©上特 “-B✉ 国上人生 L Contents Structure of the respiratory tract Inhalation Dosage Forms Factors governing lung deposition School of Pharmacy Metered dose inhalers(MDIs) Chen Jian Dry powder inhalers(DPIs) 2013.5 cheniian @situ.edu.cn ·Nebulizers 国生一 圈上生 Structure of the respiratory tract Inhalation Dosage Forms .The lung is a series of bifurcating tubes Respiratory diseases .Trachea ·Asthma ·Bronchi Chronic obstructive pulmonary diseases ·Bronchiole (COPDs) .Alveolus Non-respiratory diseases Surface area of the airways increases with each generation 国坠生 Structure of the respiratory tract Drugs could be absorbed quickly in lung Pulmonary vasculature forms a separate circuit from the systemic circulation: The total surface area very big The main pulmonary artery starts in the right The membrane of lung epithelia is thin ventricle,then it divides into two branches for the The blood supply is abundant left and right lungs.Drugs absorbed into the pulmonary circulation will avoid the first-pass hepatic effect,although they could be metabolized in the respiratory tract. 1
1 Inhalation Dosage Forms School of Pharmacy Chen Jian 2013.5 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Contents • Structure of the respiratory tract • Factors governing lung deposition • Metered dose inhalers (MDIs) • Dry powder inhalers (DPIs) • Nebulizers Shanghai Jiao Tong University Inhalation Dosage Forms • Respiratory diseases • Asthma • Chronic obstructive pulmonary diseases (COPDs) • Non-respiratory diseases Shanghai Jiao Tong University Structure of the respiratory tract • The lung is a series of bifurcating tubes • Trachea • Bronchi • Bronchiole • Alveolus • Surface area of the airways increases with each generation Shanghai Jiao Tong University Drugs could be absorbed quickly in lung • The total surface area very big • The membrane of lung epithelia is thin • The blood supply is abundant Shanghai Jiao Tong University Structure of the respiratory tract Pulmonary vasculature forms a separate circuit from the systemic circulation: • The main pulmonary artery starts in the right ventricle, then it divides into two branches for the left and right lungs. Drugs absorbed into the pulmonary circulation will avoid the first-pass hepatic effect, although they could be metabolized in the respiratory tract
图生 国上认连 Advantages of inhalation dosage forms for systemic diseases Advantages of inhalation dosage forms for .A noninvasive'needle-free'delivery system; pulmonary diseases Suitable for a wide range of substances from small High concentrations directly to the disease site; molecules to very large proteins, Minimizes risk of systemic side-effects Enormous absorptive surface area and a highly permeable Rapid clinical response; membrane in the alveolar region; Bypass the barriers to therapeutic efficacy; The slow clearance in the lung results in prolonged Achieve a similar or superior therapeutic effect at a residency in the lung. fraction of the systemic dose .A low enzymatic environment that is devoid of hepatic first-pass metabolism; 国生一 圈上生 Particles transit through the airway of the lung Physicochemical factors governing lung deposition according to three mechanisms Aerodynamic diameter Inertial impaction ·Size Sedimentation ·Morphology ·Diffusion ·Density ·lygroscopicity ·Particle velocity 国垫生 国活生 Physiological factors governing lung Factors affecting absorption deposition Factors affecting deposition Inhaled volume ·Drug properties ·Flow rate ·Molecular weight ·Breath holding Kow 2
2 Shanghai Jiao Tong University Advantages of inhalation dosage forms for pulmonary diseases • High concentrations directly to the disease site; • Minimizes risk of systemic side-effects • Rapid clinical response; • Bypass the barriers to therapeutic efficacy; • Achieve a similar or superior therapeutic effect at a fraction of the systemic dose. Shanghai Jiao Tong University Advantages of inhalation dosage forms for systemic diseases • A noninvasive ‘needle-free’ delivery system; • Suitable for a wide range of substances from small molecules to very large proteins; • Enormous absorptive surface area and a highly permeable membrane in the alveolar region; • The slow clearance in the lung results in prolonged residency in the lung; • A low enzymatic environment that is devoid of hepatic first-pass metabolism; Shanghai Jiao Tong University Particles transit through the airway of the lung according to three mechanisms • Inertial impaction • Sedimentation • Diffusion Shanghai Jiao Tong University Physicochemical factors governing lung deposition • Aerodynamic diameter • Size • Morphology • Density • Hygroscopicity • Particle velocity Shanghai Jiao Tong University Physiological factors governing lung deposition • Inhaled volume • Flow rate • Breath holding Shanghai Jiao Tong University Factors affecting absorption • Factors affecting deposition • Drug properties • Molecular weight • KO/W
