IMPLANTABLE AND INSERTABLE DRUG DELIVERY DEVICES

Drug delivery systems that you have to implant in patient body or insertables that can be inserted
in eyes, vagina etc

Advantages of implantable drug system

- They avoid limitations of oral drug delivery which are:

- Drug bioavailability — drug is not soluble enough to be absorbed by the gastrointestinal
system (GITS) or there is extensive first pass hepatic metabolism.
- Drug stability — drug is not stable in the GITS.
- Drug toxicity — Efficacious concentrations at the target site require systemic concentrations
that are toxic or produce unacceptable side effects.
- Duration of release—in order to be effective, the drug must be able to be delivered in a
controlled and sustained manner for more than 24 h.
- Drug half life is too short — drug loses its potency too quickly to be effective.
- Implantable avoid all these issues

Advantages of IDDS

- Patient compliance improved — patient does not need to think about taking medication
throughout the dosing interval of the IDDS. Less dosing required.
- Fewer side effects — controlled release and usually much lower dose with improved control
at site of action for extended periods of time; adverse effects away from site of action are
minimized; peaks and valleys in plasma drug concentration from repeated immediate release
dosing are avoided.
- Lower dose — because we can control drug release. if action is site specific, drug has to
overcome fewer biological barriers, such as first pass hepatic effects, before coming to the
active receptor.
- Drug stability improved — protection of drug being too rapidly metabolized.
- Suitability over IV administration — hospital stay may not be required for chronic
- illnesses.
- Drug allergy—if allergic or other adverse reaction to drug is experienced, immediate removal
of implant is possible, this is not the case with IV

Limitations of IDDS

- Some IDDS require minor surgery for implant and explant — this lowers patient acceptance
and raises the desire for a less invasive alternative.
- Cost/benefit ratio — the IDDS may not be cost effective enough for
reimbursement/insurance coverage. Patient and doctor acceptance would be lowered.
- Training — implanting (and potential explanting) may require specialized training.
- IDDS are more complex than oral dosage forms — FDA will take longer to approve it
- Pain and discomfort — if an IDDS has this effect, patient acceptance is lowered.
Non-degradable and biodegradable implantable drug delivery systems

Non-degradable:

- Will remain intact in body and not broken down

- Membrane enclosed reservoir and matrix controlled systems (monolithic)
- Silicones, acrylates and their copolymers, ethylene vinyl acetate copolymers (PEVA),
vinylidene, fluoride copolymers, and urethanes.
- Contraceptives like Norplant®, Implanon®

Biodegradable:

- Doesn’t have to be removed, will be eliminated, is broken down

- Polyesters based upon lactic and glycolic acids derivatives
- Polyanhydrides, poly(orthoesters), and poly(phosphoesters)
- Complexity
- development cost
- regulatory body is more harsh as drug is broken down so can be toxic
- availability of polymers with the exact physical properties needed

Implantables and birth control

- Developed and trademarked by the Population Council in 1980, introduced in certain
countries worldwide in 1983,
- Approved by the USFDA in December 1990, and was marketed in the US starting February
1991
- So far, approved in over 60 countries.

Norplant®

- is a 5-year contraceptive system containing levonorgestrel (LNG) hormone

- encapsulated into 6 thin, flexible silicone capsules (Silastic tubing) that are implanted
subcutaneously
- after 5 years, you have to remove it and you have to remove 6 of the capsules which caused
problems for pts so it was removed from the market in 2002

Implanon®

- they came up with Implanon

- international market in 1998 and the US in 2006
- Single rod
- Used as contraceptive
- IDDS is 4 cm long and 2 mm wide
- PEVA core (reservoir) containing 68 mg of etonogestrel. The rod is covered with a PEVA rate
controlling membrane
- release drug to prevent ovulation for a 3-year period
- Easier subcutaneous insertion and removal than Norplant®
- Nesterone™ and Capronor™ are underdevelopment
 -

Implantables and ocular diseases

Vitrasert®

- Treatment of cytomegalovirus (CMV) retinitis ganciclovir and is implanted intravitreally

- Over-coated with polyvinyl alcohol
- release the drug over 5–8 months
- polymer capsule

Ozurdex®

- Developed by Allergan, Inc. and was approved by FDA in 2009.

