DRUG DELIVERY TO RESPIRATORY SYSTEM
PRESENTED BY
M.G.P.LAKSHMI
Y12MPH413
I/IIM.PHARM CEUTICS
CHALAPATHI
INSTITUTE OF PHARM...
CONTENTS
1. INTRODUCTION
2. ADVANTAGES AND LIMITATIONS
3. ANATOMY & PHYSIOLOGY OF NASAL CAVITY
4. MECHANISM OF NASALABSORP...
INTRODUCTION
 The physiologic evolution of nose was primarily to serve the respiratory and olfactory necessity.
 The fir...
ADVANTAGES
1) Drug degradation that is observed in the gastrointestinal tract is absent.
2) Hepatic first pass metabolism ...
LIMITATIONS
1) The histological toxicity of absorption enhancers used in nasal drug delivery system is not yet clearly
est...
ANATOMY & PHYSIOLOGY OF NASAL CAVITY
10/4/2013 6
 The nasal cavity consists three main regions:
1) Nasal vestibule
2) Respiratory region
major drug absorption.
15-20 % of...
MECHANISM OF NASALABSORPTION
The absorbed drugs from the nasal cavity must pass through the mucus layer; it is the first s...
Mucoadhesive Carrier
Hydration and swell of polymer
Hydrophilic Macromolecular drug
Internal Absorption
Interaction with M...
10/4/2013 10
Theory Mechanism of bioadhesion Comments
Electronic theory Attractive electrostatic forces between
glycoprote...
FACTORS INFLUENCING NASAL DRUG ABSORPTION
1) Physiochemical properties of drug.
Molecular size.
Lipophilic-hydrophilic bal...
STRATEGIES TO IMPROVE NASAL ABSORPTION
• Various strategies used to improve the bioavailability of the drug in the nasal m...
IDEAL PENETRATION ENHANCER
1. It should lead to an effective increase in the absorption of the drug.
2. It should not caus...
STRATEGIES TO IMPROVE NASAL ABSORPTION
10/4/2013 14
 Permeation enhancers
Type of compound Examples Mechanisms of action
...
NASAL ENZYME INHIBITORS
Nasal metabolism of drugs can be eliminated by using the enzyme inhibitors.
Mainly for the formula...
STRUCTURAL MODIFICATION
Modification of drug structure without altering pharmacological activity is
one of the lucrative w...
PRODRUG APPROACH
Prod rug approach is mainly meant for optimizing favourable physicochemical
properties such as solubility...
PARTICULATE DRUG DELIVERY
Particle design is an increasingly important role in absorption enhancement. Microspheres,
nanop...
FORMULATION APPROACHES
10/4/2013
 Nasal gels
 Nasal Drops
 Nasal sprays
 Nasal Powder
 Liposome
 Microspheres
Nasal Gels
High-viscosity thickened solutions or suspensions
Advantages:
• reduction of post-nasal drip due to high viscos...
Liposome's
• Liposomal Nasal solutions can be formulated as drug alone or in
combination with pharmaceutically acceptable ...
Nasal sprays
• Both solution and suspension formulations can be formulated into nasal
sprays.
• Due to the availability of...
EVALUATION TESTS
For Nasal Gels
Mucoadhesive testing
• A 1x1 cm piece of goat nasal mucosa was tied to a glass slide
using...
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 tub...
MARKETED DRUGS Local Delivery
Drug Brand Main
Excipients
Supplier Main Indications
Azelastine Astelin Benzalkonium
chlorid...
Systemic Delivery
Drug Brand Main
Excipients
Supplier Main
Indications
Nicotine Nicotrol NS Disodium
phosphate,
sodium
dih...
PATENTED DRUGS FOR NASAL DELIVERY
Cited Patent
Filing date
Issue date
Original Assignee Title
US3874380 May 28, 1974 1975 ...
RECENT ADVANCES
• Currently,the majority of intranasal products on the market are
targeted toward local relief or the prev...
