Transcript WiltgenSpr2013x

Wrapping Drugs in Butter: Developing a New Oral Delivery
System for Amphotericin B
Hilary Wiltgen, Shane Hodgson, Joe Heimann & Dr. Scott Hartsel
Department of Chemistry  University of Wisconsin-Eau Claire Eau Claire, WI
54702
Abstract
One of the most common serious
diseases of the developing world is
almost unknown in this country. It is
Leishmanaisis, also known as kalaazar. After malaria, this is the most
common fatal parasitic infection in
the world. It is difficult to treat and
has demonstrated increasing rates of
resistance toward many main-line
drugs. Fortunately, there is a drug
which is very effective, almost never
generates resistance and is very
inexpensive—Amphotericin B (AmB).
The problem is that this drug is not available in a stable oral form which would
be advantageous in tropical climates. The most common preparation of AmB
is administered intravenously as a micellar dispersion. This dispersion shows
poor selectivity between mammalian and parasite cells and hence increased
human toxicity. However, by employing lipid carrier complexes, a formulation
can be implemented to control the toxicity, specificity, solubility, and stability
of this drug and improve digestive tract absorption. Our objective was to
develop and establish procedures for testing and characterization of novel
orally-available lipid drug delivery formulas for AmB. We have evaluated
these and other lipid mixtures by stopped-flow spectroscopy to clarify the
relationship between composition and drug activity in in vitro model systems.
Background
Leishmaniasis**:
Parasitic disease transmitted by the bite of a sand fly
Types of Leishmaniasis:
• Visceral -- migration of parasites to internal organs
• Cutaneous -- visible lesions on surface of the skin (most
common)
Symptoms:
• Fever
• Weight loss
• Swelling of liver and spleen
• Skin lesions/ulcers
Drug Stability
Amphotericin B
A polyene antifungal drug commonly used to treat systemic fungal and parasitic
infections
Anti-fungal Properties:
• Preference for ergosterol in cell membrane
• Transmembrane channel formation leads to ion
leakage
Problems:
• Poor sterol selectivity
• High toxicity
• IV infusion required
• Degradation with exposure to light
• Associated with high fever, chills, nausea, etc.
Lipid & SEDDS
Formulations
FUNGIZONE
% Bound to Serum = 6.7%
% Bound to Serum = 2.7%
Self-Emulsifying Drug Delivery Systems (SEDDS)1:
Mono- and Di- glycerides and PEGG-esters that form emulsions spontaneously in
stomach and gastrointestinal fluid
SEDDS Characteristics:
 Can emulsify hydrophobic drugs
 Can carry hydrophobic drugs into the lymph or blood circulatory
system
 Allows oral absorption of Amphotericin
 Reduces toxicity of some drugs
AMBISOME
% Bound to Serum = 0.0%
Reduced toxicity
Cost effective
Stable at room temperature
No hospitalization or IV
infusion
Current Formulations of Amphotericin:

Reduced stability of Amphotericin in serum can be
shown by Stopped-Flow Spectroscopy
Future studies on SEDDS will determine whether
stability correlates with toxicity reduction and oral
delivery

Exist as lipid-complex mixtures
Ambisome and Amphotec exhibit reduced
toxicity compared to Fungizone
 Still must be delivered
intravenously
Stability in serum is correlated with lower
toxicity
Measuring Drug Stability with Stopped-Flow Spectroscopy:
References
1. Wasan, E. K. (2009). Development and characterization of oral lipidbased amp b formulations with enhanced drug solubility.
International Journal of Pharmaceutics, 372(1-2), 76-84.
2. TORRADO, J. J., et. al (2007). Amphotericin b formulations and drug
targeting. JOURNAL OF PHARMACEUTICAL SCIENCES, 97(7), 24052425.
Acknowledgements
Dissociation of Amphotericin is measured by a shift in wavelengths from short
wavelength aggregated from to long wavelength monomer form
Stability will be tested in:
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Phosphate Buffer Saline (PBS)
Human Serum Albumin (HSA)
% Bound to Serum = 2.6%
Conclusions
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AMPHOTEC
Binding to serum albumin is correlated to greater toxicity2
Benefits of orally available systems:
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**2nd largest parasitic killer in the world
HEATED FUNGIZONE
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Gastrointestinal Fluid
Artificial Stomach Juice
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University of Wisconsin – Eau Claire Chemistry Department
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