1. Presented by-Prajakta chavanM.PHARM (Ist semester)PHARMACEUTICSGuided by-Dr. S.N.DHOLE(Prof. pharmaceuticsdept )MODERN COLLEGE OF PHARMACY(FOR LADIES),MOSHI,PUNE

2. CONTENT- INTRODUCTION ANATOMY & PHYSIOLOGY OF NASAL CAVITY MECHANISM OF NASAL ABSORPTION FACTORS AFFECTING NASAL DRUG ABSORPTION APPLICATION EVALUATION MARKETED PREPERATION LITERATURE SURVEY CONCLUSION REFERENCE2 3. INTRODUCTION-Nasalmucosa has been considered as a potential administration route to achieve faster and higherlevel of drug absorptionNasal therapy is the recognized form of treatment in the Ayurvedic systems of Indian medicine,and also called as NASAYA KARMAIt offers a needleless solution to drug delivery.It is a useful delivery method for drugs that are active in low doses.But it show no minimal oral bioavailability such as proteins and peptides.One of the reasons for low degree of absorption of peptides and proteins via the nasal route israpid movement away from the absorption site in the nasal cavity due to the mucociliaryclearance mechanism.Hormones and steroidsThis route is used for administration of systemic medications as well as for local effects.3 4. Topical administration includes the treatment of congestion, rhinitis, sinusitis and related allergicor chronic conditions and has resulted in a variety of different medications including corticoids,antihistamines, anticholinergic and vasoconstrictorsTo deliver therapeutics into the nasal cavities, i.e., nasal drops as multiple or single doseformulation, aqueous nasal sprays, nasal gel pump, pressurized MDIs and dry powder inhalers.4 5. ADVANTAGES- Drug degradation that is observed in the gastrointestinal tract is absent. Hepatic first pass metabolism is avoided. Rapid drug absorption and quick onset of action can be achieved. The bioavailability of larger drug molecules can be improved by means of absorption enhanceror other approach. The nasal bioavailability for smaller drug molecules is good.Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal drugdelivery.Nasal route is an alternate to parental route, especially, for protein and peptide drugs.Convenient for the patients, especially for those on long term therapy, when compared withparental medication. Drugs possessing poor stability in g.i.t. fluids are given by nasal route. Polar compounds exhibiting poor oral absorption may be particularly suited for this route ofdelivery system5 6. DISADVANTAGES- The histological toxicity of absorption enhancers used in nasal drug delivery systemis not yet clearly established. Relatively inconvenient to patients when compared to oral delivery systems sincethere is a possibility of nasal irritation. Nasal cavity provides smaller absorption surface area when compared to GIT. There is a risk of local side effects and irreversible damage of the cilia on the nasalmucosa, both from the substance and from constituents added to the dosage form. Certain surfactants used as chemical enhancers may disrupt and even dissolve themembrane in high concentration. There could be a mechanical loss of the dosage form into the other parts of therespiratory tract like lungs because of the improper technique of administration.6 7. ANATOMY & PHYSIOLOGY OF NASAL CAVITY-Thenasal cavity-1) extends posterior to the nasopharynx2) the nasal vestibule, opens to the face through the nostril.3 main regions-nasal vestibule,olfactory region respiratory region.The surface area in the nose is enlarged about 150cm2 by the lateral walls of the nasalcavity which includes a folded structure.This folded structure consists of three turbinates superior, median the inferiorThe main nasal airway having the narrow passages usually has 1-3mm wide and thesenarrows structures are useful to nose to carry out its main functions.The nasal cavity is covered with a mucous membranei.e. 1)non-olfactory2)olfactory epithelium 7 8. .In non-olfactory area includes- the nasal vestibule ,covered with skin-like stratified squamousepithelium cellsIn respiratory region,-it has typical airways in the epithelium covered with numerous microvilli,resulting in a large surface area available for drug absorption and transport.Mucus layer is propelled in a direction from the anterior towards the posterior part of the nasalcavity. The goblet cells are present in the mucus membrane which covers the nasal turbinate andthe atrium. It secretes mucus as mucus granules which swell in the nasal fluid to contribute to themucus layerCOMPOSITION-95% water, 2 % mucin, 1% salts, 1% of proteins such as albumin,immunoglobulins, lysozyme and lactoferrin, and 1% lipids .8 9. Mechanism of Nasal Absorption:(1,7)The two mechanisms-First mechanism: It involves an aqueous route of transport, which is also known as the paracellular route butslow and passive.There is an inverse log-log correlation between intranasal absorption and the molecular weightof water soluble compounds.The molecular weight greater than 1000 Daltons show poor bioavailability 8.Second mechanism: It involves transport through a lipoidal route known as the transcellular process. It is responsible for the transport of lipophilic drugs that show a rate dependency on theirlipophilicity.Drugs can also cross cell membranes by an active transport route via carrier-mediated means ortransport through the opening of tight junctions.example - chitosan, a natural biopolymer from shell fish opens tight junctions between epithelialcells to facilitate drug transport9 10. 