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Lecture 3: PRINCIPLES of CONTROLLED DRUG DELIVERY 

• Controlled Drug Delivery versus Sustained Release

o Controlled Drug Delivery Active agent combined with other components to produce delivery

system DDS are usually macroscopic

Involve combinations of active agents with inert polymeric materials

ust include a component that can be engineered to regulate an

essential characteristic such as duration of release! rate of release ortargeting

ust have a duration of action longer than one day

o Sustained Release

Achieved by mi"ing active agent with e"cipients to alter agent#s rate

of dissolution in $I tract or adsorption from local in%ection site &ssentially achieved by drug formulation

• 'iocompatibility

o (illiam#s definition: ability of a material to perform with an appropriate host

response in a specific applicationo odified definitions

Long)term implanted devices: ability of the device to perform intended

functions with a desired degree of incorporation in the host! withouteliciting any undesirable local or systemic effects in that host

Short)term implantable devices: ability to carry out its intended

function with flowing blood! with minimum interaction between thedevice and blood that adversely affects device performance andwithout inducing uncontrolled activation of cellular plasma proteincascades

*issue &ngineering +roducts: biocompatibility of a scaffold or matri"

refers to the ability of the device to perform as a substrate that willsupport appropriate cellular activity! including facilitation of molecular and mechanical signaling systems to optimi,e tissue regeneration!

without eliciting any undesirable effects in those cells or any local orsystemic responses in the eventual host

• 'iocompatible 'iomaterials

o 'iomaterials divided into - ma%or classes

POLYMERS - will be focused on

etals

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Ceramics .including carbons! glass ceramics! glasses/

 0atural materials .both plants and animals/

o +olymers

olecular weight

In polymer synthesis! polymer is produced with a distribution ofmolecular weights

Linear polymers used in biomedical applications generally have a

number average molecular weight in the range of 12! to4! and weight average molecular weight from 2! to3!

Increasing molecular weight corresponds to increasing physical

 properties *acticity

Arrangement of substituents around the e"tended polymer chain

Isotactic 5 chains located on the same side of ,ig),ag chain

Syndiotactic 5 chains have substituents alternating from side to

side Atactic 5 substituents appear at random on either side of chain

Crystallinity

+olymers either amorphous or semicrystalline! never completely

crystalline *endency of polymer to crystalli,e enhanced by small side groups

and chain regularity echanical properties

6ltimate mechanical properties of polymers at large deformations

important in selecting polymers for biomedical applications 6ltimate strength 5 stress at or near failure

7atigue behavior 5 how a polymer withstands cycles of stress and

release *hermal properties

*g 5 temperature at which all long)range segmental polymeric

motion ceases 8aries from polymer to polymer 

+olymers used below *g tend to be hard and glassy and below

*g tend to be rubbery

*g always below *m

*arget region for biomedical applications is rubbery plateau region

above *g where long)range segmental motion is occurring butthermal energy is insufficient to overcome entanglementinteractions that inhibit flow

Crystalline polymers tend to be tough and ductile

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Chemically cross)lin9ed polymers e"hibit modulus versus

temperature behavior analogous to that of linear amorphous polymers! until flow regime is approached

•Controlled Release Delivery Systems

I Diffusion Controlled Systems

• Reservoir Systems

Diffusion through planar membranes

o Drug release from reservoir into e"ternal solution in three steps

Dissolution of drug in polymer 

Diffusion of drug across polymer membrane

Dissolution of drug into e"ternal phase

o Assumptions

 0o bul9 flow .no convection/

 0o generation;consumption of drug

Drug is dilute within material

Drug release is controlled by thic9ness and composition of

surrounding membrane Diffusion through cylindrical membranes

o Drug must dissolve in polymer before diffusing through

cylinder wallo C4 .from e<uation in lecture slides/ most generally e<uals the

solubility of drug in the polymer if the drug concentration inthe polymer is very high

Commercially available reservoir systems

o =cusert>

System delivers pilocarpine! a drug that reduces pressure in

the eye! used to treat glaucoma +laced in lower eye lid

Administered medicine for one wee9 

(as not successful due to patient compliance 5 patients felt

more comfortable using the regular drops that placing aforeign ob%ect in eye? and pricing 5 device was five timesmore e"pensive than regular drops

