MECCANISMI DI RILASCIO DI FARMACI
DA MATRICI POLIMERICHE
MARIO GRASSI
UNIVERSITA’ di TRIESTE
Dipartimento di Ingegneria Chimica e dei Materiali
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
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.
PHYSICAL CROSSLINKS (weak)
ENTANGLEMENTS
(TOPOLOGICAL
CONSTRAINS)
CONNECTING
DISORDERED
ZONES
Van der Walls,
dipole-dipole,
hydrogen bonding,
Coulombic
hydrophobic interactions
ORDERED
ZONES
POLYSACCARIDES (GLUCANS, XANTHAN)
PHYSICAL CROSSLINKS (strong)
Ca++ Ca++ Ca++ Ca++ Ca++ Ca++
EGGS BOX STRUCTURE
Ca
+
Ca2++
O
INTERACTION BETWEEN
THE BIVALENT ION AND
GULURONIC UNIT
O
OH
OH
HO
O
O
OH
O
OH
O
O
ALGINATES
OH
CHEMICAL CROSSLINKS (strong: covalent bond)
SCLEROGLUCAN
CROSSLINKED WITH
BORAX
T. Coviello et al., Int. J. Biol. Macromolecules, 32 (2003) 83
GEL SUPERPOROSI
a) Monomer dilution
e) Oxidant
a) Monomer dilution
b) Neutralization
f) Reductant
b) Neutralization
c) Crosslinker
g) Bicarbonate
c) Crosslinker
f) Reductant
d) Foaming aid
g) Bicarbonate
d) Foaming aid
and stabilizer
SPH
e) Oxidant
thermal initiator
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]).
MATRICI LIPOFILE: Topologia
SOLVENTE
DELL’AMBIENTE
DI RILASCIO
ECCIPIENTE LIPOFILO
ECCIPIENTE IDROFILO
DRUG
COMPRESSE
POLIMERO
Farmaco
+
Eccipienti
+
SISTEMA POROSO
SISTEMI INORGANICI POROSI: ZEOLITI
MCM-41 transmission electron micrograph. Hexagonally
arranged 4.0 nm sized pores can be detected
Hexagonal
Array
Surfactant
Micelles
Micellar
Rod
Silicate
a
Silicate
b
Calcination
MCM-41
Two possible pathways for the formation of MCM-41:
(a) liquid-crystal initiated b) silicate-initiated
POROSITA’
FARMACO
2*RD
RP
CATENE
POLIMERICHE
RD/RP
0.01
MEZZO POROSO
Il moto del farmaco
avviene nel fluido di
rilascio che riempe i
canali le cui pareti
sono costituite dal
polimero
ZONA 0.1
MEZZO CONTINUO
INTERMEDIA
Il moto del farmaco
avviene tra le maglie
del reticolo polimerico
contenenti anche le
molecole del fluido di
rilascio
DIFFUSIONE
R=0
DRUG
R = Rp
De = Dw *e/t
TORTUOSITA’
Lc/Rp
POROSITA’ Vv/VT
FISICA DEL PROBLEMA:
IL RILASCIO
farmaco
solvente
Fronte di
swelling6
Matrice secca:
Fronte di
in questa condizione il principio attivo non erosione6
può diffondere nel reticolo polimerico
TRE DIVERSI FRONTI: UNA COMODA SEMPLIFICAZIONE
Fronte di
swelling
Fronte di
diffusione
Fronte di
erosione
Matrice rigonfiata
DRUG
Matrice
non
rigonfiata
SOLVENTE
SWELLING STATE
DRY STATE
Driving force
DmH2O
Chem. Pot. Dif.
Counter force
K(T)
Chem. Pot. Dif.
Crosslink density
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
tp = polymeric chain relaxation time
ts = solvent characteristic diffusion time ( L /Ds)
2
tp << ts
FICK law holds
(constant diffusion
coefficient)
tp  ts
tp >> ts
FICK law does
not hold
FICK law holds
(concentration
dependent diffusion
coefficient)
D
F   C L  C0 
h
C0
h
FICK LAW
CL
F instantaneously modifies with the concentration gradient
D(t )
CL  C0 
F 
h
C0
h
FICK LAW
CL
F does not instantaneously modify with the concentration gradient:
F is also time dependent (D=D(t))
100 Mt+
SOLVENT UPTAKE
110
100
90
80
70
60
50
40
30
20
10
0
Rd = 10
0

