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Implants in Drug Delivery

Infusion Devices
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Implantable drug delivery system
Drug delivery into the blood stream
Drug delivery to the specific site
Molecules of interest:
Insulin, steroids, chemotherapeutics,
antibiotics, analgesics, total parenteral
nutrition, heparin
Critical questions on implants
Erodibility
Irritation
Carcinogenicity
dose dumping
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Examples of devices
Birth control occlusion devices
Dental implants
Breast implant
Focal epilepsy treatment
Heart valve repair
Biosensors
Drug infusion tubes
Intravitreal drug delivery devices
Pain management
Prostate cancer treatment
Spinal repair devices
Stents (coronary, peripheral, GI)
Vascular grafts
Implants in drug delivery
Polymeric Implants
Norplant
Capronor
Jaddelle
Pumps
Alzet
Duros
Alzamer
Implants for delivery of chemotherapeutic agents
Recent advances in implants and related devices
Future prospects
Polymeric Implants (mainly for contraceptive
delivery)

Biodegradable implants
Nonbiodegradable implants
Silicone
Ethyl Vinyl acetate
PLGA/ PGA
Polymers used in medicine
Introduced for a chronic period
Cardiovascular surgery, orthopedics, plastic surgery
Stability of materials used
Presence is transient
Sterilization challenges
Biological properties of Polymers
Chemical composition, ingredients, fabrication
methodologies
Blood incompatibility, clotting, thrombosis
Affect plasma protein, enzyme, clotting factor (platelet,
erythrocytes, leukocytes)
Carcinogenesis induced by chemical and/or physical
mechanism
Injury or sensitization to blood elements leading to
hemolysis and aggregation of leukocytes
Adverse drug responses
Alzamer depot
Alzamer depot
ALZAMER depot platform deliver biopharmaceutical agents and small molecule compounds
for periods of days to a month. While traditional depot therapeutics are comprised of
microspheres, ALZAMER technology offers a nonaqueous polymer solution for the
stabilization of macromolecules and a unique state-of-the-art delivery profile.
Depot injections offer the benefit of sustained delivery of biologically active macromolecules
and small molecule compounds.
ALZAMER depot technology is designed to deliver these agents for periods of days to a
month.
Drawbacks of traditional biodegradable polymer delivery platforms include side effects
associated with high initial drug release on implantation (drug burst), poor drug stability and
complex processing requirements. Through the use of a nonaqueous polymer solution,
ALZAMER technology overcomes these problems by decreasing exposure of the drug to
water until it is released into the body.
Other depot injections, which use microspheres, are typically porous in nature and can lose
up to 40 percent of drug upon injection, creating high initial blood levels. ALZAMER depot
technology is designed to sustain drug delivery over an extended period with a low initial
drug burst. ALZAMER technology does not form a porous matrix upon injection, enabling
dose-sparing and long-term administration. This is accomplished through control of the
internal depot morphology and constant drug dissolution rates.
Alzamer depot
WHAT IT DOES
ALZAMER depot is designed for sustained delivery of small molecules and
biopharmaceuticals for periods of weeks to months. The ALZAMER depot
injection technology can deliver therapeutics both locally and systemically
and is composed of stabilized drug particles in a PLGA polymer solution.
Low Drug Burst: The ALZAMER proprietary formulation provides an
alternative to the high burst and complex manufacturing processes often
associated with other depots.
Maintained Protein Stability: ALZAMER formulations isolate the protein
in a non-aqueous polymer solution to prevent premature exposure
to water, which maintains better drug stability and helps minimize burst
while controlling release over long periods of time.
Low Cost Processing: Preloaded syringes and standard manufacturing
equipment, solvents and polymers may reduce processing costs.
Alzamer depot
Levonorgestrel-PLA
implant
25
PLA:PEG4000 10:2, 40mg LNG
PLA:PEG4000 10:1, 40mg LNG
Daily LNG released (mg)

