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Implantable Infusion Pumps: Insights For Your Next Animal Dosing Study

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A webinar for scientists interested in the use of implantable pumps as an alternative to repetitive injections when administering compounds to laboratory animals.

The administration of compounds and dosing methodologies are important considerations when planning experiments using laboratory animals. Injections are often used for animal dosing, but repeated injections over prolonged periods may be inadequate for some compounds (i.e. those with short half-lives) and can lead to great variations in serum concentrations. They are also stressful to the animal and inconvenient for the researcher. Implantable infusion pumps are useful drug delivery tools for preclinical research and drug development. They offer a reliable and convenient alternative to injections and other repetitive dosing methods. They allow greater control and accuracy in drug delivery, thus reducing dosing errors, ensuring stable dose levels and minimizing adverse effects. ALZET® Osmotic Pumps have been used in preclinical research for nearly four decades to successfully deliver a wide range of experimental agents. iPRECIO® programmable pumps have been developed more recently to facilitate highly demanding dosing requirements.

In this exclusive webinar sponsored by DURECT Corporation, Mr. José Gadea describes the features, benefits and applications of implantable pumps. Discussion focuses on clarifying the most common misconceptions circulating within the research community about implantable infusion pumps. This information is intended to help researchers make more informed decisions when choosing the most appropriate dosing method for their study.

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Implantable Infusion Pumps: Insights For Your Next Animal Dosing Study

  1. 1. Implantable Infusion Pumps: Insights For Your Next Animal Dosing Study A webinar for scientists interested in the use of implantable pumps as an alternative to repetitive injections when administering compounds to laboratory animals. Presenter, José Gadea, clarifies misconceptions surrounding the use of implantable pumps and presents facts supporting their value in preclinical research.
  2. 2. InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services. JOIN FOR FREE AT WWW.INSIDESCIENTIFIC.COM
  3. 3. Implantable Infusion Pumps: Insights For Your Next Animal Dosing Study José R. Gadea Sr. Product Marketing Manager, DURECT Corporation
  4. 4. Thank you to our event sponsor Toll Free: 877-922-5938 (U.S. & Canada) Phone: 408-253-8574 Fax: 408-865-1406 E-mail: alzet@durect.com To place orders online from North America, click here For international ordering information, click here
  5. 5. 1. Overview of Laboratory Animal Dosing Options 2. Brief History of Implantable Pumps 3. Features, Benefits and Applications of Implantable Pumps 4. Helpful Tips for Planning Studies 5. Myths About Implantable Pumps 6. Q&A What are we going to cover today?
  6. 6. Laboratory Animal Dosing Options Injections Implantable Pumps Ambulatory Pumps Tethered Infusion Pellets Gavage Food & Water
  7. 7. Laboratory Animal Dosing Options Implantable Pumps Ambulatory Pumps Tethered Infusion Pellets Gavage Food & Water Advantages • Relatively simple • Quick method • Inexpensive Limitations • Inadequate for some drugs (short half-life) • Time consuming (multiple dosing) • Animal stress (handling, pain) • Inconsistent dosing • Negative influence on experimental results
  8. 8. Laboratory Animal Dosing Options Injections Implantable Pumps Ambulatory Pumps Tethered Infusion Pellets Gavage Advantages • Relatively simple • Quick method • Inexpensive Limitations • Inadequate for some drugs (water solubility, palatability) • Inconsistent dosing (according to drinking/feeding pattern) • Negative influence on experimental results
  9. 9. Laboratory Animal Dosing Options Advantages • Perceived as simple • Inexpensive Limitations • Technical difficulty • High level of animal stress (tissue trauma, mortality) • Inconsistent dosing • Negative influence on experimental results Injections Implantable Pumps Ambulatory Pumps Tethered Infusion Pellets Food & Water
