Controlled drug release

OBJECTIVES:

Gradual release

Ability to target an organ

PROBLEM: avoid under and overdosing

The ideal case is a constant

level of drug in body fluid

TRADITIONAL

METHODS

Classical topic of Pharmacokinetics

Two new approaches:

• Microparticle systems: Release from small spherical beads

• Targeting of drug

MICROPARTICLE SYSTEMS:

Release from small spherical beads,

to control the release kinetics

First generation materials borrowed from other fields:

o  Polyurethanes

oPolysiloxanes

oPMMA

oPolyvynilalcohol

oPolyethylene

oPolyivynilpyrrolidone

Second-generation materials chosen for:

CHEMICAL INERTNESS, NO IMPURITY RELEASE, THEIR STRUCTURE, EASE OF PRODUCTION

Poly 2-hydroxymethylmetacrilateoPoly N-vynilpyrrolidoneoPolymethylmetacrilate oPolyvynilalcoholoPolyacrilic AcidoPolyacrilamideoCopolimers polyethilene-vynilacetate.oPolyethilenic glicol

Most recent materials are BIODEGRADABLE POLYMERS:

  Polylactic acid (PLA)

o Polyglicolic acid (PGA)

o Copolimers of PLA and PGA

o Polyanhydrides

o Polyorthoesthers

 

Materials actually used vary in chemical composition and the type of drug they carry

POLYMERIC BEADS

Release Mechanisms

oDIFFUSION

oPARTICLE DEGRADATION

oSWELLING FOLLOWED BY DIFFUSION

Release Mechanisms

oDIFFUSION

oPARTICLE DEGRADATION

oSWELLING FOLLOWED BY DIFFUSION

DIFFUSION takes place when the drug flows through the polymeric material.

Kinetics described by Fick’s law

Either at the MACROSCOPIC scale (e.g. through pores) or at the MOLECULAR scale.

THE DRUG may:

o Be finely dissolved (homogeneous microbead)

o Be finely dispersed into the polymeric matrix (monolithic microbead)

o Constitute an internal nucleus, immersed in a polymeric matrix (reservoir microbead)

o Be embedded in an internal matrix coated externally by a layer of a different polymeric material (double-wall microbeads).

HOMOGENEOUS MICROBEADS

The drug is dissolved inside a NON POROUS polymeric matrix .

Transport involves molecular diffusion through and along the polymeric segments.

Release takes place at the surface (the drug has always the highest concentration at the centre)

                                                                                

      

A SIMILAR MECHANISM OPERATES WITH MONOLITHIC MICROBEADS

RESERVOIR MICROBEADS

The drug is concentrated at the center with a negative concentration GRADIENT from center to surface

A releasable eccipient with a reverse concentration gradient keeps costant the fraction released

In this way the release rate is practically costant

                                                                                

     

RELEASE MECHANISM IN A DOUBLE-WALLMICROBEAD

In each case by solving the appropriate version of Fick’s equation, the time dependence of the amount of released drug may be evaluated

Release Mechanisms

oDIFFUSION

oPARTICLE DEGRADATION

oSWELLING FOLLOWED BY DIFFUSION

Microbeads made of biodegradable polymers

Most polymers degradate by hydrolysis of the polymer chain, yielding biocompatible fragments at lower MW.

                                                                               

      Schematic representation of a bioerodible microbead

Release from biodegradable systems:

a) Bulk bioerosion

b) Surface bioeresion

Microbeads of a copolymer between polyglicolic and poylactic acids (PLGA) for oral or underskin release: example of bulk erosion.

Original microbeads of PLGA 60:40

PLGA after 133 days in water

Polyorthoesthers: surface bioerosion, as after 16 weeks the core of the microbead is untouched

Release Mechanisms

oDIFFUSION

oPARTICLE DEGRADATION

oSWELLING FOLLOWED BY DIFFUSION

Such systems are unable to release until placed in a suitable biological medium

Release triggered by changes in the environment:

• pH• temperature• ionic strength

Release from microbeads reservoir (a) homogeneous (b) Controlled by swelling

Schematic representation of a release system controlled by swelling: when solvent A penetrates the (vitreous) polymer B, the drug C is released through the newly formed gel

Release systems for diabetes treatment

HYPERGLYCEMY: increase of sugars in the blood because of reduced insulin secretion

Insulin Glucose

insulin secreted by pancreas induces the decrease of glucose from blood

Alterations in diabetes:

1 decrease in utilization of glucose

2 use of alternative energy source (fatty tissue and proteins)

SYSTEMS FOR CONTROLLED RELEASE OF INSULIN

A mechanism often used

Functionalization with glucoso-oxidase (enzyme) of polymers (N,N-dimethyl-aminoethyl-metacrylate or polyacrilamide) impregnated with insulin.

Oxidation reaction of glucose catalyzed by the enzyme causes a decrease in pH with swelling of the polymer and release of insulin

Drug Targeting

Carrier delivering the drug at the chosen siteE.g. magnetic particles With tumors: neoplastic tissues show high permeability to carriers

A viable system: liposomes

Structures with double layers formed by amfiphilic molecules (surfactants)

Similarity with the cell wall

Structure of a lipid molecule (lecithin) and of a double lipidic layer (self-assembling structure)

Various types of lipids and corrisponding self-assembing structures

A widespread use of surfactants: synthesis of mesoporous

systems

C. T. Kresge et al., Nature, 1992, 359, 710-712

Synthetic approach: use of surfactant in the synthesis batch to form large pores MESOPORES

AMORPHOUS SILICA WALLS

SOL-GEL SYNTHESISmesoporous

porosity is controlled by synthesis conditions

Hydrophilic heads pointing outside allow solubility in water

Aqueous phase also present within the liposome

Within the membrane: lipophilic compartment

LIPOSOMES (dimension less than one micron)

LIPOSOMES: fabrication

Coating with a polyethylenglicole (PEG), an inert substance which does not alert the immune system

Because of the presence of both hydrophilic and lipophilic parts, liposomes may carry either POLAR MOLECOLES (within the aqueous phase) or APOLAR MOLECULES (wither the bilayer).

FUNCTIONALIZED LIPOSOMES

(terminal groups with affinity for specific cellular receptors)

LIPOSOMES MODIFIED TO HAVE A LARGER AFFINITY WITH CANCER CELLS

Liposome only releases drug when in contact with target!

Liposomal Delivery in Transdermal Applications

Because of the external layer liposomes may cross lipophilic structures, like those of the skin.

Mechanism of inclusion into the cell!

The end