SEMINAR ON intranasal drug delivery

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

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

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

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

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

6. LIMITATIONS Adversely affected by pathological conditions(cold or allergies may alter significantly the nasal bioavailability) Irritation of nasal mucosa by drugs Volume that can be delivered into nasal cavity is restricted to 25–200 μl Normal defence mechanisms like mucocillary clearance and ciliary beating affects the permeability of drug Enzymatic barrier to permeability of drugs Interspecies variability is observed in this route Absorption enhancers cause irritation.

7. NASAL CAVITY :ANATOMY, PHYSIOLOGY • 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.

8. Anatomy And Histology Of Human Nasal Cavity

9. Cross-sectional View a – nasal vestibule d – middle turbinate b – palate e – superior turbinate c – inferior turbinate f – nasopharynx

10. Human Nasal Epithelium Characteristics

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 5.5–6.5 in adults and 5.0–7.0 in infants. • Nasal epithelium is covered with a thin mucus layer (5 μm 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

12. MUCOCILIARY CLEARANCE(MCC)

13. Barriers To Nasal Absorption • Nasal mucosal lining • Enzymes present in nasal cavity • 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 Tmaxfor 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.

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

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

16. FACTORS INFLUENCING NASAL DRUG ABSORPTION

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.

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.

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

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 <10 μm, then particles will be deposited in the upper respiratory tract, whereas if particle size is <0.5 μm then it will be exhaled. Size between 5–7 μm will be retained in the nasal cavity. Site and pattern of deposition

21. STRATEGIES TO INCREASE NASALDRUG ABSORPTION

22. Prodrugs To improve the solubility of poorly soluble drugs. Ex: the l-dopa has a low water solubility of 1.65 mg/Ml, Testosterone, Estradiol Kao et al. produced various prodrugs of L-Dopa and the solubility was increased to 660 mg/mL with butyl ester prodrug. To improve its lipophilic character, ultimately increasing its transport across a biological membrane

23. To improve enzymatic stability of drugs. For example, Yang et al. stated that L-aspartate- β-ester prodrug of acyclovir was more permeable and less labile to enzymatic hydrolysis than its parent drug. • It is a a powerful strategy to increase the bioavailability of peptides. Choice of salt form Cancer patients treated with nasally administered morphine gluconate experienced rapid onset of pain relief and good pain scores (Fitzgibbon et al., 2003; Pavis et al., 2002).

24. Co-solvents Diazepam and Clonazepam are administered to suppress epileptic convulsions requires rapid onset of action. However, these are poorly soluble and nasal formulations comprised of cosolvents demonstrated a Tmax of <5 min, and a pharmacodynamic response was seen in 1.5 min in a rabbit model (Li et al.,2000) • Enzymatic inhibitors • Proteases and Peptidases inhibitors - bestatine, amastatin, boroleucin, borovalin, and comostate amylase, puromycin, bacitracin (Ex: leucine enkephalin and human growth hormone) • Trypsine inhibitors – leupeptine and aprotinin (against degradation of calcitonin). • Certain absorption enhancers - bile salts and fusidic acid.

25. Absorption enhancers They improve the absorption of poorly permeable molecues across nasal epithelium. • Physicochemical effects • By alterig the physicochemical properties of a drug in the formulation. • Membrane effects • Induce reversible modifications of the structure of epithelial barrier. • Modifying the phospholipidic bilayer, • Increasing membrane fluidity by • a) Extraction or leaching of membrane components ( proteins) • b) Creating disorders in the phospholipids domain in the membrane. • Reversed micelle formation between membranes. • Opening tight junctions between epithelial cells.

26. Nasal Absorption Promoting Systems

27. Chitosan • Due to its biodegradability, biocompatibility and bioadhesive property, lower toxicity, it is widely used in intranasal formulations. • It interacts with protein kinase C system and opens the tight junctions between epithelial cells. • It also enhances the dissolution rate of low water soluble drugs. • Most studied drugs are insulin and morphine • Cyclodextrins • As complexing agents to improve nasal drug absorption by increasing drug solubility and stability. (2-hydroxypropyl-cyclodextrin increased the solubility of progesterone 88-fold.) • They interact with the lipophilic components of membranes changing their permeability.

28. A nasal product (Aerodiol) containing 17-estradiol solubilized in dimethyl-cyclodextrin is marketed for menopausal symptoms. • Mucoadhesive drug delivery systems • Mucoadhesion implies the attachment of the drug delivery system to the mucus, involving an interaction between mucin and a synthetic or natural polymer is called mucoadhesive. • Mucoadhesives mostly used in IN delivery are chitosan, alginate and cellulose or its derivatives. • Carbapol 934P and polycarbophil are mucoadhesive polymers that inhibit the trypsin proteolytic enzyme and therefore, increase the stability of peptide drugs.

