Download Lecture 3: PRINCIPLES of CONTROLLED DRUG DELIVERY

Lecture 3: PRINCIPLES of CONTROLLED DRUG DELIVERY
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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
 Must include a component that can be engineered to regulate an
essential characteristic such as duration of release, rate of release or
targeting
 Must have a duration of action longer than one day
o Sustained Release
 Achieved by mixing active agent with excipients to alter agent’s rate
of dissolution in GI tract or adsorption from local injection site
 Essentially achieved by drug formulation
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Biocompatibility
o William’s definition: ability of a material to perform with an appropriate host
response in a specific application
o Modified 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
 Tissue Engineering Products: biocompatibility of a scaffold or matrix
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 optimize tissue regeneration,
without eliciting any undesirable effects in those cells or any local or
systemic responses in the eventual host
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Biocompatible Biomaterials
o Biomaterials divided into 4 major classes
 POLYMERS - will be focused on
 Metals
 Ceramics (including carbons, glass ceramics, glasses)
 Natural materials (both plants and animals)
o Polymers
 Molecular 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 25,000 to
100,000 and weight average molecular weight from 50,000 to
30,000
 Increasing molecular weight corresponds to increasing physical
properties
 Tacticity
 Arrangement of substituents around the extended polymer chain
 Isotactic – chains located on the same side of zig-zag chain
 Syndiotactic – chains have substituents alternating from side to
side
 Atactic – substituents appear at random on either side of chain
 Crystallinity
 Polymers either amorphous or semicrystalline, never completely
crystalline
 Tendency of polymer to crystallize enhanced by small side groups
and chain regularity
 Mechanical properties
 Ultimate mechanical properties of polymers at large deformations
important in selecting polymers for biomedical applications
 Ultimate strength – stress at or near failure
 Fatigue behavior – how a polymer withstands cycles of stress and
release
 Thermal properties
 Tg – temperature at which all long-range segmental polymeric
motion ceases
 Varies from polymer to polymer
 Polymers used below Tg tend to be hard and glassy and below
Tg tend to be rubbery
 Tg always below Tm
 Target region for biomedical applications is rubbery plateau region
above Tg 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-linked polymers exhibit 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 external solution in three steps
 Dissolution of drug in polymer
 Diffusion of drug across polymer membrane
 Dissolution of drug into external phase
o Assumptions
 No bulk flow (no convection)
 No generation/consumption of drug
 Drug is dilute within material
 Drug release is controlled by thickness and composition of
surrounding membrane
 Diffusion through cylindrical membranes
o Drug must dissolve in polymer before diffusing through
cylinder wall
o C1 (from equation in lecture slides) most generally equals the
solubility of drug in the polymer if the drug concentration in
the polymer is very high
 Commercially available reservoir systems
o Ocusert®
 System delivers pilocarpine, a drug that reduces pressure in
the eye, used to treat glaucoma
 Placed in lower eye lid
 Administered medicine for one week
 Was not successful due to patient compliance – patients felt
more comfortable using the regular drops that placing a
foreign object in eye; and pricing – device was five times
more expensive than regular drops
Norplant® implants and subsequent
insertion
o Norplant®
 Consists of 6 silicone rods with 36mg of levonorgestrel
dissolved in polymer matrix
 Implanted under skin in upper arm
 Delivers progestin (hormone) continuously for up to five
years
 Discontinued due to multiple lawsuits in the USA
o Transdermal Systems
Global sales among TDD products
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Transdermal patches are the primary transdermal
technology approved by the FDA
 FDA has approved, in 22 years, 35 patch products,
spanning 13 molecules
 Market approached $1.2 billion in 2001 in the US
alone, based on 11 molecules ($2.5 billion in US,
European markets, and Japan)
Enables steady blood-level profile, thus reducing side
effects and sometimes improved efficacy
Most common technology is drug-in-adhesive (shown in
the figure below)
Active systems (iontophoresis, electroporation,
sonophoresis, magnetophoresis) and microneedle systems
(3M’s MTS, mentioned previously) are also being
investigated for delivery of peptides and macromolecules
Classification of Transdermal Drug Delivery Devices

All marketed with
Alza’s D-TRANS®
technology – clear
patch with up to 20mg
per day of drug
Successful Systems
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Estraderm® (estradiol) – Alza
NicoDerm® CQ® (nicotine) - Alza
Duragesic® (fentanyl) – Alza
Testoderm® (testosterone) – Alza
Transderm-Nitro® (nitroglycerine)- Alza
 Tulobuterol (Asthma patch, Japan)
 AVEVA
 Gel matrix adhesive technology produces minimal
irritation to the stratum corneum
 Oversaturation of adhesive polymer with
medication induces partial drug crystallization
which translates into higher drug concentrations in
patch
 Asthma patch (tulobuterol) in Japan is an approved
patch
AVEVA’s gel matrix adhesive
technology with crystal reservoir
technology

