Approaches to the development of Implantable drug delivery system

(Parenteral drug delivery system)

Prepared by: Paresh K Bharodiya

09PCT07

Guided by: Dr. Ajay B. Solanki

Department of pharmaceuticsA.R College & G.H Patel Institute of Pharmacy

12/05/2010

List of contents Effect of physicochemical properties on parenteral absorption Introduction

Approaches to design implantable drug delivery systems(a) Controlled drug delivery by diffusion process Polymer membrane permeation- controlled drug delivery Matrix diffusion-controlled drug delivery Microreservior partition-controlled drug delivery system Membrane matrix hybrid-type drug delivery system

(b) Controlled drug delivery by activation process Osmotic pressure Vapor pressure Magnetically Hydration Hydrolysis

(c) Controlled drug delivery by feed back regulated mechanism Bioerosion Bioresponce

REFRENCES

Effect of Physicochemical Properties on Parenteral Absorption

Drug particle in suspensionDissolution

Drug solutes in solution

Partitioning

Drug solution in tissue fluid

Absorption Systematic circulation

Target tissue Elimination

Rate of dissolution of solid in formulation vehicleParticle size and crystal habitpH of the formulationpKa of drugLipophillicity of the drugTissue fluid/vehicle partition coefficientSolubility of drug at biological fluid at injection sitePresence of other ingredients in the formulation and

their interaction with the drug molecule

Implantable drug delivery systeman introduction

Implantable drug delivery systems are placed completely under the skin — usually in a convenient but inconspicuous location. The patient is aware of only a small bump under the skin.

designed to transmit drugs and fluids into the bloodstream without the repeated insertion of needles.

well suited to the drug delivery requirements of insulin, steroids, chemotherapeutics, antibiotics, analgesics, total parenteral nutrition, and heparin

There is little chance of infection or interference with daily activities Because the device is completely subcutaneous, with no opening in the skin

In 1861 Lafarge pioneered the concept of IDDS for long term continuous administration of crystalline hormone in the form of solid steroid pellet

But the release profile was not constant and can not be readily controlled in terms of precision of the release rate and duration of action

While it is possible to surgically implant and remove drug-concentrative devices or polymeric matrices, the requirement for such intervention could have a significant negative impact on the acceptability

Two approaches to this problem seem possible1. Use of implanted electrically driven pumps2. Use of erodible implants

Approaches to the development of Implantable drug delivery system

Number of approaches have been developed to achive controlled administration of drugs via implantation

(1) Controlled drug delivery by diffusion processDiffusion of the drug out of the device or solvent into the

polymer ultimately contributes to the drug-release processRelease of the drug from the device is preprogrammed at a

specific rate profileThis is accomplished by a system design which controls

molecular diffusion of drug in or and/or across barrier medium surrounding the system

This systems can be further sub classified in to number of classes

(A) Polymer membrane permeation- controlled drug delivery using

1. Non porous membrane2. Micro porous membrane3. Semi permeable membrane

Here the drug formulation is totally or partially encapsulated within a drug reservoir compartment and the drug release surface is covered by a rate limiting polymeric membrane having a specific permeability for drug

drug reservoir

polymeric membrane

Drug contained in a formulation

• The dug reservoir can exist in to a solid , suspension or in a solution form and polymeric membrane fabricated in the form of non porous{homogenous or heterogeneous}, micro porous or semipermiable membrane.

• Encapsulation of drug formulation in to the reservoir compartment can be done by

1. Injection molding2. Spray coating 3. microencapsulation Different shapes of the systems like sphere , cylinder or

sheet can be fabricated• An example of this type of implantable drug delivery

system is A NORPLANT SUBDERMAL IMPLANT and OCUSERT SYSTEM

(b) Polymer Matrix diffusion-controlled drug delivery

In this type of preplanned drug delivery system the drug reservoir is prepared by homogenous dispersion of drug particles in a rate controlling polymer matrix fabricated from either a lipophillic or a hydrophilic polymer

The drug dispersion in a polymer matrix is done by 1. Blending finely divided drug particles with a liquid polymer or

a viscous base followed by cross linking of the polymer chain2. Mixing the drug with a polymer at an elevated temperature 3. Dissolving drug and polymer in a common solvent followe by

solvent evaporation at elevated temperature or under vacuumThe resultant drug polymer dispersion is then molded or

extruded to form a drug delivery devices of various shapesExample is a nitro-dur TDDS

Drug release

Drug release

Drug depleted zone Gel layer

Drug reservoir{dispersion}

Lipophillic polymer Non swollable matrix

Hydrophilic polymerSwollable matrix

(C) Microreservior partition-controlled drug delivery system

In this type drug reservoir is fabricated by micro dispersion of aqueous suspension of a drug using a high energy dispersion technique in to a biocompatible polymer such as silicone elastomer to form a homogenous dispersion of many discrete , unreachable microscopic drug reservoir