©上特 - 国人线 Metered dose inhalers Metered dose inhalers ·Aerosol Propellant-driven metered dose inhaler Pressurized metered dose inhaler .Pressurized aerosol 圈卢生Definition and Classification 圈上生 Pharmaceutical aerosol Advantages of the aerosol ·Absorb quickly It may be defined as an aerosol product Minimum contamination containing therapeutically active ingredients ·Improve stability dissolved,suspended,or emulsified in a Convenient to use propellant or a mixture of solvent and propellant Avoid first pass metabolism in GIT and liver and intended for inhale or topical administration Accurate dose or administration into body cavities. Suitable for local or systemic agents Non-invasive;Patient friendly 国坠生一 圈生 Disadvantages of the aerosol Metered dose inhaler ·Expensive ·Propellants Product concentrate ·Cooling effect .Container Patient coordination ·Valve 3
3 Metered dose inhalers Shanghai Jiao Tong University Metered dose inhalers • Aerosol • Propellant-driven metered dose inhaler • Pressurized metered dose inhaler • Pressurized aerosol Shanghai Jiao Tong University Definition and Classification Pharmaceutical aerosol • It may be defined as an aerosol product containing therapeutically active ingredients dissolved, suspended, or emulsified in a propellant or a mixture of solvent and propellant and intended for inhale or topical administration or administration into body cavities. Shanghai Jiao Tong University Advantages of the aerosol • Absorb quickly • Minimum contamination • Improve stability • Convenient to use • Avoid first pass metabolism in GIT and liver • Accurate dose • Suitable for local or systemic agents • Non-invasive; Patient friendly Shanghai Jiao Tong University Disadvantages of the aerosol • Expensive • Cooling effect • Patient coordination Shanghai Jiao Tong University Metered dose inhaler • Propellants • Product concentrate • Container • Valve
国卢生 国生 Propellant is responsible for developing the proper General requirements for propellants pressure within the container,and it expels the Vapor pressure higher than atmosphere product when the valve is opened and aids in the ·No toxicity atomization or foam production of the product. ·Inert Non-flammable,non-explosive ·No color,.no odor Cheap 国丝生一 国生一 ©Type of propellant Advantages ofhydrofluoroalkane (HFA) Low inhalation toxicity Chlorofluorocarbon (CFC) High chemical stability ·High purity Hydrofluorocarbons(HFAs) ·Not ozone depleting ©Disadvantages of hydrofluoroalkane(HFA)） ·Poor solvents Minor greenhouse effect ·High cost 国坠生 Propellants 圈生 Propellants Hydrofluoroalkane (HFA)propellants The pressure of aerosol is critical to its .Tetrafluoroethane(HFA134a) performance.It can be controlled by the type Heptafluoropropane (HFA227) and amount of propellants. Mixture of propellants f f Change vapor pressure C-C-H Change liquid density F- ·Change solvency HFA-134a HEA-227 4
4 Shanghai Jiao Tong University Propellant is responsible for developing the proper pressure within the container, and it expels the product when the valve is opened and aids in the atomization or foam production of the product. Shanghai Jiao Tong University General requirements for propellants • Vapor pressure higher than atmosphere • No toxicity • Inert • Non-flammable, non-explosive • No color, no odor • Cheap Shanghai Jiao Tong University Type of propellant • Chlorofluorocarbon (CFC) • Hydrofluorocarbons (HFAs) Shanghai Jiao Tong University Advantages of hydrofluoroalkane (HFA) • Low inhalation toxicity • High chemical stability • High purity • Not ozone depleting Disadvantages of hydrofluoroalkane (HFA) • Poor solvents • Minor greenhouse effect • High cost Shanghai Jiao Tong University Propellants Hydrofluoroalkane (HFA) propellants • Tetrafluoroethane (HFA134a) • Heptafluoropropane (HFA227) Shanghai Jiao Tong University Propellants The pressure of aerosol is critical to its performance. It can be controlled by the type and amount of propellants. Mixture of propellants • Change vapor pressure • Change liquid density • Change solvency
图生一 Propellants 国生 ©Raoult'slaw ©Formulation of MDI P.=N.P9=po ·Solution aerosols na+np P.=N,Po=m po ·Suspension aerosols na+np P=P+P 国丝生一 图上生 ©Formulation of MDI ©Formulation of MDI ·Solution aerosols ·Suspension aerosols Reduce initial particle size to less than 5um ·Propellant Control moisture content ·Cosolvent Use drug derivatives having minimum solubility ·Surfactant Adjust density of propellant and drug particles Use dispersing agents 国生一 圆生 ©Valve ©Container ·Plastic coated glass Metal (aluminum)container ·Plastic container 5