Delivery of non-peptide Pharmaceuticals
• Adrenal corticosteroids
• Sex hormones: 17ß-estradiol, progesterone, norethindro...
Delivery of peptide-based pharmaceuticals
• Peptides and proteins are hydrophilic polar molecules of high molecular
weight...
• Delivery of Drugs to Brain through Nasal Cavity
Conditions like Parkinson’s disease, Alzheimer’s disease or pain
10/4/20...
PULMONARY DRUG DELIVERY SYSTEM
10/4/2013 32
INTRODUCTION
• The respiratory tract is one of the oldest routes used for the
administration of drugs. Over the past decad...
• The drug used for asthma and COPD eg.- β2-agonists such as
salbutamol (albuterol), Terbutalin formoterol, corticosteroid...
ADVANTAGES OF PULMONARY DRUG
DELIVERY.
• It is needle free pulmonary delivery.
• It requires low and fraction of oral dose...
THE RESPIRATORY TRACT
10/4/2013 36
• The human respiratory system is a complicated organ system
of very close structure–function relationships.
The system co...
FORMULATION APPROACHES
• Pulmonary delivered drugs are rapidly absorbed except large
macromolecules drugs, which may yield...
• Pulmonary bioavailability largely depends on the physical
properties of the delivered protein and it is not the same for...
AEROSOLS
• Aerosol preparations are stable dispersions or suspensions of solid
material and liquid droplets in a gaseous m...
DEVICES
Nebulizers
• Nebulizers are widely used as aerosolize drug solutions or
suspensions for drug delivery to the respi...
Jet nebulizers Ultrasonic nebulizers
10/4/2013 42
Dry powder inhalers(DPI)
• DPIs are bolus drug delivery devices that contain solid drug in a dry
powder mix (DPI) that is ...
Metered Dose Inhalers (MDI)
• Used for treatment of respiratory diseases such as asthma and COPD.
• They can be given in t...
Advantages of MDI
• It delivers specified amount of dose.
• Small size and convenience.
• Usually inexpensive as compare t...
Active Ingredient Brand Manufacturer Country
Terbutaline 0.25mg Bricanyl AstraZeneca UK
Beclometasone
dipropionate 250mcg
...
Active Ingredient Brand Manufacturer Country
Salbutamol pressurised
inhalation (100µg)
Asthalin Cipla India
albuterol Vent...
Cited Patent
Filing date Issue date
Original Assignee
Title
US2470296 Apr 30, 1948 May 17, 1949 INHALATOR
US2533065 Mar 8,...
Cited Patent Filing date Issue date Original
Assignee
Title
US6254854 May 11, 2000 Jul 3, 2001 The Penn
Research
Foundatio...
RECENT ADVANCES
The Aerogen Pulmonary Delivery Technology
AeroDose inhaler.
AeroNeb portable nebulizer
10/4/2013 50
• AeroGen specializes in the development, manufacture, and
commercialization of therapeutic pulmonary products for
local a...
The AERx device (with dosage forms).
The AERx dosage form.
AERx nozzle array.
The AERx Pulmonary Drug Delivery System
10/4...
• The AERx aerosol drug delivery system was developed to efficiently
deliver topical and systemically active compounds to ...
The Spiros Inhaler Technology
10/4/2013 54
• The inhaler has an impeller that is actuated,when the patient inhales,
to disperse and deliver the powder aerosol for in...
A) Blisterdisk powder storage system.
B) The interior of a well in a
blisterdisk. Aerosol generator “core” technology
10/4...
The DirectHaler™ Pulmonary device platform
10/4/2013 57
• DirectHaler™ Pulmonary is an innovative and new device for
dry powder Each pre-metered, pre-filled pulmonary dose has it...
REFERENCES
• Chien Y.W., Su K.S.E., Chang S.F., Nasal Systemic Drug Delivery, Ch. 1, Marcel-
Dekker, New York 1-77.
• Illu...
CONCLUSION
• The lung has served as a route of drug administration for thousands of
years. Now a day’s pulmonary drug deli...
