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)
Primary 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 :
 Slow 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.
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12. PATHWAYS FOR NASAL ABSORPTION

13. Nose to Brain
Non-invasive delivery of therapeutic agents to
CNS.
Olfactory neural pathway provides both an
intraneuronal and extraneuronal pathway into
the brain.
Intraneuronal 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
Nasal 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. ‘Ideal’ drug candidate for nasal delivery
Appropriate aqueous solubility to provide desired dose in about 25-200 μL 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. MUCOSALATOMIZATION 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 B12
deficiency
500 μg 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 μg ) 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 μg 30 min Bone pain, Urinary retention,
numbness/tingling of hands &
feet, headache, reduced libido.
Nafarelin acetate
(Nasal spray)
Precocious puberty;
endometriosis
100 μL (200 μg) 10 – 40
min
Hot flashes, loss of libido,
vaginal dryness, osteoporosis,
emotional lability.
Estradiol
(Nasal Spray)
Hormone
Repacement Therapy
150 μg 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 μg 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)
• Epilepsy (diazepam, carbamazepine)
• Pain (chitosan-morphine)
• Antimicrobial cephalexin to Rats.

41. CONCLUSION

42. Thank You