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Welcome! DRUG DELIVERY
Nasal Drug Delivery System Medical aspects Formulation Development Applications Conclusion
Avoidance of hepatic first-pass metabolism Rate of absorption comparable to IV medication Rapid onset of pharmacological action
User-friendly, painless, non-invasive, needle-free administration mode
Lower dose & hence lower side effects Useful for both local & systemic drug delivery For CNS drugs, better site for rapid onset of action Eg. Inhalation anesthesia, Morphine etc.
Continue… 5 Highly vascularized sub-epithelial layer allowing rapid and direct absorption into systemic circulation Less hostile biochemical environment in comparison to GIT Improved patient compliance and comfort in compared to IV route Avoiding First-pass metabolism .
rapid removal of the therapeutic agent from the site of absorption is difficult ¢ Pathologic conditions such as cold or allergies may alter significantly the nasal bioavailability .Limitations 6 ¢ Once administered.
100 m2 (in normal adult) for drug absorption . which includes the nasal mucosa hypopharynx large airways & small airways Provides a relatively large mucosal surface area of approx.Anatomy 7 The respiratory tract.
Cross-sectional view 8 a – nasal vestibule b – palate c – inferior turbinate d – middle turbinate e – superior turbinate (olfactory mucosa) f – nasopharynx .
Poor bioavailability .for drug with a molecular weight >1000 Daltons. The second mechanism involves • Transport through a lipoidal route is also known as the transcellular process • Responsible for the transport of lipophillic drugs • Rate of absorption is dependent on lipophilicity of drug 9 .Three major mechanisms of drug absorption:• • • • First mechanism involves an aqueous route of transport. Also known as the paracellular route Slow and passive Absorption is inversely proportional to the molecular weight of water-soluble compounds.
10 .Third mechanism • An active transport route via carrier-mediated means or transport through the opening of tight junctions. a natural biopolymer from shellfish. opens tight junctions between epithelial cells to facilitate drug transport. chitosan. • For examples.
cocaine. • Cytochrome P450 dependent mono oxygenases has been reported to catalyse the metabolism of xenobiotics.. malic enzymes.. phenacetin. • Insulin zinc free was hydrolysed slowly by leusine aminopeptidase. Oxidoreductase. • PG of E series was inactivated 15 hydroxyprostaglandin dehydrogenase . steroid hydroxylases. lysosomal proteinases. Esterase. nasal decongestants. nitrosamine progesterone etc.. Lactate dehydrogenase. Hydrolases. nocotine.Nasal enzymes 11 • Cytochrome P 450 dependent monooxygenases. etc.
Nasal enzymes – contd. 12 •Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats .
acute sinusitis.Nasal pH 13 • Nasal secretion of adult : 5.5-6. • Lysozyme in the nasal secretion helps as antibacterial and its activity is diminished in alkaline pH .7 • It becomes alkaline in conditions such as acute rhinitis.5 • Infants and children: 5-6.
14 Therapeutic class of drugs for nasal route .
More recently. Antibiotics 5.Therapeutic class of drugs 15 1. Antifungal 6. Corticosteroids 3. β2 adrenergic agonists 2. Antiviral 4. vaccines .
Drugs commonly administered through pulmonary route include 1.anticholinergic 5. Salbutamol .corticosteroid 4. Budesonide . Sodium Chromoglycate – mast cell stabilizer 16 .β2 adrenergic agonist 3.β2 adrenergic agonist 2. Terbutaline Sulphate . Ipratropium Bromide .
emetics. 17 Acute pain-relief Smoke cessation Migraine Osteoporosis Vit-B12 deficiency Potential to deal with insulin dependent diabetes. CNS drug delivery etc.Treatment of…. cancer therapy. . rheumatoid arthritis.
18 Formulation Developme nt .
Formulation Development 19 Dosage form Dosage form Factors affecting drug Factors affecting drug absorption absorption Formulation Formulation considerations considerations Physiological Pharmaceutical .
Dosage forms 20 Liquid drop Liquid spray/nebulizers Aerosol Suspension spray/nebulizers Gel Sustained release .