Matrix Systems
 Useful for release of proteins
 Drug molecules dissolved or disperse throughout a solid polymer
phase with homogeneous dispersion
 Materials utilized are biodegradable polymers which slowly dissolve
 Rate of polymer degradation/dissolution controls the rate of drug
delivery
 High surface area-to-volume ratio increases release rate by allowing
direct access to the matrix exterior to more particles
 Rate of release decreases with time since drug molecules near matrix
surface are released first
 A model slab has a cumulative release proportional to t  release
rate decreases with t
o If matrix is formed as a hemisphere, zero-order kinetics can be
obtained
o Longer diffusion distance for molecules on outside of
hemisphere balanced by increase in surface area
 Pseudo-state approximation
o Drugs loaded as fine solid particles  drug concentration
within matrix higher than drug solubility in aqueous solution
o Boundary between dissolved and dispersed drug is present
which moves from outer surface of matrix to the center as
release proceeds
o This implies linear concentration gradient from solid/dissolved
drug interface to releasing surface
o Requires that total concentration is much higher than drug
solubility
 Commercialized Systems
o Salvona - DermaSal®
 H2O soluble patch
 Ingredients dissolved in a polymer matrix
 Matrix disintegrates after adhesion, yet utilizes no
adhesives
Cross-section of
DermaSal®
patch
o Valera – Hydron Implant Technology
 Vantas® - long duration LHRH therapy for advanced
prostate cancer (Indevas Pharmaceuticals)
 Hydron – hydrogel polymers spun into small tubes 1” long
and 1/8” diameter
 Contains micropores for drug diffusion
 Nonbiodegradable
 1-year continuous, near zero-order release rates
Vantas® implant (Valera)
II.
Swelling Controlled Systems
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Incorporation of drug within a hydrophilic polymer that swells when in an
aqueous 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
Example of an elementary osmotic pump - OROS® (Alza)
OROS® - best for water-soluble compounds
OROS® Oral Delivery Technology Variations
 Drugs marketed with this device
o Procardia XL®
 After incorporation of OROS® technology, drug’s use
expanded to treatment of angina and hypertension
o Concerta® - once-a-day treatment of Attention Deficit
Hyperactivity Disorder (ADHD)
o Ditropan XL® - once-a-day treatment of overactive bladder

Example of osmotic driven system - Duros® Implant Technology
 Titanium alloy cylinder
 Non-biodegradable
 Viadur® (leuprolide)- once-a-year implant for treatment of advanced
prostate cancer
Duros® Implant Technology
III.
Biodegradable Systems
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Advantage - Supporting matrix will dissolve after drug release  no
residual material remains in tissue
Disadvantage – release of large quantities of potentially harmful polymer
degradation products into body
Materials should
 Degrade in a controllable fashion
 Degrade into naturally occurring or inert chemicals
Bioerosion – physical process of dissolution of a polymer matrix or
microsphere, in which a solid material slowly losses mass and eventually
disappears
 Occurs once constituent polymer molecules become sufficiently small
and then dissolve
 Two idealized patterns of erosion
o Bulk erosion
 Polymer disappears uniformly throught the material
 Microporous matrix becomes spongy, with water-filled
holes becoming larger until matrix is no longer
mechanically stable
o Surface erosion
 Polymer disappears from the surface, so matrix becomes
progressively smaller with time
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Bulk erosion
Surface erosion
Preferred since drug release from slowly shrinking matrix
could be more predictable
 Potentially provides constant rate of polymer erosion
Biodegradation – decrease in MW of polymer within matrix after
placement within biological environment
 Biologicals - enzymes
 Hydrolytic breakdown – H2O degradation
Most commonly used polymers
 poly(lactic acid) , poly(glycolic acid) and copolymers
o pGA – simplest, aliphatic, linear polyester
o pLa – hydrophobic
o Properties controlled by MW and copolymerization
o Different copolymers degrade at varying rates
o No linear relationship between ratio of glycolic acid to lactic
acid and physicomechanical properties of the corresponding
copolymers (e.g., 50:50 copolymers degrade more rapidly than
either pGA or pLA)
 poly(anhydride)
o Contain the most hydrolytically unstable polymer linkage
o Degrade by surface erosion without need to incorporate
excipients into device formulation
o To control degradation, hydrophobic polymers can be
polymerized via anhydride linkages to prevent or control water
penetration into matrix – rate of degradation is adjusted
 Aliphatic poly(anhydrides) degrade within days
 Aromatic poly(anhydrides) degrade over several years
 Possess excellent in vivo biocompatibility
 poly(ortho esters)
o Alzamer® - 1970s by Alza Corporation
o Degradation produces a diol and a lactone, which is converted
to γ-hydroxybutyric acid
 Process is autocatalytic
o A compound such as sodium bicarbonate must be incorporated
into polymeric matrix to prevent abrupt degradation and
erosion
IV.
Liposomes
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Term introduced by Bangham et al. to describe one or more concentric
lipid bilayers incorporating an equal number of aqueous compartments
Form spontaneously in aqueous media
Size and shape can be varied by changing mixture of phospholipids,
degree of saturation of the fatty acid side chains, and conditions of
formation
Hydrophobic drugs may be loaded into liposome membranes while
hydrophilic drugs can be loaded into aqueous core regions
Disappear rapidly in blood
 t1/2 may be increased by coupling to water-soluble polymers (e.g.,
PEG)
Commercially available liposome systems
 Alza – Stealth® Liposomal Technology
o For IV drug delivery
o Incorporate PEG coating
o Basis for Doxil® (doxorubicin HCl liposome suspension)
anticancer agent
Half-life of various anticancer agents
 Amphotericin B
o Amphocil
o AmBiosome – liposomal amphotericin B
o ABLC – Amphotericin B lipid complex
 Amphotericin B complexed with dimiristoyl
phosphatidylcholine and dimiristoyl phosphatidylglycerol
 Lesser concentrations of drug achieved in blood but higher
in liver, spleen, and lungs
 Renal concentration similar
 Reduced toxicity and increased action, allowing for
administration of higher dosages