Implantable drug delivery

Implantable drug delivery

Intended
Learning Objectives

At the end of this
lecture student will be able to:

• Enlist drawbacks of orally administered medications

• Enumerate potential advantages of IDDS

• Outline ideal requirements of IDDS

• Classify IDDS

• Give examples for Non-biodegradable IDDS and their design

• Enlist drawbacks of non-biodegradable implants

• Explain the nature of carriers/polymers used in their
fabrication

• Enlist methods for fabrication

• Discuss the design and application of some biodegradable
IDDS

• Summarize their disadvantages

• Explain the working principle in propellent driven pumps

• Explain the working principle in electromechanical pumps

• Summarize the advantages of MEMS and IMD’s

• Illustrate mechanism of drug release from implants

• Outline current applications of IDDS

• Infer current challenges in development of IDDS

• Enlist the types of dynamic implantable pumps

• Explain the driving force for drug release in osmotic
implants

• Discuss design and working of some osmotic pumps

History

• Concept of Implantable delivery – Dates back to 1938

• Deansby and Parkes – Compressed pellets of crystalline
estrone to study their effect upon male chickens

• 1960’s – Folkman and Long – drug release rates controlled
by a polymeric membrane Iinvestigated the use of silicone rubber (Silastic) for
long-term drug delivery at a systemic level

Potential
problems with oral drug delivery

•   Bioavailability

•   Stability

•   Toxicity

•   Duration of
release

•   Irregular
absorption

Potential
Advantages of implantable drug delivery system

Ideal locations for implantation of
drug-depot devices

➢
Subcutaneous tissue or intramuscular tissue

• Due to high fat content that facilitates slow drug
absorption, minimal innervation, good hemoperfusion, and a lower possibility of
localized inflammation (low reactivity to the insertion of foreign materials)

➢ Cardiac or carotid arteries as sites for drug-eluting stents (DES),
delivering therapy to intravascular locations

➢
Others – Intravaginal, intravascular, intraocular, Intrathecal, intracranial,
and peritoneal

Purpose of
IDDS

Systemic therapeutic
effects

• Implants are typically administered SC, intramuscularly,
or intravenously, whereby the incorporated drug is delivered from the implant
and absorbed into the blood circulation

Local effects

• Placed into specific body sites, where the drug acts
locally, with relatively negligible absorption into the systemic circulation

Implants are typically designed to release the incorporated
drug in a controlled manner, allowing the adjustment of release rates over
extended periods of time, ranging from several days to years

Ideal
Requirements

• Should be designed to substantially reduce the need for
frequent drug administration over the prescribed treatment duration

• Should be environmentally stable, biocompatible, sterile

• Should be readily implantable and retrievable by medical personnel
to initiate or terminate therapy

• Additionally, it must enable rate-controlled drug release
at an optimal dose

• Should be easy to manufacture and provide cost-effective
therapy over the treatment duration

Classification
of IDDS

Passive Systems

• Passive systems can be further classified into nondegradable
and degradable implants

• These typically have no moving parts or mechanisms

Active Systems

• Active systems employ some energy-dependent method for
providing a positive driving force to modulate drug release

• These energy sources may be as diverse as osmotic pressure
gradients or electromechanical drives

PASSIVE
IMPLANTS

• Passive implants tend to be relatively simple, homogenous
and singular devices,

• Typically comprising the simple packaging of drugs in a biocompatible
material or matrix

• They do not contain any moving parts, and depend on a
passive, diffusion-mediated phenomenon to modulate drug release

• Delivery kinetics are partially tunable by the choice of
drug, its concentration, overall implant morphology, matrix material and
surface properties

Nondegradable
implantable drug delivery systems

• Membrane-enclosed reservoirs and matrix-controlled systems

• Matrix materials used in all these systems are typically
polymers

• Commonly used polymers include elastomers such as
silicones and urethanes, acrylates and their copolymers, and copolymers
vinylidenefluoride and polyethylene vinyl acetate (PEVA)

Matrix Type

• The drug is typically dispersed homogeneously throughout
the matrix material

Reservoir Type

• Characterized by a compact drug core, surrounded by a
permeable nondegradable membrane, the permeability and thickness of which
controls the diffusion of the drug into the body

Nondegradable
reservoir implant

Norplant.

