NASAL AND PULMONARY DRUG DELIVERY SYSTEM

nasal and pulmonary drug delivery system v.manimaran lecturer. department of pharmaceutics. srm college of pharmacy. unit vii...

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UNIT VII

NASAL AND PULMONARY DRUG DELIVERY SYSTEM V.MANIMARAN LECTURER DEPARTMENT OF PHARMACEUTICS SRM COLLEGE OF PHARMACY

NASAL DRUG DELIVERY CONTENTS y y y y y y y y y y y 2

INTRODUCTION ADVANTAGES AND DISADVANTAGES ANATOMY & PHYSIOLOGY OF NASAL CAVITY MECHANISM OF DRUG ABSORPTION FORMULATION APPROACHES EVALUATION TEST MARKETED PREPARATIONS PATENTED PREPARATIONS RECENT ADVANCES CONCLUSIONS REFERENCES 22-Apr-12

NASAL DRUG DELIVERY

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INTRODUCTION: y In ancient times the Indian Ayurvedic system of medicines used nasal

route for administration of drug and the process is called as “Nasya” y Intranasal drug delivery is now recognized to be a useful and reliable alternative to oral and parenteral routes. Undoubtedly, the intranasal administration of medicines for the symptomatic relief and prevention or treatment of topical nasal conditions has been widely used for a long period of time. y However, recently, the nasal mucosa has seriously emerged as a therapeutically viable route for the systemic drug delivery.

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y In general, among the primary targets for intranasal administration are

pharmacologically active compounds with poor stability in gastrointestinal fluids, poor intestinal absorption and/or extensive hepatic first-pass elimination, such as peptides,proteins and polar drugs. The nasal delivery seems to be a favourable way to circumvent the obstacles for blood-brain barrier (BBB) allowing the direct drug delivery in the biophase of central nervous system (CNS)-active compounds. It has also been considered to the administration of vaccines.

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ADVANTAGES y Hepatic first pass metabolism avoided. y Rapid drug absorption and quick onset of action. y Bioavailability of larger drug molecules can be improved by means of y y y y y

absorption enhancer. BA for smaller drug molecules is good. Convenient for long term therapy, compared to parenteral medication. Drugs possessing poor stability G.I.T fluids given by nasal route. Easy and convenient. Easily administered to unconscious patients.

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DISADVANTAGES • Pathologic conditions such as cold or allergies may alter significantly

the nasal bioavailabilty. • The histological toxicity of absorption enhancers used in nasal drug delivery system is not yet clearly established. • Relatively inconvenient to patients when compared to oral delivery systems since there is a possibility of nasal irritation. • Nasal cavity provides smaller absorption surface area when compared to GIT.

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ANATOMY & PHYSIOLOGY OF NASAL CAVITY

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Fig:1

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• The nasal cavity consists three main regions:

1) Nasal vestibule 2) Respiratory region major drug absorption. 15-20 % of the respiratory cells covered by layer of long cilia size 2-4 μm. 3) Olfactory region small area in the roof of the nasal cavity of about 10 cm2 drug is exposed to neurons thus facilitate it across the cerebrospinal fluid. • Normal pH of the nasal secretions in adult Æ 5.5-6.5. • Infants and young children Æ 5.0- 6.7. • Nasal cavity is covered with a mucous membrane.Mucus secretion is composed of 95%- water,2%-mucin,1%-salts,1%-of other proteins 9 such as albumin,lysozyme and lactoferrin and 1%-lipids. 22-Apr-12

MECHANISM OF DRUG ABSORPTION •

Paracellular (intercellular)

Slow and passive absorption of peptides and proteins associated with intercellular spaces and tight junctions. •

Transcellular : Transport

of lipophilic drugs passive diffusion/active transport.

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Transcytotic: Particle is

taken into a vesicle and transferred to the cell.