5 Shanghai Jiao Tong University Propellants Raoult’s law a b b a b b b b b a a b a a a a P P P P n n n P N P P n n n P N P 0 0 0 0 Shanghai Jiao Tong University Formulation of MDI • Solution aerosols • Suspension aerosols Shanghai Jiao Tong University Formulation of MDI • Solution aerosols • Propellant • Cosolvent • Surfactant Shanghai Jiao Tong University Formulation of MDI • Suspension aerosols • Reduce initial particle size to less than 5um • Control moisture content • Use drug derivatives having minimum solubility • Adjust density of propellant and drug particles • Use dispersing agents Shanghai Jiao Tong University Container • Plastic coated glass • Metal (aluminum) container • Plastic container Shanghai Jiao Tong University Valve
国生 国生 ©Preparation of MDI ©Pressure filling ·Pressure filling The product concentrate is quantitatively placed in the aerosol container.This method is used for ·Cold filling most Pharmaceutical formulations(aerosols) Advantages: Avoid moisture contamination Reduce lost of propellant 国丝生一 图上生 ④Cold filling ©Evaluation of MDI The product concentrate the propellant must be Emitted dose cooled Disadvantage:Aqueous systems cannot be filled, water turns to ice at this low temp. Particle sizing 国上人烤 neae 圈生 Active research area because Dry powder inhalers(DPIs) .Automatic coordination between dose delivery and inhalation ·No propellants Potential drug stability advantages High dose carrying capacity 6
6 Shanghai Jiao Tong University Preparation of MDI • Pressure filling • Cold filling Shanghai Jiao Tong University Pressure filling • The product concentrate is quantitatively placed in the aerosol container. This method is used for most Pharmaceutical formulations (aerosols) • Advantages: • Avoid moisture contamination • Reduce lost of propellant Shanghai Jiao Tong University Cold filling • The product concentrate & the propellant must be cooled • Disadvantage: Aqueous systems cannot be filled, water turns to ice at this low temp. Shanghai Jiao Tong University Evaluation of MDI • Emitted dose • Particle sizing Dry powder inhalers (DPIs) Shanghai Jiao Tong University Active research area because • Automatic coordination between dose delivery and inhalation • No propellants • Potential drug stability advantages • High dose carrying capacity
国生一 Dry Powder Inhalers 国生 Dry Powder Inhalers Formulation design of dry powder inhaler Formulation design of dry powder inhaler Low aerodynamic diameters Dry powder particles of suitable size range, Low inter-particulate forces generally considered between I and 6 um,can be readily produced. However,such particles have high surface area to mass ratio,making them highly cohesive/adhesive in nature. 国生一 图上生 图Carrier 图Carrier To overcome agglomerate,coarse carrier is The balance of interparticle forces is very used for the micronized drug. important,because a drug particle needs to be The drug is blended with and distributed over strongly attached to the carrier,yet becomes the surface of the coarse carrier. easily detached on aerosolisation to form a fine particle cloud 国坠生 圈生一 Pre-metered single dose ©Devices ·Spinhaler Pre-metered single dose Pre-metered multidose as single units Multidose bulk reservoir 7
7 Shanghai Jiao Tong University Dry Powder Inhalers Formulation design of dry powder inhaler • Low aerodynamic diameters • Low inter-particulate forces Shanghai Jiao Tong University Dry Powder Inhalers Formulation design of dry powder inhaler • Dry powder particles of suitable size range, generally considered between 1 and 6 μm, can be readily produced. • However, such particles have high surface area to mass ratio, making them highly cohesive/adhesive in nature. Shanghai Jiao Tong University Carrier • To overcome agglomerate, coarse carrier is used for the micronized drug. • The drug is blended with and distributed over the surface of the coarse carrier. Shanghai Jiao Tong University Carrier • The balance of interparticle forces is very important, because a drug particle needs to be strongly attached to the carrier, yet becomes easily detached on aerosolisation to form a fine particle cloud Shanghai Jiao Tong University Devices • Pre-metered single dose • Pre-metered multidose as single units • Multidose bulk reservoir Shanghai Jiao Tong University Pre-metered single dose • Spinhaler
国生 国生 Pre-metered multidose as single units Multidose bulk reservoir Diskhaler:GlaxoSmithKline Turbuhaler:AstraZeneca 1 2 3 iece cover 45 国上人烤 emete 国上生一 Nebulizers ④Nebulizer Liquid content is atomized by mechanical pressure. Produce a constant stream of aerosol particles. 国丝生一 圈生 Advantages of nebulizer Disadvantages of nebulizer Applicable to more varieties of drug Expensive and cumbersome equipment Need minimal coordination for inhalation Treatment times are somewhat lengthy Works with low inspiratory flows Medicine can be easily contaminated Breath-hold is not required for efficacy An external power source is needed 8