20

15

10

0
0 6 13 20 28 38 46 52 59 65 71 80 88 97
Time (days)
Naltrexone-PLA implant
50

40
% Released

30

20

10

0
0 50 100 150 200
Time (days)
Contraceptive biodegradable
implants
A programmed rate of release of steroids
Mechanism of steroid release
Erosion, diffusion, polymer degradation
Polymers: poly lactide-co-glycolide, poly
caprolactone
Steroids: norethisterone, levonorgestrel
Mode of action
High blood level: central inhibition of ovulation
Low level: alterations in cervical mucus, sperm
migration, ovum transport and implantation
Capronor
Design
Hollow capsules of poly caprolactone containing
steroid in ethyl oleate (suspension vehicle)
Capsule ends are heat-sealed
Reservoir-type device
Degradable polymer (18 - 24 months)
Carbon dioxide and water
Subcutaneous injection in ischial area
Steroid
Progestin-only (LNG)
Duration of use
1 year
Release rate
Diffusion
Nonbiodegradable implants
Subdermal implantation of silastic capsules or rods
Effectiveness not depend on patient compliance
Longer duration of action
Termination of action by removing the implant
Possibility of implant migrating
Norplant
Medical-grade silastic capsule 34 mm long containing
levonorgestrel
6 capsules subdermally (5 mm incision)
Used for 5 years
Norplant
FDA approved
Design
Reservoir consisting of 6 capsules
containing crystalline
levonorgestrel in Silastic
membrane
Steroid
Low dose progestin-only
Duration of use
5 years
70 g/day first few months,
30 g/day thereafter
0.25 ng/mL therapeutic dose www.populationcouncil.org
(Norplant 20x min dose) 07.01.03
Release rate
Diffusion controlled
Jadelle
Design
two flexible cylindrical implants (2.5 mm in
diameter and 43 mm in length)
consisting of a dimethylsiloxane/
methylvinylsiloxane copolymer core enclosed in
thin-walled silicone tubing
Subcutaneous injection in ischial area
Steroid
Progestin-only (LNG)
Duration of use
2 year
Release rate
Diffusion
Implanon
FDA approved
Design
Single rod system of poly ethylene vinyl acetate
Core is drug-loaded matrix surrounded by rate
limiting membrane
Steroid
3-keto desogestrel (more potent than LNG)
Duration of use
3 years
Release rate
Diffusion controlled
Comparison
Blood serum levels of Depo-Provera and

Norplant compared to OCs



Gliadel
GLIADEL Wafer: polyanhydrid membranes (sebacic
acid) containing carmustine (r=2 cm) (192 mg:7.7 mg)
The only FDA-approved chemotherapeutic implant for use
during neurosurgical resection.
Designed to deliver carmustine directly into the surgical
cavity created when a brain tumor is resected.
Carmustine alkylates DNA and RNA and crosslinks DNA.
Since 1997, over 20,000 procedures have been
performed with GLIADEL in more than 15 countries
including both academic and community medical centers.
Recurrent Glioblastoma Multiforme 1

Phase 3 randomized, double-blind, multicenter, study of the safety and efficacy of GLIADEL Wafer vs placebo in surgery
involving 222 patients with recurrent malignant glioma who had failed initial surgery and radiation therapy. Chemotherapy was
withheld at least 4 weeks (6 weeks for nitosoureas) prior to and 2 weeks after surgery.
Zoladex
Goserelin Acetate
3.6 mg drug
Ploy D, L lactic acid and glycolic acid 13-14 mg; acetic acid
28 day; 3 months 10 mg
Prostrate cancer
Subcutaneosly
Upper abdominal wall
White colored 1.5 mm cylinder
Comparison of Controlled Release System Designs

Polymer Non-degradable Non-degradable Degradable Degradable

Design Reservoir Matrix Reservoir Matrix

Release
Removal
Rupture
Low Mw
High Mw
Duration 5 years 2 years 1-2 years < 1 year

