1. DRUG DELIVERY TO RESPIRATORY SYSTEM Department Of Pharmaceutics

2. CONTENTS ----- Introduction ----- Background & historical perspective ----- Structure & function of pulmonary system ------Factors affecting particle deposition Physiochemical Properties ------Drug delivery devices Metered dose inhalers Dry Powder inhalers Nebulizers -------References

3. INTRODUCTION  Drugs through the nasal route have shown better systemic bioavailability than oral administration by self medication.  The systemic bioavailability of some peptide & protein drugs with low nasal absorption has been improved by co-administering them with absorption promoters, enzyme inhibitors or microspheres fabricated from bioadhesives & bioerodible polymers.  Intranasal administration appears to be an alternative to the parenterals for systemic drug delivery. ADVANTAGES: Avoidance of hepatic first –pass elimination, gut wall metabolism. Rate &extent of absorption and the plasma concentration Vs time profiles are relatively comparable to that obtained by i.v medication. Large surface area of absorption ~ 75 m 2,thin (0.1 to 0.5µm) alveolar epithelium permitting rapid absorption. High bioavailability. Ease &convenience of intranasal drug administration.

4. Background & historical perspective  Inhaled therapies have existed for at least 5000 years Modern drug therapy can be traced to the propellant- driven metered-dose inhaler (pMDI) of the 1950s The surge in interest that has arisen in the last decade relates to the chlorofluorocarbon (CFC) propellant ban and the development of biotechnology products.  In addition, the burgeoning biotechnology industry of the late 1980s and early 1990s actively sought alternative methods of delivering macromolecular drugs, which were difficult to deliver in therapeutic doses by the oral or parenteral route.

5. THE ANATOMY OF THE LUNGS SHOWING THE MAJOR AIRWAY SUBDIVISIONS

6. PHYSIOLOGY OF LUNGS  Lung function is intimately linked with the structural features of the airways & lung parenchyma.  The airways of the lungs provide a pathway of normally low resistance to the bulk flow of air into & out of the lung periphery where alveoli perform the essential function of gas exchange. Lungs are divided into two compartments or zones: (a)The conducting zone & (b)The respiratory zone. THE WEIBEL SYMMETRICAL BRANCHING MODEL OF THE LUNG

7. (a)The conducting zone consists of first 16 generations of airways, comprised of trachea which bifurcates into two main stem bronchi, the conducting bronchioles and ends with terminal bronchioles, which are devoid of alveoli. Function: To move air by bulk flow into &out of the lungs during each breath. (b) The respiratory zone consists of all structures that participate in gas exchange & begins with respiratory bronchioles containing alveoli. These bronchioles sub – divide into additional respiratory bronchioles giving rise to alveolar ducts & finally to alveolar sac.  Upper airways are used to predict aerosol deposition in the lungs.  Most lung deposition models are based on the influence of particle size on aerosol deposition. Breathing parameters such as breathing frequency and tidal volume, play a key role in lung deposition.  Average respiratory rate is approximately 15 breaths/min with a tidal volume of 500ml and a residence time for tidal air is 3 seconds.

8.  The most important parameter that defines the site of deposition of aerosol drugs including protein & peptides, within the respiratory tract is the particle characteristics of the aerosol.  The nature of aerosol droplets is dependent on its mass median aerodynamic diameter (MMAD) which is a function of particle size, shape & density.  Particle charge and air velocities within in the airways is also an important attribute. PARTICLE SIZE INFLUENCE  Good distribution throughout the lung requires particles with an aerodynamic diameter between 1 &5 mm.  To target the alveolar region, the aerosol droplet diameter should not be more than 3mm.  Particles with diameter that are greater than 6mm are deposited in the oropharynx.  Smaller particles less than 1mm are exhaled during normal tidal breathing.

9. Factors affecting particle deposition Physicochemical properties: The drug delivery by aerosols is deposited by inertial impaction, sedimentation& diffusion.  INERTIAL IMPACTION : Employed to sample aerosols aerodynamically for characterization of particle size. LARGER drug particles of 5µm diameter is deposited by this mechanism.  SEDIMENTATION: (A) Particle settle under gravity. (B) Rate of settling is proportional to square root of particle diameter.  DIFFUSION: The principle of Brownian motion is responsible for particle deposition under the influence of impaction with gas molecules in the airways.

10. AEROSOL – DELIVERY DEVICES Aerosols are stable dispersions or suspensions of solid material & liquid droplets in a gaseous medium. The size of the solid particles or liquid droplets in aerosol ranges from 1-10µm expressed as Aerodynamic diameter & is given as d ae = ρ 1/2 d  Droplet formation may be characterized in terms of the nature of the propulsive forces and the liquid being dispersed. Dry particles, which are delivered from suspension in pMDIs or from DPIs alone or from a blend, must be prepared in respirable sizes. The production of respirable aerosol particles can be achieved by MICRONISATION of the drug. This involves the introduction of bulk particles on a gas stream into the path of an opposing gas stream under pressure. Particles impact on each other and are ground into small particles,then passed through cyclone separator and are collected in a vessel or a bag filter. The particles produced should be less than 5µm in size, which is suitable for lung deposition. ALERNAIVE METHODS FOR PRODCTION Spray drying -particles produced are frequently spherical. Supercritical fluid method –involves controlled crystallization of drugs from dispersion in supercritical fluids, carbon dioxide.

