1

A SEMINAR ON A SEMINAR ON BIODEGRADABLE POLYMERSBIODEGRADABLE POLYMERS

Department of pharmaceuticsDepartment of pharmaceutics

AISSMS COLLEGE OF PHARMACYAISSMS COLLEGE OF PHARMACYPUNEPUNE

Date: 1.10.2009Date: 1.10.2009

2

CONTENTSCONTENTS Definition Definition Ideal characteristicsIdeal characteristics Advantages and DisadvantagesAdvantages and Disadvantages Polymers erosion mechanismPolymers erosion mechanism Polymers drug release mechanismPolymers drug release mechanism Classification of polymers along with Classification of polymers along with

their applicationtheir application Product based on biodegradable Product based on biodegradable

polymerspolymers References References

BIODEGRADABLE BIODEGRADABLE POLYMERSPOLYMERS

DEFINITION:DEFINITION:

The natural ability of chemical The natural ability of chemical substance to be broken down into substance to be broken down into less complex compounds having less complex compounds having fewer carbon atoms by body fluids fewer carbon atoms by body fluids or enzymes or microorganism. or enzymes or microorganism.

OROR

It is defined as the breakdown It is defined as the breakdown of polymer into its components of polymer into its components monomers or oligomers upon monomers or oligomers upon coming in contact with body fluids, coming in contact with body fluids, enzymes and microbial flora.enzymes and microbial flora.

4

IDEAL CHARACTERISTICS IDEAL CHARACTERISTICS OF BIODEGRADABLE OF BIODEGRADABLE

POLYMERSPOLYMERS Minimal side effects after Minimal side effects after

introduction into body.introduction into body. In vivo degradation at well defined In vivo degradation at well defined

rate.rate. Degradation products should be Degradation products should be

nontoxic and easily excreted.nontoxic and easily excreted. Free from any toxic endogenous Free from any toxic endogenous

impurities or residual chemical.impurities or residual chemical. Should be inert in nature.Should be inert in nature. Should have relative stability.Should have relative stability.

5

ADVANTAGES OF ADVANTAGES OF BIODEGRADABLE BIODEGRADABLE

POLYMERSPOLYMERS Useful for delivery of synthetic drugs as Useful for delivery of synthetic drugs as

well as proteins and biotechnological well as proteins and biotechnological products .products .

No need subsequent retrival of the No need subsequent retrival of the delivery. delivery.

Better drug utilization and improved Better drug utilization and improved patients compliance. patients compliance.

Targeted specific part of body hence Targeted specific part of body hence reduce side effect.reduce side effect.

Provide controlled rate of drug release. Provide controlled rate of drug release.

6

DISADVANTEGES OF DISADVANTEGES OF BIODEGRADABLE BIODEGRADABLE

POLYMERSPOLYMERS Difficult to formulate a biodegradable Difficult to formulate a biodegradable

system system Carrier must be human friendly.Carrier must be human friendly. Some polymers do not have detail Some polymers do not have detail

information about its information about its biodegradability, kinetic, stability biodegradability, kinetic, stability profile.profile.

7

POLYMERS EROSION POLYMERS EROSION MECHANISMMECHANISM

Bioerosion : physical process that Bioerosion : physical process that result in weight loss of polymer result in weight loss of polymer devices.devices.

Two types of erosionTwo types of erosion

1.chemical erosion1.chemical erosion

2.physical erosion 2.physical erosion

8

Chemical erosionChemical erosion Mechanism 1Mechanism 1

Type 1A] Degradation in these Type 1A] Degradation in these system can occur either at cross system can occur either at cross links to form soluble backbone links to form soluble backbone polymeric chains provide high polymeric chains provide high molecular weight,molecular weight,

Type 2B] At the main chain to Type 2B] At the main chain to form water soluble fragments. form water soluble fragments. Provide low molecular weight Provide low molecular weight fragments.fragments.

Mechanism 2Mechanism 2

water insoluble macromolecule water insoluble macromolecule with side groups converted in with side groups converted in water soluble polymer by water soluble polymer by ionization, protonation or ionization, protonation or hydrolysis of groups.hydrolysis of groups.

Mechanism 3 Mechanism 3

Degradation of insoluble Degradation of insoluble polymers with labile polymers with labile bonds .hydrolysis of labile bond bonds .hydrolysis of labile bond causes scisson of polymer causes scisson of polymer backbone. backbone.

