©上特 “-Bwl 圈上人线 Contents Structure of the respiratory tract Factors governing lung deposition Inhalation Dosage Forms .Physicochemical factors Physiological factors School of Pharmacy Chen Jian ·Metered dose inhalers(MDIs)气雾剂 2012.3 ·Nebulizers喷雾剂 cheniian situ.edu.cn ·Dry powder inhalers(DPIs)粉雾剂 国生一 Structure of the respiratory tract Nasal cavity Pulmonary drug delivery Respiratory diseases Teminal bronchioles Non-respiratory diseases Larynx- Trachea Left bronchus- Diaphragm 国达生 Structure of the respiratory tract Drugs could be absorbed quickly in lung Pulmonary vasculature forms a separate The total surface area of alveoli is 70~100m2 circuit from the systemic circulation: The membrane oflung epithelia is thin The main pulmonary artery starts in the right ventricle (右心室)，then it divides into two branches for the left The surface area of capillary vessel is 90m2 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 2012.3 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Contents • Structure of the respiratory tract • Factors governing lung deposition • Physicochemical factors • Physiological factors • Metered dose inhalers (MDIs) 气雾剂 • Nebulizers 喷雾剂 • Dry powder inhalers (DPIs) 粉雾剂 Shanghai Jiao Tong University Pulmonary drug delivery • Respiratory diseases • Non-respiratory diseases Structure of the respiratory tract Shanghai Jiao Tong University Drugs could be absorbed quickly in lung • The total surface area of alveoli is 70~100m2 • The membrane of lung epithelia is thin • The surface area of capillary vessel is 90m2 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 （右心室）, 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
国必生 国上认生 Particles transit through the airway of the lung Physicochemical factors governing lung deposition according to three mechanisms Aerodynamic properties Inertial impaction ·Size .Sedimentation ·Morphology ·Diffusion ·Density ·Hygroscopicity Moving speed of particles 国生一 国生 Physiological factors governing lung deposition Factors affecting absorption Inhaled volume Factors affecting lung deposition ·Flow rate ·Drug properties ·Breath holding ·Molecular weight ·Konw 国坠生 Definition and Classification Metered dose inhalers Pharmaceutical aerosol ·Aerosol .It may be defined as an aerosol product .Propellant-driven metered dose inhaler containing therapeutically active ingredients Pressurized metered dose inhaler dissolved,suspended,or emulsified in a propellant or a mixture of solvent and propellant ·Pressurized aerosol and intended for inhale or topical administration or administration into body cavities. 2
2 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 properties • Size • Morphology • Density • Hygroscopicity • Moving speed of particles Shanghai Jiao Tong University Physiological factors governing lung deposition • Inhaled volume • Flow rate • Breath holding Shanghai Jiao Tong University Factors affecting absorption • Factors affecting lung deposition • Drug properties • Molecular weight • KO/W 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
国生 国生 Advantages of the aerosol ·Absorb quickly Disadvantages of the aerosol .Minimum contamination ·Expensive ·Improve stability ·Cooling effect Convenient to use Avoid first pass metabolism in GIT and liver Patient coordination ·Accurate dose Suitable for local or systemic agents .Non-invasive;Patient friendly 国生一 国生 ④Classification ④Classification Based on the dispersion systems Based on the administration route ·Solution aerosols(溶液型气雾剂) ,Inhalation aerosols(吸入气雾剂) ·Suspension aerosols(混悬型气雾剂) ·Non-inhalation aerosols(非吸入气雾剂)：dermal,, nasal,vaginal,rectal ·Emulsion aerosols(乳剂型气雾剂) ·Space aerosol(空间气雾 Based on the phase of the components ·Two phases aerosols(二相气雾剂) Based on the working way of valve ·Metered dose aerosols(定量气雾剂 ·Three phases aerosols(三相气雾剂 ·Non-metered dose aerosols(非定量气雾剂) 国丝生 国生 Metered dose inhaler Propellant is responsible for developing the proper ·Propellants抛射剂 pressure within the container,and it expels the product when the valve is opened and aids in the Product concentrate atomization or foam production of the product. ·Container ·Valve 3
