Drug Delivery To Lung And Physiological Basis


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Drug Delivery To Lung And Physiological Basis :




Physiology of the Respiratory System:

5-Mar-11 Drug Delivery To Lung 3 Physiology of the Respiratory System

Anatomy and Physiology of the Respiratory System…:

5-Mar-11 Drug Delivery To Lung 4 Anatomy and Physiology of the Respiratory System… Respiratory system of man consists Upper Respiratory Tract: Consists of nose, nasal passages, paranasal sinuses, mouth, eustachian tube, the pharynx to the oesophagus, the laryinx and trachea Lower Respiratory Tract: Consists of lungs (both air passage ways and respiratory units)

Lower Respiratory Tract:

5-Mar-11 Drug Delivery To Lung 5 Lower Respiratory Tract The Lung Human lung comprises of left and right lung, are divided into slightly unequal proportions Each lung is supplied by a major branch of the bronchial tree The tissue substance of a lung includes air passages, alveoli, blood vessels, connective tissues, lymphatic vessels and nerves

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5-Mar-11 Drug Delivery To Lung 6 Trachio-bronchial tree: The system is divided into two zones Conducting (central) Region: - Trachea, bronchioles, terminal and respiratory bronchioles Respiratory (peripheral) Region: - Respiratory bronchioles and alveolar regions The trachea branches into two main bronchi Further branching of the bronchi results in terminal bronchioles is divided to produce respiratory bronchioles, which connect the alveolar ducts then leading the alveolar sacs These contain 2-6 x 10 8 alveoli, producing a surface area of about 70-80 m 2 in a adult male

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5-Mar-11 Drug Delivery To Lung 9 Pulmonary blood supply The total surface area of the alveolar capillary is 60-80sqm and capillary blood volume is 100-200 ml This large surface area permits rapid absorption and removal of any substance that penetrate the alveoli capillary membrane Thus they produce good sink conditions for drug absorption

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5-Mar-11 Drug Delivery To Lung 10 Lung permeability: Highly permeable to water, lipophilic materials and most gases Hydrophilic substances with large molecular size and ionic species have limited permeability The alveolar type-1 cells with their tight junctions limit the penetration of molecules with a diameter less than 1.2 nm. The normal alveolar epithelium is almost impermeable to protein and small solutes. In contrast, micro vascular endothelium has better permeation for substances over a large range of molecular weight

Lung deposition and particle size:

5-Mar-11 Drug Delivery To Lung 11 Lung deposition and particle size Deposition of drug/aerosol in the airways depends on four factors The physico- chemical properties of drug The formulation The delivery/liberative device The patient (breathing pattern and clinical status) The particle size of aerosol is usually standardized by calculation of its “ aerodynamic diameter ” to deliver particles to different areas of lung

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5-Mar-11 Drug Delivery To Lung 12 Definition: The aero dynamic diameter of a particle is the diameter of a unit density sphere (1 gm/cm 3 ) having the same terminal settling velocity (in still air) as the particle under consideration. It is derived from stoke’s law D a = ( ρ p / ρ 0 ) 1/2 D g Where, ρ p is the particle density, ρ 0 is the standard particle density (1 gm/cm 3 ) D g is the geometric diameter of the particle

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5-Mar-11 Drug Delivery To Lung 14 Lung deposition: - Occurs mainly by 3 mechanisms 1) inertial impaction Where a bifurcation occurs in the respiratory tract, the air stream changes direction and particles with in the air stream having, sufficiently high momentum, will impact on the airway walls rather than follow the changing air stream Particles > 5 µ m and particularly > 10 µ m are deposited by this mechanism

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5-Mar-11 Drug Delivery To Lung 15 2) gravitational sedimentation: As the remaining small particles move on to the central lung the air velocity gradually decreases to much lower values and the force of gravity becomes important Particles 1-5 um are deposited From stoke’s law particles settling under gravity will attain constant terminal settling velocity Ut Ut = ρ gd 2 /18 ŋ Thus, gravitational sedimentation of an Inhaled particle is dependent on its size and density in addition to its residence time in the airways

