NASAL

Welcome! DRUG DELIVERY

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SYSTEM

CONTENTS
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Nasal Drug Delivery System Medical aspects Formulation Development Applications Conclusion

Merits
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Avoidance of hepatic first-pass metabolism Rate of absorption comparable to IV medication Rapid onset of pharmacological action

User-friendly, painless, non-invasive, needle-free administration mode

Merits.. .

Lower dose & hence lower side effects Useful for both local & systemic drug delivery For CNS drugs, better site for rapid onset of action Eg. Inhalation anesthesia, Morphine etc.

Continue
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Highly

vascularized sub-epithelial layer allowing rapid and direct absorption into systemic circulation Less hostile biochemical environment in comparison to GIT Improved patient compliance and comfort in compared to IV route Avoiding First-pass metabolism

Limitations
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Once administered, rapid removal of the therapeutic agent from the site of absorption is difficult

Pathologic conditions such as cold or allergies may alter significantly the nasal bioavailability

Anatomy
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The respiratory tract, which includes

the nasal mucosa hypopharynx large airways & small airways Provides a relatively large mucosal surface area of approx. 100 m2 (in normal adult) for drug absorption

Cross-sectional view
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a nasal vestibule b palate

c inferior turbinate d middle turbinate e superior turbinate (olfactory mucosa) f nasopharynx

Three major mechanisms of drug absorption: First mechanism involves an aqueous route of transport, Also known as the paracellular route Slow and passive Absorption is inversely proportional to the molecular weight of water-soluble compounds. Poor bioavailability - for drug with a molecular weight >1000 Daltons.

The second mechanism involves Transport through a lipoidal route is also known as the transcellular process Responsible for the transport of lipophillic drugs Rate of absorption is dependent on lipophilicity of drug
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Third mechanism An active transport route via carrier-mediated means or transport through the opening of tight junctions. For examples, chitosan, a natural biopolymer from shellfish, opens tight junctions between epithelial cells to facilitate drug transport.

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Nasal enzymes
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Cytochrome P 450 dependent monooxygenases, Lactate dehydrogenase, Oxidoreductase, Hydrolases, Esterase, malic enzymes, lysosomal proteinases, steroid hydroxylases., etc., Cytochrome P450 dependent mono oxygenases has been reported to catalyse the metabolism of xenobiotics, nasal decongestants, nocotine, cocaine, phenacetin, nitrosamine progesterone etc., Insulin zinc free was hydrolysed slowly by leusine aminopeptidase, PG of E series was inactivated 15 hydroxyprostaglandin dehydrogenase

Nasal enzymes contd.

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Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats

Nasal pH
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Nasal secretion of adult : 5.5-6.5 Infants and children: 5-6.7 It becomes alkaline in conditions such as acute rhinitis, acute sinusitis. Lysozyme in the nasal secretion helps as antibacterial and its activity is diminished in alkaline pH

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Therapeutic class of drugs for nasal route

Therapeutic class of drugs

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1. 2 adrenergic agonists 2. Corticosteroids 3. Antiviral 4. Antibiotics 5. Antifungal 6. More recently, vaccines

Drugs commonly administered through pulmonary route include 1. Terbutaline Sulphate - 2 adrenergic agonist 2. Salbutamol - 2 adrenergic agonist 3. Budesonide - corticosteroid 4. Ipratropium Bromide - anticholinergic 5. Sodium Chromoglycate mast cell stabilizer

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Treatment of.
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Acute pain-relief Smoke cessation Migraine Osteoporosis Vit-B12 deficiency Potential to deal with insulin dependent

diabetes, rheumatoid arthritis, emetics, cancer therapy, CNS drug delivery etc.

