Pulmonary/ lung drug Delivery Sytem
- 1. LUNG DELIVERY SYSTEMS Presented By: S.Krishnam Raju M.Pharmacy 1st yr.- 2nd sem Department of Pharmaceutics 18004P-1021 University College of Pharmaceutical Sciences, Kakatiya University, Warangal, 506009 UCPSc 1
- 2. Contents 1. Introduction 2. Macro- and Microstructure of the air ways for Drug Delivery a) Types of Airway Zones b) Cell types in Lungs 3. Aerosol Deposition Mechanisms 4. Drug elimination from Lungs 5. Controlled transport for Pulmonary Drug Delivery 6. Fundamentals of Particle Size 7. Recent developments in Delivery Device with Formulation 8. References UCPSc 2
- 3. Introductio n Low bioavailability is one of the major issues for many drugs. Currently one of the best route for improve bioavalability. These system widely used in ancient period. The recordings include: Eber papyrus 1554 BC –inhalation of black henbane.( Egypt) Hippocrates 460-377 BC- Asthma treatment through pot like device. Christopher Bennet 1654- TB (Bennet inhaler) Frist DPI used in 1864.The Device is designed by Alfred Newton. In 1865 improved inhaler known as Dr.Nelsons improved inhaler. The era between 1950-1955’s known for pMDIs. UCPSc 3
- 4. Macro- and Microstructure of the air ways for Drug Delivery Conducting Airway • Constitutes: mouth/nose, trachea, bronchi, bronchioles, terminal bronchioles. • Gas Transport, humidification and temperature maintain. • Improper function- Increased Surface tension & bronchoconstriction results inefficient drug delivery • Surface area 2-3 m2 Respiratory Airway • Bronchioles, Alveolar ducts, and Alveolar Sacs. • Gas exchange due to inherent physical characteristics. • Alveolar ducts 1mm connected alveoli. Polyhedral chamber of Alveoli 250 μm diameter. • Surface area 102m2 . UCPSc 4
- 5. Types of Airway Zones Conducting zone: Bifurcates 17 times. Respiratory zone: Bifurcates 6 times. Branching increases Surface Area & Decreases Air velocity. UCPSc 5
- 6. Cell Types IN LUNGS Conducting zone: 1.Basal: Progenitor cell 2.Neuroendocrine: secrete peptide hormones (K cell) 3.Ciliated columnar cells: Major part of Mucociliary escalator 4.Non-ciliated: 1. Goblet- Mucus secretion 2. Clara-Surfactants, protease inhibitors, detoxification. 5.Smooth muscle: contraction, relaxation 6.Mast: response-antigen recognition. Distal Zone: 1.Alveolar type 1 (AT1) 2.Alveolar type 2 (AT2) UCPSc 6
- 7. Continue… • Distal zone: Consist Receptors, Capillary endothelial cells, Alveolar Macrophages. Receptors in LUNG: include mainly β – receptors ( β1 - alveolar walls, β2 – mainly in AT1, AT2, and also in other cells) Feature Alveolar type 1 (AT1) Alveolar type 2 (AT2) Ratio 1 2 Alveolar Surface area covered 95% 5% Diameter 50-100 μm 10 μm Function Highest water permeability, Transport of Macromolecules Production, secretion, recycling of lung surfactant & AT 1 cell production Cell Junctions Both connected by Tight & Gap junctions UCPSc 7
- 8. Aerosol Drug Deposition Mechanisms • Mainly by 3 mechanisms: I. Impaction II. Sedimentation III. Diffusion Two other mechanisms include: Interception Electrostatic Precipitation. UCPSc 8
- 10. Drug Elimination From LUNGS Possible routes of Elimination: I.Dissolution II.Mucociliary& Cough clearance III.Alveolar macrophages IV.Metabolism UCPSc 10
- 11. Continue ..Dissolution: 10- 30 mL in lung. Lining varies from 5-10 μm to 0.01-0.08 μm. Hydrophobicity of drug: salbutamol sulphide (logp -2 =250 mg/mL) fluticasone propionate(logp 5 =0.1 μg/mL) Mucociliary and Cough: ciliated cells in epithelium transport mucus to proximal direction. Mucus in healthy about 10-20mL/day and thickness 30 μm and movement in 1mm/ min peripheral & 20mm/min trachea. Alveolar macrophages: transport to mucociliary escalator or translocation to tracheobronchial lymph or lysosomal degradation. Optimal size (1.5 – 3 μm) can be prone to Phagocytosis. Metabolism: CYP1B1, CYP2B6, CYP2E1, CYP2J2, CYP3A5, and CYP1A1 ( the latter being highly induced in smokers). UCPSc 11
- 12. Mucociliary Escalator Mucus production increases in disease conditions ( bronchitis 10 times more than normal). But clearance decreases. Cough is important when mucus clearance is decreased, about 60% drug removed from COPD patients UCPSc 12
- 13. Controlled transport for Pulmonary drug Delivery •By 4 ways mainly I.Surfactant Assisted II.Aerosol Submersion III.Regulation of Mucociliary Escalator IV.Controlling Diffusion UCPSc 13
- 16. III. Regulation of Mucociliary Escalator Mucociliary escalator can be altered to either enhance or further limit transport through the addition of mucoactive compounds or through modifications to particle properties Example: Mucolytics 1. DNase 2. Thiolagents( N-acetyl cysteine) UCPSc 16
