Transcript Controlled Drug Delivery

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Pharmaceuticals, whether orally ingested or transdermally
delivered, are presented with significant and specific
biological barriers that impede absorption and distribution
◦ Skin
◦ Blood-brain barrier
◦ GI epithelium
 Physiological
 Tight junctions-gate function
 Adherens junctions-cell-cell adhesion
 Desmosomes-attached to cellular cytoskeleton
 Biochemical
 Chemical
The chemical structure of a drug determines its solubility and
permeability profiles. The concentration at the intestinal lumen and the
permeation of the drug across the intestinal mucosa are responsible for
the rate and extent of absorption
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Physiological
◦ Mucus layer-produced by goblet
cells; 100-150 microns thick
layer; filter for molecules with
MW of 600-800 Daltons;
composed of glycoproteins; turn
over 12-24 hours
◦ Columnar epithelium-joined by
tight junctions; enterocytes;
goblet cells; endocrine cells;
paneth cells
 Hydrophobic drugs
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Transcellular pathway
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Paracellular pathway-restricted by
pore sizes of tight junctions
Receptor-mediated uptake
Efflux pumps
 Hydrophilic drugs
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Biochemical-Biotransformation
◦ Great inter-individual variability in metabolism of drugs
 Absorption, distribution, metabolism, excretion
◦ Enzymes in GI system both mammalian and bacterial origins
◦ Pre-systemic and first-pass metabolism
 Stomach
 HCL and proteolytic pepsins
 Duodenal region of small intestine
Within brush border and enterocytes
Esterases
Peptidases
CYP superfamily
 P450 enzymes
 CYP3A4-70% of intestinal CYP
 Residence time of drug within enterocyte influences metabolism
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Liver-based enzymes include esterases, CYP enzymes,
flavin-containing monoxygenase enzymes,
glucuronosyl transferases, sulfotransferases
A technique or method in which
active
chemicals
are
made
available to a specified target at a
rate and duration designed to
accomplish a specific effect
Maintain drug at appropriate therapeutic level
for a specified period of time
Sustained Drug Action
Localized Drug Action
Targeted Drug Action
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Single dose
◦ Immediate release of drug
◦ Acute therapeutic treatment
Multiple-dose administration
◦ Sustained therapy
◦ Variations in drug levels during treatment period
◦ Patient compliance
Nonimmediate-release devices
◦ Delayed release
 Multiple doses in single dose form
◦ Prolonged release
 Extends release of drug
◦ Controlled release
 Maintains constant release rate
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Maintain more consistent level of drug with fewer doses
◦ Pros
 Fewer and lower doses possible
 Less potential side effects
 More effective therapeutic mechanism of action
◦ Cons
 Inability to stop delivery
Two types of controlled
◦ Reservoir
 Drug loaded into reservoir as solid or liquid
 Drug released by diffusion through semipermeable
membrane
 Osmotic pressure provides driving force
◦ Matrix
 Drug dispersed evenly in solid polymer matrix
 Dissolution of matrix
 Diffusion of drug from insoluble matrix
University of Washington
Engineered Materials
Matrix System
Reservoir System
Bioerodible System
Sigma-Aldrich Chemicals
Langer, R. Science 1990, 249, 1527.
Kost, J.; Langer, R. Trends in Biotechnology 1984, 2, 47.
Heller, J.; Sparer, R. V.; Zenter, G. M. Poly(ortho esters)
In Biodegradable polymers as drug delivery systems
Chasin, M.; Langer, R., Eds.; Marcel Dekker: New York, 1990.
Science Notes 1999
Written by Kathleen Wong
Illustrated by Anya Illes
The Patch
https://www.youtube.com/watch?v=dTdW8q9hukw
3M
The first transdermal patch to be approved was a three day
patch for motion sickness (scopolamine)-1979
The first block buster patch was designed to mediate
smoking (nicotine)-1989
Transdermal Patch versus Sublingual Administration
Snapshot of the over 20 approved TDDS
Therapy
Motion Sickness
Anti-angina
Hypertension
Smoking Cessation
Hormone Replacement Therapy
Pain Management
Drug Delivered by TDD
Scopolamine
Nitroglycerine
Clonidine
Nicotine
Estradiol
Estradiol/Progestin
Testosterone
Fentanyl
Lidocaine
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Upon application of TDDS
◦ Drug diffuses down concentration gradient
◦ Second drug reservoir established in stratum corneum
◦ Absorption in dermal capillary bed
 Delay between TDDS application and minimum effective
concentration
 Time to reach steady state plasma concentrations varies
and depends upon drug
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Steady state flux is determinative of drug
penetration
◦ Necessary drug characteristics
 Low molecular mass/high diffusion coefficient
 <500D
 Adequate solubility in oil
 High lipophilicity
 Moderately high partition coefficient- ratio
of concentrations of a compound in a mixture of
two immiscible phases at equilibrium (water and oil)
 Low required daily dose
 <2mg
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Reduces first-pass effect and GI incompatibility
Sustains therapeutic drug levels
Permits self-administration
Non-invasive (no needles or injections)
Improves patient compliance
Reduces side effects
Allows removal of drug source & Termination of
further administration, if necessary
Administration of drugs with:
- A very short half-life
- Narrow therapeutic window
- Poor oral absorption
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Poor diffusion of large molecules
Skin irritation
Limited By:
◦ Dose of the drug
◦ Molecular weight of drug
◦ Crystalline state
◦ Melting point
The two most important components for TDDS are skin
and drug. These are the two limiting factors as well
Reservoir TDDS
Drug held in gel or solution
Delivery is determined by rate-controlling membrane between
reservoir and skin
Tighter (than matrix design) control of delivery rates
Potential for burst of drug release
Matrix TDDS
Matrix incorporates drug into an adhesive polymer matrix
Dose of drug delivered depends upon amount of drug held
in the matrix and area of patch applied to skin
Formulation of drug/polymer matrix limits rate of drug
delivery
Diffusion Pathways Through Skin
Additional Routes of Drug Penetration
Pharmanet.com
Fig. 5. Timeline showing transdermal patches date
of approval by the FDA. Novartis launched eight
different transdermal patches to the market
during the last three decades, while Johnson &
Johnson, Bayer, and Watson Labs launched 12 in
aggregate during the last two decades.