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o  0orplant>

Consists of @ silicone rods with 3@mg of levonorgestreldissolved in polymer matri"

Implanted under s9in in upper arm

Delivers progestin .hormone/ continuously for up to five

years Discontinued due to multiple lawsuits in the 6SA

o *ransdermal Systems

 0orplant> implants and subse<uentinsertion

$lobal sales among *DD products

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*ransdermal patches are the primary transdermal

technology approved by the 7DA 7DA has approved! in 11 years! 32 patch products!

spanning 43 molecules ar9et approached 41 billion in 14 in the 6S

alone! based on 44 molecules .12 billion in 6S!&uropean mar9ets! and Bapan/

&nables steady blood)level profile! thus reducing side

effects and sometimes improved efficacy

ost common technology is drug)in)adhesive .shown inthe figure below/

Active systems .iontophoresis! electroporation!

sonophoresis! magnetophoresis/ and microneedle systems.3#s *S! mentioned previously/ are also beinginvestigated for delivery of peptides and macromolecules

Successful Systems

&straderm> .estradiol/ 5 Al,a

 0icoDerm> C> .nicotine/ ) Al,a

Duragesic> .fentanyl/ 5 Al,a

*estoderm> .testosterone/ 5 Al,a

Classification of *ransdermal Drug Delivery Devices

All mar9eted with Al,a#sD)*RA0S> technology 5 clear patch with up to1mg per day of drug

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*ransderm)0itro> .nitroglycerine/) Al,a

*ulobuterol .Asthma patch! Bapan/

A8&8A

$el matri" adhesive technology produces minimal

irritation to the stratum corneum =versaturation of adhesive polymer with

medication induces partial drug crystalli,ationwhich translates into higher drug concentrations in patch

Asthma patch .tulobuterol/ in Bapan is an approved

 patch

A8&8A#s gel matri" adhesivetechnology with crystal reservoir

technology

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• atri" Systems

6seful for release of proteins

Drug molecules dissolved or disperse throughout a solid polymer

 phase with homogeneous dispersion aterials utili,ed are biodegradable polymers which slowly dissolve

Rate of polymer degradation;dissolution controls the rate of drug

delivery igh surface area)to)volume ratio increases release rate by allowing

direct access to the matri" e"terior to more particles Rate of release decreases with time since drug molecules near matri"

surface are released first A model slab has a cumulative release proportional to t∴release

rate decreases with t

o If matri" is formed as a hemisphere! ,ero)order 9inetics can be

obtainedo Longer diffusion distance for molecules on outside of

hemisphere balanced by increase in surface area +seudo)state appro"imation

o Drugs loaded as fine solid particles∴drug concentration

within matri" higher than drug solubility in a<ueous solutiono 'oundary between dissolved and dispersed drug is present

which moves from outer surface of matri" to the center asrelease proceeds

o *his implies linear concentration gradient from solid;dissolved

drug interface to releasing surfaceo Re<uires that total concentration is much higher than drug

solubility Commerciali,ed Systems

o Salvona ) DermaSal>

1= soluble patch

Ingredients dissolved in a polymer matri"

atri" disintegrates after adhesion! yet utili,es no

adhesives

Cross)section ofDermaSal>

 patch

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o 8alera 5 ydron Implant *echnology

8antas> ) long duration LR therapy for advanced

 prostate cancer .Indevas +harmaceuticals/ ydron 5 hydrogel polymers spun into small tubes 4E long

and 4;FE diameter  Contains micropores for drug diffusion

 0onbiodegradable

4)year continuous! near ,ero)order release rates

II Swelling Controlled Systems

• Incorporation of drug within a hydrophilic polymer that swells when in an

a<ueous environment

• Drug molecules cannot diffuse out of device without water molecules

diffusing in

• Devices have a semi)permeable membrane that allows water movement

into device but prevents salt and drug from diffusing out

• Drug molecules diffuse out due to the pressure increase brought on by the

volumetric increase of the device

• &"ample of an elementary osmotic pump ) =R=S> .Al,a/

8antas> implant .8alera/

=R=S> ) best for water)soluble compounds

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Drugs mar9eted with this device

