Nasal and pulmonary delivery system - Nainesh patel

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Nasal and Pulmonary Delivery system

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Nasal and pulmonary delivery system - Nainesh patel

  1. 1. Nasal and Pulmonary Delivery System Nainesh Patel Email :naineshp@glenmarkpharma.com (M) +9191586595011
  2. 2. Nasal Delivery Platforms2
  3. 3. Nasal Delivery System.  The nasal route is commonly used for the delivery of drugs to alleviate a number of local disorders such as sinus congestion and allergic rhinitis.  It is also begging utilized as an alternative to oral and injection methods for the systemic delivery of a variety of drug including vaccines, proteins and peptides.3
  4. 4. Advantages of Nasal delivery.  The large surface area for absorption in the nose ,coupled with the high density of blood vessels, enables efficient absorption into the blood stream.  Rapid onset of action compared to oral delivery.  Avoiding enzyme degradation of the drug with in the GI tract and first pass hepatic metabolism.  Painless delivery compared to Injection delivery.4
  5. 5. Targeting the Nose5
  6. 6. Regulatory /Analytical Application for Nasal spray.  CMC specifications for Nasal spray  Bioequivalence In vitro test  One time characterization study6
  7. 7. CMC specifications for Nasal spray.  Appearance  Osmolality,  Identification  Viscosity  Assay  Pump delivery  Related substance  Spray content uniformity  Particulate matter  Spray pattern  Microbial limits  Net content  Plume geometry  Leachable and Exactable  Droplet size distribution.  Weight loss on stability  Particle size distribution.  pH7
  8. 8. Bioequivalence In vitro test  Appearance  Priming and Repriming  Spray pattern  Plume geometry  Small droplet size by Cascade Impactor  Droplet size distribution by Laser Diffraction  Microscopy for suspension.8
  9. 9. One time characterization study.  Appearance  Priming and repriming in various orientations  Device robustness ( Shaking, Dropping, Vibrating )  Effect of dosing orientation (60°,75°and 90°)  Profiling of sprays near container exhaustion (tail off characteristics)  Preservative effectiveness  Photo stability  Cleaning instructions9
  10. 10. Test and Related method/Instrument  Appearance- By visual method  Identification- By FTIR/HPLC/TLC  Assay- By HPLC  Related substance- By HPLC  Particulate matter- By visual/By Instrument  Microbial limits- By Micro  Net content- By Analytical balance  Leachable and Exactable By HPLC/GC/GC MS  Weight loss on stability- By Analytical balance10
  11. 11. Test and Related method/Instrument  Pump Delivery -By NSP UA actuator  Spray pattern -By ADSA-Spray view  Plume geometry -By ADSA-Spray view  Droplet size -Spraytec-Malvern  Small droplet size by ACI -Expansion chamber with ACI11
  12. 12. pMetered Dose Inhaler & Dry Powder Inhaler Delivery Platforms.12
  13. 13. pMDI & DPI Delivery System.  Inhaled drug product are becoming increasingly popular means of local or systemic therapy via lungs.  (a) locally(directly) to treat lung diseases such as asthma and chronic obstructive pulmonary diseases(COPD) and to deliver locally-acting drugs such as antibiotics and antiviral directly to the lungs to curb infection.  (b) systemically, for example in pain relief and anesthetic applications.13
  14. 14. Advantage of pMDI & DPI Delivery System.  Pulmonary delivery offers a number of advantages compared to the more traditional oral and parental routes.  Directly targets the lung.  Rapid onset of drug action.  Drug effective in relatively low doses.  Fewer side effects.  Avoids hepatic metabolism.  Injection-free administration.14
  15. 15. Regulatory /Analytical Application for pMDI & DPI.  CMC specifications for Metered Dose Inhaler  Bioequivalence In vitro test (Till date no draft/Finial guidance for In vitro study.)  One time characterization study15
  16. 16. CMC specifications for pMDI &DPI.  Appearance and color  Dose content uniformity  Identification through container life.  Microbial limits  Particle size distribution  Water or Moisture content  Microscopic evaluation.  Assay of Dehydrated  Spray pattern Alcohol(if used as co  Plume geometry solvent)  Leak rate  Net content  Pressure Testing  Assay (drug content)  Valve delivery (shot weight)  Related substance  Leachable and Exactable  Dose content uniformity.16
