Pulmonary Drug Delivery System (MDIs and DPIs)

Pulmonary Drug Delivery System Page 1

Assignment On Pulmonary Drug Delivery System (MDIs and DPIs)

Submitted By

1. Md. Mahamudul Hossain 5. Jannat Ara Haque ID: 123-007-062 ID: 123-043-062

2. Arfia Chowdhury 6. Shuvankar Biswas ID: 123-008-062 ID: 123-045-062

3. Jakaria Sheak 7. Jannatul Ferdous ID: 123-028-062 ID: 123-044-062

4. Mohammed Nasir Uddin 8. Momo Ashrafi ID: 123-032-062 ID: 131-009-062 Semester: Summer, 2013 Course Name: Applied Pharmaceutics & Pharmaceutical Technology Course Code: MPP-6101

Submission Date: 07, December, 2013

Submitted To Md. Istiak Ahamed Lecturer Department of Pharmacy Primeasia University


Content Page No. Introduction ................................................................................................................ 3

Pulmonary Drug Delivery System ............................................................................. 3

Pulmonary System ..................................................................................................... 3

Physiology of Route of Administration .................................................................... 4

Applications of Pulmonary Route ............................................................................. 6

Mechanism of Action ................................................................................................ 6

Mechanism of Drug Absorption ............................................................................... 7

Pulmonary Drug Delivery ......................................................................................... 7

Methods of Inhalation delivery ................................................................................. 8

Factors Affecting Pulmonary Drug Delivery ........................................................... 11

Advantages of Pulmonary Drug Delivery ................................................................ 14

Limitations of Pulmonary Drug Delivery .................................................................. 14

Some Example of Pulmonary Drug Marketed in Bangladesh .................................. 15

Conclusion ................................................................................................................ 16

Reference ................................................................................................................... 16


Pulmonary Drug Delivery System (MDIs and DPIs)

Advantages and Limitations of DDS Physiology of Route of Administration Factors Affecting the Drug Absorption Examples of Some Delivery System (Market Preparations)

Introduction

Pulmonary route was use to treatment of different respiratory diseases from the last decade. The inhalation therapies involved the use of leaves from plants, vapors from aromatic plants, balsams, and myhrr. Through, around the turn of the 19th century, with the invention of liquid nebulizers, these newer treatments developed into valid pharmaceutical therapies. In the 1920 s adrenaline can introduce as a nebulizer solution, in 1925 nebulizer porcine insulin was use in investigational studies in diabetes, and in 1945 pulmonary delivery of the newly revealed penicillin was investigate. Steroids had been introduced in between 1950s for the treatment of asthma and nebulizers were enjoy widely use. In 1956 the pressured metered dose inhaler (pMDI) was placed, over the last 5 decades, helped by the advances in molecule design and drug discovery the pMDI was raised to become the major stay for the asthma treatment. It may found that certain drugs taken by pulmonary route are readily absorbed by the alveolar region direct in to blood circulation. Pulmonary route having many advantages over other routes of supervision for the treatment of particular disease states, specifically lung associated bigger protein molecules may degrade into the gastrointestinal situation and are excreted through the first pass metabolism into the liver which can be transferred through the pulmonary route if deposited in the respiratory passage of the lungs. (1)

Pulmonary Drug Delivery System

Pulmonary drug delivery describes various systems, devices, formulations & method of delivery of drugs to the lung for the treatment of diseases of the respiratory tract. For systemic delivery via the drug, once the drug is administered they readily pass into the blood stream without the need of any enhancers. (2)

Pulmonary System

The human pulmonary system is a complicated organ system of very close structurefunction relationships.

The pulmonary system consists of two regions-

1. The conducting air way region 2. Respiratory regions


The airway is further divided into many folds: nasal cavity and the associated sinuses, and the nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles. The respiratory region consists of respiratory bronchioles, alveolar ducts, and alveolar sacs (3)

Physiology of Route of Administration

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 the respiratory tract (4).

