RECENT ADVANCES IN PULMONARY DRUG

DELIVERY

Presented by: SAMIKSHA SAWANT M.Pharm (IP) 2nd

SemGuided by: Dr. (Mrs.) Shruti

Shrikhande

Pulmonary drug delivery is an important research area which impacts the treatment of illnesses including asthma, chronic obstructive pulmonary disease and various other diseases

Pulmonary delivery of the drug has develop into an attractive target as the lung is capable of absorbing pharmaceuticals either for local

deposition or for systemic delivery.

The development of an inhalation therapy which is efficient and safe depends not only on a pharmacologically active molecule, but also

on a delivery system

Advantages of pulmonary drug delivery

It is needle free pulmonary delivery.

It requires low and fraction of oral dose

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.

Disadvantages of pulmonary drug delivery

Oropharyngeal deposition

gives local side effect.

Patient may have difficulty

using the pulmonary

drug devices correctly.

Drug absorption

may be limited by the physical barrier of the mucus layer.

Various factors affect drug

delivery to the lungs,

including physiological

and pharmaceutica

l barrier.

Delivery devices are required to target drug

delivery

Anatomy of respiratory tract

Mechanism of particle deposition

Low Efficiency of inhalation

system

Less drug mass per puff

Poor formulation stability for

drug

Improper dosing reproducibility

Optimum particle size Challenges in

pulmonary drug delivery

RECENT ADVANCES IN PULMONARY DRUG DELIVERY INCLUDES

• Recent advances in pulmonary drug delivery devices

• Recent Advances in formulation of pulmonary drug delivery

• Recent Advances in applications of pulmonary drug delivery

Advances in formulation of pulmonary drug delivery

Recent advances in inhalation therapy have sparked considerable interest in the development of novel particle technologies for respiratory drug formulation

Microparticles Nanoparticles Micelles Liposomes Cyclodextrins Large porous particles Lactose carrier system

MicroparticlesThe microparticle (size1-999 μm) includes the microspheres and the microcapsules.

Biodegradable microspheres, designed from natural or synthetic polymers, have been largely used

Pulmonary administration of aerosolized microspheres allows a sustained and prolonged release of drugs for respiratory diseases

Solid lipid microparticles, is a carrier that has not been up to now much studied especially for pulmonary administration

The active substance studied is salbutamol acetonide , synthesized in order to get a more lipophilic substance and thereby to allow a more effective incorporation of this drug into solid lipid Microparticles.

Nanoparticles • They are also constituted of polymers or lipids and drugs bound either

at the surface of the particles either encapsulated into the vector. • A pulmonary drug delivery system to treat tuberculosis offers a

number of advantages over current oral medications. By delivering antibiotics via inhalation, the infected tissues of the lung are directly targeted while maintaining lower systemic drug concentrations and toxicity.

• Studies on pulmonary delivery of para-amino salicylic acid in rats have shown this method to allow for minimal inhibitory drug concentrations to be reached in lung tissue

• Studies on the use of polymeric nanoparticles for drug delivery have shown that it is possible to encapsulate and deliver a range of proteins and drug molecules.

• Lipid and polymeric shells around the drug are promising delivery method because lower density, which causes them to deposit in the alveolar region and avoid elimination from the lungs.

Micelles

Colloidal systems, such as micellar show great promise as carriers in

pulmonary drug delivery systems

Drugs can be trapped in the core of a

micelle and transported at greater

concentrations

Hydrophilic shell can form around the

micelle, effectively protecting the contents

In addition, the outer shell may prevent recognition by the reticuloendothelial

system, and therefore early elimination from

the bloodstream.

Liposomes• The use of liposomal drug formulations for aerosol delivery

has many advantages- aqueous compatibility, sustained pulmonary release to maintain therapeutic drug levels and facilitated intra-cellular delivery particularly to alveolar macrophages.

• Liposomes have been studied for years and used as a means of delivering phospholipids to the alveolar surface for treatment of neonatal respiratory distress syndrome.

• More recently, they have been investigated as a vehicle for sustained release therapy in the treatment of lung disease, ‐gene therapy and as a method of delivering therapeutic agents to the alveolar surface for the treatment of systemic diseases.

Cyclodextrins

Due to the complete or partial inclusion of the drug into the cavity, the drug with Cyclodextrins, becomes more

soluble into the medium

Beta-Cyclodextrins seems to be the more used for pharmaceutical development, due to the size of its

cavity, the complexation efficiency with drugs and their relatively low production costs.