  17. 17. One time characterization study.  Determination of Appropriate storage conditions.  Stability of primary(unprotected)package.  Temperature cycling.  Effect of resting time.  Priming and repriming in various orientations.  Effect of storage on the particle size distribution.  Drug deposition on mouth piece and/or Accessories.  Cleaning instructions.  Profiling of sprays near container exhaustion (tail off characteristics).  Plume geometry.  Microbial challenge.  In vitro Dose Proportionality.  Effect of varying flow rate.17
  18. 18. Instrument and various technique used for Nasal Spray, Metered Dose Inhaler, Dry Powder Inhaler.18
  19. 19. Basic set up for determination of Aerodynamic particle size.19
  20. 20. Aerodynamic particle size by Anderson Cascade Impactor.20
  21. 21. Aerodynamic particle size by Anderson Cascade Impactor.  Anderson cascade impactor is mimic of the pulmonary track and Lungs.  Cascade impactor testing is the principal technique and key parameters for determining metrics that describe Aerodynamic particle size distribution of Orally Inhaled Products. Like MDI,DPI and Nasal spray.  Based on Aerodynamic particle size distribution data, we can predicted and optimized of drug deposition characteristic in the human respiratory tract.  Cascade impactor operates on the principle of internal impaction. i.e separation is provided on the basis of difference in inertia –a function of particle size and velocity.21
  22. 22. Aerodynamic particle size by NGI Next generation Impactor.22
  23. 23. Aerodynamic particle size by NGI Next generation Impactor.  Next Generation Impactor (NGI) is mimic of the pulmonary track and Lungs.  Next Generation Impactor (NGI) testing is advanced technique and key parameters for determining metrics that describe Aerodynamic particle size distribution of Orally Inhaled Products. Like MDI,DPI and Nasal spray.  Based on Aerodynamic particle size distribution data, we can predicted and optimized of drug deposition characteristic in the human respiratory tract.  Cascade impactor operates on the principle of internal impaction. i.e separation is provided on the basis of difference in inertia –a function of particle size and velocity.23
  24. 24. Moisture content by coulometer with Automated actuation.24
  25. 25. Basic Actuation system for Nasal spray and pMDI. • Reduce operators induced subjectivity. •Actuation parameters relevant to patient use.25
  26. 26. Droplet size Distribution by Spraytec- Malvern UK.26
  27. 27. Droplet size Distribution by Spraytec- Malvern UK.27
  28. 28. Droplet size Distribution by Spraytec.  A typical nasal spray formulation consists of a bottle with a metered spray pump, containing the drug suspended or dissolved in a aqueous medium.  Pump actuation by the patient delivers drug laden droplets in to the nasal cavity.  Most nasal spray pumps produces droplets in the size range from 20 µm to 120 µm. It is critically important that the droplets are of a size that enables their deposition within the nasal passages.  If droplet are too small (< 10µm), particle/droplet may pass through the nasal passages and deposit in the lungs. Potentially allowing deposition of drug and Excipients not approved for pulmonary absorption. If droplet are too large, particle/droplet may trapped in nostril.28
  29. 29. Spray pattern and Plume geometry by ADSA-Innova system-US29
  30. 30. Spray pattern and Plume geometry by ADSA-Innova system-US Spray pattern Plume geometry30
  31. 31. Spray pattern and Plume geometry -Theory  Automated testing of nasal spray pumps yields test data that are more reliable than the data that result from manual methods. That is because spray patterns depend so heavily on actuation velocity and acceleration. For example: • High actuation velocity and acceleration produce smaller droplets in a more atomized cloud. • Low actuation velocity and acceleration levels produce larger droplets in more stream-like sprays.  The FDA requires these two tests spray pattern and plume geometry in submissions for approval of drugs.31
