1. PREPARATION FOR INHALATION. Drugs under pressure.

2. Drugs that are under pressure - preparation for inhalation Propellant Based-Metered Dose Inhalers this drug that are in special containers (canister) under the gas pressure and containing one or more active ingredients, as the solutions, emulsions or suspensions, which are released from canister in the aerosol, liquid or soft form due pressing on the valve. Aerosol is a dispersion of solid or liquid particles of medicine substances in the gas, the size of which depends on the prescription.

3. Features of pMDI The drug product consists of: container, actuator, formulation and protective packaging; dosing performance is highly dependent on the design of the device. The drug delivered to the patient consists of: API, excipients, propellant and/or solvent. Aerosolization of the formulation from the pressurized canister is highly transient, complex and rapid. The concept of classical bioequivalence and bioavailability is not usually applicable for inhalation aerosols.

4. The advantage of the preparation for inhalation : Ease of use, aesthetics, hygiene. Availability of high efficiency at relatively low cost drugs. Use the metered device providing exact dosing. Preparations for inhalation give rapid therapeutic effect. Canister is tightly closed, ensuring sterility and the drug protecting from the impact of the external factors. When a large number of manipulations do not need a large number of staff.

5. Disadvantages of the drug under pressure:  relatively high cost;  possibility of explosion of the canister due impact or high temperature;  air pollution by drugs and propellants at the manipulation.

6. Classification of the drug under pressure Pharmaceutical – are composed of the canister, valve- spray systems and content of different consistency, which are released from canister at the pressing on the valve due propellant. The structure of this product includes MS, auxiliary substances and propellants. Medical – this means one or more MS in the form of solid or liquid particles, obtained by means of special stationary and intended primarily for inhalation administration.

7. 1.inhalation, 2.otolaryngology, 3.dermatological, 4.dental, 5.proctologic et al. Classification of the pharmaceutical drug under pressure by appointment:

8. Pharmaceutical drug under pressure topical (skin) therapy for local anaesthesia and cooling for sports injuries; sub-lingual sprays for angina pectoris; nasal sprays for allergic rhinitis and sinusitis; vaginal foams for contraception; rectal foams for colitis.

9. Formulation Active Pharmaceutical Ingredients Micronized Spray Dried Freeze Dried Others Excipients / Surfactants (improve valve lubrication, enhance API solubility and increase homogeneity of the suspension) Propellants - HFA 134a and 227 Solvents - ethanol (increase API solubility, increase miscibility of the surfactant and lower vapour pressure of propellant)

10. Principal Control Factors Momentum (Particle/Droplet Size and Mass, Morphology, Shape and Velocity) Particle Design Formulation Aerosol Generation Plume Manipulation (delivery system specific) Delivery Timing Relative to Aspiratory Cycle Synchronize propulsion and inhalation dynamics

11. Closure Container System/Primary Packaging Container/canister (reservoir) Coated (chemically or plasma) Uncoated high grade aluminium Valve (seal and volume control) Retention – Gaskets need to prime Non-retention no need to prime Nozzle (modify the rate of flow, speed, direction, mass, shape, pressure of stream) Actuator/Mouthpiece (affect spray pattern and droplet/particle size)

12. Canisters and valve-spray devices 1 - canister; 2 - sprayer - mouthpiece; 3 - metering valve; 4 - siphon tube; 5 - solution of MS; 6 - a vapour of the propellant; 7 - propellant. Capacity from 3 ml to 3 litters. a - two-phase system; b - three-phase system; ba

13. Types 1.Two-phase system. (Gas & liquid) 2. Three-phase system. (Gas, liquid, solid/liquid).

14. Classification of canisters depend on material 1.Metal 2.Glass 3.Plastic 4.Combined

15. Requirements to the glass canisters: should withstand the internal pressure (at least 2 MPa) should be resistant to impact should be chemically and thermally stable should not have internal stresses of glass should have a uniform thickness of the walls and bottom should have a minimum flat surfaces

16. Requirements to the another canisters: Plastics must be employed to coat the glass to improve safety characteristics or to coat metal containers to improve corrosion resistance and enhances the stability of formulation. Suitable metals include stainless steel, aluminium and tin-plated steel.

17. Classification of the metering valve depend on principle of operation: 1. Spring in force when you click vertically down on the actuator; 2. Oscillated springless when you click by the side on the actuator; 3. Valves with screw valve.

18. Classification of the metering valve depend on the way of fixing to the canister: 1. fixed by decompressing on the vertical walls; 2. by the process of rolling of the valve body on the special walls; 3. by screw metering valve on the neck canister.

19. Classification of the metering valve depend on appointment: 1. standard valves for liquid products, 2. for the foams; 3. for the viscous products; 4. for the powders and suspensions.

20. Types of the Nebulizers Conventional Tee Nebulizers Standard jet nebs w/ reservoir tubing Venturi nebulizers Passive and Active venturi nebulizer Breath actuated nebulizers Ultrasonic nebulizers Vibrating mesh

21. Types of the actuators: 1. for inhalation, 2. for the treatment of the asthma, 3. for suspension, 4. for film forming composition; 5. nozzles dental, rectal, vaginal.

