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Pulmonary drug delivery system [PDDS]

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Pulmonary drug delivery system [PDDS]

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Pulmonary route used to treat different respiratory diseases from last decade.
The inhalation therapies involved the use of leaves from plants, vapours from aromatic plants, balsams, and myhrr.
Pulmonary drug delivery is primarily used to treat conditions of the airways, delivering locally acting drugs directly to their site of action.
Delivery of drugs directly to their site of action reduces the dose needed to produce a pharmacological effect.

Pulmonary route used to treat different respiratory diseases from last decade.
The inhalation therapies involved the use of leaves from plants, vapours from aromatic plants, balsams, and myhrr.
Pulmonary drug delivery is primarily used to treat conditions of the airways, delivering locally acting drugs directly to their site of action.
Delivery of drugs directly to their site of action reduces the dose needed to produce a pharmacological effect.

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Pulmonary drug delivery system [PDDS]

  1. 1. 1 Pulmonary drug delivery system Mr. Sagar Kishor Savale [Department of Pharmaceutics] avengersagar16@gmail.com 2015-2016 Department of Pharmacy (Pharmaceutics) | Sagar Savale 6/19/2016 Sagar kishor Savale
  2. 2. Introduction • Pulmonary route used to treat different respiratory diseases from last decade. • The inhalation therapies involved the use of leaves from plants, vapours from aromatic plants, balsams, and myhrr. • Pulmonary drug delivery is primarily used to treat conditions of the airways, delivering locally acting drugs directly to their site of action. • Delivery of drugs directly to their site of action reduces the dose needed to produce a pharmacological effect. 26/19/2016 Sagar kishor Savale
  3. 3. 3 • The respiratory tract is one of the oldest routes used for the administration of drugs.Over the past decades inhalation therapy has established itself as a valuable tool in the local therapy of pulmonary diseases such as asthma or COPD (Chronic Obstructive Pulmonary Disease) . • This type of drug application in the therapy of these diseases is a clear form of targeted drug delivery. • Currently, over 25 drug substances are marketed as inhalation aerosol products for local pulmonary effects and about the same number of drugs are in different stages of clinical development. Introduction 6/19/2016 Sagar kishor Savale
  4. 4. 4 • The drug used for asthma and COPD e.g..- β2-agonists such as salbutamol (albuterol), Terbutalin formoterol, corticosteroids such as budesonide, Flixotide or beclomethasone and mast-cell stabilizers such as sodium cromoglycate or nedocromi,. • The latest and probably one of the most promising applications of pulmonary drug administration is 1) Its use to achieve systemic absorption of the administered drug substances. 2) Particularly for those drug substances that exhibit a poor bioavailability when administered by the oral route, as for example peptides or proteins, the respiratory tract might be a convenient port of entry. 6/19/2016 Sagar kishor Savale
  5. 5. Anatomy and physiology of lungs • The human respiratory system is a complicated organ system of very close structure-function relationships • The system consist of regions  1-the conducting airways  2-the respiratory region 56/19/2016 Sagar kishor Savale
  6. 6. 6 THE RESPIRATORY TRACT 6/19/2016 Sagar kishor Savale
  7. 7. 7 • The human respiratory system is a complicated organ system of very close structure–function relationships. The system consisted of two regions: The conducting airway The respiratory region. • 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 • The human respiratory tract is a branching system of air channels with approximately 23 bifurcations from the mouth to the alveoli.The major task of the lungs is gas exchange, by adding oxygen to, and removing carbon dioxide from the blood passing the pulmonary capillary bed. 6/19/2016 Sagar kishor Savale