8 Shanghai Jiao Tong University Pre-metered multidose as single units • Diskhaler: GIaxoSmithKline Shanghai Jiao Tong University Multidose bulk reservoir • Turbuhaler: AstraZeneca Nebulizers Shanghai Jiao Tong University Nebulizer • Liquid content is atomized by mechanical pressure. • Produce a constant stream of aerosol particles. Shanghai Jiao Tong University Advantages of nebulizer • Applicable to more varieties of drug • Need minimal coordination for inhalation • Works with low inspiratory flows • Breath-hold is not required for efficacy Shanghai Jiao Tong University Disadvantages of nebulizer • Expensive and cumbersome equipment • Treatment times are somewhat lengthy • Medicine can be easily contaminated • An external power source is needed
国生 国生 Formulations are usually solution. ©Nebulizer Suspensions can also be formulated. ·Air jet system However,particle size of drug must be ·Ultrasonic system significantly smaller than the droplet size. The formulation must be sterile and isotonic to avoid stimulation of pulmonary tract. 国丝生一 圈上生 ®Air--jet nebulizer ©Air-jet nebulizer .Air-jet nebulizer devices .A high-pressure stream of gas stream exits the orifice utilize a pressurized gas .The high speed jet produces low lateral pressure at the outlet to create the aerosol It draws the liquid into the gas stream Drug particles. The high shear shatters the liquid into droplets 国垫生 圈生 ®Air-jet nebulizer ®Air-jet nebulizer ·Baffle Emitted droplets size depends on Large droplets impact on the Jet design,orifice diameter baffle surface and fall back .Gas pressure,density and flow rate Fine aerosol exit the air-jet Concentration,surface tension and viscosity of nebulize. drug solution 9
9 Shanghai Jiao Tong University Formulations are usually solution. Suspensions can also be formulated. However, particle size of drug must be significantly smaller than the droplet size. The formulation must be sterile and isotonic to avoid stimulation of pulmonary tract. Shanghai Jiao Tong University Nebulizer • Air jet system • Ultrasonic system Shanghai Jiao Tong University Air-jet nebulizer • Air-jet nebulizer devices utilize a pressurized gas to create the aerosol particles. Shanghai Jiao Tong University Air-jet nebulizer • A high-pressure stream of gas stream exits the orifice • The high speed jet produces low lateral pressure at the outlet • It draws the liquid into the gas stream • The high shear shatters the liquid into droplets Shanghai Jiao Tong University Air-jet nebulizer • Baffle • Large droplets impact on the baffle surface and fall back • Fine aerosol exit the air-jet nebulize. Shanghai Jiao Tong University Air-jet nebulizer • Emitted droplets size depends on • Jet design, orifice diameter • Gas pressure, density and flow rate • Concentration, surface tension and viscosity of drug solution
国生一 国生 ©Nebulizer Nebulizer Ultrasonic system ·Ultrasonic system US wave is formed by a piezoelectric crystal -Therapeutic mist It is converted into high-frequency acoustic vibrations The vibrations disrupt the surface and create oscillation waves The oscillation waves will produce an aerosol cloud at the solution surface High-frequency source 图生一 国生 New types of nebulizer Respimat Soft MistTM Inhaler The secret of Respimat is the extremely fine nozzle Respimat Soft MistTM Inhaler system. When the medication solution is forced through it, two fine jets of liquid are produced. The two jets of liquid converge at an optimised angle The impact of these converging jets generate the soft mist. 国垫生 圈生一 Learning objectives Respimat Soft MistTM Inhaler Concept:MDI,DPI,nebulizer,propellant, cold filling,pressure filling ·The mist is extremely fine(5.8μn average) It moves slowly,which is the basis for high Mechanisms of particle deposition in respiratory tract lung deposition. No requirement for forceful inspiration. 10
10 Shanghai Jiao Tong University Nebulizer • Ultrasonic system Shanghai Jiao Tong University Nebulizer • Ultrasonic system • US wave is formed by a piezoelectric crystal • It is converted into high-frequency acoustic vibrations • The vibrations disrupt the surface and create oscillation waves • The oscillation waves will produce an aerosol cloud at the solution surface Shanghai Jiao Tong University New types of nebulizer • Respimat Soft MistTM Inhaler Shanghai Jiao Tong University Respimat Soft MistTM Inhaler • The secret of Respimat is the extremely fine nozzle system. • When the medication solution is forced through it, two fine jets of liquid are produced. • The two jets of liquid converge at an optimised angle • The impact of these converging jets generate the soft mist. Shanghai Jiao Tong University Respimat Soft MistTM Inhaler • The mist is extremely fine (5.8 µm average). • It moves slowly, which is the basis for high lung deposition. • No requirement for forceful inspiration. Shanghai Jiao Tong University Learning objectives Concept: MDI, DPI, nebulizer, propellant, cold filling, pressure filling Mechanisms of particle deposition in respiratory tract