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SEMINAR ONintranasal drug deliveryDEPARTMENT OF PHARMACEUTICS,UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES,KAKATIYA UNIVERSITY, WARANGAL.

BYV. SANDEEP KUMARM.PHARMACY II ASEMESTER2010

Clinical testing of IN Morphine gluconate comparedwith traditional IM and oral products

INTRODUCTIONCONTENTS INTRODUCTIONANATOMY AND PHYSIOLOGY OF NASAL CAVITYBARRIERS TO NASAL ABSORPTIONFACTORS INFLUENCING NASAL DRUG ABSORPTIONSTRATEGIES TO INCREASE NASAL DRUG ABSORPTIONNOSE TO BRAIN DELIVERYINTRANASAL DELIVERY OF VACCINESINTRANASAL DELIVERY OF PEPTIDE AND PROTEINE DRUGSANIMAL MODELS FOR NASAL ABSORPTION STUDIESTHERAPEUTIC AREAS SUTIABLE FOR INTRANASAL DELIVERYCONCLUSIONREFERENCES

Avoidance of hepatic first-pass metabolism

Non-invasive, Painless, needle-free administration mode

Rate of absorption comparable to IV medicationSelf-medication is possible through this routeEasily accessible (even easier to access than IM or IV sites)

Avoids degradation of drug in gastrointestinal tract resultingfrom acidic or enzymatic degradationResults in rapid absorption and onset of effectADVANTAGESResults 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 deliveryOffers lower risk of overdose

Direct transport into systemic circulation and CNS is possible .ADVANTAGES.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 drugEnzymatic barrier to permeability of drugsVolume that can be delivered into nasal cavity is restricted to25200 l

Interspecies variability is observed in this route

Irritation of nasal mucosa by drugs

Absorption enhancers cause irritation.

LIMITATIONS 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 cm2) 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, PHYSIOLOGY7

Anatomy And Histology Of Human Nasal CavityCross-sectional View

a nasal vestibuled middle turbinate b palatee superior turbinate c inferior turbinatef nasopharynx

Human Nasal Epithelium CharacteristicsNasal secretionsNasal secretion contains sodium, potassium, calcium, mucus glycoproteins, albumins, immunoglobulins IgA, IgG, lysozymes, cytochrome P450 dependent monooxygenases, lactate dehydrogenase, oxidoreductases, hydrolases like steroid hydrolases

Nasal pHIt 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

MUCOCILIARY CLEARANCE(MCC) 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 Tmax 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. Barriers To Nasal AbsorptionNasal mucosal liningEnzymes present in nasal cavityMucociliary clearance (MCC)

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

Transport Of Drugs Across Nasal Epithelium

A- Transcellular passive diffusion, B- Paracellular passive diffusion, C-Carrier mediated , D- Transcytosis , E- Effluxt ransport FACTORS INFLUENCING NASAL DRUG ABSORPTION

NASAL PHYSIOLOGICAL FACTORS Blood flow and neuronal regulationHuang 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 variationpH of nasal cavity Mucociliary clearance (MCC)The clearance of a drug product from the nasal cavity is influenced by the site of deposition.

Polar drugs are the most affected by MCC.Inter-individual variability observed in MCC.Enzymatic degradationTransporters and efflux systemsPhysicochemical properties of drugs Molecular weight Lipophilicity pKaLipophilic 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.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.SolubilityDrugs poorly soluble in water and/or requiring high doses may constitute a problem as allowable volume of drug solution is low for intranasal drug administrationPROPERTIES OF THE FORMULATIONpHViscosityOsmolarityPharmaceutical excipientsArea of nasal mucus membrane exposedDosage formDevice related factorParticle size of the droplet or powderIf the particle size is