  8. 8. Anatomy and physiology of lungs 86/19/2016 Sagar kishor Savale
  9. 9. Lung region 9 1. Nasopharynx region: (NP) 2. Tracheobronchial region: (TB) 3. Alveolar region: (AV) 6/19/2016 Sagar kishor Savale
  10. 10. Types of cells present in lungs Bronchi 10 1) Ciliated cells 2) Goblet cells 3) Serous cells 4) Brush cells 5) Clara cells 1) Ciliated cells 2) Clara cells Bronchioles Alveoli 1) Type-1 pneumocytes 2) Type-2 pneumocytes 6/19/2016 Sagar kishor Savale
  11. 11. Factors affecting pulmonary drug delivery • Inertial impaction • Sedimentation • Brownian diffusion Mechanism of particle deposition in the airways 116/19/2016 Sagar kishor Savale
  12. 12. Physiological factors affecting particle deposition in the airways • Lung morphology • Inspiratory flow rate • Co-ordination of aerosol generation with inspiration • Tidal volume • Breath holding • Disease states 126/19/2016 Sagar kishor Savale
  13. 13. Pharmaceutical factors affecting aerosol deposition • Aerosol velocity • Size • Shape • Density • Physical stability 136/19/2016 Sagar kishor Savale
  14. 14. Advantages of pulmonary drug delivery • The dose needed to produce a pharmacological effect can be reduced • Low concentrations in the systemic circulation are associated with reduced systemic side-effects • Rapid onset of action • Avoidance of gastrointestinal upset • Avoidance of intestinal and hepatic first-pass metabolism 146/19/2016 Sagar kishor Savale
  15. 15. Disadvantages of pulmonary drug delivery • Complex delivery devices are required to target drugs to the airways and these devices may be inefficient. • Aerosol devices can be difficult to use • Various factors affect the reproducibility of drug delivery to the lungs, including physiological (respiratory maneuver) and pharmaceutical (device, formulation) variables. • Drug absorption may be limited by the physical barrier of the mucus layer and the interactions of drugs with mucus. • Mucociliary clearance reduces the retention time of drugs within the lungs. Efficient drug delivery of slowly absorbed drugs must overcome the ability of the lung to remove drug particles by mucociliary transport. 156/19/2016 Sagar kishor Savale
  16. 16. 16 CHALLENGES IN PULMONARY DRUG DELIVERY  Low Efficiency of inhalation system Aerosol system should have to produce optimum size particles because they are too small, they will be exhaled. If the particles are too large, they affects on the oropharynx and larynx.(0.5-1mm)  Less drug mass per puff To get adequate effect with the pulmonary drug delivery practical delivery of many drug which require milligram doses but With most existing systems, the total amount of drug per puff delivered to the lower respiratory tract is too low less than 1000 mcg.  Poor formulation stability for drug Most traditional drugs are crystalline, in the case of corticosteroids, and highly moisture sensitive drugs are unstable.  Improper dosing reproducibility Reason for Poor dosing reproducibility like worsening of diseases’, problem in device, un stabality of formulation. 6/19/2016 Sagar kishor Savale
  17. 17. 17 FORMULATION APPROACHES • Pulmonary delivered drugs are rapidly absorbed except large macromolecules drugs, which may yield low bioavailability due to enzymatic degradation and/or low mucosal permeability. • Pulmonary bioavailability of drugs could be improved by including various permeation enhancers such as surfactants, fatty acids, and saccharides, chelating agents and enzyme inhibitors such as protease inhibitors. • The most important issue is the protein stability in the formulation: the dry powder formulation may need buffers to maintain the pH, and surfactants such as Tween to reduce any chance of protein aggregation. The stabilizers such as sucrose are also added in the formulation to prevent denaturation during prolonged storage. 6/19/2016 Sagar kishor Savale