Cyclodextrins have been studied to encapsulate drugs and to be used in this application to target drugs into

the lungs.

Cyclodextrins are able to complex with testosterone, salbutamol

Large porous particles• Pulmospheres are the new type of aerosol formulation is the

large porous hollow particles,. • They have low particle densities, excellent dispersibility and

can be used in both MDI and DPI delivery systems.• Pulmospheres are made of phosphatidylcholine, the primary

component of human lung surfactant. • The large size of Pulmospheres allows them to remain in the

alveolar region longer than their nonporous counterparts by avoiding phagocytic clearance

• After intratracheal administration into rats, only 8% and 12.5% of macrophages contain Pulmospheres particles immediately and 48 h after inhalation, respectively, compared with 30% and 39% of macrophages containing nonporous particles during a similar time interval.

Lactose carrier systems• The cohesive powders with poor flow arises if the

surface electric forces associated with the particles exceed the gravitational force acting upon them

• To overcome this problem, the drug is blended with a coarse carrier system, such as lactose

• Marketed dry powder inhalers contain either the drug alone or mixed with a bulk carrier, usually lactose

• Lactose has an established safety profile and improves the flow properties of the formulation necessary for reproducible filling and promoting dosing accuracy

Advances in drug delivery devices

• Inhalation drug delivery system by metered ‐dose inhalers

• Inhalation drug delivery system by -dry powder inhalers

• Inhalation drug delivery system by nebulizer‐

Metered dose inhalers• The Pressurized metered dose inhaler consists of a pressurized

canister and a chamber outfitted with a mouthpiece and protective cover.

• The canister contains a medication, a surfactant and/or a solvent, and a liquid propellant such as chlorofluorocarbon.

Advances......• New devices have improved the design characteristics and

drug formulations• They have incorporation of valves, dose counters, have

decreased the velocity of inspired dose particles and increased fine particle dose

• The new designs deliver a more consistent dose throughout the life of the canister, thus eliminating the tail off effect

Propellants • Chlorofluorocarbon-driven

devices deliver reduced doses when exposed to cold.

• Hydrofluoroalkane driven canisters deliver consistent doses even when exposed to temperatures as low as –20°c.

• The new generation of Pressurized metered dose inhaler produces a warmer spray, which should alleviate the cold freon effect (interruption of inspiration) experienced by some patients in the past

Spacers • MDI to be used together with spacers

patients to coordinate firing the dose with initiating inhalation.

• Spacing devices have a holding chamber and a one-way valve that opens during inspiration and closes during expiration

• They slow down and suspend small droplets of aerosolized medication for 1-2 seconds, allows time for some of the propellant around the particles of to evaporate

• This increases pulmonary drug deposition, reducing impaction in the oropharynx and side effects

• Allow the patient to obtain a suitable dose of medication in three to four tidal breaths.

Autohaler• Autohalers can be very useful to

people who have trouble with the timing and coordination that is needed to use a puffer, because you only need to be able to seal your lips around the mouthpiece and breathe in

• In the late 1970s, the Autohaler was introduced, which initially required high inspiratory flow rates for good performance, besides being very noisy.

• The current Autohaler overcomes these limitations, since it is quiet and can be triggered by a flow of only 30 L/min

Easibreathe Inhaler

• The Easibreathe is a pMDI actuator

• It resembles the Autohaler, but is simpler to use

• The Easibreathe contains a pneumatic system

• An internal vacuum restrains an operating spring. The vacuum is released by a valve which operates in response to the patient’s inhalation allowing the spring to fire the canister releasing a dose.

• Actuation occurs in synchrony with inhalation at only 20 L/min

K-Haler

• The K-haler is breath-activated,

• Breakthrough technology is a clever valve: the K-haler’s big idea revolves around the K-valve.

• The valve is a kinked tube.• When a patient breathes in

normally, the kink straightens, releasing a single dose right down into the lungs.

MD turbo• MD Turbo is a breath-actuated inhaler that can accommodate

various pMDI products. It incorporates technology, with which actuation only occurs at a pre-determined inspiratory flow.

• The device is designed to help patients better coordinate inhalation with activating the drug canister in an inhaler.

Smartmist Device• Smartmist A sophisticated microprocessor-

controlled pMDI actuator device and a standard pMDI canister.

• Patient using SmartMist just begins to slowly inhale. The system senses one's breathing pattern and automatically delivers a prescribed amount of medicine at the right time.

• If a patient breathes in correctly, a green light appears on SmartMist. If patients breathe medicine in too fast, a red light comes on.

