NASAL DRUG DELIVERY SYSTEM Welcome! [Company Name] Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor Department of Pharmaceutics KLE University, Belgaum – 590010 Karnataka, INDIA [Company Name] 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

CONTENTS Novel Drug Delivery System Global trends in drug delivery systems Nasal Drug Delivery System Medical aspects Formulation Development Applications Conclusion 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

NOVEL DRUG DELIVERY SYSTEM - an overview 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

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% 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

By 2010, the US drug delivery market alone will be worth $30 billion 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

There are great opportunities for companies investing in R&D for new, improved drug delivery system, allowing for improved therapeutic absorption and efficacy in patients 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Why Novel Drug Delivery system? To optimize drug’s therapeutic effect, 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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

 Enhancements to existing systems 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. 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. polar organics and other poorly absorbed therapeutics 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Novel drug delivery companies have existed since the late 1960s, when Alza and Elan pioneered the oral methods of enhanced drug delivery The introduction of hypodermic devices but especially metered dose inhalers & nasal sprays, promoted the concept and absolute need for specific drug delivery systems for specific diseases 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Today there are between 300 & 350 companies worldwide with an interest in drug delivery, 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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Drug Delivery Systems Oral Inject-able Mucosal Topical Trans-dermal Ocular Vaginal/Anal Needle Nasal Active Needle-less Buccal Passive Pulmo-nary 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Global drug delivery market by administration mode Nasal 2% Ocular 2% Injectable/Implant 3% Oral 53% Transdermal 8% Inhalation 32% 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

NASAL DRUG DELIVERY SYSTEM 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Inhalation/pulmonary drug delivery system includes  Metered dose inhalers  Dry powder inhalers  Inhalation solutions & suspensions (for nebulizers)  Inhalation nasal sprays 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Historically, 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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Annual growth of locally acting products 30% 11% Annual growth of locally acting products Annual growth of systemically acting products 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Drug development time 10 – 14 years New Chemical Entity 2 – 5 years Nasal Drug Delivery 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Drug development cost $300-600 mio New Chemical Entity $50 mio Nasal Drug Delivery 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Merits... 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. 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

NASAL ROUTE - medical aspects 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Nasal site of drug spray & absorption Cross-sectional view Nasal site of drug spray & absorption Pathways for nasal absorption 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Cross-sectional view a – nasal vestibule d – middle turbinate b – palate e – superior turbinate (olfactory mucosa) c – inferior turbinate f – nasopharynx 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Site of drug spray & absorption 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Pathways for nasal absorption  Absorption through the olfactory neurons - transneuronal absorption. Olfactory epithelium is considered as a portal for substances to enter CNS  Absorption through the supporting cells & the surrounding capillary bed - venous drainage  Absorption into the cerebrospinal fluid 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Transneuronal absorption Olfactory nerve – 1st cranial sensory nerve 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Venous drainage 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Nasal enzymes Cytochrome P 450 dependent onooxygenases, Lactate dehydrogenase, Oxidoreductase, Hydrolases, Esterase, lactic dehydogenase, malic enzymes, lysosomal proteinases, steroid hydroxylases., etc., Cytochrome P450 dependent mono oxygenases has been reported to catalyse the metabolism of xenobiotics, nasal decongestants, nocotine, cocaine, phenacetin, nitrosamine progesterone etc., Insulin zinc free was hydrolysed slowly by leusine aminopeptidase, PG of E series was inactivated 15 hydroxyprostaglandin dehydrogenase 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Nasal enzymes – contd., Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Nasal pH Nasal secretion of adult : 5.5-6.5 Infants and children: 5-6.7 It becomes alkaline in conditions such as acute rhinitis, acute sinusitis. Lysozyme in the nasal secretion helps as antibacterial and its activity is diminished in alkaline pH 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Therapeutic class of drugs for nasal route 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Therapeutic class of drugs 1. 2 adrenergic agonists 2. Corticosteroids 3. Antiviral 4. Antibiotics 5. Antifungal 6. More recently, vaccines 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Drugs commonly administered through pulmonary route include 1. Terbutaline Sulphate - 2 adrenergic agonist 2. Salbutamol - 2 adrenergic agonist 3. Budesonide - corticosteroid 4. Ipratropium Bromide - anticholinergic 5. Sodium Chromoglycate – mast cell stabilizer 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Formulation Development 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Factors affecting drug absorption Formulation considerations Formulation Development Dosage form Factors affecting drug absorption Formulation considerations Physiological Pharmaceutical 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Liquid spray/nebulizers Suspension spray/nebulizers Dosage forms Liquid drop Liquid spray/nebulizers Aerosol Suspension spray/nebulizers Gel Sustained release 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Factors affecting drug absorption 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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Physiological effects - Drug metabolism in the respiratory tract & reduction of systemic effect - Protein binding - Mucociliary transport causing increased or decreased drug residence time 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Physiological effects.... - Local toxic effects of the drug Eg., edema, cell injury, or altered tissue defenses - Local or systemic effects of propellants, preservatives, or carriers 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Physico-chemical properties of a drug candidate Pharmaceutical Physico-chemical properties of a drug candidate Methods to enhance drug absorption - Spray pump devices 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