  18. 18. 18 • Pulmonary bioavailability largely depends on the physical properties of the delivered protein and it is not the same for all peptide and protein drugs. • Insulin liposomes are one of the recent approaches in the controlled release aerosol preparation. Intratracheal delivery of insulin liposomes (dipalmitoylphosphatidyl choline:cholesterol ,7:2) have significantly enhanced the desired hypoglycemic effect. • The coating of disodium fluorescein by hydrophobic lauric acid is also an effective way to prolong the pulmonary residence time by increasing the dissolution half time. In another method, pulmonary absorption properties were modified for protein/peptide drug (rhGCSF)in conjugation with polyethylene glycol (PEGylation) to enhance the absorption ofthe protein drug by using intratracheal instillation delivery in rat. 6/19/2016 Sagar kishor Savale
  19. 19. 19 AEROSOLS • Aerosol preparations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium. The drugs, delivery by aerosols is deposited in the airways by: gravitational sedimentation, inertial impaction, and diffusion. Mostly larger drug particles are deposited by first two mechanisms in the airways, while the smaller particles get their way into the peripheral region of the lungs by following diffusion. • There are three commonly used clinical aerosols: 1. Jet or ultrasonic nebulizers, 2. Metered–dose Inhaler (MDI) 3. dry-powder inhaler (DPI) • The basic function of these three completely different devices is to generate a drug-containing aerosol cloud that contains the highest possible fraction of particles in the desired size range. 6/19/2016 Sagar kishor Savale
  20. 20. 20 AEROSOL •Definition A suspension of very fine liquid or solid particles in a gas. •Key to aerosol therapy is aerosol particle •Respirable range:1-5 micron •80%drugs deposited in oropharynx •10% in walls of inhaler •10% in the lungs ( SP Newman et.al.1985 ) 6/19/2016 Sagar kishor Savale
  21. 21. 21 AIM OF AEROSOL THERAPY •To deliver a therapeutic dose of the selected agents to the desired site of action. •Choice of route for drug delivery -Directly to the site of action -Therapeutic action with side Effects: high therapeutic index, greater efficacy & safety 6/19/2016 Sagar kishor Savale
  22. 22. 22 •In mechanically ventilated patients -51%within nebulizer unit -2.2%IN Rt LUNG &0.9% IN Lt LUNG (SH Thomas M fiddler et.Al.1993) •In clinical settings, medical aerosols are generated with atomizer, nebulizer or inhalers –devices that physically disperse matter into small particles & suspend them into a gas. 6/19/2016 Sagar kishor Savale
  23. 23. 23 CHARACTERISTICS OF THERAPEUTIC AEROSOLS • Effective use of aerosols requires an understanding of characteristics of the aerosols. • Aerosol output (wt /minute) • Emitted dose This tells little about the amount of drug reaching the targeted site of action. 6/19/2016 Sagar kishor Savale
  24. 24. 24 •A substantial proportion of particles that leave a nebulizer may never reach the lungs. •Effectiveness of medical aerosols depends on amount of aerosol particles deposition to the lower respiratory tract & deposition of aerosol influenced by many other factors. 6/19/2016 Sagar kishor Savale
  25. 25. 25 FACTORS INFLUENCING DEPOSITION • Physical & chemical properties of aerosols • Anatomy of the respiratory tract • Physiological factors 6/19/2016 Sagar kishor Savale
  26. 26. 26 PHYSICAL & CHEMICAL PROPERTIES OF AEROSOLS GRAVITY • Aerosol size must be >1 microns because at this mass gravity loses its influence on particles. ( Chantal Darquenne , G Kim Prisk et.al.2000 ) •Gravity influence is in direct relation with particle mass •Greater mass—tendency to undergo proximal airway deposition 6/19/2016 Sagar kishor Savale
  27. 27. 27 INERTIAL IMPACTION Water particles Gas molecules 6/19/2016 Sagar kishor Savale
  28. 28. 28 PARTICLE SIZE •Aerosol particle size depends upon : -- nebulizer chosen --Method used to generate aerosol •It is not possible to visually determine whether a nebulizer is producing an optimal size particles… •Aerosols traverse tubular strs in which turbulent flow is the rule… •>Particle size---- gravity influence 6/19/2016 Sagar kishor Savale
  29. 29. 296/19/2016 Sagar kishor Savale