• This IDDS was developed and trademarked by the Population Council
in 1980, introduced worldwide in 1983

• It was approved by the US FDA in December 1990, following which
marketing in the United States was initiated in February 1991

• This contraceptive system consists of six thin, flexible
silicone capsules (silastic tubing), each loaded with 36 mg of the hormone
levonorgestrel

• When implanted SC, typically on the inside upper arm of female
users it is capable of offering contraceptive protection for up to 5 years

Implanon

• FDA-approved, launched on the international market in
1998, eventually entering the United States in 2006

• It is a single-rod implant (length 4 cm, width 2 mm) and
consists of a PEVA core (reservoir) that encapsulates 68 mg of etonogestrel and
releases the drug over 3 years

• The rate of drug release is controlled by a PEVA membrane
covering the rod

• Protection from pregnancy can be extended beyond the
initial 3 years upon removal and immediate replacement with a fresh implant

• Designed for easier subcutaneous insertion and removal
than

Drug eluting Stents
(DES)

• Revolutionized the treatment of vascular disease

• Specifically, in the case of coronary artery disease
(CAD), DES may reduce restenosis typically seen in bare-metal stents by

• 60% – 75%

• Frequently deployed for opening blockages and maintaining
patency in a coronary artery

• A DES is normally a three-component system, comprising a
scaffold (or stent) for ensuring vascular luminal patency, a matrix or coating
(polymer) to control drug release, and a drug to inhibit neointimal restenosis

• Release of drugs from these coatings is typically
diffusion-controlled

Drug Eluting Stents (DES)

Vitrasert

•   Example of an
implant delivering antiviral drug

•   Developed and
commercialized for the treatment of cytomegalovirus (CMV) retinitis

• The system releases ganciclovir, following an intravitreal
implantation of a compressed tablet of the drug

• The tablet is coated with polyvinyl alcohol (PVA), then
partially over-coated with PEVA, and finally affixed to a PVA suture Stub

Biodegradable
Implants

• To overcome the drawbacks of non-biodegradable implants

• Advantage of biodegradable systems is that the
biocompatible polymers used for fabricating these delivery systems are
eventually broken down into safe metabolites and absorbed or excreted by the
body

• Based on polymers such as

– Poly (lactic acid) (PLA)

– Poly (lactic-co-glycolic acid) (PLGA)

– Poly (caprolactone) (PCL)

– or their block copolymer variants with other polymers

• The polymers used in fabrication of these implants contain
labile bonds that are prone to degradation by hydrolysis or enzymes, such as ester,
amide, and anhydride bonds

• Complete degradation of the implant post-drug release

• This makes makes surgical removal of the implant after the
conclusion of therapy unnecessary

• This reduces potential complications with explantation

• Increases patient acceptance and compliance

Methods for
simple implant fabrication

Examples of
drugs incorporated into implants

Incorporated into PLGA and PLA polymers

• Antibiotics

• Antiviral drugs

• Anticancer drugs

• Analgesics

• Steroids

Implants of
protein and peptide drugs

• Protein and peptide drugs – highly susceptible to acidic
and enzymatic degradation

• Lipid implants are more useful

• Good tissue biocompatibility and ability to protect the
drug

• Other acid stable drugs can also be incorporated into
lipid implants

• Lipid implants can easily be produced by compression or by
the twin-screw extrusion process

Commercial
Biodegradable Implants

• Gliadel wafer for the treatment of brain tumors

• Zoladex for treatment of advanced prostate cancer and
advanced breast cancer

• Profact or
Suprefact Depot for treatment of hormone – responsive cancers, such as
prostate cancer or breast cancer and in assisted reproduction

Gliadel

• Earliest examples of a biodegradable IDDS-Approved by the FDA
in 1996

• It consists of biodegradable polyanhydride disks (1.45 cm
in diameter and 1.0 mm thick)

• Designed to deliver the chemotherapeutic drug, bis-
chloroethylnitrosourea (BCNU) or carmustine, directly into the cavity created
after surgical resection of the tumor (high-grade malignant glioma)

• The biodegradable polyanhydride copolymer in a 20:80 molar
ratio of poly [bis (p-carboxyphenoxy)propane:sebacic acid]

Zoladex

• Biodegradable implant containing goserelin acetate, which is
a decapeptide analogue of Lutinizing Hormone-Releasing Hormone (LH-RH)