1. Effect of particle size 2. Effect of molecular size 3. Effect of solution pH 4. Effect of drug lipophilicity 5. Effect of drug concentration 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Effect of particle size (aerodynamic size distribution) - Access to distal airways is a function of particle size - Large particles (> 7 microns) will be lost in the gastrointestinal tract - Small particles (< 3 microns) will be lost in exhaled breathe - Intermediate particles (3 to 7 microns) reach the actual site of action 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

2. Effect of molecular size - Higher the molecular size, lower the nasal absorption - A good systemic bioavailability can be achieved for molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

2. Effect of molecular size..... - With the assistance of absorption enhancer, 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. 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

3. Effect of solution pH dissociation constant (pKa) of the molecule - Nasal absorption is pH dependent - 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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

4. Effect of drug lipophilicity - Polar (water soluble) drugs tend to remain on the tissues of the upper airway - Non-polar (lipid soluble) drugs are more likely to reach distal airways - Lipid soluble drugs are absorbed more rapidly than water soluble drugs 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

5. Effect of drug concentration - Absorption depends on the initial concentration of the drug - The absorption follows first-order kinetics 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Methods to enhance nasal absorption of drugs Structural modification Salt or ester formation Formulation design 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

SPRAY PUMP DEVICES - Unidose - Bidose - Multidose 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Bidose Unidose 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Multidose 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

LEADING PUMP SUPPLIERS Pfeiffer, Germany Valois, France Becton Dickinson, France Nemo, Spain 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Applications Delivery of non-peptide pharmaceuticals Delivery of peptide-based pharmaceuticals Delivery of diagnostic drugs 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

1. Delivery of non-peptide pharmaceuticals Drugs with extensive pre-systemic metabolism, such as - progesterone - estradiol - propranolol - nitroglycerin - sodium chromoglyate can be rapidly absorbed through the nasal mucosa with a systemic bioavailability of approximately 100% 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

2. Delivery of peptide-based pharmaceuticals Peptides & proteins have a generally low oral bioavailability because of their physico-chemical instability and susceptibility to hepato-gastrointestinal first-pass elimination Eg. Insulin, Calcitonin, Pituitary hormones etc. Nasal route is proving to be the best route for such biotechnological products 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

3. Delivery of diagnostic drugs Diagnostic agents such as  Phenolsulfonphthalein – kidney function  Secretin – pancreatic disorders  Pentagastrin – secretory function of gastric acid 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

CONCLUSION 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

11% for locally acting drugs 30% for systemically acting drugs 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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

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 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Attractive for delicate molecules allowing systemic administration without significant degradation 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Nasal drug delivery system offers flexibility for multiple formulations ranging from nasal drop to suspension spray 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

Recent activities indicate a bright prospect for site-specific delivery of biotechnological products such as Insulin & other hormones 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

THANK YOU Cell No: 00919742431000; E-mail: bknanjwade@yahoo.co.in 03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041