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Pulmonary drug delivery system.

This document provides an overview of pulmonary drug delivery systems. It discusses the anatomy and physiology of the lungs, advantages and disadvantages of pulmonary delivery, and different technologies used. Aerosols, propellants, and container types are described. Current pulmonary delivery devices discussed include metered dose inhalers, dry powder inhalers, and nebulizers. The document also covers evaluation methods for pharmaceutical aerosols and pulmonary drug delivery systems such as cascade impactors and in vitro and in vivo tests.

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PULMONARY DRUG DELIVERY SYSTEM SUBMITTED TO SUBMITTED BY PROF. ASGAR ALI MOHD IMRAN DEPARTMENT OF PHARMACEUTICS MPHARM (Pharmaceutics) II Sem. SPER , JAMIA HAMDARD SPER, JAMIA HAMDARD
CONTENT • Introduction • Anatomy and physiology of lungs • Advantage and disadvantage of Pulmonary Drug Delivery system. • Aerosols , propellants & container types. • Current technologies for pulmonary drug delivery. • New technologies for pulmonary drug delivery. • Evaluation of Pharmaceutical Aerosols & PDDS.
INTRODUCTION • Pulmonary drug delivery is primarily used to treat conditions of the airways, delivering locally acting drugs directly to their site of action. • Delivery of anti-asthmatic and other locally acting drugs directly to their site of action reduces the dose needed to produce a pharmacological effect, while the low concentrations in the systemic circulation may also reduce side-effects. • The drugs which are administered by pulmonary route are not only for lungs delivery but it goes to systemic circulation and produce the effect where it is desired through out the body. For Eg. A product containing ergotamine tartrate is available as an aerosolized dosage inhaler for the treatment of migraine & Volatile anesthetics, including, halothane, are also given via the pulmonary route.
• In recent years, the possibility of utilizing the pulmonary route for the systemic delivery of peptides and other molecules which are not absorbed through the gastrointestinal tract has also been explored.
Anatomy & Physiology of Lungs 1. Lungs region 2. Nasopharyngeal region 3. Tracheo-bronchial region 1. Alveolar region
1) Lung regions The respiratory tract starts at the nose and terminates deep in the lung at an alveolar sac. There are a number of schemes for categorizing the various regions of therespiratory tract. 2) Nasopharyngeal region (NP region) This is also referred to as the “upper airways”, which involves the respiratory airways from the nose down to the larynx. 3) Tracheo-bronchial region (TB region) This is also referred to as the “central” or “conducting airways”, which starts at the larynx and extends via the trachea, bronchi, and bronchioles and ends at the terminal bronchioli.
4) Alveolar region This is also referred to as the “respiratory airways”, “peripheral airways” or “pulmonary region”, Comprising the respiratory bronchioles, alveolar ducts and alveoli . Drugs administered by inhalation for local action in the airways. COPD=chronic obstructive pulmonary disease. Drug Disease Examples b2-adrenoceptor agonists Asthma, COPD salbutamol, terbutaline, fenoterol, salmeterol Corticosteroids Asthma , COPD budesonide, beclomethasone Anticholinergic Asthma , COPD ipratropium bromide Anti-inflammatory Asthma nedocromil, cromoglycate
Advantage of PDDS • Inhaled drug delivery puts drug where it is needed. • It requires low and fraction of oral dose i.e. drug content of one 4 mg tablet of salbutamol equals to 40 doses of meter doses. • Pulmonary drug delivery having very negligible side effects since rest of body is not exposed to drug. • Onset of action is very quick with pulmonary drug delivery. • Degradation of drug by liver is avoided in pulmonary drug delivery. • In asthma and diabetes requires long term treatment if it is given by pulmonary drug delivery safety is maximum because rest of body is not exposed to drug.
Disadvantage of PDDS • Low Efficiency of inhalation system • Poor formulation stability for drug • Improper dosing reproducibility
Aerosols Aerosol is a pressurized dosage forms containing one or more therapeutic active ingredients which upon actuation emit a fine dispersion of liquid and/or solid materials in a gaseous medium.
COMPONENTS OF AEROSOLS 1. Propellant 2. Container 3. Valve and actuator 4. Product concentrate
PROPELLANTS • Responsible for developing proper pressure within the container. • Provide driving force to expel the product from the container. TYPES OF PROPELLANTS (a) Liquefied gases Propellants (b) Compressed gases Propellants
PROPELLANTS TYPES Depending on the route of administration and use, I) Type-I Propellant A- Liquefied Gas 1) For oral and inhalation (Fluorinated hydrocarbons) • Tri-chloro-mono-flouro methane (propellant 11) • Di-chloro di-fluro methane (propellant 12) 2) Topical Pharmaceutical aerosols (Hydrocarbons) • Propane • Butane II) Type-II Propellant B - Compressed Gas Propellants 1) Compound gases • Nitrogen • Carbon di-oxide
LIQUEFIED GAS PROPELLANTS Exist as liquids under pressure. Because the aerosol is under pressure propellant exists mainly as a liquid, but it will also be in the head space as a gas. 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.
