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Controlled drug release

Controlled drug release. OBJECTIVES: Gradual release Ability to target an organ. PROBLEM: avoid under and overdosing. TRADITIONAL METHODS. The ideal case is a constant level of drug in body fluid. Classical topic of Pharmacokinetics Two new approaches:

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Controlled drug release

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  1. Controlled drug release

  2. OBJECTIVES: • Gradual release • Ability to target an organ PROBLEM: avoid under and overdosing

  3. TRADITIONAL METHODS The ideal case is a constant level of drug in body fluid

  4. Classical topic of Pharmacokinetics • Two new approaches: • Microparticle systems: Release from small spherical beads • Targeting of drug

  5. MICROPARTICLE SYSTEMS: Release from small spherical beads, to control the release kinetics

  6. First generation materials borrowed from other fields: • Polyurethanes • Polysiloxanes • PMMA • Polyvynilalcohol • Polyethylene • Polyivynilpyrrolidone

  7. Second-generation materials chosen for: • CHEMICAL INERTNESS, NO IMPURITY RELEASE, THEIR STRUCTURE, EASE OF PRODUCTION • Poly 2-hydroxymethylmetacrilate • Poly N-vynilpyrrolidone • Polymethylmetacrilate • Polyvynilalcohol • Polyacrilic Acid • Polyacrilamide • Copolimers polyethilene-vynilacetate. • Polyethilenic glicol

  8. Most recent materials are BIODEGRADABLEPOLYMERS: • Polylactic acid (PLA) • Polyglicolic acid (PGA) • Copolimers of PLA and PGA • Polyanhydrides • Polyorthoesthers

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

  10. POLYMERIC BEADS

  11. Release Mechanisms • DIFFUSION • PARTICLE DEGRADATION • SWELLING FOLLOWED BY DIFFUSION

  12. Release Mechanisms • DIFFUSION • PARTICLE DEGRADATION • SWELLING FOLLOWED BY DIFFUSION

  13. 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.

  14. THE DRUG may: • Be finely dissolved (homogeneousmicrobead) • Be finely dispersed into the polymeric matrix (monolithicmicrobead) • Constitute an internal nucleus, immersed in a polymeric matrix (reservoirmicrobead) • Be embedded in an internal matrix coated externally by a layer of a different polymeric material (double-wall microbeads).

  15. 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)

  16. A SIMILAR MECHANISM OPERATES WITH MONOLITHIC MICROBEADS

  17. RESERVOIR MICROBEADS The drug is concentrated at the center with a negativeconcentrationGRADIENT 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

  18. RELEASE MECHANISM IN A DOUBLE-WALLMICROBEAD

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

  20. Release Mechanisms • DIFFUSION • PARTICLE DEGRADATION • SWELLING FOLLOWED BY DIFFUSION

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

  22. Schematic representation of a bioerodible microbead

  23. Release from biodegradable systems: • Bulk bioerosion • Surface bioeresion

  24. 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

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

  26. Release Mechanisms • DIFFUSION • PARTICLE DEGRADATION • SWELLING FOLLOWED BY DIFFUSION

  27. Such systems are unable to release until placed in a suitable biological medium • Release triggered by changes in the environment: • pH • temperature • ionic strength

  28. 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

  29. Release systems for diabetes treatment

  30. HYPERGLYCEMY: increase of sugars in the blood because of reduced insulin secretion Insulin Glucose

  31. 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)

  32. 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

  33. Drug Targeting

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

  35. A viable system: liposomes Structures with double layers formed by amfiphilic molecules (surfactants) Similarity with the cell wall

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

  37. Various types of lipids and corrisponding self-assembing structures

  38. A widespread use of surfactants: synthesis of mesoporous systems

  39. mesoporous SOL-GEL SYNTHESIS Synthetic approach: use of surfactant in the synthesis batch to form large pores MESOPORES porosity is controlled by synthesis conditions AMORPHOUS SILICA WALLS C. T. Kresge et al., Nature, 1992, 359, 710-712

  40. LIPOSOMES (dimension less than one micron) Hydrophilic heads pointing outside allow solubility in water Aqueous phase also present within the liposome Within the membrane: lipophilic compartment

  41. LIPOSOMES: fabrication Coating with a polyethylenglicole (PEG), an inert substance which does not alert the immune system

  42. 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).

  43. FUNCTIONALIZED LIPOSOMES (terminal groups with affinity for specific cellular receptors)

  44. LIPOSOMES MODIFIED TO HAVE A LARGER AFFINITY WITH CANCER CELLS

  45. Liposome only releases drug when in contact with target!

  46. 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!

  47. The end

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