THANK YOU
10/4/2013 61
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Drug delivery to respiratory system

  1. 1. DRUG DELIVERY TO RESPIRATORY SYSTEM PRESENTED BY M.G.P.LAKSHMI Y12MPH413 I/IIM.PHARM CEUTICS CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES 10/4/2013 1
  2. 2. CONTENTS 1. INTRODUCTION 2. ADVANTAGES AND LIMITATIONS 3. ANATOMY & PHYSIOLOGY OF NASAL CAVITY 4. MECHANISM OF NASALABSORPTION 5. THEORIES OF MUCOADHESION 6. FACTORS INFLUENCING NASAL DRUG ABSORPTION 7. STRATEGIES TO IMPROVE NASALABSORPTION 8. FORMULATION APPROACHES 9. EVALUATION TESTS 10. RECENT ADVANCES 11. PULMONARY DRUG DELIVERY SYSTEM 12. REFERENCES 13. CONCLUSION 10/4/2013 2
  3. 3. INTRODUCTION  The physiologic evolution of nose was primarily to serve the respiratory and olfactory necessity.  The first nasal drug delivery system was for re establishing normal nasal conditions the mucosa in particular , that is affected in various diseases.  Thus at first the nasal administration of drug was primarily employed for local drug effects.  Nasally administered small drugs display a rapid absorption that is comparable to intravenousaly administered drugs.  Nasal mucosa has been considered as a potential ad-ministration route to achieve faster and higher level of drug absorption because it is permeable to more com-pounds than the gastrointestinal tract due to lack of pancreatic and gastric enzymatic activity, neutral pH of the nasal mucus and less dilution by gastrointestinal contents.  In recent years many drugs have been shown to achieve better systemic bioavailability through nasal route than by oral administration. Nasal therapy, has been recognized form of treatment in the Ayurvedic systems of Indian medicine, it is also called “NASAYA KARMA” 10/4/2013 3
  4. 4. ADVANTAGES 1) Drug degradation that is observed in the gastrointestinal tract is absent. 2) Hepatic first pass metabolism is avoided. 3) Rapid drug absorption and quick onset of action can be achieved. 4) The bioavailability of larger drug molecules can be improved by means of absorption enhancer or other approach. 5) The nasal bioavailability for smaller drug molecules is good. 6) Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal drug delivery. 7) Studies so far carried out indicate that the nasal route is an alternate to parenteral route, especially, for protein and peptide drugs. 8) Convenient for the patients, especially for those on long term therapy, when compared with parenteral medication. 9) Drugs possessing poor stability in g.i.t. fluids are given by nasal route. 10) Polar compounds exhibiting poor oral absorption may be particularly suited for this route of delivery. 10/4/2013 4
  5. 5. LIMITATIONS 1) The histological toxicity of absorption enhancers used in nasal drug delivery system is not yet clearly established. 2) Relatively inconvenient to patients when compared to oral delivery systems since there is a possibility of nasal irritation. 3) Nasal cavity provides smaller absorption surface area when compared to GIT. 4) There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa, both from the substance and from constituents added to the dosage form. 5) Certain surfactants used as chemical enhancers may disrupt and even dissolve membrane in high concentration. 6) There could be a mechanical loss of the dosage form into the other parts of the respiratory tract like lungs because of the improper technique of administration. 10/4/2013 5
  6. 6. ANATOMY & PHYSIOLOGY OF NASAL CAVITY 10/4/2013 6
  7. 7.  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  5.5-6.5.  Infants and young children  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 such as albumin,lysozyme and lactoferrin and 1%-lipids. 10/4/2013 7
  8. 8. MECHANISM OF NASALABSORPTION The absorbed drugs from the nasal cavity must pass through the mucus layer; it is the first step in absorption. Small, unchanged drugs easily pass through this layer but large, charged drugs are difficult to cross it. two mechanisms have been predominantly used, such as:- a) First mechanism- It involves an aqueous route of transport, which is also known as the paracellular route but slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water-soluble com-pounds. The molecular weight greater than 1000 Daltons having drugs shows poor bioavailability . b) Second mechanism- It involves transport through a lipoidal route and it is also known as the transcellular process. It is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drug also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions . 1: Parts of nasal cavity consists of a – nasal ves-tibule, b – palate, c–inferior turbinate, d-middle tur-binate, e – superior turbinate (olfactory mucosa),f –nasopharynx 10/4/2013 8