2) Nasopharyngeal 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

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 bronchioles.

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. The term pulmonary can be misleading since some authors use it with reference to the whole lung, while others control its use to the alveolar region. In this chapter pulmonary refers to the whole lung. The use of upper respiratory tract (i.e. NP plus trachea) and lower respiratory tract is also common place.


Fig: Different regions of the human pulmonary system

Pulmonary epithelium

The lung contains more than 40 different cell types, of which more than six line the airways. The diversity of pulmonary epithelia can be illustrated by examining its structure at three principal levels.

The bronchi

These are lined predominantly with ciliated and goblet cells. Some serous cells, brush cells and Clara cells are also present with few Kulchitsky cells.

The bronchioles

These are primarily lined with ciliated cuboidal cells. The frequency of goblet and serous cells decreases with progression along the airways while the number of Clara cells increases.

The alveolar region

T his is devoid of mucus and has a much flatter epithelium, which becomes the simple squamous type, 0.10.5 m thick. Two principal epithelial cell types are present:

Type-I Pneumocytes: Thin cells offering a very short airways-blood path length for the diffusion of gases and drug molecules. Type-I pneumocytes occupy about 93% of the surface area of the alveolar sacs, despite being only half as abundant as type-II cells.


Type-II Pneumocytes: Cuboidal cells that store and secrete pulmonary surfactant. Alveolar macrophages account for ~ 3% of cells in the alveolar region. These phagocytic cells scavenge and transport particulate matter to the lymph nodes and the mucociliary escalator.

Ciliated Cells

In the trachea bronchial region, a high proportion of the epithelial cells are ciliated such that there is a near complete covering of the central airways by cilia. Towards the periphery of the tracheobronchial region, the cilia are less abundant and are absent in the alveolar region. The ciliated cells each have about 200 cilia with numerous interspersed microvilli, of about 12 m in length. The cilia are hair-like projections about 0.25 m in diameter and 5 m in length. They are submersed in an epithelial lining fluid, secreted mainly from the serous cells in the sub-mucosal glands. The tips of the cilia project through the epithelial lining fluid into a layer of mucus secreted from goblet cells. The cilia beat in an planned fashion to propel mucus along the airways to the throat (4).

Applications of Pulmonary Route

Applications of pulmonary route consists-

Anti-asthamatic drugs Anti neoplastic drugs Anti diabetic drugs (insulin treatment) Anti viral drugs COPD Anti tubercular drugs Anti migraine (Ergotamine) Pulmonary arterial hypertension (iloprost) In acute lung injury (Prostaglandin E) (5)

Mechanism of Action

As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. As a major port of entry, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness of inhaled medications.

Inhalation of drugs for the treatment of local diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and chronic bronchitis, has been commonplace for many years.


The therapeutic effect of aerosolized therapies is dependent upon the dose deposited and its distribution within the lung. The influence of the latter on the effectiveness of inhaled therapies is less clear. Ruffin and colleagues demonstrated that a small dose of histamine aerosol deposited predominantly in the large conducting (central) airways was as effective in increasing airway obstruction as an 11-fold greater dose of histamine aerosol deposited diffusely, suggesting that the receptors for histamine reside mainly in the large airways and that surface concentration of a drug affects response.

Since particle size affects the lung deposition of an aerosol, it also can influence the clinical effectiveness of a drug. Johnson and colleagues showed that the bronchodilation response to cumulative doses of ipratropium bromide delivered either as a 3.3-m or 7.7-m aerosol was identical, whereas the response to salbutamol was significantly greater with the finer (3.3 m) aerosol, suggesting targeting drug aerosol to the location of their receptors in the lung does influence its effectiveness. (6)

Mechanism of Drug Absorption

Drug diffusion occurs through alveoli. Absorption through aqueous pores by carrier mediated transport. Phagocytosis of insoluble particles allow absorption of compounds with low lipophilicity &

or high molecular weight (2).

