1. DRUG DELIVERY TO LUNGS PRESENTED BY V.RAVALI(M.PHARMACY) PHARMACEUTICS

2. Contents: Introduction Physiology of respiratory system Disorders of lungs Strategies in pulmonary delivery Challenges in pulmonary delivery Approaches in pulmonary delivery Control delivery of drugs to lungs Interactions of excipients Methods of aerosol analysis Applications Marketed products Recent and future development Summary Conclusion References

3. Introduction: Pulmonary route possesses many advantages over other routes of administration for the treatment of specific disease states, particularly lung associated large protein molecules which degrade in the gastrointestinal conditions and are eliminated by the rst pass metabolism in the liver can be delivered via the pulmonary route if deposited, in the respiratory zone of the lungs. Devices used to deliver drug by pulmonary route area based on one of three platforms pressurized metered dose inhaler, nebulizer and dry powder.

4. Anatomy and physiology of the respiratory system: Respiratory system of man consists Upper respiratory tract: Consists of nose, nasal passages, para nasal sinuses, mouth, eustachian tube, the pharynx to the esophagus, the larynx and trachea Lower respiratory tract: Consists of lungs (both air passage ways and respiratory units) Lower respiratory tract The lung: Human lung comprises of left and right lung, are divided into slightly unequal proportions Each lung is supplied by a major branch of the bronchial tree The tissue substance of a lung includes air passages, alveoli, blood vessels, connective tissues,

5. Pulmonary blood supply: The total surface area of the alveolar capillary is 60-80sqm and capillary blood volume is 100-200 ml. This large surface area permits rapid absorption and removal of any substance that penetrate the alveoli capillary membrane. Thus they produce good sink conditions for drug absorption.

6. Lung permeability: Lungs are highly permeable to water, lipophilic materials and most gases. And Hydrophilic substances with large molecular size and ionic species have limited permeability. The alveolar type-1 cells with their tight junctions limit the penetration of molecules with a diameter less than 1.2 nm. The normal alveolar epithelium is almost impermeable to protein and small solutes. In contrast, micro vascular endothelium has better permeation for substances over a large range of molecular weight.

7. Disorders of lungs: Acute bronchitis: Chronic bronchitis: Bronchiectasis: Asthma: Pulmonary hemorrhage Pulmonary emphysema: Pulmonary edema:

8. Advantages of pulmonary drug delivery: Non invasive method . Effective drug targeting to the lungs for relatively common tract diseases such as asthma, emphysema and chronic bronchitis. Provides very rapid onset of action avoid gastrointestinal tract problems such as poor solubility, low bioavailability, gut irritability, unwanted metabolites, food effects and dosing variability. Pulmonary drug delivery having very negligible side effects

9. Strategies of pulmonary delivery: Lung deposition and particle size: Deposition of drug/aerosol in the airways depends on four factors. The physico chemical properties of drug The formulation The delivery/liberative device The patient (breathing pattern and clinical status) The breathing parameters, such as breathing frequency and tidal volumes also play a key role in deposition of particles in lungs.

10. Lung deposition: Lung deposition Occurs mainly by 3 mechanisms. They are Inertial impaction Gravitational sedimentation Brownian motion Inertial impaction: Where a bifurcation occurs in the respiratory tract, the air stream changes direction and particles within the air stream having, sufficiently high momentum, will impact on the airway walls rather than follow the changing air stream. Particles > 5m and particularly > 10m are deposited by this mechanism.

11. Gravitational sedimentation: As the remaining small particles move on to the central lung, the air velocity gradually decreases too much lower values and the force of gravity becomes important. Particles 1-5 um are deposited. Thus, gravitational sedimentation of an Inhaled particle is dependent on its size and density in addition to its residence time in the airways. Brownian motion: The finest particles enter the periphery of the lung where they can contact with the walls of the airways as the result of Brownian motion (particle diffusion). Particles smaller than 0.5 um are deposited. The

12. Drug absorption via the lung: Major physiological factors that affect pulmonary absorption are Mucociliary transport in the airways that constantly drains fluid and solid particle (bacteria) in a counter current flow to the oral cavity. The epithelial cells in the alveoli are covered by a thin layer of so called epithelial lining fluid. This fluid is in turn is covered by a monolayer of lung surfactant. The epithelial cell layer forms the major barrier to absorption of drug molecule. After passing the alveolar epithelium, the molecule enters the interstitium being part of the extra cellular space in side the tissue. Finally, for passage into the blood the molecule have to pass the endothelial membrane of the capillaries, separating the interstitial space from