o +rocardia GL>

After incorporation of =R=S> technology! drug#s use

e"panded to treatment of angina and hypertension

o Concerta> ) once)a)day treatment of Attention Deficityperactivity Disorder .ADD/

o Ditropan GL> ) once)a)day treatment of overactive bladder 

• &"ample of osmotic driven system ) Duros> Implant *echnology

*itanium alloy cylinder 

 0on)biodegradable

8iadur> .leuprolide/) once)a)year implant for treatment of advanced

 prostate cancer 

=R=S> =ral Delivery *echnology 8ariations

Duros> Implant *echnology

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III 'iodegradable Systems

• Advantage ) Supporting matri" will dissolve after drug release∴no

residual material remains in tissue

• Disadvantage 5 release of large <uantities of potentially harmful polymer

degradation products into body

• aterials should

Degrade in a controllable fashion

Degrade into naturally occurring or inert chemicals

• 'ioerosion 5 physical process of dissolution of a polymer matri" or

microsphere! in which a solid material slowly losses mass and eventuallydisappears =ccurs once constituent polymer molecules become sufficiently small

and then dissolve *wo ideali,ed patterns of erosion

o 'ul9 erosion

+olymer disappears uniformly throught the material

icroporous matri" becomes spongy! with water)filled

holes becoming larger until matri" is no longermechanically stable

o

Surface erosion +olymer disappears from the surface! so matri" becomes

 progressively smaller with time +referred since drug release from slowly shrin9ing matri"

could be more predictable +otentially provides constant rate of polymer erosion

• 'iodegradation 5 decrease in ( of polymer within matri" after

 placement within biological environment 'iologicals ) en,ymes

ydrolytic brea9down 5 1= degradation

• ost commonly used polymers

 poly.lactic acid/ ! poly.glycolic acid/ and copolymers

o  p$A 5 simplest! aliphatic! linear polyester 

o  pLa 5 hydrophobic

o +roperties controlled by ( and copolymeri,ation

o Different copolymers degrade at varying rates

o  0o linear relationship between ratio of glycolic acid to lactic

acid and physicomechanical properties of the corresponding

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copolymers .eg! 2:2 copolymers degrade more rapidly thaneither p$A or pLA/

 poly.anhydride/

o Contain the most hydrolytically unstable polymer lin9age

o Degrade by surface erosion without need to incorporate

e"cipients into device formulationo *o control degradation! hydrophobic polymers can be

 polymeri,ed via anhydride lin9ages to prevent or control water penetration into matri" 5 rate of degradation is ad%usted

Aliphatic poly.anhydrides/ degrade within days

Aromatic poly.anhydrides/ degrade over several years

+ossess e"cellent in vivo biocompatibility

 poly.ortho esters/

o Al,amer> ) 4Hs by Al,a Corporation

o Degradation produces a diol and a lactone! which is converted

to J)hydro"ybutyric acid +rocess is autocatalytic

o A compound such as sodium bicarbonate must be incorporated

into polymeric matri" to prevent abrupt degradation anderosion

I8 Liposomes

• *erm introduced by 'angham et al to describe one or more concentric

lipid bilayers incorporating an e<ual number of a<ueous compartments

• 7orm spontaneously in a<ueous media

• Si,e and shape can be varied by changing mi"ture of phospholipids!

degree of saturation of the fatty acid side chains! and conditions offormation

• ydrophobic drugs may be loaded into liposome membranes while

hydrophilic drugs can be loaded into a<ueous core regions

• Disappear rapidly in blood

t4;1 may be increased by coupling to water)soluble polymers .eg!

+&$/

'ul9 erosion

Surface erosion

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• Commercially available liposome systems

Al,a 5 Stealth> Liposomal *echnology

o 7or I8 drug delivery

o Incorporate +&$ coating

o 'asis for Do"il> .do"orubicin Cl liposome suspension/

anticancer agent

Amphotericin '

o Amphocil

o Am'iosome 5 liposomal amphotericin '

o A'LC 5 Amphotericin ' lipid comple"

Amphotericin ' comple"ed with dimiristoyl

 phosphatidylcholine and dimiristoyl phosphatidylglycerol Lesser concentrations of drug achieved in blood but higher

in liver! spleen! and lungs Renal concentration similar 

Reduced to"icity and increased action! allowing for

administration of higher dosages

alf)life of various anticancer agents