  30. 30. 30 •1-5 micron MMAD important determinant of its deposition efficacy in LRT •1-3 micron greater deposition 6/19/2016 Sagar kishor Savale
  31. 31. Recent technologies of pulmonary drug delivery • Nebulizers • Metered Dose Inhaler(MDI) • Dry Powder Inhaler(DPI) 316/19/2016 Sagar kishor Savale
  32. 32. Nebulizer • A nebulizer is a device used to administer medication to patient in the form of a mist inhaled into the lungs • It is commonly used in treating cystic fibrosis, asthma, and other respiratory diseases • There are two basic types of nebulizers: • 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. • 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 326/19/2016 Sagar kishor Savale
  33. 33. 33 •It is an electric nebulizer •Working principle : piezoelectric effect ultrahigh frequency current piezoelectric transducer ultrahigh frequency vibrations disk vibration couplant (water bath) 6/19/2016 Sagar kishor Savale
  34. 34. 34 FEATURES OF ULTRASONIC NEBULIZER •More expensive •Heats up during operation , Less noise •Less Rx time •Large average particle size ( Joseph L Rau et.al.2002 ) •Large output rate •0.5 to 3 microns – 90 % of particles within effective range 6/19/2016 Sagar kishor Savale
  35. 35. 35 INDICATIONS FOR NEBULIZER •Useful in children , Handicapped person , Seriously ill patients •Ventilated patients •Elderly individuals •High doses can be given •Combination drugs can be given 6/19/2016 Sagar kishor Savale
  36. 36. 36 •Enhancement of secretion clearance •Sputum induction •Humidification of respired gases •Prevent dehydration •Prevent or relieve bronchospasm 6/19/2016 Sagar kishor Savale
  37. 37. 37 Jet nebulizers Ultrasonic nebulizers 6/19/2016 Sagar kishor Savale
  38. 38. 38 NEBULIZER 6/19/2016 Sagar kishor Savale
  39. 39. Jet nebulizer 396/19/2016 Sagar kishor Savale
  40. 40. 40 Jet nebulizer 6/19/2016 Sagar kishor Savale
  41. 41. Ultrasonic nebulizer 416/19/2016 Sagar kishor Savale
  42. 42. 42 Ultrasonic nebulizer 6/19/2016 Sagar kishor Savale
  43. 43. 436/19/2016 Sagar kishor Savale
  44. 44. 446/19/2016 Sagar kishor Savale
  45. 45. 45 HAZARDS OF NEBULIZER •Bronchospasm •Over hydration •Delivery of contaminated aerosols •Tubing condensation •Swelling of retained secretions 6/19/2016 Sagar kishor Savale
  46. 46. 46 DRUGS FOR NEBULIZATION •Distilled water or normal saline •Mucolytics : mesna , acetylcysteine •Beta 2 agonists : salbutamol , terbutalin , fometerol , salmeterol •Antimuscarinic : ipratropium bromide •Steroids : budesonide •Antibiotics •Antifungal 6/19/2016 Sagar kishor Savale
  47. 47. 47 TECHNIQUE FOR USING NEBULIZER • 1. Place drug solution in nebulizer, employing a fill volume 2-6 ml •2. Place nebulizer in Inspiratory line • 3. Ensure airflow of 6-8 L/min through the nebulizer. • 4. Ensure adequate tidal volume ( 500 ml in adults). Attempt to use duty cycle > 0.3, if possible. 6/19/2016 Sagar kishor Savale
  48. 48. 48 •5. Observe nebulizer for adequate aerosol generation throughout use. •6. Disconnect nebulizer when all medication is nebulized or when no more aerosol is being produced. 6/19/2016 Sagar kishor Savale
  49. 49. 49 Metered Dose Inhalers (MDI) • Used for 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 microns. • Used to minimize the number of administrations errors. • It can be deliver measure amount of medicament accurately. 6/19/2016 Sagar kishor Savale
  50. 50. 50 Advantages of MDI • It delivers specified amount of dose. • Small size and convenience. • Usually inexpensive as compare to dry powder inhalers and nebulizers. • Quick to use. • Multi dose capability more than 100 doses available. Disadvantages of MDI • Difficult to deliver high doses. • There is no information about the number of doses left in the MDI. • Accurate co-ordination between actuation of a dose and inhalation is essential. 6/19/2016 Sagar kishor Savale
  51. 51. 516/19/2016 Sagar kishor Savale
  52. 52. Metered dose inhalers 526/19/2016 Sagar kishor Savale
