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 or
targeting
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 application
o odified definitions
Long)term implanted devices: ability of the device to perform intended
functions with a desired degree of incorporation in the host! without
eliciting 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 the
device and blood that adversely affects device performance and
without inducing uncontrolled activation of cellular plasma protein
cascades
*issue &ngineering +roducts: biocompatibility of a scaffold or matri"
refers to the ability of the device to perform as a substrate that will
support 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 or
systemic responses in the eventual host
'iocompatible 'iomaterials
o 'iomaterials divided into - ma%or classes
POLYMERS - will be focused on
etals
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 of
molecular weights
Linear polymers used in biomedical applications generally have a
number average molecular weight in the range of 12!333 to
433!333 and weight average molecular weight from 23!333 to
33!333
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 but
thermal energy is insufficient to overcome entanglement
interactions that inhibit flow

Crystalline polymers tend to be tough and ductile

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 wall
o C4 .from e<uation in lecture slides/ most generally e<uals the
solubility of drug in the polymer if the drug concentration in
the 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 a
foreign ob%ect in eye? and pricing 5 device was five times
more e"pensive than regular drops
o 0orplant>
Consists of @ silicone rods with 3@mg of levonorgestrel
dissolved 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<uent
insertion
$lobal sales among *DD products
*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 A4:1 billion in 1334 in the 6S
alone! based on 44 molecules .A1:2 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 in
the figure below/
Active systems .iontophoresis! electroporation!
sonophoresis! magnetophoresis/ and microneedle systems
.3#s *S! mentioned previously/ are also being
investigated for delivery of peptides and macromolecules
Successful Systems
&straderm> .estradiol/ 5 Al,a
0icoDerm> CC> .nicotine/ ) Al,a
Duragesic> .fentanyl/ 5 Al,a
*estoderm> .testosterone/ 5 Al,a
Classification of *ransdermal Drug Delivery Devices
All mar9eted with Al,a#s
D)*RA0S> technology
5 clear patch with up to
13mg per day of drug
*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,ation
which translates into higher drug concentrations in
patch
Asthma patch .tulobuterol/ in Bapan is an approved
patch
A8&8A#s gel matri" adhesive
technology with crystal reservoir
technology
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
Digh 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
obtained
o 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 solution
o 'oundary between dissolved and dispersed drug is present
which moves from outer surface of matri" to the center as
release proceeds
o *his implies linear concentration gradient from solid;dissolved
drug interface to releasing surface
o Re<uires that total concentration is much higher than drug
solubility
Commerciali,ed Systems
o Salvona ) DermaSal>
D1= soluble patch
Ingredients dissolved in a polymer matri"
atri" disintegrates after adhesion! yet utili,es no
adhesives
Cross)section of
DermaSal>
patch
o 8alera 5 Dydron Implant *echnology
8antas> ) long duration LDRD therapy for advanced
prostate cancer .Indevas +harmaceuticals/
Dydron 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
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 Deficit
Dyperactivity Disorder .ADDD/
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
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 eventually
disappears
=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 longer
mechanically 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
Dydrolytic brea9down 5 D1= 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
copolymers .e:g:! 23:23 copolymers degrade more rapidly than
either p$A or pLA/
poly.anhydride/
o Contain the most hydrolytically unstable polymer lin9age
o Degrade by surface erosion without need to incorporate
e"cipients into device formulation
o *o control degradation! hydrophobic polymers can be
polymeri,ed via anhydride lin9ages to prevent or control water
penetration into matri" 5 rate of degradation is ad%usted
Aliphatic poly.anhydrides/ degrade within days
Aromatic poly.anhydrides/ degrade over several years
+ossess e"cellent in vivo biocompatibility
poly.ortho esters/
o Al,amer> ) 4HI3s by Al,a Corporation
o Degradation produces a diol and a lactone! which is converted
to J)hydro"ybutyric acid
+rocess is autocatalytic
o A compound such as sodium bicarbonate must be incorporated
into polymeric matri" to prevent abrupt degradation and
erosion
I8: Liposomes
*erm introduced by 'angham et al: to describe one or more concentric
lipid bilayers incorporating an e<ual number of a<ueous compartments
7orm spontaneously in a<ueous media
Si,e and shape can be varied by changing mi"ture of phospholipids!
degree of saturation of the fatty acid side chains! and conditions of
formation
Dydrophobic drugs may be loaded into liposome membranes while
hydrophilic drugs can be loaded into a<ueous core regions
Disappear rapidly in blood
t4;1 may be increased by coupling to water)soluble polymers .e:g:!
+&$/
'ul9 erosion
Surface erosion
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 DCl 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
Dalf)life of various anticancer agents