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Mucoadhesive Carrier

Interaction with Mucus

Hydration and swell of polymer Drug release

Hydrophilic Macromolecular drug Cilliary clearance

Enzymatic Metabolism

Internal Absorption 11

Fig:2 Scheme of Mucoadhesive Nasal Drug Delivery

THEORIES OF MUCOADHESION Theory Electronic theory

Mechanism of bioadhesion

Comments

Attractive electrostatic forces between glycoprotein mucin network and the bioadhesive material

Electron transfer occurs between the two forming a double layer of electric charge at the interface

Adsorption theory Surface forces resulting in chemical bonding

Wetting theory

Diffusion theory

Fracture theory 12

Strong primary forces: covalent bonds Weak secondary forces: ionic bonds, hydrogen bonds and van der Waal’s forces

Ability of bioadhesive polymers to spread and develop intimate contact with the mucus membranes

Spreading coefficients of polymers must be positive Contact angle between polymer and cells must be near to zero

Physical entanglement of mucin strands and the flexible polymer chains Interpenetration of mucin strands into the porous structure of the polymer substrate

For maximum diffusion and best bioadhesive strength: solubility parameters (δ) of the bioadhesive polymer and the mucus glycoproteins must be similar

Analyses the maximum tensile stress developed during detachment of the BDDS from the mucosal surfaces

Does not require physical entanglement of bioadhesive polymer chains and mucin strands, hence appropriate to study the bioadhesion 22-Apr-12 of hard polymers, which lack flexible chains

FORMULATION APPROACHES ™ Nasal gels ™ Nasal Drops ™ Nasal sprays ™ Nasal Powder ™ Liposome ™ Microspheres 13

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y

Nasal Gels





High-viscosity thickened solutions or suspensions Advantages: • reduction of post-nasal drip due to high viscosity • reduction of taste impact due to reduced swallowing • reduction of anterior leakage of the formulation Reduction of irritation by using emollient excipients.

y

Nasal Drops

y

Nasal drops are one of the most simple and convenient systems developed for nasal delivery. The main disadvantage of this system is the lack of the dose precision and therefore nasal drops may not be suitable for prescription products. It has been reported that nasal drops deposit human serum albumin in the nostrils more efficiently 22-Apr-12 than nasal sprays.

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Nasal sprays • Both solution and suspension formulations can be formulated into

nasal sprays. • Due to the availability of metered dose pumps and actuators, a nasal spray can deliver an exact dose from 25 to 200 μm.The particles size and morphology (for suspensions)of the drug and viscosity of the formulation determine the choice of pump and actuator assembly.

Nasal Powder • This dosage form may be developed if solution and suspension dosage

forms cannot be developed e.g., due to lack of drug stability. • The advantages to the nasal powder dosage form are the absence of preservative and superior stability of the formulation. However, the suitability of the powder formulation is dependent on the solubility, particles size, aerodynamic properties and nasal irritancy of the active drug and /or excipients. Local application of drug is another advantage of this system. 15

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Liposomes • Liposomal Nasal solutions can be formulated as drug alone or in

combination with pharmaceutically acceptable excipients. • Administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose,the particles of the formulation have diameters of less than 50 microns.

Microspheres • Specialized systems becoming popular for designing nasal products,

as it provides prolonged contact with the nasal mucosa • Microspheres (in the powder form) swell in contact with nasal mucosa to form a gel and control the rate of clearance from the nasal cavity.Thus increases the absorption and bioavailability by adhering to the nasal mucosa and increase the nasal residence time of drug. • The ideal microsphere particle size requirement for nasal delivery should range from 10 to 50 µm as smaller particles. 22-Apr-12 16