29. NOVEL DRUG FORMULATIONS • Liposomes • They can effectively encapsulate small and large molecules with a wide range of hydrophilicity and pKa values . • They enhance nasal absorption of peptides such as insulin and calcitonin by increasing their membrane penetration (attributed to the increasing nasal retention of peptides, protection of the entrapped peptides from enzymatic degradation ). • Novel mucoadhesive multivesicular liposomes for transmucosal insulin delivery has been investigating. • Lliposomal drug delivery systems were also reported as useful for influenza vaccine and non-peptide drugs such as nifedipine.

30. Microspheres • Microspheres based on mucoadhesive polymers (chitosan, alginate) present advantages for IN delivery. • Microspheres may also protect the drug from enzymatic metabolism. • Wang et al. have investigated gelatin microspheres as a IN delivery system for insulin . • Positive results are found for nasal delivery of • Metoclopramide microspheres of alginate/chitosan • Carbamazepine chitosan microspheres • Carvedilol alginate microspheres

31. Nose to brain delivery • New and developing approach to deliver drugs to the brain. • Improved delivery to the brain via the IN route has been reported for some low-mol.wt drugs as well as therapeutic peptides and proteins . • Nose to brain delivery has been reported either in humans or animal models of Alzheimer’s disease, brain tumours, epilepsy, pain and sleep disorders . • Nose to the CNS may occur via olfactory neuroepithelium. • Since central nervous bioavailability of drugs, transported by the olfactory-pathway is estimated to be 0.01% to 0.1%, only very potent drugs may reach therapeutic levels

33. Possible routes of transport between the nasal cavity and the brain and CSF

34. Efflux transporters impair drug concentration in the brain after IN administration [Graff and Pollack 2003]. P-glycoprotein, an ATP-dependent efflux pump, preventing the influx of a drug (D) from nasal membrane to CNS

36. Human clinical testing of IN Apomorphin, Sublingual and subcutaneous dosing in 12 subjects

37. INTRANASAL DELIVERY OF VACCINES • Nasal mucosa houses lymphatic tissues involved in the first line defense against airborne microorganism. • In humans the NALT is known as the Waldeyer´s Ring. Reasons for exploiting the nasal route for vaccine delivery. • The nasal mucosa is the first site of contact with inhaled pathogens. • The nasal passages are rich in lymphoid tissue. • Creation of both mucosal and systemic immune responses. • Low cost, patient friendly, non-injectable, safe.

38. The majority of the invading pathogens enter the body via mucosal surfaces. Therefore, mucosal sites have a potentialas first line of defense against entering pathogens. • Nasal secretions are known to contain immunoglobulins (IgA, IgG, IgM, IgE), and neutrophils and lymphocytes in the mucosa . • Nasal vaccine delivery stimulates the production of local secretory IgA and IgG • Nasal vaccine systems based on live or attenuated whole cells, split cells, proteins or polysaccharides and with and without various adjuvants were investigating.

39. Nasal Drug Products for Vaccination Available in the Market

41. 2009 H1N1 “flu shot” vaccine

42. 2009 H1N1 Nasal Spray Vaccine

43. The chitosan nasal delivery system has been tested for influenza, and diphtheria vaccine in various animal models and in man. • Bioadhesive property and transient effect on the tight junctions of chitosan lead to an improved immune response. • It has been reported that Ab levels were similar for IM conventional influenza vaccine and nasal administration of the chitosan-influenza vaccine. • Due to its positive charge chitosan gets complexed with negatively charged DNA plasmids and self-assembling into nanoparticulate systems for improved delivery of DNA. • Nasal delivery of DNA plasmid expressing epitopes of respiratory syncytial virus (RSV) to produce an effective vaccine.

44. INTRANASAL DELIVERY OF PEPTIDE AND PROTEIN DRUGS • Being hydrophilic polar molecules of relatively high molecular weight, are poorly absorbed across biological membranes with low bioavailabilities . • This low uptake may adequate for some commercial products such as desmopressin and calcitonin ( 3432 Da, 3% (Novartis Pharmaceuticals, 2006). • Novel formulation strategies • Absorption enhancers • Bioadhesive agents • Absorption enhancing effect of different cyclo-dextrins (rats,rabbits), medium chain fatty acid (rats), sodium tauro-24, 25-dihydrofusidate (sheep) on intranasally administered insulin in rats and rabbits was obsrved.

45. Bioavailabilities of peptides and proteins administered IN in the absence of absorption enhancers

46. Bioavailabilities of peptides and proteins administered IN in the presence of absorption enhancers

47. The clearance half- life can be increased with starch microspheres of insulin (SMS). • Insulin administered in combination with SMS resulted in 497% increase in AUC for plasma insulin as compared to insulin solution. • The AUC increased by 1657% compared to insulin solution when an enhancer lysophosphatidyl choline was used with insulin and SMS. • Successfully intranasally administered proteins include oxytocin, buserelin, desmopressin, luteinizing hormone releasing hormone, growth hormone and adrenocorticotrophic hormone.

48. Nasal Drug Products (Proteins and Peptides) for Systemic Drug Delivery on the Market

49. Nasal Drug Products (Non-Peptide) for Systemic Drug Delivery on the Market

50. ANIMAL MODELS FOR NASAL ABSORPTION STUDIES