  9. 9. Mucoadhesive Carrier Hydration and swell of polymer Hydrophilic Macromolecular drug Internal Absorption Interaction with Mucus Drug release Enzymatic MetabolismCilliary clearance Scheme of Mucoadhesive Nasal Drug Delivery10/4/2013
  10. 10. 10/4/2013 10 Theory Mechanism of bioadhesion Comments Electronic theory 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 Strong primary forces: covalent bonds Weak secondary forces: ionic bonds, hydrogen bonds and van der Waal’s forces Wetting theory 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 Diffusion theory 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 Fracture theory 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 of hard polymers, which lack flexible chains THEORIES OF MUCOADHESION
  11. 11. FACTORS INFLUENCING NASAL DRUG ABSORPTION 1) Physiochemical properties of drug. Molecular size. Lipophilic-hydrophilic balance. Enzymatic degradation in nasal cavity. 2) Nasal Effect Membrane permeability. Environmental pH. Mucociliary clearance. Cold, rhinitis. 3) Delivery Effect Formulation (Concentration, pH, osmolarity). Delivery effects. Drugs distribution and deposition. Viscosity. 10/4/2013 11
  12. 12. STRATEGIES TO IMPROVE NASAL ABSORPTION • Various strategies used to improve the bioavailability of the drug in the nasal mucosa which includes 1. To improve the nasal residence time 2. To enhance nasal absorption 3. To modify drug structure to change physicochemical properties. Several methods have been used to facilitate the nasal absorption of drugs includes:  Nasal enzyme inhibitors  Permeation enhancers:- a) nhibit enzyme activity; b) Reduce mucus viscosity or elasticity; c) Decrease mucociliary clearance; d) Open tight junctions; e) Solubilize or stabilize the drug.  Prodrug approach.  Structural modification.  Particulate drug delivery. 10/4/2013 12
  13. 13. IDEAL PENETRATION ENHANCER 1. It should lead to an effective increase in the absorption of the drug. 2. It should not cause permanent damage or alteration to the tissues. 3. It should be non irritant and nontoxic. 4. It should be effective in small quantity. 5. The enhancing effect should occur when absorption is required. 6. The effect should be temporary and reversible. 7. It should be compatible with other excipients. 10/4/2013 13
  14. 14. STRATEGIES TO IMPROVE NASAL ABSORPTION 10/4/2013 14  Permeation enhancers Type of compound Examples Mechanisms of action Bile salts (and derivatives) Sodiumdeoxycholate,sodiumglycocholate , sodium taurodihydrofusidate Disrupt membrane, open tight junctions, enzyme inhibition, mucolytic activity Surfactants SLS, saponin, polyoxyethylene-9-lauryl ether Disrupt membranes Chelating agents Ethylenediaminetetraacetic acid(EDTA), salicylates Open tight junction Fatty acids Sodium caprylate, sodium laurate, phospholipids Disrupt membranes Bio adhesive materials Powders Carbopol, starch microspheres, chitosan Reduce nasal clearance, open tight junctions Liquids Chitosan, carbopol Reduce nasal clearance, open tight junction Miscellaneous Cyclodextrins Disrupt membranes, open tight
  15. 15. NASAL ENZYME INHIBITORS Nasal metabolism of drugs can be eliminated by using the enzyme inhibitors. Mainly for the formulation of proteins and peptide molecule development enzyme inhibitors like peptidases and proteases are used. The absorption enhancers like salts and fusidic acid derivatives also shows enzyme inhibition activity to increase the absorption and bioavailability of the drug . The other enzyme inhibitors commonly used for the enzymatic activity are tripsin, aprotinin, borovaline, amas-tatin, bestatin and boroleucin inhibitors. 10/4/2013 15