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5-Mar-11 Drug Delivery To Lung 16 3) Brownian motion The finest particles enter the periphery of the lung where they can contact with the walls of the airways as the result of Brownian motion (particle diffusion) Particles smaller than 0.5 um are deposited The particle diffusion is inversly proportional to particle size. Other methods include interception and electrostatic attraction

Drug absorption via the lung:

5-Mar-11 Drug Delivery To Lung 17 Drug absorption via the lung Passive Diffusion Endocytosis Fecilitated Diffusion

Drug absorption via the lung…:

5-Mar-11 Drug Delivery To Lung 18 Drug absorption via the lung… Major physiological factors that affect pulmonary absorption are Muco ciliary transport in the airways that constantly drains fluid and solid particle (bacteria) in a counter current flow to the oral cavity The epithelial cells in the alveoli are covered by a thin layer of so called epithelial lining fluid. This fluid is in turn is covered by a monolayer of lung surfactant The epithelial cell layer forms the major barrier to absorption of drug molecule After passing the alveolar epithelium, the molecule enters the interstitium being part of the extra cellular space in side the tissue Finally, for passage into the blood the molecule have to pass the endothelial membrane of the capillaries, separating the interstitial space from the blood

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5-Mar-11 Drug Delivery To Lung 19 Macrophages can also form a functional barrier for some particular drug substances during pulmonary absorption for an efficient pulmonary absorption process, the alveolar membrane seems to be an optimal absorption site for a number reasons in contrast to the airways, there is hardly any Muco ciliary clearance from the alveoli the alveolar membrane forms the largest surface area in the lung. the area of the alveoli is 43-102 m 2 , which is large in comparison to the surface area of the airways which have cumulative area of about 2.5 m 2 The alveolar epithelium is thinner and leakier than bronchial epithelium

Formulation and delivery of therapeutic inhaation aerosols:

5-Mar-11 Drug Delivery To Lung 20 Formulation and delivery of therapeutic inhaation aerosols Metered dose inhaler Dry powder inhaler Nebulizers

Metered dose inhalers:

5-Mar-11 Drug Delivery To Lung 21 Metered dose inhalers Anatomy of a Metered Dose Inhaler (MDI)

Metered dose inhalers…:

5-Mar-11 Drug Delivery To Lung 22 Metered dose inhalers… In MDIs, drug is either dissolved or suspended in a liquid propellent mixture together with other excipients, including surfactants, lubricants for the valve mechanism and cosolvents A predetermined dose is released as a spray on actuatation metering valve After actuating the canister, expansion of the propellent when exposed to atmospheric pressure aerosolizes the drug. This active process consumes heat and thus cools both aerosol and canister As it travels through the air, the aerosol warms and the propellent evaporates, reducing the particle size to the desirable range The high speed gas flow helps to break up the liquid into a fine spray of droplets

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5-Mar-11 Drug Delivery To Lung 23 1) Containers: Aluminium container with a capacity of 10-30ml 2) Propellents: Chloro Fluoro Carbons (CFCs) Trichlorofluoro methane (CFC-11), dichloro difluro methane (CFC-12) and dichloro tetrafluro methane (CFC-114) Hydrofluoro Alkanes(HFAs) Trifluro Monofluro Ethane (HFA-134a) & Hectafluoro Propane (HFA-227) These are poor solvents for the surfactants. Ethonal is used to dissolve the surfactants

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5-Mar-11 Drug Delivery To Lung 24 3) Metering valve: Reproducible delivery of small volume (25-100 μ l) of product Metering valve in MDIs are used in the inverted position Depression of the valve stem allows the contents of the metering chamber to be discharged through the orifice in the valve stem and made available to the patient After actuation the metering chamber refills with liquid from the bulk and is ready to dispense the next dose To prevent undesirable layering of medication the canister should be shaken between each puff

