Polymer in pharmaceutics by prof. TARiQUE khan sir. AACP Akkalkuwa

Tarique Khan

CONTENTS

INTRODUCTION TO POLYMERS

CLASSIFICATION OF POLYMERS

GENERAL MECHANISM OF DRUG RELEASE

APPLICATION IN CONVENTIONAL DOSGAE FORMS

APPLICATIONS IN CONTROLLED DRUG DELIVERY

BIODEGRADABLE POLYMERS

NATURAL POLYMERS

REFERENCESS

7th Sept. 2010 KLECOP, Nipani1

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INTRODUCTION

A polymer is a very large molecule in which one or two small units is repeated over and over again

The small repeating units are known as monomers

Imagine that a monomer can be represented by the letter A. Then a polymer made of that monomer would have the structure:

-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A


In another kind of polymer, two different monomers might be involved

If the letters A and B represent those monomers, then the polymer could be represented as:

-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A

A polymer with two different monomers is known as a copolymer.


Chemistry of the polymers

Polymers are organic, chain molecules They can, vary from a few hundreds to

thousands of atoms long. There are three classes of polymers that we

will consider:-

a. Thermo-plastic - Flexible linear chains

b. Thermosetting - Rigid 3-D network

c. Elastomeric - Linear cross-linked chains


THERMOPLASTICS

In simple thermoplastic polymers, the chains are bound to each other by weaker Van der Waal’s forces and mechanical entanglement.

Therefore, the chains are relatively strong, but it is relatively easy to slide and rotate the chains over each other.


ELASTOMERS

Common elastomers are made from highly coiled, linear polymer chains.

In their natural condition, elastomers behave in a similar manner to thermoplastics (viscoelastic)

– i.e. applying a force causes the chains to uncoil and stretch, but they also slide past each other causing permanent deformation.

This can be prevented by cross-linking the polymer chains


Polymers can be represented by – 3-D solid models

– 3-D space models

– 2-D models


MOLECULAR STRUCTURE

The mechanical properties are also governed by the structure of the polymer chains.

They can be:

Linear Network (3D)

Branched

Cross-linked


POLYMER MOLECULES

Before we discuss how the polymer chain molecules are formed, we need to cover some definitions:

The ethylene monomer looks like

The polyethylene molecule looks like:


Polyethylene is built up from repeat units or mers.

Ethylene has an unsaturated bond. (the double bond can be broken to form two single bonds)

The functionality of a repeat unit is the number of sites at which new molecules can be attached.


MOLECULAR WEIGHT

When polymers are fabricated, there will always be a distribution of chain lengths.

The properties of polymers depend heavily on the molecule length.

There are two ways to calculate the average molecular weight:

1 Number Average Molecular Weight

2. Weight Average Molecular Weight


Number Average Molecular Weight

Mn= Σ Xi Mi

Where, xi = number of chains in the ith weight range

Mi = the middle of the ith weight range Weight Average Molecular Weight

Mw = Σ Wi Mi

Where, wi = weight fraction of chains in the ith range

Mi = the middle of the ith weight range


MOLECULAR SHAPE

The mechanical properties of a polymer are dictated in part by the shape of the chain.

Although we often represent polymer chains as being straight,

They rarely are.


The carbon – carbon bonds in simple polymers form angles of 109º

Contd…



POLYMER CRYSTALLINITY

Thermoplastic polymers go through a series of changes with changes in temperature. (Similar to ceramic glasses)

In their solid form they can be semi-crystalline or amorphous (glassy).



CRYSTALLINE THERMOPLASTIC

The ability of a polymer to crystallize is affected by:1. Complexity of the chain: Crystallization is easiest for

simple polymers (e.g. polyethylene) and harder for complex polymers (e.g. with large side groups, branches, etc.)

2. Cooling rate: Slow cooling allows more time for the chains to align

3. Annealing: Heating to just below the melting temperature can allow chains to align and form crystals

4. Degree of Polymerization: It is harder to crystallize longer chains

5. Deformation: Slow deformation between Tg and Tm can straighten the chains allowing them to get closer together.


CLASSIFICATION POLYMERS: ON BASIS OF INTERACTION WITH WATER: Non-biodegradable hydrophobic Polymers

E.g. polyvinyl chloride, polyethylene vinyl acetate Soluble Polymers E.g. HPMC, PEG Hydrogels E.g. Polyvinyl pyrrolidine BASED ON POLYMERISATION METHOD: Addition Polymers E.g. Alkane Polymers Condensation polymers E.g. Polysterene and Polyamide Rearrangement polymers BASED ON POLYMERIZATION MECHANISM: Chain Polymerization Step growth Polymerization


BASED ON CHEMICAL STRUCTURE: Activated C-C Polymer Polyamides, polyurethanes Polyesters, polycarbonates Polyacetals, Polyketals, Polyorthoesters Inorganic polymers Natural polymers BASED ON OCCURRENCE: Natural polymers E.g. 1. Proteins-collagen, keratin,

albumin, 2. carbohydrates- starch, cellulose Synthetic polymers E.g. Polyesters, polyamides

Contd….


