Lecture 18:
Drug Delivery: Controlled Release Chemically-controlled Devices
3.051J/20.340J Materials for Biomedical Applications, Spring 2006
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Drug Delivery System (DDS)
Controlling delivery rate and Site-specific delivery of drugs
Current drug administration
Minimum effective level Toxic level
. Controlled (or Sustained) Release
Drug conc
Time
2
Even though controlled release can be achieved…
Spread over body Site-specific delivery
Active or passive targeting
might cause side effect.
3
Table Controlled Release DDS
D iffusion-controlled DDS
Reservoir and monolithic systems
W ater penetration-controlled DDS
Osmotic and swelling-controlled systems
C
hemically-controlled DDSBiodegradable reservoir and monolithic systems
Biodegradable polymer backbones with pendant drugs
R esponsive DDS
Physically- and chemically-responsive systems
Mechanical, magnetic- or ultrasound-responsive systems Biochemically-responsive; self-regulated systems
P
articulate DDS MicroparticulatesPolymer-drug conjugates
Polymeric micelle systems Ratner, et al. Biomaterials Science
Liposome systems 4
Chemically-controlled DDS
Drug Bioerodible or biodegradable matrix
time
Drug Deg.
conc.
Drug Drug
conc. conc.
time time
5
Four major classes of matrix in DDS
Poly(lactic acid) and its copolymers with poly(glycolic acid)
O CH C CH3O
O CH2 C O O CH C
CH3O Safe degraded products
Acid-induce inflammatory
PLA P(LA-co-GA)
Polyanhydrides
C O
O C3H6 O C O O
C C4H8 C O
O O
First degradation rate Hydrolytic instability
Poly(bis-(p-carboxyphenoxy)propane-co-sebacic anhydride)
Polyorthoesters
O O
O O
O R O
Well studied by 21st century Good property R: PLGA
Polyphosphoesters
P O R O O
R'
First degradation rate
Hydrolytic instability, high cost6
H O
O C O
O C O
O H O
O R
R
Environmentally responsive systems
1. Temperature responsive systems
C O NH
LCST: 32°C
Poly(N-isopropyl acrylamide)
T
HO O
O O
H
Pluronics® 37°C
T
37°C
Gelation Bioerosion
Polymer-drug solution
HO C O
O C O
O
R O
R H
Hydrophob
Hydrophilic R: -H, -C H3
7 ic
Environmentally responsive systems
2. pH responsive systems
“ “ Proton Sponge Proton Sponge ” ”
Endocytosis of drug
Formation of acidsome
Transfer to lysosome
Digestion in lysosome pH 5-6
NH2 NH3+ H+
Poly(L-lysi
HN
CH C O
(CH2)4 NH2
Chitosan
O CH2OH
HO NH2
O
ne)
8
Second key point in DDS
1. Controlling release rate 2. Site-specific delivery
Particulate system
Passive targeting Active targeting
Particulate should be
between 10 to 200 nm.
Spleen Liver
Lungs
RES
Reticuloendothelial system
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Passive targeting of particulate by EPR effect
Discontinuous endothelialium
Blood vessel
Endothelial cells
Cancer
Enhanced permeability and retention (EPR) effect
Disorganization of tumor vasculature
Poor lymphatic drainage 10
Micro (nano) capsules and spheres 1
Capside vehicle PEO-protein conjugates
protein drug PEO chain
Capside
RNA Virus
Drug
Immunogenic response Prolong circulation Lowering activity
11
Micro (nano) capsules and spheres 2
Polymeric micelles
Hydrophilic Hydrophobic
Amiphilic block copolymer
Above CMC Drug
l. , ,
O N
H
C H
N C
HN H O
C OH
O O C
O HO
Yokoyama et a Cancer Res 1991 51, 3229.