9

Polymers & their Polymers & their chemical mechanism of chemical mechanism of

erosionerosion Gelatin Gelatin CollagenCollagen PolyanhydridesPolyanhydrides Polycaprolactone & Polycaprolactone &

it’s copolymer it’s copolymer Poly (ortho esters)Poly (ortho esters) Poly (lactic acids)Poly (lactic acids) Poly (glycolic acid)Poly (glycolic acid) Poly (vinyl alcohol)Poly (vinyl alcohol)

Type 1Type 1Type 1 & Type 2Type 1 & Type 2Type 3Type 3

Type 3 Type 3 Type 3Type 3Type 3Type 3Type 3Type 3Type 1Type 1

10

Physical erosionPhysical erosion

Heterogeneous Heterogeneous erosion erosion

called surface called surface erosion, polymer erosion, polymer erode only at surface erode only at surface and maintain it’s and maintain it’s physical integrity. physical integrity.

Homogenous Homogenous erosion called bulk erosion called bulk erosion hydrolysis erosion hydrolysis occur at even rate occur at even rate throughout the throughout the polymer matrix.polymer matrix.

11

DRUG RELEASE MECHANISMS OF DRUG RELEASE MECHANISMS OF BIODEGRADABLE POLYMERSBIODEGRADABLE POLYMERS

In mechanism 1 the drug In mechanism 1 the drug is attached to polymer is attached to polymer backbone by labile bond, backbone by labile bond, shows higher reactivity to shows higher reactivity to breakdown. breakdown.

Mechanism 2 drug Mechanism 2 drug release is controlled by release is controlled by biodegradable membrane biodegradable membrane surrounded by core surrounded by core containing drug . containing drug .

Mechanism 3 Mechanism 3 homogeneously dispersed homogeneously dispersed drug in biodegradable drug in biodegradable polymers released by polymers released by erosion diffusion or erosion diffusion or combination of both. combination of both.

12

CLASSIFICATION OF CLASSIFICATION OF BIODEGRADABLE BIODEGRADABLE

POLYMERS.POLYMERS. Synthetic Synthetic NaturalNatural

Lactide & glycolides. Collagen.Lactide & glycolides. Collagen.

Polyanhydride Gelatin. Polyanhydride Gelatin.

Poly-E-Caprolactone. Albumin.Poly-E-Caprolactone. Albumin.

Polyphosphazenes. Starch Polyphosphazenes. Starch

Pseudo(amino acid) Dextran.Pseudo(amino acid) Dextran.

13

SYNTHETIC BIODEGRADABLE SYNTHETIC BIODEGRADABLE POLYMERS ALONG WITH THEIR POLYMERS ALONG WITH THEIR

COPOLYMERSCOPOLYMERS1)Lactide & glycolides Poly [lactic acid] (PLA)1)Lactide & glycolides Poly [lactic acid] (PLA) Poly [glycolic acid] (PGA)Poly [glycolic acid] (PGA)

Poly [ lactide-co-glycolic] (PLGA)Poly [ lactide-co-glycolic] (PLGA)

2)Polyanhydride Poly [carboxy-phenoxy- propane] Sebasic 2)Polyanhydride Poly [carboxy-phenoxy- propane] Sebasic acidacid

(PCPP-SA(PCPP-SA) ) Poly [terepthalic acid] Sebasic acid (PTA-Poly [terepthalic acid] Sebasic acid (PTA-

SASA))

3)Polyphosphaazenes Hydrophobic groups like fluoro alkoxy side 3)Polyphosphaazenes Hydrophobic groups like fluoro alkoxy side group group

aryl groups ,poly tetra fluoro ethylene.aryl groups ,poly tetra fluoro ethylene. Hydrophilic groups like short chain alkyl Hydrophilic groups like short chain alkyl

amino amino side groups.side groups.4)Poly-E-caprolactone Copolymer derived from poly ethylene glycol,4)Poly-E-caprolactone Copolymer derived from poly ethylene glycol, polystyrene.polystyrene. Copolymer with lactide & glycolidesCopolymer with lactide & glycolides

5)Pseudo (amino acid) Tyrosine derived poly (amino) carbonate5)Pseudo (amino acid) Tyrosine derived poly (amino) carbonate

14

POLYMERS AND THEIR POLYMERS AND THEIR APPLICATIONAPPLICATION

Lactide & glycolidesLactide & glycolides

Considered as GRAS product by FDAConsidered as GRAS product by FDA GRAS [Generally recognized as safe]GRAS [Generally recognized as safe]

Synthesis by ring opening melt Synthesis by ring opening melt condensation of cyclic dimers such as condensation of cyclic dimers such as Lactide & glycolides.Lactide & glycolides.