STRATEGIES TO IMPROVE NASAL ABSORPTION ƒ Permeation enhancers Type of compound Bile

salts

Examples

Mechanisms of action

(and Sodium

derivatives)

deoxycholate,

glycocholate,

sodium Disrupt membrane, open tight junctions, sodium enzyme inhibition, mucolytic activity

taurodihydrofusidate Surfactancts

SLS, saponin, polyoxyethylene-9-lauryl Disrupt membranes ether

Chelating agents

Ethylenediaminetetraacetic acid(EDTA), Open tight junction salicylates

Fatty acids

Sodium

caprylate,

sodium

laurate, Disrupt membranes

phospholipids Bioadhesive materials

Carbopol, starch microspheres, chitosan

junctions

Powders Liquids 17

Reduce nasal clearance, open tight

Chitosan, carbopol

Reduce nasal clearance,22-Apr-12 open tight junction

y Prodrug approach y The absorption of peptides like angiotensin II, bradykinin, vasopressin

and calcitonin are improved when prepared into enamine derivatives.

y Structural modification y Chemical modification of salmon calcitonin to ecatonin (C-N bond

replaces the S-S bond) showed better bioavailability.

y Particulate drug delivery y Microspheres, nanoparticles and liposomes y Nasal enzyme inhibitors 9 peptidases and proteases 9 tripsin, aprotinin, borovaline, amastatin, bestatin and boroleucin 18

inhibitors.

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Evaluation tests For Nasal Gels • Mucoadhesive testing • A 1x1 cm piece of goat nasal mucosa was tied to a glass slide

using thread. Microparticles spread on the tissue specimen and the prepared glass slide was hung on one of the groves of a USP tablet disintegration test apparatus.The tissue specimen was given regular up and down movements in the beaker of the disintegration apparatus containing phosphate buffer pH 6.4. • Time required for complete washing of microparticles was noted. • In vitro drug diffusion study • The drug diffusion from different formulation was determined using treated cellophane membrane and Franz diffusion cell. • Drug was placed on cellophane membrane in the donor compartment contained phosphate buffer (pH 6.4). • Samples were analyzed spectrophotometrically. 19

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• In vitro drug release studies of the gels • 1 ml of the gel was taken into a small test tube. The open end of the

test tube was closed with the nasal membrane of the pig by tying it with a thread. Then this was placed in a beaker containing the media.

• Measurement of Gelation Temperature (T1) and Gel

Melting Temperature (T2): • A 2ml aliquot of gel was taken in a test tube, immersed in a water bath. • The temperature of water bath was increased slowly and left to

equilibrate for 5min at each new setting. • The sample was then examined for gelation, the meniscus would no longer moves upon tilting through 900. i.e GELATION temp T1. • Further heating of gel causes liquefaction of gel and form viscous liquid and it starts flowing, this temperature is noted as T2 GEL MELTING temp. 22-Apr-12 20

MARKETED DRUGS Drug

Brand

Local Delivery Main Excipients

Supplier

Azelastine

Astelin

Benzalkonium Meda chloride, Pharmaceuticals edetate disodium,

Beclometasone

Beconase

Microcrystalline cellulose, carboxymethyl cellulose sodium, benzalkonium chloride

Levocabastine

Livostin

Jansen-Cilag Benzalkonium chloride, edetate disodium, disodium phosphate

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Main Indications

GlaxoSmithKline

Management/ treatment of symptoms of seasonal and perennial 22-Apr-12 rhinosinusitis

Drug

Brand

Main Excipients

Supplier

Olapatadine

Patanase

Benzalkonium chloride, dibasic sodium phosphate, edetate disodium

Alcon Laboratories

Sodium cromoglicate

Nasalcrom

Benzalkonium chloride, edetate disodium

Sanofi-Aventis

Mupirocin

Bactroban

Paraffin and a mixture of glycerin esters (Softisan 649)