- intravitreal implant containing 0.7mg of dexamethasone
- Made of PLGA (biodegradable polymer)
- Used for treatment of macular edema due to branch retinal vein occlusion (BRVO) or central
retinal vein occlusion (CRVO)
- Ozurdex®is administered
- by a specially designed injector with a 22-gauge needle into the vitreous cavity.
Implantables and cancer delivery
Gliadel® wafer

- This system was approved by the FDA in 1996

- dime-sized biodegradable polyanhydride disks
- (polifeprosan 20 and consists of poly[bis(p-carboxyphenoxy)propane:sebacic acid] in a 20:80
molar ratio)
- delivers the chemotherapeutic drug BCNU (carmustine) directly into the surgical cavity after
brain tumour to make sure all the cancer cells are gone

Zoladex®

- AstraZeneca
- Used for palliative treatment of prostrate and breast cancer
- Goserelin acetate is a potent synthetic peptide analog of luteinizing hormone–releasing
hormone (LHRH)
- Available in 2 doses: 3.6 mg of goserelin for 1 month or 10.8mg of goserelin for 3 months
- Poly(D,L-lactic-co-glycolic acid) (PLGA)
- Combination of diffusion-and erosion-controlled mechanisms

Implantable pump systems

Advantages:

- Avoid the barrier of the GI tract – pass first pass metabolism

- Convenience over injections, repeated needle and syringe
- Patient compliance is assured.
- Release rates can be faster than diffusion-limited systems.
- Electronically based systems offer the potential for remote adjustment of the delivery rate or
coupling of an implantable sensor to the pump to create feedback controlled drug delivery

Osmotic pumps
- Osmosis is the movement of water through a semi-permeable membrane in response to high
solute (usually ionic) concentration. Moves from high to low conc

-
- Water movement from one area to another will be influenced by the osmotic and
hydrostatic pressure
- where dV / dt is the volume flux of water across the membrane
- Δπ and ΔP are, respectively, the osmotic and hydrostatic pressure differences
- across the semipermeable membrane
- Lp is the membrane mechanical permeability coefficient
- σ is the reflection coefficient (usually ~1),
- A is the membrane area and l Is the thickness of the membrane
DUROS®

- We use sodium chloride salts to exert osmotic pressure so water can move in and system can
start releasing the drug
- Implanted subcutaneously (under the skin)
- one month up to one year
- Delivery of GnRH analog leuprolide for the palliative treatment of prostate cancer (Viadur®
system)
- A miniature syringe and consists of:
- An outer cylindrical reservoir (titanium alloy or a biocompatible rigid polymer)
- A rate-controlling membrane (semipermeable polyurethane polymer)
- osmotic agents (tablets containing primarily NaCl combined with other pharmaceutical
excipients)
- elastomeric piston
- the drug formulation in the drug reservoir (DMSO)
- Diffusion moderator/orifice
- Semi permeable membrane which will allow water from the surrounding tissue to go to the
Duras pump:
- What happens in the pump: high osmotic pressure caused by sodium chloride causes water
to flow in from semipermeable membrane. This causes piston to move towards the drug
reservoir chamber which will push the drug towards the orifice and be released from this site

Infusion pumps

Medtronic Paradigm® Revel™ Insulin Pump

- cannula portion of the total delivery system is implanted under the skin
- pump portion is worn outside the body
- subcutaneous infusions of very minute amounts of insulin with automatic changes in delivery
rate or dose at specified intervals.
- This gives flexible of dosing. They can inject insulin dose when needed

-
Infusaid® pump

- which is a fully implantable fixed rate pump that contains

- chamber for a fluorocarbon propellant
- fluorocarbon propellant will release pressure which will release the drug at a fixed rate
over time
- drug formulation chamber by a metal bellows in a disk-shaped titanium housing
- vapour pressure of the propellant creates a constant pressure source at fixed temperature

Insertables
- Drug delivery systems can be placed or “inserted” into a number of body sites.
- A number of sites or routes have been utilized for therapy including ocular, transurethral,
vaginal and intrauterine.
- Local therapy can be achieved (e.g. delivery of drugs into the eye via ocular inserts for eye
irritation etc )
- Systemic therapy can be achieved (e.g. via release of the drug and transport across a
permeable biological surface into the bloodstream like contraception).

The Ocusert®

- For treatment of glaucoma.

- elliptical shaped planar inserted into the cul-de-sac of the eye.
- The system consists of an inner drug reservoir containing pilocarpine and a polyethylene
vinyl acetate(PEVA) outer rate-control membrane.
- The system delivers drug at constant order for 1 week

-
Progestasert® (ALZA Corporation)

- Intrauterine device used for contraception

- Hormone cylinder
- T shaped plastic frame – helps to fit in the uterus
- rate-controlling cylindrical PEVA reservoir containing progesterone dispersed in silicone oil.
- The arms of the “T” were also constructed of PEVA

Mirena® intrauterine system

- which delivers levonorgestrel. The system consists of a T-shaped polyethylene frame. The
vertical part of the “T” has a reservoir of a mixture of the drug and polydimethylsiloxane.
- The reservoir is surrounded by a silicone membrane and has a duration of up to 5 years

Vaginal rings

- Used as contraceptive delivery system.

- NuvaRing® is constructed of PEVA and delivers two drugs: ethinylestradiol and etonogestrel
up to 21 days.
- The ring is inserted by the user before day 5 of the cycle and removed after 21 days.