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Formulation Developme nt

Formulation Development
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Dosage form Dosage form Factors affecting drug Factors affecting drug absorption absorption Formulation Formulation considerations considerations

Physiological Pharmaceutical

Dosage forms 20 Liquid drop Liquid spray/nebulizers Aerosol Suspension spray/nebulizers Gel Sustained release

The factors influencing nasal drug absorption

A) Physiochemical properties of drug. Molecular size. Lipophilic-hydrophilic balance. B) Nasal Effect Membrane permeability. Environmental pH Mucociliary clearance Cold, rhinitis. Enzymatic degradation in nasal cavity. C) Delivery Effect Formulation (Concentration, pH, osmolarity) Delivery effects Drugs distribution and deposition. Formulation effect on mucociliary clearance. Toxic effect on ciliary function and epithelial membranes.
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Factors affecting drug absorption 22

Drug concentration Vehicle of drug delivery Mucosal contact time Degree of drugs ionization pH of the absorption site Size of the drug molecule Relative lipid solubility

Physiological effects 23 Drug metabolism in the respiratory tract & reduction of systemic effect Protein binding Mucociliary transport causing increased or decreased drug residence time

Physiological effects.... -

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Local toxic effects of the drug

Eg., edema, cell injury, or altered tissue defens

Local or systemic effects of propellants, preservatives, or carriers

Pharmaceutical
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Physico-chemical properties of a drug candidate Methods to enhance drug absorption Spray pump devices

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1. Effect of particle size 2. Effect of molecular size 3. Effect of solution pH 4. Effect of drug lipophilicity 5. Effect of drug concentration

1. Effect of particle size

(aerodynamic size distribution)
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- Access to distal airways is a function of particle size - Large particles (> 7 microns) will be lost in the gastrointestinal tract - Small particles (< 3 microns) will be lost in exhaled

breathe - Intermediate particles (3 to 7 microns) reach the actual site of action

2. Effect of molecular size

- Higher the molecular size, lower the nasal absorptionsystemic bioavailability can be achieved for - A good molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used

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2. Effect of molecular size.....

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- With the assistance of absorption enhancer, a good bioavailability can be extended to a molecular weight of at least 6000 Daltons Absorption enhancers: Polyacrylic acid Sodium Glycocholate Sodium Deoxycholate Polysorbate 80 etc.

3. Effect of solution pH
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Nasal absorption is pH dependent

- Absorption is higher at a pH lower than the dissociation constant (pKa) of the molecule - Absorption is lower as the pH increases beyond the dissociation constant

4. Effect of drug lipophilicity

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- Lipid soluble drugs are absorbed more rapidly than water soluble drugs and are more likely to reach distal airways Polar (water soluble) drugs tend to remain on the
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tissues of the upper airway

5. Effect of drug concentration

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Absorption depends on the initial concentration of

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the drug - The absorption follows first-order kinetics

Methods to enhance nasal absorption of 33 drugs Structural modification Salt or ester formation Formulation design

SPRAY PUMP DEVICES

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- Unidose - Bidose - Multidose

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Bidose

Unido

Multidose
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LEADING PUMP SUPPLIERS 37 Pfeiffer, Germany Valois, France Becton Dickinson, France Nemo, Spain

Applicatio 38 ns Delivery of non-peptide

pharmaceuticals Delivery of peptide-based pharmaceuticals Delivery of diagnostic drugs

1. Delivery of non-peptide pharmaceuticals

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Drugs with extensive pre-systemic metabolism, such as progesterone, estradiol, propranolol, nitroglycerin, sodium chromoglyate can be rapidly absorbed through the nasal mucosa with a systemic bioavailability of approximately 100%

2. Delivery of peptide-based pharmaceuticals

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Peptides & proteins have a generally low oral bioavailability because of their physico-chemical instability and susceptibility to hepatogastrointestinal first-pass elimination Eg. Insulin, Calcitonin, Pituitary hormones etc. Nasal route is proving to be the best route for such biotechnological products

3. Delivery of diagnostic drugs

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Diagnostic agents such as Phenolsulfonphthalein kidney function Secretin pancreatic disorders Pentagastrin secretory function of gastric acid

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O C N

IO S LU C N

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Nasal drug delivery offers rapid onset of action with lower dose & minimal side effects Has an advantage of site-specific delivery with improved therapeutic effects

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Attractive for delicate molecules allowing systemic administration without significant degradation

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Nasal drug delivery system offers flexibility for multiple formulations ranging from nasal drop to suspension spray

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Recent activities indicate a bright prospect for site-specific delivery of biotechnological products such as Insulin & other hormones