  10. 10. Laboratory Animal Dosing Options Advantages • Quick procedure • Readily available for some drugs Limitations • Not available for many drugs • Require customization • Costly • Inconsistent dosing (not continuous) Injections Implantable Pumps Ambulatory Pumps Tethered Infusion Gavage Food & Water
  11. 11. Laboratory Animal Dosing Options Advantages • Dose control • High volumes • Stability and solubility Limitations • Costly equipment • Require maintenance • Potential risk of catheter clotting or disconnection • Increased risk of infection • Animal stress • Restrict animal movement • Prevents social housing Injections Implantable Pumps Ambulatory Pumps Pellets Gavage Food & Water
  12. 12. Laboratory Animal Dosing Options Advantages • Dose control • High volumes • Stability and solubility Limitations • Costly equipment • Require maintenance • Animal stress • Restrict animal movement • Require a jacket • Potential risk of catheter clotting or disconnection • Increased risk of infection Injections Implantable Pumps Tethered Infusion Pellets Gavage Food & Water
  13. 13. Implantable Infusion Pumps Limitations • Surgery required • Formulation as solutions • Learning curve (programming) • Cost depending on alternatives Benefits • Automatic dosing • Dose control • Improved efficacy • Reduced side effects • Animal welfare • Better data
  14. 14. A Brief History • Developed by ALZA Corporation and commercialized in 1977 • DURECT Corp. acquired ALZET line in 2000 (Cupertino, California, USA) • Specialty pharmaceutical with proprietary drug delivery technologies • Manufactures and distributes ALZET® pumps worldwide • Authorized distributor of iPRECIO® pumps in North America since Oct. 2012 • Developed by Primetech Corporation (Tokyo, Japan) • Manufacturer and distributor of medical and analytical science products • Manufacturer of iPRECIO® Programmable Pumps • iPRECIO SMP-101L: March 2007 • iPRECIO SMP-200: July 2009 • iPRECIO SMP-300: April 2014
  15. 15. ALZET Osmotic Pumps • Miniature infusion devices for continuous dosing of unrestrained lab animals • Chronic delivery at controlled rates • Continuous delivery of a wide range of agents • Short half-life compounds • Nearly 17,000 publications
  16. 16. • Small size: mice & young rats • Reliable: 16,500+ pubs (40 yrs) • Fully implantable – no stress • Convenient alternative to injections • Chronic delivery • Simple & easy to use • Cost-effective • Continuous administration ALZET Pumps: Key Features and Benefits
  17. 17. Benefits of Continuous Administration • Automatic and undisturbed dosing • Stable drug levels • Improved therapeutic efficacy • Reduced side effects • Drug savings
  18. 18. ALZET Osmotic Pump: Principle of Operation
  19. 19. Outer semi-permeable membrane Osmotic layer Impermeable drug reservoir
  20. 20. Outer semi-permeable membrane Osmotic layer Impermeable drug reservoir
  21. 21. ALZET Pumps: Easy to Use
  22. 22. ALZET Pump Selection • Animal size • Route of administration • Duration of infusion • Drug solubility • Choose the smallest pump possible taking into account agent solubility • Solubility issues: choose a pump with larger reservoir volume or faster flow rate ALZET Tip: Use the online interactive pump selector tool
  23. 23. ALZET Pump: Agent Selection Broad agent compatibility: • Peptides, hormones, nanoparticles, steroids, radioisotopes, chemotherapeutic agents, growth factors, antibiotics, and pharmaceuticals Molecular size: • Delivery is independent of the compound’s molecular weight, physical conformation, or chemical properties MYTH - ALZET pumps can’t deliver large size compounds FACT - Molecules of any molecular weight can be delivered
  24. 24. ALZET Pump: Agent Requirements Stability: • Compound must be stable at 37o C for study duration Solubility: • Compound must remain in solution for duration of the study • Precipitate can block the exit port of the pump, catheter or cannula tip
  25. 25. ALZET Pump: Vehicle Selection Optimum vehicle: • Compound solubility • Tissue compatibility • Pump compatibility • pH for compound stability • Sterility