- 20. Mass Mean Aerodynamic Diameter (MMAD) UCPSc 20
- 22. Recent developments in Devices with formulation •Devices : I.Nebulizers & MDLI II.Pressurized Metered Dose inhalers (pMDIs) III.Drug Powder Inhalers • Formulations (NDDS) I.Liposomes II.Nanoparticles III.Gene delivery UCPSc 22
- 23. Nebulizer s The Jet Nebulizer: Liquid broken by air turbulences then Impaction on Baffle. The renebulization occurs to more than 90% (or dead volume mostly 2 ml) of molecules nebulized. Not suitable for Liposomes & Macromolecular APIs ( due to damage of Integrity). UCPSc 23
- 24. Continue .. Ultrasonic nebulizer: Consist a Piezoelectric crystal that vibrates at high frequencies (1-3MHz) to generate a fine slow- moving mist of droplets. Droplet formation: 1. By capillary wave formation (at high frequency) 2. By cavitation (at low frequency) Not used for Suspensions, Thermo labile drugs. Used for Liposomes. UCPSc 24
- 25. Continue … Adaptive Aerosol Technology: During first 3 breaths, AAD calculates when to pulse the aerosol. In subsequent breaths, AAD pulses aerosol during the first 50%-80% of inspiration(blue shade). AAD systems deliver drug until all the preprogramed dose has been received. UCPSc 25
- 26. Pressurized Metered Dose Inhalers: • Future directions: 1) Nanosuspensions for poorly soluble drugs: Severely hindered –limited solubility – lead to unwanted toxic effects. NPs with HFA based systems can avoid such problems- due to higher dissolution rates results improved bioavailability. Examples: Recent studies 1. Itraconazole – in HFA227 – physical stability over 2 years. 2. Griseofluvin, cholesterol acetate (100-1000nm) – aq.solubility increased up to 5-10 fold than the micronized form. UCPSc 26
- 27. Continue … 2) Polymeric Nanocarriers: Used to 1. encapsulate drugs & biomolecules 2. As protective depots for fragile molecules 3. Enhance bioavailability 4. Suitable for different route of administration 5. Control release of encapsulant They appropriate sizes to avoid alveolar macrophages. Biocompatible & biodegradable polymers used ( polyesters (PLA & PLGA) , polyanhydrides, chitosan, polybutylcynoacrylates, and polyacrylates). UCPSc 27
- 28. Polymeric nanocarriers: Not stable in HFA i.e. Not Dispersible. Fig. a) SEM of polymeric NC b) 2mg/mL in HFA227 after 5min of mechanical energy input. c) In this 15 min of mechanical energy input. UCPSc 28
- 29. Continue. . 3) Oral inhalation delivery of Biomolecules in pMDIs: OI is most advantageous route for biomolecule due to physiology of the lung tissue. These include peptides, oligonucleotides, and proteins used in the treatment of diabetes, cystic fibrosis, and cancer. Disease Peptide/protein Cystic fibrosis(CF) DNase (approved) Lung transplant Cyclosporine A Cancer/Pneumocystis carnii Interferon- ,Interleukin-2Ƴ Osteoporosis Calcitonin parathyroid hormone Anaemia Erythropoietin Diabetes insipidus dDAVP (1-deaminocysteine-8 D-arginine vasopressin) UCPSc 29
- 30. Drug Powder Inhalers(DPI) • DPI Development: Comprised of 3 regions- air inlet , powder-holding chamber, drug outlet Particle in flow subjected to 2 forces: 1. Body forces- gravity& electromagnetism- force/unit mass 2. Surface forces- shear or tangential forces- force/unit area Tangential forces important for powder de-agglomeraization. Recent DPIs contain tangential inlets opening into a cylindrical chamber to generate a high cyclone within the device. • Example: NEXTTM DPI (US patent NO.7, 107,988) UCPSc 30
- 31. Continue … • Computational fluid dynamics (CFD) analysis used to optimize the design and dimensions of chamber, and the resulting geometry was shown to eliminate “dead spots” where the drug deposition may have occurred. • Strategies used in development: 1. Mechanical forces- low density beads 2. Pneumatic forces- compressed gas, vacuum, synthetic jet technology 3. Sustained exposure to flow stream- Air classifier Technology 4. Vibration- induced Dispersion- capsule vibrations, Aeroelastic vibrations, Piezoelectric Dispersion. UCPSc 31
- 32. Liposome s: Liposomes are more advantages than others NDDS for pulmonary due to: 1.Ability to solubilize soluble drugs. 2.Capacity to provide a reservoir for sustained release, prolonging local and systemic therapeutic levels. 3.Facilitation of intracellular delivery of drugs especially to alveolar macrophages. 4.Avoidance of local irritation of lung tissue. 5.Ability to target specific cell populations using surface-bound ligands or antibodies. 6.Potential to be absorbed across the epithelium intact to reach the systemic circulation. UCPSc 32