  53. 53. 53 Metered Dose Inhalers (MDI) Active Ingredient Brand Manufacturer Country Salbutamol pressurized inhalation (100µg) Asthalin Cipla India albuterol Ventolin GlaxoSmithKline India levalbuterol HCl Xopenex 3M Pharmaceuticals U.S.A. Fluticasone50 μg Flixotide GlaxoSmithKline New Zealand Formoterol Fumarate12 mcg Ultratech India 6/19/2016 Sagar kishor Savale
  54. 54. 546/19/2016 Sagar kishor Savale
  55. 55. 55 Dry powder inhalers (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 sizes 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 the 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. Advantages Propellant-free. Less need for patient co-ordination. Less formulation problems. Dry powders are at a lower energy state, which reduces the rate of chemical degradation.6/19/2016 Sagar kishor Savale
  56. 56. 56 Disadvantages Dependency 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 Unit-Dose Devices • Single dose powder inhalers are devices in which a powder containing capsule is placed in a holder. The capsule is opened within the device and the powder is inhaled. Mulitidose Devices • This device is truly a metered-dose powder delivery system. The drug is contained within 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. 6/19/2016 Sagar kishor Savale
  57. 57. 576/19/2016 Sagar kishor Savale
  58. 58. Dry powder inhalers 58 For successful delivery of drug particles into the lung requires that particle size should be controlled to <5 μm Spinhaler 6/19/2016 Sagar kishor Savale
  59. 59. Dry powder inhalers 59 Rotahaler Turbuhaler 6/19/2016 Sagar kishor Savale
  60. 60. 606/19/2016 Sagar kishor Savale
  61. 61. 61 MARKETED DRUGS DRY POWDER INHALER Active Ingredient Brand Manufacturer Country Terbutaline 0.25mg Bricanyl AstraZeneca UK Beclometasone dipropionate 250mcg Becloforte Cipla Limited India Fluticasone propionate Flixotide GlaxoSmith Kline United Kingom Salbutamol Salbutamol Dry Powder Capsules Cipla Limited India Ipratropium Bromide 20 mcg ATEM Chiesi Farmaceutici Italy Xinafoate Seretide Evohaler GlaxoSmithKline UK 6/19/2016 Sagar kishor Savale
  62. 62. Applications •For Asthma: B-adrenergic agents- eg.salbutamol,terbutaline •Pulmonary Infections:(Pulmonary aspargillosis) • Antibiotics eg. Erythromycin & amphotericine-B •Cardiovascular agents:Nifedipine,Nitroglycerine 626/19/2016 Sagar kishor Savale
  63. 63. 63 COMPARISION BETWEEN MDI &DPI • High velocity aerosols • Requires coordination • Time consuming to teach • Requires slow & deep breathing only • Aerosol velocity depends on inspiratory flow rate • No coordination needed • Easy to teach • Requires high insp flow >28 l/min 6/19/2016 Sagar kishor Savale
  64. 64. 64 PATENTED DRUGS Cited Patent Filing date Issue date Original Assignee Title US2470296 Apr 30, 1948 May 17, 1949 INHALATOR US2533065 Mar 8, 1947 Dec 5, 1950 Micropulverized Therapeutic agents US4009280 Jun 9, 1975 Feb 22, 1977 Fisons Limited Powder composition for inhalation therapy US5795594 Mar 28, 1996 Aug 18, 1998 Glaxo Group Limited Salmeterol xinafoate with controlled particle size US6136295 Dec 15, 1998 Oct 24, 2000 MIT Aerodynamically light particles for pulmonary drug deliver 6/19/2016 Sagar kishor Savale
  65. 65. 65 RECENT ADVANCES The Aerogen Pulmonary Delivery Technology AeroDose inhaler. AeroNeb portable nebulizer 6/19/2016 Sagar kishor Savale
  66. 66. 66 The AERx device (with dosage forms). The AERx dosage form. AERx nozzle array. The AERx Pulmonary Drug Delivery System 6/19/2016 Sagar kishor Savale
  67. 67. 67 • The AERx aerosol drug delivery system was developed to efficiently deliver topical and systemically active compounds to the lung in a way that is independent of such factors as user technique or ambient conditions. • A single-use,disposable dosage form ensures sterility and robust aerosol generation. This dosage form is placed into an electronically controlled mechanical device for delivery. • After the formulation is dispensed into the blister, a multilayer laminate is heat-sealed to the top of the blister. This laminate, in addition to providing the same storage and stability functions as the blister layer, also contains a single-use disposable nozzle array. 6/19/2016 Sagar kishor Savale
