Intranasal route of drug administration

Intranasal route of drug administration

1. INTRANASAL ROUTE MODERATOR - DR. VANDANA ROY PRESENTED BY - DR. SAHIL KUMAR

2. OUTLINE Introduction Nasal Anatomy & Physiology Mechanisms and Pathways of Nasal Absorption Factors Affecting Nasal Absorption Merits and Demerits Delivery Systems and Dosage Forms Enhancing Nasal Absorption Evaluation of Nasal Formulations Applications Conclusion

3. INTRODUCTION Transmucosal routes - bypass first pass effect. “ Nasya ” Tobacco snuff, cocaine, opium Early 1980s - introduction as promising systemic delivery alternative to invasive administrations. Peptide therapeutics, hormones, and vaccines being delivered through nasal cavity. Circumvent obstacles BBB.

4. Nasal route permeable to more compounds than GIT. ( Krishnamoorthy R et al., 1998; Kisan R et al ., 2007) P rimary targets. Nasal delivery suitable for drugs with following criteria: • ineffective orally • used chronically • used in small doses • rapid entry to systemic circulation desirable.

5. NASAL ANATOMY

6. NASAL VESTIBULE RESPIRATORY REGION Tight junctions. Mucus secretion 95 % water, 2 % mucin, rest proteins and salts . Mucin may trap large molecular weight drugs, such as peptides.

7. OLFACTORY REGION The nasal cavity also contains nasal associated lymphoid tissue (NALT), situated in the nasopharynx .

8. NASAL PHYSIOLOGY BLOOD FLOW MUCOCILIARY CLEARANCE (MCC) 5 mm/min , 15‐20 min. ENZYMATIC DEGRADATION Carboxyl esterase, aldehyde dehydrogenases, epoxide hydrolases, glutathione S‐transferases and Cytochrome P450 isoenzymes. Proteolytic enzymes (amino peptidases and proteases). Peptides may also form complexes with Igs in the nasal cavity. TRANSPORTERS AND EFFLUX SYSTEMS – Ciliated epithelial cells and sub mucosal vessels of human olfactory region contain P‐ gp .

9. NASAL SECRETIONS Viscosity Solubility Diurnal variation pH - pH of formulation should be between 4.5 to 6.5 for better absorption. ENVIRONMENTAL CONDITIONS PATHOLOGICAL CONDITIONS

10. MECHANISMS OF ABSORPTION First step in the absorption of drug from the nasal cavity is passage through the mucus . Subsequently absorption may occur via: transcellular & paracellular . Paracellular route : S low and passive. Inverse log-log correlation b/w intranasal absorption and molecular wt of water-soluble compounds.

11. Drugs also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions . C D

12. PATHWAYS FOR NASAL ABSORPTION

13. Nose to Brain N on-invasive delivery of therapeutic agents to CNS. O lfactory neural pathway provides both an intraneuronal and extraneuronal pathway into the brain. I ntraneuronal pathway - axonal transport ( hours to days). Extraneuronal pathway - bulk flow transport through perineural channels within minutes. Trigeminal neural pathway -rapidly delivering protein therapeutic agents .

14. FACTORS AFFECTING NASAL ABSORPTION I) Nasal Physiological factors II) Physicochemical Properties of Drugs III) Physicochemical Properties of Formulation

15. Physico -chemical properties of the drug MOLECULAR WEIGHT AND SIZE Lipophilic drugs - direct relationship b/w molecular weight and drug permeation whereas water soluble compounds have inverse relationship. SOLUBILITY A drug should have appropriate aqueous solubility for increased dissolution. LIPOPHILICITY N asal mucosa is primarily lipophilic in nature.

16. pKA AND PARTITION COEFFICIENT CHEMICAL STATE OF DRUG Chemically altering a drug molecule by adding a bio cleavable lipophilic moiety .

17. ‘ I deal ’ drug candidate for nasal delivery Appropriate aqueous solubility to provide desired dose in about 25-200 μ L volume of formulation administration per nostril . Low dose. Appropriate nasal absorption properties. No nasal irritation from the drug. A suitable clinical rationale for nasal dosage forms, e.g. rapid onset of action. No toxic nasal metabolites. No offensive odors/aroma associated with the drug. Suitable stability characteristics .

18. Physicochemical properties of formulation PHYSICAL FORM OF FORMULATION Viscous formulations may help in minimizing nasal drip. pH Nasal formulation should be adjusted to appropriate pH to avoid irritation. OSMOLARITY Isotonic formulation is preferred . BUFFER CAPACITY Nasal formulations are generally administered in small volumes. Hence , nasal secretions may alter pH of the administrated dose .