- 33. Continue … • Another reason- chemical similarity with lung surfactant. • Human lung Surfactant consist of • Recent studies - liposomes consisting DPPC or DPPC: DPPG can easily enter into surfactant pool without disturbing normal metabolic activity or stimulating alveolar macrophage activity Lipids Proteins 1. Phospholipids (80%) Mainly dipalmitoylphosphatidylcholine (DPPC), phosphatidyl glycerol, phosphatidyl inositol. 1. Four types of Surfactant proteins (SPs) SP-A, SP-B, SP-C, and SP-D 2. Neutral lipids (8%) Cholesterol, fatty acids. 2. SP-A & SP-D are Large & glycosylated water soluble molecules. SP-B & SP-C are Small & highly hydrophobic small peptides UCPSc 33
- 34. Nanoparticles for Pulmonary drug Delivery Use of inhaled nanoparticle therapeutics has been limited. Currently no inhaled nanoparticle formulation is approved; however, successful clinical studies have been completed (e.g., nano- bedesonide). Upon Aerosolization - interpaticulate forces > inertial separation, resulting in aggregates of uncontrolled size. To overcome this problems in nanoparticles, pharmaceutical scientists have investigated the use of both liquid and solid carriers as well as particle engineering to improve aerosolization and provide appropriate aerodynamic diameters for deep lung deposition UCPSc 34
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- 36. Pulmonary Delivery of Plasmid DNA for Disease Prevention and Therapy: • There are 3 challenges in drug development: Delivery, Delivery, and Delivery. 1. Frist Delivery- to deposit an aerosol DNA at correct site in the lung, maintaining DNA integrity in lieu of shear forces necessary to produce aerosol droplet sizes suitable for inhalation. 2. Second - enable the uptake of DNA carrier systems by, if possible, the correct target cells. 3. Last aspect – to obtain successful transfection, i.e., the successful expression and processing of protein encoded in the DNA delivered. Lipoplexes and Polyplexes: In Non-viral delivery, DNA is usually condensed by electrostatic interaction with either cationic lipids to form so-called Lipoplexes or cationic polymers (Polyplexes). Recent use of an improved lipid, the Genzyme lipid (GL-67), called the “gold standard” in pulmonary gene delivery. UCPSc 36
- 38. Pulmonary Delivery of Plasmid DNA for Disease Prevention and Therapy: From above equation electrostatic sprays –lowest destabilizing effect for aerosolized pDNA, while highest for jet nebulizers. DNA degradation/destabilization also occurs in vibrating mesh nebulizers (due to the interaction of molecule with vibrating grid), Ultrasonic nebulizers (due to cavitation i.e., the collapse of air bubbles creating shock waves, which can damage DNA). DNA can be stabilized – “naked” DNA, complexation with positively charged molecular entities, condensing and compacting DNA. Results increase in transfection efficiency. UCPSc 38
- 39. Concept of Polyplex transfection 1. Formation of polyplex formation by condensation of DNA and polymer 2. Polyplex Endocytosis & Endosomal Uptake 3. Endosomal escape 4. transport through cytoplasm and nuclear localization 5. intracellular dissociation of 6. plasmid DNA from polymer UCPSc 39
- 40. References 1. Hugh D.C Smyth, Anthony J. Hickey, Controlled Pulmonary Drug Delivery: (2011), 1- 17, 21-45,101-120,143-230,283-380. 2. N.R. Labiris, M.B. Dolovich, Pulmonary drug delivery. Part 1: Physiological factors affecting therapeutic effectiveness of aerosolized medications.2003; 65-72. 3. J. S. Patton, C. S. Fishbum and J. G. Weers, The Lungs as a Portal of Entry for Systemic Drug Delivery, Proceedings of the American thoracic society, 2004; 338-344. 4. J. S. Patton, C. S. Fishbum. And J. G. Weers, The Lungs as a Portal of Entry for Systemic Drug Delivery, Proceedings of the American thoracic society, 2004; 340-352. 5. J. Heyder, Deposition of inhaled particles in the human respiratory tract and Consequences for regional targeting in respiratory drug delivery. Proc Am Thorac Soc. 2004:315-320. 6. B. V. Wickert, B.J. Gonzalez- Rothi, Amikacin liposomes: characterization, aerosolization and in vitro activity against Mycobacterium avium-intracellulare in alveolar macrophages. Int. J. Pharm. 78, 1992; 227-235. 7. V.Ravichandiran, K.Masilamani, S.Satheshkumar, D.Joseprakash, Drug delivery to lungs. Volume 10, Issue 2, September – October 2011; Article-017 8. S.P.Vyas and RP.Khar. Controlled drug delivery; concepts and advances, Vallabh Prakashan, New Delhi, 2002, 315-382. UCPSc 40
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