13. Macrophages can also form a functional barrier for some particular drug substances during pulmonary absorption. For an efficient pulmonary absorption process, the alveolar membrane seems to be an optimal absorption site for a number reasons. In contrast to the airways, there is hardly any Muco ciliary clearance from the alveoli. The alveolar membrane forms the largest surface area in the lung. The area of the alveoli is 43-102 m2, which is large in comparison to the surface area of the airways which have cumulative area of about 2.5 m2. The alveolar epithelium is thinner and leakier than

14. Challenges in pulmonary drug delivery: Low efficiency of inhalation system: Efficiency of presently available inhalation systems has generally too low which is important challenge in pulmonary drug delivery. Optimum aerosol particle size is very important for deep lung delivery. Optimum particle size for deep lung deposition is 15 mm. Aerosol system should have to produce optimum size particles because they are too small, they will be exhaled. If the particles are too large, they affects on the oropharynx and larynx. Less drug mass per puff: To get adequate effect with the pulmonary drug delivery practical delivery of many drug which require milligram doses but with most existing systems, the total amount of drug per puff delivered

15. Poor formulation stability for drug: Most traditional small molecule asthma drugs are crystalline and, in the case of corticosteroids, relatively moisture resistant in the dry state. They are also rather stable in liquids as compared to most macromolecules, which are unstable in the liquid state, amorphous, And highly moisture sensitive in the dry state. Improper dosing reproducibility. Following are reason for Poor dosing reproducibility like worsening of diseases, problem in device, unstability of formulation. To get maximum dose reproducibility patient education play important role.

16. Approaches of pulmonary delivery: Metered dose inhaler Dry powder inhaler Nebulizers

17. Meter dose inhalers: In MDIs, drug is either dissolved or suspended in a liquid propellant mixture together with other excipients, including surfactants, lubricants for the valve mechanism and co solvents By this MDIS a predetermined dose is released as a spray on actuation metering valve.

18. Spacers and breath actuated MDIs: Spacers are positioned between the MDIs and the patient. The dose from an MDI is discharged directly into the reservoir prior to the inhalation. Disadvantage of spacers is they may cumbersome. The breath actuated device overcomes the coordination problem of conventional MDI without adding bulk to the device. However a substantial inspiratory flow rate is required for its operation.

19. Dry powder inhalers (DPIs): Dry powder systems are occasionally prepared from the pure drug substance. More frequently blend with lactose are prepared. The lactose blends consist of respirable drug particles and large (50-150) exicipient particles. The excipient is included as diluents to aid in dispensing the drug and as a fluidizing agent to assist dispersion. Current challenges facing the development of these systems for macromolecules include moisture control, efficient powder manufacturing, reproducible powder filling, unit dose packaging and development of efficient reliable aerosol

20. A) Flex haler B) Diskus C) Disc haler D) Hand haler E) Aerolizer Advantages: Disadvantages:

21. Precautions of DPI: Keep your dry powder inhaler in a dry place at room temperature. Never place the DPI in water. Never shake or breathe into the DPI. Never use a spacer device with your DPI. Unlike other inhaled medications, you may not taste, smell, or feel the dry powder. This experience may be different from what you are used to. As long as you are following the directions, you will get your full dose of medication. If you are using a corticosteroid medication, rinse your mouth and gargle after using the DPI. Do not

22. Nebulizers: Nebulizers are among the oldest devices used for delivery of therapeutic agents. These formulations are conforms to sterile product preparations. The mechanism of delivery is either air blast or air jet and ultrasonic systems. Droplet delivery from an air blast nebulizer is governed by the surface tension, density and viscosity of the fluid. Current challenges facing the development of liquid systems for macromolecules are formulation stability, unit dose packing, high payload delivery and development of efficient reliable devices.

23. Nebulizer Jet nebulizer: Ultra sonic nebulizer:

24. How to use nebulizer: Assemble the nebulizer according to its instructions. These are the basic steps: Connect the hose to an air compressor. Fill the medicine cup with your prescription. Attach the hose and mouthpiece to the medicine cup. Place the mouthpiece in your mouth. Breathe through your mouth until all the medicine is used. (Often this takes about 10 - 15 minutes). Some people use a nose clip to help them breathe only through the mouth. Others prefer to use a mask. Wash the medicine cup and mouthpiece with water, and air-dry until your next treatment.

