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MECCANISMI DI RILASCIO DI FARMACI DA MATRICI POLIMERICHE

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Presentazione sul tema: "MECCANISMI DI RILASCIO DI FARMACI DA MATRICI POLIMERICHE"— 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
LIQUID PHASE CROSSLINKS POLYMERIC CHAINS 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

3 Schneider et al. J. American Chemical Society, 2002.
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) ORDERED ZONES CONNECTING DISORDERED ZONES Van der Walls, dipole-dipole, hydrogen bonding, Coulombic hydrophobic interactions POLYSACCARIDES (GLUCANS, XANTHAN)

5 INTERACTION BETWEEN THE BIVALENT ION AND GULURONIC UNIT
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 SPH SAP a) Monomer dilution c) Crosslinker b) Neutralization
d) Foaming aid and stabilizer e) Oxidant f) Reductant g) Bicarbonate 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
MATRICI LIPOFILE: Topologia ECCIPIENTE LIPOFILO ECCIPIENTE IDROFILO DRUG SOLVENTE DELL’AMBIENTE DI RILASCIO

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 Two possible pathways for the formation of MCM-41:
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’ RD/RP 0.01 0.1 MEZZO CONTINUO MEZZO POROSO ZONA INTERMEDIA
Il moto del farmaco avviene tra le maglie del reticolo polimerico contenenti anche le molecole del fluido di rilascio 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 RD/RP 0.01 0.1 ZONA INTERMEDIA

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

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

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

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

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

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

21 SOLVENT UPTAKE Legge di FICK De = cost * t

22 DRUG RELEASE De = cost * t Legge di FICK

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

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

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

26 SURFACE EROSION BULK EROSION

27 SURFACE EROSION: MECHANISM Semicrystalline polymers
Amorphous polymers

28 Disentanglements: REPTATION

29 RELEASE FROM ERODING SYSTEM

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

31 = crosslinking monomers
IMPRINTED POLYMERS MOLECULAR IMPRINTING COMPLEX FORMATION I I = initiator = template = functional monomers = crosslinking monomers 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 a = Ka1/Ka2 1 ≤ a ≤ 8

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

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

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

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

39 CARICAMENTO: FLUIDI SUPERCRITICI
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 + CO2 Farmaco incorporato in forma cristallina e amorfa ESTRAZIONE CO2 P.p. caricata per solvent swelling Solvente solubilizzato in CO2

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

41 polimero farmaco Mezzi macinanti

42

43

44

45 BIBLIOGRAFIA Pharmacos 4, Eudralex Collection, Medicinal Products for Human Use: Guidelines. Volume 3C, p. 234 (internet site: 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 Colombo, P 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), , 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 swellable crosslinked polymer particles. J. Contr. Rel. 68, , 2000.


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