GlaxoSmithKline Eradication of nasal staphylococci

Triamcinolone acetonide

Nasacort

Microcrystalline cellulose, CMC sodium, polysorbate 80

Sanofi Aventis

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Main Indications

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Systemic Delivery Drug

Brand

Nicotine

Nicotrol NS

Disodium phosphate, sodium dihydrogen phosphate, citric acid

Pfizer

Smoking cessation

Oxytocin

Syntocinon

Citric acid, chlorobutanol, sodium chloride

Novartis

Labour induction; lactation stimulation

Buserelin

Suprefact

Sodium hydroxide, sodium chloride, sodium dihydrogen

Sanofi-Aventis

Treatment of prostate cancer

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Main Excipients

Supplier

Main Indications

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Drug

Brand

Main Excipients

Salmon calcitonin

Miacalcin

Sodium chloride, Novartis benzalkonium chloride, hydrochloric acid

Sumatriptan

Imigran

GlaxoSmithKline Treatment of Potassium dihydrogen migraine and Sumatriptan cluster headaches Imigran phosphate, Potassium dibasic sodium dihydrogen phosphate cluster headaches anhydrou

Estradiol

Aerodiol

Methylbetadex, sodium chloride

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Supplier

Servier laboratories

Main Indications Treatment of postmenopausal osteoporosis

Hormone replacement 22-Apr-12 therapy

Marketed products

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PATENTED DRUGS FOR NASAL DELIVERY Cited Patent

Filing date

Issue date

Original Assignee

Title

US3874380

May 28, 1974

1975

Dual nozzle Intranasal drug delivery

US4895559

Oct 11, 1988

Jan 23, 1990

Nasal pack syringe

US6610271

Feb 21,2001

Dec15,2002

Intranasal Tech.Inc.(ITI)

The lorazepam nasal spray

US4767416

Dec 1, 1986

Aug 30, 1988

Johnson & Johnson Patient Care, Inc.

Spray nozzle for syringe

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Cited Patent

Filing date

Issue date

Original Assignee

US5064122

Aug 10, 1990

Nov 12, 1991

Toko Yakuhin KogyoKabushii Kaisha

Disposable nozzle adapter for intranasal spray containers

US5601077

Aug 7, 1991

Feb 11, 1997

Becton, Dickinson and Company

Nasal syringe sprayer with removable dose limiting structure

US8118780

Aug 23, 2004

Feb 21, 2012

Liebel-Flarsheim Company

Hydraulic remote for a medical fluid 22-Apr-12 injecto

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Title

RECENT ADVANCES y Currently,the majority of intranasal products on the market are targeted

toward local relief or the prevention of nasal symptoms. The trend toward the development of intranasal products for systemic absorption should rise considerably over the next several years. The development of these products will be in a wide variety of therapeutic areas from pain management to treatment for erectile dysfunction. y However, the primary focus of intranasal administration, correlated with increasing molecular scientific knowledge and methods, will be the development of peptides, proteins, recombinant products, and vaccines. The nasal cavity provides an ideal administration site for these agents because of its accessibility, avoidance of hepatic first-pass metabolism, and large vascular supply. y Future technologies in the intranasal arena will be concentrated on improved methods for safe, efficient delivery systems primarily for molecular agents, but also for numerous therapeutic categories. 28

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Delivery of non-peptide Pharmaceuticals • • • • • • • • • • 29

Adrenal corticosteroids Sex hormones: 17ß-estradiol, progesterone, norethindrone, and testosterone. Vitamins: vitamin B Cardiovascular drugs: hydralazine, Angiotensin II antagonist, nitroglycerine, isosobide dinitrate, propanolol. CNS stimulants: cocaine, lidocaine Narcotics and antagonists: bupemorphine, naloxane Histamine and antihistamines: disodium cromoglycate, meclizine Antimigrane drugs: dierogotamine, ergotamine, tartarate Phenicillin, cephalosporins, gentamycin Antivirals: Phenyl-p-guanidine benzoate, enviroxime. 22-Apr-12

Delivery of peptide-based pharmaceuticals Peptides and proteins are hydrophilic polar molecules of high molecular weight, poorly absorbed. • Absorption enhancers like surfactants, glycosides, cyclodextrin and glycols increase the bioavailability. Examples are insulin, calcitonin, pituitary hormones etc. •

Delivery of diagnostic drugs •

Phenolsulfonphthalein is used to diagnose kidney function. Secretin for Pancreatic disorders of the diabetic patients.