• SmartMist keeps track of how much medicine a patient has taken over time.

Soft mist devices• A device known as "soft mist" is thus

named because it uses a spring-like mechanism to drive the liquid through its end, generating an aerosol cloud for 1 to 1.5 seconds.

• An example is the Respimat

manufactured by Boehringer Ingelheim, Germany, which is portable, propellant-free, easy to use, and can carry several doses.

• In addition, spacers, batteries or any power source are not required for its operation. In adults, lung deposition with this device is around 40%.

Turbuhaler• It is a multi dose breath-actuated

metered-dose inhaler that is comprised of components and a metal spring.

• It turbuhaler uses the force of inspiration to lift particles that are deposited onto a dosing disc within the container into the respiratory system.

• When a patient inhales through the turbuhaler, the fine powder medication moves through the inhalation channel toward a disaggregation zone, which consists of two spiral channels designed to create turbulent air flow in the mouthpiece

Inspiromatic dry powder inhaler• It works with extremely low inhalation

flow rates and assures optimal drug delivery

• The Inspiromatic dry powder inhaler incorporates:

1. An active powder de-agglomerator based on a micro-pump and vortex to deliver fine particles, independent of the patient’s inhalation abilities;

2. Sensors to monitor patient inhalation; and a built-in data logger that stores all data whenever the patient uses the device.

3. Interface that guides the patient and assures proper inhalation technique

Twisthaler• The example of Twisthaler is

that contains the inhaled corticosteroid mometasone

• The Twisthaler will need to be thrown out 45 days after this date or when the dose counter reads "00."

• While holding the Twisthaler upright, twist the white cap counter clockwise.

• As you twist and lift off the cap, the dose counter will decrease by one and the dose will be loaded

NEXThaler• Fostair NEXThaler

(formoterol/beclometasone) is the first dry powder inhaler delivering extrafine drug particles to be launched in the UK.

• It contains formoterol and beclometasone which is delivered as extrafine particles to improve lung deposition and allowing a lower dose of corticosteroid to be given.

• It is “intuitive to use” and utilises a dose counter that only decreases when a dose has been correctly inhaled (compared with existing dose counters that decrease when a dose has been primed or loaded),

HandiHaler• The HandiHaler can be

successfully used by patients, who are not able to generate high inspiratory flows.

• With inspiratory flow rates of 20 to 60 l/min the HandiHaler releases consistently between 55-60% of the metered dose.

• Due to the high sensitivity of tiotropium bromide to humidity the HandiHaler has to be loaded with a single drug capsule before each use. During inhalation the capsule vibrates which can be noticed acoustically.

Easyhaler• It is a multiple dose powder

inhaler was designed to be a reliable alternative to pressurized MDIs

• The novel device will deliver at least 200 preloaded doses and the dose delivery system is similar as with an MDI.

• Dosing of the Easyhaler powder device is based on the gravitational flowability of the inhalation powder.

• An active ingredient is commonly mixed with flowable carrier material.

Beurer Ultrasonic Portable Nebuliser

• Beurer ultrasonic nebulizer is effective and versatile and can be used at home and during travel, when access to mains power supply is not possible.

• Low levels of noise generated by the Beurer ultrasonic nebulizer make it pleasant and discreet in use.

• Used for the treatment of the upper and lower respiratory tract, colds, asthma, respiratory disease etc

• High nebulisation capacity ( >0.25 ml/min. )

• Small and compact: ideal for travel with the supplied portable storage case

Vibrating Mesh Nebulizer

• In this technology a mesh/membrane with 1000-7000 laser drilled holes vibrates at the top of the liquid reservoir, and thereby pressures out a mist of very fine droplets through the holes.

• This technology is more efficient than having a vibrating piezoelectric element at the bottom of the liquid reservoir, and thereby shorter treatment times are also achieved.

• The high nebulization capacity (>0.25 ml/min) device offers short inhalation time.

Aerosonic Micromesh nebuliser• The Aerosonic Micromesh

nebuliser makes inhalation quite simple with its technology.

• Adults, children and older people simply inhale the escaping aerosol over the mouthpiece or the mask in short time.

• The Micromesh helps people of all age groups with asthma, chronic obstructive lung

• Small and easy , Noiseless ,Battery – operated, Low power consumption, Simple Operation, Automatic Shutdown at the end of the inhalation

Advances in Mask Bottom Load Aerosol Mask Front Load Aerosol Mask

• Does not directs aerosol towards the mouth.