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Advantages and disadvantages of MDIs:

5-Mar-11 Drug Delivery To Lung 26 Advantages and disadvantages of MDIs Advantages: Portability, low cost and disposability Many doses (up to 200) are stored in the small canister and dose delivery is re producible Protect the drug from oxidative degradation and microbiological contamination Disadvantages: They are inefficient at drug delivery vaporization of the droplet is hindered by low volatility of CFC-11

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5-Mar-11 Drug Delivery To Lung 27 Their in corrective use by patient. Reported problem include failure to remove the protective cap covering the mouth piece, the inhaler being used inverted failure to shake the canister failure to inhale slowly and deeply inadequate breath holding poor inhalation/actuation synchronization The delivery efficiency of MDI depends on patient breathing pattern, inspiratory flow rate and hand mouth coordination The optimal conditions for inhaling MDI aerosols are actuation of device at the start of inhalation, Inspiratory flow rate of < 50liters per min followed by 10 seconds breath holding at the end of inspiration

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5-Mar-11 Drug Delivery To Lung 28 Spacers and breath actuated MDIs: Spacers are positioned between the MDIs and the patient The dose from an MDI is discharged directly into the reservoir prior to the inhalation Disadvantage of spacers is they may cumbersome The breath actuated device overcomes the coordination problem of conventional MDI with out adding bulk to the device However a substantial inspiratory flow rate is required for its operation

Types of medicines are available as MDIs, including: :

5-Mar-11 Drug Delivery To Lung 29 Types of medicines are available as MDIs, including: bronchodilators (ProAir HFS, Proventil HFA, Ventolin HFA, Maxair, or Alupent) inhaled steroids (Azmacort, Flovent, Pulmicort, Qvar) combination of long-acting bronchodilator and inhaled steroid ( ADVAIR HFA, Symbicort) cromolyn (Intal) nedocromil (Tilade) ipratropium bromide (Atrovent).

Dry Powder Inhalers:

5-Mar-11 Drug Delivery To Lung 30 Dry Powder Inhalers Aerolizer FlexHaler Diskus DiscHaler HandiHaler

Dry Powder Inhaler…:

5-Mar-11 Drug Delivery To Lung 31 Dry Powder Inhaler… The drug is inhaled as cloud of fine particles The drug is either preloaded in an inhalation device or filled into hard gelatin capsules or foil glister discs, which are loaded into a device prior to use DPIs have several advantages over MDIs propellant free and do not contain excipients, other than carrier they are breath actuated, avoiding the problems of inhalation/actuation coordination encountered with MDIs. Less potential for formulation problems Less potential problems with drug stability

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5-Mar-11 Drug Delivery To Lung 32 Disadvantages of DPIs: Liberation of the powder from the device and the deaggregation of the particles are limited by the patients ability to inhale, which in the case of respiratory disease may be impaired An increase in turbulent airflow created by an increase in inhaled air velocity increases the de aggregation of emerging particles, but also increases the potential for inertial impaction in the upper airways and throat, so a compromise has to be found DPIs are exposed to ambient atmospheric conditions, which may reduce formulation stability DPIs are generally less efficient at drug delivery than MDIs

Formulating DPI:

5-Mar-11 Drug Delivery To Lung 33 Formulating DPI To produce particles of suitable size, drug powders are usually micronized The high energy powders produced have poor flow properties The flowability of powder affected by physical properties To improve the flow property, poorly flowing drug particles are generally mixed with large carrier particles (usually 30-50um) of an excipient, usually lactose

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5-Mar-11 Drug Delivery To Lung 34 Once liberated from the device, the turbulent airflow generated with in the inhalation device should be sufficient for the de aggregation of the drug or carrier aggregates

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5-Mar-11 Drug Delivery To Lung 35 Unit Dose Devices with drug in hard gelatin capsules The first DPI device developed was the spinhaler for the delivery of sodium chromoglycate. Each dose, contained in a hard gelatin capsules, is loaded individually into the device. The capsule, placed in a loose fitting rotor, is pierced by two metal needles an either side of capsule. Inhaled air flow through the device cause a turbo vibratory air pattern as the rotor rotates rapidly, resulting in the powder being dispersed through the capsule walls and out through the perforation into the air. A minimum air flow rate of 35-40ltrs per minute through the device is required to produce adequate vibrations through the rotor.

