©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