19. SOLUBILISERS PRESERVATIVES Nasal formulations usually contain preservatives to protect them from microbial contamination . Eg benzalkonium chloride and benzoyl alcohol. ANTIOXIDANTS Example sodium metabisulfite , sodium bisulfate and tocopherol. HUMACTANTS Examples like glycerin and sorbitol.

20. MERITS Non – invasive, rapid, easily accessible, self-administration possible thus improved convenience and compliance . Highly vascularized mucosal surface area for dose absorption. Direct absorption into blood avoids GI destruction & hepatic first pass metabolism . Improved bioavailability. Bypasses the BBB and targets the CNS , reducing systemic exposure thus systemic side effects. Direct contact site for vaccines with lymphatic tissues. Reduce risk of infectious disease transmission .

21. Can be easily administered to unconscious patients. Alternate to parenteral route especially for proteins and peptides. Unsuitable drug candidates for oral route can be successfully given via nasal route . Convenient route when compared with parenteral route for long term therapy . Side effects are reduced due to low dose . Offers lower risk of overdose . Minimal aftertaste.

22. DEMERITS Delivery volume in nasal cavity is restricted to 25–200 μL . Smaller absorption surface compared with GIT . Delivery is expected to decrease with increasing molecular weight of drug. Enzymatic barrier to permeability of drug. Some therapeutic agents may be susceptible to partial degradation in the nasal mucosa . Adversely affected by pathological conditions.

23. Possibility of nasal irritation hence inconvenient compared with oral route . Frequent use of this route may result in mucosal damage . Normal defense mechanisms like Muco -Ciliary Clearance and ciliary beating reduces the residence time of drug . (Histological) toxicity occurring due to absorption enhancers yet not established . Once the drug administered cannot be removed.

24. Differences from Other Routes Compared to ORAL medications, intranasal medication delivery results in: Faster delivery to the blood stream and higher blood levels. Avoids destruction by stomach acid and intestinal enzymes. Avoids destruction by hepatic first pass metabolism. Compared to IV medications, intranasal medication delivery results in: Comparable blood levels to IV route.

25. Liquid dosage forms NASAL DROPS Eg . Ephedrine, Xylometazoline . NASAL SPRAYS Solution/Suspension formulations. Metered dose pumps. Eg . Desmopressin, Nafarelin. NASAL EMULSIONS Not been studied as extensively as other liquid nasal delivery systems. Eg Clonazepam, Nimodipine , Risperidone. DELIVERY SYSTEMS

26. MUCOSAL ATOMIZATION DEVICE (M.A.D)

27. Semi-solid dosage forms NASAL GELS Thickened solutions or suspensions, of high-viscosity. Advantages - reduction of post-nasal dripping, taste impact due to reduced swallowing, anterior leakage of the formulation. Eg . Phenylephrine.

28. Solid dosage forms NASAL POWDERS Drug stability . Eg . Nafarelin, Sumatriptan . NASAL INSERT Novel , bioadhesive , solid dosage forms for prolonged systemic drug delivery. Eg . Oxymetazoline .

29. Breath actuated bi-directional drug delivery

30. ENHANCING NASAL ABSORPTION Nasal Enzyme Inhibitors Nasal metabolism of drugs can be eliminated by using the enzyme inhibitors. Mainly for the formulation of proteins and peptide molecules. Prodrug Approach Intranasal drugs commonly administered as solutions. Lipophilic drugs easily pass through biomembranes , however they are poorly water soluble .

31. Permeation enhancers Act via one of the following mechanisms: -Reduce mucus viscosity; -Decrease MCC; -Open tight junctions; and -Solubilize or stabilize the drug. Increasing the rate at which drug passes through the nasal mucosa . Surfactants , fatty acid salts, phospholipids, cyclodextrins and glycols. Bioadhesive polymer Improves retention - making an adhesive force between formulation and nasal mucosa, minimization of MCC.

32. Structural modification The chemical modification of drug molecule has been commonly used to modify the physicochemical properties of a drug such as molecular size, molecular weight, Pka and solubility. Salmon calcitonin.

33. Particulate drug delivery LIPOSOMES Advantage - effective encapsulation of small & large molecules with wide range of hydrophilicity & pKa . Increasing nasal retention of peptides. Protection of the entrapped peptides from enzymatic degradation. MICROSPHERES Microspheres are usually based on muco -adhesive polymers (chitosan, alginate). Protect the drug from enzymatic metabolism and sustain drug release . NANOPARTICLES Adjuvant in vaccines or as drug carriers, in which the active substance is dissolved, entrapped, encapsulated , adsorbed or chemically attached.

