MECCANISMI DI RILASCIO DI FARMACI DA MATRICI POLIMERICHE

MARIO GRASSI

UNIVERSITA’ di TRIESTEDipartimento di Ingegneria Chimica e dei Materiali

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

(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.

PHYSICAL CROSSLINKS (weak)

ENTANGLEMENTS (TOPOLOGICAL CONSTRAINS)

ORDERED ZONES

CONNECTING DISORDERED

ZONES

Van der Walls, dipole-dipole,

hydrogen bonding, Coulombic

hydrophobic interactions

POLYSACCARIDES (GLUCANS, XANTHAN)

PHYSICAL CROSSLINKS (strong)

Ca++ Ca++Ca++ Ca++ Ca++Ca++

EGGS BOX STRUCTURE

OO O

OH

OH

OHOH

OH

O

O OH

O

OCa 2+Ca++

INTERACTION BETWEEN THE BIVALENT ION AND

GULURONIC UNIT

ALGINATES

CHEMICAL CROSSLINKS (strong: covalent bond)

SCLEROGLUCAN CROSSLINKED WITH

BORAX

T. Coviello et al., Int. J. Biol. Macromolecules, 32 (2003) 83

GEL SUPERPOROSI

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

ECCIPIENTE LIPOFILOECCIPIENTE IDROFILO

DRUG

SOLVENTE DELL’AMBIENTE

DI RILASCIO

MATRICI LIPOFILE: Topologia

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

Surfactant Micelles

Micellar Rod

Hexagonal Array

Calcination

MCM-41

Silicate

a

Silicate

b

Two possible pathways for the formation of MCM-41: (a) liquid-crystal initiated b) silicate-initiated

POROSITA’

RD/RP

0.01 0.1ZONA INTERMEDIAMEZZO 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*RD RP

Il moto del farmaco avviene tra le maglie del reticolo polimerico contenenti anche le molecole del fluido di rilascio

DIFFUSIONE

R = 0

R = Rp

DRUG

De = Dw */ TORTUOSITA’ Lc/Rp

POROSITA’ Vv/VT

farmaco

Fronte di erosione6

solvente

Fronte di swelling6

Matrice secca:

in questa condizione il principio attivo non può diffondere nel reticolo polimerico

FISICA DEL PROBLEMA:IL RILASCIO

Matrice non

rigonfiata

Matrice rigonfiata

Fronte di diffusioneFronte di

swelling

Fronte di erosione

DRUG

SOLVENTE

TRE DIVERSI FRONTI: UNA COMODA SEMPLIFICAZIONE

DRY STATE

Driving forceH2O

Chem. Pot. Dif.

Counter forceK(T)

Chem. Pot. Dif.

SWELLING STATE

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 p

depending on local solvent concentration and

temperature

p = polymeric chain relaxation time

s = solvent characteristic diffusion time ( L2/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

0L CCh

DF

F instantaneously modifies with the concentration gradient

FICK LAWCL

C0

h

0L

)(CC

h

tDF

F does not instantaneously modify with the concentration gradient:

F is also time dependent (D=D(t))

FICK LAWCL

C0

h

0102030405060708090

100110

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8

(t+)0.5

100

Mt+

De = 0

De = 1

De = 10

De = infinito

Rd = 10

50.tt tK

M

MM

Legge di FICKDe = cost *

SOLVENT UPTAKE

1

10

100

0.1 1 10 100td

+

100

Mt+

De = 0

De = 1

De = 10

De = infinito

DRUG RELEASE

De = cost *

Legge di FICK

Farmaco

Matrice

Ricristallizzazione ed accumulo nell’ambiente

di rilascio

Diffusione del farmaco

Agente rigonfiante

Dissoluzione ericristallizazione

RICRISTALLIZZAZIONE7

POLIMORFO A

FORMA ANIDRA

AMORFO

T, P, SA

+

+

+

SOLVENTE

SOLVENTE

SOLVENTE

POLIMORFO B

T, P, SB

FORMA IDRATA

CRISTALLO

SA >> SB

EROSION

CHEMICAL REASONS1. Hydrolysis2. Chemical reaction3. Enzyme attack

PHYSICAL REASONS1. hydrodynamic

EROSION

SURFACE EROSION1. CHEMICAL 2. PHYSICAL

BULK EROSION1. CHEMICAL

SURFACE EROSION

BULK EROSION

SURFACE EROSION: MECHANISM

Semicrystalline polymers

Amorphous polymers

Disentanglements: REPTATION

RELEASE FROM ERODING SYSTEM

ECCIPIENTE LIPOFILOECCIPIENTE IDROFILO

DRUG

SOLVENTE DELL’AMBIENTE

DI RILASCIO

DISSOLUZIONE

DIFFUSIONE

MATRICI LIPOFILE: rilascio

IMPRINTED POLYMERSMOLECULAR IMPRINTINGMOLECULAR IMPRINTING

I

I

I

I

I

I

I = initiator

= template

= functional monomers

= crosslinking

monomers

COMPLEX FORMATION

CROSSLINKING

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

MTTMk

k

f

rMacromolecular sites concentration

Template concentration

TMkR ff Forward reaction (binding)

MTkR rr Backward reaction (un-binding)

TM

MT

Kk

kK

dr

fa

1

Association constant

SELECTIVITY

= Ka1/Ka2

1 ≤ ≤ 8

APA A P

A

AP

AA P

AA

A

A

AA

A

A

A

A

NETWORK SWELLING:DRUG CAN BE RELEASED

EXAMPLE : SWELLING CONTROL

PA

A

PA

APA A

PA

A

= DRUG

A =ANALYTE

P = PROTEIN

IMPRINTED FILM

DRUG

HYDROGEL

EXAMPLE 2: TARGETED DELIVERY

R CELLULAR RECEPTOR

TISSUES OR CELLULAR LINING

R

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

CARICAMENTO: SOLVENT SWELLING

Farmaco

Polvere polimerica

1a soluzione

2a soluzioneFarmaco incorporato in forma cristallina e

amorfa

Allontanamento del solvente

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

CARICAMENTO: FLUIDI SUPERCRITICI

Polvere polimerica

Farmaco +

Farmaco incorporato in forma cristallina e amorfa

CARICAMENTO: COMACINAZIONE

Mulino: energia meccanica

polimerofarmaco

Mezzi macinanti

BIBLIOGRAFIA1) 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).

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.