CHLORO FLUORO CARBONS 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 .
HYDROCARBONS • Can be used for water based aerosols and topical use. Advantages • Inexpensive • Excellent solvents • It does not cause ozone Disadvantages • Inflammable • Unknown toxicity produced Example Propane - Propellant A-108 Isobutane - Propellant A-31 Butane - Propellant A-17
HYDROFLUORO CARBONS AND HYDRO CHLORO FLUORO CARBONS •These compounds break down in the atmosphere at faster rate than cfcs. • Lower ozone destroying effect Advantages: Low inhalation toxicity High chemical stability High purity Not ozone depleting EXAMPLES: HEPTAFLUORO PROPANE (HFA-227) TETRAFLUOROETHANE (HFA-134A) DIFLUOROETHANE - PROPELLANT 152A CHLORODIFLUOROMETHANE - PROPELLANT 22 CHLORODIFLUOROETHANE - PROPELLANT 142 B Disadvantages Poor solvent High cost
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
CONTAINERS They must be able to withstand pressures as high as 140 to 180 psig (pounds per sq. inch gauge) at 130 ° F. AEROSOL CONTAINERS A. Metals i. Tinplated steel ii. Aluminum iii. Stainless steel B. Glass I. Uncoated glass II. Plastic coated glass
TIN PLATED STEEL CONTAINERS It consist of a sheet of steel plate, this sheet is coated with tin by electrolytic process . 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. Welding eliminates soldering process, Saves considerable manufacturing time and decreases the product/container interaction. Recent developments in welding include Soudronic system and Conoweld system.
ALUMINIUM CONTAINERS Used for inhalation and topical aerosols . Manufactured by impact extrusion process. Light in weight, less fragile, Less incompatibility due to its seamless nature. Greater resistance to corrosion . Pure water and pure ethanol cause corrosion to Al containers. Added resistance can be obtained by coating inside of the container with organic coating like phenolic , vinyl or epoxy and polyamide resins.
STAINLESS STEEL CONTAINERS Used for inhalation aerosols ◦ Advantage : Extremely Strong. Resistant to many materials.  No need for internal coating. ◦ Disadvantage : Costly
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 of glass aerosol containers  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.
VALVES ◦ To delivered the drug in desired form. ◦ To give proper amount of medication. ◦ Not differ from valve to valve of medication in pharmaceutical preparation. ◦ Types - Continuous spray valve - High speed production technique. - Metering valves ◦ Dispersing of potent medication at proper dispersion/ spray approximately 50 to 150 mg ±10 % of liquid materials at one time use of same valve.
Valve components Ferrul or mount cap  Valve body or housing  Stem  Gasket  Spring  Dip tube
ACTUATORS These are specially designed buttons which helps in delivering the drug in desired form i.e., spray, wet stream, foam or solid stream. TYPES OF ACTUATORS: • Spray actuators • Foam actuators • Solid steam actuators • Special actuators
Continued… ◦ SPRAY ACTUATORS: • It can be used for topical preparation, such as antiseptics, local anesthetics and spray on bandages etc. • It allows the stream of product concentrate and propellant to pass through various openings and dispense as spray. ◦ FOAM ACTUATORS: • It consist of large orifice which ranges from 0.070—0.125 inch. ◦ SOLID STREAM ACTUATORS: • These actuators are required for dispensing semi solid products such as ointments . ◦ SPECIAL ACTUATORS: • These are used for a specific purpose. • It delivers the medicament to the appropriate site of action such as throat, nose, dental and eyes etc.
RECENT ADVANCES IN PULMONARY DRUG DELIVERY DEVICES Following types of inhalation devices are present 1. Inhalation drug delivery system by ‐ nebulizer 2. Inhalation drug delivery system by - metered dose inhalers 3. Inhalation drug delivery system by ‐ dry powder inhalers
1. Nebulizer Nebulizers used today for drug delivery to the respiratory tract and are particularly useful for the treatment of hospitalized or nonambulatory patients. Mainly there are two general types of nebulizer systems, i. The ultrasonic and ii. The air jet  The ultrasonic nebulizer uses a piezoelectric crystal, vibrating at a high frequency (usually 1–3 MHz), to generate a fountain of liquid in the nebulizer chamber; the higher the frequency, the smaller the droplets produced The jet nebulizer functions by the Bernoulli principle by which compressed gas (air or oxygen) passes through a narrow orifice, creating an area of low pressure at the outlet of the adjacent liquid feed tube. This results in the drug solution being drawn up from the fluid reservoir and shattering into droplets in the gas stream.
