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NASAL

DRUG DELIVERY SYSTEM

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CONTENTS
Novel Drug Delivery System

Global trends in drug delivery systems
Nasal Drug Delivery System Medical aspects Formulation Development Applications Conclusion

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NOVEL DRUG DELIVERY SYSTEM - an overview

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Novel drug delivery is one of the fastest growing healthcare sectors. with sales of drugs incorporating novel drug delivery systems increasing @ an annual rate of 15% 4 .

the US drug delivery market alone will be worth $30 billion 5 .By 2010.

allowing for improved therapeutic absorption and efficacy in patients 6 . improved drug delivery system.There are great opportunities for companies investing in R&D for new.

convenience and dose To enhance a product’s life-cycle To improve `patient compliance To target drug delivery To control overall healthcare costs To facilitate biological drug delivery 7 .Why Novel Drug Delivery system? To optimize drug’s therapeutic effect.

polar organics and other poorly absorbed therapeutics 8 . sustained release oral dosage forms to reduce dosing frequency  Commercially enabling delivery systems that provide viable alternatives for therapeutics that are not fully developed and marketed because there are limited practical means of administration Eg.The Novel Drug Delivery industry is comprised of companies seeking to develop  Novel alternatives to existing delivery systems Eg. implantable pumps  Enhancements to existing systems Eg.

when Alza and Elan pioneered the oral methods of enhanced drug delivery The introduction of hypodermic devices but especially metered dose inhalers & nasal sprays.Novel drug delivery companies have existed since the late 1960s. promoted the concept and absolute need for specific drug delivery systems for specific diseases 9 .

operating in a fierce environment where the number of drug launches using proven delivery technology is growing More novel technologies such as pulmonary delivery of insulin or needle-less human growth hormone injections are under development and are yet to be commercialized 10 .Today there are between 300 & 350 companies worldwide with an interest in drug delivery.

Drug Delivery Systems Oral Injectable Mucosal Topical Transdermal Ocular Vaginal/ Anal Needle Needleless Nasal Buccal Pulmonary Active Passive 11 .

Global drug delivery market by administration mode Nasal 2% Ocular 2% Injectable/ Implant 3% Transdermal 8% Inhalation 32% Oral 53% 12 .

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Inhalation/pulmonary drug delivery system includes  Metered dose inhalers  Dry powder inhalers  Inhalation solutions & suspensions (for nebulizers)  Inhalation nasal sprays 14 .

nasal drug delivery system has received interest since ancient times Therapy through intranasal administration has been an accepted form of treatment in the Ayurvedic system of Indian medicine 15 .Historically.

Nasal Drug Delivery System & Opportunity Annual market growth Development time vis-a-vis new chemical entity Development cost vis-a-vis new chemical entity Merits Limitations 16 .

30% 11% Annual growth of locally acting products Annual growth of systemically acting products 17 .

Drug development time 10 – 14 years New Chemical Entity 2 – 5 years Nasal Drug Delivery 18 .

Drug development cost $300-600 mio New Chemical Entity $50 mio Nasal Drug Delivery 19 .

Merits 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 20 .

Lower dose & hence lower side effects Useful for both local & systemic drug delivery For CNS drugs. better site for rapid onset of action Eg.. 21 .Merits. Inhalation anesthesia.. Morphine etc.

Limitations  Once administered. 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 22 .

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 The respiratory tract, which includes the
  

nasal mucosa hypopharynx large airways & small airways

 provides a relatively large mucosal surface area of

approx. 100 m2 (in normal adult) for drug absorption

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Cross-sectional view Nasal site of drug spray & absorption Pathways for nasal absorption

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Cross-sectional view

a – nasal vestibule b – palate c – inferior turbinate

d – middle turbinate e – superior turbinate (olfactory mucosa) f – nasopharynx

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Site of drug spray & absorption 27 .

transneuronal absorption.venous drainage  Absorption into the cerebrospinal fluid 28 . Olfactory epithelium is considered as a portal for substances to enter CNS  Absorption through the supporting cells & the surrounding capillary bed .Pathways for nasal absorption  Absorption through the olfactory neurons .

Transneuronal absorption Olfactory nerve – 1st cranial sensory nerve 29 .

Venous drainage 30 .

malic enzymes.Nasal enzymes •Cytochrome P 450 dependent onooxygenases. •PG of E series was inactivated 15 hydroxyprostaglandin dehydrogenase 31 . Oxidoreductase. •Cytochrome P450 dependent mono oxygenases has been reported to catalyse the metabolism of xenobiotics. nasal decongestants... nocotine. Hydrolases. steroid hydroxylases. phenacetin. Lactate dehydrogenase. •Insulin zinc free was hydrolysed slowly by leusine aminopeptidase. etc. nitrosamine progesterone etc. Esterase. cocaine. lactic dehydogenase.. lysosomal proteinases.

.Nasal enzymes – contd. •Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats 32 .

