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 !!

3 / 50

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

8 / 50

- 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

9 / 50

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

10 / 50

Design of protein release matrix

11 / 50

How are proteins released from hydrophobic matrixes?

Þ “Supersaturation” of proteins

Þ Tortuous channels for protein release

Tortuous channels for protein re-lease

12 / 50

Sustained protein release matrix

13 / 50

Prolease microspheres

14 / 50

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

15 / 50

Microsphere preparation

16 / 50

PLGA Microspheres

17 / 50

SEM of microspheres prepared by W/O/W

50 μm

* Sinha, Trehan; JCR, 2003.

Injectable microspheres on the mar-ket

18 / 50

Drug Release Mechanisms

19 / 50

Two hydrolysis mechanisms

20 / 50

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

21 / 50

Drug release from biodegradable polymers

22 / 50

(a) Bulk-eroding sys-tem

(b) Surface-eroding system

Erodible Matrices/Micro-spheres

Drug release from biodegradable polymers

23 / 50

Microsphere protein delivery

24 / 50

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

25 / 50

Injectable depot DDS

Sol GelTemperature

pH

Sol-Gel

Transition

Sol-Gel Transition Injectable Hydrogels

Biomedical injectable hydrogels

26 / 50

•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

27 / 50

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

28 / 50

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

29 / 50

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

30 / 50

Injectable depot DDS

31 / 50

In vitro degradation of ReGel In vitro degradation of ReGel in water (23% w/w)

32 / 50

Complete degradation in 6-8 weeks !!

Protein delivery applications of ReGel

33 / 50

In vitro release of

Insulin from ReGelEfficacy of ReGel/insulin

Injectable depot DDS

34 / 50

35

Injectable depot DDS

OncoGel: 1 week post injection

36 / 50

Promising delivery applications

37 / 50

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)