Pulmonary Drug Delivery System

Pulmonary Drug Delivery System, Aerosols, Propellant's, Containers Types, Preparation and Evaluation

1. PULMONARY DRUG DELIVERY SYSTEM SILAMBARASAN I DEPT OF PHARMACEUTICS MTPG & RIHS

2. CONTENT Introduction of PDDS Definition Advantages Disadvantages Anatomy And Physiology Of Respiratory Tract Mechanism Of PDDS Barrier Of PDDS Factor Affecting PDDS Aerosol History Advantage Disadvantage Components Of Aerosol Types Of Aerosol Evaluation Application Recent development References 2

3. INTRODUCTION I nhalation therapy has established itself as a valuable tool in the local therapy of pulmonary diseases such as Asthma or COPD for several decades. Carrier like Microparticles,Nanoparticles ,Liposomes can be used in lung targeting . Optimum particle size is important for delivery of drugs. Currently, over 25 drug substances are marketed as inhalation aerosol products for local pulmonary effects and about the same number of drugs are in different stages of clinical development. 3

4. 4 DEFINITION

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6. 6 DISADVANTAGES Some drug may produce irritation or toxicity . Some drug retained in lungs and clearence of drugs may be difficult . Difficulty in producing optimum particle size . Amount of drug delivered per puff is less which may be ineffective for certain therapy. Patient have difficulty to usage of drug delivery device.

7. 7 ANATOMY AND PHYSIOLOGY OF RESPIRATORY TRACT

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9. LUNGS Protected by Ribcage. Left lung is slightly smaller than Right lung. It is supported by diaphragm at the bottom of lungs. Major function is exchange of gases. About 100 million alveoli present in each lungs. About 10 % blood circulate through lungs (450 ml). 9

10. MECHANISM OF PULMONARY DRUG DELIVERY 10

11. BARRIER IN PULMONARY DRUG DELIVERY 11

12. FACTORS AFFECTING PDDS 12

13. AEROSOLS It is pressurized dosage form . Aerosol is a system that depends on the power of a compressed or liquefied gas to expels the content from the container. Also called as Pressure package, Pressurized package . 13

14. HISTORY In 1942, Goodhue & Sullivan ,Dept of Agriculture ,USA developed Aerosol insecticide . In early 1950,Aerosol used for Topical administration to treat burns, minor cuts etc. In 1955, Epinephrine Pressurized package was developed to treat Asthma. 14

15. ADVANTAGE Stability is high Directly applied to affected area Rapid onset of action Irritation produced by mechanical application of topical medication is reduced No direct contact with medicament. No microorganism can enter. 15

16. DISADVANTAGE Costly Disposal of empty aerosol container is difficult Allergic in some cases Explosive Some formulation is difficult Sometime propellants may cause toxic reactions. 16

17. COMPONENTS OF AEROSOLS Propellant Container Valve and actuator Product concentrate 17

18. 1) PROPELLANTS Responsible for developing proper pressure within the container . Provide driving force to expel the product from the container . Aids in atomization. TYPES OF PROPELLANTS Liquefied gases Propellants Compressed gases Propellants 18

19. PROPELLANT TYPES Depending upon route of administration and use, 19

20. A ) LIQUIFIED GAS PROPELLANTS At room temperature and pressure ,they are gases . Liquefied by lowering the pressure & increasing the temperature. When liquefied gases are placed into a sealed container, they immediately separate in liquid and vapor phase. The product is used up , as the valve is opened, some of the liquid propellant turns to gas and keeps the head space full of gas. In this way the pressure in the can remains essentially constant and the spray performance is maintained. 20

21. CHLOROFLUORO CARBON 21 Advantages Chemical inertness Lack of toxicity Non flammability. Lack of explosiveness . Disadvantages High cost It depletes the ozone layer Examples Trichloromonofluoromethane – Propellant 11 Dichlorodifluoromethane - Propellant 12 Dichlorotetrafluoroethane - Propellant 114 Propellant of choice for oral and inhalation.