11. A. Propellant – Driven Metered Dose Inhalers The formulation of pMDI consists of : (1) Propellant, (2) Drug (3) Co solvents & (4)Surfactants. (1)PROPELLENTS – Serves both as an energy source to expel the formulation from the valve in the form of rapidly evaporating droplets & as a dispersion medium for the drug and other excipients. It may be of a number of different types: CFCs, hydrofluoroalkanes. Alternative propellant is 1,1,1,2- tetrafluoroethane.. ADVANTAGES: (A)Non flamable (B)Low pulmonary toxicity (C)High chemical stability & purity (D)Compatibility with commonly used packaging materials.

12. Combination of three most widely used CFCs, trichlorofluoromethane (CFC-11), dichlorodifluoromethane (CFC-12) & 1,2 – diclorotetrafluoromethane (CFC-114) are combined in varying ratios to achieve a desirable combination of vapour pressure, liquid density, & solvency. The VAPOR PREESURE indicates the force of emission of droplets from the metering valve of the inhaler. It is derived from the difference between the product vapor pressure & atmospheric pressure. The DENSITY of the propellant may be matched to the drug particles to assist in the suspension formulation stability. The CO SOLVENCY, typically ethanol, may be used to bring drug into solution. A small amount of surfactants (sorbitan trioleate, oleic acid)may be dispersed in propellant systems & can aid in suspension stability &in valve lubrication. Theoretical approach – to predict the droplet formation from a pMDI, followed by experimental validation studies.

13. The container components: canister, valve & actuator. The therapeutic usefulness of this device stems from the accurate metering of small doses of drug, which is achieved by a small but complex metering valve. The valve stem is fitted with a actuator which is used as mouth piece,,,,drug delivery is within 30ms- 1.

14. Performance is evaluated in terms of drug and component physical and chemical compatibilites. particle size & emitted dose determinants are required. Through – life performance should be evaluated as this is multi dosing reservoir system. The influence of temperature & humidity on stability & performance of the product should also be considered. B. DRY POWDER INHALERS The forces of interaction between particles are barriers to their flow and dispersion. Those major interaction forces are vandeerwaal, electrostatic, and capillary forces. Drug is micronized but diluents have larger particle size causing deposition in upper respiratory track, while active agent penetrate further into lung. Ex: Aero haler and Spin haler methods. 1. Aero haler has plastic tubular device, loaded with a sifter cartridge and metal ball containing finely powdered formulation. The air stream produced by patient inhaling causes metal ball to strike cartridge thus shaking out small amount of powder into air stream.

15. SPINHALER Tubular plastic device which is loaded with gelatin capsule containing powder is pierced by two pins. When patient inhales, the rotor spins the cap with eccentric movement Powder from the capsule thrown into air stream Only 50% of dose is achieved and the remaning is lost by deposition in mouth and back of throat Other models : turbuhaler and diskus type. SPINHALER DISKUS TYPE

16. HYDRODYNAMIC NEBULIZER System that prepares a film of water of aerosol formation by flowing it over hallow sphere. A small orifice in sphere expels gas at supersonic velocity. This high velocity gas rupture the thin film of water and produces a continuous dispersion of fine, liquid particles.

17. ULTRASONIC It consists of piezo-electric crystal which produce high frequency sound waves in the liquid in nebulizing unit. The surface waves produce small droplets which are conducted away by an air stream for inhalation. The droplet diameter depends on driving frequency and liquid Properties usually range from 4-10µm ADVANTAGESOF NEBULIZERS Adjustment of air flow to suit inhalation rate of patient. Large quantity of drug can be delivered through continuous nebulization of aqueous solutions.

18. LATEST DEVELOPMENT (1)ARADIGM has developed AER X pulmonary technology, which helps in delivering morphine &insulin into lungs. (2)ALKERMES has designed an inhalation technology (AIR) which helps in delivering efficient dry powder of small molecules, peptide & protein drug particles deep into lungs. (3)AIR insulin is the second inhaled insulin therapy to be available in the market after EXUBERA from PFIZER.

19. REFERENCES: MODERN PHARMACEUTICS Fourth Edition, Revised and Expanded edited by Gilbert S. Banker University of Iowa, Iowa City, Iowa Christopher, T. Rhodes University of Rhode, Island Kingston, Drug delivery to pulmonary system.(CHAPTER 14) PHARMACEUTICAL PARTICULATE CARRIERS THERAPEUTIC APPLICATIONS Alain Rolland Vol-61 Dekker Publications. (PAGE NO: 31- 59) PHYSIOLOGICAL PHARMACEUTICALS BIOLOGICAL BARRIERS TO DRUG ABSORPTION By Clive g.Wilson and Neena Washington. CONTROLLED AND TARGETED DRUG DELIVERY ADVANCES AND CONCEPTS By S.P Vyas And R.P. Khar.