BIODEGRADABLE BIODEGRADABLE POLYMERSPOLYMERS

Biodegradable Polymer

Biodegradable polymers degrade within the body as a result of natural biological processes.

They are broken down into biologically acceptable molecules that are metabolized and removed from the body via normal metabolic pathways.

• Inert

• Permeability

• Biodegradability

• Bio-compatilibility

Ideal Characteristics Of Polymers In Biodegradable Delivery System

BIODEGRADATIONBIODEGRADATION

ENZYMATIC DEGRADATION HYDROLYSIS

BULK EROSION SURFACE EROSION

Mechanism Of Biodegradable PolymersMechanism Of Biodegradable Polymers

POLYMER DEGRADATION

The degradation is primarily the process of chain cleavage leading to a reduction in molecular weight. On the other hand, erosion is the sum of all processes leading to the loss of mass from a polymer matrix.

Degradation Schemes The degradation of the polymer can be through either bulk

erosion (as in poly(α-hydroxy esters)) or surface erosion (as in polyanhydrides, poly(orthoesters)).

Generally Hydrophobic Polymers degraded by these mechanisms.

Enzymatic degradation Hydrolysis

Bulk Erosion : In this process hydrolysis occurs throughout the bulk of the polymer. The matrix can disintegrate before drug depletion, and a large burst in rate of drug delivery can take place.

Surface Erosion: In a surface erosion process hydrolysis of the polymer is confined to the outer surface, and the interior of the matrix remains essentially unchanged.

Type I Erosion It is evident with water-

soluble polymers cross-linked to form a three-dimensional network.

Erosion can occur by cleavage of cross-links (type IA) or cleavage of the water-soluble polymer backbone (type IB)

Type II Erosion

It occurs with polymers that were earlier water-insoluble but converted to water-soluble forms by hydrolysis, ionization or protonation of a pendant group.

Type III Erosion

High molecular weight, water-insoluble macromolecules are converted to small, water-soluble molecules by a hydrolytic cleavage of labile bonds in the polymer backbone.

Factors Influence the Degradation Behavior

Chemical Structure and Chemical Composition Molecular Weight Presence of Low Mw Compounds (monomer, oligomers,

solvents, plasticizers, etc) Presence of Ionic Groups Presence of Chain Defects Configurational Structure Morphology (crystallinity, presence of microstructure,

orientation and residue stress) Processing methods & Conditions Method of Sterilization Storage History Site of Implantation Physiochemical Factors (shape, size) Mechanism of Hydrolysis (enzymes vs water)

SYNTHETIC POLYMERS

♦ Aliphatic Poly (ester)s

Poly (glycolic acid) (PGA) Poly (lactic acid) (PLA) Poly (ε-caprolactone) Poly (para-dioxanone) Poly (hydroxybutyrate) Poly (ß-malic acid)

♦ Polyphosphoesters

♦ Polyanhydrides

♦ Poly (ortho esters)

♦ Polyphosphazenes Hydrophilic Hydrophobic Insoluble Surface-active Insoluble biodegradable Imidazolyl derivatives Glyceryl derivatives Glucosyl derivatives

♦ Poly (amino) Acids and Pseudopoly (amino) Acids

Poly-L-glutamic acid Poly-L-Lysine (PLL) Hydroxyproline-derived

Polyesters Tyrosine-derived poly

(iminocarbonates)

POLY (GLYCOLIC ACID) ---(--O—C-CH2---)n

POLY (LACTIC ACID) --(--O---C—CH---)n

POLY (CAPROLACTONE) --(--O—C---(CH2)5---)n

First polymers used in medicine dated back to 1954. Most commercialized class of Polymers

ex : ADRIAMYCIN®

Bio compatible & Bio resorbable Synthesis & Co polymerisation can be easily done t ½ ranges from weeks (PLA) to years (PCL).

APPLICATIONS : (1) Sutures, ligatures etc. (2) DECAPEPTYL ® , LUPRON DEPOT ®

Lactide/Glycolide Polymers

DEGRADATION IS MAINLY BY

(1) ENZYMATIC

(2) HYDROLYTIC

(3) MICROBIAL

ENZYMATIC

Esterase, pronase, bromelain

HYDROLYSIS

R—COO---R1 + H2O R—COOH + R1 –OH

MICROBIAL DEGRADATION • Fungi – ‘ FUSARIUM MONILIFORMAE’ • YEAST- ‘CRYPTOCOCCUS’

POLY PHOSPHO ESTERS O --(--P---O---R---O--)-- Poly (Phosphate ) OR1

O --(--P---O---R---O--)-- Poly (Phosphonate) R1

Highly Adjustable properties Good Biocompatabilty High Degradability High Mol.wt gives good strength

Drug Release Get degraded within 6 months T1/2 is from 2 to 4 months.. Degradation products – phosphates & alcohol.

Applications Paclitaxel, Cisplatin, Plasmid DNA.

Sterilisation & stability Highly susceptible to hydrolysis in open air. Should be stored in a desiccators. Sterilization only by gamma irradiation.