5-6.5 •Infants and children: 5-6.7 •It becomes alkaline in conditions such as acute rhinitis. •Lysozyme in the nasal secretion helps as antibacterial and its activity is diminished in alkaline pH 33 .Nasal pH •Nasal secretion of adult : 5. acute sinusitis.

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Antiviral 4.Therapeutic class of drugs 1. More recently. vaccines 35 . Antibiotics 5. 2 adrenergic agonists 2. Corticosteroids 3. Antifungal 6.

Salbutamol . Terbutaline Sulphate .2 adrenergic agonist 2.2 adrenergic agonist 3. Budesonide .Drugs commonly administered through pulmonary route include 1.corticosteroid 4. Ipratropium Bromide .anticholinergic 5. Sodium Chromoglycate – mast cell stabilizer 36 .

Formulation Development 37 .

Formulation Development Dosage form Factors affecting drug absorption Formulation considerations Physiological Pharmaceutical 38 .

Dosage forms Liquid drop Liquid spray/nebulizers Aerosol Suspension spray/nebulizers Gel Sustained release 39 .

Drug concentration Factors affecting drug absorption 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 40 .

Physiological effects Drug metabolism in the respiratory tract & reduction of systemic effect Protein binding Mucociliary transport causing increased or decreased drug residence time 41 .

..Physiological effects. edema.. or altered tissue defenses - Local or systemic effects of propellants.. preservatives. or carriers 42 . cell injury. - Local toxic effects of the drug Eg.

Pharmaceutical - Physico-chemical properties of a drug candidate Methods to enhance drug absorption Spray pump devices 43 .

1. Effect of drug concentration 44 . Effect of drug lipophilicity 5. Effect of molecular size 3. Effect of particle size 2. Effect of solution pH 4.

Effect of particle size (aerodynamic size distribution) .Access to distal airways is a function of particle size .Small particles (< 3 microns) will be lost in exhaled breathe .Large particles (> 7 microns) will be lost in the gastrointestinal tract .Intermediate particles (3 to 7 microns) reach the actual site of action 45 .1.

2. Effect of molecular size . lower the nasal absorption .Higher the molecular size.A good systemic bioavailability can be achieved for molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used 46 .

With the assistance of absorption enhancer. 47 .. 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... Effect of molecular size. ..

3. Effect of solution pH .Absorption is higher at a pH lower than the dissociation constant (pKa) of the molecule .Absorption is lower as the pH increases beyond the dissociation constant 48 .Nasal absorption is pH dependent .

Lipid soluble drugs are absorbed more rapidly than water soluble drugs 49 .Non-polar (lipid soluble) drugs are more likely to reach distal airways . Effect of drug lipophilicity .Polar (water soluble) drugs tend to remain on the tissues of the upper airway .4.

The absorption follows first-order kinetics 50 . Effect of drug concentration .Absorption depends on the initial concentration of the drug .5.

Methods to enhance nasal absorption of drugs Structural modification Salt or ester formation Formulation design 51 .

Multidose 52 .SPRAY PUMP DEVICES .Bidose .Unidose .

Bidose Unidose 53 .

Multidose 54 .

Spain 55 . France Nemo. France Becton Dickinson. Germany Valois.LEADING PUMP SUPPLIERS Pfeiffer.

Applications Delivery of non-peptide pharmaceuticals Delivery of peptide-based pharmaceuticals Delivery of diagnostic drugs 56 .

Delivery of non-peptide pharmaceuticals Drugs with extensive pre-systemic metabolism. such as .nitroglycerin .sodium chromoglyate can be rapidly absorbed through the nasal mucosa with a systemic bioavailability of approximately 100% 57 .progesterone .estradiol .propranolol .1.

Calcitonin.2. Nasal route is proving to be the best route for such biotechnological products 58 . Insulin. Delivery of peptide-based pharmaceuticals Peptides & proteins have a generally low oral bioavailability because of their physico-chemical instability and susceptibility to hepatogastrointestinal first-pass elimination Eg. Pituitary hormones etc.

Delivery of diagnostic drugs Diagnostic agents such as  Phenolsulfonphthalein – kidney function  Secretin – pancreatic disorders  Pentagastrin – secretory function of gastric acid 59 .3.

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Nasal route is a part of drug delivery strategy that is emerging to be a fastest growing drug delivery system with an annual growth of 11% for locally acting drugs & 30% for systemically acting drugs 61 .

Nasal drug delivery offers such benefits as Rapid onset of action with lower dose & minimal side effects Has an advantage of site-specific delivery with improved therapeutic effects 62 .

Attractive for delicate molecules allowing systemic administration without significant degradation 63 .

Nasal drug delivery system offers flexibility for multiple formulations ranging from nasal drop to suspension spray 64 .

Recent activities indicate a bright prospect for site-specific delivery of biotechnological products such as Insulin & other hormones 65 .

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