3 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 Classification • Based on the dispersion systems • Solution aerosols (溶液型气雾剂) • Suspension aerosols (混悬型气雾剂) • Emulsion aerosols (乳剂型气雾剂) • Based on the phase of the components • Two phases aerosols (二相气雾剂) • Three phases aerosols (三相气雾剂) Shanghai Jiao Tong University Classification • Based on the administration route • Inhalation aerosols (吸入气雾剂) • Non-inhalation aerosols (非吸入气雾剂) : dermal, nasal, vaginal, rectal • Space aerosol (空间气雾剂) • Based on the working way of valve • Metered dose aerosols (定量气雾剂) • Non-metered dose aerosols (非定量气雾剂) Shanghai Jiao Tong University Metered dose inhaler • Propellants 抛射剂 • Product concentrate • Container • Valve 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
国生一 国上人生 General requirements for propellants ©Type of propellant Vapor pressure higher than atmosphere ·No toxicity ·Chlorofluorocarbon(CFC)氟氯烷经 ·Inert ·Hydrofluorocarbons(HFAs)氢氟烷烃 Non-flammable,non-explosive ·Dimethyl ether ·No color,no odor .Hydrocarbon ·Cheap ·Compressed gas 国生一 Propellants 国生一 ©Advantages of hydrofluoroalkane(HFA)氢氟烷烃 Hydrofluoroalkane (HFA) Low inhalation toxicity High chemical stability ·Tetrafluoroethane四氟乙烷HFA134a) ·High purity ·Heptafluoropropane七氟丙皖(HFA227) Not ozone depleting Disadvantages of hydrofluoroalkane (HFA) ·Poor solvents Minor greenhouse effect ·High cost HFA-134 国生 Propellants 国生 Propellants The pressure of aerosol is critical to its 圈Raoult'slaw performance.It can be controlled by the type and amount of propellants. P=N.Po na po Mixture of propellants na+np Change vapor pressure Change liquid density B=N,Po= 一Pg n。+n Change solvency P=P+P 4
4 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)氟氯烷烃 • Hydrofluorocarbons (HFAs)氢氟烷烃 • Dimethyl ether • Hydrocarbon • Compressed gas Shanghai Jiao Tong University Propellants Advantages of hydrofluoroalkane (HFA)氢氟烷烃 • 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 Hydrofluoroalkane (HFA) • Tetrafluoroethane 四氟乙烷(HFA134a) • Heptafluoropropane 七氟丙烷(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 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
国生 Formulation design 国上生 Product concentrate is the active ingredients ©Container of the aerosol combined with the required adjuncts to prepare a stable and efficacious ·Plastic coated glass product. Metal (aluminum)container ·Active Ingredients Plastic container Solvent or co-solvent Surface active agent ·Others 图上生一 Valve(Metered dose valve) 国生 ©Cap(封帽) Stem(阀门杆) ©Rubber ferrule(橡胶封圈)Spring(弹簧) ©Formulation of MDI ©Metering chamber(定量杯)Dip tube(浸入管) Solution aerosols @Actuator(推动钮) Cosolvent ·Stabilizer ·Surfactant (毕)气粥外形 国坠生一 国话生 ©Formulation of MDI ©Preparation of MDI ·Suspension aerosols ·Pressure filling Control moisture content Reduce initial particle size to less than 5um ·Cold filling Use drug derivatives having minimum solubility .Adjust density of propellant and drug particles Use dispersing agents 5
5 Shanghai Jiao Tong University Formulation design Product concentrate is the active ingredients of the aerosol combined with the required adjuncts to prepare a stable and efficacious product. • Active Ingredients • Solvent or co-solvent • Surface active agent • Others Shanghai Jiao Tong University Container • Plastic coated glass • Metal (aluminum) container • Plastic container Shanghai Jiao Tong University Valve (Metered dose valve) Cap (封帽) Stem (阀门杆) Rubber ferrule (橡胶封圈) Spring (弹簧) Metering chamber (定量杯) Dip tube(浸入管) Actuator (推动钮) Shanghai Jiao Tong University Formulation of MDI • Solution aerosols • Cosolvent • Stabilizer • Surfactant Shanghai Jiao Tong University Formulation of MDI • Suspension aerosols • Control moisture content • Reduce initial particle size to less than 5um • Use drug derivatives having minimum solubility • Adjust density of propellant and drug particles • Use dispersing agents Shanghai Jiao Tong University Preparation of MDI • Pressure filling • Cold filling
