Principles of Pharmacology: Chapter 54 Drug Delivery Modalities

- Drugs are typically administered in either pill or injection form which limit control over rate &
localization.
- Advanced drug delivery systems alter 4 pharmocokinetic properties:
o (1) absorption of the drug, including the period of time over which it is released into the
systemic circulation or at its final site of action.
o (2) distribution of the drug, whether it be to the entire body or a specific tissue or organ
system.
o (3) metabolism of the drug, either to be avoided entirely or used to convert a prodrug to an
active form.
o (4) elimination of the drug
- Oral administration of small molecules is the most common method of drug delivery.
o Advantages: ease of use & low cost
o Disadvantages: incomplete absorption, metabolism of drug during absorption & 1
st
pass
metabolism can decrease bioavailability of drug.
o Only small molecules can be absorbed thru the intestine
o Sustained or extended release formulations can prolong plasma drug concentrations w/
less frequent doses.
Pill or capsule solubility was modified w/ inert substances known as excipients
(cellulose derivatives of wax)
o Techniques are being developed for delivery of larger molecules in drug-carrying vehicles,
including liposomes & microspheres.
Liposomes, small vesicles w/ lipid bilayer membranes, are lipophilic & can be taken
up by intestinal Peyers patches when targeted to M cells.
Polyanhydride microspheres, which adhere strongly to the intestinal mucosal
surface, have been shown to penetrate intestinal epithelium.
o Another potential approach to delivering proteins orally involves targeting the drug to the
colon, which has lower levels of protease activity than the upper gastrointestinal tract.
o Another approach involves carrier molecules that may be able to shuttle large molecules
across the epithelial linin of the intestine.
- Pulmonary Delivery:
o Disadvantages: Very little drug is reproducibly delivered to the lung (less than 10%),
particles often accumulate in the mouth & throat, & are immediately exhaled. Components
of the immune system & macrophages in the lung can clear some of the drug before it can
act. Many patients use their inhalers incorrectly; not shaking inhaler well enough, pressing
inhaler too early or too late. Incorrect use further reduces delivery efficacy.
o Aerosol formulations have been improved by adjusting several properties of the particles.
Optimized particle chemistry & surface morphology can minimize undesirable
particle-particle aggregation.
Particle solubility can be modified to influence the rate of therapeutic release once
delivered.
o The lung offers several potential advantages for noninvasive, systemic delivery of
molecules:
Large alveolar surface area, thin tissue lining, & limited #s of proteolytic enzymes
make the lung an ideal location for proteins & peptides to enter bloodstream.
o One approach to achieving increased delivery efficiency is the design of large, highly
porous aerosol particles w/ low densities. Such particles tend to aggregate less than
smaller, denser particles, resulting in more efficient aerosolization.
These particles have an aerodynamic diameter, a parameter based on both density
& actual particle dimensions, similar to conventional aerosol particles; thus, can
reach the deep parts of the lung thru an airstream. Once deposited, the particles can
escape clearance by alveolar macrophages, b/c phagocytosis of particles by
macrophages diminishes w/ increasing particle size.
- Transdermal Delivery:
o The stratum corneum, composed of lipids & keratinocytes, is the outermost skin layer & the
major barrier to transdermal transport. Small, lipophilic drugs have been successfully
delivered thru the skin into the systemic circulation by passive diffusion at low flux rates,
thereby avoiding 1
st
-pass metabolism.
o Provides greater bioavailability while remaining noninvasive, & often associated w/ fewer
adverse effects than conventional oral dosage forms.
o Iontophoresis is one approach to enhancing the transport of charged low molecular mass
molecules thru the skin.
Involves the application of low-voltage electric pulses for long time periods.
Electroporation: high-voltage pulses have been shown to induce temporary pores.
Can potentially allow systemic delivery of large, charged molecules.
o Ultrasound enhancement of drug delivery thru skin, termed sonophoresis. Application of
ultrasound to the skin results in cavitation, the formation of tiny air-filled spaces in lipid
bilayers of the stratum corneum. The net result of cavitation is disordering of lipid
bilayers, enhancing diffusivity of the drug thru the skin.
Sonophoresis does not damage the skin.
Sonophoresis can also be used to remove diagnostic samples from the extracellular
space under the stratum corneum.
- Polymer-Based Delivery Systems
o Gradually release drugs into their surroundings.
o Advantage: both controlled release & targeting of drugs.
o Drug delivery from a polymer-based system can be achieved via 3 general mechanisms:
(1) diffusion
(2) chemical reaction
(3) solvent activation
- Diffusion from either a reservoir or a matrix is the most common release mechanism.
o In a reservoir system, the drug is contained w/in a polymer membrane thru which it
diffuses over time.
o Levonorgestrel, a synthetic progestin, is stored in small silicone
tubes implanted in the arm & the drug diffuses slowly thru the
polymer capsule over 5 yrs.
o Reservoir systems are limited by size of the drug molecules being
delivered.