  26. 26. • Acids and bases • Artificial CSF • Cremophor EL (< 25%) • Culture media • Cyclodextrins • Dextrose (<5%) • Dimethyl formamide (<25%) • DMSO (<50%) • DMSO/PEG (50/50%) • DMSO/Ethanol (50/15%) • Glycerol • Methyl Pyrrolidone (<12.5%) • Phosphate buffer • PEG 300 or 400 • Propylene glycol • Ringer’s solution • Saline (0.9%) • Serum • Solutol (<30%) • Triacetin (<5%) • Tween 80 (<2%) • Water ALZET Pump: Vehicle Selection
  27. 27. • Acids and bases • Artificial CSF • Cremophor EL (< 25%) • Culture media • Cyclodextrins • Dextrose (<5%) • Dimethyl formamide (<25%) • DMSO (<50%) • DMSO/PEG (50/50%) • DMSO/Ethanol (50/15%) • Glycerol • Methyl Pyrrolidone (<12.5%) • Phosphate buffer • PEG 300 or 400 • Propylene glycol • Ringer’s solution • Saline (0.9%) • Serum • Solutol (<30%) • Triacetin (<5%) • Tween 80 (<2%) • Water ALZET Pump: Vehicle Selection
  28. 28. ALZET Pump: Solubility Challenges • Acids and bases • Artificial CSF • Cremophor EL (< 25%) • Culture media • Cyclodextrins • Dextrose (<5%) • Dimethyl formamide (<25%) • DMSO (<50%) • DMSO/PEG (50/50%) • DMSO/Ethanol (50/15%) • Glycerol • Methyl Pyrrolidone (<12.5%) • Phosphate buffer • PEG 300 or 400 • Propylene glycol • Ringer’s solution • Saline (0.9%) • Serum • Solutol (<30%) • Triacetin (<5%) • Tween 80 (<2%) • Water
  29. 29. Vehicle Combination Concentration 1 DMSO PEG 50% 50% 2 DMSO PEG Ethanol 50% 35% 15% 3 PEG 300 Cremophor ELP Glycofurol Ethanol Propylene Glycol 25% 25% 25% 15% 10% (3) Gullapalli et al. Drug Delivery, 2012; 19(5): 239–246 ALZET Pump: Solubility Challenges
  30. 30. ALZET Pump: Viscous Solutions MYTH - ALZET pumps can’t deliver viscous solutions FACT - ALZET pumps are capable of delivering homogeneous solutions with a viscosity of less than 100,000 cP or mPa s.
  31. 31. ALZET Pump: Drug Formulation MYTH – Using nominal specifications for dose calculations FACT – Use actual pumping rate and fill volume listed on the specifications sheet for each lot of pumps when making dose calculations Model 2002 (Lot #10196-08) Nominal Actual Release Rate 0.5 ml/hr 0.53 ml/hr Fill Volume 200 ml 216 ml Duration 14 days 16.1 days
  32. 32. ALZET Pump: Filling • Use aseptic technique • Weigh pump and flow moderator before filling • Use the filling tube provided • Fill the pumps with the curved end down • Fill with the flow moderator removed • A small amount of backpressure is normal Expert tip: If you experience too much pressure, angle the needle slightly to allow air to escape, or insert and remove the flow moderator a few times to widen the opening.
  33. 33. ALZET Pump: Priming Priming is essential when: • Immediate pumping is required • A catheter is used with the pump • A viscous solution is delivered • The drug solution may have acute toxic effects Priming ensures that the pumps deliver at their specified pumping rate at time of implantation. To prime, place the filled ALZET pumps into an aqueous solution at 37 C for a specified time (3-60 hours depending on pump model).
  34. 34. ALZET Pump: Routes of Administration Subcutaneous Intraperitoneal
  35. 35. ALZET Pump: SC Implantation Procedure The usual site for SC implantation in rats and mice is on the back, slightly posterior to the scapulae. Procedure: • Anesthetize and shave the animal • Make a mid-scapular incision suitable for the pump • Create a subcutaneous pocket by blunt dissection using a hemostat • Insert the pump into the pocket, delivery portal first • Close the incision with wound clips MYTH - ALZET pump implantation is too difficult FACT – The SC implantation procedure can be performed in under a minute
  36. 36. Minimum Size for Implantation of ALZET Pumps ALZET Models 1003D, 1007D, 1002, 1004 2001D, 2001, 2002, 2004, 2006 2ML1, 2ML2, 2ML4 MICE Subcutaneous 10 g 20 g N/A Intraperitoneal 20 g N/A N/A RATS Subcutaneous 10 g 20 g 150 g Intraperitoneal 20 g 150 g 300 g Note: Estimates based on experience with Sprague Dawley rats and Swiss Webster mice.
  37. 37. ALZET Pump: Implantation MYTH - ALZET pumps restrict animal movement FACT – Rodents have very loose skin on the back. ALZET pumps are used in mice and rats that are used in various behavioral tests (I.e., open field, rotarod, Morris water task, swim test, etc.)
