Degradable polymers and drug delivery system
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Transcript of Degradable polymers and drug delivery system
Degradable polymers and degradable depot DDS
Tae Gwan Park, Ph. D.
Department of Biological SciencesKorea Advanced Institute of Science and Technology
Daejeon, Republic of Korea 305-701Tel. 82-42-350-2621, FAX 82-42-350-2610
Therapeutic protein drugs
2 / 50
Negligible oral bioavailability - Invasive routes
Short biological half-life - Degradation by enzymes
Multiple administration
- Inconvenient for patients
- Increased medical costs
Sustained protein release matrix !!
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Poly(lactic-co-glycolic acid)
Biocompatible, biodegradable
Controllable degradation: Molecular weight, lactide/glycolide ratio
U.S. FDA approved polymer
OO
OH
CH3
O
O
nm
H
Lactic acid Glycolic acid
Biomedical and DDS applications
HOOH
CH3
O
HOOH
O
H2O (Hydrol-ysis)
Esterase (en-zyme)
Poly(lactic-co-glycolic acid) (PLGA)
Degradation mechanisms
1. anhydride > ester > carbonate bond
Degradability: susceptibility of the linkage to hydrolysis
2. copolymer (PLGA) > homopolymer (PLA, PGA)
Copolymerization: overall crystallinity of polymer ↓
3. PLGA > poly(lactic acid)
Methyl group ⇒
hydrolytically stable
(JBMR, 11:711, 1977)
Surgical suture Wound dressing Anti-adhesion film
Biomedical applications
AD
VE
NC
ED
TIS
SUE
SC
IEN
CE
, IN
C.
Biodegradable
porous scaffold
Stem cells, chondrocytes, osteoblast, hepatocytes,
endothelial cells
In vitro or in vivo culture
Tissue engineering
Biomedical applications
Sustained release of therapeutic proteins
Improved efficacy Good in vivo stability Reduced administration
frequency
Angiogenic growth factor- releas-ing injectable microsphereIschemic heart disease
Drug delivery devices
Biomedical applications
Various biodegradable polymers
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- Biocompatibility: monomer, oligomer, polymer, stabilizer, initiator, subsequent metabolites
- Three synthetic degradable polymers (PLA, PGA, PLGA) are widely used in clinical trials.
Poly(glycolide-lactide) copolymer (PLGA)
Polyhydroxybutyrate (PHB)Copolymer with polyhydroxyvalerate (PHV) to increase
flexibility and processability
Very slowly degraded in physiological condition
PolycaprolactoneDegaded at a slower pace than PLA (over a year)
Various biodegradable polymers
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Poly(ortho ester)Surface erosion
Controlled release drug delivery
Polyanhydride
Aliphatic polyanhydrides degrade within days; aromatic polyanhydride over several years
The most reactive and hydrolytically unstable polymer
Degraded by surface erosion
Polyphosphazine
A group of inorganic polymers whose backbone
consists of nitrogen-phosphorous bonds
Preparation of sustained release ma-trix
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Design of protein release matrix
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How are proteins released from hydrophobic matrixes?
Þ “Supersaturation” of proteins
Þ Tortuous channels for protein release
Tortuous channels for protein re-lease
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Sustained protein release matrix
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Prolease microspheres
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Lab scale prolease process Cross section of prolease microsphere
Protein suspension
Atomizer
Atomized Droplets
Liquid Nitrogen
Frozen Microspheres
Extraction (ethanol)Release Modifier 1-5 m
Lyophilized Drug Substance 1-5 m
PLGA Microsphere 25-180 m
Microsphere preparation
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Microsphere preparation
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PLGA Microspheres
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SEM of microspheres prepared by W/O/W
50 μm
* Sinha, Trehan; JCR, 2003.
Injectable microspheres on the mar-ket
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Drug Release Mechanisms
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Two hydrolysis mechanisms
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Surface erosion :
Degradation from a surface
ex) poly(ortho)esters and polyanhydrides
Bulk erosion :
Degradation takes place throughout an entire device simultaneously
ex) PLA, PGA, PLGA, PCL
Degradation of biodegradable poly-mers
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Drug release from biodegradable polymers
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(a) Bulk-eroding sys-tem
(b) Surface-eroding system
Erodible Matrices/Micro-spheres
Drug release from biodegradable polymers
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Microsphere protein delivery
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Biodegradable polymer microspheres – poly(lactic-co-glycolic acid) (PLGA) for protein delivery
(e.g. Lupron Depot®, Nutropin Depot®)
Fabrication of protein loaded microspheres: A double-emulsion (-solvent evaporation)
method. --- Use of water-immiscible, volatile organic sol-
vent (e.g. methylene chloride, chloroform)
---Harsh preparation condition
Problems : Initial burst effect Slow or no release Protein denaturation
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Injectable depot DDS
Sol GelTemperature
pH
Sol-Gel
Transition
Sol-Gel Transition Injectable Hydrogels
Biomedical injectable hydrogels
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•ReGelTM
PLGA-PEO-PLGA triblock copolymers
Depot Formulation for Paclitaxel (Phase I)
Acidic microenvironment problem
•ReGelTM
PLGA-PEO-PLGA triblock copolymers
Depot Formulation for Paclitaxel (Phase I)
Acidic microenvironment problem
Sol GelT < RT
T > RT
•Pluronic® (Poloxamers)
PEO-PPO-PEO
No DDS commercial products
Rapid dissolution problem
•Pluronic® (Poloxamers)
PEO-PPO-PEO
No DDS commercial products
Rapid dissolution problem
HO CH2CH2O CHCH2O
CH3
CH2CH2O H99 9965
HO CH(CH3)CO
O
CH2CO
O
CH2CH2O CCH2O CCH2(CH2)O H
O O
y z x z y
•Polyphosphazenes•Polyphosphazenes
Structure of block copolymer hydro-gels
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Flower micelle
Core-shell micelle
Amphiphilic copolymers self-associate into micelles
upon passing a critical concentration (CMC) or
temperature (CMT) at relatively low concentration.
ReGel
(PLGA-PEO-PLGA)
HyGel
(PEO-PLGA-PEO),
Pluronic
(PEO-PPO-PEO)
Structure of block copolymer hydro-gels
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At higher concentration, micelles interact to occur gelation:
The interaction depends on the structure of block copolymer.
Inter-micelle physical cross-links Entanglement of packed micelle coronas
ReGel
(PLGA-PEO-PLGA)PEO-PLGA-PEO,
Pluronic
LCST behavior of hydrogels
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Amphiphilic copolymers associate on increasing temp.
They belong to a class of materials exhibiting LCST
(lower critical solution temperature) behaviors.
Phase
separation
Polymer-rich
Polymer-poor
Injectable depot DDS
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Injectable depot DDS
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In vitro degradation of ReGel In vitro degradation of ReGel in water (23% w/w)
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Complete degradation in 6-8 weeks !!
Protein delivery applications of ReGel
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In vitro release of
Insulin from ReGelEfficacy of ReGel/insulin
Injectable depot DDS
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35
Injectable depot DDS
OncoGel: 1 week post injection
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Promising delivery applications
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Hormones: Human growth hormone (hGH) Insulin Erythropoietin (EPO) Granulocyte-colony stimulating factor (G-CSF) Interferon (IFN) Luteinizing hormone-releasing hormone (LH-RH)
Growth factors: Vascular endothelial growth factor (VEGF) Epidermal growth factor (EGF) Basic fibroblast growth factor (b-FGF) Transforming growth factor-β (TGF- β)