• Inefficient because of impaction of aerosol onto bridge of mask

• PVC soft Plastic• Directs aerosol to mouth

• Prevent impaction of aerosol.• Minimizes eye and face deposition.• Elongated mass “snout” create a

“reservoir” where the aerosol velocity slows down and congregated before

inhalation by the patients which increases “respirable” dose.

Advances in applications• Application of pulmonary drug delivery in asthma and

chronic obstructive pulmonary diseases• Recent role of pulmonary delivery in patients on

ventilators• New use of pulmonary delivery in diabetes• In Angina pectoris• In pulmonary arterial hypertension• Inhaled drug delivery for tuberculosis therapy• Recent use of pulmonary delivery for bone disorder• Current use of pulmonary delivery of opioids as pain

therapeutics

• Pulmonary delivery in cystic fibrosis: 1. N-Acetylcysteine -The mucolytic agents have been

used by pulmonary route to help in sputum clearance. It will help to liquefy tenacious secretions and make their clearance easier. Recently newer mucolytic agent, nacystelyn, has been developed for delivery via a dry powder inhaler.

2. Recombinant human deoxyribonuclease aerosol- Nowadays deoxyribonuclease is given by pulmonary route.

3. Tobramycin- Spray dried Tobramycin powders containing Nanoparticles for pulmonary delivery. Tobramycin is commonly used to treat patients with cystic fibrosis.

References• Pressurized Metered Dose Inhalers and Add-on Device, by Claudio

Terzano , Pulmonary Pharmacology & Therapeutics , 351–366. (http://www.researchgate.net/profile/Claudio_Terzano/publication/

11746463_Pressurized_metered_dose_inhalers_and_add-on_devices/links/0912f506546d74326f000000.pdf)

• Article on “Advances in inhalation therapy in pediatrics”, Journal of Pediatrics -2013, Vol 86, No. 5, 2010, 367-375

(http://www.scielo.br/pdf/jped/v86n5/en_v86n5a04.pdf)• Article on K-Haler inhaler Dry Powder Inhalers: Factors Associated with Device Use, Siegfried

Wieshammer, Jens Dreyhaupt , 2010, Vol 1, 95-10• Recent advances in pulmonary drug delivery system: A Review by

Siraj Shaikh, Sayyed Nazim, International Journal of Applied Pharmaceutics, Vol 2, Issue 4, 2010, 27-31

(http://www.ijaponline.org/Vol2Issue4/126.pdf)

• Pulmonary Drug Delivery- A Review Article by Chaturvedi N.P, Solanki H, International Journal of Applied Pharmaceutics, Vol 5, Issue 3, 2013, 7-10

(http://www.ijaponline.org/Vol5Issue3/156.pdf) • Drug Delivery and its Developments for Pulmonary System

by R. Sunitha, K. Suria Prabha and P.Muthu Prasanna, International Journal of Pharmaceutical, Chemical and Biological Sciences, 2011, Vol 1, 66-82

(http://www.ijpcbs.com/files/110-11.pdf)• Pulmonary Drug Delivery System by Karhale Ashish,

Chaudhari Hiralal, Ughade Prajkta., Baviskar Dheeraj, Jain Dinesh, International Journal of PharmTech Research, 2012, Vol.4, No.1,293-305

(http://sphinxsai.com/2012/pharm/PHARM/PT=41%28293-305%29JM12.pdf)

• Pulmonary Delivery Innovative Technologies (http://ondrugdelivery.com/publications/Pulmonary.pdf)

• Recent advances in pulmonary drug delivery using large, porous inhaled particles by David A. Edwards, Abdelaziz Ben-Jebria and Robert Langer, Journal of Applied Physiology,379-385

(ap.physiology.org/content/jap/85/2/379.full.pdf)• Pulmonary Delivery: Innovative Approaches and Perspectives

by Carlotta Marianecci, Luisa Di Marzio, Federica Rinaldi1, Journal of Biomaterials and Nanobiotechnology, 2011, Vol 2, 567-575

(http://www.scirp.org/journal/jbnb) • Recent Advances in Pulmonary Drug Delivery System Chhayani

Rahul, Khachar Krupraj , Patel V, An International Journal of Pharmaceutical Sciences, Vol - 4, Issue - 3, Apr-Jul 2013

• Solid Lipid Microparticles (SLMS): An Effective Lipid Based Technology for Controlled Drug Delivery by Chukwuebuka. E. Umeyor, Franklin. C. Kenechukwu, Emmanuel. M. Uronnachi, American Journal of Pharmatech Research, 2012; Vol 2, 2249-3387

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