Delivery of Vaccines through Nasal Routs • • •

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Anthrax and influenza are treated by using the nasal vaccines prepared by using the recombinant Bacillus anthracis protective 22-Apr-12 antigen (rPA) and chitosan respectively.

• Delivery of Drugs to Brain through Nasal Cavity

Conditions like Parkinson’s disease, Alzheimer’s disease or pain

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CONCLUSION y Considering the widespread interest in nasal drug delivery and the

potential benefits of intranasal administration, it is expected that novel nasal products will continue to reach the market. They will include not only drugs for acute and long term diseases, but also novel nasal vaccines with better local or systemic protection against infections. y The development of drugs for directly target the brain in order to attain a good therapeutic effect in CNS with reduced systemic side effects is feasible. However, it was also stated that intranasal route presents several limitations which must be overcome to develop a successful nasal medicine Physiological conditions, physicochemical properties of drugs and formulations are the most important factors determining nasal drug absorption. 32

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• The use of prodrugs, enzymatic inhibitors, absorption enhancers,

mucoadhesive drug delivery systems and new pharmaceutical formulations are, nowadays, among the mostly applied strategies. Each drug is one particular case and, thus, the relationship between the drug characteristics, the strategies considered and the permeation rate is essential.

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PULMONARY DRUG DELIVERY SYSTEM

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CONTENTS y y y y y y y y y

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INTRODUCTION ADVANTAGES AND LIMITATIONS THE RESPIRATORY TRACT FORMULATIONS APPROACHES AND DEVICES MARKETED PREPARATIONS PATENTED PREPARATIONS RECENT ADVANCES CONCLUSIONS REFERENCES

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INTRODUCTION y 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) . y This type of drug application in the therapy of these diseases is a clear form of targeted drug delivery. y 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.

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y The drug used for asthma and COPD eg.- 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,. y 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. 37

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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.

LIMITATIONS y Stability of drug in vivo. y Transport. y Targeting specificity. y Drug irritation and toxicity. y Immunogenicity of proteins y Drug retention and clearance. 38

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THE RESPIRATORY TRACT

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Fig:4

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y 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. y The airway is further divided into many folds: nasal cavity and the associated sinuses, and the nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles. y The respiratory region consists of respiratory bronchioles, alveolar ducts, and alveolar sacs y 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. 40

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FORMULATION APPROACHES y Pulmonary delivered drugs are rapidly absorbed except large

macromolecules drugs, which may yield low bioavailability due to enzymatic degradation and/or low mucosal permeability. y 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. y 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. 41

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y Pulmonary bioavailability largely depends on the physical properties

of the delivered protein and it is not the same for all peptide and protein drugs. y 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. y 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. 42

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AEROSOLS y 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. y There are three commonly used clinical aerosols: 1. Jet or ultrasonic nebulizers, 2. Metered–dose Inhaler (MDI) 3. dry-powder inhaler (DPI) y 43

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. 22-Apr-12

DEVICES Nebulizers y Nebulizers are widely used as aerosolize drug solutions or suspensions

for drug delivery to the respiratory tract and are particularly useful for the treatment of hospitalized patients. y Delivered the drug in the form of mist. y There are two basic types:

1) Air jet 2) Ultrasonic nebulizer

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Jet nebulizers

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Fig:5

Ultrasonic nebulizers

Fig:6

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Dry powder inhalers(DPI) y DPIs are bolus drug delivery devices that contain solid drug in a dry

powder mix (DPI) that is fluidized when the patient inhales. y DPIs are typically formulated as one-phase, solid particle blends.The drug with particle sizes of less than 5µm is used y 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. y DPIs are a widely accepted inhaled delivery dosage form, particularly in Europe, where they are currently used by approximately 40% of asthma patients. Advantages 9 Propellant-free. 9 Less need for patient co-ordination. 9 Less formulation problems. 9 Dry powders are at a lower energy state, which reduces the rate of chemical degradation. 22-Apr-12 46

Disadvantages 9 Dependency on patient’s inspiratory flow rate and profile. 9 Device resistance and other design issues. 9 Greater potential problems in dose uniformity. 9 More expensive than pressurized metered dose inhalers. 9 Not available worldwide

Unit-Dose Devices y 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.