  38. 38. Intravenous Brain cannulation Targeted Delivery • Blood vessels • Central Nervous System – Cerebral ventricles, brain tissue, Spinal Cord • Peripheral nerves • Various organs and tissues – Tumor, bone, eye, ear, muscle, wound ALZET Pump: Routes of Administration
  39. 39. ALZET Pump: Catheter Applications 1. To delay drug delivery • Pump filled with drug • Catheter filled with vehicle 2. To reduce drug waste • Pump filled with vehicle • Catheter filled with drug 3. To deliver incompatible solvents
  40. 40. 1. Measurement of plasma levels 2. Measurement of residual volume 3. In vitro release rate testing ALZET Pump: Verifying Delivery MYTH – Weighing pumps at the end of the study to confirm delivery FACT – The weight of a partially empty pump or cutting a pump is not a reliable means of verifying pump performance
  41. 41. iPRECIO Programmable Pump 24.8 mm 15.0 mm H: 7.2 mm Weight: 3.3 g 19.2 mm H: 9.7 mm Weight: 7.9 g 38.7 mm SMP-300 SMP-200
  42. 42. iPRECIO Pump: Key Features • Implantable • Refillable • Programmable
  43. 43. • Fully implantable in mice, rats and larger animals • SMP-200: >230 grams • SMP-300: >22 grams • Unrestrained dosing • Group housing • Reduced animal stress iPRECIO Pump: Implantable
  44. 44. • In vivo refilling via percutaneous access • Eliminate multiple surgeries • Increasing dose studies • Multiple drugs • Poor drug stability/solubility iPRECIO Pump: Refillable MYTH – iPRECIO pumps can be reused FACT – iPRECIO pumps are refillable, but not reusable
  45. 45. • Full control and flexibility over dosing protocols • Set your own infusion protocol: start/stop time, flow rate, duration, etc • Download infusion protocol to the pump via communication device • SMP-200: IR communication • SMP-300: wireless communication iPRECIO Pump: Programmable
  46. 46. iPRECIO Pump: Programmable • Constant/variable dosing • Delayed delivery • Dose escalation • Chronic bolus
  47. 47. • Accurate and reliable “Rotary Finger” mechanism (Pulse micro-motor) • Microprocessor and associated circuitry for pump control (CPU, memory) • Power source (battery) • Fluidics (Reservoir, catheter, filling port) • Pump programming and communication interface (software and base station) iPRECIO Pump: Key Components
  48. 48. iPRECIO SMP-200 Bottom ViewTop View
  49. 49. Antenna: 50 mm titanium wire (0.1 mm OD) inside PU tubing (0.4mm OD) Top ViewBottom View iPRECIO SMP-300
  50. 50. iPRECIO Pump: Mechanism of Operation Patented "Rotary Finger" mechanism • A micro-motor slowly revolves in a clockwise direction turning the cam with its four projections. • In each quarter rotation, a single cam projection sequentially pushes up each of the seven finger pins. • This continuous cycle compresses the liquid filled tube, creating a peristaltic-like movement of the fluid. • As the solution moves through the tube, it is expelled from the pump reservoir into the test subject. Rotary Finger Mechanism • Accuracy: +/- 5% • Each pump calibrated at factory
  51. 51. iPRECIO® Management System IMS-200 • Data communication Device UCD-200 • USB cable • iPRECIO® Software Installation CD • iPRECIO® Users Manual • (2) AAA cell batteries iPRECIO® Management System iPRECIO® Management System IMS-300 • Data communication Device UCD 300 • LAN cable • iPRECIO® Software Installation CD • iPRECIO® Users Manual
  52. 52. iPRECIO Programming (SMP-200) 1. Enter study details • Name/ID • Date • User • Animal: species/strain/age • Route • Duration • Compound name and concentration • Groups / # of animals
  53. 53. iPRECIO Programming (SMP-200) 2. Enter group details • Est. min and max animal weight • Drug concentration • Select infusion mode/group • Instant vs. delayed • Select flow rate mode/group • Constant vs. variable
  54. 54. iPRECIO Programming (SMP-200) 3. Enter animal details • Individual animals per group • Animal ID • Weight • Sex • Set infusion mode • Start date/time • End date/time • Detect pump
  55. 55. iPRECIO Programming (SMP-200) 4. Pump information • Individual pump programming • Step 1-10 – Dose – Duration – Start/end time – Flow rate • Program pump • Print report
  56. 56. iPRECIO Programming (SMP-300) Monitor function: Allows the user to follow the infusion profile in detail. Refill dates/exchange dates and alarms are also managed and displayed here.
