The efficacy of rifapentine, an oral antibiotic used in the treatment of tuberculosis, is reduced due to its degradation at gastric pH and low solubility at intestinal pH. We aimed to improve delivery properties in vitro by incorporating rifapentine into pH-responsive amorphous solid dispersions with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). Most amorphous solid dispersions reduced rifapentine release at gastric pH, with the best performing polymer CASub showing >31-fold decrease in area under the curve compared to rifapentine alone. Lower solubility at gastric conditions was accompanied by a reduction in the acidic degradation product 3-formylrifamycin, as compared to rifapentine alone. Certain formulations also showed enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with the best performing polymer HPMCAS showing almost a 4-fold increase in total area under the curve compared to rifapentine alone. These in vitro results suggest that delivery of rifapentine via amorphous solid dispersion with cellulose polymers may improve bioavailability in vivo. / Master of Science in Life Sciences / Rifapentine is an antibiotic that is used in the treatment of tuberculosis. Although it is an effective drug, it has limitations caused by digestion and its low ability to dissolve in water. The environment of the human stomach, which contains strong acid, can destroy the drug making it ineffective against the bacteria that cause tuberculosis. The low ability to dissolve in water is also a problem because in order for the drug to be absorbed, it must be dissolved first. Improving these characteristics of this drug could lead to advancements in the treatment and elimination of tuberculosis. The strategy we used to enhance the characteristics of this drug is called amorphous solid dispersion. This system holds the drug in a very easy to absorb form and releases it as such. Many amorphous solid dispersion formulations in combination with other drugs have shown improved ability to dissolve the drugs and protection of drugs from destruction in harsh conditions such as the stomach acid. Various derivatives of natural cellulose (a chain of sugars, called a polysaccharide, which is a major component of all plants) were used as part of this system, to stabilize the drug and to help dissolve it. We found that these amorphous solid dispersions did help to release and dissolve the drug in large concentrations and protect the drug from the stomach acid. Since we have seen positive results here, the next step is to use these systems in an animal study.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/86613 |
| Date | 14 July 2017 |
| Creators | Winslow, Christopher Jonathan |
| Contributors | Food Science and Technology, Neilson, Andrew P., Edgar, Kevin J., Fernandez-Fraguas, Cristina |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Thesis |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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