22. HYDROCARBONS Can be used for water based aerosols and topical use. 22 Advantages Inexpensive Excellent solvents It does not cause ozone depletion Disadvantages Inflammable Unknown toxicity produced Example Propane - Propellant A-108 Isobutane - Propellant A-31 Butane - Propellant A-17

23. HYDROFLUORO CARBONS AND HYDRO CHLORO FLUORO CARBONS These compounds break down in the atmosphere at faster rate than CFC. Lower ozone destroying effect. 23 Disadvantages : Poor solvent High cost Advantages: Low inhalation toxicity High chemical stability High purity Not ozone depleting EXAMPLE HEPTAFLUORO PROPANE (HFA-227) TETRAFLUOROETHANE (HFA-134A) DIFLUOROETHANE - PROPELLANT 152A CHLORODIFLUOROMETHANE - PROPELLANT 22 CHLORODIFLUOROETHANE - PROPELLANT 142 B

24. B )COMPRESSED GAS PROPELLANTS Compressed gas propellants occupy the head space above the liquid in the can. When the aerosol valve is opened the gas 'pushes' the liquid out of the can. The amount of gas in the headspace remains the same but it has more space , and as a result the pressure will drop during the life of the can. Spray performance is maintained however by careful choice of the aerosol valve and actuator . Examples: Carbon dioxide, Nitrous oxide and Nitrogen 24

25. 2) CONTAINERS They must be able to withstand pressures as high as 140 to 180 psig at 130 ° F . AEROSOL CONTAINERS Metals Tinplated steel Aluminum Stainless steel Glass Uncoated glass Plastic coated glass 25

26. TIN PLATED CONTAINER It consist of a sheet of steel plate , this sheet is coated with tin by electrolytic process . These sheets are lithographed at this point . The coated sheet is cut into three pieces ( top , bottom and body ) . The top, bottom are attached to body by soldering . When required it is coated with organic material usually oleoresin, phenolic, vinyl or epoxy coating . Recent developments in welding include Soudronic system and Conoweld system . 26

27. ALUMINIUM CONTAINERS Used for inhalation and topical aerosols . Manufactured by impact extrusion process . Light in weight, less fragile , l ess incompatibility due to its seamless nature . Greater resistance to corrosion . Pure water and pure ethanol cause corrosion to Aluminum containers. Added resistance can be obtained by coating inside of the container with organic coating like phenolic , vinyl or epoxy and polyamide resins. 27

28. STAINLESS STEEL CONTAINER Used for inhalation aerosols. ADVANTAGE : Extremely Strong. Resistant to many materials . No need for internal coating. DISADVANTAGE : Costly 28

29. GLASS CONTAINERS These containers are preferred because of its Aesthetic value and absence of incompatibilities . These containers are limited to the products having a lower pressure (33 psig) and lower percentage of the propellant . Used for topical and MDI aerosols . TWO TYPES 1)Uncoated Glass container 2)Plastic coated glass container 29

30. CONT, UNCOATED GLASS CONTAINER: Less cost and high clarity and contents can be viewed at all times. PLASTIC COATED GLASS CONTAINERS: These are protected by plastic coating that prevents the glass from shattering in the event of breakage . 30

31. 3 A) VALVES Used to seal the aerosol container . To delivered the drug in desired form such as spray, foam etc. To deliver given amount of medication . TYPES 1) Continuous spray valve 2 ) Metering valves 31

32. CONTINUOUS SPRAY VALVE Used for topical aerosols . Valves assembly consists : • Ferrule or mounting cup • Valve body or housing • Stem • Dip tube • Gasket • Spring 32

33. FERRULE OR MOUNTING CUP : • Used to attach valve to container . • Made from Tin plated steel, Al , Brass . • Underside of the valve cup is coated with single or double epoxy or vinyl resins. VALVE BODY OR HOUSING : • Made up of Nylon or Derlin and contains a opening at the point of attachment of dip tube. (0.013 to 0.080 inch) STEM : • Made from Nylon or Derlin , brass and stainless steel can also be used. (orifice - 0.013 to 0.030 inch). 33