• It uses PLGA or PLA as a carrier, in which the drug is
dispersed in the polymer matrix using hot-melt extrusion method

• For commercial use, the implant is distributed in the form
of a prefilled syringe

• The drug is continuously released over a period of 1 or 3 months

Profact
Depot or Suprefact Depot

• Contain buserelin acetate (gonadotropin releasing hormone
agonist) and carrier in 75:25 molar ratio

• PLGA is used as a drug carrier

• The implant is designed for 2- and 3-month drug release

• The duration of action depends upon the relative ratio of
drug and PLGA in the implants

Disadvantages
of Biodegradable IDDS

• Higher complexity, development cost, regulatory requirements,
and the lack of availability of polymers with the exact physical properties
needed, including mechanical strength and tunable degradation kinetics

• In general, the development of biodegradable systems is a
more complicated task than formulating nondegradable systems

• When fabricating new biodegradable systems, variables to be
taken into consideration include the in vivo degradation kinetics of the
polymer, which must ideally remain constant to maintain sustained release of
the drug. Unfortunately, these can be highly variable, depending upon patient
age and disease state

• In comparison to metal implants, biodegradable implants
may also be more expensive, due to additional costs associated with specialized
materials and regulatory approval

Dynamic
Implants

• Dynamic implant systems utilize a positive driving force
to enable and control drug release

• Able to modulate drug doses and delivery rates much more
precisely than passive systems

• Higher cost, both in terms of complexity and actual device
price

Implantable
Pump Systems

Driving force in Implantable pumps

1.   Osmosis

2.   Propellant-driven
fluids

3.   Electromechanical
drives

➢ Generate pressure gradients
and enable controlled drug release

Osmotic
Pumps

• The first osmotic pump was devised by Australian
pharmacologists, Rose and Nelson, who developed an implantable osmotic pump in
1955, named the Rose and Nelson osmotic pump

• Disadvantage –
Water to be loaded prior to use

• Higuchi and Leeper made a few modifications to this design
and introduced it to the pharmaceutical world in the year 1973

• In 1975, a design known as the elementary osmotic pump
came into existence and was patented by the Alza Corporation in 1976

Elementary
Osmotic Pump – OROS

• Drug reservoir surrounded by a semipermeable membrane, which
allows a steady inflow of surrounding fluids into the reservoir through osmosis

• A steady efflux of the drug then ensues via the drug
portal, an opening in the membrane, as a result of the hydrostatic pressure
built on the drug reservoir.

• Nearly constant or zero-order drug release is maintained
until complete depletion of the drug packaged in the reservoir

DUROS
leuprolide implant – VIADUR

• Approved as the first implantable osmotic pump for humans in
the United States in the year 2000

• DUROS devices can be designed to deliver therapy for time
ranging from several weeks to as long as 1 year

• Can potentially deliver a broad array of therapeutic
molecules. It is particularly suitable for potent peptides and proteins that require
chronic dosing

• Specifically, the Viadur system has been marketed for the
palliative treatment of prostate cancer via the delivery of the GnRH analog
leuprolide

• Cylindrically shaped device consists of a reservoir made
of an  inert  titanium 
alloy,  capped  at 
one  end  by 
a  water- permeable membrane

• At  the  other 
end,  it  is 
capped  by  a 
diffusion  moderator, through
which drug formulation is released from the drug reservoir.

• The cylinder diameter ranges from 4 to 10 mm and the
length is typically 45 mm, although smaller or larger systems may be designed,
based on requirements of drug loading and the implantation site

• The drug formulation, piston, and osmotic engine are contained
inside the cylinder

• The piston separates the drug formulation from the osmotic
engine and seals the osmotic engine compartment from the drug reservoir

• The diffusion moderator is designed, in conjunction with
the drug formulation, to prevent body fluid from entering the drug reservoir
through the orifice

• The specially designed, semipermeable polyurethane polymer
membrane enables control of delivery rate, and is chosen for specific water
permeability and antifouling properties during in vivo operation

• Drug may be loaded into the reservoir in either dissolved
or suspended formulations in suitable and approved solvents

ALZET Pump

• This device operates by osmotic displacement and is able
to deliver drug controlled rates over delivery windows between 24 h and 6 weeks

