MECCANISMI DI RILASCIO DI FARMACI DA MATRICI POLIMERICHE MARIO GRASSI UNIVERSITA’ di TRIESTE

1. MECCANISMI DI RILASCIO DI FARMACI DA MATRICI POLIMERICHE MARIO GRASSI UNIVERSITA’ di TRIESTE Dipartimento di Ingegneria Chimica e dei Materiali

2. CROSSLINKS STRUTTURA DELLE MATRICI POLIMERICHE LIQUID PHASE POLYMERIC CHAINS MATRICES ARE COHERENT SYSTEMS MADE UP BY A POLYMERIC NETWORK TRAPPING A CONTINUOUS LIQUIDPHASE. THEY SHOW MECHANICAL PROPERTIES IN BETWEEN THOSE OF SOLIDS AND LIQUIDS

3. 20 mm 0.2 mm Schneider et al. J. American Chemical Society, 2002. (a) Laser scanning confocal microscopy. Green regions are fluorescently stained self-assembled peptide, and black regions are water-filled pores and channels. (b) CryoTEM. Dark structures are selfassembled peptide scaffold, while lighter gray areas are composed of vitrified water.

4. PHYSICAL CROSSLINKS (weak) ENTANGLEMENTS (TOPOLOGICAL CONSTRAINS) CONNECTING DISORDERED ZONES Van der Walls, dipole-dipole, hydrogen bonding, Coulombic hydrophobic interactions ORDERED ZONES POLYSACCARIDES (GLUCANS, XANTHAN)

5. PHYSICAL CROSSLINKS (strong) Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ Ca++ EGGS BOX STRUCTURE INTERACTION BETWEEN THE BIVALENT ION AND GULURONIC UNIT ALGINATES

6. CHEMICAL CROSSLINKS (strong: covalent bond) SCLEROGLUCAN CROSSLINKED WITH BORAX T. Coviello et al., Int. J. Biol. Macromolecules, 32 (2003) 83

7. GEL SUPERPOROSI

8. a) Monomer dilution e) Oxidant b) Neutralization f) Reductant c) Crosslinker g) Bicarbonate d) Foaming aid and stabilizer SPH a) Monomer dilution e) Oxidant thermal initiator b) Neutralization f) Reductant c) Crosslinker d) Foaming aid g) Bicarbonate SAP Figure 6.2. Schematic representation of steps involved in the production of Super porous hydrogels (SPH) and Super absorbent polymers (SPA) (with permission from ref.[46]).

9. SOLVENTE DELL’AMBIENTE DI RILASCIO ECCIPIENTE LIPOFILO ECCIPIENTE IDROFILO DRUG MATRICI LIPOFILE: Topologia

10. COMPRESSE POLIMERO Farmaco Eccipienti + + SISTEMA POROSO

11. SISTEMI INORGANICI POROSI: ZEOLITI MCM-41 transmission electron micrograph. Hexagonally arranged 4.0 nm sized pores can be detected

12. Hexagonal Array Surfactant Micelles Micellar Rod Silicate Silicate Calcination a b MCM-41 Two possible pathways for the formation of MCM-41: (a) liquid-crystal initiated b) silicate-initiated

13. POROSITA’ 2*RD RP FARMACO CATENE POLIMERICHE RD/RP 0.01 0.1 MEZZO CONTINUO MEZZO POROSO Il moto del farmaco avviene tra le maglie del reticolo polimerico contenenti anche le molecole del fluido di rilascio Il moto del farmaco avviene nel fluido di rilascio che riempe i canali le cui pareti sono costituite dal polimero ZONA INTERMEDIA

14. DIFFUSIONE R = 0 DRUG R = Rp TORTUOSITA’ Lc/Rp POROSITA’ Vv/VT De= Dw *e/t

15. FISICA DEL PROBLEMA: IL RILASCIO farmaco solvente Fronte di swelling6 Matrice secca: in questa condizione il principio attivo non può diffondere nel reticolo polimerico Fronte di erosione6

16. Fronte di diffusione Fronte di erosione Fronte di swelling Matrice rigonfiata DRUG Matrice non rigonfiata SOLVENTE TRE DIVERSI FRONTI: UNA COMODA SEMPLIFICAZIONE

17. SWELLING STATE DRY STATE Driving force DmH2O Chem. Pot. Dif. Counter force K(T) Chem. Pot. Dif. Crosslink density

18. Polymeric chains pass from one equilibrium state to another one due to the incoming solvent The time required to get the new equilibrium condition is the so called relaxation time tp depending on local solvent concentration and temperature

19. tp << ts tp ts tp >> ts FICK law holds (constant diffusion coefficient) FICK law holds (concentration dependent diffusion coefficient) FICK law does not hold tp = polymeric chain relaxation time ts = solvent characteristic diffusion time ( L2/Ds)

20. C0 C0 h h FICK LAW FICK LAW CL CL F instantaneously modifies with the concentration gradient F does not instantaneously modify with the concentration gradient: F is also time dependent (D=D(t))

21. SOLVENT UPTAKE Legge di FICK De = cost * t

22. DRUG RELEASE Legge di FICK De = cost * t

23. Agente rigonfiante Matrice Farmaco Dissoluzione e ricristallizazione Diffusione del farmaco Ricristallizzazione ed accumulo nell’ambiente di rilascio