PEO
Poly(aspartic acid)
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Paclitaxel incorporating micellar nanoparticle
Hydrophilic shell
Hydrophobic core
HN PhOH
O O
O Ph
AcO
OH AcOH O OBz
O OH
Paclitaxel(Taxol®) or PTX
85 nm
0 0.01
1 100 10000
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Drug conc/µg/mL
48 72 0
0 10
4 PTX
PTX
PTX-micelle PTX-micelle
Saline 8
20 30
Time after Administration/h Days after Initial Treatment
Relative Tumour Size
Figure by MIT OCW. Hamaguchi et al. British J Cancer, 2005, 92, 1240. 13
Micro (nano) capsules and spheres 3
Liposomes
CH2 CH O H2C
O C C
O
O O
P O CH2
-O O CH2 N+ CH3
CH3 H3C
Hydrophilic head
Lipid bilayer
Liposome
Hydrophobic tails
C12-C20
Small unilamellar vesicle (SUV): ~ 50 nm Large unilamellar vesicle (LUV): > 1 µm
Multilamellar vesicle
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15
Preparation of liposomes
1. Lipid thin film preparation
2. Swelling thin film
3. Ultrasound treatment
4. Extrusion
Glass surface
Air
Lipids are cast on a glass surface
Addition of aqueous media Tearing off from glass
Formation of liposomes
with various shapes and sizes
Reconstruction of lipid membrane Size: ~ 100 nm
Alfredsson, Current Opinion in Colloid & Interface Science, 2005, 10, 269. 16
Cryo-TEM image of cationic liposomes
Photo removed for copyright reasons.
Active targeting
Polymer drug conjugate PK2
(Phase I/II)Poly(N-(2-hydroxypropyl)methacrylamide)
Ringsdorf’s model
CH2 C CH2 CH2
CH3 CH3 CH3
C C C
NH CH2 CHOH CH3
O O O
Gly Gly
Phe Leu Gly C NH
Phe Leu Gly C NH
O O
O OH
O
O OH
OH
OCH3
HO HO O O OHHO HO
Galactosamine
Spacer
Saccharides, Peptides, etc.
Water soluble
polymer backbone Doxorubicin
Duncan R and Kopecek J et al.,
Ringsdorf, J Polym Sci Polymer Symp, 1975, 51, 135 Biochimica et Biophysuca Acta, 1983, 755, 518 17
Biodegradable spacer Drug
Oligoesters, oligopeptides
Targeting residue
Targeting residue
O NH
OH OH
COO- H3C OH
O
CH2OH
OH Sialic acid or
Saccharide determinants
Neuramic acidTerminal residue of carbohydrate chain
Gl in
Gl lipi ycoprote
yco d
O OH
H
H HO
H
OH
H OH H
OH
Galactose
Saccaride residue next to neuramic acid
3Galβ1
Neu5Acα2 4GlcNAcβ1
± Fucα1 6 Manα1
Neu5Acα2 3Galβ1 4GlcNAcβ1 2 6 6
Manβ 4GlcNAcβ1 4GlcNAc Asn 3Galβ1
Neu5Acα2 4GlcNAcβ1 4 3 1
Manα1 Typical surface carbohydrate 4GlcNAcβ1
2 connected to Asn of protein 18 Galβ1
Julyan et al., J Contr Release, 1999, 57, 281 19
Tissue distribution of
123I labeled PK2
CH2C CH2 CH2CH3 CH3 CH3
C C C
NH CH2 CHOH CH3
O O O
Gly Gly
Phe Leu Gly C NH
Phe Leu Gly C NH
O O
O OH
O
O OH
OH
OCH3
HO HO O O OHHO HO
Photos removed for copyright reasons.
Third key point in DDS
1. Controlling release rate 2. Site-specific delivery
+3. Drug formulation
H2N R NH2 Cl C O
R' C Cl O
NH C O
R' C O R
NH
Interfacial polymerization of polyamides
Water soluble
Diamine monomer
Drug-loading particle
Emulsion formed with 20
Drug and acid dichloride monomer
Emulsification of polymer and drug
+
H2 ilizi l
p
l i l
Aqueous phase
O & stab ng agent
Organ c phase
Po ymer & drug
drug- oad ng po ymer
i Preci itation of
Coacervation of polymer and drug
-
+
l l l (+) l l l ( )
Po ye ectro yte Po ye ectro yte
& drug
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What are the drugs?
Typical anticancer drugs
-Cl Pt
Cl- NH3+
+H3N
HN PhOH
O O
O Ph
AcO
OH AcOH O OBz
O OH
O
O OCH3
OH
OH
OH O CH2OH
O OH H2N
O
O O
OCH3 OH
O O NH
OH OH
CH3
H3C
H O O O
O
Cisplatin Paclitaxel(Taxol®) Doxorubicin Neocarzinostatin
chromophore
High molecular weight drugs
Proteins, peptides, hormones, cytokines DNAs and RNAs etc.
Bioactive compounds
Bioactive compounds are not stable are not stable ! !
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Summary
1. Controlling release rate
Degradable matrix
Environmentally responsive matrix, Proton sponge
2. Site-specific delivery
Passive targeting
EPR effect, RESActive targeting Targeting residue
3. Drug formulation
Denature or deactivation
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