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Development of liposome formulations of ethambutol, rifampicin, and isoniazid for pulmonary treatment of tuberculosis Wiens, Theresa M.
Abstract
Current tuberculosis treatment consists of rifampicin, isoniazid, ethambutol, and pyrazinamide taken orally over a 6 to 12 month period. Although successful when followed correctly, the drugs are relatively toxic, and drug resistance develops when treatment is not followed to completion. Simplification of this protocol, resulting in decreased duration and/or dosage, has been identified as a goal for new TB therapies by the Global Alliance for TB Drug Development and would be a significant improvement in tuberculosis therapy, leading to increased compliance and disease eradication. We have developed liposomal formulations of three first-line anti-tuberculosis drugs, isoniazid, rifampicin, and ethambutol, which are suitable for pulmonary delivery, with the goal of improving the pharmacokinetics of each drug such that concentrations will be maintained at the disease site for prolonged periods. All three drugs have been formulated using a remote loading method into sphingomyelin/cholesterol (SM/CHOL) (63/37, mol/mol) liposomes. Although isoniazid and rifampicin have been formulated into liposomes previously, this lipid composition and loading technique has not been utilized for these drugs. In addition, no ethambutol formulation or a formulation combining two drugs, such as the isoniazid and ethambutol formulation developed in this thesis, has been described previously. Each formulation has been optimized in terms of drug/lipid ratio, buffering capacity, and loading kinetics and is capable of encapsulating 76-100% of available drug. Characterization of these formulations in vitro showed prolonged release kinetics, suggesting that drug pharmacokinetics can be altered, in vivo. Stability studies also indicate that each formulation is stable over 2 months at 5°C. Our hypothesis is that liposome encapsulation of isoniazid, ethambutol, and rifampicin by remote loading will maintain efficacy in vitro against Mycobacteria. In vitro susceptibility testing against M. bovis Bacille Calmette-Guerin (BCG), as a model organism for Mycobacterium tuberculosis, showed equivalent activity of each liposome formulation in comparison to the free drug in culture and in a THP-1 human macrophage infection model. Fluorescent microscopy also showed that the liposomes are taken up by infected macrophages, although they do not localize to the same compartment as M. bovis BCG. Our opinion is that significant improvements in the therapeutic profile of firstline agents can be achieved by optimizing drug delivery to the disease site. The results presented in this thesis suggest that all four liposome formulations have the potential to be administered by pulmonary delivery, providing an alternative approach to the treatment of tuberculosis. The potential for altered pharmacokinetics in vivo will also permit decreased dosing and frequency of administration, resulting in improved compliance and ultimately decreasing the development of resistance, increasing eradication and decreasing relapse rates.
Item Metadata
Title |
Development of liposome formulations of ethambutol, rifampicin, and isoniazid for pulmonary treatment of tuberculosis
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2003
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Description |
Current tuberculosis treatment consists of rifampicin, isoniazid, ethambutol,
and pyrazinamide taken orally over a 6 to 12 month period. Although successful
when followed correctly, the drugs are relatively toxic, and drug resistance develops when treatment is not followed to completion. Simplification of this protocol,
resulting in decreased duration and/or dosage, has been identified as a goal for new
TB therapies by the Global Alliance for TB Drug Development and would be a significant improvement in tuberculosis therapy, leading to increased compliance and disease eradication. We have developed liposomal formulations of three first-line anti-tuberculosis drugs, isoniazid, rifampicin, and ethambutol, which are suitable for pulmonary delivery, with the goal of improving the pharmacokinetics of each drug such that concentrations will be maintained at the disease site for prolonged periods. All three drugs have been formulated using a remote loading method into
sphingomyelin/cholesterol (SM/CHOL) (63/37, mol/mol) liposomes. Although isoniazid and rifampicin have been formulated into liposomes previously, this lipid
composition and loading technique has not been utilized for these drugs. In addition,
no ethambutol formulation or a formulation combining two drugs, such as the
isoniazid and ethambutol formulation developed in this thesis, has been described
previously. Each formulation has been optimized in terms of drug/lipid ratio, buffering capacity, and loading kinetics and is capable of encapsulating 76-100% of available drug. Characterization of these formulations in vitro showed prolonged release kinetics, suggesting that drug pharmacokinetics can be altered, in vivo. Stability studies also indicate that each formulation is stable over 2 months at 5°C.
Our hypothesis is that liposome encapsulation of isoniazid, ethambutol, and
rifampicin by remote loading will maintain efficacy in vitro against Mycobacteria. In
vitro susceptibility testing against M. bovis Bacille Calmette-Guerin (BCG), as a
model organism for Mycobacterium tuberculosis, showed equivalent activity of each liposome formulation in comparison to the free drug in culture and in a THP-1 human
macrophage infection model. Fluorescent microscopy also showed that the liposomes
are taken up by infected macrophages, although they do not localize to the same
compartment as M. bovis BCG. Our opinion is that significant improvements in the therapeutic profile of firstline
agents can be achieved by optimizing drug delivery to the disease site. The
results presented in this thesis suggest that all four liposome formulations have the
potential to be administered by pulmonary delivery, providing an alternative approach
to the treatment of tuberculosis. The potential for altered pharmacokinetics in vivo will also permit decreased dosing and frequency of administration, resulting in
improved compliance and ultimately decreasing the development of resistance,
increasing eradication and decreasing relapse rates.
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Extent |
4806547 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-11-03
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0091398
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2003-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.