Degradable polymers and drug delivery system

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Degradable polymers and degradable depot DDS Tae Gwan Park, Ph. D. Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon, Republic of Korea 305-701 Tel. 82-42-350-2621, FAX 82-42-350-2610

description

Biopolymeric materials

Transcript of Degradable polymers and drug delivery system

Page 1: 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

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Therapeutic protein drugs

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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)

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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)

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Surgical suture Wound dressing Anti-adhesion film

Biomedical applications

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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

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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

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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)

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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

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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

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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

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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

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* 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

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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

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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

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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

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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)

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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

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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

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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 !!

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Protein delivery applications of ReGel

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In vitro release of

Insulin from ReGelEfficacy of ReGel/insulin

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Injectable depot DDS

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Injectable depot DDS

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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)