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

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Presentazione sul tema: "MECCANISMI DI RILASCIO DI FARMACI DA MATRICI POLIMERICHE MARIO GRASSI UNIVERSITA’ di TRIESTE Dipartimento di Ingegneria Chimica e dei Materiali."— Transcript della presentazione:

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

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

3 (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. 20  m 0.2  m Schneider et al. J. American Chemical Society, 2002.

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

5 PHYSICAL CROSSLINKS (strong) Ca ++ EGGS BOX STRUCTURE Ca ++ 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 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]). a) Monomer dilution c) Crosslinker b) Neutralization d) Foaming aid and stabilizer e) Oxidant f) Reductant g) Bicarbonate SPH a) Monomer dilution c) Crosslinker b) Neutralization d) Foaming aid e) Oxidant thermal initiator f) Reductant g) Bicarbonate SAP

9 ECCIPIENTE LIPOFILO ECCIPIENTE IDROFILO DRUG SOLVENTE DELL’AMBIENTE DI RILASCIO 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 Surfactant Micelles Micellar Rod Hexagonal Array Calcination MCM-41 Silicate a b Two possible pathways for the formation of MCM-41: (a) liquid-crystal initiated b) silicate-initiated

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

14 DIFFUSIONE R = 0 R = R p DRUG D e = D w *  /  TORTUOSITA’ L c /R p POROSITA’ V v /V T

15 farmaco Fronte di erosione 6 solvente Fronte di swelling 6 Matrice secca: in questa condizione il principio attivo non può diffondere nel reticolo polimerico FISICA DEL PROBLEMA: IL RILASCIO

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

17 DRY STATE Driving force  H2O Chem. Pot. Dif. Counter force K(T) Chem. Pot. Dif. SWELLING STATE 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  p depending on local solvent concentration and temperature

19  p = polymeric chain relaxation time  s = solvent characteristic diffusion time (  L 2 /Ds)  p <<  s FICK law holds (constant diffusion coefficient)  p >>  s FICK law holds (concentration dependent diffusion coefficient)  p   s FICK law does not hold

20 F instantaneously modifies with the concentration gradient FICK LAW CLCL C0C0 h F does not instantaneously modify with the concentration gradient: F is also time dependent (D=D(t)) FICK LAW CLCL C0C0 h

21 Legge di FICK De = cost *  SOLVENT UPTAKE

22 DRUG RELEASE De = cost *  Legge di FICK

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

24 RICRISTALLIZZAZIONE 7 POLIMORFO A FORMA ANIDRA AMORFO T, P, S A SOLVENTE POLIMORFO B T, P, S B FORMA IDRATA CRISTALLO S A >> S B

25 EROSION CHEMICAL REASONS 1.Hydrolysis 2.Chemical reaction 3.Enzyme attack PHYSICAL REASONS 1.hydrodynamic EROSION SURFACE EROSION 1.CHEMICAL 2.PHYSICAL BULK EROSION 1.CHEMICAL

26 SURFACE EROSION BULK EROSION

27 SURFACE EROSION: MECHANISM Semicrystalline polymers Amorphous polymers

28 Disentanglements: REPTATION

29 RELEASE FROM ERODING SYSTEM

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

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

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 Macromolecular sites concentration Template concentration Forward reaction (binding)Backward reaction (un-binding) Association constant

34 SELECTIVITY  = K a1 / K a2 1 ≤  ≤ 8

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

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

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

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

39 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). Farmaco Polvere polimerica CARICAMENTO + CO 2 Farmaco incorporato in forma cristallina e amorfa ESTRAZIONE CO 2 P.p. caricata per solvent swelling Solvente solubilizzato in CO 2 CARICAMENTO: FLUIDI SUPERCRITICI

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

41 polimero farmaco Mezzi macinanti

42

43

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45 BIBLIOGRAFIA 1)Pharmacos 4, Eudralex Collection, Medicinal Products for Human Use: Guidelines. Volume 3C, p. 234 (internet site: 3/home.htm).http://pharmacos.eudra.org/F2/eudralex/vol- 3/home.htm 2)Israel G. in Modelli Matematici nelle Scienze Biologiche, a cura di P. Freguglia, Edizioni Quattro Venti, Urbino, pag. 134 (1998). 3)Lapasin R, Pricl S, Rheology of Industrial Polysaccharides; Theory and Applications, Chapman and Hall, London, )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, )A. Kydonieus (Ed.), Treatise on Controlled Drug Delivery, Marcel Dekker, New York, 1992, pp )Colombo, P Swelling-controlled release in hydrogel matrices for oral route. Adv. Drug. Dev. Rev., 11, 37 – 57 7)Nogami H, Nagai T, Youtsunagi T. Dissolution phenomena of organic medicinals involving simultaneous phase changes. Chem. Pharm. Bull. 17(3), , )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, )Grassi M, Colombo I, Lapasin R. Drug release from an ensemble of swellable crosslinked polymer particles. J. Contr. Rel. 68, , 2000.


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