Implantable Infusion Pumps: Insights For Your Next Animal Dosing Study

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

mailto:[email protected]

http://www.alzet.com/ordering/ordering.html

http://www.alzet.com/ordering/

http://www.alzet.com/


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


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


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)



Advantages

• Perceived as simple

• Inexpensive

Limitations

• Technical difficulty

• High level of animal stress (tissue trauma, mortality)

• Inconsistent dosing


Injections

Implantable Pumps

Ambulatory Pumps

Tethered Infusion

Pellets

Food & Water


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


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


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: Solubility Challenges



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


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


3. Enter animal details• Individual animals per group

• Animal ID

• Weight

• Sex

• Set infusion mode

• Start date/time

• End date/time

• Detect pump


4. Pump information• Individual pump programming

• Step 1-10– Dose

– Duration

– Start/end time

– Flow rate

• Program pump

• Print report


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

mailto:[email protected]

http://www.alzet.com/ordering/ordering.html

http://www.alzet.com/ordering/

Thank You!

José R. Gadea Sr. Product Marketing Manager,DURECT Corporation

Contact Information:

[email protected]

Phone: 800-692-2990

For additional information on the solutions presented in this webinar please visit www.alzet.com


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Implantable Infusion Pumps: Insights For Your Next Animal Dosing Study