25. Controlled delivery of drugs to lungs: Sustained release from a therapeutic aerosol can prolong the residence of an administered drug in the airways or alveolar region, minimize the risk of adverse effects by decreasing its systemic absorption rate, and increase patient compliance by reducing dosing frequency. A sustained-release formulation must avoid the clearance mechanisms of the lung, the mucociliary escalator of the conducting airways and macrophages in the alveolar region. Liposomes: Liposomes, as a pulmonary drug delivery vehicle, have been studied for years and used as a means of delivering phospholipids to the alveolar surface for treatment of neonatal respiratory distress syndrome. More recently, they have been investigated as a vehicle for sustained-release therapy in the treatment of lung disease, gene therapy and as a method of

26. Large porous particles: A new type of aerosol formulation is the large porous hollow particles, called Pulmospheres. They have low particle densities, excellent dispersibility and can be used in both MDI and DPI delivery systems. These particles can be prepared using polymeric or no polymeric excipients, by solvent evaporation and spray-drying techniques. Pulmospheres are made of phosphatidylcholine, the primary component of human lung surfactant. It has also been shown that Pulmospheres can increase systemic bioavailability of certain drugs

27. Deep-lung delivery of therapeutic proteins: For many years, medical science has been looking for an alternative to injections for the delivery of macromolecule drugs. Due principally to their size, these molecules, mostly proteins and peptides, cannot naturally and efficiently pass through the skin or nasal membranes without the use of penetration enhancers, such as detergents or electrical impulses. If administered orally, they are digested or degraded before they reach the blood stream. Therefore, oral, transdermal and nasal routes of delivery are inefficient for these molecules. In contrast, research has shown that many of those same molecules are absorbed naturally and quickly into the bloodstream if they are delivered to the deep

28. Transcytosis: The body absorbs peptides and proteins into the blood stream by a natural process known as Transcytosis, which occurs deep in the lung. Transcytosis allows drug molecules to move across an impermeable cell membrane without creating holes in the cells and destroying the barrier. The process is performed by trillions of tiny membrane bubbles, or transcytotic vesicles. Small molecules and peptides are also thought to be absorbed through the lung surface by an analogous process called para cellular transport.

29. Both transcytosis and paracellular transport are sophisticated cell processes mediated by complex cell machinery. The result of these two processes is a noninvasive means of delivering proteins and peptides to the bloodstream with relatively high bioavailability and without the use of penetration enhancers. Because the molecules are delivered rapidly into the bloodstream, there is a much more rapid onset of action than with any other non-i.V. delivery method.

30. INTERACTIONS OF EXCIPIENTS:

31. Methods of aerosol size analysis: The regional distribution of aerosols in the airways can be measured directly using gamma scintigraphy, by radiolabelling droplets or particles, usually with the short half-life gamma emitter technetium 99m (99mTc). However, more commonly in vitro measurements of aerosol size are used to predict clinical performance. The principal methods that have been employed for size characterization of aerosols are : Microscopy, Laser diffraction Cascade impaction Time of flight Phase doppler technique

32. Applications pulmonary drug delivery: Pulmonary delivery could also be used for delivery of vaccines. Inhaled vaccines may be used to prevent influenza, pneumonia, tuberculosis, measles, cytomegalovirus, asthma, and mucosal-entry diseases such as sexually transmitted diseases including HIV. Pulmonary delivery could also replace some oral drugs due to the much faster onset of action with improved absorption and avoidance of first pass losses with delivery through the GI tract. pulmonary delivery of macromolecule drugs like protiens and peptides.

33. Marketed products: For Asthma XOPENEX (levalbuterol HCl) Inhalation Solution ALVESCO (ciclesonide) Inhalation Aerosol For Allergies OMNARIS (ciclesonide) Nasal Spray ZETONNA (ciclesonide) Nasal Aerosol For COPD: BROVANA (arformoterol tartrate) Inhalation Solution

34. Recent developments: A. AERx AeroDose B. Respimat C.

35. Conclusion : As more efficient pulmonary delivery devices and sophisticated formulations become available, physicians and health professions will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung's clearance mechanisms and be retained within the lung for longer periods. The more efficient, user-friendly delivery devices may allow for smaller total deliverable doses, decrease unwanted sideeffects and increase clinical effectiveness and patient compliance.

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