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

Design Feature	Summary of Potential Advantages
Localized delivery	Drug(s) are released in immediate vicinity of implant. Action may be diffusion, limited to the specific location of implantation
Improved patient compliance	Patient does not need to comply with repeated and timely intake of medication throughout the implantation period. Compliance is limited to one-time implantation (and potential removal in the case of nonbiodegradable implants)
Minimized systemic side effects	Controlled release for extended periods of time and localized dosing possible with at site of action; adverse effects away from site of action are minimized; peaks and valleys in plasma drug concentration from repeated intermediate release dosing are avoided
Lower dose	Localized implantation of site specific drugs can avoid first pass hepatic effects, thereby reducing dose required to ensure systemic bioavailability
Improved drug stability	Protection of drug undergoing rapid degradation in the gastrointestinal and hepatobiliary system
Suitability over direct administration	Hospital stay or continuous monitoring by healthcare staff may not be required for chronic illnesses
Facile termination of drug delivery	If allergic or other adverse reaction to drug is experienced, discontinuation of therapy by implant removal is possible

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

Sl. No.	Technology Involved
1	Injectable formulations that subsequently form depot-like implants in situ at the location in tissue Example: poly(caprolactone) (PCL)
2	Thermoforming by melt extrusion
3	Solvent evaporation
4	Compression molding from powder or pellet form

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

Design Feature	Summary of Potential Advantages
Localized delivery	Drug(s) are released in immediate vicinity of implant. Action may be diffusion, limited to the specific location of implantation
Improved patient compliance	Patient does not need to comply with repeated and timely intake of medication throughout the implantation period. Compliance is limited to one-time implantation (and potential removal in the case of nonbiodegradable implants)
Minimized systemic side effects	Controlled release for extended periods of time and localized dosing possible with at site of action; adverse effects away from site of action are minimized; peaks and valleys in plasma drug concentration from repeated intermediate release dosing are avoided
Lower dose	Localized implantation of site specific drugs can avoid first pass hepatic effects, thereby reducing dose required to ensure systemic bioavailability
Improved drug stability	Protection of drug undergoing rapid degradation in the gastrointestinal and hepatobiliary system
Suitability over direct administration	Hospital stay or continuous monitoring by healthcare staff may not be required for chronic illnesses
Facile termination of drug delivery	If allergic or other adverse reaction to drug is experienced, discontinuation of therapy by implant removal is possible

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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