34. GASKET : • Made from Buna-N and neoprene rubber. SPRING : • Made from Stainless steel . • Used to hold gasket in place. DIP TUBE : • Made from Poly ethylene or poly propylene. • Inner diameter 0.120 – 0.125 inch. • However for Capillary dip tube inner diameter is 0.050 inch and for highly viscous products it is 0.195 inch. 34

35. METERING VALVES Used for dispensing of potent medication . Operates on the principle of a chamber whose size determines the amount of medication dispensed. Approximately 50 to 150 mg ±10 % of liquid materials can be dispensed at one time. 35

36. 3 B) ACTUATORS These a r e spec i ally de s igned bu t t on s which h el p s in del i ve r ing the dru g in desired form i.e., spray, wet stream, foam or solid stream . TYPES OF ACTUATORS : Spray actuators Foam actuators Solid steam actuators Special actuators 36

37. 37 SPECIAL ACTUATORS It delivers the medicament to the appropriate site of action such as throat, nose, dental and eyes etc.

38. RECENT ADVANCES IN PULMONARY DRUG DELIVERY DEVICES Following types of inhalation devices are present Nebulizers Metered dose inhaler(MDI) Dry powder inhaler(DPI) 38

39. 1) NEBULIZER Nebulizers deliver relatively large doses of drugs as either aqueous solution or suspension. Nebulizer used today for drug delivery to the respiratory tract and are particularly useful for the treatment of hospitalized or non ambulatory patients. Two types of Nebulizers A ) Ultrasonic Nebulizer B )Air jet Nebulizer 39

40. A) ULTRASONIC NEBULIZER -The ultrasonic nebulizers uses piezoelectric crystal , vibrating at high frequency (usually 1-3 MHz) to generate a fountain of liquid in the nebulizer chamber.(higher the frequency, smaller the droplets produced) -Not suitable for thermoliable drugs . 40

41. B ) AIR JET NEBULIZER The jet of high-velocity gas is passed either tangentially or coaxially through a narrow Venturi nozzle, typically 0.3-0.7 mm in diameter. An area of negative pressure, where the air jet emerges, causes liquid to be drawn up a feed tube from a fluid reservoir. 41

42. CONT, ADVANTAGE: The nebulizer can transport large doses of drugs to the lungs than MDI or DPI. The treatment of acute asthma in an emergency care unit. Rapid absorption, higher bioavailability . Avoidance of liver first pass metabolism . Avoidance of metabolism by the gastrointestinal tract. DISADVANTAGE: Higher costs. The need for higher drug doses to achieve a therapeutic result. 42

43. 2)METERED DOSE INHALER (MDI) Used for the treatment of respiratory diseases such as asthma and COPD . They can be given in the form of suspension or solution. Particle size of less than 5 microns. Used to minimize the number of administration errors. It can delivered measured amount of medicament accurately . 43

44. CONT, ADVANTAGES It delivers specified amount of dose Small size and convenience Usually expensive as compared to dry powder inhalers and nebulizers Quick to use 44 DISADVANTAGES Difficult to deliver high doses There is no information about the number of dose left in MDI Accurate co ordination between actuation of dose and inhalation is essential

45. 3) DRY POWDER INHALER(DPI) DPIs are bolus drug delivery devices that contain solid drug in a dry powder mix that is fluidized when the patient inhales. The drug with particle size of less than 5µm is used . Dry powder formulations either contain the active drug alone or have a carrier powder (e.g. lactose) mixed with drug to increase flow properties of drug. DPIs are a widely accepted inhaled delivery dosage form, particularly in Europe., where they are currently used by approximately 40% of asthma patients . 47

46. CONT, ADVANTAGE Propellant-free . Less need for patient co-ordination. Less formulation problem . DISADVANTAGE Delivery on patient’s inspiratory flow rate and profile. Device resistance and other design issues . Greater potential problems in dose uniformity. More expensive than pressurized metered dose inhalers . 48