Degradation by homogenous erosion.Degradation by homogenous erosion.

Can be easily fabricated into Can be easily fabricated into microspheres,implants and fibersmicrospheres,implants and fibers

15

APPLICATIONSAPPLICATIONS

L-PLA are suitable for sustain release of L-PLA are suitable for sustain release of -Narcotic antagonist -Narcotic antagonist

[naltrexone,naloxone] for morphine [naltrexone,naloxone] for morphine dependence.dependence.

-anticancer agents -anticancer agents [cisplatin,cyclophosphamide][cisplatin,cyclophosphamide]

-steroids [norethisterone]to prolong its -steroids [norethisterone]to prolong its effects.effects.

PLA and PGA are suitable for PLA and PGA are suitable for antimalarial drugs [quinazolin]antimalarial drugs [quinazolin]

Poly DL-lactide co glycolides formulated Poly DL-lactide co glycolides formulated with various antibiotics with various antibiotics [ampicilline,polymixin,chloramphenicol][ampicilline,polymixin,chloramphenicol]

16

Local anesthetics [lidocaine,xylocaine] Local anesthetics [lidocaine,xylocaine] are formulated with homo and co-are formulated with homo and co-polymers of lactide and glycolides.polymers of lactide and glycolides.

In formulation of veterinary products In formulation of veterinary products [melatonin loaded system for sheep for [melatonin loaded system for sheep for production of fur.production of fur.

Bioactive agents like polypeptides Bioactive agents like polypeptides [LHRH,calcitonin] and vaccine [LHRH,calcitonin] and vaccine [antigen, antibody] can given with this.[antigen, antibody] can given with this.

co-polymers used formulate co-polymers used formulate biotechnology products.biotechnology products.

17

POLYANHYDRIDEPOLYANHYDRIDE

Better biocompatibility with body tissueBetter biocompatibility with body tissue

Rate of hydrolytic degradation at the Rate of hydrolytic degradation at the surface of the polymer system is faster surface of the polymer system is faster than the of rate of penetration into the than the of rate of penetration into the bulk of the polymers matrix hence use bulk of the polymers matrix hence use for water liable drugs for water liable drugs

Polycondensation,dehydrochlorination Polycondensation,dehydrochlorination and dehydrative coupling synthesize and dehydrative coupling synthesize this polymers.this polymers.

18

APPLICATIONAPPLICATION CPP-SA used to formulate anticancer agents CPP-SA used to formulate anticancer agents

[carmustine] –used in treatment of [carmustine] –used in treatment of glioblastoma multiforme,which is a type glioblastoma multiforme,which is a type brain cancer.brain cancer.

Angiotensin inhibitors formulate with PTA-Angiotensin inhibitors formulate with PTA-SA.SA.

Cortisone acetate is formulated with PTA-Cortisone acetate is formulated with PTA-SA.SA.

Formulation of drug bethanechol which is Formulation of drug bethanechol which is potent acetyl choline esterase-resistant potent acetyl choline esterase-resistant cholinomimetic for Alzheimer’s disease.cholinomimetic for Alzheimer’s disease.

19

POLYPHOSPHAZENESPOLYPHOSPHAZENES

Long chain backbone of alternative Long chain backbone of alternative nitrogen and phosphorus atom with nitrogen and phosphorus atom with two groups attached to each other.two groups attached to each other.

Two types of polyphosphazenes.Two types of polyphosphazenes. 1) Strong hydrophobic like 1) Strong hydrophobic like

fluoroalkoxy side fluoroalkoxy side chain, chain, aryloxy phophazenes.aryloxy phophazenes.

2) Hydrophilic polyphosphazenes 2) Hydrophilic polyphosphazenes contain short chain of aryl amine contain short chain of aryl amine side groups, alkyl ether side chain. side groups, alkyl ether side chain.

20

Good candidate for implantable device Good candidate for implantable device which is easy to fabricate and flexible.which is easy to fabricate and flexible.

They are surface tailored to retard the They are surface tailored to retard the blood clotting. blood clotting.

Amphiphillic polyphosphazenes have Amphiphillic polyphosphazenes have both hydrophilic and hydrophobic both hydrophilic and hydrophobic groups.groups.

Certain derivative shows hydrogel Certain derivative shows hydrogel characteristics such as they swell up characteristics such as they swell up into gel.into gel.

21

APPLICATIONAPPLICATION Drug containing COOH groups (salicylic Drug containing COOH groups (salicylic

acid) could be linked to this polymer by acid) could be linked to this polymer by amide linkage to prepare controlled release amide linkage to prepare controlled release prodrug.prodrug.