  68. 68. 68 The Spiros Inhaler Technology 6/19/2016 Sagar kishor Savale
  69. 69. 69 • The inhaler has an impeller that is actuated,when the patient inhales, to disperse and deliver the powder aerosol for inhalation.The core technology was initially developed to overcome the patient coordination required for metered-dose inhalers and the inspiratory effort required for first-generation dry powder inhalers in treating asthma. • All motorized Spiros powder inhaler platforms use the same core technology to achieve powder dispersion that is relatively independent of inspiratory flow rate over a broad range. The high-speed rotating impeller provides mechanical energy to disperse the powder. • The Spiros DPI blister disk powder storage system is designed for potentially moisture-sensitive substances (e.g., some proteins, peptides, and live vaccines). The blister disk powder storage system contains 16 unit doses. 6/19/2016 Sagar kishor Savale
  70. 70. 70 A) Blisterdisk powder storage system. B) The interior of a well in a blisterdisk. Aerosol generator “core” technology 6/19/2016 Sagar kishor Savale
  71. 71. 71 The DirectHaler™ Pulmonary device platform 6/19/2016 Sagar kishor Savale
  72. 72. 72 • DirectHaler™ Pulmonary is an innovative and new device for dry powder Each pre-metered, pre-filled pulmonary dose has its own DirectHaler™ Pulmonary device. • The device is hygienically disposable and is made of only 0,6 grammes of Polypropylene. DirectHaler™ Pulmonary offers effective, accurate and repeatable dosing in an intuitively easy-to-use device format.  Sensitive powders  Deep lung delivery  High drug payloads  New types of combination dosing • The powder dose is sealed inside the cap with a laminate foil strip,which is easily torn off for dose-loading into the PowderWhirl chamber, before removing the cap and delivering the dose. 6/19/2016 Sagar kishor Savale
  73. 73. 73 Newer Development Dr Reddy's launches 'Dose Counter Inhalers' in India Friday, April 16, 2010 Dr Reddy's Laboratories (DRL) has launched an innovation in the metered dose inhaler (MDI) space with launch of 'Dose Counter Inhalers (DCI) for the first time in India. This the first MDI in India that gives patients an advance indication of when the inhaler is going to be empty. DCI is a new drug delivery device with a single device having 120 metered doses. There is a window in the inhaler that changes color from green to red. Green indicates the inhaler is full and red indicates the inhaler is empty. Half green and half red in the window indicate it's time to change the inhaler. 6/19/2016 Sagar kishor Savale
  74. 74. 74 •John J. Sciarra, Christopher J. Sciarra, Aerosols. In: Alfonso R. Geearo, editor. Remington: Science and practice of pharmacy, second edition.vol-1.New York: Lippincott Williams and Wilkins publication; 2001.p.963-979. •Anthony J. Hickey, Physiology of airway. In: Anthony J. Hickey, editor. Pharmaceutical inhalation aerosols technology, second edition.vol-54.New York: Marcel Dekker;1992.p.1-24. •Paul J. Atkins, Nicholas P. Barker, Donald P. Mathisen, The design and development of inhalation drug delivery system. In : Anthony J. Hickey, editor. Pharmaceutical inhalation aerosols technology, second edition.vol-54.New York: Marcel Dekker;1992.p.155-181. •Critical Reviews in Therapeutic Drug Carrier Systems 14(4): 395-453. •International Pharmaceutcial Aerosol Consortium, 1997. Ensurin patient care- the role of the HFC MDI. •Metered dose pressurized aerosols and the ozone layer. European Resp. J.3:495-497. •Jain N. K, “Advances in Controlled and Novel Drug Delivery” 1st ed.(2010), CBS Publishers and Distributors Pvt.Ltd. New Delhi, pp.120-156. •Karhale A.A.et al(2012) “Pulmonary Drug Delivery system” International journal of PharmTech Research(4)1,pp.293-305. •Sunitha et al(2011) “Drug Delivery and its Development for Pulmonary System” International Journal of Pharmaceutical, Chemical and Biological Sciences(1)1,pp.66-82 References 6/19/2016 Sagar kishor Savale

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