• The drug to be delivered is filled into a core reservoir,
which is isolated from a chamber, containing an osmotic salt, by a
semipermeable membrane

• Due to the presence of a high concentration of salt in a
chamber surrounding the reservoir, water enters the pump through the
semipermeable layer

• The entry of water increases the volume in the salt
chamber, causing compression of the flexible reservoir and delivery of the drug
solution into the host via the exit port

Advantages
and Limitation of Osmotic Pumps

Advantages

• Mitigates the “initial burst effect” that is inherent in
other systems, particularly in degradable matrices

• This level of control over a sustained period can be
particularly important in the delivery of critical medication for chronic pain
management

• The advantages justify the additional cost, complexity,
and need for implantable systems

• Limitation –
Limited volume of drug can be delivered

Propellant
Infusion Pumps

• Utilizes propellant gas instead of an osmotic agent to generate
a constant positive pressure for zero-order release

• The use of a compressible medium, such as gas, allows for
a larger volume of drug to be stored and released

• Example: Infusaid

Infusaid –
Fully implantable fixed-rate pump

• Consists of two chambers separated by a flexible titanium
bellows

➢ One chamber acts as a drug
reservoir

➢ The other is the sealed power
supply containing the two-phase fluorinated hydrocarbon   charging fluid (Propellent chamber)

• The vapor pressure of the charging fluid exerts a constant
pressure on the bellows

• This forces drug from the drug reservoir through an outlet
filter and flow restrictor into the sideport and finally into a catheter for
delivery to a chosen regional or systemic site

• The overall package is approximately 9 cm in diameter by 3
cm in height and has been utilized for insulin delivery, anticoagulant therapy,
and cancer chemotherapy

• The sideport, accessible through a silicone septum, is
used for bolus injections via a transcutaneous special INFUSAID needle

• The sideport feature permits direct bolus injections to
the target site while completely bypassing the pump mechanism

• The centrally located silicone septum allows for filling
and emptying the drug reservoir also via a transcutaneous special INFUSAID
needle

Electromechanical
Systems

• Osmotic and propellent driven systems – Suitable for ONLY small
volumes of medication

What should be an ideal pump for long term treatment?

• Larger implant

• Ability to replenish the drug solution from time to time

• Ability to treat chronic diseases requiring daily infusion
of medication

• Electrically powered mechanical pumps, with moving parts and
advanced control systems

Example: Synchromed pump

• Developed by Medtronic Inc.

• Peristaltic pump implant, featuring external
micro-electronic control of the delivery rate

• Pain management using intrathecal delivery of opioids

• Treatment of severe spasticity using baclofen

Synchromed
Pump

• The pump consists of

➢ An outer titanium shell that
encases the pump mechanism and controller

➢ Reservoir holding the drug
solution, and a battery

• It can be conveniently refilled with a needle and syringe
via a silicone rubber septum on the system

• The implant dimensions are 8.8 cm in diameter and 2.5 cm thickness

• The system is typically implanted in the abdominal cavity

Micro Electromechanical Systems (MEMS)

• This technology enables the manufacture of small devices
using microfabrication techniques

• MEMS technology has been used to construct micro-
reservoirs, micropumps, nano-porous membranes, nanoparticles, valves, sensors,
micro-catheters, and other structures using biocompatible materials appropriate
for drug administration

Implantable
Medical Devices (IMDs)

• Electronic devices implanted within the body to treat a
medical condition, monitor the state, or improve the functioning of a body part

Examples

• Pacemakers and defibrillators to monitor and treat cardiac
conditions

• Neuro-stimulators for deep-brain stimulation in cases such
as epilepsy or Parkinson’s disease

IMD’s for
Drug Delivery

An ideal IMD would

✓ protect the drug from the body
until needed

✓ Allow continuous or pulsatile
delivery of both liquid and solid drug formulations

✓ Be controllable by the
physician or patient

•  Drug  is 
sealed  in  reservoirs  that 
release  the  drug 
upon certain electrical stimuli

• The timing and rate of drug release can be controlled and
tailored based on the patient needs

• Continuous or pulsatile delivery can be achieved

• Example: ChipRx

ChipRx

• Implantable, single-reservoir device

• The release mechanism employs polymeric artificial muscles
that surround and control micrometer-sized holes, and that open to release drug