24. T, P, SA T, P, SB POLIMORFO A SOLVENTE POLIMORFO B + FORMA ANIDRA SOLVENTE FORMA IDRATA + AMORFO SOLVENTE CRISTALLO + SA>>SB RICRISTALLIZZAZIONE7

25. PHYSICAL REASONS • hydrodynamic • CHEMICAL REASONS • Hydrolysis • Chemical reaction • Enzyme attack • SURFACE EROSION • CHEMICAL • PHYSICAL • BULK EROSION • CHEMICAL EROSION EROSION

26. SURFACE EROSION BULK EROSION

27. SURFACE EROSION: MECHANISM Semicrystalline polymers Amorphous polymers

28. Disentanglements: REPTATION

29. RELEASE FROM ERODING SYSTEM

30. MATRICI LIPOFILE: rilascio SOLVENTE DELL’AMBIENTE DI RILASCIO DISSOLUZIONE ECCIPIENTE LIPOFILO ECCIPIENTE IDROFILO DRUG DIFFUSIONE

31. IMPRINTED POLYMERS I I I COMPLEX FORMATION I I CROSSLINKING I I = initiator WASHING = template = functional monomers = crosslinking monomers MOLECULAR IMPRINTING

32. IMPRINTED POLYMERS: CHARACTERISTICS Binding affinity: a measure of how well the template molecule is attracted to the binding site Selectivity : the ability to differentiate between the template and other molecules Binding capacity : the maximum amount of template bound per mass or volume of polymer

33. BINDING AFFINITY Forward reaction (binding) Backward reaction (un-binding) Association constant Macromolecular sites concentration Template concentration

34. SELECTIVITY a = Ka1/Ka2 1 ≤ a≤ 8

35. A A A A A A A A A A A A A A A A A A A A A P P P P P P P P P A A A A = PROTEIN = DRUG NETWORK SWELLING: DRUG CAN BE RELEASED A =ANALYTE EXAMPLE : SWELLING CONTROL

36. EXAMPLE 2: TARGETED DELIVERY TISSUES OR CELLULAR LINING HYDROGEL DRUG CELLULAR RECEPTOR IMPRINTED FILM R R

37. 1) SWELLING 5)DIFFUSION 3) DISSOLUTION Solid drug 2) EROSION Polymeric network 4) RE-CRYSTALLIZATION 6)DRUG-POLYMER INTERACTION 8)MATRIX GEOMETRY 7)DRUG DISTRIBUTION 9)MATRICES POLYDISPERSION

38. CARICAMENTO: SOLVENT SWELLING 1a soluzione Polvere polimerica Farmaco Farmaco incorporato in forma cristallina e amorfa 2a soluzione Allontanamento del solvente

39. CARICAMENTO: FLUIDI SUPERCRITICI CARICAMENTO ESTRAZIONE +CO2 CO2 Farmaco P.p. caricata per solvent swelling Polvere polimerica Farmaco incorporato in forma cristallina e amorfa Solvente solubilizzato in CO2 I fluidi supercritici hanno una densità comparabile a quella dei liquidi (alto potere solvente) ed una viscosità comparabile con quella dei gas (alto coefficiente di diffusione).

40. + Polvere polimerica Farmaco Mulino: energia meccanica Farmaco incorporato in forma cristallina e amorfa CARICAMENTO: COMACINAZIONE

41. polimero Mezzi macinanti farmaco

45. BIBLIOGRAFIA • Pharmacos 4, Eudralex Collection, Medicinal Products for Human Use: Guidelines. Volume 3C, p. 234 (internet site: http://pharmacos.eudra.org/F2/eudralex/vol-3/home.htm). • Israel G. in Modelli Matematici nelle Scienze Biologiche, a cura di P. Freguglia, Edizioni Quattro Venti, Urbino, pag. 134 (1998). • Lapasin R, Pricl S, Rheology of Industrial Polysaccharides; Theory and Applications, Chapman and Hall, London, 1995. • Coviello T, Grassi M, Rambone G, Santucci E, a Carafa M , Murtas E, Riccieri F M, Franco Alhaique F. Novel hydrogel system from scleroglucan: synthesis and characterization J. Contr. Rel. 60, 367–378, 1999. • A. Kydonieus (Ed.), Treatise on Controlled Drug Delivery, Marcel Dekker, New York, 1992, pp. 54-55. • Colombo, P. 1993. Swelling-controlled release in hydrogel matrices for oral route. Adv. Drug. Dev. Rev., 11, 37 – 57 • Nogami H, Nagai T, Youtsunagi T. Dissolution phenomena of organic medicinals involving simultaneous phase changes. Chem. Pharm. Bull. 17(3), 499-509, 1969. • Lee P I, Initial concentration distribution as a mechanism for regulating drug release from diffusion controlled and surface erosion controlled matrix systems, J. Contr. Rel. 4, 1–7, 1986. • Grassi M, Colombo I, Lapasin R. Drug release from an ensemble of swellablecrosslinked polymer particles. J. Contr. Rel. 68, 97-113, 2000.