Used as hydrogel:Used as hydrogel: Intraocular lenses.Intraocular lenses. Soft tissue prosthesis (artificial Soft tissue prosthesis (artificial

replacement replacement for a missing tissue)for a missing tissue).. Substrate for enzyme and antigen.Substrate for enzyme and antigen.

Polymer bound platinum antitumor agent Polymer bound platinum antitumor agent are available having better therapeutic are available having better therapeutic effect & good pharmacokinetics properties. effect & good pharmacokinetics properties.

22

POLY-E-CAPROLACTONEPOLY-E-CAPROLACTONE

Shows heterogeneous degradation Shows heterogeneous degradation by micro-organism in the by micro-organism in the environment.environment.

Good biodegradability and high Good biodegradability and high permeability & lack of toxicity.permeability & lack of toxicity.

Synthesis by oxidation of Synthesis by oxidation of cyclohexanone with per acetic acid.cyclohexanone with per acetic acid.

23

APPLICATIONAPPLICATION

Drug like tetracycline, 5-fluoro Drug like tetracycline, 5-fluoro Uracil, chlorpromazine, naloxanes Uracil, chlorpromazine, naloxanes are given with this polymers.are given with this polymers.

polymer Fiber used to control the polymer Fiber used to control the release of herbicide in an aquatic release of herbicide in an aquatic environment. environment.

Reservoir devices for delivery of Reservoir devices for delivery of steroid like levonorgestrol.steroid like levonorgestrol.

24

PSEUDOPOLY(AMINO PSEUDOPOLY(AMINO ACID)ACID)

Give good mechanically strong implants Give good mechanically strong implants but have gross toxicity and tissue but have gross toxicity and tissue incompatibility.incompatibility.

Synthetic poly (amino acid) derived from Synthetic poly (amino acid) derived from single amino acid is insoluble has high single amino acid is insoluble has high melting point & can not be processed into melting point & can not be processed into various shapes.various shapes.

Pseudo peptide denote peptide in which Pseudo peptide denote peptide in which some or all amino acid are linked by bonds some or all amino acid are linked by bonds other than conventional peptide linkage. other than conventional peptide linkage.

25

APPLICATIONAPPLICATION

Polymer used for antigen delivery Polymer used for antigen delivery that is for effective vaccination.that is for effective vaccination.

Very useful in delivery of variety Very useful in delivery of variety of veterinary product.of veterinary product.

Suitable for delivery of important Suitable for delivery of important peptides like enkephalins.peptides like enkephalins.

26

NATURAL POLYMERSNATURAL POLYMERS

ADVANTAGESADVANTAGES readily available natural readily available natural

polymers.polymers. relatively inexpensive.relatively inexpensive. chemical modification is possible chemical modification is possible

easily.easily.

27

COLLAGENCOLLAGEN

Unique structural properties therefore it Unique structural properties therefore it can fabricated into variety of forms can fabricated into variety of forms including films, inserts.including films, inserts.

Collagen is found in animal tissue Collagen is found in animal tissue usually present in the tissue of skin and usually present in the tissue of skin and tendon.tendon.

Has advantages of easy purification and Has advantages of easy purification and isolation in large isolation in large quantities,biocampatibility,non toxic to quantities,biocampatibility,non toxic to most tissue. most tissue.

28

APPLICATIONAPPLICATION

Pilocarpine films used for controlling Pilocarpine films used for controlling elevated intraocular pressure.elevated intraocular pressure.

Gentamycin films to treat bacterial Gentamycin films to treat bacterial eye infection. eye infection.

Collagen shield made from porcine Collagen shield made from porcine source and given to patients with source and given to patients with corneal abrasion or after corneal corneal abrasion or after corneal surgery.surgery.

29

ALBUMINALBUMIN Major plasma constituent in body Major plasma constituent in body

and features like reported and features like reported biodegradation, lack of toxicity, biodegradation, lack of toxicity, non- antigenicity and readily non- antigenicity and readily available. available.

APPLICATIONAPPLICATION 1. Drugs like 1. Drugs like

doxorubicin,mitomycine,5-doxorubicin,mitomycine,5-fluorouracil are given because tumor fluorouracil are given because tumor cells ability to take up albumin.cells ability to take up albumin.

30

STARCHSTARCH

Most abundant biodegradable Most abundant biodegradable polymers which belong to class of polymers which belong to class of polysaccharide.polysaccharide.