BASED ON BIO-STABILITY: Bio-degradable Non Bio-degradable

Contd….


CHARACTERISTICS OF AN IDEAL POLYMER

Should be versatile and possess a wide range of mechanical, physical, chemical properties

Should be non-toxic and have good mechanical strength and should be easily administered

Should be inexpensive

Should be easy to fabricate

Should be inert to host tissue and compatible with environment


CRITERIA FOLLOWED IN POLYMER SELECTION

The polymer should be soluble and easy to synthesis

It should have finite molecular weight

It should be compatible with biological environment

It should be biodegradable

It should provide good drug polymer linkage


There are three primary mechanisms by which active agents can be released from a delivery system: namely,

Diffusion, degradation, and swelling followed by diffusion

Any or all of these mechanisms may occur in a given release system

Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device. The diffusion can occur on a macroscopic scale as through pores in the polymer matrix or on a molecular level, by passing between polymer chains

GENERAL MECHANISM OF DRUG RELEASE FROM POLYMER


Drug release from typical matrix release system


For the reservoir systems the drug delivery rate can remain fairly constant.

In this design, a reservoir whether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix is surrounded by a film or membrane of a rate-controlling material.

The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir.

This polymer coating is uniform and of a nonchanging thickness, the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery system. The system shown in Figure a is representative of an implantable or oral reservoir delivery system, whereas the system shown in b.


Drug delivery from typical reservoir devices: (a) implantable or oral systems, and (b) transdermal systems.



ENVIRONMENTALLY RESPONSIVE SYSTEM

It is also possible for a drug delivery system to be designed so that it is incapable of releasing its agent or agents until it is placed in an appropriate biological environment.

Controlled release systems are initially dry and, when placed in the body, will absorb water or other body fluids and swell,

The swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment.


Examples of these types of devices are shown in Figures a and b for reservoir and matrix systems.

Most of the materials used in swelling-controlled release systems are based on hydrogels, which are polymers that will swell without dissolving when placed in water or other biological fluids. These hydrogels can absorb a great deal of fluid and, at equilibrium, typically comprise 60–90% fluid and only 10–30% polymer.


Drug delivery from (a) reservoir and (b) matrix swelling-controlled release systems.


Stimulus Hydrogel Mechanism

pH Acidic or basichydrogel

Change in pH-swelling- release of

drug

Ionic strength Ionic hydrogel Change in ionic strength change in concentration of ions inside gel change in swelling release of

drug

Chemical species Hydrogel containing electron-accepting groups

Electron-donating compounds formation of charge/transfer complex change in swelling release of drug


Enzyme-substrate

Hydrogel containing immobilized enzymes

Substrate present enzymatic conversion product changes swelling of gel release of drug

Magnetic Magnetic particles dispersed in alginate microshperes

Applied magnetic field change in pores in gel change in swelling release of drug

Thermal Thermoresponsive hrydrogel poly(N-isopro-pylacrylamide

Change in temperature change in polymer-polymer and water-polymer interactions change in swelling release of drug


APPLICATIONS

The pharmaceutical applications of polymers range from their use as binders in tablets

Viscosity and flow controlling agents in liquids, suspensions and emulsions

Polymers are also used as film coatings to disguise the unpleasant taste of a drug, to enhance drug stability and to modify drug release characteristics.

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Applications in Conventional Dosage Forms

7th Sept. 2010 KLECOP, Nipani

Tablets : - As binders

- To mask unpleasant taste - For enteric coated tablets

Liquids : - Viscosity enhancers

- For controlling the flow Semisolids :

- In the gel preparation - In ointments

In transdermal Patches35

Applications In Controlled Drug Delivery

Reservoir Systems - Ocusert System

- Progestasert System- Reservoir Designed Transdermal Patches

Matrix Systems Swelling Controlled Release Systems Biodegradable Systems Osmotically controlled Drug Delivery


BIO DEGARADABLE POLYMERS


BIO DEGRADABLE POLYMER

Biodegradable polymers can be classified in two:

Natural biodegradable polymer

Synthetic biodegradable polymer

Synthetic biodegradable polymer are preferred more than the natural biodegradable polymer because they are free of immunogenicity & their physicochemical properties are more predictable &reproducible