  32. 32. Spray pattern and Plume geometry -Theory  The FDA recommends that test labs use automated actuation systems to reduce variability in these measurements due to operator factors. Automated actuation also increases measurement sensitivity, in order to detect differences among products.  During product development, analysts can use these measurements to design a delivery system that accounts for the properties of the fluid that carries the drug. Automated testing also helps to find acceptable tolerances for variables of interest during stability testing. Lastly, quality control of release grade products requires highly consistent test methods and sensitive measurement technologies.32
  33. 33. Emitted dose by Glass Twin Impinger.33
  34. 34. Emitted dose by Glass Twin Impinger.  Glass Twin impinger developed at GSK lab.UK and it is recognized as apparatus A in Ph.Eur.2.9.18.  It is designed such that at a flow rate 60.0 L/min through the impinger.  The particle cut off diameter is 6.4 microns. Particle smaller than 6.4 microns pass in to the lower impingement chamber.  The value of the Glass Twin impinger, particularly with respect to routine quality control application.  Glass Twin impinger used for routine QC applications.34
  35. 35. Delivered Dose by DUSA. (Dose Unit Sampling Apparatus) For pMDI/ DPI For Nasal spray35
  36. 36. Delivered Dose by DUSA. (Dose Unit Sampling Apparatus)  The Delivered dose is the total amount of drug emitted from the medical device and hence available to the patient/user.  It is used to perform those tests specified in the pharmacopoeia relating to Delivered or emitted dose namely “Delivered Dose Uniformity and Delivered Dose Uniformity over the Entire contents.  It is designed such that at a flow rate 28.3 L/min including filter and inhaler..36
  37. 37. Small Droplet size by Anderson cascade Impactor.37
  38. 38. Small Droplet size by ACI.  A two-liter or larger induction port (expansion chamber) is preferred to this test.  The total mass of drug below the top stage is of primary interest.  The total mass of drug collected on all stages and accessories is recommended to be between 85 and 115 percent of label claim on a per actuation basis.38
  39. 39. Brief Summary of Sophisticated Instrument. Instrument/Make Application Anderson Cascade Impactor- Aerodynamic particle size Distribution Westech Scientific Instruments- for MDI,DPI and Nasal spray. UK/Copley Scientific ,UK Next Generation Impactor- Aerodynamic particle size Distribution Copley Scientific ,UK for MDI,DPI and Nasal spray. Aerosol Drug Spray Determination of Spray pattern and Analyser(ADSA) Plume geometry for MDI and Nasal Innova system ,USA, spray. SPRAY VIEW® -Image Therm, Determination of Spray pattern and Proveris Scientific,USA. Plume geometry for MDI and Nasal spray Spraytec-Malvern, UK. Droplet size distribution by laser diffraction for MDI and Nasal spray39
  40. 40. Brief Summary of sophisticated Instrument. Instrument/Make Application Glass Expansion chamber- Determination of Small droplet size Westech Scientific Instruments-UK/Copley for Nasal spray. Scientific ,UK Delivered Dose Uniformity Apparatus.(DUSA)- Determination of Uniformity of Westech Scientific Instruments-UK/Copley Delivery Scientific ,UK Glass Twin Impinger.- Determination of Emitted dose Copley Scientific ,UK./Westtech Delivery Instrument. New High Capacity Pump Model HCP5. Common Utilities for Testing. Westech Scientific Instruments-UK/Copley Scientific ,UK. Copley Inhaler Testing Data Analysis Software. To calculate MMAD and GSD. (CITDAS –V-3.00)40
  41. 41. Regulatory bodies.  ANVISA (Brazil) : Pharmaceutical Equivalence and Bioequivalence of Nasal Spray and Aerosol Drug.  EMEA (Europe) -Nasal spray-inhalation-suspension 2006.  Health Canada (Canadian guidelines)-Nasal spray-inhalation November 2003.  CDER (US): Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products - Chemistry, Manufacturing, and Controls Documentation.  CDER (US): Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation.  US Pharmacopeia :601-Aerosole, Nasal sprays, Metered Dose Inhalers and Dry powder inhalers.41
  42. 42. 42
  43. 43. Thank You!43

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