10 11. 1)DRUG CONCENTRATION-Higherconcentration not only causes increased bioavailability but also leads to the toxicity to thenasal epithelium.2)PH of the formulation-PH -4.56.53)MOLECULAR WEIGHT OF THE DRUG-Therate of permeation is highly sensitive to molecular size for compounds with MW 300Daltons.4)RELATIVE LIPID SOLUBILITY-Lipophilicdrugs naloxone, buprenorphine, testosterone and 17a-ethinyl- oestradiol5)MUCOCILIARY CLEARENCE(MCC)-Functions-To prevent noxious substances (allergens, bacteria, viruses, toxins etc.) from reaching the lungs.The mucus transport rate is 6 mm/min.6)RHINITIS- symptoms,hyper secretion, itching and sneezing mainly caused by the viruses, bacteria or irritants .It is caused by chronic or acute inflammation of the mucous membrane of the nose.11 12. Strategies to improve Nasal Absorption-1) To improve the nasal residence time2 To enhance nasal absorption3) To modify drug structure to change physicochemical properties1)To improve the nasal residence time-polymers-methylcellulose, hydroxy propyl methyl cellulose or polyacrylic acidE.g- insulin solution(carbopol and CMC)Biodegradable microspheres2)To enhance nasal absorption- General requirement of an ideal penetration enhancer-1. It should lead to an effective increase in the absorption of the drug2. It should not cause permanent damage or alteration to the tissue3. It should be non irritant and nontoxic.4. It should be effective in small quantity5. The enhancing effect should occur when absorption is required 12 13. Classification-3)Modifying drug structure:molecular size, molecular weight, Pka and solubility.SolventsAlkyl methylsulphoxidepyrrolidone1-Dodecylazacycloheptane 2-oneSurfactant13 14. 14 15. DOSAGE FORMS-LIQUID FORMULATIONPOWDER FORMULATIONNASAL GELNASAL DROPNASAL SPRAY15 16. 1)LIQUID NASAL FORMULATION-Advantages-humidifyingeffect is convenient and useful in crusts and drying of mucous membranes.Drawback-Microbiological stability, irritation and allergic rhinitis ,short residence time.1)Instillation and Rhinyle Catheter:Catheters are used to deliver the drops to a specified region of nasal cavity easily.The formulation is placed in the tube. One end is positioned in the nose, and the solution isdelivered into the nasal cavity by blowing through the other end by mouth16 17. Compressed Air Nebulizer-Nebulizer is a device used to administer medication in theform of a mist, inhaled into the lungs.These pharmaceuticals are inhaled instead of ingestion.Compressed air is filled into the device. It is in order to target their effect to the respiratory tract,which speeds onset of action of the medicine and reducesside effects, compared to other alternative intake routes.This device is not suitable for the systemic delivery ofdrug by patient himself.Corticosteroids and Bronchodilators such assalbutamol (Albuterol USAN) are often used andsometimes in combination with ipratropium17 18. Metered-dose pump spray-Solutions, emulsions or suspensionsThe three main types available for local effect areantihistamines, corticosteroids, and topicaldecongestantsMetered- dose pump sprays include the container, thepump with the valve and the actuator.The dose accuracy of metered-dose pump sprays isdependent on the surface tension and viscosity of theformulation.For solutions with higher viscosity, special pump andvalve combinations are available in the market18 19. POWDER DOSAGE FORM-Drypowder inhaler-Active drug is delivered for local or systemic effectvia the pulmonary route .It contain solid drug, suspended or dissolved in anon polar volatile propellant or in dry powder inhalerthat is fluidized when the patient inhales.Asthma, bronchitis, emphysema andCOPD,diabetesmellitus.Operator puts the mouthpiece of the inhaler intotheir mouth and takes a deep inhalation, holding theirbreath for 5-10 seconds .Dose less than a few tens of milligrams in a singlebreath .Large dose-provocation of cough.19 20. NASAL GELNasal gels are high-viscosity thickened solutionsor suspensions.The advantages reduction of post-nasal drip due to highviscosity,reduction of taste impact due to reducedswallowing,reduction of anterior leakage of the formulation,reduction of irritation by using soothing/emollientexcipients and target delivery to mucosa for betterabsorption.20 21. NASAL SPRAY-Both solution and suspension formulations can beformulated into nasal sprays.Due to the availability of metered dose pumps andactuators, a nasal spray can deliver an exact dosefrom 25 to 200 m.The particles size and morphology (forsuspensions)of the drug and viscosity of theformulation determine the choice of pump andactuator assembly21 22. 