FACTORS AFFECTING BIODEGRADATION OF POLYMERS

PHYSICAL FACTORS Shape & size Variation of diffusion coefficient Mechanical stresses CHEMICAL FACTORS Chemical structure & composition Presence of ionic group Distribution of repeat units in multimers configuration structure Molecular weight Morphology Presence of low molecular weight compounds


Processing condition Annealing Site of implantation Sterilization process PHYSICOCHEMICAL FACTORS Ion exchange Ionic strength pH

CONTD


ADVANTAGES OF BIODEGRADABLE POLYMERS IN DRUG DELEVERY

Localized delivery of drug

Sustained delivery of drug

Stabilization of drug

Decrease in dosing frequency

Reduce side effects

Improved patient compliance

Controllable degradation rate


ROLE OF POLYMER IN DRUG DELIVERY

The polymer can protect the drug from the physiological environment & hence improve its stability in vivo.

Most biodegradable polymer are designed to degrade within the body as a result of hydrolysis of polymer chain into biologically acceptable & progressively small compounds.

TYPES OF POLYMER DRUG DELIVERY SYSTEM:

MICRO PARTICLES: These have been used to deliver therapeutic agents like doxycycline.

NANO PARTICLES: delivery drugs like doxorubicin, cyclosporine, paclitaxel, 5- fluorouracil etc


POLYMERIC MICELLES: used to deliver therapeutic agents.

HYDRO GELS: these are currently studies as controlled release carriers of proteins & peptides.

POLYMER MORPHOLOGY:

The polymer matrix can be formulated as either micro/nano-spheres, gel, film or an extruded shape.

The shape of polymer can be important in drug release kinetics.


Application For specific site drug delivery- anti tumour agent

Polymer system for gene therapy

Bio degradable polymer for ocular, non- viral DNA, tissue engineering, vascular, orthopaedic, skin adhesive & surgical glues.

Bio degradable drug system for therapeutic agents such as anti tumor, antipsychotic agent, anti-inflammatory agent and biomacro molecules such as proteins, peptides and nucleic acids


BIO DEGRADABLE POLYMERS FOR ADVANCE DRUG DELIVERY

Polymers play an vital role in both conventional as well as novel drug delivery. Among them , the use of bio degradable polymer has been success fully carried out.

Early studies on the use of biodegradable suture demonstrated that these polymers were non- toxic & biodegradable.

By incorporating drug into biodegradable polymer whether natural or synthetic, dosage forms that release the drug in predesigned manner over prolong time


DRUG RELEASE MECHANISM The release of drugs from the erodible polymers occurs

basically by three mechanisms,

I. The drug is attached to the polymeric backbone by a labile bond, this bond has a higher reactivity toward hydrolysis than the polymer reactivity to break down.

II. The drug is in the core surrounded by a biodegradable rate controlling membrane. This is a reservoir type device that provides erodibility to eliminate surgical removal of the drug-depleted device.

III. a homogeneously dispersed drug in the biodegradable polymer. The drug is released by erosion, diffusion, or a combination of both.

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Schematic representation of drug release mechanisms In mechanism 1, drug is released by hydrolysis of polymeric bond. In mechanism 2, drug release is controlled by biodegradable membrane. In mechanism 3, drug is released by erosion, diffusion, or a combination of both


POLYMER EROSION MECHANISM

The term 'biodegradation' is limited to the description of chemical processes (chemical changes that alter either

the molecular weight or solubility of the polymer) ‘Bioerosion' may be restricted to refer to physical

processes that result in weight loss of a polymer device. The erosion of polymers basically takes place by two

methods:-

1. Chemical erosion

2. Physical erosion


CHEMICAL EROSION

There are three general chemical mechanisms that cause bioerosion

1. The degradation of water-soluble macromolecules that are crosslinked to form three-dimensional network.

As long as crosslinks remain intact, the network is intact and is insoluble.

Degradation in these systems can occur either at crosslinks to form soluble backbone polymeric chains (type IA) or at the main chain to form water-soluble fragments (type IB). Generally, degradation of type IA polymers provide high molecular weight, water-soluble fragments, while degradation of type IB polymers provide low molecular weight, water soluble oligomers and monomers



2. The dissolution of water-insoluble macromolecules with side groups that are converted to water-soluble polymers as a result of ionization, protonation or hydrolysis of the groups. With this mechanism the polymer does not degrade and its molecular weight remains essentially unchanged. E.g. cellulose acetate

3. The degradation of insoluble polymers with labile bonds. Hydrolysis of labile bonds causes scission of the polymer backbone, thereby forming low molecular weight, water-soluble molecules. E.g. poly (lactic acid), poly (glycolic acid)

The three mechanisms described are not mutually exclusive; combinations of them can occur.


PHYSICAL EROSION

The physical erosion mechanisms can be characterized as heterogeneous or homogeneous.

