Transcript Chap. 4 Implants in Drug Delivery

Implants in Drug Delivery
R. Dinarvand, PhD
Prof of Pharmaceutics
Introduction

Implantable drug delivery system



Molecules of interest:


Drug delivery into the blood stream
Drug delivery to the specific site
Insulin, steroids, chemotherapeutics, antibiotics,
analgesics, total parenteral nutrition, heparin
Critical questions on implants





Erodibility
Irritation
Carcinogenicity
dose dumping
duration
Examples of devices













Birth control occlusion devices
Breast implant
Dental implants
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


Biodegradable implants
Nonbiodegradable implants
(mainly for contraceptive delivery)

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 po
lymer 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 mac
romolecules 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), po
or drug stability and complex processing requirements. Through the use of a no
naqueous 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 a
nd can lose up to 40 percent of drug upon injection, creating high initial blood l
evels. ALZAMER® depot technology is designed to sustain drug delivery over an
extended period with a low initial drug burst. ALZAMER® technology does not fo
rm a porous matrix upon injection, enabling dose-sparing and long-term admini
stration. 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 mo
lecules and biopharmaceuticals for periods of weeks to months.
The ALZAMER® depot injection technology can deliver therapeu
tics both locally and systemically and is composed of stabilized
drug particles in a PLGA polymer solution.
Low Drug Burst: The ALZAMER® proprietary formulation provide
s an alternative to the high burst and complex manufacturing pr
ocesses 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 help
s minimize burst while controlling release over long periods of ti
me.
Low Cost Processing: Preloaded syringes and standard manufac
turing equipment, solvents and polymers may reduce processin
g costs.
Alzamer depot
LNG-PLA implant
25
Daily LNG released (mg)
PLA:PEG4000 10:2, 40mg LNG
PLA:PEG4000 10:1, 40mg LNG
20
15
10
5
0
0
6
13 20 28 38 46 52 59 65 71 80 88 97
Time (days)
Naltrexone-PLA implant
50
% Released
40
30
20
10
0
0
50
100
Time (days)
150
200
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
levonorgestr
®
el in Silastic membrane
Steroid
 Low dose progestin-only
Duration of use
 5 years
 70 µg/day first few months,
 30 µg/day thereafter
 0.25 ng/mL therapeutic dose (
Norplant 20x min dose)
Release rate
 Diffusion controlled
www.populationcouncil.org
07.01.03
Jadelle




Design
 two flexible cylindrical implants (2.5 mm in diamete
r and 43 mm in length)
 consisting of a dimethylsiloxane/ methylvinylsiloxa
ne 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 acet
ate
 Core is drug-loaded matrix surrounded by ra
te 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 OC’s
®
Gliadel
• GLIADEL® Wafer: polyanhydrid membranes containing ca
rmustine (r=2 cm)
• The only FDA-approved chemotherapeutic implant for use
during neurosurgical resection.
• Designed to deliver carmustine directly into the surgical c
avity created when a brain tumor is resected.
• Carmustine alkylates DNA and RNA and crosslinks DNA.
• Since 1997, over 20,000 procedures have been performe
d 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.
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
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 performance of
the pump
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 device’s self sealing septum
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
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
Fig. 3. Miniature osmotic pump with flow moderator.
Duros
The DUROS® implant is a miniature cylinder made from a titanium alloy, which protect
s 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 de
livered from a port at the other end of the cylinder at a controlled rate appropriate to t
he 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. P
owered by osmosis, the technology incorporates a miniature titaniu
m cylinder and can provide continuous drug delivery for up to one y
ear. Viadur® (leuprolide acetate implant), the first marketed product
to incorporate DUROS®, is indicated for the palliative treatment of a
dvanced prostate cancer.
 Chronic Condition Delivery: Chronic conditions often require long-ter
m 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 conditio
ns is highly dependent on patient compliance. DUROS®, which can
be applied and removed in an outpatient setting, helps promote com
pliance.
 Enhanced Drug Stability: A common concern with long-term drug del
ivery is how the body's environment will affect protein stability. The
design and non-aqueous formulation of DUROS® enhances drug st
ability until release.

Duros
Miniosmotic pumps for systemic drug delivery

Administer bleomycin for 1 week to tumorbearing mice
1.
2.
3.

Twice-daily injection
An injection on the first and third days
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
14
3
 C-dopamine HCl, H-sodium methotrexate
 Concentrated in brain tissue
14
Lipid soluble drug : C-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


Bioerodible implants


Semipermeable membrane
1.
Immobilized glucose oxidase
2.
Crosslinked hydrophobic polybasic hydrogel
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)