- In chemical reaction-based systems, part of the system is designed to degrade over time.
Degradation can involve either a chemical or enzymatic reaction.
o Covalent bonds that connect the drug to a polymer are cleaved by endogenous enzymes.
o Polymer-drug complexes are typically administered intravenously, & the use of water-
soluble polymers increases the biological half-life of the drug
considerably.
o Most insoluble polymers exhibit bulk erosion (i.e. the entire matrix
dissolves at the same rate), which results in larger pores & a more sponge-
like & unstable structure. This pattern of degradation makes constant
release rates difficult to achieve & creates possible risk of dose-dumping.
Can be engineered by using hydrophobic monomers connected by
anhydride bonds. The hydrophobic monomers exclude water from the interior of
the polymer matrix, eliminating bulk erosion. This design allows the polymer to
degrade from the outside only.
- Solvent activation, in which the solvent does not react w/ the polymer chemically, but rather
initiates drug release via swelling or osmosis of the system.
o The constant osmotic influx of water thru the membrane forces the drug out of the pill thru
a hole, controlling release.
- Intelligent Delivery:
o Pulsatile delivery desirable to mimic the bodys natural pattern of producing chemicals.
o Magnetic beads were incorporated in the polymer matrix together w/ a supply of insulin.
System implanted where insulin was slowly released by diffusion out of the matrix. When
an oscillating magnetic field was applied externally, movement of the magnetic beads w/in
the matrix caused alternating expansion & contraction of the drug-carrying pores which
squeezed out insulin, resulting in higher dose delivery.
o Ultrasound delivered at an appropriate frequency can cause cavitation in the polymer,
disrupting the porous architecture to facilitate faster drug release.
o Applying an electric current to certain polymers can induce electrolysis of water at the
polymer surface, lowering local pH & disrupting hydrogen bonding w/ the complex. The
polymer subsequently degrades at a faster than normal rate, allowing transient release of
larger drug doses.
o A silicon microchip delivery system offers even more control over release system. The
microchip contains reservoirs covered in a thin gold film that can be dissolved. B/c the
reservoirs can be loaded & opened individually, almost limitless possibilities.
- Targeting: accurate targeting allows for larger, more effective doses to reach the tissues of interest
w/out risking the toxic effects of systemic delivery.
o Many tissues are accessed practically only via the bloodstream, making targeted delivery
difficult.
- Passive Targeting exploits vascular differences b/w the target tissue & other tissues to deliver
drugs selectively.
o For example, high molecular mass polymer-drug complexes accumulate in some tissues to
a greater extent than in normal tissues b/c the tumor has more permeable capillary beds.
o Can also conjugate polymer-drug to be constructed in such a way as to allow enzymatic
cleavage of the drug after the complex has left the bloodstream & been taken up by tumor
cells.
- Active Targeting, the polymer-drug conjugate is linked to a molecule that is recognized specifically
by cell receptors in the tissue of interest.
- Liposome-Based Delivery Systems:
o Drugs attached to a single polymer chain are stable structures that can remain in the
circulation for long periods of time. However, these polymer chains can accommodate only
small amounts of drug, thus limiting the dose per unit volume administered.
o Potentially high drug-carrying capacity of liposomes, small vesicles w/ lipid bilayer
membranes.
Important considerations in the design of liposome-based delivery systems include
tissue targeting & protection from the immune system.
B/c liposomes w/ the PEG moiety (stealth liposomes) have a prolonged circulation
time (days), larger doses can be administered w/out the risk of drug toxicity.
- Conclusions
o Drug levels can be continuously maintained in a therapeutically desirable range. Sustained
release oral formulations, large particles that can be inhaled & many polymer-based
designs have this desirable property.
o Harmful adverse effects can be reduced by preventing transient high peak blood levels of
drug. Designs that alter absorption kinetics, targeted delivery systems (e.g. antibody-
labeled polymer-drug complexes), & systems that avoid 1
st
-pass liver metabolism (e.g.
transdermal delivery of drugs normally taken orally) achieve this goal.
o The total amt of drug required can be reduced, as w/ advanced inhaler designs. Both a
decrease in the @ of required dosages & a less invasive administration route contribute to
improved patient adherence.
o Pharmaceuticals w/ short half-lives, such as peptides & proteins, can be successfully
delivered using controlled-release polymer-based delivery systems.