In heterogeneous erosion, also called as surface erosion, the polymer erodes only at the surface, and maintains its physical integrity as it degrades. As a result drug kinetics are predictable, and zero order release kinetics can be obtained by applying the appropriate geometry. Crystalline regions exclude water. Therefore highly crystalline polymers tend to undergo heterogeneous erosion. E.g polyanhydrides


Homogeneous erosion, means the hydrolysis occurs at even rate throughout the polymeric matrix. Generally these polymers tend to be more hydrophilic than those exhibiting surface erosion. As a result, water penetrates the polymeric matrix and increases the rate of diffusion. In homogeneous erosion, there is loss of integrity of the polymer matrix. E.g poly lactic acid


Natural polymers

Polymers are very common in nature

some of the most widespread naturally occurring substances are polymers Starch and cellulose are examples

Green plants have the ability to take the simple sugar known as glucose and make very long chains containing many glucose units

These long chains are molecules of starch or cellulose

If we assign the symbol G to stand for a glucose molecule, then starch or cellulose can be represented as:

-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-


NATURAL POLYMERS

Natural polymers remains the primary choice of formulator because

- They are natural products of living organism - Readily available - Relatively inexpensive - Capable of chemical modification

Moreover, it satisfies most of the ideal requirements of polymers.

But the only and major difficulty is the batch- to-batch reproducibility and purity of the sample.


Examples :1) Proteins :

- Collagen : Found from animal tissue. Used in absorbable sutures, sponge wound dressing, as drug delivery vehicles- Albumin : Obtained by fabrication of blood from healthy donor. Used as carriers in nanocapsules & microspheres- Gelatin : A natural water soluble polymer Used in capsule shells and also as coating material in microencapsulation.


2) Polysaccharides :- Starch : Usually derivatised by introducing acrylic

groups before manufactured int microspheres.Also used as binders.

- Cellulose : Naturally occuring linear polysaccharide. It

is insoluble in water but solubility can be obtained by substituting -OH group.

Na-CMC is used as thickner, suspending agent, and film formers.

3) DNA & RNA :They are the structural unit of our body. DNA

is the blueprint that determines everything of our body.


CURRENTLY AVAILABLE POLYMERS FOR CONTROLLED RELEASE

Diffusion controlled systems

Solvent activated systems

Chemically controlled systems

Magnetically controlled systems


DIFFUSION CONTROLLED SYSTEM

Reservoir type Shape : spherical, cylindrical, disk-like Core : powdered or liquid forms Properties of the drug and the polymer : diffusion rate

and release rate into the bloodstream Problems : removal of the system, accidental rupture

Matrix type Uniform distribution and uniform release rate No danger of drug dumping


SOLVENT ACTIVATED SYSTEM

Osmotically controlled system Semipermeable membrane Osmotic pressure decrease concentration gradient Inward movement of fluid : out of the device through

a small orifice Swelling controlled system

Hydrophilic macromolecules cross-linked to form a three-dimensional network

Permeability for solute at a controlled rate as the polymer swells


CHEMICALLY CONTROLLED SYSTEMS

Pendant-chain system Drug : chemically linked to the backbone Chemical hydrolysis or enzymatic cleavage Linked directly or via a spacer group

Bioerodable or biodegradable system Drug : uniformly dispersed Slow released as the polymer disintegrates No removal from the body Irrespective of solubility of drug in water


MAGNETICALLY CONTROLLED SYSTEMS

Cancer chemotherapy Selective targeting of antitumor agents Minimizing toxicity

Magnetically responsive drug carrier systems Albumin and magnetic microspheres High efficiency for in vivo targeting Controllable release of drug at the microvascular

level


RECENTLY DEVELOPED MARKETED FORMULATIONS

Medisorb • Microencapsulation by PLA, PGA, PLGA • Drug release : week to one year

Alzamer • Bioerodible polymer : release at a controlled rate • Chronic disease, contraception, topical therapy


USE OF FEW POLYMERS IN DRUG DELIVERY

Poly(L-lactic acid) for release of progesterone, estradiol, dexamethasone

Copolymer of gluconic acid and –ethyl-L-glutamte as bioerodible monolithic device

PLA, PGA, PLGA for parenteral administration of polypeptide Sustained release (weeks or months)

Orahesive® : sodium carboxymethyl cellulose, Pectin, gelatin

Orabase ® : blend in a polymethylene/mineral oil base


REFERENCES

Novel drug delivery systems – Y.W.Chien – Dekker 50

Bio–adhesive drug delivery system –

Dekker 98 Encyclopedia of controlled drug delivery

systems. www.google.com


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Health & Medicine

Polymer in pharmaceutics by prof. TARiQUE khan sir. AACP Akkalkuwa