• The polymeric ring expands or contracts in response to an electrical
signal transmitted through a conducting polymer that contacts a swellable
hydrogel

Advances in
IMD’s

• IMD’s with communication and networking functions, usually
known as telemetry

• Medical personnel can access data and re-configure the
implant remotely, i.e., without the patient being physically present in a
medical facility

• Allow healthcare providers to constantly monitor the patient’s
condition and to

Drug
Release from Implants

Non-Biodegradable
Implants

• Passive diffusion

Biodegradable
Implants

• Diffusion, degradation or a combination of both

Current
Therapeutic Applications

Chronic diseases

• Cardiovascular disease

• Cancer

• Diabetes

• Ocular therapy

• Pain Management

Infectious diseases

Neurological and CNS
related

Women health

Current
Challenges in the Development of IDDS

• Biocompatibility-related Issues

• Patient Compliance

• Regulatory Aspects

• Cost-effectiveness

Summary

Potential problems with oral drug delivery

• Bioavailability

• Stability

• Toxicity

• Duration of release

• Irregular absorption

Potential
Advantages of implantable drug delivery system

Ideal Requirements of
IDDS

• Should be designed to substantially reduce the need for
frequent drug administration over the prescribed treatment duration

• Should be environmentally stable, biocompatible, sterile

• Should be readily implantable and retrievable by medical
personnel to initiate or terminate therapy

• Additionally, it must enable rate-controlled drug release
at an optimal dose

• Should be easy to manufacture and provide cost-effective
therapy over the treatment duration

Classification of
IDDS

Passive Systems

• Passive systems can be further classified into
nondegradable and degradable implants

• These typically have no moving parts or mechanisms

Active Systems

• Active systems employ some energy-dependent method for
providing a positive driving force to modulate drug release

• These energy sources may be as diverse as osmotic pressure
gradients or electromechanical drives

• Drawbacks of
non-biodegradable implants – Needs surgical removal after therapy and
cosmetic related issues

• Nature of carriers/polymers
used in their fabrication – Should contain that are prone to degradation by
hydrolysis or enzymes, such as ester, amide, and anhydride bonds

• Methods for
fabrication – Injectable, melt extrusion, solvent evaporation, compression
molding

• Design and
application of some biodegradable IDDS – Gliadel, Zoladex, Profact

• Disadvantages –
Cost, regulatory concerns, degradability kinetics

• Dynamic Implants –
Utilise certain driving force for drug release

• Types –
Osmotic, propellent driven, electromechanical driven

• Osmotic pumps –
elementary osmotic pump (OROS), Higuchi and Leeper, DUROS, ALZET

Propellant Infusion
Pumps

• Utilizes propellant gas instead of an osmotic agent to
generate a constant positive pressure for zero-order release

• The use of a compressible medium, such as gas, allows for
a larger volume of drug to be stored and released

• Example: Infusaid

Electromechanical Systems

• Osmotic and propellent driven systems – Suitable for ONLY
small volumes of medication

What should be an ideal pump for long term treatment?

• Larger implant

• Ability to replenish the drug solution from time to time

• Ability to treat chronic diseases requiring daily infusion
of medication

Micro
Electromechanical Systems (MEMS)

• This technology enables the manufacture of small devices
using microfabrication techniques

• MEMS technology has been used to construct
microreservoirs, micropumps, nano-porous membranes, nanoparticles, valves,
sensors, micro-catheters, and other structures using biocompatible materials
appropriate for drug administration

Implantable Medical
Devices (IMDs)

• Electronic devices implanted within the body to treat a
medical condition, monitor the state, or improve the functioning of a body part

Examples

• Pacemakers and defibrillators to monitor and treat cardiac
conditions

• Neuro-stimulators for deep-brain stimulation in cases such
as epilepsy or Parkinson’s disease

Drug Release from
Implants

Non-Biodegradable Implants -Passive diffusion

Biodegradable Implants – Diffusion, degradation or a
combination of both

Current Therapeutic
Applications

1. Chronic
diseases

• Cardiovascular disease

• Cancer

• Diabetes

• Ocular therapy

• Pain Management

2. Infectious
diseases

3. Neurological
and CNS related

4. Women health

Current Challenges in
the Development of IDDS

• Biocompatibility-related Issues

• Patient Compliance

• Regulatory Aspects

• Cost-effectiveness

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