47. TYPES OF DPI’s UNIT-DOSE DEVICES Single dose powder inhalers are device in which a powder containing capsule is placed in a holder. The capsule is opened with in the device and the powder is inhaled. MULTI DOSE DEVICE This device is truly a metered-dose powder delivery system . The drug is contained with in a storage reservoir and can be dispensed into the dosing chamber by a simple back and forth twisting action on the base of the unit 49

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50. EVALUATION TESTS A. Flammability and combustibility : 1 . Flash point 2 . Flame Projection B. Physicochemical characteristics : 1 . Vapour pressure 2 . Density 3 . Moisture content 4 . Identification of Propellants 52

51. C. Performance: 1 . Aerosol valve discharge rate 2 . Spray pattern 3 . Dosage with metered valves 4 . Net contents 5 . Foam stability 6 . Particle size determination D. Biological testing : 1 . Therapeutic activity 2 . Toxicity studies 53

52. A) FLAMMABILITY AND COMBUSTIBILITY 1. Flash point: Apparatus : Tag Open Cup Apparatus Product is chilled to 25°F and test liquid temperature is allowed to increase slowly and the temperature at which vapors ignite is called as Flash Point . 2. Flame Projection: Product is sprayed for 4 sec into a flame and the flame is extended ,exact length is measured with a ruler. 54

53. B) PHYSICOCHEMICAL CHARACTERISTICS PROPERTY METHOD 1. Vapour Pressure » Pressure gauge » Can Puncturing Device. 2 . Density » Hydrometer, » Pycnometer. 3. Moisture » Karl Fisher Method, » Gas Chromatography. 4. Identification of propellants » Gas Chromatography, » IR Spectroscopy. 55

54. C)PERFORMANCE 1. Aerosol valve discharge rate : • Contents of the aerosol product of known weight is discharged for specific period of time. • By reweighing the container after the time limit, the change in the weight per time dispensed gives the discharge rate ( g/sec ). 56

55. 2 . Dosage with metered valves : • Reproducibility of dosage can be determined by: » Assay techniques » Accurate weighing of filled container followed by dispensing of several doses . Containers are then reweighed and difference in weight divided by number of doses dispensed gives average dose. 57

56. 3 . Net Contents : • Tared cans that have been placed onto the filling lines are reweighed and the difference in weight is equal to the net contents . • In Destructive method : weighing a full container and then dispensing as much of the content as possible . The contents are then weighed . This gives the net content. 58

57. 4 . Foam stability : Methods : Visual Evaluation, Time for given mass to penetrate the foam, Time for given rod that is inserted into the foam to fall , Rotational Viscometer. 5 . Particle Size Determination : Methods : Cascade Impactor, Light Scattering Decay. 59

58. a ) Cascade Impactor : Principle : Stream of particles projected through a series of nozzles and glass slides at high velocity, larger particle are impacted first on lower velocity stage and smaller particles are collected at higher velocity stage . 60

59. D)BIOLOGICAL TESTING 1.Therapeutic Activity : » For Inhalation Aerosols : dosage of the product is determined and is related to the particle size distribution. » For Topical Aerosols : adsorption of therapeutic ingredient is determined. 2.Toxicity : » For Inhalation Aerosols : exposing test animals to vapors sprayed from aerosol container. » For Topical Aerosols : Irritation and Chilling effects are determined. 61

60. APPLICATION OF PDDS 62

61. NEWER DEVELOPMENT Dr Reddy's launches 'Dose Counter Inhalers' in India Friday, April 16,2010. This the first MDI in India that gives patients an advance indication of when the inhaler is going to be empty . DCI is a new drug delivery device with a single device having 120 metered doses . There is a window in the inhaler that changes color from green to red . 63

62. REFERENCES “The Theory & Practice Of Industrial Pharmacy” by Leon Lachman , H.A.Lieberman . “Aulton’s pharmaceutics” by Michael E .Aulton, Kevin M.g Taylor www.slideshare.net 64

63. THANK YOU 65