22. Propellants For pressurized metered dose inhalations propellants perform the essential function of expelling the material from the container by supplying the necessary pressure within the aerosol system. They are liquefied or compounded gases having vapor pressures exceeding employed to obtain the necessary delivery and spray characteristics of the aerosol.

23. The commonly used propellants in aerosol systems are hydrocarbons, especially the fluorochloro derivatives of methane and ethane (Table ), the butanes and pentanes and compressed gases are used.

24. Commonly used propellants in aerosol systems Propellants Molecular weight Vapor pressure 011(CCl3F) 137.4 13.4 012(CCl2F2) 120.9 94.5 114(C2Cl2F4) 170.9 27.6 134(CH2FCF3) 102.0 96.0 227(CHF2C2F5) 170.0 72.6

25. Classification of the propellants depend on the vapor pressure: 1. The main, can create their own pressure not less than 0.2 MPa, 2. Auxiliary - propellants creating a pressure less than 0.1 MPa.

26. Classification of the propellants depend on the states of aggregation: 1) Liquefied gases: Freon, propane, butane, isobutane, vinyl and metylhloryd et al. 2) Compressed (difficulty liquefied) gases: nitrogen, nitrogen oxide, carbon dioxide; 3) easy volatile organic solvents: metylenhloryd, ethylene chloride, etc.

27. Stages of the Drugs under pressure production: 1.Sanitary preparation of production 2.Preparation of concentrate - MS solution 3.Release him from insoluble impurities 4.Packing in containers 5.Sealing 6.Filling propellant 7.Check the strength and impermeability 8.Standardization 9.Design package for transportation

28. The advantages of the emulsion systems – foams: - provides economical dosing -better contact with the mucous membrane, provides long-acting of the MS, -under the influence of body temperature they increase in the volume, filling all vacancies and channels in the rectum or vagina -can move in proximal direction, and during 4 hours provide a high concentration of MS.

29. Factors that affect on the stability of the foams: concentration of the foam agent, presence of the electrolyte pH, viscosity of the solution concentration and type of the propellant, presence of the additives.

30. The indicators used to evaluate the foam: appearance issuing its type of container (smooth, jerky, loud) stability and lifetime, elastic properties of the foam drying as a percentage of the time, wetting properties, density, viscosity, dispersion.

31. Classification of the foams Classes of the foams Aqueous: aqueous phase, surface active agents, propellant. Aqueous alcohol: water ethyl alcohol, foam, propellant. Nonaqueous : vegetable oil or mineral oil, surface active agents propellant

32. Suspension under pressure - a heterogeneous dispersed systems are characterized by the presence of th insoluble in liquid concentrate solid phase. Classification by composition: 1. They propellant may be included in the soluble phase or dispersion medium. 2. The active substance is dispersed in non- volatile solvent.

33. The main factors affecting on the quality of suspensions: 1.physical and chemical properties of the substances; 2.correlation between the components of the filler; 3.features of the design and material of the packaging; 4.temperature conditions of the maintenances container.

34. Canisters Production: Monoblock aluminium containers are made from flat pieces forming presses for impact type. Glass containers are made of neutral borosilicate glass on the automatic glass forming machines by double firing in horizontal furnaces. Plastic ones are made by vacuum forming or molding by pressure on the molding machines.

35. Methods of filling of the containers by propellants: 1. Filling pressure (primary) 2. Low-temperature method or "cold filling“ 3. Method of filling by the compressed gases 4. Method of filling by the soluble compressed gases.

36. The steps of filling containers: A. Washing, rinsing and drying of the containers 2. Blowing of the containers with sterile air 3. Filling the container with solution of concentrates 4. Remove air from the container by th e drop of liquid propellant 5. Sealing of container by consolidation valve 6. Filling the propellant under pressure 7. Check for leaks and strength.

37. Storage: avoid impacts, direct sunlight, high temperature.

38. Aerosol Testing Devices Cascade Impactors-Provides aerodynamic particle sizing and gives qty. of specific drug at a specific size - Anderson Cascade, Marple Miller and Next Generation Impactor Laser Diffraction Shines a laser beam through a particle and measure the refraction of the laser light to determine the size of the particle. Converts particle size to an equivalent sphere. - Malvern Mastersizer and Malvern Spraytech Breath Simulation- Harvard Pump Dose Assessment: - Filter Collection for weight analysis - Spectrophotometry / HPLC to assess drug presence

39. Aerosol Testing Cascade Impactors Advantages Provides aerodynamic particle size Provides how much specific drug at a specific size Cascade Impactors Disadvantages Continuous flow rate Long test times Requires testing to determine amount of drug on each stage During nebulizer testing (Specifically on Anderson impactor), drug may roll to the next stage if plate is overfilled Evaporation during test understates particle size Laser testing Advantages Speed / Cost /Efficiency. Measures particle size in real time Laser testing Disadvantages Can only measure the particle size distribution of solution based drugs. With a suspension, does not differentiate between the carrier and the drug Does not take into account the aerodynamics of a particle (How does the particle look to a specific flow?) Does not measure the quantity of drug in specific particle size ranges

40. Summary Primary packaging design of an aerosol delivery system is an integral part of its function Optimizing the principal design control factors of the drug product component will enhance the delivery efficiency and improve the consistency of the delivered dose Knowledge of optimizing these factors give us the edge on delivering innovative therapeutic agents