Examples Norplant Jadelle CapronorTM Microspheres


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Pumps (mainly as insulin delivery devices)
Peristaltic pumps
Fluorocarbon propellants
Osmotic pumps
Miniosmotic pumps
systemic drug delivery
local drug delivery
patterned drug delivery
Positive displacement pumps
Controlled release micropump (CRM)
Other devices
Implantable pump
External control of the drug delivery
Driving force : pressure difference by osmosis action
or by direct mechanical actuation not concentration
difference
Artificial pancreas : electromechanical devices for
control of hyperglycemia in insulin-dependent
diabetes
Characteristics of ideal pump
Deliver prescribed rate for extended periods
Reliability, chemical, physical and biological
stability
Compatible with drug
Noninflammatory, nonantigenic, noncarcinogenic,
nonthrombogenic, overdose protection
Convenient to use by patients and health
professionals
Long reservoir and battery life, easy
programmability, implantable under local
anesthesia
Simple means to monitor the status and
Peristaltic pumps
Solenoid-driven peristaltic pump by Sandia Lab.
Portable pump (rotary or stepper motor)
Delivery of 2.1 ml , 30 psi
0.7mm thick type 304 stainless steel casting
Coated with silastic for biocompatibility
Programmable drug administration device (DAD)
by Medtronic
Refillable reservoir, electronic control module, integral
battery, peristaltic driven pump
Venous access port
Percutaneous insertion of syringe-mounted
hypodermic needle through the devices self sealing
septum
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Fig.1 Cross section view of DAD
Fluorocarbon propellant
Constant-rate pump (Infusaid) by Blackshear et al.
Inner chamber : drug solution
Outer chamber : fluorocarbon liquid
Fluorocarbon vaporize and compress the inner chamber
Drug solution : through fine-bore Teflon capillary tubing
(flow regulator) and through an intravascularly located
silicone delivery catheter
Deliver insulin or heparin at a constant flow rates in the 1
to 5 ml/d range
Absence of external power
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Osmotic pumps
Alza osmotic minipump (Alzet)
Flexible impermeable diaphragm
surrounded by a sealed layer containing
an osmotic agent (within a cellulose
ester semipermeable membrane)
Polyethylene catheter is inserted into
the innermost chamber for delivery
Fig. 2. Schematic representation of a generic
osmotic pump
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Duros
The DUROS implant is a miniature cylinder made from a titanium alloy, which protects and
stabilizes the drug inside, using ALZA's proprietary formulation technology. Water enters into one
end of the cylinder through a semipermeable membrane; the drug is delivered from a port at the
other end of the cylinder at a controlled rate appropriate to the specific therapeutic agent.
Duros
WHAT IT DOES
DUROS implant technology is designed for the long-term
delivery of potent small molecules, peptides, proteins and
macrocolecules. Powered by osmosis, the technology
incorporates a miniature titanium cylinder and can provide
continuous drug delivery for up to one year. Viadur
(leuprolide acetate implant), the first marketed product to
incorporate DUROS, is indicated for the palliative treatment
of advanced prostate cancer.
Chronic Condition Delivery: Chronic conditions often
require long-term treatment and multi-day dosing regimens.
DUROS can provide precise delivery with a single
application of up to one year.
Improved Patient Compliance: Success in treatment chronic
conditions is highly dependent on patient compliance.
DUROS, which can be applied and removed in an outpatient
setting, helps promote compliance.
Enhanced Drug Stability: A common concern with long-term
drug delivery is how the body's environment will affect protein
stability. The design and non-aqueous formulation of
DUROS enhances drug stability until release.
Duros
Miniosmotic pumps for systemic drug
delivery
Administer bleomycin for 1 week to
tumor-bearing mice
1. Twice-daily injection
2. An injection on the first and third days
3. A continuous infusion by osmotic pump
Efficacy : tumor size
greater reduction by infusion
Toxicity : hydroxyproline content of the lung
Less pulmonary fibrosis by infusion regimen
Miniosmotic pumps for local drug
delivery
Catheter attached to the exit port of an implantable
osmotic pump to perfuse a discrete location distant
from the site of implantation
Spatial distribution of drug in brain tissue by
microperfusion
Polar drug
14C-dopamine HCl, 3H-sodium methotrexate
Concentrated in brain tissue
Lipid soluble drug : 14C-antipyrine
Escaped across BBB and removed by the circulation
Other devices
Implantable pump for the delivery of
insulin
Electrolytic pump
Pressure of gases evolved at the electrodes
Electroosmosis
To drive water across a cation-exchange
membrane to pressurize a drug reservoir
Delivery of chemotherapeutic agents using
implants

Programmable drug administration device


(DAD)
Chronotherapy : administer at different times
during the circadian cycle
Application of DAD
Terminal cancer pain management
Intractable spasticity management
Cancer chemotherapy
DAD for effective relief of intractable cancer
pain using morphine sulfate delivered
intrathecally
DAD in cancer chemotherapy
Chronotherapeutic : affect the drug toxicity,
side effect and therapeutic results
Time-modified administration of floxuridine
Low level administration in the early morning
A stepwise dosage increase from late morning into
early afternoon
Peak delivery rates from late afternoon into early
evening
A decreased dosage in the final intervals
Insulin pump
Semipermeable membrane
1. Immobilized glucose oxidase
2. Crosslinked hydrophobic polybasic hydrogel
Bioerodible implants
Polylactides, caprolactone polymers or copolymers
Biological signal
Chemical transducer and feedback
Detection of glucose and pH as well as ionic change
detection
Temperature, pressure or mechanical transduced
changes (ex: blood pressure, blood flow, gut motility)
Electrical activity (electrocardiogram and
electroencephalogram)
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