Multidose Devices y 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.

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Dry Powder inhalers

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Metered Dose Inhalers (MDI) y Used for treatment of respiratory diseases such as asthma and COPD. y They can be given in the form of suspension or solution. y Particle size of less than 5 microns. y Used to minimize the number of administrations errors. y It can be deliver measure amount of medicament

accurately.

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Advantages of MDI y It delivers specified amount of dose. y Small size and convenience. y Usually inexpensive as compare to dry powder inhalers and nebulizers. y Quick to use. y Multi dose capability more than 100 doses available.

Disadvantages of MDI y Difficult to deliver high doses. y There is no information about the number of doses left in the MDI. y Accurate co-ordination between actuation of a dose and inhalation is

essential. 50

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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 Cipla Limited Powder Capsules

India

Ipratropium Bromide 20 mcg

ATEM

Italy

Xinafoate

Seretide Evohaler GlaxoSmithKline

52

Chiesi Farmaceutici

UK 22-Apr-12

Metered Dose Inhalers (MDI) Active Ingredient

Brand

Manufacturer

Country

Salbutamol pressurised inhalation (100µg)

Asthalin

Cipla

India

albuterol

Ventolin

GlaxoSmithKline

India

levalbuterol HCl

Xopenex

3M Pharnaceuticals

U.S.A.

Fluticasone50 μg

Flixotide

GlaxoSmithKline

New Zealand

Ultratech

India

Formoterol Fumarate12 mcg 53

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PATENTED DRUGS Filing date

Issue date

US2470296

Apr 30, 1948

May 17, 1949

US2533065

Mar 8, 1947

Dec 5, 1950

Cited Patent

Original Assignee

Title INHALATOR Micropulverized Therapetic agents

US4009280

Jun 9, 1975

Feb 22, 1977

Fisons Limited

US5795594

US6136295 55

Mar 28, 1996

Aug 18, 1998

Glaxo Group Limited

Dec 15, 1998

Oct 24, 2000

MIT

Powder composition for inhalation therapy

Salmeterol xinafoate with controlled particle size Aerodynamically 22-Apr-12 light particles for pulmonary drug

Cited Patent

Filing date

Issue date

Original Assignee

Title

US6254854

May 11, 2000

Jul 3, 2001

The Penn Research Foundation

Porous particles for deep lung delivery

US6921528

Oct 8, 2003

Jul 26, 2005

Advanced Inhalation Research, Inc

Highly efficient delivery of a large therapeutic mass aerosol

US7842310

Nov 19, 2002

Nov 30, 2010

Pharmaceutical Becton, Dickinson compositions in and Company particulate form

US7954491

Jun 14, 2004

Jun 7, 2011

Low dose Civitas Therapeutics, Inc pharmaceutical powders for 22-Apr-12 inhalations

RECENT ADVANCES The Aerogen Pulmonary Delivery Technology

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AeroDose inhaler.

AeroNeb portable nebulizer 22-Apr-12

• AeroGen specializes in the development, manufacture, and

commercialization of therapeutic pulmonary products for local and systemic disease. y The technology being developed at AeroGen consists of a proprietary aerosol generator (AG) that atomizes liquids to a predetermined particle size. y AeroGentechnologies produce a low-velocity, highly respirable aerosol that improves lung deposition of respiratory drugs and biopharmaceuticals. y These delivery platforms accommodate drugs and biopharmaceuticals formulated as solutions, suspensions, colloids, or liposomes.