Pulmonary Drug Delivery

The drugs can be administered by pulmonary route utilizing two techniques:

Aerosol inhalation (also used in intranasal applications) and Intratracheal instillation.

By applying aerosol technique, we could achieve more uniform distribution with greater extent of penetration into the peripheral or the alveolar region of the lung, but this costs more and also faced with difficulty in measuring the exact dose inside the lungs. In contrary to this, instillation process is much simple, not expensive and has non-uniform distribution of drugs (7).

Inhaleables

Advanced technology for pulmonary delivery is expanding a category of drugs called Inhaleables defined as respiratory & systemic therapies administered simply by inhaling (2).

Aerosols

Aerosol preparations are stable suspensions of solid material & liquid droplets in a gaseous medium. The drug delivery by aerosols is deposited in the airways by: Gravitational sedimentation Diffusion


The term atomizer is used for a device that generates an aerosol & may be powdered by electrically/mechanically.

A dose can be removed without contamination of remaining material. The medication can be delivered directly to the affected area in a desired form such as spray or stable form. Irritation produced by mechanical application of topical medication is reduced or eliminated. Minimum contamination. Maximum stability (2).

Formulation of aerosol

Aerosol product essentially consists of two components: Product concentrate Propellant Product concentrate consist of active ingredients or mixture of active ingredients. Other necessary agents such as solvents, antioxidants & Surfactants (2).

Intratracheal Inhalation

This technique delivers a small amount of solution into the lungs by syringe. This route provides a rapid and quantifiable method of drug delivery to the lungs. The drug deposition is localized and uneven and only small absorptive area is used for the absorption from deposition.

Methods of Inhalation delivery

There are three commonly used methods of Inhalation delivery-

A. MeteredDose Inhaler (MDI) and B. Dry-Powder Inhaler (DPI) C. Jet or Ultrasonic Nebulizers

The metereddose inhalers are most frequently used aerosol delivery system. The dry-powder-inhalers are designed to deliver drug/excipients powder to the lungs (2).

A. Metered Dose Inhalers (MDIs)

Metered dose inhalers (MDIs) are a device that helps to deliver a specific amount of medication to the lungs. It is commonly used to treat asthma, chronic obstructive pulmonary disease (COPD). It is composed of 4 essential components.

1. The base formulation- drug, propellant, excipients. 2. The container. 3. Metering valve. 4. The actuator (mouth piece).


Fig: Metered-dose inhalers

Propellant

Propellant Single or blend of various propellants are used. It is selected to give the desired vapour pressure, solubility & particle size. Propellants can be with active ingredients in many different ways producing products with varying characteristics. Depending on the type of aerosol system utilized, the pharmaceutical aerosol may be dispensed as fine mist, wet spray & semi-solid or solid.

Commonly CFC propellants are used because of their low pulmonary toxicity, high chemical stability and purity and compatibility, Non-inflammable. But now a days the CFC propellants are replaced with Hydrofluoroalkanes (HFAs) as these CFC cause the ozone depletion effect. Examples: trichlorofluromethane dichlorodifluoromethane 1.2.dichlorotetrafluromethane (2).

Surfactants

These are added to maintain the drug in dispersed state & promote stability of formulation. It is also lubricates the valve. Examples: oleic acid, sorbitol.

Containers & valve

Usually the container is made up of aluminum or glass. Glass containers are normally plastic coated or laminated to enhance their ability to ensure internal pressures of high magnitude.

Metering valves

These are designed to release a fixed volume of product during each actuation. Usually valves volumes range from 25 to 100 ml although larger volumes are available.

B. Dry Powder Inhalers

This device dispenses a powder in a stream of inspired air. These are environmentally friend since they do not require CFC propellants for drug dispersion. Self medication is possible (2).


Fig.: Dry Powder Inhalers

Types of Dry Powder Inhaler Two types of dry powder inhaler

1. Passive dry powder inhaler Ex: Disc Inhaler, Easy haler 2. Active dry powder inhaler Ex: spiors, prohaler.

Advantages

Advantages Product and formulation stability High drug volume delivery per puff low susceptibility to microbial growth Applicable to both soluble and insoluble drugs Self medication is possible

Disadvantages

Hygroscopic powders have chances to particle growth. Accurate dose is required.