Mt
De = 0
De = 1
De = 10
De = infinito
0.2
0.4
Mt
0.5

Kt
M
Legge di FICK
0.6
0.8
1
1.2
1.4
1.6
(t+)0.5
De = cost * t
1.8
DRUG RELEASE
100 Mt+
100
10
De = 0
De = 1
De = 10
De = infinito
Legge di FICK
1
0.1
1
td
+
10
100
De = cost * t
Agente rigonfiante
Matrice
Farmaco
Dissoluzione e
ricristallizazione
Diffusione del farmaco
Ricristallizzazione ed
accumulo nell’ambiente
di rilascio
RICRISTALLIZZAZIONE7
T, P, SA
T, P, SB
POLIMORFO A
SOLVENTE
POLIMORFO B
SOLVENTE
FORMA IDRATA
SOLVENTE
CRISTALLO
+
FORMA ANIDRA
+
AMORFO
+
SA >> SB
EROSION
PHYSICAL REASONS
1. hydrodynamic
CHEMICAL REASONS
1. Hydrolysis
2. Chemical reaction
3. Enzyme attack
EROSION
SURFACE EROSION
1. CHEMICAL
2. PHYSICAL
BULK EROSION
1. CHEMICAL
SURFACE EROSION
BULK EROSION
SURFACE EROSION: MECHANISM
Semicrystalline
polymers
Amorphous
polymers
Disentanglements: REPTATION
RELEASE FROM ERODING SYSTEM
MATRICI LIPOFILE: rilascio
SOLVENTE
DELL’AMBIENTE
DI RILASCIO
ECCIPIENTE LIPOFILO
ECCIPIENTE IDROFILO
DRUG
DISSOLUZIONE
DIFFUSIONE
IMPRINTED POLYMERS
MOLECULAR IMPRINTING
I
I
I
COMPLEX
FORMATION
I
I
I
CROSSLINKING
I = initiator
= template
= functional
monomers
= crosslinking
monomers
WASHING
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
BINDING AFFINITY
M   T  MT 
kf
Macromolecular
sites concentration
kr
Template
concentration
Rf  k f M T 
Forward reaction (binding)
Rr  kr MT 
Backward reaction (un-binding)
kf

1
MT 
Ka 


Association
k r K d M T 
constant
SELECTIVITY
a = Ka1/Ka2
1≤a≤8
EXAMPLE : SWELLING CONTROL
A
A
A
A
A
A
P
= PROTEIN
A
A
A
= DRUG
A =ANALYTE
NETWORK SWELLING:
DRUG CAN BE RELEASED
EXAMPLE 2: TARGETED DELIVERY
TISSUES OR CELLULAR LINING
HYDROGEL
R
DRUG
IMPRINTED
FILM
R
CELLULAR
RECEPTOR
1) SWELLING
5) DIFFUSION
3) DISSOLUTION
Solid drug
2) EROSION
4) RE-CRYSTALLIZATION
Polymeric network
6) DRUG-POLYMER
INTERACTION
7) DRUG DISTRIBUTION
8) MATRIX
GEOMETRY
9) MATRICES
POLYDISPERSION
CARICAMENTO: SOLVENT SWELLING
Farmaco
Polvere
polimerica
2a soluzione
Allontanamento del
solvente
1a soluzione
Farmaco incorporato
in forma cristallina e
amorfa
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).
CARICAMENTO
Farmaco
+ CO2
ESTRAZIONE
CO2
P.p. caricata per solvent
swelling
Polvere polimerica
Farmaco incorporato in
forma cristallina e amorfa
Solvente
solubilizzato in CO2
CARICAMENTO: COMACINAZIONE
+
Farmaco
Polvere
polimerica
Mulino: energia meccanica
Farmaco incorporato in forma
cristallina e amorfa
polimero
farmaco
Mezzi macinanti
BIBLIOGRAFIA
1)
Pharmacos 4, Eudralex Collection, Medicinal Products for Human Use: Guidelines.
Volume 3C, p. 234 (internet site: http://pharmacos.eudra.org/F2/eudralex/vol3/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, 1995.
4)
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.
5)
A. Kydonieus (Ed.), Treatise on Controlled Drug Delivery, Marcel Dekker, New York,
1992, pp. 54-55.
6)
Colombo, P. 1993. 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), 499-509, 1969.
8)
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.
9)
Grassi M, Colombo I, Lapasin R. Drug release from an ensemble of swellable
crosslinked polymer particles. J. Contr. Rel. 68, 97-113, 2000.