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5-Mar-11 Drug Delivery To Lung 36 Another unit dose DPI is the rota haler , which is a simple two piece device The gelatin capsule is inserted into an orifice at the rear of the device and when the two sections are rotated a fin on the inner barrel pulls the two halves of the capsule apart During inhalation, the freed half of the capsule spins, dispersing its contents, which are inhaled through the mouth piece Others include the aerohaler and cyclohaler

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5-Mar-11 Drug Delivery To Lung 37 Multi dose devices with drug in foil blister: The drug is mixed with a coarse lactose carrier and filled into an Aluminium foil blister disc which is loaded into the device on a support wheel Each disc contains 4 or 8 doses of drug and blisters are pierced with a needle as a result of mechanical liverage on the lid The foil blisters are numbered

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5-Mar-11 Drug Delivery To Lung 38 Multi dose devices with drug preloaded in inhaler: Drug/carrier mix is preloaded into the device in foil covered blister pockets containing 60 doses The foil lid is pealed off the drug containing pockets, as each dose is advanced, with the blisters and lids being wound up separately with in the device which is discarded at the end of the operation Reservoir type of device, in which a dose is accurately measured and delivered from a drug reservoir Ex: click haler DPI, drug blend is stored in the device

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5-Mar-11 Drug Delivery To Lung 39 Metering cups are filled by gravity The device can hold up to 200 doses and incorporates a dose counter Turbuhaler , has overcome the need for both a carrier and loading of individual doses The device contains a large number of doses of undiluted, loosely aggregated micronized drug, which is stored in reservoir from which it flows onto rotating disc in the dosing unit The fine holes in the disc are filled and excess drug is removed by scrapers As the rotating disc is turned by moving a turning grip back and forth, one metered dose is presented to the inhalation channel A dose indicator is incorporated

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5-Mar-11 Drug Delivery To Lung 40 Non-breath actuated devices: Battery powered impeller to de aggregate the drug powder Compressed air is used to disperse drug from a unit dose package into a large holding chamber, from which it is inhaled by the patient

Caring for your DPI:

5-Mar-11 Drug Delivery To Lung 41 Caring for your DPI Keep your dry powder inhaler in a dry place at room temperature. Never place the DPI in water. Never shake or breathe into the DPI. Never use a spacer device with your DPI. Unlike other inhaled medications, you may not taste, smell, or feel the dry powder. This experience may be different from what you are used to. As long as you are following the directions, you will get your full dose of medication. If you are using a corticosteroid medication, rinse your mouth and gargle after using the DPI. Do not swallow.


5-Mar-11 Drug Delivery To Lung 42 Nebulizers These are applied to aerosolize drug solutions or suspension Two types of nebulizers are jet and ultrasonic

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5-Mar-11 Drug Delivery To Lung 43 Functions by the Bernoulli principle 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 drug solution being drawn up from the fluid reservoir and shattered into droplets in the gas Jet nebulizer :

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5-Mar-11 Drug Delivery To Lung 44 Ultra sonic nebulizer: It uses a piezoelectric crystal vibrating at the high frequency usually 1-3 MHz To generate a fountain of liquid in the Nebulizer chamber The higher the frequency, the smaller the droplet produced disadvantages: Time consuming Inefficient Large amount of drug wastage,