C. Nebulizer

Nebulizer Nebulizers are those that aerosolize aqueous solutions of water-soluble drugs 0r suspensions & solvent-water based solutions of water- insoluble substances. Nebulizer have been successfully employed for drug delivery to the lung. It is also used for local drug delivery to trachea for local anesthesia (2).

There are two types of Nebulizer

1. Pneumatic Nebulizer : It derives from pressurized gas source ex:- jet or hydro dynamic 2. Electrical Nebulizer : It operates from an electric source ex:-ultra sonic Nebulizer


Factors Affecting Pulmonary Drug Delivery

1) Mechanisms of particle deposition in the airways

Effective resistance mechanisms may have involved may reduces the burden of external particles enter the airways, and clearing those it may achieve something in being stored. Therapeutic aerosols are two-phase colloidal systems in that the drug is contained in a dispersed phase they may have a solid, liquid or combination of the two, based on the method and formulation of aerosol generation. Evidently for effective therapy, the drug must have obtain able to the lung in aerosol droplets or particles that deposit in the specific lung region and in sufficient quantity to be effective. The respiratory resistance mechanisms of mucociliary clearance and phagocytosis by macrophages may act upon insoluble particles. Aerosol particle dissolution they may slow and the drug may then subsequently to be subject to enzymatic deprivation before it reaches to its specific site of pharmacological action. Aerosols for pulmonary drug delivery are transported from the mouth (5).

2) Inertial impaction

This is the main deposition mechanism for particles >1 m in the upper tracheo-bronchial regions. A particle having a large momentum it may not able to follow the altering direction of the inspired air as it transferred the bifurcations and it will show result to collide with the airway walls as it continues on its original course.

Description of particle deposition mechanisms at an airway branching site 5 Impaction it mainly occurs near the bifurcations, certainly the impaction of particles from tobacco smoke on the bifurcations may be one cause why these sites are often the foci for lung tumors. The prospect of inertial impaction will be dependents upon particle momentum, thus particles with higher densities or larger diameter and those travelling in airstreams of higher velocity will show superior impaction.

3) Sedimentation

By the settling under gravity the particles may deposited. It becomes highly important for particles that reach airways where the airstream velocity is relatively low, e.g. the bronchioles and alveolar region. The fraction of particles depositing by this mechanism it may dependent upon the time the particles use in these regions.

4) Brownian diffusion

This is of minor significance for particles >1 m. Particles smaller than this size are displaced by a sequentially bombardment of gas molecules, which may results in particle collision with the airway walls. The chances of particle deposition by diffusion increases with the particle size decreases. Brownian diffusion is also more common in regions where airflow is very low or absent, e.g. in the alveoli. Another method of deposition, that of interception, is of important for fibers but it may not for drug delivery. Generally:-


Particles bigger than 10 m will have impact in the upper airways and are rapidly removed by swallowing, coughing and mucociliary processes.

The particles in the size range 0.55 m may break away from impaction in the upper airways and may deposit by sedimentation and impaction in the lower TB and A regions. If the aerosol particle size is between the 3 and 5 m then deposition it mainly occur in the TB region. If the particles are smaller than the 3 m then appreciable deposition in the A region is likely to occur.

A. PHYSIOLOGICAL FACTORS AFFECTING PARTICLE DEPOSITION IN THE AIRWAYS

1) Lung morphology

Each successful production of the tracheobronchial tree produces airways of falling diameter and length. Every bifurcation results in an increase possibility for impaction and the decrease in airway diameter is associated with a smaller displacement necessary a particle to make contact with a surface.

2) Inspiratory flow rate

When the inspiratory flow rate increases they enhance deposition by impaction in the first few generations of the TB region. The increase in flow not only increase particle momentum but also result in an increase in turbulence, mostly in the larynx and trachea, which itself will enhance impaction in the proximal tracheo-bronchial region.