· Enzymatic degradation in nasal cavity. osmolarity) · Delivery effects · Drugs distribution and deposition. rhinitis. · Formulation effect on mucociliary clearance. C) Delivery Effect · Formulation (Concentration.The factors influencing nasal drug absorption A) Physiochemical properties of drug. · Toxic effect on ciliary function and epithelial membranes. B) Nasal Effect · Membrane permeability. 21 . · Molecular size. · Lipophilic-hydrophilic balance. · Environmental pH · Mucociliary clearance · Cold. pH.
Factors affecting drug absorption 22 Drug concentration Vehicle of drug delivery Mucosal contact time Degree of drug’s ionization pH of the absorption site Size of the drug molecule Relative lipid solubility .
Physiological effects 23 Drug metabolism in the respiratory tract & reduction of systemic effect Protein binding Mucociliary transport causing increased or decreased drug residence time - .
.. edema. or altered tissue defens - Local or systemic effects of propellants. - 24 Local toxic effects of the drug Eg. cell injury. or carriers ... preservatives.Physiological effects.
Pharmaceutical 25 - Physico-chemical properties of a drug candidate Methods to enhance drug absorption Spray pump devices .
Effect of drug lipophilicity 5.26 1. Effect of molecular size 3. Effect of solution pH 4. Effect of drug concentration . Effect of particle size 2.
1. Effect of particle size (aerodynamic size distribution) 27 .Access to distal airways is a function of particle size .Intermediate particles (3 to 7 microns) reach the actual site of action .Small particles (< 3 microns) will be lost in exhaled breathe .Large particles (> 7 microns) will be lost in the gastrointestinal tract .
Effect of molecular size . lower the nasal absorptionsystemic bioavailability can be achieved for .2.Higher the molecular size.A good molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used 28 .
... Effect of molecular size.. a good bioavailability can be extended to a molecular weight of at least 6000 Daltons Absorption enhancers: Polyacrylic acid Sodium Glycocholate Sodium Deoxycholate Polysorbate 80 etc.2. .With the assistance of absorption enhancer. 29 .
Absorption is lower as the pH increases beyond the dissociation constant .3. Effect of solution pH 30 - Nasal absorption is pH dependent .Absorption is higher at a pH lower than the dissociation constant (pKa) of the molecule .
Lipid soluble drugs are absorbed more rapidly than water soluble drugs and are more likely to reach distal airways Polar (water soluble) drugs tend to remain on the - tissues of the upper airway .4. Effect of drug lipophilicity 31 .
5.The absorption follows first-order kinetics . Effect of drug concentration 32 Absorption depends on the initial concentration of - the drug .
Methods to enhance nasal absorption of 33 drugs Structural modification Salt or ester formation Formulation design .
Unidose .SPRAY PUMP DEVICES 34 .Multidose .Bidose .
35 Bidose Unido .
Multidose 36 .
Germany Valois. France Becton Dickinson. Spain .LEADING PUMP SUPPLIERS 37 Pfeiffer. France Nemo.
Applicatio 38 ns Delivery of non-peptide pharmaceuticals Delivery of peptide-based pharmaceuticals Delivery of diagnostic drugs .
nitroglycerin. such as progesterone. sodium chromoglyate can be rapidly absorbed through the nasal mucosa with a systemic bioavailability of approximately 100% . Delivery of non-peptide pharmaceuticals 39 Drugs with extensive pre-systemic metabolism.1. propranolol. estradiol.
Delivery of peptide-based pharmaceuticals 40 Peptides & proteins have a generally low oral bioavailability because of their physico-chemical instability and susceptibility to hepatogastrointestinal first-pass elimination Eg. Insulin. Calcitonin. Nasal route is proving to be the best route for such biotechnological products .2. Pituitary hormones etc.
3. Delivery of diagnostic drugs 41 Diagnostic agents such as • Phenolsulfonphthalein – kidney function • Secretin – pancreatic disorders • Pentagastrin – secretory function of gastric acid .
42 O C N IO S LU C N .
43 • Nasal drug delivery offers rapid onset of action with lower dose & minimal side effects • Has an advantage of site-specific delivery with improved therapeutic effects .
44 Attractive for delicate molecules allowing systemic administration without significant degradation .
45 Nasal drug delivery system offers flexibility for multiple formulations ranging from nasal drop to suspension spray .
46 Recent activities indicate a bright prospect for site-specific delivery of biotechnological products such as Insulin & other hormones .
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