain disadvantages. Painful. Less patient compliance.

24. ADVANTAGES OFFERED BY NASAL GEL PREPARATIONS Deposition effect on absorption . When nasal gel formulation deposited in the anterior portion offers a large nasal residence time and low permeability area, while on other hand posterior portion provides high permeability and gives shorter residence time. But these both residence times is more than other dosage form such as spray, solution powders.

25. How to Use Nasal Gel Close the nostril that is not receiving the medication. Do this by gently pressing on that side of your nose. Gently insert the bottle tip into the other nostril. Breathe in deeply through that nostril as you squeeze the bottle. Repeat if directed. If directed, repeat steps 1–4 for the other nostril.

26. Nasal Powder It is used in case of drug instability Absence of preservatives, Local application, Stability of formulation. How do you use nasal powder? Giving the dose Hold Device between fingers and thumb. Do not push Plunger yet. Insert Tip gently in one nostril until finger(s) touch the outside of the nose. Push Plunger firmly all the way in. Dose is complete when the Green Line disappears.

27. Nasal Aerosols It contains active drug, surfactant, co-solvent, propellant

28. ASSIGNMENT 1. Difference between nasal drop and nasal spray. 2. Give five example of nasal spray. 3. List five example of nasal aerosol and how it is applied.