3) Co-ordination of aerosol generation with inspiration

The energy of aerosol particles generated from pressurized metered dose inhalers (p MDIs, is largely govern by the pMDI formulation rather than the subjects IFR. pMDI aerosol droplets will be travelling at velocities of 2,5003,000 cm s1. A failure to co-ordinate actuation of the p-MDI during the early on phase of the inspiratory plan will result in near total particle impaction in the oropharnygeal area.

4) Tidal volume

An increased IFR will usually be connected with an enlarge in the volume of air inhaled in one breath, the tidal volume. Obviously an increase in tidal volume will result in penetration of aerosol particles deeper into the TB and A regions and a better chance for deposition inside these regions.

5) Breath holding

Increasing the time between the end of inspiration and the start of exhalation increase the time for sedimentation to occur. Breath-holding is normally used to optimize pulmonary drug delivery.


6) Disease states

Bronchial obstruction as seen in different pulmonary disorders may associated with the larger local airflows and turbulence and this will result in localized deposition in the larger airways of the trachea-bronchial region. The bronchoconstriction of asthma has a more influence on exhalation than inhalation and thus deposition by sedimentation may be superior than normal.

B. PHARMACEUTICAL FACTORS AFFECTING AEROSOL DEPOSITION

1) Aerosol velocity

The aerosols formed by nebulizers and dry powder inhalers (DPIs) are transported into the lung by entrainment on inspired air. In difference, pMDIs generate aerosol droplets with velocities greater than the inspiratory airflow and therefore the aerosol will have a greater affinity to impact in the oropharyngeal region.

2) Size

Marketable devices do not lead to monodispersed particles and frequently the size distribution is extensive and the particles may show varying shapes. Consequently a number of terms are used to adequately characterize an aerosol sample:- The geometric standard deviation (GSD) is defined as the size ratio at 84.2% on the cumulative frequency curve to the median diameter. This assumes that the sharing of particle sizes is Lognormal. A monodisperse, i.e. ideal aerosol, has a GSD of 1, although in practice an aerosol with a GSD of 1.22 are referred to as polydispersed or heterodispersed.

3) Shape

Particles which are non-spherical will have at smallest amount one physical dimension which is superior than the aerodynamic diameter. Ecological fibers 50 m in length can reach the A region because they align with the inspired airflow. Such materials then impact in the airways by a procedure of interception with the airway walls.

4) Density

Particles having densities less than 1 g cm3 (unit density) may have a mean physical diameter larger than the aerodynamic limit. Most micronized drugs for inhalation will contain particle densities around 1, although materials created by freeze-drying or spraydrying methods are likely to be appreciably less dense.

5) Physical stability

Therapeutic aerosols are often inherently actually unstable since they have a high concentration of particles and their close immediacy may lead to mutual repulsion or other inter-particulate reactions. Aerosol particles generate by DPIs may be hygroscopic and, during their passageway throughout the


high humidity environments of the airways, may enlarge in size and thus have a greater chance of being prematurely deposited. It be supposed to not be assumed, however, that the uptake of water vapor will always occur.

6) Pulmonary delivery devices

Current inhalation devices are separated into three different categories, the refinement of the nebulizer and the evolution of two types of compact portable devices, dry powder inhaler (DPI) and metered-dose inhaler (MDI) (5).

Advantages of Pulmonary Drug Delivery

1) It is needle free pulmonary delivery.

2) It requires small and fraction of oral dose.

3) Low concentration in the systemic circulation is associated with reduced systemic side effects.

4) It furnish very rapid onset of action similar to I.V.route (2).

5) Avoidance of gastrointestinal upset

6) Degradation of drug by liver is avoided in pulmonary drug delivery (8)

7) It supplies drugs into the blood stream directly.

8) It provides a non-invasive method of drugs delivery.

Limitations of Pulmonary Drug Delivery

1) Oropharyngeal deposition gives local side effect.