34. EVALUATION OF NASAL FORMULATIONS Rat model sodium pentobarbital ( i.p .). neck and the trachea is cannulated with a polyethylene tube . Another tube is inserted through the oesophagus towards the posterior region of the nasal cavity. The passage nasopalatine tract is sealed so that the drug solution is not drained from the nasal cavity through the mouth . The drug solution is delivered to the nasal cavity through the nostril or through the cannulation tubing . Femoral vein is used to collect the blood samples.

35. Rabbit Model Rabbits (approx. 3 kg) anaesthetized by i.m . injection of a combination of ketamine and xylazine . The rabbit's head held in upright position and nasal spray administered into each nostril. The blood samples collected by an indwelling catheter in the marginal ear vein or artery. In vitro diffusion studies Nasal mucosa of sheep separated from sub layer bony tissues. After complete removal of blood from mucosal surface, attached to donor chamber tube. The donor chamber tube placed such a way that it just touches the diffusion medium in recipient chamber. Samples (0.5 ml) from recipient chamber withdrawn at predetermined intervals.

36. APPLICATIONS LOCAL DELIVERY Oxymetazoline ( Nasal spray), Xylometazoline ( Nasal spray, nasal drops), Ephedrine ( Nasal drops) – Symptomatic relief of nasal congestion. Azelastine , Levocabastine , Olapatadine ( Nasal spray) - Seasonal and perennial allergic rhinitis and non-allergic perennial rhinitis. Fluticasone, Beclomethasone dipropionate , Mometasone , Triamcinolone acetonide , Flunisolide , Budesonide (Nasal spray, suspension)- Seasonal and perennial allergic rhinitis and non-allergic perennial rhinitis . Cromolyn sodium ( Nasal spray, suspension ) - Symptomatic prevention and treatment of seasonal or perennial rhinitis. Neomycin sulfate (Nasal Cream) – Nasal infection.

37. Drug Indication Dose delivered / actuation Peak Levels at Adverse Effects Nicotine (Nasal Spray) [ Nicotrol - NS 10 mg/ ml] Smoking Cessation 0.5 mg (1 dose = 2 sprays) 4-15 min Hot feeling in the back of nose/throat, runny nose throat irritation, watering eyes, Sneezing, coughing, tachycardia Cyanocobalamin (Nasal Spray) [ Nascobal ] Vitamin B 12 deficiency 500 μ g 1-2 hours Headache, sore throat, swollen tongue, nausea, tingling and rhinitis. Calcitonin-salmon (Nasal Spray) Post-menopausal osteoporosis 0.09 ml (200 CSU) 13-15 min Hypersensitivity Reactions, rhinitis, epistaxis, ulceration, backpain , arthralgia Desmopressin acetate (Nasal Spray) Diabetes insipidus, Hemophilia A, von Willebrand’s disease 0.1 ml (10 μ g ) 25 min Transient headache, nausea, nasal congestion, rhinitis, flushing, mild abdominal cramps SYSTEMIC DELIVERY

38. Drug Indication Dose delivered / actuation Peak Levels at Adverse Effects Buserelin (Nasal Spray) Prostatic carcinoma 100 μ g 30 min Bone pain, Urinary retention, numbness/tingling of hands & feet, headache, reduced libido. Nafarelin acetate (Nasal spray) Precocious puberty; endometriosis 100 μ L (200 μ g) 10 – 40 min Hot flashes, loss of libido, vaginal dryness, osteoporosis, emotional lability. Estradiol (Nasal Spray) Hormone Repacement Therapy 150 μ g 60 min Breast tenderness, headache, fluid retention; hair loss, nausea. spotting or breakthrough bleeding. Oxytocin (Nasal Spray) Promote milk ejection in breast feeding 40 IU 3 min Headache, water intoxication Sumatriptan (Nasal spray) Migraine 5 mg 60 min Local irritation , hypersensitivity, chest/ throat tightness, arrhythmia, MI Fentanyl (Nasal spray) Management of pain. 100 μ g 5-16 min Vomiting, nausea, constipation, Dizziness, hypersensitivity, shallow breathing

39. NASAL VACCINES Especially against respiratory infections. IgG and IgA. May be important against HIV and Hepatitis B virus. Live attenuated influenza vaccine ( FluMist ) – Nasal Spray Suspension. (adenovirus‐vectored influenza, group B meningococcal native, attenuated respiratory syncytial virus and parainfluenza 3 virus).

40. CNS DELIVERY Delivery of drugs to CNS; impenetrable nature of BBB. Olfactory neuro-epithelium, trigeminal nerve system. Alzheimer’s disease ( mucoadhesive emulsion of Tacrine ) Tumors (5-FU) E pilepsy (diazepam, carbamazepine) Pain (chitosan-morphine) Antimicrobial cephalexin to Rats.

41. CONCLUSION

42. Thank You