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5-Mar-11 Drug Delivery To Lung 45 Formulation of Nebulizer fluids: These are formulated in water, occasionally with the addition of co solvents and with the addition of surfactants for suspension formulations Stabilizers such as anti oxidants and preservatives may also be included The physical property of drug formulations may have an effect on nebulization rates and particle size The viscosity, ionic strength, osmolarity, pH and surface tension may prevent the nebulization of some formulations

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5-Mar-11 Drug Delivery To Lung 46 A number of Meter liquid inhalers, including AERx, AeroDose and Respimat have been developed AERx Respimat AeroDose

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5-Mar-11 Drug Delivery To Lung 47 How to use Nebulizer: Nebulizers can be used to treat asthma, chronic obstructive pulmonary disease (COPD), and other conditions where inhaled medicines are indicated. Nebulizers deliver a stream of medicated air to the lungs over a period of time. Assemble the nebulizer according to its instructions. These are the basic steps: Connect the hose to an air compressor. Fill the medicine cup with your prescription. Attach the hose and mouthpiece to the medicine cup. Place the mouthpiece in your mouth. Breathe through your mouth until all the medicine is used. (Often this takes about 10 - 15 minutes). Some people use a nose clip to help them breathe only through the mouth. Others prefer to use a mask. Wash the medicine cup and mouthpiece with water, and air-dry until your next treatment.

Controlled delivery of Drugs to the Lung:

5-Mar-11 Drug Delivery To Lung 48 Controlled delivery of Drugs to the Lung Liposomes have the potential to produce controlled delivery to the Lung, since they can be prepared with phospholipids endogenous to the lung as surfactants. Biodegradable micro spheres (MS) such as albumin MS and Polly (Lactaid/ or Glycolide) co-polymer MS are also being investigated The prodrug approach Conjugation of drug to macro molecules Sparingly soluble forms and co precipitates Complexes with cyclo dextrins

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5-Mar-11 Drug Delivery To Lung 49 Large porous particles: A new type of aerosol formulation is the large porous hollow particles, called Pulmospheres They have low particle densities, excellent dispersibility and can be used in both MDI and DPI delivery systems These particles can be prepared using polymeric or non polymeric excipients, by solvent evaporation and spray-drying techniques Pulmospheres are made of phosphotidylcholine, the primary component of human lung surfactant. They are prepared in a two-step process. In the first step, an oil-in-water emulsion is prepared using oils, such as perfluorocabron or perfluoroctyl ethane The oil phase serves as a ‘blowing agent’ during the spray drying step, retarding shrinkage of droplets while simultaneously creating pores in the particle surface. The second step in the preparation is the spray-drying of the emulsion.

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5-Mar-11 Drug Delivery To Lung 50 Traditional therapeutic powders consist of particles with a mass density of 1 ± 0.5 g cm−3 and mean geometric diameters of <5 µm to maximize peripheral deposition. Pulmospheres are lighter and larger than the typical dry powder particles with a mass density of approximately 0.4 g cm−3 and geometric diameter of >5 µm. By virtue of their hollow and porous characteristics, Pulmospheres give rise to smaller aerodynamic diameters than their geometric diameter. Because of their large size and low mass density, the particles can aerosolize more efficiently (less aggregation) than smaller nonporous particles, resulting in higher respirable fractions of the formulation. The large size of Pulmospheres allows them to remain in the alveolar region longer than their nonporous counterparts by avoiding phagocytic clearance.

Deep-lung delivery of therapeutic proteins::

5-Mar-11 Drug Delivery To Lung 51 Deep-lung delivery of therapeutic proteins : Taking advantage of the body’s ability to transfer large molecules through the lungs is a better way to deliver drugs than sticking people with needles. Macromolecules, notably proteins and peptides, are large delicate compounds that usually can be administered only by injection. Pulmonary delivery provides a direct route to the circulation, increasing patient compliance with a minimum of discomfort and pain, and is a cost-effective option for pharmaceutical and biotechnology companies. Most researchers believe that proteins absorption occurs in the alveoli, where the body absorbs peptides and proteins into the bloodstream by a natural process known as transcytosis.