Depending on the physicochemical properties of the drug and the desired rate of drug release , the device can be further coated with polymer to modify mechanism and rate of release

example is the transdermal nitro disc system

Polymer matrix

Microscopic Drug reservoir

{liquid compartment}

Coating membrane

Polymer -solution interface

(d) Membrane matrix hybrid-type drug delivery system

This device is a hybrid of Polymer Matrix diffusion-controlled drug delivery and Polymer membrane permeation- controlled drug delivery system aim is to take advantage of controlled release kinetic offered by Polymer membrane permeation- controlled drug delivery system and to avoid risk of dose dumping from reservoir compartment of this type of drug delivery system

Drug reservoir is formed by dispersion of drug in to a polymer matrix which is further coated by a semi permeable polymeric membrane

Example is a norplant II sub dermal system

(II) Controlled drug delivery by activation process

In this type release of the drug is activated by some physical , chemical, or biological process and/or by the energy supplied externally and the rate of release is than regulated by the processes applied or input of energy

Based on the processed applied these activation modulated drug delivery system can be classified in to

1. Osmotic pressure activated2. Vapor pressure activated3. Magnetically activated4. Hydrolytic-activated5. Hydration activated

Osmotic pressure activated drug delivery system In this type of controlled drug delivery system

the release of the drug takes place due to osmotic pressure

Drug reservoir which can be either a solid or a suspension is contained in a semipermiable housing

The release is activated through a specially formed orifice and rate of release is modulated by controlling the osmotic gradient

Thus release rate is dependent on water permeability of membrane, solubility of osmogen, effective surface area of semipermiable housing as well as osmotic gradient

Representatative example of this type of implantable controlled release drug delivery system is alzet osmotic pump

Alzet osmotic pump

Vapor pressure activated implantable drug delivery system

The drug reservoir which ids a solution formulation is contained in to an infusate chamber

By freely movable bellow the chamber is a pumping system physically separated from the vapors pressure chamber which contains vaporizable fluids such as a fluorocarbon

The fluorocarbon vaporizes at body temperature creating a vapor pressure that pushes bellow to move upward and forces the drug solution to get delivered

Magnetically activated implantable drug delivery system

• A magnetic wave triggered mechanism is incorporated in to drug delivery device and drug can be triggered to be released at varying rate depending on the magnitude and duration of the electromagnetic energy applied

Magnetic ring

Coated polymer

Magnet inside polymer matrix

Hydration activated drug delivery system

This system depends on the hydration induced swelling process by tissue fluid at implantable site to activate drug release

In this system drug reservoir is dispersed in to swollable polymer matrix fabricated from hydrophilic polymer that become swollen upon hydration

Drug is released from microscopic water filled pore channels in to the polymer matrix and

Release rate of drug is controlled by swelling of the polymer matrix

Hydrolysis activated drug delivery system

Release of drug is activated by hydrolysis of a bioerodable polymer by the cell fluid at the implantation site

Biodegradable polymer like1. Co(lactic-glycolic)polymer 2. Poly(orthoester)3. Poly(anhydride) are used in fabrication of this

type of implantable drug delivery system This system is made by dispersing loading dose of a

drug with a biodegradable polymer , which is then molded in to pellet or a bead shaped implant

Example is a LHRH{goserelin} releasing biodegradable sub dermal implant

(c) Controlled drug delivery by feed back regulated mechanism

using this group of controlled drug delivery system the release of a drug is activated by some biochemical molecule in the body and its concentration at the implantable site via feedback mechanism

And the rate of controlled release of drug is regulated by the concentration of biochemical substance detected by a sensor in the feedback mechanism

Bioerosion regulated drug delivery system This system consist of a drug dispersed in to a

biodegradable polymer matrix like poly vinyl methyl ether and is coated with immobilized urease in a neutral pH.in the presence of urea urease at the surface of drug delivery system metabolize urea to form ammonia causing increase in pH at which polymer degrades leading to drug release

U

U

U

U U

U

UU

U U UU

U

U

UHydrocortisone

Urea Ammonia

Urease

Alkaline pH

Polymer

Erosion

Hydrocortisone release

Bioresponce activated drug delivery system Drug reservoir is contained in a device enclosed by a

bioresponsive polymer membrane whose permeability is controlled by conc. of a biochemical agent contained where the system is located

Example is a glucose triggered insulin delivery system in which insulin reservoir is capsulated within hydrogel membrane having amineNR2 groups

In alkaline pH NR2 is neutral and membrane is unsellable and impermeable to insulin

As glucose, triggering agent penetrates in to membrane it is oxidized to glucuronic acid by enzyme glucose oxidise contained in a membrane

NR2 groups are protonated and hydro gel membrane becomes swollable and permeable for insulin.

Amt of release is dependant on the concentration of glucose entering in to membrane

REFRENCES

1. NOVEL DRUG DELIVERY SYSTEM, Yie. W Chien, second edition, marcel dekker inc, page 381

2. DRUG DELIVERY SYSTEMS, Vasant V. Ranade Mannfred A. Hollinger Second Edition,