  16. 16. STRUCTURAL MODIFICATION Modification of drug structure without altering pharmacological activity is one of the lucrative ways to improve the nasal absorption. The chemical modification of drug molecule has been commonly used to modify the physicochemical properties of a drug such as molecular size, molecular weight, Pka and solubility are favourable to improve the nasal absorption of drug. Example, :- chemical modification of salmon calcitonin to ecatonin (C-N bond replaces the S-S bond) showed better bioavailability than salmon calcitonin 10/4/2013 16
  17. 17. PRODRUG APPROACH Prod rug approach is mainly meant for optimizing favourable physicochemical properties such as solubility, taste, odour, stability, etc. Prod rug is usually referred as promoiety, it is to cover the undesired functional groups with another functional groups. This prod rug approach is mainly for improving the nasal bioavailability especially for the proteins and peptides to enhance the membrane permeability along with increased enzymatic stability. The prod rug undergoes enzymatic transformation to release the active medicament, when it crosses the enzymatic and membrane barrier. The absorption of peptides like angiotensin II, bradykinin, caulein, arnosine, enkephalin, vasopressin and calcitonin are improved by pr e-pared into enamine derivatives, these agents showed absorption enhancement with prod rug approach. 10/4/2013 17
  18. 18. PARTICULATE DRUG DELIVERY Particle design is an increasingly important role in absorption enhancement. Microspheres, nanoparticles and liposome's are all systems which can be used as carriers to encapsulate an active drug. The properties of these can be varied to maximize therapeutic efficacy. Overall, this can result in increased absorption efficacy and stability and reduced toxicity of the active ingredient. Systems can be designed to be muco adhesive to increase the retention time and facilitate sustained release. Microspheres are mainly increase the absorption and bioavailability by adhering to the nasal mucosa and increase the nasal residence time of drug . The microspheres prepared by using polymers like dextrin, chitosan, biodegradable starch microspheres successfully improved the bioavailability of various drugs. Liposome's are amphiphilic in nature are well characterized for favourable permeation of drugs through the biological membranes, so the water soluble drugs have been delivered to nasal drugs. Cationic liposome's are having good permeation capacity than negatively charged anionic liposome's. 10/4/2013 18
  19. 19. FORMULATION APPROACHES 10/4/2013  Nasal gels  Nasal Drops  Nasal sprays  Nasal Powder  Liposome  Microspheres
  20. 20. 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. Nasal Drops 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 than nasal sprays. 10/4/2013 20
  21. 21. Liposome's • 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. 10/4/2013 21
  22. 22. 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. 10/4/2013 22
  23. 23. 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. 10/4/2013 23
  24. 24. 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. 10/4/2013 24
  25. 25. MARKETED DRUGS Local Delivery Drug Brand Main Excipients Supplier Main Indications Azelastine Astelin Benzalkonium chloride, edetate disodium, Meda Pharmaceuticals Beclometasone Beconase Microcrystalline cellulose, carboxymethyl cellulose sodium, benzalkonium chloride GlaxoSmithKline Levocabastine Livostin Benzalkonium chloride, edetate disodium, disodium phosphate Jansen-Cilag Management/ treatment of symptoms of seasonal and perennial rhinosinusitis10/4/2013 25
  26. 26. Systemic Delivery Drug Brand Main Excipients Supplier Main Indications 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 Sanofi-Aventis Treatment of prostate cancer 10/4/2013 26
  27. 27. 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 10/4/2013 27
  28. 28. RECENT ADVANCES • 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. • 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. • 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. 10/4/2013 28
  29. 29. Delivery of non-peptide Pharmaceuticals • 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. 10/4/2013 29
  30. 30. 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 • Anthrax and influenza are treated by using the nasal vaccines • prepared by using the recombinant Bacillus anthracis protective • antigen (rPA) and chitosan respectively. 10/4/2013 30