It consist of glycopyranose units which It consist of glycopyranose units which under hydrolysis yields D-glucose.under hydrolysis yields D-glucose.

APPLICATIONAPPLICATION

starch microspheres used for starch microspheres used for intranasal administration of insulin. intranasal administration of insulin.

31

GELATINGELATIN

It is protinaceous biodegradable It is protinaceous biodegradable polymers obtained from partial polymers obtained from partial hydrolysis of collagen derived from hydrolysis of collagen derived from skin, connective tissue and bones of skin, connective tissue and bones of animal. animal.

Two typesTwo types

a] Type A : acid treated .a] Type A : acid treated .

b] Type B : alkali treated.b] Type B : alkali treated.

mostly fabricated into microspheres. mostly fabricated into microspheres.

32

APPLICATIONAPPLICATION Good carrier systems for number of Good carrier systems for number of

anticancer agents that is tumors anticancer agents that is tumors which do not take albumin redially which do not take albumin redially take up gelatin.take up gelatin.

Used as an immunoadjuvant because Used as an immunoadjuvant because gelatin is susceptible to macrophage gelatin is susceptible to macrophage recognition. The gelatin containing recognition. The gelatin containing the antigen can carry it directly to the antigen can carry it directly to the macrophages and antigen is the macrophages and antigen is released as gelatin degrades which released as gelatin degrades which leads to enhance production of leads to enhance production of antigen specific antibodies.antigen specific antibodies.

33

DextranDextran

It is a carbohydrate used to It is a carbohydrate used to prepare hydrogel, which is prepare hydrogel, which is biodegradable and biodegradable and biocompatible. Usually available biocompatible. Usually available as microspheresas microspheres

ApplicationApplication

Acts as a good carrier for a Acts as a good carrier for a variety of drugs, proteins. variety of drugs, proteins.

34

OTHER NATURALLY OCCURING OTHER NATURALLY OCCURING POLYMERS POLYMERS

Hyaluronic acid Hyaluronic acid Fibrinogen Fibrinogen Deacetylated Chitin: aid weight loss Deacetylated Chitin: aid weight loss

and cholesterol lowering agents.and cholesterol lowering agents. CarragenanCarragenan Alginate Alginate

35

SOME PRODUCT BASED ON SOME PRODUCT BASED ON BIODEGRADABLE POLYMERSBIODEGRADABLE POLYMERS

1. 1. Zoladex (Astra zeneca) : Zoladex (Astra zeneca) : Is supplied as sterile biodegradable product containing Is supplied as sterile biodegradable product containing

goserlin acetate equivalent to 3.6 mg of goserlin given as goserlin acetate equivalent to 3.6 mg of goserlin given as sub cutaneous injection with continuous release over 28 sub cutaneous injection with continuous release over 28 days. It dispersed in matrix of DL lactic & glycolic acid. days. It dispersed in matrix of DL lactic & glycolic acid.

2. Lupron depot :2. Lupron depot : FDA cleared PLGA product FDA cleared PLGA product microsphere formulation based on degradable polymers microsphere formulation based on degradable polymers

of polylactic acid & poly (lactic/glycolic acid).of polylactic acid & poly (lactic/glycolic acid).3 Gliadel wafer.3 Gliadel wafer. contain cancer chemotherapeutic drug carmustinecontain cancer chemotherapeutic drug carmustine fabricated from poly (caboxyphenoxy propane: sebacic fabricated from poly (caboxyphenoxy propane: sebacic

acid) acid)

36

REFERENCES Biodegradable polymers as Drug delivery

systems Mark chasin, Robert Langer,volume 45.

Indian Journal of pharmaceutical sciences sep-oct 2007.69(5):609-

734. V. B. Kotwal, Maria Saiffee, Nazma Inamdar and Kiran Bhise, Allana College of Pharmacy, K. B. Hidayatullah Road, Azam Campus, Pune - 411 001, India.

Encyclopedia of pharmaceutical Technology volume 2 : James swarbrick, James.c.Boylan,P-1

37

REFERENCES Catia Bastioli, Handbook of Biodegradable Polymers,Rapra

Technology Limited,UK,4-18.

Polymers for Controlled for controlled Drug Delivery

Peter J.Tarcha,Ph.D.Abbott Laboratories, North Chicago,Illinois,CRS Press,Bostone P 127-147.

Polymeric Drugs & Drug delivery systems, Raphael M.Ottenbrite ,Ph.D,Sung Wan Kim,Ph.D.CRS press new york 57-112.

Handbook of biodegradable polymers editor castia Bastioli rapra technology, UK 1-25.

38