Advanced Drug Delivery Reviews, 2012
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Limited by the barrier of the skin
http://www.sciencedirect.com/science/journal/09396411
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Permeation Enhancers
◦ Chemical
◦ Iontophoresis
◦ Phonophoresis
Disruption of ordered bilayer by insertion of
amphiphilic molecules or extraction of lipids
using solvents and surfactants
Figure 7: Basic principle of iontophoresis. A
current passed between the active electrode and
the indifferent electrode repelling drug away from
the active electrode and into the skin.
Rate of drug delivery
scales with electrical current
Primarily used for rapid delivery
of analgesic
Basf.com
Figure 6: Basic principle of phonophoresis.
Ultrasound pulses are passed through the probe
into the skin fluidizing the lipid bilayer by the
formation of bubbles caused by cavitation.
Basf.com
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Combinations of chemical enhancers
Biochemical enhancers
Electroporation
Microneedles
Thermal ablation
Microdermabrasion
All of the methods listed above share the same goal-disruption
of the stratum corneum to optimally deliver drug without
significant skin irritation
Figure 8: Basic principle of electroporation.
Short pulses of high voltage current are
applied to the skin producing hydrophilic
pores in the intercellular bilayers via
momentary realignment of lipids.
Diffusion through long-lived
electropores
Basf.com
Liquid Jet Injector
Micro-scale devices for transdermal drug delivery
Anubhav Aroraa, b,
Mark R. Prausnitzc, 1,
Samir Mitragotria, b,
Fig. 1. Schematic of drug delivery
using liquid jet injector (Mitragotri,
2006): (a) formation of liquid jet, (b)
initiation of hole formation due to
impact of jet on skin surface, (c)
development of hole inside skin with
progress of injection, (d) deposition of
drug at the end of hole in a near
spherical or hemispherical pattern
(spherical pattern shown).
Microneedles
Fig. 3. Schematic of drug delivery using different designs
of microneedles: (a) solid microneedles for permeabilizing
skin via formation of micron-sized holes across stratum
corneum. The needle patch is withdrawn followed by
application of drug-containing patch, (b) solid
microneedles coated with dry drugs or vaccine for rapid
dissolution in the skin, (c) polymeric microneedles with
encapsulated drug or vaccine for rapid or controlled
release in the skin, (d) hollow microneedles for injection of
drug solution.
http://www.youtube.com/watch?annotation_id=annotation
_808480&feature=iv&src_vid=2Pp4CE4F3jI&v=8v5z9ZTLrg
Micro-scale devices for transdermal drug delivery
Anubhav Aroraa, b,
Mark R. Prausnitzc, 1,
Samir Mitragotria, b,
Thermal Ablation
Fig. 4. Schematic of drug delivery
using thermal ablation: (a) microelectrodes are pressed against the
skin, (b) skin is ablated via heating due
to RF energy or resistive heating in the
electrodes, (c) after removing the
ablation device, (d) micropores formed
are covered with drug patch for
delivery.
Powder Injection
Micro-scale devices for transdermal drug delivery
Anubhav Aroraa, b,
Mark R. Prausnitzc, 1,
Samir Mitragotria, b,
Fig. 2. Schematic of drug delivery
using powder injector (modified from
Mitragotri (2006)): (a) ejection of
particles from nozzle, (b) impact of
particles on skin surface, (c)
penetration of particles across stratum
corneum, (d) completion of delivery.
Particles which penetrate into the skin
are mostly distributed in stratum
corneum and viable epidermis.
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Therapeutic indication
Desired drug delivery profile
◦ Dose level, duration, etc.
Skin adhesion profile
Application site
Ease of application
Patch size, shape, appearance, comfort
Wear period
Packaging
Patch disposal
Patch cost
Adverse Events
Irritation
Rupture of reservoir and overdose