One of the most common serious diseases of the developing world is almost unknown in this country. It is Leishmanaisis, also known as kala-azar. 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).

Wrapping Drugs in Butter: Developing a New Oral Delivery System for Amphotericin B

Department of Chemistry University of Wisconsin-Eau Claire Eau Claire, WI 54702

Hilary Wiltgen, Shane Hodgson, Joe Heimann & Dr. Scott Hartsel

Abstract

Background

Amphotericin B

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.

Leishmaniasis**:

Symptoms:•Fever•Weight loss

**2nd largest parasitic killer in the world

Anti-fungal Properties:•Preference for ergosterol in cell membrane•Transmembrane channel formation leads to ion

leakage

Types of Leishmaniasis:• Visceral -- migration of parasites to internal organs • Cutaneous -- visible lesions on surface of the skin (most

common)

Lipid & SEDDS Formulations

Conclusions

Acknowledgements University of Wisconsin – Eau Claire Chemistry Department University of Wisconsin – Eau Claire Office of Research and

Sponsored Programs (ORSP) University of Wisconsin – Eau Claire Learning and Technology

Services

Drug Stability

Parasitic disease transmitted by the bite of a sand fly

•Swelling of liver and spleen •Skin lesions/ulcers

A polyene antifungal drug commonly used to treat systemic fungal and parasitic infections

Problems:• Poor sterol selectivity•High toxicity•IV infusion required•Degradation with exposure to light•Associated with high fever, chills, nausea,

etc.

Benefits of orally available systems: Reduced toxicity Cost effective Stable at room temperature No hospitalization or IV

infusion

Phosphate Buffer Saline (PBS) Human Serum Albumin (HSA)

Measuring Drug Stability with Stopped-Flow Spectroscopy:

Stability will be tested in:

Self-Emulsifying Drug Delivery Systems (SEDDS)1:

Mono- and Di- glycerides and PEGG-esters that form emulsions spontaneously in stomach and gastrointestinal fluid

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

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

Dissociation of Amphotericin is measured by a shift in wavelengths from short wavelength aggregated from to long wavelength monomer form

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

SEDDS Characteristics:

Current Formulations of Amphotericin:

Gastrointestinal Fluid Artificial Stomach Juice

FUNGIZONE

AMPHOTEC

% Bound to Serum = 6.7%

AMBISOME

% Bound to Serum = 0.0%

Binding to serum albumin is correlated to greater toxicity2

HEATED FUNGIZONE

% Bound to Serum = 2.7%

% Bound to Serum = 2.6%

References

2. TORRADO, J. J., et. al (2007). Amphotericin b formulations and drug targeting. JOURNAL OF PHARMACEUTICAL SCIENCES, 97(7), 2405-2425.

1. Wasan, E. K. (2009). Development and characterization of oral lipid-based amp b formulations with enhanced drug solubility. International Journal of Pharmaceutics, 372(1-2), 76-84.