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.

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.

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3. Implantable Infusion Pumps:
Insights For Your Next Animal Dosing Study
José R. Gadea Sr. Product Marketing Manager,
DURECT Corporation

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. 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. Laboratory Animal Dosing Options
Injections
Implantable
Pumps
Ambulatory
Pumps
Tethered
Infusion
Pellets
Gavage
Food &
Water

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. 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. 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. 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. 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. 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. 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. 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. 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. • 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. Benefits of Continuous Administration
• Automatic and undisturbed dosing
• Stable drug levels
• Improved therapeutic efficacy
• Reduced side effects
• Drug savings

18. ALZET Osmotic Pump: Principle of Operation

19. Outer semi-permeable
membrane
Osmotic layer
Impermeable drug reservoir

20. Outer semi-permeable
membrane
Osmotic layer
Impermeable drug reservoir

22. ALZET Pumps: Easy to Use

23. 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

24. 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

25. 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

26. ALZET Pump: Vehicle Selection
Optimum vehicle:
• Compound solubility
• Tissue compatibility
• Pump compatibility
• pH for compound stability
• Sterility

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. • 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

29. 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

30. 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

31. 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.

32. 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

33. 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.

34. 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).

35. ALZET Pump: Routes of Administration
Subcutaneous Intraperitoneal

36. 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

37. 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.

38. 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.)

39. 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

40. 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

41. 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

42. 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

43. iPRECIO Pump: Key Features
• Implantable
• Refillable
• Programmable

44. • 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

45. • 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

46. • 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

47. iPRECIO Pump: Programmable
• Constant/variable dosing
• Delayed delivery
• Dose escalation
• Chronic bolus

48. • 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

49. iPRECIO SMP-200
Bottom ViewTop View

50. Antenna: 50 mm titanium wire (0.1 mm OD) inside PU tubing (0.4mm OD)
Top ViewBottom View
iPRECIO SMP-300

51. 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

52. 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

53. 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

54. 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

55. 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

56. iPRECIO Programming (SMP-200)
4. Pump information
• Individual pump programming
• Step 1-10
– Dose
– Duration
– Start/end time
– Flow rate
• Program pump
• Print report

57. 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.

58. 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

59. 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

60. 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

61. 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

62. 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

63. iPRECIO Pump: Filling

64. iPRECIO Applications: SC & IP Infusion
Subcutaneous Intraperitoneal

65. iPRECIO Applications: IV Infusion

66. iPRECIO Applications: Brain Infusion
Brain Cannula
break-off Post
Dental
cement
Anchor
screw
Outlet
Tubing
SMP-200 SMP-300

67. 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

68. 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

69. 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