22 23. Delivery of Non-Peptide Pharmaceuticals:Molecular weight (below 1000 daltons) small non-peptide lipophilic drug.Drugs with extensive pre-systemic metabolism,1) progesterone,2) estradiol,3) propranolol,4) nitroglycerin,5) sodium chromoglyatecan be rapidly absorbed through the nasal mucosa with a systemic bioavailability ofapproximately 100% .23 24. Delivery of Peptide-Based Pharmaceuticals:Peptides & proteins have generally a low oral bioavailability because of theirphysicochemical instability and susceptibility to hepato-gastrointestinal first passelimination.Examples - insulin, calcitonin, pituitary hormones .Use of absorption enhancers like surfactants, glycosides, cyclodextrin and glycolswill increase the bioavailability.Nasal route is proving to be the best route for such biotechnological products24 25. Delivery of Drugs to Brain through Nasal Cavity:It is useful in condition like, Parkinsons disease, Alzheimers disease or pain becauseit requires rapid and/or specific targeting of drugs to the brain. It increase the fraction ofdrug that reaches the CNS after nasal delivery.The olfactory region located at the upper remote parts of the nasal passages offers thepotential for certain compounds to circumvent the blood-brain barrier and enter into thebrain.25 26. Delivery of Vaccines through Nasal Route:it stimulates the production of local secretory IgA .IgG antibodies, providing anadditional first line of defense, which helps to eliminate the pathogen before it becomesestablished.Delivery of Diagnostic Drugs:Phenolsulfonphthalein -used to diagnose the kidney function .Secretin- Pancreatic disorders of the diabetic patients Pentagastrin-secretory function of gastric acid26 27. EVALUATION OF NASAL FORMULATION-Invitro diffusion studies-The nasal mucosa of sheep was separated from sub layer bony tissues .stoned in distilled water containing few drops at genatamycin injectionAfter the complete removal of blood from muscosal surface, is attached todonor chamber tube.The donor chamber tube is placed such a way that it just touches thediffusion medium in recipient chamberAt predetermined intervals, samples (0.5 ml) from recipient chamber arewith draw and transferred to amber colored ampoulesThe samples withdrawn is suitably replaced. The samples are estimated fordrug content by suitable analytical technique. Temperature is maintained at37 oC.27 28. B) In Vivo Nasal Absorption studies-Rabbit Model1. It is relatively cheap, readily available and easily maintained in laboratory settings2. It permits pharmacokinetic studies as with large animals3. The blood volume is large enough (approx. 300ml)4. To allow frequent blood sampling (l-2ml)In the anaesthetized model, the rabbit is anaesthetized by an intramuscular injection of acombination of ketamine and xylazine.The rabbit's head is held in an upright position and the drug solution is administered by nasalspray into each nostril.During the experiment the body temperature of the rabbit is maintained at 37C with the help of aheating pad.The blood samples are collected by an indwelling catheter in the marginal ear vein or artery.28 29. Rat Model-PROCEDURE:The rat is anaesthetized by intraperitoneal injection of sodium pentobarbital.An incision is made in the neck and the trachea is cannulated with a polyethylene tube.Another tube is inserted through the oesophagus towards the posterior region of thenasal cavity.The passage of the nasopalatine tract is sealed so that the drug solution is not drainedfrom the nasal cavity through the mouth. The drug solution is delivered to the nasalcavity through the nostril or through the cannulation tubing.The blood samples are collected from the femoral vein. As all the probable outlets ofdrainage are blocked, the drug can be only absorbed and transported into the systemiccirculation by penetration and/or diffusion through nasal mucosa29 30. MARKETED PREPERATIONMARKETED FORMULATION ACTIVE INGREDIENTOtrivine adult nasal drop Xylometazoline hydrochloride0.1w /vDymista nasal spray , suspension Azelastinehydrochloride,fluticasoneproprionateImitrex nasal spray sumatriptanStimate nasal spray Desmopressin acetateMiacalcic nasal spray CalcitoninVibrocil gel Phenylephrine,dimethindene maleateAstelin nasal spray Azelastine hydrochloride30 31. Literature Survey31 32. NASAL DRUG DELIVERY OFFERS SUCH BENEFITS AS,-Rapid onset of action with lower dose & minimal side effects.-Has an advantages of site specific delivery with improved therapeutic effect-Attractive for delicate molecule allowing systemic circulation without significantdegradation.Nasal drug delivery offers flexibility for multiple formulation ranging from nasaldrop to nasal spray.Recent activities indicate a bright prospect for site specific delivery ofbiotechnological product such as insulin & other harmones.32 33. 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