Slide 1

DEPARTMENT OF PHARMACEUTICS, UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES, KAKATIYA UNIVERSITY, WARANGAL. BY V. SANDEEP KUMAR M.PHARMACY II ASEMESTER 2010

Slide 2

Clinical testing of IN Morphine gluconate compared with traditional IM and oral products

Slide 3

CONTENTS INTRODUCTION ANATOMY AND PHYSIOLOGY OF NASAL CAVITY BARRIERS TO NASAL ABSORPTION FACTORS INFLUENCING NASAL DRUG ABSORPTION STRATEGIES TO INCREASE NASAL DRUG ABSORPTION NOSE TO BRAIN DELIVERY INTRANASAL DELIVERY OF VACCINES INTRANASAL DELIVERY OF PEPTIDE AND PROTEINE DRUGS ANIMAL MODELS FOR NASAL ABSORPTION STUDIES THERAPEUTIC AREAS SUTIABLE FOR INTRANASAL DELIVERY CONCLUSION REFERENCES

Slide 4

Avoidance of hepatic first-pass metabolism Non-invasive, Painless, needle-free administration mode Rate of absorption comparable to IV medication Self-medication is possible through this route Easily accessible (even easier to access than IM or IV sites) Avoids degradation of drug in gastrointestinal tract resulting from acidic or enzymatic degradation Results in rapid absorption and onset of effect

Slide 5

Results in higher bioavailability thus uses lower dose & hence lower side effects Useful for both local & systemic drug delivery Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal drug delivery Offers lower risk of overdose Direct transport into systemic circulation and CNS is possible.

Slide 6

Adversely affected by pathological conditions(cold or allergies may alter significantly the nasal bioavailability) Normal defence mechanisms like mucocillary clearance and ciliary beating affects the permeability of drug Enzymatic barrier to permeability of drugs Volume that can be delivered into nasal cavity is restricted to 25200 l Interspecies variability is observed in this route Irritation of nasal mucosa by drugs Absorption enhancers cause irritation.

Slide 7

Major functions of the nasal cavity are breathing and olfaction. Nasal vasculature is richly supplied with blood to fulfill the basic functions such as heating and humidification, mucociliary clearance and immunological functions. Relatively large surface area (~150 cm 2 ) because of the presence of ~400 microvilli per cell. It is divided by middle (or nasal) septum into two symmetrical halves, each one opening at the face through nostrils and extending posterior to the nasopharynx. NASAL CAVITY :ANATOMY, PHYSIOLOGY

Slide 8

Slide 9

Cross-sectional View a nasal vestibuled middle turbinate b palatee superior turbinate c inferior turbinatef nasopharynx

Slide 10

Slide 11

Nasal secretions Nasal secretion contains sodium, potassium, calcium, mucus glycoproteins, albumins, immunoglobulins IgA, IgG, lysozymes, cytochrome P450 dependent monooxygenases, lactate dehydrogenase, oxidoreductases, hydrolases like steroid hydrolases Nasal pH It varies between 5.56.5 in adults and 5.07.0 in infants. Nasal epithelium is covered with a thin mucus layer (5 m thick) and organized in two distinct layers: an external, viscous and dense(gel), and an internal, fluid and serous(watery). Nasal mucus layer consists of 95% of water, 2.5-3% of mucin, and 2% of electrolytes, proteins, lipids, enzymes, antibodies, sloughed epithelial cells and bacterial products

Slide 12

MUCOCILIARY CLEARANCE(MCC)

Slide 13

Lipophilic drugs are generally well absorbed with the pharmacokinetic profiles identical to those obtained after an I.V injection and bioavailabilities approaching 100%. Ex: fentanyl where the T max for both i.v and nasal administration is 7 min or less and the bioavailability was near to 80%. Nasal permeability of polar drugs especially large mol.wt polar drugs such as peptides and proteins is low. Polar drugs with mol.wt below 1000 Da will generally pass the membrane using paracellular route. Nasal mucosal lining Enzymes present in nasal cavity Mucociliary clearance (MCC)

Slide 14

Tight junctions can open and close to a certain degree, when needed. Proteins through endocytotic transport process but only in low amounts. Clearance of the administered formulation from the nasal cavity due to the mucociliary clearance mechanism. Especially for drugs that are not easily absorbed and formulations that are not mucoadhesive. Aldehyde dehydrogenase, glutathione transferase, epoxide hydrolases, cytochrome P-450-dependent monooxygenases, carboxyl esterases ex: nasal decongestants, alcohols, nicotine and cocaine. Aminopeptidases, exopeptidases, endopeptidases are involved in in pre systemic degradation of peptides and proteins

Slide 15

Transport Of Drugs Across Nasal Epithelium A- Transcellular passive diffusion, B- Paracellular passive diffusion, C-Carrier mediated, D- Transcytosis, E- Effluxt ransport

Slide 16

Slide 17

NASAL PHYSIOLOGICAL FACTORS Blood flow and neuronal regulation Huang et al showed that phenylephrine, a vasoconstrictor agent, inhibited the absorption of acetylsalicylic acid in nasal cavity. Kao et al. stated that nasal absorption of dopamine was relatively slow and incomplete probably due to its own vasoconstrictor effect. Nasal secretions Viscosity of nasal secretion Diurnal variation pH of nasal cavity Mucociliary clearance (MCC) The clearance of a drug product from the nasal cavity is influenced by the site of deposition.

Slide 18

Polar drugs are the most affected by MCC. Inter-individual variability observed in MCC. Enzymatic degradation Transporters and efflux systems Physicochemical properties of drugs Molecular weight Lipophilicity pKa Lipophilic drugs well absorbed through transcellular mechanisms with nasal bioavailability near to 100%( lower than 1 kDa). Absorption of lipophilic drugs bigger than 1 kDa is significantly reduced.

Slide 19

Rate of permeation of polar drugs is highly sensitive to mol.wt if it is higher than 300 Da. For some small polar molecules only a 10% bioavailability is suggested. The value may go down to 1% for large molecules such as proteins. Huang, C.H. et al. studied absorption of benzoic acid at pH 7.19 (99.9% of the drug existed in ionized form) it was found that >10% of drug was absorbed. Solubility Drugs poorly soluble in water and/or requiring high doses may constitute a problem as allowable volume of drug solution is low for intranasal drug administration

Slide 20

PROPERTIES OF THE FORMULATION pH Viscosity Osmolarity Pharmaceutical excipients Area of nasal mucus membrane exposed Dosage form Device related factor Particle size of the droplet or powder If the particle size is