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5-Mar-11 Drug Delivery To Lung 52 Transcytosis of inhaled insulin. Exubera molecules become trapped in the alveoli and are taken up in vesicles by the alveolar epithelial cells. These insulin-containing vesicles are then released between the epithelial cells and the alveolar capillary endothelial cells. Insulin molecules are then taken up within vesicles by endothelial cells, transported across them and then released into the alveolar capillary.

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5-Mar-11 Drug Delivery To Lung 53 Many macromolecules are formulated as dry powders because they are more stable as solids than as liquids. Many new agents are now under investigation for pulmonary delivery: interleukin-1 receptor (asthma therapy), heparin (blood clotting), human insulin (diabetes), α-1 anti trypsin (emphysema and cystic fibrosis), interferons (multiple sclerosis and hepatitis B and C), and calcitonin and other peptides (osteoporosis).

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Methods of aerosol size analysis:

5-Mar-11 Drug Delivery To Lung 55 Methods of aerosol size analysis The regional distribution of aerosols in the airways can be measured directly using gamma scintigraphy, by radiolabelling droplets or particles, usually with the short half-life gamma emitter technetium 99m (99mTc). However, more commonly in vitro measurements of aerosol size are used to predict clinical performance. The principal methods that have been employed for size characterization of aerosols are microscopy, laser diffraction cascade impaction Time of flight phase doppler technique

How to use a Turbuhaler®:

5-Mar-11 Drug Delivery To Lung 56 How to use a Turbuhaler® Unscrew the cover and remove it Holding the device upright, turn the coloured wheel one way and back the other way, until it clicks - it is now loaded Breathe out Place the mouthpiece between your lips and tilt your head back slightly Breathe in deeply and forcefully Hold your breath for 10 seconds or as long as you can Remove the Turbuhaler from your mouth, and breathe out If a second dose is prescribed, repeat the steps If your Turbuhaler;reg; contains a corticosteroid medicine, rinse you mouth out and gargle with water after you use it, to prevent a local yeast infection (thrush) in your mouth, and hoarseness in your throat.

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5-Mar-11 Drug Delivery To Lung 58 CONCLUSION


5-Mar-11 Drug Delivery To Lung 59 REFERENCES G.Molema, D.K.F. Meijer, Drug targeting organ-specific stratigies, copy right © 2001, Wiley VCH verlag GmbH. Gilbert S. Banker and Christopher T. Rhodes, Modern Pharmaceutics, Second edition, Volume 40, Marcel dekker, INC. James Swarbrick, Encyclopedia of Pharmaceutical Technology, Third Edition, Volume 2 and Volume 4. Leon Lachman, Herbert A. Lieber Man, Juseph L. Kanig, The theory and Practice of Industrial pharmacy, third edition, Varghese publishing house. M.E. Aulton, Pharmaceutics, The science of Dossage form design. Second edition, 2002. Remington, The Science and Practice of Pharmacy, 21st edition, Volume – I, published by Wolters Kluwer health (India) Pvt. Ltd. New Delhi. S.P. Vyas and Roop K. Khar, Controlled Drug Delivery, First edition, 2002, Vallabh Prakashan. A. Mishra and N.K. Jain, Progress in Controlled and Novel drug delivery system, CBS publishers and distributors, New Delhi, 2004. Yie W. Chien, Kenneth S.E. Su, Shyi – Feu Chang. Nasal Systemic Drug Delivery, Marcel Dekker, INC Volume 39. Optimizing Deposition of Aerosolized Drug in the lung: A Review, from Medscape General medicine Review Article, Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications, NR Labris and MB Dolovich, Department of Medicine, Mc Master University, Hamilton, Ontario, Canada. Invited Review, The controlled delivery of drugs to the lung, International journal of pharmaceutics 124(1995) 149-164. www.aapspharmsci.org/view.asp.

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5-Mar-11 Drug Delivery To Lung 60 Thank U


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