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The AERx Pulmonary Drug Delivery System

The AERx dosage form.

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The AERx device (with dosage forms).

AERx nozzle array.

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y 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. y 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. y 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.

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The Spiros Inhaler Technology

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y 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. y 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. y 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. 62

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A) Blisterdisk powder storage system. B) The interior of a well in a blisterdisk. 63

Aerosol generator “core” technology 22-Apr-12

The DirectHaler™ Pulmonary device platform

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• 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. • 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. 9 9 9 9 65

Sensitive powders Deep lung delivery High drug payloads New types of combination dosing 22-Apr-12

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. 66

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CONCLUSION y The lung has served as a route of drug administration for thousands of

years. Now a day’s pulmonary drug delivery remains the preferred route for administration of various drugs. Pulmonary drug delivery is an important research area which impacts the treatment of illnesses including asthma, chronic obstructive pulmonary disease and various diseases. Inhalation gives the most direct access to drug target. In the treatment of obstructive respiratory diseases, pulmonary delivery can minimize systemic side effects, provide rapid response and minimize the required dose since the drug is delivered directly to the conducting zone of the lungs . y It is a needle free several techniques have been developed in the recent past, to improve the Quality of pulmonary drug delivery system without affecting their integrity. Because of advancement in applications of pulmonary drug delivery it is useful for multiple diseases. So pulmonary drug delivery is best route of administration. 67

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REFERENCES

y Chien Y.W., Su K.S.E., Chang S.F., Nasal Systemic Drug Delivery, y

y

y y y

y

Ch. 1, Marcel-Dekker, New York 1-77. Illum.L, Jorgensen.H, Bisgard.H and Rossing.N, Bioadhesive microspheres as a potential nasal drug delivery system. Int. J.of Pharmaceutics 189-199. Jain S.K, Chourasia M. K and Jain. R. K, Development and Characterization of Mucoadhesive Microspheres Bearing Salbutamol for Nasal Delivery. Drug delivery 11:113-122 Martin. A, Bustamante. P and Chun A.H, Eds. Physical Pharmacy, 4th Edn, B. J. waverly Pvt. Ltd. Aulton M.E. “ Pharmaceutics – The science of dosage form design” Churchill Livingston., 494. Hussain A, Hamadi S, Kagoshima M, Iseki K, Dittert L. Does increasing the lipophilicity of peptides enhance their nasal absorption. J Pharm Sci 1180-1181. Illum L. In: Mathiowitz E, Chickering DE, Lehr CM Ed, Bioadhesive formulations for nasal peptide delivery: Fundamentals, Novel Approaches and Development. Marcel Dekker. New York 507-539.

68

22-Apr-12

• Sharma PK, Chaudhari P, Kolsure P, Ajab A, Varia N. Recent trends in

nasal drug delivery system ‐ an overview. 2006; 5: vol 4. • 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 22-Apr-12 Resp. J.3:495-497. 69

y Mygind N, Dahl R. Anatomy, physiology and function of the nasal y y

• y

cavities in health and disease. Adv Drug Del Rev 1998; 29. Grace, J., and Marijnissen, J., 1994. “A review of liquid atomization by electric means”. Journal of Aerosol Science 25, pp. 1005–1019. Ashhurst I, Malton A, PrimeD and Sumby B, “Latestadvances in The Development of dry-powder inhalers”, PSTT 2000,Vol 3, No 7, pp 246-256. Clark AR. Medical aerosol inhalers. Past,present and future. Aerosol Sci Technol.1995;22:374–391. P.Quinet, C.A.Young, F.Heritier, The use of dry powder inhaler devices by elderly patients suffering from chronic obstructive pulmonary disease, Annals of Physical and Rehabilitation Medicine 53 (2010) 69–76. http://www.pharmabiz.com http://www.lungusa.org http://www.ijrps.pharmascope.org

• y y 70

22-Apr-12

71

22-Apr-12