  57. 57. iPRECIO Pump: Key Specs Comparison SMP-300 SMP-200 Size [L] x [W] x [H] (Weight/volume) 24.8 x 15.0 x 7.2 mm (3.3 g / 2.15 cc) 38.7 x 19.2 x 9.7mm (7.9 g / 7.20 cc) Communication Wireless Infrared Animal Species Mice or larger Rats or larger Animal Size Suggested: 25 g (Min. 22 g) Suggested: 230 g (Min. 160 g) Reservoir Volume 130 μL 900 μL Flow Rate (Setting Resolution) 0.1 – 10.0 μL/hr (0.1 μL/hr) 0.1 – 30.0 μL/hr (0.1 μL/hr) Duration Up to 47 days Up to 6 months
  58. 58. Battery Life: iPRECIO SMP-200 Flow Rate Continuous Infusion Total Infusion Volume(Time) (hours) 1.0 μL/hr 6 months 4,328 hr 4.3 mL 8.5 μL/hr 1 month 669 hr 5.6 mL 19.0 μL/hr 1.8 weeks 307 hr 5.8 mL 30.0 μL/hr 1 week 196 hr 5.8 mL
  59. 59. Comm. Interval Every Minute Every 2 hrs Every 6 hrs Every 24 hrs None Flow Rate (ul/hr) Time (days) Time (days) Time (days) Time (days) Time (days) 0.1 16 37 42 45 47 1.0 14 28 31 32 33 5.0 10 15 15 16 16 10.0 7 9 9 9 9.0 Battery Life: iPRECIO SMP-300
  60. 60. iPRECIO Pump: Vehicle Selection Not Compatible Vehicles • Acids (< pH 1.8) • Bases (> pH 14) • Benzyl-alcohol (>10%) • Oils (Corn, Mineral, Sesame) • DMSO (100%) • DMSO: ethanol (50:50) • DMSO:PEG 400/300/200 (50:50) • Ethyl Oleate • Solutol® (>30%) Short Term Use Vehicles • PEG 300/400 (100%) < 45 days • Cremophor EL (25%) < 30 days • PEG 400/PG/Water (30:50:20) < 30 days Viscous solutions • Viscosity up to 20 cP has been evaluated • Higher viscosity not recommended • Difficult to aspirate through 27G needle
  61. 61. iPRECIO Pump: Agents Angiotensin II Ang II antagonists Cardiovascular drugs Corticotropin-rel. hormone Dobutamin Epinephrine Estradiol GPR54 Agonist Nicotine Olanzapine Pentobarbital Reproductive hormones Serotonin (5-HT) Valsartan Verapamil Vitamin B12
  62. 62. iPRECIO Pump: Filling
  63. 63. iPRECIO Applications: SC & IP Infusion Subcutaneous Intraperitoneal
  64. 64. iPRECIO Applications: IV Infusion
  65. 65. iPRECIO Applications: Brain Infusion Brain Cannula break-off Post Dental cement Anchor screw Outlet Tubing SMP-200 SMP-300
  66. 66. Complete Dosing Solution Species Mice & Larger Mice & Larger Dosing Continuous Continuous, Variable, Bolus Durations 1-42 days <45 days (SMP-300); <6 months (SMP-200) Refillable No Yes Infusion Volumes Small Small & large Compound Requirement Soluble & Stable Low solubility and stability Accuracy > 10% > 5% Infusion Rates Fixed Programmable Cost Cost-effective High budget studies
  67. 67. Contact for Help and Resources Toll Free: 877-922-5938 (U.S. & Canada) Phone: 408-253-8574 Fax: 408-865-1406 E-mail: alzet@durect.com To place orders online from North America, click here For international ordering information, click here
  68. 68. Thank You! José R. Gadea Sr. Product Marketing Manager, DURECT Corporation Contact Information: jose.gadea@durect.com Phone: 800-692-2990 For additional information on the solutions presented in this webinar please visit www.alzet.com

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