POLY ANHYDRIDES

HO--[---(C—R1----C)n1-----O-----(C---R2---C-)n2--]n3---OH

General structure

• Two carboxylic groups at each end

• High Degradation rate

• Degrade by Surface Erosion

• Aromatic P.A’s are slower degrading

• Copolymerisation can control degradation rate

• Biological tests in Rabbits proved them Non-mutagenic

APPLICATIONS : 1) Peptides for osteomylites.

2) Protiens for brain tumour.

Drug Release Mostly they degrade by Surface Erosion (S.E)

Their t1/2 is less than 30 days.

Due to S.E. proportion of drug released alters with time.

Drug Stability Primary amine containing drugs react at pH 7.2. The above reaction is not seen below pH 5.0. They are ideal when action is required for 1 week They have more application as parentrals.

POLY OLEFINS Properties A polyolefin is a polymer produced from a simple olefin (also

called an alkene with the general formula CnH2n) as a monomer.

Carbon Chain based Polymers. They contain Double & Triple bonds extensively. Presence of substituents like cyanoacryl groups enhance

degradation rate. Introduction of vinyl group makes them more stable

ex : Teflon

Applications

1) Sutures, catheters, implants.

2) Membrane barrier for drugs.

POLY AMIDESPROPERTIES : A polyamide is a polymer containing monomers of amides

joined by peptide bonds. These are generally called as ‘NYLONS’. They are generally slow degrading. By Introduction of copolymers like ‘L-Aspartic Acid', nearly

40% of polymer Is degraded within 1 week. Mainly degraded In vivo by Non-specific ‘Amidases’ They are more stable when compared to other Polymers.

APPLICATIONS :

• Haemofiltration Membranes.

• Dressings, sutures etc.

ADVANTAGES Play an essential role in Formulation of CDDS. Patient compliance is improved. Bio compatible. Help in adjusting duration of action of drug. Most of them are Inert. Copolymerisation can be done.

DISADVANTAGES Expensive. Drug release cannot be 100% predicted.

NATURAL POLYMERSThese are the polymers obtained from natural resources, and

are generally non-toxic.

NATURAL POLYMERS

PROTEINS Polysaccharides

Ex: COLLAGEN ALBUMIN FIBRIN

Ex : DEXTRAN CHITOSAN STARCH

ADVANTAGES : 1) Readily & Abundantly Available. 2) Comparatively Inexpensive. 3) Non toxic products. 4) Modified to get semi synthetic forms.

PROTEINS

ALBUMINADVANTAGES

• It is a major plasma protein component.• It accounts for more than 55% of total protein in

human plasma.• It is used to design particulate drug delivery systems.

Factors Affecting Drug Release From Albumin Microspheres

• Physicochemical properties and the concentration of the drug.

• Interaction between the drug and the albumin matrix.• Size and density of microspheres.• Nature and degree of cross-linking.• Presence of the enzymes and pH in the environment.

USES

• Albumin micro-spheres are used to deliver drugs like Insulin, Sulphadiazene, 5-fluorouracil, Prednisolone etc.

• It is mainly used in chemotherapy, to achieve high local drug concentration for relatively longer time.

COLLAGENADVANTAGES It is a major structural protein in animals It is used as sutures ,Dressings, etc. Readily isolated & purified in large quantities. Can be processed in variety of forms .

DISADVANTAGES Chance of antigenic response. Variability in drug release kinetics. Poor mechanical strength.

SODIUM ALGINATE

• Since the use of organic solvents and high temperature is not required even viable bacteria and viruses can be employed.

• It protects the antigens and the vaccines against degradation in GIT.

• It acts as an adjuvant.

USES

• Alginates are particularly used as carriers of peptides and other sensitive drug molecules since particulate carriers can be easily prepared in aqueous solution at room temperature.

• Alginate micro-spheres are efficiently used for oral delivery of vaccines.

POLYSACCARIDESDEXTRAN • Dextran is a complex branched polysaccharide made of many

glucose molecules joined into chains of varying lengths. • It consists of α-D-1,6-glucose-linked glucan with side-chains

linked to the backbone of Polymer.• Mol.wt ranges from 1000 to 2,00,000 Daltons

• Enzymes from moulds such as ‘PENCILLIUM’ degrade it.

APPLICATIONS

1) Replacement of Blood loss.

2) Thrombosis Prophylaxis.

3) Improvement of Rheology.

CHITOSAN

• It consists of B-1-4 linked 2 amino-2-deoxy gluco –pyranose moieties.

• Commercially manufactured by N-deacetylation of Chitin which is obtained from Mollusc shells.

• It is soluble only in acidic pH i.e. when amino group is protonated.

• Thereby it readily adheres to bio membranes.• It is degraded mainly by Glycosidases & lysozymes.

ADVANTAGES Free availability, Biocompatibility, Biodegradability Bioadhesive, unique properties.

ENVIRONMENTALLY RESPONSIVE POLYMERS

Thermosensitive Polymers e.g. Poly (N-alkyl substututed acrylamides)

Electrically and Chemically Controlled Polymers

e.g. PEG & Poly(methacrylic acid) (PMMA), collagen, Poly(pyrrole)

pH Sensitive polymers e.g. Poly(2-ethylacrylic acid) (PEAA)

Azopolymers

MISCELLANEOUS POLYMERS

Polymeric Phospholipids Polyethyleneimine Polyamidoamine Polyethylene Glycol