2) Patient may have difficulty using the pulmonary drug devices correctly

3) Drug absorption may be limited by the physical barrier of the mucus layer.

4) Various factors affect the reproducibility on drug delivery on the lungs, including

physiological and pharmaceutical barrier.

5) The lungs are not only accessible surface for drug delivery complex but also delivery devices

are required to target drug delivery (9).

6) Poor patient compliance.

7) It can provide irritant activity.

8) Aerosol can increase bronco constriction.

9) High cost of manufacturing (2).


Some Example of Pulmonary Drug Marketed in Bangladesh SL.

No. Generic Name Brand Name Company Indication Dose

1 Salbutamol Azmasol Inhaler

Beximco Pharmaceuticals ltd

Bronchodilator 100mcg/puff

2 Levosalbutamol Levoster Inhaler

Square Pharmaceuticals ltd


3 Salmetrol Xinafoate

Salmate Inhaler Square Pharmaceuticals ltd


4 Ipratropium Iprexl Inhaler Square Pharmaceuticals ltd


5 Tiotropium Norven Inhaler Square Pharmaceuticals ltd


6 Beclomethasone Beclomin Inhaler

Square Pharmaceuticals ltd

Steroid 100mcg/puff

7 Fluticasone Seretide Inhaler

GSk Pharmaceuticals ltd

Steroid 250mcg/puff

8 Budesonide Aeronid Inhaler

Beximco Pharmaceuticals ltd.

Steroid 100mcg/puff

9 Sodium Chromoglycate

Intal 5 Inhaler Sanofi Aventis Pharmaceuticals ltd

Mast Cell Stabilizer

5mg

10 Formoterol Efo Inhaler Square Pharmaceuticals ltd

Bronchodilator 12mcg/Capsule


Conclusion

As discussed in this review, the pulmonary drug delivery field is truly one of the mostly popular areas in todays applied pharmaceutical research and its development. Certainly, still at this time, the more information is collected the more related question marks are surfacing covering the area of lung physiology and diseases, lung deposition, intelligent inhalation devices, delivery of biopharmaceuticals. Absorption enhancement, controlled drug release in the lung and, last but not least. As more efficient pulmonary drug delivery devices and sophisticated formulations become may available, physicians and health professions will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lungs clearance mechanisms and be retained within the lung for longer periods. The more efficient, user-friendly delivery devices may allow for smaller total deliverable doses, decrease unwanted side-effects and increase clinical effectiveness and patient compliance. Some of the key determinants for successful dispersion of pharmaceutical powders suitable for inhalation are reviewed with an emphasis on the practical significance.

Reference

1. Derek I.D., & Jesse Z., Review on dry powder platform for pulmonary drug

delivery.,Particuology., 2008, 225238.

2. http://www.authorstream.com/Presentation/NAGESHVANKADARA-1395362-pulmonary-

drug-delivery-sysytem/

3. Critical Reviews in Therapeutic Drug Carrier Systems 14(4): 395-453, 1997.

4. Remingtons Pharmaceutical science, vol-1., 1990,18, 863-864.

5. Karhale Ashish A. Chaudhari Hiralal S., Ughade Prajkta L.,Baviskar Dheeraj T., Jain Dinesh

K;Int.J.PharmTech Res.2012,4(1)

6. Maryam A, Sheikh A. Alcohol based pressurized metered dose inhalers for use in asthma: a

descriptive study. Prim Care Respir J 2008; 17(2): 111-113

7. International Pharmaceutcial Aerosol Consortium, 1997. Ensuring patient care- the role of the

HFC MDI.

8. Banker G.S. and Rhodes T. R., Modern Pharmaceutics, Marcel Dekker, 4, 529-586.

9. Cole R.B. & Mackay A.D., Concepts of pulmonary physiology.,In Essentials of respiratory

disease, New York, Churchill Livingstone, 1990, 3, 4960.

Documents

Pulmonary Drug Delivery System (MDIs and DPIs)