implantable infusion pumps: insights for your next animal dosing study
TRANSCRIPT
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.
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Implantable Infusion Pumps: Insights For Your Next Animal Dosing Study
José R. Gadea Sr. Product Marketing Manager,DURECT Corporation
Thank you to our event sponsor
Toll Free: 877-922-5938 (U.S. & Canada)
Phone: 408-253-8574
Fax: 408-865-1406
E-mail: [email protected]
To place orders online from North America,click here
For international ordering information,click here
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?
Laboratory Animal Dosing Options
Injections
Implantable Pumps
Ambulatory Pumps
Tethered Infusion
Pellets
Gavage
Food & Water
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
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
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
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
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
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
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
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
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
• 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
Benefits of Continuous Administration
• Automatic and undisturbed dosing
• Stable drug levels
• Improved therapeutic efficacy
• Reduced side effects
• Drug savings
ALZET Osmotic Pump: Principle of Operation
Outer semi-permeable membrane
Osmotic layer
Impermeable drug reservoir
Outer semi-permeable membrane
Osmotic layer
Impermeable drug reservoir
ALZET Pumps: Easy to Use
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
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
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
ALZET Pump: Vehicle Selection
Optimum vehicle:
• Compound solubility
• Tissue compatibility
• Pump compatibility
• pH for compound stability
• Sterility
• 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
• 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
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
Vehicle Combination Concentration
1DMSO
PEG50%50%
2DMSO
PEGEthanol
50%35%15%
3
PEG 300Cremophor ELP
GlycofurolEthanol
Propylene Glycol
25%25%25%15%10%
(3) Gullapalli et al. Drug Delivery, 2012; 19(5): 239–246
ALZET Pump: Solubility Challenges
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.
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
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.
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).
ALZET Pump: Routes of Administration
Subcutaneous Intraperitoneal
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
Minimum Size for Implantation of ALZET Pumps
ALZET Models1003D, 1007D, 1002,
10042001D, 2001, 2002,
2004, 20062ML1, 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.
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.)
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
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
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
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
iPRECIO Pump: Key Features
• Implantable
• Refillable
• Programmable
• 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
• 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
• 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
iPRECIO Pump: Programmable
• Constant/variable dosing
• Delayed delivery
• Dose escalation
• Chronic bolus
• 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
iPRECIO SMP-200
Bottom ViewTop View
Antenna: 50 mm titanium wire (0.1 mm OD) inside PU tubing (0.4mm OD)
Top ViewBottom View
iPRECIO SMP-300
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
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
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
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
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
iPRECIO Programming (SMP-200)
4. Pump information• Individual pump programming
• Step 1-10– Dose
– Duration
– Start/end time
– Flow rate
• Program pump
• Print report
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.
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
Battery Life: iPRECIO SMP-200
Flow Rate
Continuous InfusionTotal 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
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
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
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
iPRECIO Pump: Filling
iPRECIO Applications: SC & IP Infusion
Subcutaneous Intraperitoneal
iPRECIO Applications: IV Infusion
iPRECIO Applications: Brain Infusion
Brain Cannula
break-off PostDental
cement
Anchor
screw
Outlet
Tubing
SMP-200 SMP-300
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
Contact for Help and Resources
Toll Free: 877-922-5938 (U.S. & Canada)
Phone: 408-253-8574
Fax: 408-865-1406
E-mail: [email protected]
To place orders online from North America,click here
For international ordering information,click here
Thank You!
José R. Gadea Sr. Product Marketing Manager,DURECT Corporation
Contact Information:
Phone: 800-692-2990
For additional information on the solutions presented in this webinar please visit www.alzet.com