Continued.. Advantage:  The nebulizer can transport more drugs to the lungs than MDI or DPI.  The treatment of acute asthma in an emergency care unit.  Rapid absorption, higher bioavailability, therefore, lower doses .  Avoidance of liver first pass metabolism.  Avoidance of metabolism by the gastrointestinal tract. Disadvantage:  Lack of possibility  Higher costs  The need for higher drug doses to achieve a therapeutic result
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 micros. Used to minimize the number of administrations errors.  It can be delivery measure amount of medicament accurately.
Advantage of MDI It delivers specified amount of dose. Small size and covenience. Usually inexpensive as compare to dry powder inhalers and nebulizers. Quick to use. Disadvantage of MDI Difficult to delivery high doses. There is no information about the number of dose left in the MDI Accurate co-ordination between actuation of a dose and inhalation is essential Continued…
Dry Powder inhaler (DPI) DPIs are bolus drug delivery devices that contain solid drug in a dry powder mix (DPI) that is fluidized when the patient inhales. DPIs are typically formulated as one-phase, solid particle blends. 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.
Continued… Advantage Propellant-free. Less need for patient co-ordination. Less formulation problem Dry powders are at a lower energy state, which reduces the rate of chemical degradtion 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. Not available worldwide
Today there are essentially two types of DPIs Unit-Dose Devices Single dose powder inhalers are device in which a powder containing capsule is placed I a holder. The capsule is opened with in the device and the power 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
Evaluation of PDDS  Cascade impactors  In- vitro  In- vivo  Continuous cell cultures  Primary cell culture  Air-Interface culture  Passive Inhalation  Whole body exposure system  Head only or nose only exposure system  Direct intratracheal administration  Intranasal administration
Cascade impactors Cascade impactors operate on the principle of inertial impaction. Each stage of the impactor comprises a series of nozzles or jets through which the sample laden air is drawn, directing any airborne towards the surface of the collection plate for that particular stage. Whether a particular particle impacts on that stage is dependent on its aerodyanamic diameter. particle having sufficient inertia will impact on that particular stage collection plate, whilst smaller particle will remain entrained in the air stream and pass to the next stage where the process is repeated. The stage are normally assembled in a stock or row in order of decreasing particle size. As the jets get smaller, the air velocity increases such that smaller particles are collected.
Conti…  At the end of the test, the particle mass relating to each stage is recovered using a suitable solvent and then analysed usually using HPLC to determine the amount of drug actually present.  The Ansdersen Cascade impactor (ACI) is most commonly used impactor with in the pharma indusrty for the testing of inhaled products.  The ACI is an 8-stage cascade impactor suitable for measuring the aerodynamic particle size distribution (APSD) of both MDIs and DPIs.  This is also used to measure parameters like Fine Particle Fraction(FPF) and mass median aerodynamic diameter(MMAD) Limitation  Measurement in cascade impactors are done at room temperature and at low relative humidity which is not representative of human airways ambient conditions.
In vitro In vitro model is used in this method it is significant that epithelial cells form a tense monolayer in order to characterize the natural epithelial barrier. Monolayer tension and reliability are classically assessed by measuring Tran’s epithelial electrical resistance (TEER) and potential difference crosswise the monolayer. Monolayers of lung epithelial cells permit the categorization of drug transport and evaluation of potential drug and formulation toxicity.
In vivo Animal study is carried out to get information on drug deposition, metabolism, absorption and kinetic profile as well as drug and formulation tolerability Non-human primates are use only in advanced research By contrast, small rodents (mice, models for preliminary studies on pulmonary drug delivery Human branching is symmetric, in contrast monopodial branching of non human primates mammals. Different mucociliary clearance Large mammals have longer airways than small rodents
Continuous cell cultures Continuous cell cultures are supplementary reproducible and easier to utilize than primary cell cultures but they frequently do not have the differentiated morphology and the biochemical characteristics of the original tissue. There are a small number of cell lines resulting from alveolar epithelial cells. A549 is a type II alveolar epithelial cell line that originates from human lung adenocarcinoma. It can be very helpful in metabolic and toxicological studies
Air-interface cultures Air-interface cultures (AIC) are models that permit aerosol particles to place straight onto semi-dry apical cell surface. Drug deposition and dissolution take place in a small volume of cell lining fluid, a circumstances that mimics more directly deposition on the lung surface invivo. The AIC show greater similarity to airways epithelial morphology, with superior glycoprotein discharge, more prominent microvilli
Passive inhalation During passive inhalation of aerosolised drugs, animals are kept awake and allowed to breathe normally. The devices most frequently used for generating aerosols are nebulisers. Passive inhalation is principally used in the mouse and less frequently in larger animals (rat, guinea-pig, dog ). The drug concentration in the aerosol is determined by sampling the test atmosphere and quantifying the drug in the sample.