  31. 31. • Delivery of Drugs to Brain through Nasal Cavity Conditions like Parkinson’s disease, Alzheimer’s disease or pain 10/4/2013 31
  32. 32. PULMONARY DRUG DELIVERY SYSTEM 10/4/2013 32
  33. 33. INTRODUCTION • 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. 10/4/2013 33
  34. 34. • 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,. • 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. 10/4/2013 34
  35. 35. 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 • Stability of drug in vivo. • Transport. • Targeting specificity. • Drug irritation and toxicity. • Immunogenicity of proteins • Drug retention and clearance. 10/4/2013 35
  36. 36. THE RESPIRATORY TRACT 10/4/2013 36
  37. 37. • 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. 10/4/2013 37
  38. 38. 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. 10/4/2013 38
  39. 39. • 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 liposome's are one of the recent approaches in the controlled release aerosol preparation. Intratracheal delivery of insulin liposome's (dipalmitoylphosphatidyl choline:cholesterol ,7:2) have significantly enhanced the desired hypoglycaemic effect. • The coating of disodium fluoresce in 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 of the protein drug by using intratracheal instillation delivery in rat. 10/4/2013 39
  40. 40. 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. 10/4/2013 40
  41. 41. DEVICES Nebulizers • 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. • Delivered the drug in the form of mist. • There are two basic types: 1) Air jet 2) Ultrasonic nebulizer 10/4/2013 41
  42. 42. Jet nebulizers Ultrasonic nebulizers 10/4/2013 42
  43. 43. 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. 10/4/2013 43
  44. 44. 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. 10/4/2013 44
  45. 45. 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. 10/4/2013 45
  46. 46. 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 MARKETED DRUGS Dry Powder Inhaler 10/4/2013 46
  47. 47. 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 Formoterol Fumarate12 mcg Ultratech India Metered Dose Inhalers (MDI) 10/4/2013 47
  48. 48. 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 Therapetic 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 PATENTED DRUGS 10/4/2013 48
  49. 49. 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 Becton, Dickinson and Company Pharmaceutical compositions in particulate form US7954491 Jun 14, 2004 Jun 7, 2011 Civitas Therapeutics, Inc Low dose pharmaceutical powders for inhalations10/4/2013 49
  50. 50. RECENT ADVANCES The Aerogen Pulmonary Delivery Technology AeroDose inhaler. AeroNeb portable nebulizer 10/4/2013 50
  51. 51. • AeroGen specializes in the development, manufacture, and commercialization of therapeutic pulmonary products for local and systemic disease. • The technology being developed at AeroGen consists of a proprietary aerosol generator (AG) that atomizes liquids to a predetermined particle size. • AeroGentechnologies produce a low-velocity, highly respirable aerosol that improves lung deposition of respiratory drugs and biopharmaceuticals. • These delivery platforms accommodate drugs and biopharmaceuticals formulated as solutions, suspensions, colloids, or liposomes. 10/4/2013 51
  52. 52. The AERx device (with dosage forms). The AERx dosage form. AERx nozzle array. The AERx Pulmonary Drug Delivery System 10/4/2013 52
  53. 53. • 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. 10/4/2013 53
  54. 54. The Spiros Inhaler Technology 10/4/2013 54
  55. 55. • 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. 10/4/2013 55
  56. 56. A) Blisterdisk powder storage system. B) The interior of a well in a blisterdisk. Aerosol generator “core” technology 10/4/2013 56
  57. 57. The DirectHaler™ Pulmonary device platform 10/4/2013 57
  58. 58. • 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. 10/4/2013 58
  59. 59. REFERENCES • Chien Y.W., Su K.S.E., Chang S.F., Nasal Systemic Drug Delivery, 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. 10/4/2013 59
  60. 60. CONCLUSION • 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 . • 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. 10/4/2013 60
  61. 61. THANK YOU 10/4/2013 61
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