国生一 国生 ④Evaluation of MDI ④Nebulizer Leakages and weaknesses Liquid content is atomized by Emitted time and emitted dose mechanical pressure. Particle size distribution Produce a constant stream of aerosol Emitted rate and emitted amount particles. ·Sterile Formulations and devices are ·Microorganism developed by independent companies. 国生一 国生 Nebulizers enable treatment of patients that Drawbacks of traditional nebulizers require higher doses of drug .Cumbersome have difficulties with conventional inhalers ·Long timescale Have a complexity of device assembly with low efficiency and high variability in drug delivery 国生 圈生 Formulations are usually solution. ©Air-jet nebulizer Suspensions can also be formulated. Air-jet nebulizer devices utilize a pressurized However,particle size of drug must be gas to create the aerosol particles.The gas significantly smaller than the droplet size. stream is passed over the solution,creatinga liquid film.This film breaks apart due to The formulation must be sterile and breakage of surface tension forces,forming isotonic to avoid stimulation of pulmonary aerosol particles tract. 6
6 Shanghai Jiao Tong University Evaluation of MDI • Leakages and weaknesses • Emitted time and emitted dose • Particle size distribution • Emitted rate and emitted amount • Sterile • Microorganism Shanghai Jiao Tong University Nebulizer • Liquid content is atomized by mechanical pressure. • Produce a constant stream of aerosol particles. • Formulations and devices are developed by independent companies. Shanghai Jiao Tong University Nebulizers enable treatment of patients that • require higher doses of drug • have difficulties with conventional inhalers Shanghai Jiao Tong University Drawbacks of traditional nebulizers • Cumbersome • Long timescale • Have a complexity of device assembly with low efficiency and high variability in drug delivery 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 Air-jet nebulizer • Air-jet nebulizer devices utilize a pressurized gas to create the aerosol particles. The gas stream is passed over the solution, creating a liquid film. This film breaks apart due to breakage of surface tension forces, forming aerosol particles
国生一 国上人生 New types of nebulizer Dry powder inhaler(DPI)is an active research area because .HaloLite adaptive aerosol delivery system Automatic coordination between dose delivery and inhalation Omron MicroAir NE-U22 ·No propellants Respimat Soft MistTM Inhaler Potential drug stability advantages High dose carrying capacity 图上生一 Dry Powder Inhalers 国生 ④Powder .Low aerodynamic diameters ©Devices ·Small physical size .Low particle density(e.g porous particles) Pre-metered single dose Shape (e.g.,elongated particles) Rough surface (to increase air drag force) Pre-metered multidose as single units Low inter-particulate forces Rough surface(to reduce particle interaction) Multidose bulk reservoir Surface composition(to reduce surface energy) Low bulk density (loose particle packing to reduce particle contacts) Using fine carriers 国生 Learning objectives Category of inhalation dosage forms Concept:propellant,cold filling,pressure filling Mechanisms of particle deposition in respiratory tract 7
7 Shanghai Jiao Tong University New types of nebulizer • HaloLite adaptive aerosol delivery system • Omron MicroAir NE-U22 • Respimat Soft MistTM Inhaler Shanghai Jiao Tong University Dry powder inhaler (DPI) is an active research area because • Automatic coordination between dose delivery and inhalation • No propellants • Potential drug stability advantages • High dose carrying capacity Shanghai Jiao Tong University Dry Powder Inhalers Powder • Low aerodynamic diameters • Small physical size • Low particle density (e.g., porous particles) • Shape (e.g., elongated particles) • Rough surface (to increase air drag force) • Low inter-particulate forces • Rough surface (to reduce particle interaction) • Surface composition (to reduce surface energy) • Low bulk density (loose particle packing to reduce particle contacts) • Using fine carriers Shanghai Jiao Tong University Devices • Pre-metered single dose • Pre-metered multidose as single units • Multidose bulk reservoir Shanghai Jiao Tong University Learning objectives Category of inhalation dosage forms Concept: propellant, cold filling, pressure filling Mechanisms of particle deposition in respiratory tract