Whole body exposure system In whole body aerosol exposure system, animals are placed in a sealed plastic box that is connected to a nebuliser or a generator of dry powder aerosol. There is potential drug absorption across the skin after deposition on the animal fur,from the nasal mucosa and from the gastrointestinal tract.
Head-only or nose-only exposure systems In the head-only or nose-only exposure systems, the animal is attached to the exposure chamber and only the head or the nose is in contact with the aerosol. The systems can be designed for delivering drugs to one or to several animals Compared with the whole body exposure system, the head-only or nose-only exposure systems offer several advantages.
E X P O S U R E O F R O D E N T S TO A E R O S O L S . ( A ) N O S E - O N LY E X P O S U R E . T H E R E S T R A I N T ( R ) P R E V E N T S LO S S O F A E R O S O L B Y L E A K A G E A R O U N D T H E A N I M A L . T H E S M A L L O P E N I N G AT T H E B OT TO M A L LO W S T E M P E R AT U R E R E G U L AT I O N O F T H E A N I M A L T H R O U G H T H E TA I L ; I N T R AT R A C H E A L I N S T I L L AT I O N ( B ) A N D O R O P H A R Y N G EA L A S P I R AT I O N ( C ) U S E S C O M M E R C I A L O R S E L F - D E S I G N E D S Y R I N G ES F O R M A N U A L A P P L I C AT I O N O F A E R O S O L .
Direct intratracheal administration Dry powders can be delivered intratracheally using a powder- insufflator or by generating a powder aerosol. It is done to measure drug deposition and systemic drug absorption. Advantages of intratracheal administration of drugs include the perfect control of the drug dose delivered, the absence of drug losses in the instrumentation (except for liquid and powder aerosols), the bypassing of nasal passages
Illustration of PLV in a preterm infant. 1. The ventilator warms and oxygenates PFC liquid during slow instillation. 2. As liquid enters the side port of the endotracheal tube, the ventilator carries PFC to the distal areas of the lung. 3. As PFC liquid accumulates in the lungs, atelectasis regions of the lungs are expanded from A to B. 4. Oxygen and carbon dioxide are exchanged between alveolar PFC liquid and blood passing through the pulmonary capillaries. 5. Carbon dioxide is removed in expired gases by the ventilator.
Intranasal administration Intranasal administration is mostly known for local drug delivery to the nasal mucosa but it can also be used for intrapulmonary drug administration in mice. Intranasal administration is performed on the anaesthetized mouse kept in a vertical position. With the help of a micropipette, the solution is deposited on a nostril and is simply aspirated in respiratory airways during breathing.
Current Application of pulmonary drug delivery Application of pulmonary drug delivery in Asthma and COPD Treatment of asthma advances had done in drugs such levosalbutamol inhalers which show greater efficacy as compare to salbutamol. COPD means chronic obstructive pulmonary diseases Treatment of COPD tiotropium inhalers are present in market. Recent role pulmonary delivery inpatients on ventilators Using baby mask this is recent advancements in applications of pulmonary drug delivery. This mask is attached to spacer for small tidal volumes and low inspiratory flow rates infant and young Childers
Continued… New use of pulmonary delivery in diabetes  Insulin inhalers would work much like asthma inhalers. The products fall into two main groups the dry powder formulations and solution, which are delivered through different patented inhaler systems. E.g. Novel pMDI formulations for pulmonary delivery of proteins In migraine Ergotamine via metered dose inhaler was used successfully to treat migraine headache
Conti….
Continued… Application of pulmonary drug delivery in cancer chemotherapy Inhaled chemotherapy seems a logical approach to treat lung cancer Aerosol delivery of the anticancer agent’s difluoro methyl ornithine and 5-fluorouracil reduced lung tumors in mice 50 %and 60 %, respectively. Interleukin-2 stimulates immune function in cancer patients, but injections cause fever, malaise, and local swelling Diagnostic application pulmonary drug delivery Pulmonary drug delivery is not only useful for therapeutic purpose but also for diagnosis purpose. example, inhalation of aerosols of methacholine and histamine is responsiveness in asthma.
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